Search

Background Neglected tropical diseases (NTDs) primarily affect the poorest populations, often living in remote, rural areas, urban slums or conflict zones. Arboviruses are a significant NTD category spread by mosquitoes. Dengue, Chikungunya, and Zika are three arboviruses that affect a large proportion of the population in Latin and South America. The clinical diagnosis of these arboviral diseases is a difficult task due to the concurrent circulation of several arboviruses which present similar symptoms, inaccurate serologic tests resulting from cross-reaction and co-infection with other arboviruses. Objective The goal of this paper is to present evidence on the state of the art of studies investigating the automatic classification of arboviral diseases to support clinical diagnosis based on Machine Learning (ML) and Deep Learning (DL) models. Method We carried out a Systematic Literature Review (SLR) in which Google Scholar was searched to identify key papers on the topic. From an initial 963 records (956 from string-based search and seven from a single backward snowballing procedure), only 15 relevant papers were identified. Results Results show that current research is focused on the binary classification of Dengue, primarily using tree-based ML algorithms. Only one paper was identified using DL. Five papers presented solutions for multi-class problems, covering Dengue (and its variants) and Chikungunya. No papers were identified that investigated models to differentiate between Dengue, Chikungunya, and Zika. Conclusions The use of an efficient clinical decision support system for arboviral diseases can improve the quality of the entire clinical process, thus increasing the accuracy of the diagnosis and the associated treatment. It should help physicians in their decision-making process and, consequently, improve the use of resources and the patient’s quality of life., Author summary Neglected tropical diseases (NTDs) primarily affect the poorest populations, often living in remote, rural areas, urban slums or conflict zones. Arboviruses are a significant NTD category spread by mosquitoes. Dengue, Chikungunya, and Zika are three arboviruses that affect a large proportion of the population in Latin and South America. The clinical diagnosis of these arboviral diseases is a difficult task due to the concurrent circulation of several arboviruses which present similar symptoms and, sometimes, inaccurate test results. In this paper, we present the state of the art of studies investigating the automatic classification of arboviral diseases based on Machine Learning (ML) and Deep Learning (DL) models. Results show that current research is focused on the classification of Dengue, primarily using tree-based ML algorithms. The use of an efficient clinical decision support system for arboviral diseases can improve the quality of the entire clinical process, thus increasing the accuracy of the diagnosis and the associated treatment. It should help physicians in their decision-making process and, consequently, improve the use of resources and the patient’s quality of life.

Extensive research shows that residential segregation has severe health consequences for racial and ethnic minorities. Most research to date has operationalized segregation in terms of either poverty or race/ethnicity rather than a synergy of these factors. A novel version of the Index of Concentration at the Extremes (ICERace-Income) specifically assesses racialized economic segregation in terms of spatial concentrations of racial and economic privilege (e.g., wealthy white people) versus disadvantage (e.g., poor Black people) within a given area. This multidimensional measure advances a more comprehensive understanding of residential segregation and its consequences for racial and ethnic minorities. The aim of this paper is to critically review the evidence on the association between ICERace-Income and health outcomes. We implemented the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines to conduct a rigorous search of academic databases for papers linking ICERace-Income with health. Twenty articles were included in the review. Studies focused on the association of ICERace-Income with adverse birth outcomes, cancer, premature and all-cause mortality, and communicable diseases. Most of the evidence indicates a strong association between ICERace-Income and each health outcome, underscoring income as a key mechanism by which segregation produces health inequality along racial and ethnic lines. Two of the reviewed studies examined racial disparities in comorbidities and health care access as potential explanatory factors underlying this relationship. We discuss our findings in the context of the extant literature on segregation and health and propose new directions for future research and applications of the ICERace-Income measure.

The burden of cardiometabolic diseases is increasing worldwide. Early detection of high-risk individuals is essential for appropriate diagnosis, better treatment outcomes, quality of life and lower health related costs. Aims: The overall aim of this thesis is to investigate the possible associations between plasma proneurotensin (Pro-NT) and risk of cardiovascular disease (CVD), type 2 diabetes (T2D), impaired glucose regulation, as well as diet-induced obesity in different study populations. As Pro-NT appears to be a novel risk marker for cardiometabolic morbidity and mortality, we also wanted to study the effects of dietary fat intake on circulating plasma Pro-NT and triglyceride levels. This thesis is based on epidemiological data from three population-based cohorts, The Malmö Preventive Project (MPP), The Malmö Diet and Cancer study- Cardiovascular Cohort (MDC-CC) and The MEDIM cohort (impact of Migration and Ethnicity on Diabetes in Malmö). Paper I, in this cohort including an elderly population, we identified that Pro-NT predicts incident CVD in both genders, but incident T2D in women only, after 5.4 years of follow up. Paper II, in a population based cohort of Iraqi and Swedish born men and women, higher Pro-NT levels were observed both in the Iraqi- vs Swedish-born group. However, elevated plasma Pro-NT was associated with impaired glucose regulations assessed as insulin secretion and action and HbA1c in the Iraqi-population only. Paper III, we found prompt increases in plasma Pro-NT every hour for four hours, after an oral lipid load in healthy individuals. Post-lipid rise of circulating plasma Pro-NT correlated with the changes in plasma triglyceride levels, irrespective of cream and olive oil. Paper IV, in this longitudinal study, we identified that high Pro-NT levels predicted all-cause mortality (ACM) and cause- specific mortalities (CSM) due to CVD, gastrointestinaltract (GIT) diseases, mental and behavioral diseases, and diseases of unspecific causes, in both gender. Conclusion: This thesis shows that circulating Pro-NT is a biomarker that in an elderly population predicts CVD in both gender, but T2D in women only . Irrespective of gender, Pro-NT predicts ACM and CSM. Pro-NT is more strongly associated with impaired glucose regulation in a Middle Eastern immigrant population and may partly explain the increased T2D in this group. Furthermore, oral lipid intake increases Pro-NT levels, which facilitates triglyceride increase in blood in healthy individuals, supporting intestinal lipid absorption as being one key action of Pro-NT.

Background & methods National protests in the summer of 2020 drew attention to the significant presence of police in marginalized communities. Recent social movements have called for substantial police reforms, including “defunding the police,” a phrase originating from a larger, historical abolition movement advocating that public investments be redirected away from the criminal justice system and into social services and health care. Although research has demonstrated the expansive role of police to respond a broad range of social problems and health emergencies, existing research has yet to fully explore the capacity for health insurance policy to influence rates of arrest in the population. To fill this gap, we examine the potential effect of Medicaid expansion under the Affordable Care Act (ACA) on arrests in 3,035 U.S. counties. We compare county-level arrests using FBI Uniform Crime Reporting (UCR) Program Data before and after Medicaid expansion in 2014–2016, relative to counties in non-expansion states. We use difference-in-differences (DID) models to estimate the change in arrests following Medicaid expansion for overall arrests, and violent, drug, and low-level arrests. Results Police arrests significantly declined following the expansion of Medicaid under the ACA. Medicaid expansion produced a 20–32% negative difference in overall arrests rates in the first three years. We observe the largest negative differences for drug arrests: we find a 25–41% negative difference in drug arrests in the three years following Medicaid expansion, compared to non-expansion counties. We observe a 19–29% negative difference in arrests for violence in the three years after Medicaid expansion, and a decrease in low-level arrests between 24–28% in expansion counties compared to non-expansion counties. Our main results for drug arrests are robust to multiple sensitivity analyses, including a state-level model. Conclusions Evidence in this paper suggests that expanded Medicaid insurance reduced police arrests, particularly drug-related arrests. Combined with research showing the harmful health consequences of chronic policing in disadvantaged communities, greater insurance coverage creates new avenues for individuals to seek care, receive treatment, and avoid criminalization. As police reform is high on the agenda at the local, state, and federal level, our paper supports the perspective that broad health policy reforms can meaningfully reduce contact with the criminal justice system under historic conditions of mass criminalization.

Knowledge management is positioned as an enabler of ICH Q10, and the visibility and availability of product and process knowledge across the entire pharmaceutical product lifecycle is vital to the sustained success of an organization and to the effectiveness of an organization’s pharmaceutical quality system as defined by ICH Q10. This paper illustrates where knowledge management has a role to play within each product lifecycle phase. This paper goes on to further define phase-appropriate KM methods and tools to help address these needs and create end-to-end product and process knowledge visibility and availability.

Background Vocal fold nodules (VFNs) are the main cause of paediatric dysphonia. Voice therapy is recommended as the preferable treatment option for VFNs in children. Aim The aim of this systematic review is to provide an overview of the existing literature concerning the effects of voice therapy in children with VFNs. Methods & Procedures This systematic literature review was developed following the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. The Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (via PubMed) and Embase were searched and the grey literature was checked. The search strategy was based on three concepts: VFNs, voice therapy and children. Two examiners independently determined article eligibility and extracted all relevant data from the included studies. The methodological quality of the included study was assessed using the QualSyst tool. Main contributions By identifying, evaluating and summarizing the results of all relevant studies about voice therapy in paediatric VFNs, this systematic review makes the available evidence more accessible to voice therapists, otolaryngologists and other relevant stakeholders. Conclusions & Implications 24 studies were included in this systematic review. Eight studies (8/24) reported a significant improvement for at least one outcome parameter after voice therapy. However, five papers (5/24) could not demonstrate significant changes after voice therapy. All studies that did not test for significance (11/24) found improvements for one or more outcome parameters. The overall quality of the included studies is adequate (55%). In sum, there is some evidence that voice therapy is effective in children with VFNs, but further well-designed research, especially randomized controlled trials, is necessary to confirm these results. WHAT THIS PAPER ADDS What is already known on the subject Voice therapy is preferable in children with VFNs because of the phonotraumatic nature of the nodules and the associated high recurrence rate after phonosurgery. Most voice therapists in clinical practice offer an eclectic voice therapy programme, consisting of direct and indirect voice therapy techniques. What this study adds to existing knowledge This systematic review provides a clear overview of the available evidence concerning the effects of voice therapy in paediatric VFNs. There is some evidence that voice therapy is an effective treatment option in children with VFNs, but well-designed research is scarce on this subject. What are the potential or actual clinical implications of this work? This review shows that effectiveness studies with strong designs are very scarce in children with VFNs. Clinicians should be aware that few therapy techniques have been thoroughly investigated in this population. However, this review may guide voice therapists when creating a treatment plan for a child with VFNs because it identifies, evaluates and summarizes the results of all relevant individual studies about voice therapy in paediatric VFNs. Voice therapy seems to be effective in treating paediatric patients with VFNs, given the fact that a considerable number of included studies report significant improvements after voice therapy. Both direct and indirect therapy approaches appear to have a positive effect on the phonation of children with VFNs.

Evidence exists regarding the impact of flourishing in individuals living with chronic pain, but there are currently no reviews which collate the literature on flourishing in adolescents living with chronic pain and their parents. Therefore, the aim of this scoping review was to map and review the current literature, to document how flourishing is defined and understood in the literature, and to identify gaps in the field. Six databases were searched (Web of Science, Medline, Embase, APA PsycNet and the Cochrane Central Register of Controlled Trials). In addition, a limited gray literature search was conducted. The resulting data were collated and reported in relation to the review questions, by examining the included papers to search for the presence of flourishing. Database searches resulted in 7326 papers after duplicate removal, with eight remaining papers being assessed for full-text eligibility. Following full-text screening, a final four papers were included in the review. Within the papers, flourishing was defined in relation to commonalities of benefit finding, enhanced maturity and growth, and social support. Gaps in the literature and directions for future research are considered. This review suggests that there is a dearth of knowledge and research regarding flourishing among adolescents living with chronic pain and their parents, despite aspects of flourishing identified in limited literature. This warrants further investigation.

Background The ligaments in the knee are prone to injury especially during dynamic activities. The resulting instability can have a profound impact on a patient’s daily activities and functional capacity. Musculoskeletal knee modelling provides a non-invasive tool for investigating ligament force-strain behaviour in various dynamic scenarios, as well as potentially complementing existing pre-planning tools to optimise surgical reconstructions. However, despite the development and validation of many musculoskeletal knee models, the effect of modelling parameters on ligament mechanics has not yet been systematically reviewed. Objectives This systematic review aimed to investigate the results of the most recent studies using musculoskeletal modelling techniques to create models of the native knee joint, focusing on ligament mechanics and modelling parameters in various simulated movements. Data sources PubMed, ScienceDirect, Google Scholar, and IEEE Xplore. Eligibility criteria for selecting studies Databases were searched for articles containing any numerical ligament strain or force data on the intact, ACL-deficient, PCL-deficient, or lateral extra-articular reconstructed (LER) knee joints. The studies had to derive these results from musculoskeletal modelling methods. The dates of the publications were between 1 January 1995 and 30 November 2021. Method A customised data extraction form was created to extract each selected study’s critical musculoskeletal model development parameters. Specific parameters of the musculoskeletal knee model development used in each eligible study were independently extracted, including the (1) musculoskeletal model definition (i.e., software used for modelling, knee type, source of geometry, the inclusion of cartilage and menisci, and articulating joints and joint boundary conditions (i.e., number of degrees of freedom (DoF), subjects, type of activity, collected data and type of simulation)), (2) specifically ligaments modelling techniques (i.e., ligament bundles, attachment points, pathway, wrapping surfaces and ligament material properties such as stiffness and reference length), (3) sensitivity analysis, (4) validation approaches, (5) predicted ligament mechanics (i.e., force, length or strain) and (6) clinical applications if available. The eligible papers were then discussed quantitatively and qualitatively with respect to the above parameters. Results and discussion From the 1004 articles retrieved by the initial electronic search, only 25 met all inclusion criteria. The results obtained by aggregating data reported in the eligible studies indicate that considerable variability in the predicted ligament mechanics is caused by differences in geometry, boundary conditions and ligament modelling parameters. Conclusion This systematic review revealed that there is currently a lack of consensus on knee ligament mechanics. Despite this lack of consensus, some papers highlight the potential of developing translational tools using musculoskeletal modelling. Greater consistency in model design, incorporation of sensitivity assessment of the model outcomes and more rigorous validation methods should lead to better agreement in predictions for ligament mechanics between studies. The resulting confidence in the musculoskeletal model outputs may lead to the development of clinical tools that could be used for patient-specific treatments.

This study assesses the practices and views of Scottish dairy farmers relating to pasture-based and indoor systems. There are the debates about the environmental, economic and animal welfare implications of these systems. Indoor dairy farming is a contentious practice among the public. While this controversy is sometimes represented as a lack of public understanding, there is a need for more research on farmers’ views to facilitate discussion in the industry. A survey was posted to 909 dairy farmers in Scotland with questions about their grazing practices and attitudes to grazing and indoor systems. 254 surveys were completed, online and in paper form. There was a 26% response rate to the paper version of the survey. The results showed that 19% of respondents housed some or all the cows all year-round. 68% agreed or strongly agreed that cows should graze for part of the year and 51% agreed or strongly agreed that welfare was better if cows grazed for part of the year. These views coexisted with the view that management was more important than the type of system for determining profitability or welfare outcomes (83% and 82% strongly agree or agree respectively). Respondents whose system involved grazing and respondents who had spent longer in farming were moderately more likely to agree that cows should have access to pasture, and slightly less likely to agree that management was more important than system for determining welfare outcomes. The results indicate that the picture is more complicated than the public rejecting indoor dairy farming and those in the industry accepting it. The results showed that a majority preference for cows to graze co-existed with the view that management was more important than system. In terms of industry and policy recommendations, the research suggests that measures should be taken to safeguard farmers’ ability to graze through for instance research and advisory support on grazing; ensuring different systems are not penalised in the development of dairy sector environmental measures and recommendations; and potentially supply chains that financially rewards farmers for grazing.

Introduction Pure Neural Leprosy (PNL) is a rare clinical form of leprosy in which patients do not present with the classical skin lesions but have a high burden of the disability associated with the disease. Clinical characteristics and follow up of patients in PNL are still poorly described in the literature. Objective This paper aims to describe the clinical, electrophysiological and histopathological characteristics of PNL patients, as well as their evolution after multidrug therapy (MDT). Methods Fifty-two PNL patients were selected. Clinical, nerve conduction studies (NCS), histopathological and anti-PGL-1serology were evaluated. Patients were also assessed monthly during the MDT. At the end of the MDT, all of the patients had a new neurological examination and 44 were submitted to another NCS. Results Paresthesia was the complaint most frequently reported by patients, and in the neurological examination the most common pattern observed was impairment in sensory and motor examination and a mononeuropathy multiplex. Painful nerve enlargement, a classical symptom of leprosy neuropathy, was observed in a minority of patients and in the motor NCS axonal injuries, alone or in combination with demyelinating features, were the most commonly observed. 88% of the patients did not present any leprosy reaction during MDT. There was no statistically significant difference between the neurological examinations, nor the NCS pattern, performed before and after the MDT. Discussion The classical hallmarks of leprosy neuropathy are not always present in PNL making the diagnosis even more challenging. Nerve biopsy is an important tool for PNL diagnosis as it may guide therapeutic decisions. This paper highlights unique characteristics of PNL in the spectrum of leprosy in an attempt to facilitate the diagnosis and management of these patients., Author summary Neuropathy is responsible for most of the disability associated with leprosy disease. The pure neural leprosy (PNL), in spite of being a rare clinical presentation of that, has some singular characteristics that are still poorly studied. In this study, we selected 52 patients at the diagnosis to describe their clinical, neurophysiological and histopathological presentation patterns as well as their evolution during the multidrug therapy (MDT). We confirmed that sensitive symptoms were the most commonly described by PNL patients but neural pain is rare. Also confirmed that mononeuropathy mutiplex was the most common pattern observed at neurological examination and at the nerve conduction studies at the moment of the diagnosis. However we showed that painful nerve enlargement other cardinal signs of leprosy, besides the skin lesions, is not common in this group of patients, There was no statistically significant difference between the neurological examination and NCS performed before and after the MDT.During the MDT88.4% of the patients did not have any leprosy reaction. This may suggest that that MDT was effective in stopping disease progression. Our results highlight the difficulties in the diagnosis of PNL and the progression following MDT in an attempt to prevent further disability in PNL patients.

Hamstring strain injury (HSI) is a common non-contact injury, with most cases occurring among running-related athletes and sporting events. HSI is characterized by sharp, intense pain throughout the posterior thigh, necessitating the rapid cessation of physical activity. Injury rates are predicted to be 3–4.1 per 1000 hours of competition and 0.4–0.5 per 1000 hours of training. The rate of injuries during training sessions has increased more than in competitive matches, with an average increase of 4% per year. This scoping review aims to determine the biomechanical parameters (kinematics and kinetics) associated with recurrent hamstrings injury occur among running-related athletes. Peer-reviewed papers focusing on biomechanical risk factors associated with recurrent hamstring injury among running-related athletes (sprinters, runners, basketball players, and football or soccer players) will be eligible for inclusion. Studies from inception to May 2022 written in English or English translation will be sought for this scoping review. The proposed scoping review will be conducted in accordance with the JBI methodology for scoping reviews. The search strategy will aim to locate both published and unpublished studies. An initial limited search of PubMed will be undertaken to identify articles on the topic. The search strategy will be adapted for each database and information source, including all specified keywords and index terms. The reference list of all included sources of evidence will be screened for additional studies. Data will be extracted from papers included in the scoping review by two or more independent reviewers using a data extraction tool developed by the reviewers. The data will be presented in tabular form. A narrative summary will accompany the tabulated results and describe how the results relate to the review objective and question/s.

The proposed research revisits an old question in alcohol studies: How does the physical availability of alcohol affect alcohol sales and related problems? Along with lower beverage prices, alcohol researchers have identified greater physical availability of alcohol through retail alcohol outlets as a population health risk.1,2 The theoretical bases for these claims are easily stated; greater "full costs" for alcohol, effected by higher prices or reduced availability, are expected to be related to less sales and fewer problems.3,4 These claims are also empirically well-supported; greater beverage prices and taxes, reduced numbers and densities of outlets, and reduced hours and days of sale have been related to lower sales and fewer problems.3,5 However, while many alcohol researchers agree that there is adequate empirical support for the central tenets of "availability theory," a critical examination of theory and research methods identifies two central concerns with this work: First, from a theoretical perspective, routine social activities can reduce or eliminate convenience costs related to availability; for example, consumers may bundle alcohol purchases with other goods (e.g., groceries) reducing or eliminating convenience costs specific to the purchase of alcohol.6 Routine activities can also alter relationships between sales and problems if problems are at least partially determined by characteristics of places where alcohol is sold and consumers who go to those places (e.g., interpersonal violence at bars).7 Second, from an empirical perspective, the key mediator between availability and problems, alcohol sales, is rarely measured; comprehensive alcohol sales data are seldom available to test the impacts of availability on sales or sales on problems; comprehensive data on alcohol sales data by beverage types are unavailable for all communities in the US. Therefore, at the community level, availability studies and the regulatory efforts that could follow from such studies are theoretically and empirically uninformed. The primary regulatory consequence of this limitation to research efforts is to make it very difficult for community planners and public health practitioners to advocate for appropriate local availability controls. Since the degree to which neighborhood and community availability affects sales is unknown (because sales are not measured) and problems related to outlets may not be completely due to alcohol sales (because routine activities partly determine problems), arguments for local regulation cannot be directed at impacts related to sales per se. It can be argued that routine activities associated with outlets, not sales through outlets, are the cause of ostensibly alcohol related problems and our failure to distinguish the two leads us to erroneously attribute negative consequences to the use of alcohol that lie elsewhere. The proposed studies will strengthen our understanding of relationships between the physical availability of alcohol, alcohol sales, and related problems at the community level using a unique dataset that provides these data at the community postcode level (the Western Australia Alcohol Indicators Database, WAAID), over an extended period of time (1991-2020), from an Australian state with an alcohol retail licensing system similar to many in the US. Including measures of sales through outlets by beverage type, alcohol related morbidity, mortality and crime, Census and other environmental data, WAAID enables us to: (1) Measure the extent to which the physical availability of alcohol (i.e., concentration of different types of alcohol outlets) within neighborhoods and communities affects sales, and (2) Distinguish the degree to which concentrations of alcohol outlets per se, independent of sales made through those outlets, are associated with alcohol related problems. Assessed across approximately 350 urban, suburban, exurban and rural areas, measurements of these relationships will, for the first time, enable us to distinguish sales from outlet effects and their relationships to problems with greater geographic resolution and greater relevance to local regulation of alcohol outlets. We will relate measures of availability through outlets that arises to meet consumer demand (e.g., openings and closings of bars, restaurants and 3 types of off-premises outlets), to sales through those outlets (spirits, low- and high alcohol content beer, and wine), and assess the separable impacts of physical availability vs. alcohol sales on problems in local and surrounding geographic areas. We will do so using Bayesian Gaussian and Poisson spatial partial differential equation models developed during the current Center round that allow us to statistically assess relationships over space and time and estimate ostensibly causal relationships.8 The proposed work is ambitious but feasible, relying upon theoretical and empirical achievements in availability studies over the past 40 years, a systematic approach to modeling availability effects, and the historically deep skills and experiences of the project team. Critically, the project geographic information system (GIS) has been developed and fully supported by our collaborators at the National Drug Research Institute (NDRI), Curtin University, Western Australia. Analysis activities can begin upon onset of the project. The short-term goal of the project is to provide a systematic theoretical description and empirical assessment of the processes by which changes in the physical availability of alcohol are linked to sales and problems across communities in Western Australia. The long-term goal of the project is to provide guidelines by which effective regulatory practices that affect availability, sales and problems in these and communities in the US can be implemented. Hypothesis 1. Alcohol sales will be inversely related to economic costs (e.g., effected through taxes) and directly related to spatial availability (i.e., proximity to outlets). H1a - Most simply, this hypothesis can be tested by regressing total alcohol sales summed across outlet and beverage types over measures of beverage taxes and spatial availability (also averaged across outlet types). Tax effects will be evaluated over time within this panel. Spatial availabilitiy effects will be evaluated over space and time. Since this analysis is uninformed to the extent that beverage taxes and spatial availability are specific to beverage types (e.g., wine taxes, wine stores), analyses of sales and availability by beverage type are the next logical step to take: H1b - High- and low-alcohol beer, wine and spirits sales will be related to measures of taxes and spatial availability (now specifically measured for each outlet type). Since spatial availability measures are specific to postcodes, further elucidation of multiresolution effects related to spatial availability measures is the next step to consider: H1c - High- and low-alcohol beer, wine and spirits sales will be related to measures of taxes and spatial availability detailed at local, nearby and community levels. Finally, it is also feasible to test for cross tax (price) and cross availability (i.e., substitution) effects, H1d - As noted in the econometrics literature examing price and tax effects, increases in prices/taxes for one beverage type may lead to substitution with another type at lower cost3,115,116; the same argument can be made with regard to restrictions on physical availability and analysis models will be further detailed in these respects. Each hypothesis will be tested using constraint and likelihood ratio tests. Assessments of reductions in model uncertainty will be indicated using deviance information and Watanabe Akaike Information Criteria (DIC, WAIC).117,118 All analysis models will include the suite of potentially confounding sociodemographic measures from the Western Australia Census and Environmental covariates (see Section C.2). Impacts of outlet regulations (Section C.2) on sales will be assessed in subsequent analyses, providing an indication of the degree to which different regulations affected sales, but also the degree to which different regulations may have altered relationships of economic and physical availability measures to sales. Results of analyses using long and short data frames for state and community subsets will be compared in order to assess (a) impacts of covariates available for the short frame on estimated effects from the long frame and (b) divergences between analyses of all state postcodes vs those representing community level effects (which differ in spatial resolution). (These will be repeated for tests of all study hypotheses and will not be further discussed.) In general, alcohol taxes which affect prices are considered unaffected by demand and, for that reason, useful statistical instruments by which to assess economic availability effects.115,116 We will use the numerous changes in Western Australia taxes that affect alcohol prices for this purpose (Section C.2) and, although retail prices are not always well indexed by wholesale prices93,96,119,120, we will compare estimates to models using wholesale prices differentiated by outlet and beverage types. It is also plausible that the numbers of outlets that arise across postcodes are affected by demand. Fortunately, statistical instruments for physical availability have been identified in previous research (e.g., land and structure rents, population, income, zoning regulations57,121) and may be used to help identify availability effects.122,123 Hypothesis 2. Impacts of spatial availability on sales will be greatest for outlets which do not combine sales with other goods (e.g., bars and liquor outlets). Tests of this hypothesis follow directly from those conducted for Hypothesis 1 and can be executed within the same analytic framework. Specifically, the two parameters related to spatial availability measures for bars and liquor stores should be greater than those for restaurants and supermarkets since the latter are routinely accessed for food purchases independent of alcohol. These tests are possible because all measures of spatial availability are on the same metric. A corollary prediction here is that restrictions on spatial availability through outlets which do not combine sales with other goods will be related to greater sales through alternative outlets; sales through these outlets will be substituted by purchases through others with greater spatial availability. Hypothesis 3. Availability through outlets and sales through outlets will be separately associated with incidence of problems related to use (this will be especially the case for violent assaults that are related to human interactions in on-premises establishments). Nine problem outcomes will be considered in these analyses: hospitalizations/separations related to abuse and dependence, cirrhosis, assault injuries, suicide/self-inflicted wounds, MVCs, domestic and partner violence, other unintentional injury accidents, and crime incidents related to violent assaults and impaired driving. H3a: Each problem will be regressed over global measures of ethanol sales and spatial availability summarized across beverage and outlet types. H3b: Each problem will be regressed over specific measures of ethanol sales by beverage type and specific measures of spatial availability by outlet type. H3c: Impacts of sales and spatial availability effects will then be detailed at local, nearby and community levels. Testing protocols will follow those specified for Hypotheses 1a-1d and each of the 9 analysis models will include the suite of confounding sociodemographic and environmental covariates identified in Section C.2 and controls for economic availability effects. Critical statistical comparisons of parameters representing outlet effects will be made between models with and without ethanol sales at each stage; these provide a measure of mis-specification bias due to the omission of sales data in the estimation of outlet effects. We expect sales to substantially mediate but not eliminate effects related to spatial availability. Results of these models will be compared with those that treat spatial densities as confounding measures (i.e., marking for otherwise unmeasured area effects) and assess impacts of counts of opened vs closed outlets on problems over time.11 Hypothesis 4. Availability and sales through outlets will be heterogeneously related to problems, varying by outlet and beverage type across three different spatial scales: local postcode, nearby postcodes, and community level. As noted in Sections A.4 and A.5, we expect effects of economic and spatial availability on problems to be quite heterogeneous. The social processes underlying the etiologies of different problem outcomes can be very different (Section A.4) and affect different outcomes in different ways conditional upon measured and unmeasured local, nearby and community-level factors (Section A.5). For these reasons, we expect that the economic and spatial availability parameters estimated for local, nearby and community areas (Hypothesis 3) will statistically differ between equations. Spatial seemingly unrelated regression models can be used to assess differences in parameters across correlated equations (e.g., spsure models in R124) and provide the software necessary to ascertain large-scale structural differences related to economic and spatial availability effects called for here. We have implemented spatial multiple equation models with correlated errors in R-INLA when testing for structural differences in models predicting weekday vs weekend crime rates.125 We will implement similar multiple equation SPDE models and test for structural differences between 2 equations predicting 2 crime outcomes (violence, drink driving) and up to 7 equations predicting 7 commonly measured hospital diagnostic discharges/separations. While these methods are cumbersome to express, their goal is simple: We wish to provide single tests of whether parameters related to physical and spatial availability (a) differ in association with 2 or more problem outcomes (2 statistical tests; one for economic and another for spatial availability measures) and (b) differ when measuring local, nearby and community impacts (2 more tests). The first tests index the degrees to which measures of availability are differentially associated with problem outcomes. The second tests index the degrees to which effects differ across spatial areas (multiresolution effects). Again, results of these models will be compared to those treating spatial densities as confounding measures and assess impacts of counts of opened vs closed outlets on problems over time.11 Approach to Research Questions The proposed work relies upon pre-existing and annually updated population data made available to this project through NDRI WAAID and advanced spatial statistical models and methods developed for analyses of project data at PRC. WAAID will be the source of geocoded postcode data provided in aggregate form under a subcontract through NDRI to Dr. Chikritzhs and Mr. Gillmore. Dr. Chikritzhs and Mr. Gillmore will also aide in the development of specific measurement and analysis procedures suitable to these data, support and inform all project analyses, and support or lead publications emerging from this project. Data through 2020 will be available to PRC at the initiation of the proposed project and updated annually thereafter. Here we assume that data only through 2020 will be available. C.1. Western Australia. While we do not propose direct statistical comparisons to any US state, to assure the relevance of the proposed study to US states and communities we note that Western Australian populations, alcohol control systems, drinking and related problems are comparable to those seen in the US. Selected only on the basis of comparable population size, we use New Mexico as a comparison. In 2016, the population of Western Australia was about 2.4M people with household incomes of about AU$83K (US$61K; 0.74 exchange rate), comparable to the state of New Mexico (2.1M people, US$50K; US 2020 Census estimates). Percent native or indigenous (3% vs 11%) and White (92% vs 74%) population, percent married (49% vs 45%), employment (87% vs 92%), and households with internet connections (85% vs 75%) were roughly comparable, as were estimates of gross domestic product (AU$261B or US$193B vs US$105B). Western Australia has a much larger land area (977K vs 121K square miles) but populations are similarly distributed across post/ZIP code areas (387 postcodes vs 427 ZIPcodes). The majority of persons reside in metropolitan areas (e.g., Stirling, Wanneroo, Joondalup, and Swan in Western Australia and Albuquerque, Las Cruces, Rio Rancho, and Santa Fe in New Mexico, all with more than 80K people each). New Mexico and Western Australia license alcohol production, wholesale distribution and retail sales through outlets (vs states which monopolize aspects of production or sales67). Western Australia licenses retail sales through on- or off-premises establishments, small bars (fewer than 120 person capacity), “hotels” which often serve as bars (called such for historical reasons) and taverns, restaurants, wine, liquor, and grocery stores (“supermarkets”). Supermarkets must have a separate liquor store license and the outlet must be located either outside the market or (in only a small number of cases) within a cordoned-off area. Small convenience stores cannot sell alcohol. New Mexico has a similar license structure for retail sales, but with no constraint on the size of bars and sales allowed within grocery and convenience stores. Both states require responsible beverage service training for managers and servers, allow conditional use permits for local control, have social host laws prohibiting provision of alcohol at parties among underage drinkers, require permits for special events (e.g., fairs), allow sales on all days and over similar hours, and allow home deliveries of alcohol.68,69 The minimum legal drinking age is lower in Western Australia (18 vs 21) with a lower BAC limit for impaired driving (0.05 vs 0.08 for adults). Characteristic of the US alcohol market, license densities are greater in New Mexico than Western Australia (off-premise: ~1/2000 vs ~1/4500 persons). Evidence from survey studies shows that drinking patterns and use of drinking contexts are generally comparable between US and Australian populations with own homes the most frequently used drinking context and parties and bars the predominant contexts for heavy drinking.35,70,71 Finally, Australian and US population studies observe very much the same effects relating measures of availability through outlets (absent of controls for sales) to all problems so far examined (interpersonal violence72-74 vs 75-77; intimate partner violence78,79 vs 16,80,81; AMVCs17,82 vs 23,83,84). C.2. Project GIS. Census year-specific postcode polygon maps (shape files that delineate postcode boundaries) are maintained for all years and updated annually by the Australia Bureau of Statistics. These include SA1 Census areas that are smaller than US Census block groups and comprised of about 400 people (US block groups average about 1500 people). Annual estimates of social, demographic and economic characteristics of populations are available from the Australia Bureau of Statistics. As these data become available, they are aggregated to year-specific postcode maps by NDRI staff with SA1 data mapped to postcodes using SA1 centroids (greater than 96% of households are correctly located using this procedure). Postcode routes, like ZIPcodes in the US, are defined for the purpose of mail delivery with route sizes are responsive to population density Routes are limited by numbers of persons and businesses to whom mail is delivered and, thus, much smaller in urban areas.85 Postcodes are nested within "communities", here defined as Australian "Local Goverment Areas" (LGAs are governed towns, cities or districts) that are also represented by one or more postcodes. Out of 137 LGAs in 2020, 40 were represented by 5 or more postcodes (30 in 1991) and 4 were represented by 10 or more postcodes (8 in 1991). Data frames will consist of one long frame that runs from 1991 through 2020 (30 years) and includes locations of outlets, alcohol sales, general population characteristics, crime and hospitalizations/separations, and one short frame that will run from 2003 through 2020 (18 years) that includes these data elements, emergency department presentations, commercial business data and information on extended trading permits (see accompanying table). Both panels include a defined "community subset" of 30 LGAs comprised of 5 or more postcodes in 1991 (see Section C.3). There were 295 Western Australian postcodes in 1991, 311 in 2003, and 387 in 2020. There will be about 10,230 analysis units in the long data frame and 6,138 in the short data frame (about 6,300 and 3,780 in the community subset). All GIS work is conducted in ArcGIS86 with Geostatistical Analysis, Network Analyst, and Spatial Analyst extensions, Python open source packages Fiona, Shapely, PyProj, GeoPandas, PySAL, and proprietary Python scripts that integrate applications across datasets and sources. Data will be updated through 2020 at the beginning and through 2025 at the conclusion of the project. The project GIS allows us to assess distance, density, and topological relationships among postcodes over time. However, area mismatches will arise across years due to changes in shape, size and numbers of postcodes. Although postcodes comprehensively cover the study area, they are gerrymandered in different ways from-year-to-year with resulting impacts on estimated statistical effects (biases due to "unit misalgnments", see Section C.3). While current empirical work indicates that the impacts of misalignment on marginal effects are modest, at best, impacts on local area estimates (e.g., effects estimates for suburban areas where changes are greatest) can be substantial.15,83,87,88 We provide a means of addressing unit misalignments below, but note here that sensitivity tests will be used to bracket effects estimates using a common analysis frame (e.g., postcode areas defined in an early year) and analyses of "concurrent" postcode areas; postcodes which are identically defined from-one-year-to-the-next. Spatial Availability. The opening and closing datea and locationa of "active" alcohol outlets in Western Australia are provided in licensing data. "Active" licenses are those open and selling to customers. Locations are geocoded to street addresses with a geocoding rate better than 99%. Spatial availability indices specific to each of 6 outlet types (small bars, hotels/taverns, restaurants, wine stores, liquor stores, and supermarkets) will be constructed for each postcode in every year using Cumulative Opportunity indices calculated over 5 nearest outlets (Cp5; summed inverse distances from each postcode's SA1 population weighted centroid to the 5 nearest outlets).89 As Cp5 approaches zero, distances become large and opportunities to purchase alcohol low. Cp5 is a preferred spatial density measure that provides estimates of availability in both dense and sparsely populated areas (e.g., where alcohol may only be available in nearby postcodes).48 Within any year, the opening or closing of a new outlet takes place against the background of overall spatial availability effects and can be treated in a quasi-experimental analytic framework.11 Effects related to each opening/closing in year t can be measured in relation to spatial availability effects through year t-1. Alcohol Sales. Alcohol sales through outlets are provided by Western Australia Mental Health Commission and made available to NDRI on request. These data are provided in aggregate form by postcode and currently measure sales for 4 beverage types (high- and low-alcohol beer, wine, and spirits) and 6 outlet types (small bars, hotels/taverns, restaurants, wine and liquor stores, supermarkets). For analysis purposes, these 24 sales measures are converted to units pure ethanol using standard procedures.90-92 Sales data can be recompiled at NDRI's request to reflect other aspects of the beverage market (e.g., sales by quality class). Economic Availability. Costs of beverages purchased from wholesalers are also available for all alcohol sales. Dollar amounts within beverage-by-outlet types are summed and adjusted by the Western Australia Consumer Price Index to estimate annual wholesale prices. These are divided by total quantities of pure alcohol sold in each year to measure the average wholesale price per liter of pure ethanol; a significant cross-correlation of r=0.636 related wholesale to retail price estimates over 40 quarters of data (~2001-2010).93 Western Australia also introduced 5 tax changes affected wholesale and retail alcohol prices over the past three decades: (1) Biannual increases in beer and spirits taxes indexed to the consumer price index (CPI). (2) A 29% ad valorem Wine Equalization Tax (WET) in 2000. (3) A spirits Ready-to-Drink (RTD) tax on pre-mixed spirit beverages and Alcopops (sweetened drinks) in 2000. (4) A 10% goods and services tax on all alcoholic beverages in 2000. (5) Another Alcopops Tax introduced in 2008.133 There is accumulating evidence that alcohol taxes are directly and wholly passed through to consumers within one year of any tax hike.94-96 Impacts of these covarying measures that affect economic availability will be included in models assessing impacts related to physical availability (Section C.4). Outlet Regulations. Other regulations intended to affect sales through outlets include, first, the designation of 58 "restricted" and "dry" areas beginning in 1992 (currently there are 25 "dry" and 33 "restricted" areas within 32 postcodes) and, second, "extended trading provisions" that allow extended trading hours for outlets on a license-by-license basis (133 ETPs within 60 postcodes issued by 2015). "Restricted" areas limit trading hours, takeaway sales, types and volumes sold. "Dry" areas preclude sales. Importantly, no LGA is entirely restricted or dry. Uniquely, although hotels have functioned as taverns since the 19th century, "small bars", limited to 120 person capacity, were introduced in 2006. Alcohol Related Morbidity and Mortality. Hospital "separations" (discharges in US parlance), emergency department "presentations" (admissions), and deaths are geocoded to household residence. Diagnoses associated with each separation/presentation/death are identified by diagnostic codes using either the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) or, since 1998, ICD-10-CM. We will count diagnostic incidents and deaths for all patients 18 years of age and older. Hospital separations have several advantages when measuring health outcomes: (1) Counts of hospital separations and presentations at public hospitals within the Australian medicare system constitute a census of all hospital encounters. (2) They focus on severe cases that have been vetted using uniform standards and consistent ICD coding conditions.97 (3) They are accurate, validated and widely used to estimate diagnostic incidence and prevalence.98,99 (4) There are sufficient cases to support estimates for small population areas (e.g., areas comparable to US plain states).100 Presenting ICD-9 codes more familiar to US researchers, we will focus upon alcohol abuse and dependence (ICD-9 codes 305.0, 303.0), alcoholic cirrhosis (571.1-571.3), and injuries related to assault (E960-E969), suicide or self-inflicted wounds (E950-E959), motor vehicle accidents (E810- E819), domestic and partner violence (E967), and all other unintentional injury accidents (E800-E807, E850-E858, E860-E869, E880-E888, E900-E909, E910-E915, E916-E928, E929, E980-E989). Alcohol etiologic fractions have been calculated for each of these outcomes101,102 and, while ICD-9 diagnostic codes were used in the US to 2015, they were adopted for hospital separations in Western Australia in 1999 with codes cross-walked at that time103,104 in a manner comparable to procedures adopted in the US.105 We have considerable experience with these population level data (e.g., cirrhosis106; assaults107; suicide108; partner violence16) and will document and statistically control for impacts, if any, of diagnostic coding on tests of study hypotheses. Crime. Violent assault and drink driving (i.e., impaired driving) incidents with or without arrests are reported annually for postcodes by Western Australia police agencies. Incidents are located by address or intersection/milepost of report/arrest. Drink driving counts are contaminated by arrest incidents related to drink driving patrols ("booze buses") but these can be distinguished in available data.82 Police activity (i.e., field officers engaged in patrol activities) is reported and has been demonstrated as a confounder of measures of domestic violence and protective custody incidents, but not assault or drink driving incidents.93 Similar controls work well to assess confounding levels of enforcement effort in US studies.109 Western Australian Census Data. The Australian census is conducted every five years and annual census estimates are available by year for SA1 units reaggregated to postcodes. Data include population, employment and housing characteristics important in previous studies of alcohol sales and related problems: population size by age, gender and ethnicity, income, impoverishment, full- and part-time employment, unemployment, and residential housing characteristics (e.g., dwelling structure, tenure type, landlord type, number of bedrooms, and unoccupied housing).110 Commercial Business Data. Importantly, the commercial business data allow us to identify commercial centers with substantial retail activity, foot and motor vehicle traffic, important routine activities confounders. Environmental Data. Road network data identify transportation links between postcode areas and provide supplementary measures of roadway characteristics related to crashes. Roadway systems, geographically represented in the MWRA “Main Roads Western Australia” GIS, link rural areas, populations, businesses, and outlets and provide a better spatial framework for availability measures. For this reason, roadway distance will be used as the metric by which to calculate Cp5. The connectivity of postcodes in rural areas is also of importance since adjacent postcode boundaries may have no or few connecting roadways. Six roadway characteristics have also been identified as confounding predictors of AMVCs, total roadway length, percent highways, average speed, percent "T" intersections, curviness, and fragmentation.84 Planning and zoning data are available for LGAs and will be used to measure proportions of land area dedicated to retail trade, residential housing, and other commercial and recreational activities.111 Public transportation networks identify increased accessibility across some urban places, may reduce the need to drive and, subsequently, the incidence of motor vehicle crashes related to use. They may also lower costs of transportation to nighttime entertainment districts with associated risks for other alcohol related problems. Conjoint bus and rail stops between postcodes will be used to identify these links. Sex as a Biological Variable. While sex, gender and ethnicity are measures that will be included in all analyses and assessed as study covariates, outcome data stratified by these variables are not available in WAAID and potential subgroup differences across study outcomes cannot be further examined in this study. C.3. Statistical Analysis Framework. Numbers of postcode areas in WA grew from 295 in 1991 to 387 in 2020 with about 12% expected to change location, shape, or size each year.107 Representing different subpopulations in successive years, "unit misalignments" bias effects estimates and preclude longitudinal analyses using postcode/ZIPcode data. We developed Bayesian space-time models to statistically adjust for misalignment bias87,88 and have since improved this approach using more efficient Bayesian spatial stochastic partial differential equation models implemented in R-INLA (SPDEs).112-114 Impacts of unit misalignments are represented as changing locations of data elements (e.g., postcode centroids) on a Gaussian spatial random field underlying each SPDE model.8 The approach (a) provides a more realistic assessment of spatial relationships (i.e., continuous spatial autocovariances), (b) statistically adjusts for impacts of misalignments, and (c) allows direct modeling of temporal autoregressive effects. SPDE models represent spatial relationships among data elements using a finite element mesh that links nodes (i.e., postcode centroids) to one another in geographic space. The WAAID GIS has all geographic information needed to define the mesh with suitable projections (e.g., Australian Albers, EPSG:3577). Matern autocovariance functions measure spatial autocovariances along the mesh and enable assessments of temporal autocorrelated measurement error and temporal lag effects. Enforcing consistency across spatial analyses of project data, a common mesh will be defined for all analyses. SPDE error components will include i.i.d. unit effects, effects specific to the estimation of Matern covariance functions, multilevel error components related to multiresolution effects56, and controls for heteroskedasticity that arise due to structural components of analysis models shown in the figure accompanying Section A.5 (1). Across all analysis models, control covariates will include economic and sociodemographic measures and concurrent changes in alcohol beverage taxes and other alcohol control laws. Hypotheses will be tested within one of four data frames, long (30-year) or short (18-year) within a "full set" (Nfs~350) or "community subset" (Ncs~210) of postcode areas. Analyses of the full set will measure effects across all populations and the entire geography of Western Australia replicating methods used in many geospatial studies of alcohol problems. Analyses of the community subset will measure "local", "nearby" and "community" effects specific to 30 communities (LGAs) composed of 5 or more postcode areas. Analyses of the community subset will include data from buffered areas around communities (e.g., spatial availability measures) in order to ease concerns about edge effects. "Local" area effects are those in which independent and dependent variables are jointly measured within postcodes. "Nearby" effects are those in which a postcode dependent measure is related to independent measures summarized across adjacent postcodes (spatial lag effects). "Community" effects are those in which a postcode dependent measure is related to independent variables summarized across community postcodes. While not as highly resolved as studies which rely upon Census block group (or, within Australia, SA1) areas, analyses of data from the community subset should enable us to distinguish local, from nearby and community effects enabling more precise assessments of relationships between availability, sales and problems. Local and nearby measures must be centered on nearby and community measures to insure efficiency and interpretability of these multiresolution effects.56 Wishing to keep to otherwise standard analytic approaches to analyses of alcohol sales and problem data, semi-logarithmic Gaussian SPDEs will be applied to the assessment of alcohol sales in relation to measures of economic, physical and legal availability (e.g., beverage taxes, spatial availability, and regulatory policies). Poisson SPDEs will be applied to the assessment of problem incidence. References 1Campbell, C.A., Hahn, R.A., Elder, R., Brewer, R., Chattopadhyay, S., Fielding, P. (2009) The effectiveness of limiting alcohol outlet density as a means of reducing excessive alcohol consumption and alcohol-related harms. American Journal of Preventive Medicine, 37, 556-569. 2Popova, S., Giesbrecht, N., Bekmuradov, D., and Patra, J. (2009) Hours and days of sale and density of alcohol outlets: Impacts on alcohol consumption and damage: A systematic review. Alcohol and Alcoholism, 44, 500-516. 3Chaloupka, F.J., Grossman, M. and Saffer, H. (1998) The effects of price on the consequences of alcohol use and abuse. In: Galanter, M., Ed. Recent Developments in Alcoholism: Vol. 14, The Consequences of Alcohol. New York: Plenum Press, pp. 331–346. 4Grossman, M. (1988) Health economics of prevention of alcohol-related problems. Paper presented at the Workshop on Health Economics of Prevention and Treatment of Alcohol-Related Problems, National Institute on Alcohol Abuse and Alcoholism, Washington, DC. 5Gruenewald, P.J. (2011) Regulating Availability: How access to alcohol affects drinking and problems in youth and adults. Alcohol Research & Health 34(2):248-256. PMC3860569 6Frankeberger, J., Gruenewald, P.J. and Mair, C. (2021) Dual use of off-premise outlets for alcohol and grocery purchases: Results from the East Bay Neighborhoods Study, In press, Journal of Studies on Alcohol and Drugs. 7Graham, K. and Homel, R. (2009) Raising the Bar. New York: Taylor and Francis. 8Sumetsky, N., Mair, C., Anderson, S. and Gruenewald, P.J. (2020) A spatial partial differential equation approach to addressing unit misalignments in Bayesian Poisson space-time models. Spatial and Spatio-temporal Epidemiology. 9Freisthler, B., Lipperman-Kreda, S., Bersamin, M. and Gruenewald, P.J. (2014) Tracking the when, where, and with whom of alcohol use: Integrating ecological momentary assessment and geospatial data to examine reisk for alcohol-related problems. Alcohol Research: Current Reviews, 36, 1, 29-38. 10Texas Attorney General's Office (2016) Wal-Mart Stores, Inc., et al. v. Texas Alcoholic Beverage commission, et al. Civil Action No. 1:15-cv-00134-RP. 11Gruenewald, P.J., Sumetsky, N. Gaidus, A., Ponicki, W.R., Lee, J.P. and Mair, C. (2021a) Assessing the impacts of alcohol outlets on crime as a natural experiment: Agglomeration, churning and spatial effects. In press, Addiction. 12Gmel, G., Holmes, J., and Studer, J. (2015) Are alcohol outlet densities strongly associated with alcohol-related outcomes? A critical review of recent evidence. Drug and Alcohol Review, 35, 40-54. 13Morrison, C., Cerda, M., Gorman, D., Gruenewald, P., Mair, C., Naimi, T., Scribner, R., Stockwell, T., Toomey, T. and Wieczorek, W. (2015) Commentary on Gmel et al., (2015): Are alcohol outlet densities strongly associated with alcohol-related outcomes? A critical review of recent evidence. Drug and Alcohol Review, 35, 55-57. PMC4826631 14Gruenewald, P.J. (2016) Expert Witness Report of: Paul J. Gruenewald, Ph.D. March 18, 2016 Wal-Mart Stores, Inc., et al. v. Texas Alcoholic Beverage Commission, et al. Civil Action No. 1:15-cv-00134-RP. 15Mair, C., Gruenewald, P., Ponicki, W. and Remer, L. (2013) Varying impacts of alcohol outlet densities on violent assaults: Explaining differences across neighborhoods. Journal of Studies on Alcohol and Drugs, 74, 50-58. PMC3517264 16Cunradi, C.B., Mair, C., Ponicki, W. and Remer, L. (2012) Alcohol outlet density and intimate partner violence-related emergency department visits. Alcoholism: Clinical and Experimental Research, 36, 847-853. 17Morrison, C, Ponicki, W.R., Gruenewald, P.J., Wiebe, D.J. and Smith, K. (2016b) Spatial relationships between alcohol-related road crashes and retail alcohol availability. Drug and Alcohol Dependence,l 162, 241-244. PMC4833595 18Stockwell, T., Zhao, J., Macdonald, S., Pakula, B., Gruenewald, P.J. and Holder, H.D. (2009) Changes in per capita alcohol sales during the partial privatization of British Columbia's retail alcohol monopoly 2003-2008: a multi-level local area analysis. Addiction, 104, 1827-1836. 19Stockwell, T., Zhao, J., Macdonald, S., Vallance, K., Gruenewald, P.J., Ponicki, W.R., Holder, H. and Treno, A. (2011b) Impact on alcohol-related mortality of a rapid rise in the density of private liquor outlets in British Columbia: a local area multi-level analysis. Addiction, 107, 1218-1226. 20Stockwell, T., Auld, M.C., Zhao, J. and Martin, G. (2011a) Does minimum pricing reduce alcohol consumption? The experience of a Canadian province. Addiction, 107, 912-920. 21Stockwell, T., Zhao, J., Marzell, M., Gruenewald, P.J., MacDonals, S., Ponicki, W.R. and Martin, G. (2015) Relationships between minimum alcohol pricing and crime during the partial privatization of a Canadian government alcohol monopoly. Journal of Studies on Alcohol and Drugs, 76, 628-634. 22Rossow, I. and Norstrom, T. (2012) The impact of small changes in bar closing hours on violence. The Norwegian experince from 18 cities. Addiction, 107, 530-537. 23Lipton, R., Gaidus, A., Ponicki, W.R., and Gruenewald, P.J. (2018) Space-Time analyses of alcohol outlets and related motor vehicle crashes. Alcoholism: Clinical and Experimental Research, 42, 1113-1121. PMC5984166 24Marcus, J. and Siedler, T. (2015) Reducing binge drinking? The effect of a ban on late-night off-premise alcohol sales on alcohol-related hospital stays in Germany, IZA Discussion Papers, No. 8763, Institute for the Study of Labor (IZA), Bonn. 25Meany, B., Berning, J. and Smith, T. (2018) The effect of sunday alcohol sales bans on teen drinking in Georgia. Applied Economics Perspectives and Policy, 40, 461-481. 26Pliakas, T., Lock, K., Jones, A., Aalders, S. and Egan, M. (2018) Getting shops to voluntarily stop sellling cheap, stron geers and ciders: A time-series analysis evaluating impacts on alcohol availability and purchasing. , 41, 110-118. 27Hobday, M., Chikritzhs, T., Liang, W. and Meuleners, L. (2015) The effect of alcohol outlets, sales and trading hours on alcohol-related injuries presenting at emergency departments in Perth, Australia, from 2002 to 2010. Addiction, 110, 1901-1909. 28Holmes, J. and Meier, P.S. (2015) Commentary on Hobday et al. (2015): Inconsistent results beneath consistent conclusions – the need for a new approach to analyzing alcohol availability. Addiction, 110, 1910-1911. 29Haughwout, S.P. and Slater, M.E. (2018) Alcohol Epidemiologic Data System (AEDS), CSR, Incorporated, Contract No. HHSN275201300016C, National Institute on Alcohol Abuse and Alcoholism, Division of Epidemiology and Prevention Research. 30Iowa Alcohol Beverages Division (2021) Iowa Data. https://data.iowa.gov/Sales-Distribution/Iowa-Liquor-Sales/m3tr-qhgy. Accessed October, 19, 2021. 31Barnett, S.B.L., Coe, N.B., Harris, J.R. and Basu, A. (2020) Washington's privatization of liquor: Effects on household alcohol purchases from initiative 1183. Addiction, 115, 681-689. 32Byrnes, J., Shakeshaft, A., Petrie, D. and Doran, C. (2013) Can harms associated with high-intensity drinking be reduced by increasing the price of alcohol? Drug and Alcohol Review, 32, 27-30. 33Halonen, J.I., et al., Proximity of off-premise alcohol outlets and heavy alcohol consumption: A cohort study. Drug and Alcohol Dependence, 2013. 132(1-2): p. 295-300. 34Subbaraman, M.S., Mulia, N., Kerr, W.C., Patterson, D., Karriker-Jaffe, K.J. and Greenfield, T.K. (2020) Relationships betwween US state alcohol policies and alcohol outcomes: Differences by gender and race/ethnicity. Addiction, 115, 1285-1294. 35Gruenewald, P.J., Remer, L.R. and LaScala, E.A. (2013) Testing a social ecological model of alcohol use: The California 50 city study. Addiction, 109, 736-745. PMC4106302 36Brenner, A.B., et al., (2015) Longitudinal associations of neighborhood socioeconomic characteristics and alcohol availability on drinking: Results from the Multi-Ethnic Study of Atherosclerosis (MESA). Social Science & Medicine, 145, 17-25. 37White, V., Azar, D., Faulkner, A., Coomber, K., Durkin, S., Livingston, M., Chikritzhs, T. Room, R., and Wakefield, M. (2018) Adolescents' alcohol use and strength of policy relating to youth access, trading hours and driving under the influence: Findings from Australia. Addiction, 113, 1030-1042. 38Friesen, E., Kurdyak, P., Jewett, R., Smith, B., Hobin, E., Tanuseputro, P., and Myran, D. (2021) Associations between the physical availability of alcohol and alcohol use: Regional variation across 15 major cities in Ontario, Canada. Addiction, In press. 39Kerr, W.C. and Greenfield, T.K. (2007) Distribution of alcohol consulmption and expenditures and the impact of improved measurement on coverage of alcohol sales in the 2000 National Alcohool Survey. Alcoholism: Clinical and Experimental Research, 31, 1714-1722. 40Hadfield, P. (2009) Nightlife and Crime: Social Order and Governance In International Perspective. New York: Oxford University Press. 41Kypri, K. and Livingston, M. (2020) Incidence of assault in Sydney, Australia, throughout 5 years of alcohol trading hour rstrictions: Controlled before-and-after study. Addiction, 115, 2045-2054. 42Han, D. and Gorman, D.M. (2013) Evaluating the effects of the introduction of off-sale alcohol outlets on ciolent crime. Alcohol and Alcoholism, 48, 370-374. 43Gorman, D.M., Ponicki, W.R., Zheng, Q., Han, D., Gruenewald, P.J., and Gaidus, A. (2018) Violent crime redistribution in a city following a substantial increase in the number of off-sale alcohol outlets: A Bayesian analysis. Drug and Alcohol Review, 37, 348-355. PMC6231714 44Freisthler, B., Gruenewald, P.J., Remer, L.G., Lery, B. and Needell, B. (2007) Exploring the spatial dynamics of alcohol outlets and child protective services referrals, substantiations, and foster care entries. Child Maltreatment, 12, 114-124. 45Gruenewald, P.J., Grube, J.W., Saltz, R. and Paschall, M.J. (2018a) Environmental Approaches to Prevention: Communities and Contexts. In S.C. Miller, D.A. Fiellin, R.N. Rosenthal, R. Saitz (Eds.), Principles of Addiction Medicine: The Essentials. Chevy Chase, MD: American Society of Addiction Medicine. 46Single, E. (1988) The availability theory of alcohol related problems. In C.D. Chaudron & D.A. Wilkinson, Eds., Theories on Alcoholism, pps. 325-351, Toronto: Addiction Research Foundation. 47Stockwell, T. and Gruenewald, P.J. (2004) Controls on the physical availability of alcohol. In The Essential Handbook of Treatment and Prevention of Alcohol Problems, pps. 213-233, N. Heather and T. Stockwell, Eds., New York: John Wiley. 48Sachs, J.J., Brewer, R., Mesnick, J., Holt, J., Zhang, X., Kanny, D., Elder, R. and Gruenewald, P. (2019) Measuring alcohol outlet density: an overview for public health practitioners. In press, Journal of Public Health Management & Practice. PMC Journal – In Process 49Cohen, L.E. and Felson, M. (1979) Social change and crime trends: A routine activity approach. American Sociological Review, 44, 588-608. 50Mair, C., Sumetsky, N., Lee, J., Gruenewald, P.J. and Torso-Orkis, L. (2021) Features of off-premise alcohol outlets, neighborhood conditions and violent crime: The East Bay Neighbohoods study. In review. 51Gruenewald, P.J. (2007) The spatial ecology of alcohol problems: Niche theory and assortative drinking. Addiction, 102(6): 870-888. 52Sumetsky, N., Gruenewald, P.J., Lipperman-Kreda, S., Lee, J.P. and Mair, C. (2021) Alcohol use frequencies and associated problems across drinking contexts. In press, Journal of Studies on Alcohol and Drugs. PMC Journal - In Process 53Waller, L.A. and Godfrey, C. A. (2004) Applied Spatial Statistics for Public Health Data. New York: Wiley-Interscience. 54Banerjee, A., LaScala, E.A., Gruenewald, P.J., Freisthler, B., Treno, A. & Remer, L. (2008) Social disorganization, alcohol and other drug markets, and violence: A space-time model of community structure. In: Yonette F. Thomas, Douglas Richardson & Ivan Cheung. (Eds.), Geography and Drug Addiction. Pp. 117-130. New York: Springer. 55Cerda, M., Wheeler-Martin, K., Bruzelius, E., Ponicki, W.R., Gruenewald, P.J., Mauro, c., Crystal, S., Davis, C., Keyes, K., Hasin, D., Rudolph, K., Martins, S. (2021) Spatiotemporal analysis of the association between pain management clinic laws and opioid prescribing and overdose deaths. In press, American Journal of Epidemiology. PMC Journal - In Process 56Mair, C., Sumetsky, N., Gaidus, A., Gruenewald, P.J. and Ponicki, W. (2020) Multi-resolution analyses of neighborhood correlates of crime: Smaller is not better. American Journal of Epidemiology, in press. PMC Journal – In Process 57Morrison, C., Gruenewald, P.J. and Ponicki, W.R. (2016a) Race, ethnicity and exposure to alcohol outlets. Journal of Studies on Alcohol and Drugs, 77(1), 68-76. PMC4711321 58Lee, J.P., Ponicki, W.R., Mair, C.F., Gruenewald, P. and Ghanem, L. (2020) What explains the concentration of off-premise alcohol outlets in Black neighborhoods? In press, Social Science and Medicine - Population Health. PMC Journal - In Process 59Mair, C., Sumetsky, N., Gruenewald, P.J., and Lee, J.P. (2020) Microecological relationships between area income, off-premise alcohol outlet density, drinking patterns and alcohol use disorders: The East Bay Neighborhoods Study. In press, Alcoholism: Clinical and Experimental Research. PMC Journal – In Process PMID: 32573798 60Gruenewald, P.J., Millar, A.B., Treno, A.J., Ponicki, W.R., Yang, Z. & Roeper, P. (1996) The geography of availability and driving after drinking. Addiction 91(7): 967-983. PMID: 8688823 61Liang, W. and chikritzhs, T. (2011) Revealing the link between licensed outlets and violence: counting venues versus measuring alcohol availability. Drug and Alcohol Review, 30, 524-535. 62Kerr, W.C., Williams, E., Ye, Y., Subbaraman, M.S. and Greenfield, T.K. (2018) Survey estimates of changes in alcohol use patterns following the 2012 privatization of the Washington liquor monopoly. Alcohol and Alcoholism, 53, 470-476. 63Myran, D.T., Chen, J.T., Giesbrecht, N., and Rees, V.W. (2019) The association between alcohol access and alcohol-attributable emergency department visits in Ontario, Canada. Addiction, 114, 1183-1191. 64Lardier, D.T., Opara, I., Lin, Y., Roach, E., Herrera, A., Garcia-Reid, P. and Reid, R.J. (2021) A spatial analysis of alcohol outlet density type, abandoned properties, and police calls on aggravated assault rates in a northeastern US city. Substance Use and Misuse, 56, 1527-1535. 65LeSage, J.P. and Pace, R.K. (2009) Introduction to Spatial Econometrics. Boca Raton: CRC Press. 66Gruenewald, P.J., Freisthler, B., Remer, L.G., LaScala, E.A. and Treno, A.J. (2006) Ecological models of alcohol outlets and violent assaults: Crime potentials and geospatial analysis. Addiction 101(5): 666-677. 67Nelson, T.F., Xuan, Z., Babor, T.F., Brewer, R.D., Chaloupka, F.J., Gruenewald, P.J., Holder, H., Klitzner, M., Mosher, J.F., Ramirez, R.L., Reynolds, R., Toomey, T.L., Churchill, V. and Naimi, T.S. (2013) Efficacy and strength of evidence of U.S. alcohol control policies. American Journal of Preventive Medicine, 45, 19-28. PMC3708657 68Chikritzhs, T. (2009) Australia. In Hadfield, P. (Ed) Nightlife and Crime: Social Order and Governance in International Perspective. Oxford: Oxford University Press. 69National Institute on Alcohol Abuse and Alcoholism (2021) Alcohol Policy Information System (APIS). https://alcoholpolicy.niaaa.nih.gov, accessed September 9, 2021. 70Callinan, S., Livingston, M., Room, R. and Dietze, P. (2016) Drinking contexts and alcohol consumption: How much alcohol is consumed in different Australian locations? Journal of Studies on Alcohol and Drugs, 77, 612-619. 71Dietze, P.M., Livingston, M., Callinan, S. and Room, R. (2014) The big night out: What happens on the most recent heavy drinking occasion among young Victorian risky drinkers? Drug and Alcohol Review, 33, 346-353. 72Stevenson, R.J., Lind, B. and Weatherburn, D. (1999) The relationship between alcohol sales and assault in New South Wales, Australia. Addiction, 94, 397-410. 73Livingston, M. (2008) Alcohol outlet density and assault: A spatial analysis. Addiction, 103, 619-628. 74Morrison, C., Smith, K., Gruenewald, P.J., Ponicki, W.R., Lee, J.P. and Cameron, P. (2016c) Relating off-premises alcohol outlet density to intentional and unintentional injuries. Addiction, 111, 56-64. 75Scribner, R.A., MacKinnon, D.P. and Dwyer, J.H. (1995) The risk of assaultive violence and alcohol availability in Los Angeles county. American Journal of Public Health, 85, 335-340. 76Toomey, T.L., Erickson, D.J., Carlin, B.P., Lenk, K.M., Quick, H.S., Jones, A.M., and Harwood, E.M. (2012) The association between density of alcohol establishments and violent crime within urban neighborhoods. Alcoholism: Clinical and Experimental Research, 36, 1468-1473. 77Zhang, X., Hatcher, B., Clarkson, L., Holt, J., Bagchi, S., Kanny, d. and Brewer, R.D. (2015) Changes in density of on-premises alcohol outlets and impact on violent crime. Atlanta, Georgia, 1997-2007. Preventing Chronic Disease, 12, 140317. https://doi.org/10.5888/pcd12.140317 78Livingston, M. (2010) The ecology of domestic violence: The role of alcohol outlet density. Geospatial Health, 5, 139. https://doi.org/10.4081/gh.2010.194 79Livingston, M. (2011) A longitudinal analysis of alcohol outlet density and domestic violence: Alcohol outlet density and domestic violence. Addiction, 106, 919-925. 80Cunradi, C.B., Mair, C., Ponicki, W. and Remer, L. (2011) Alcohol outlets, neighborhood characteristics, and intimate partner violence: Ecological analysis of a California city. Journal of Urban Health, 88, 191-200. 81McKinney, C.M., Caetano, r., Harris, T.R. and Ebama, M.S. (2009) Alcohol availability and intimate partner violence among US couples. Alcoholism: Cliinical and Experimental Research, 33, 169-176. 82Chikritzhs, T. and Stockwell, T. (2006) The impact of later trading hours for hotels on levels of impaired driver road crashes and driver breath alcohol levels. Addiction, 101, 1254-1264. 83Ponicki, W.R., Gruenewald, P.J. and Remer, L.G. (2013) Spatial panel analyses of alcohol outlets and motor vehicle crashes in California: 1999-2008. Accident Analysis and Prevention, 55, 135-143. PMC4207645 84Lipton, R., Banerjee, A., Ponicki, W.R., Gruenewald, P.J. and Morrison, C. (2021) Impacts of confounding roadway characteristics on estimates of associations between alcohol outlet densities and alcohol-related motor vehicle crashes. Drug and Alcohol Review, 40, 239-246. 85Australian Bureau of Statistics (2011) Australian Statistical Geography Standard (ASGS): Volume 3 – Non ABS Structures, July 2011 (cat. no. 1270.0.55.003). 86Environmental Systems Research Institute (2016) ArcGIS V10.4. ESRI http://desktop.arcgis.com/en/arcmap/. 87Zhu L, Waller LA, Ma J. (2012) Spatial-temporal disease mapping of illicit drug abuse or dependence in the presence of misaligned ZIP codes. GeoJournal. Available at: http:// www.springerlink.com/content/r823l22137l6r505/ fulltext.pdf. Accessed August 16, 2019. 88Gruenewald, P.J., Ponicki, W.R., Remer, L.G., Waller, L.A., Zhu, L., and Gorman, D.M. (2012) Mapping the spread of methamphetamine abuse in California from 1995 to 2008. American Journal of Public Health, 103, 1262-1270. PMC3682593 89Van Meter, E., Lawson, A.B., Colabianchi, N., Nichols, M., Hibbert, J., Porter, D. and Liese, A.D. (2012) Spatial accessibility and availability measures and statistical properties in the food environment. Spatial and Spatiotemporal Epidemiology, 2, 35-47. 90Loxley, W., Chikritzhs, T. and Catalano, P. (2011) National Alcohol Sales Data Project Stage Two: Final Report. Perth (AUST): Curtin University of Technology, National Drug Research Institute. 91Chikritzhs, T., Allsop, S., Moodie, A.R., and Hall, W.D. (2010) Per capita alcohol consumption in Australia: Will the real trend please step forward? Medical Journal of Australia, 193,1-4. 92Distilled Industry Business Council of Australia (2006) Alcohol Tax in Australia. South Melbourne (AUST): DSICA. 93Symons, M., Gray, D., Chikritzhs, Skov, S., Saggers, S., Boffa, J. and Low, J. (2012) A longitudinal study of influences on alcohol consumption and related harm in Central Australia: With a particular emphasis on the role of price. National Drug Research Institute, Curtin University, Perth, Western Australia. 94Siegel, M., Grundman, J., DeJong, W., Naimi, T.S., King, C., Albers, A.B., Williams, R.S., and Jernigan, D.H. (2013) State-specific liquor excise taxes and retail prices in eight U.S. states, 2012. Substance Abuse, 34, 415-421. 95Ngo, A. and Chaloupka, F. (2019) The pass-through of alcohol taxes to prices in OECD countries. 8th Conference of the American Society of Health Economists, Washington, DC, June 23-26. 96Ally, A.K., Meng, Y., Chakraborty, R., Dobson, P.W., Seaton, J.S., Holmes, J., Angus, C., Guo, Y., Hill-McManus, D., Brennan, A. and Meier, P.S. (2014) Alcohol tax pass-through across the product and price range: Do retailers treat cheap alcohol differently? Addiction, 109, 1994-2002. 97Unick, G.J., et al., (2013) Intertwined Epidemics: National Demographic Trends in Hospitalizations for Heroin- and Opioid-Related Overdoses, 1993–2009. PLoS ONE, 8(2): p. 1-8. 98Hasegawa, K., et al., (2013a) Childhood asthma hospitalizations in the United States, 2000-2009. The Journal Of Pediatrics, 163(4): p. 1127-33.e3. 99Hasegawa, K., et al., (2013b) Trends in Bronchiolitis Hospitalizations in the United States, 2000–2009. Pediatrics, 132(1): p. 28-36. 100Ponicki, W.R., Henderson, J., Gaidus, A., Gruenewald, P.J., Lee, J.P., Moore, R.S., Davids, S., and Tilson, N. (2018) Spatial epidemiology of alcohol and drug-related health problems among Northern Plains American Indians: Nebraska and South Dakota, 2007-2012. Alcoholism: Clinical and Experimental Research, 42, 578-588. PMC5832572 101Single, E., et al., (2000) The relative risks and etiologic fractions of different causes of death and disease attributable to alcohol, tobacco and illicit drug use in Canada. CMAJ: Canadian Medical Association Journal, Journal De L'association Medicale Canadienne. 162(12): p. 1669-1675. 102Rehm, J. (2011) The Risks Associated With Alcohol Use and Alcoholism. Alcohol Research & Health. 34(2): p. 135-143. 103Chikritzhs, T., Unwin, L., Codde, J., Catalano, P. and Stockwell, T.R. (2002) Alcohol-related codes: Mapping ICD-9 to ICD-10. National Drug Research Institute. Curtin University of Technology, Perth, Western Australia, ISBN:1 74067 1872. 104Chikritzhs, T., Catalano, P., Stockwell, T.R., Donath, S., Ngo, H.T., Young, D.J. and Matthews, S. (2003) Australian Alcohol Indicators, 1990-2001; patterns of alcohol use and related harms for Australian states and territories. National Drug Research Institute, Perth, Western Australia. 105Centers for Medicare and Medicaid Services. (2019) General Equivalence Mappings. https://www.cms.gov/Medicare/Coding/ICD10/downloads/ICD-10_GEM_fact_sheet.pdf 106Ponicki, W.R. and P.J. Gruenewald (2006) The impact of alcohol taxation on liver cirrhosis mortality. Journal Of Studies On Alcohol. 67(6): p. 934-938. 107Gruenewald, P.J. and Remer, L. (2006) Changes in outlet densities affect violence rates. Alcoholism: Clinical and Experimental Research, 30, 1184-1193. 108Johnson, F.W., P.J. Gruenewald, and L.G. Remer (2009) Suicide and alcohol: do outlets play a role? Alcoholism, Clinical And Experimental Research. 33(12): p. 2124-2133. 109Caetano, R., Vaeth, P. A., Gruenewald, P. J., Ponicki, W. R., Kaplan, Z., & Annechino, R. (2021). Proximity to the US/Mexico border, alcohol outlet density and population-based sociodemographic correlates of spatially aggregated violent crimes in California. Annals of Epidemiology, 58, 42-47. 110Australian Bureau of Satistics (2021) Housing Variables. https://www.abs.gov.au/statistics/standards/housing-variables/latest-release#summary 111Western Australia Department of Planning, Lands and Heritage (2021) Local Planning Strategies, Schemes and Structure Plans. Local Planning Strategies, Schemes and Structure Plans (www.wa.gov.au), Accessed October 19, 2021. 112Blangiardo, M. and Cameletti, M. (2015) Spatial and SpatioTemporal Bayesian Models with R-INLA. Chichester, UK: John Wiley & Sons, Ltd. 113Bakka, H., Rue, H., Fuglstad, G.-A., Riebler, A., Bolin, D., ILlian, J., Krainski, E., Simpson, D. and Lindgren, F. (2018) Spatial modeling with R-INLA: A review. arXiv:1802.06350v2 [stat.ME] 8 May 2018 114Krainski, E.T., Gomez-Rubio, V., Bakka, H., Lenzi, A., Castro-Camilo, D., Simpson, D., Lindgren, F. and Rue, H. (2019) Advanced Spatial Modeling with Stochastic Partial Differential Equations using R and INLA. Boca Raton, FL: CRC Press. 115Young, D.J. and Bielinska-Kwapisz, A. (2003) Alcohol consumption, beverage prices and measurement error. Journal of Studies on Alcohol, 64, 235-238. 116Cook, P. (2007) Paying the Tab: The Costs and Benefits of Alcohol Control. Princeton: Princeton University Press. 117McElreath, R. (2016) Statistical Rethinking: A Bayesian Course with Examples in R and Stan. Boca Raton, FL: CRC Press. 118Burnham, K.P. and Anderson, D.R. (2010) Model Selection and Multimodel Inference. New York: Springer. 119Li, L. and Sexton, R.J. (2005) Retailer pricing strategies for differentiated products: The case of lettuce and bagged salads. Department of Agricultural and Resource Economics, University of California, Davis. 120Hosken, D. and Reiffen, D. (2004a) Patterns of retail price variation. The RAND Journal of Economics, 35, 128-146. 121Wen, H. and Goodman, A.C. (2013) Relationship between urban land price and housing price: Evidence from 21 provincial capitals in China. Habitat International, 40, 9-17. 122Greene, W.H. (2012) Econometric Analysis, 7th Edition. New York: Prentice Hall. 123Woolridge, J.M. (2010) Econometric Analysis of Cross Section and Panel Data. Boston, Massachusetts: MIT Press. 124Minguez, R., Lopez, F.A., and Mur, J. (2019) spsur: An R Package for Spatial Seemingly Unrelated Regressions. https://cran.r-project.org/web/packages/sp;sur/vignettes/spsur-vignette.html. 125Sumetsky, N., Mair, C., Ponicki, W.R. and Gruenewald, P.J. (2021) Microtemporal analyses of violence related to alcohol outlets; Weekends, weeknights, daytime and nighttime. In press, Drug and Alcohol Review. 126Hill, E., A. Allen, and L.A. Waller, Recent development of disease mapping and detection clusters: A comparison of focused score tests and Bayesian hierarchical models for detecting spatial disease clustering. Bulletin of National Institute of Public Health (Japan), 1999. 48: p. 102-112. 127Hoff, P., A First Course in Bayesian Statistical Methods. 2009, New York: Springer. 128Wikle, C.K. (2003) Hierarchical Models in Environmental Science. International Statistical Review. 71, 181-199. 129Cressie, N. and Wikle, C.K. (2011) Statistics for Spatio-Temporal Data. New York: Wiley. 130Gruenewald, P.J., LaScala, E.A., and Ponicki, W.R. (2018) Identifying the population sources of drinking and alcohol impaired driving: An assessment of context specific drinking risks. Journal of Studies on Alcohol and Drugs, 79, 702-709. PMC6240005 131Hodges, J. and Reich, B. (2010) Adding spatially-correlated errors can mess up the fixed effect you love. University of Minnesota Division of Biostatistics; Technical Report No. 2010-002. http:/www.biostat.umn.edu/ftp/pub/2010/rr2010-002.pdf 132Paciorek, C.J. (2010) The importance of scale for spatial-confounding bias and precision of spatial regression estimators. Statistical Science, 25, 107-125. 133Commonwealth of Australia, Parliamentary Budget Office (2015). Alcohol Taxation in Australia. Report No. 03/2015. Canberra, Commonwealth of Australia.

The aim of this article is to assess both the economic and social value of balneotherapy and spa tourism, being the first paper in carrying out this analysis. The study has been conducted in Maresme, a region of Catalonia, Spain. On the one hand, an Input-Output (IO) model with a Social Accounting Matrix (SAM) has been carried out to assess the economic value. On the other hand, a Cost-Benefit Analysis (CBA) has been used to monetise the social value in this region, taking into account, among other concepts, direct and indirect health profits, given that balneotherapy helps to alleviate various diseases. The results show that whereas the economic multiplier is 1.529 considering the direct and indirect effects and 1.712 taking into account also the induced effects, which are similar to health and medical tourism multipliers, social value generates additional positive value, given that the cost-benefit ratio is 1.858. The theoretical implications of the paper as well as the findings’ implications for policy so as to encourage investments in spa tourism are discussed.

Strong primary care does not develop spontaneously but requires a well-developed organizational planning between levels of care. Primary care-oriented health systems are required to effectively tackle unmet health needs of the population, and efficient primary care organization (PCO) is crucial for this aim. Via strong primary care, health delivery, health outcomes, equity, and health security could be improved. There are several theoretical models on how primary care can be organized. In this position paper, the key aspects and benchmarks of PCO will be explored based on previously mentioned frameworks and domains. The aim of this position paper is to assist primary care providers, policymakers, and researchers by discussing the current context of PCO and providing guidance for implementation, development, and evaluation of it in a particular setting. The conceptual map of this paper consists of structural and process (PC service organization) domains and is adapted from frameworks described in literature and World Health Organization resources. Evidence we have gathered for this paper shows that for establishing a strong PCO, it is crucial to ensure accessible, continuous, person-centered, community-oriented, coordinated, and integrated primary care services provided by competent and socially accountable multiprofessional teams working in a setting where clear policy documents exist, adequate funding is available, and primary care is managed by dedicated units.

SUMMARY Over the last decade, the focus of clinical implant research shifted from predominately survival orientated to peri-implant health and patient-centred outcomes. A stable peri-implant bone level is a prerequisite to achieve long-term implant success. Peri-implant bone level is affected by patient-, implant-, and site-specific factors. In addition, the success of an implant treatment could also be determined by the improvement in Oral Health-Related Quality of Life (OHRQoL). The introduction (Chapter 1) scrutinizes and clarifies the current literature focusing on these factors. The existing literature gives an ambiguous effect of implant-related and site-specific factors on peri-implant bone stability, showing the need for more research. Chapter 2 presents the aims of this dissertation. This thesis's first two literature studies (Chapter 3 and 4) systematically assessed the available scientific evidence. The assessment focused on whether commonly used biological parameters correspond to long-term outcomes of implant survival and reported peri-implantitis prevalence. Additionally, it also examined whether long-term peri-implant bone loss is affected by implant surface roughness. The clinical studies in this thesis (Chapter 5, 6, and 7) aimed to evaluate the effect of implant related factors such as implant micro-design (implant surface roughness), macro-design (microthreads and implant-abutment connection), and site-specific factors (soft-tissue thickness) on long-term peri-implant bone stability and peri-implant health. Additionally, we paid attention to the Oral Health-Related Quality of Life in patients restored with mandibular implant-retained overdentures. Chapter 3 (Study I) is a critical review of the literature published between 2011 and 2017, regarding the biological peri-implant parameters bleeding on probing, probing pocket depth, and bone loss. The search algorithm highlighted 4,173 papers available for further analysis, 255 papers for full article reading, and 41 fulfilled the inclusion criteria. In these 41 articles, 15 different case definitions for peri-implantitis were used. The reported prevalence of peri-implantitis ranged between 0% and 39.7%, with an overall mean weighted implant survival rate of 96.9% (89.9% - 100%). Based on 8,182 implants, the overall weighted mean bone loss was 1.1 mm after a loading time ranging from 5 to 20 years. The mean bone loss did not correlate with the reported prevalence of peri-implantitis, and the diagnostic parameters mean probing pocket depth and mean bleeding on probing. Moreover, the reported peri-implantitis prevalence did not correlate with mean probing pocket depth. However, a strong correlation was found between the reported prevalence of peri-implantitis and bleeding on probing. The survival rate showed a substantial correlation with function time, showing minor implant loss over time. We concluded that the case definition for peri-implantitis varied significantly between studies, indicating that an unambiguous definition based on a specified threshold for bone loss is not agreed upon in the literature. Chapter 4 (Study II) scrutinized the literature on long-term peri-implant bone loss and the relation with implant surface roughness and patient-related factors such as smoking and history of periodontitis. Implant systems are categorised based on the surface roughness expressed in Sa-value; minimally rough (Sa value: 0.5 – 1 μm), moderately rough (Sa value: 1 – 2 μm), and rough (Sa value: > 2 μm). In implant dentistry's early days, only minimally rough and microporous titanium plasma-sprayed rough implant systems were available. However, over time several implant modifications were done by sandblasting, acid-etching, anodic oxidation, or hydroxyapatite coating resulting in a moderately rough implant system. These modifications improved the osteoconductive and osteoinductive properties of the implant. The surface of the moderately rough implant system showed better blot cloth stabilisation, enhanced production of biological mediators, stimulate osteogenic maturation leading to higher bone-to-implant contact, and increased bonding strength of the bone to the implant. On the other hand, rougher implant systems are linked to increased bacterial adhesion with a higher risk of being affected by peri-implantitis. The search yielded 2,566 studies and 156 were selected for further reading. Only 87 reported information about surface roughness of the implants and mean bone loss after at least five years of function. In these papers in total 15,695 implants were inserted in 6,755 patients. The average weighted survival rate for these implants was 97.3% after at least 5 years of function. If 3 mm bone loss was used as a threshold to quantify peri-implantitis, less than 5% of the implants were affected. Regarding implant surface roughness, the systematic review suggests that peri-implant bone loss around minimally rough implant systems was statistically significantly less than the moderately rough and rough implant systems. No statistically significant difference was observed between moderately rough and rough implant systems. The meta-analyses showed less average peri-implant bone loss around smoother surfaces. However, due to the heterogeneity of the papers and the multifactorial cause for bone loss, the impact of surface roughness alone seems somewhat limited and of minimal clinical importance. In addition, the meta-analysis showed that smoking and history of periodontitis increased the risk for bone loss. Chapter 5 (Study III) includes two prospective split-mouth studies. Both studies included edentulous patients in need of a two-implant-supported overdenture in the mandible. The first part of Study III described the effect of the site-specific factor ‘soft-tissue thickness’ on crestal bone remodeling and peri-implant health. Twenty-six patients received two moderately rough implants. According to the manufacturer's guidelines, the control implant was installed equicrestally. The test implant was placed below crestal level to ensure at least 3 mm space for biologic width establishment on the abutment part. Initially, 26 patients were treated with one equicrestally and one subcrestally placed implant. After 36 months, 24 patients were available for follow-up. The second part of Study III determined the effect of implant surface roughness on crestal bone remodeling. As concluded in Study II, crestal bone loss might be related to the implant surface roughness. The existing literature suggests higher survival rates for moderately rough implants compared to minimally rough implants. On the other hand, recent literature and the findings of Study II suggest that implants with a minimally rough surface yield less long-term crestal bone loss. An implant with a hybrid surface combines the benefit of a moderately rough implant body and a minimally rough implant neck. To determine the effect of implant surface roughness on crestal bone loss, 23 patients received two implants: an implant with a moderately rough surface (Sa value: 1.3 μm) and a hybrid implant with a minimally rough coronal neck of 3 mm (Sa value: 0.9 μm) combined with a moderately rough body (Sa value: 1.3 μm). Apart from the difference in implant surface roughness, the two implants were identical. After 36 months, 21 patients were available for follow-up. The implant survival rate was 100% after 36 months. No differences were observed in crestal bone remodeling between the hybrid and moderately rough implant. However, initial bone remodeling was affected by initial soft tissue thickness because the equicrestal implants had implant threads exposed above bone level. Anticipating the biological width re-establishment by adapting the vertical position of the implant in relation to the available soft tissue thickness may prevent that implant threads are not fully covered by peri-implant bone. However, long-term follow-up of the study is necessary to determine the influence of early implant surface exposure and implant surface roughness on crestal bone loss, biological parameters, and implant survival. Study III also included Oral Health-Related Quality of Life for edentulous patients restored with a two-implant-supported mandibular overdenture. This patient-centred outcome was assessed with the Oral Health Impact Profile-14 (OHIP-14). The study concluded that a two-implant-supported mandibular overdenture in comparison with a conventional removable denture yields a significant improvement in the quality of life. Chapter 6 (Study IV) presented the five-year follow-up of the first part of study III, determining the effect of soft tissue thickness on crestal bone remodeling and peri-implant health. Twenty-four patients were available for the five-year follow-up. The survival rate was 100%, and only one implant showed a mean bone level higher than 2 mm. During initial bone remodeling equicrestal placement yielded 0.68 mm additional surface exposure compared to subcrestal placement. Afterwards, bone level and peri-implant health were comparable in both treatment conditions and stable up to five years. Hence, Study IV concluded that adapting the vertical position of the implant concerning the soft tissue thickness prevents early implant surface exposure caused by initial bone remodeling. However, in a well-maintained population, this has no impact on long-term prognosis. In addition, the Oral Health-Related Quality of Life was assessed using the Oral Health Impact Profile-14 (OHIP-14), concluding a stable Oral Health-Related Quality of Life over time. Chapter 7 (Study V) determines the effect of implant neck (microthreaded versus non-microthreaded) as well as the type of connection (internal conical versus external flat-to-flat) on peri-implant bone stability and peri-implant health. According to the literature, peri-implant bone loss is minimized on implants with microthreaded neck design and internal type of abutment connection, albeit that many clinical studies are biased due to confounding factors. Twenty-five patients were treated with a maxillary implant-supported bar-retained overdenture on four different implant types. Each patient received one implant with an internal connection with microthreads (I MT), one with an internal connection without microthreads (I NMT), one with an external connection with microthreads (E MT), and one with an external connection without microthreads (E NMT). Other design features, as well as surgical and prosthetic protocol, were consistent. After at least 36 months, the survival rate was 96%. It was concluded that the implant-abutment connection type (internal vs external) and the implant neck design (microthreaded vs non-microthreaded) have no clinical effect on peri-implant bone remodeling, peri-implant bone level after the initial remodeling. Furthermore, it also had no clinical effect on peri-implant health parameters, at least when implants are installed according to soft tissue thickness. Chapter 8 is the general discussion and includes clinical and future research recommendations. In addition, it highlights the social relevance of the undertaken scientific work in conjunction with a personal reflection. This PhD thesis concludes that: 1. Various peri-implantitis definitions are used in the literature, and reporting of biological parameters is often incomplete. Consistent reporting of peri-implantitis is required for scientific purposes as well as for clinical practice. 2. The peri-implantitis prevalence based on various case definitions did not correlate with the diagnostic parameters ‘mean probing pocket depth’, ‘mean bleeding on probing’, and ‘mean bone loss’. The survival rate showed a substantial correlation with function time, but implant loss over time is low. 3. In the current literature, less than 5% of the implants showed bone loss above 3 mm after at least five years in function. This result was independent of surface or implant brand, suggesting that currently reported peri-implantitis prevalence is exaggerated. 4. Rough implant systems are more prone to crestal bone loss. However, the multifactorial cause for bone loss and the heterogeneity of the studies make it difficult to draw firm conclusions. Nevertheless, more papers show less bone loss in favour of minimally rough implant systems. 5. Co-factors such as smoking or a history of periodontal disease increase the risk of bone loss. 6. The implant neck design (microthreaded vs non-microthreaded) has no influence on peri-implant bone remodeling when implants are installed in relation to soft tissue thickness allowing the formation of a 3 to 4 mm biological seal. 7. The implant-abutment connection type (internal vs external) has no influence on peri-implant bone remodeling when implants are installed in relation to soft tissue thickness allowing the formation of a 3 to 4 mm biological seal. 8. Implant surface roughness (minimally rough vs moderately rough) influences peri-implant bone remodeling nor additional bone loss when implants are installed in relation to soft tissue thickness allowing the formation of a 3 to 4 mm biologic seal. 9. Peri-implant health parameters (probing pocket depth, bleeding on probing, and plaque score) are not affected by implant design, surface texture, or abutment-connection features when implants are installed in relation to soft tissue thickness. 10. Anticipating biologic width re-establishment by adapting the vertical position of the implant in relation to the available soft tissue thickness may prevent initial peri-implant bone loss. 11. In a well-maintained population, the effect of early implant surface exposure caused by initial bone remodeling on peri-implant bone stability and biological parameters seems to be limited. 12. Implant-supported mandibular overdentures significantly improve the quality of life, with little biological complications and a high survival rate of the implants.

T In many machine learning classification problems, datasets are usually of high dimensionality and therefore require efficient and effective methods for identifying the relative importance of their attributes, eliminating the redundant and irrelevant ones. Due to the huge size of the search space of the possible solutions, the attribute subset evaluation feature selection methods are not very suitable, so in these scenarios feature ranking methods are used. Most of the feature ranking methods described in the literature are univariate methods, which do not detect interactions between factors. In this paper, we propose two new multivariate feature ranking methods based on pairwise correlation and pairwise consistency, which have been applied for cancer gene expression and genotype-tissue expression classification tasks using public datasets. We statistically proved that the proposed methods outperform the state-of-the-art feature ranking methods Clustering Variation, Chi Squared, Correlation, Information Gain, ReliefF and Significance, as well as other feature selection methods for attribute subset evaluation based on correlation and consistency with the multi-objective evolutionary search strategy, and with the embedded feature selection methods C4.5 and LASSO. The proposed methods have been implemented on the WEKA platform for public use, making all the results reported in this paper repeatable and replicable

Background Ward-Based Outreach Teams’ (WBOTs) use of mobile technologies can promote better quality and improved health services for populations in low- and middle-income countries. However, the implementation of such systems is fraught with threats to sustainability. Purpose The purpose of this study was to gain a deeper understanding of users’ views and experiences of the implementation of mHealth in a selected sub-district in North West Province, South Africa. Methods The study was qualitative, exploratory and descriptive. Data were collected from community health workers (CHWs) (n = 24) and outreach team leaders (OTLs) (n = 4) who used mobile devices loaded with the Mobenzi application through semi-structured focus group interviews, using an interview guide. Creswell’s stages of thematic analysis were used for data analysis, and codes, categories and themes were validated with the participants. Results Three themes emerged from the findings, namely the transition from a paper-based system to an electronic system; the use of the application; and reverting to paper-based documentation. The findings revealed that WBOTs considered the mHealth application as useful, easy to use, and supportive to their workflow. They experienced some technical challenges and lamented the inaccessibility of technicians. The mobile initiative’s termination caused distress among the participants, especially CHWs who had to revert to paper-based documentation to capture community health data. OTLs were concerned about the quality of health data being captured in the absence of the application. Conclusions The study concluded that community-based health care programmes that use WBOTs and mHealth technologies are essential in strengthening the health care system. WBOTs are facilitators for improving access to health care. Policy-makers and district managers will gain useful insights if they engage application users in discussions regarding future mobile health interventions for household and community-based care.

Background Work to control the gambiense form of human African trypanosomiasis (gHAT), or sleeping sickness, is now directed towards ending transmission of the parasite by 2030. In order to supplement gHAT case-finding and treatment, since 2011 tsetse control has been implemented using Tiny Targets in a number of gHAT foci. As this intervention is extended to new foci, it is vital to understand the costs involved. Costs have already been analysed for the foci of Arua in Uganda and Mandoul in Chad. This paper examines the costs of controlling Glossina palpalis palpalis in the focus of Bonon in Côte d’Ivoire from 2016 to 2017. Methodology/Principal findings Some 2000 targets were placed throughout the main gHAT transmission area of 130 km2 at a density of 14.9 per km2. The average annual cost was USD 0.5 per person protected, USD 31.6 per target deployed of which 12% was the cost of the target itself, or USD 471.2 per km2 protected. Broken down by activity, 54% was for deployment and maintenance of targets, 34% for tsetse surveys/monitoring and 12% for sensitising populations. Conclusions/Significance The cost of tsetse control per km2 of the gHAT focus protected in Bonon was more expensive than in Chad or Uganda, while the cost per km2 treated, that is the area where the targets were actually deployed, was cheaper. Per person protected, the Bonon cost fell between the two, with Uganda cheaper and Chad more expensive. In Bonon, targets were deployed throughout the protected area, because G. p. palpalis was present everywhere, whereas in Chad and Uganda G. fuscipes fuscipes was found only the riverine fringing vegetation. Thus, differences between gHAT foci, in terms of tsetse ecology and human geography, impact on the cost-effectiveness of tsetse control. It also demonstrates the need to take into account both the area treated and protected alongside other impact indicators, such as the cost per person protected., Author summary Sleeping sickness is a fatal disease in Africa caused by trypanosomes transmitted by the bite of infected tsetse flies. The World Health Organization has set the absence of new infections as a goal for 2030. To achieve this, screening and treatment of patients is supplemented by tsetse control. Tiny Targets are small insecticide-impregnated panels of blue cloth and black netting which attract and kill tsetse. To maintain the momentum in these last stages of eliminating the disease, it is important to understand the costs of vector control. This paper presents the results of two years’ cost monitoring in Bonon, an area covering 130 km2, home to 120,000 people. Since 2016, ~2,000 Tiny Targets have been deployed annually at a cost of USD 471 per km2 per year. Bonon is a degraded forested area and a relatively high number of targets was required as tsetse are present throughout. Nevertheless, the cost comes to only USD 0.5 per person protected per year. Compared to operations using Tiny Targets in Uganda and Chad, the cost was higher per km2 protected, reflecting the need to place targets throughout the area, but low per person protected compared to Chad, highlighting the need to use a range of comparators.

Background Coronavirus (COVID-19) has severely impacted lifestyles worldwide. Responses to COVID-19 have intentionally restricted the factors that encourage regular and frequent PA; opportunity, capability and motivation. However, the effects of these restrictions are likely to have differed by gender and age and different intensities of PA. This rapid review builds on previous evidence by synthesising the global impact of COVID-19 on adult PA through specific intensities and types of PA and evaluating this by gender and age. Methods A rapid systematic search of seven electronic databases (PubMed, MEDLINE, CINAHL, SPORTDiscus, Academic Search Complete, APA PsycInfo, and APA PsycArticles) was performed from December 2019 to January 2021. Studies investigating adult change in PA, exercise or sedentary behaviour due to COVID-19 were included. Results From an initial database search identifying 3,863 articles, 66 remained for synthesis after applying eligibility criteria. Results demonstrate decreases among all intensities and types of PA—walking (6 out of 7 papers), moderate-only (5 out of 6 papers), vigorous-only (5 out of 6 papers) and MVPA (4 out of 5 papers); as well as overall PA (14–72% participants reported a decrease). Reflecting that COVID-19 responses were designed to have universal effects, they also achieved whole-society decreases in PA behaviour, accented in older age groups. Conclusion There is a universal need to address the low levels of PA post-COVID-19. The consequences of decreased PA across all intensities has powerful, potentially recoverable, impacts. Universal declines have implications for public health officials and PA advocates for post-COVID-19 initiatives to promote PA.

Healthcare is an indispensable part of human life and chronic illnesses like cardiovascular diseases (CVD) have a deeply negative impact on the healthcare sector. Since the ever-growing population of chronic patients cannot be managed at hospitals, therefore, there is an urgent need for periodic monitoring of vital parameters and apposite treatment of these patients. In this paper, an Internet of Medical Things (IoMT) -based remote patient monitoring system is proposed which is based on Artificial Intelligence (AI) and edge computing. The primary focus of this paper is to develop an embedded prototype that can be used for remote monitoring of cardiovascular patients. The system will continuously monitor physiological parameters like body temperature, heart rate, and blood oxygen saturation, and then report the health status to the authenticated users. The system employs edge computing to perform multiple functionalities including health status inference using a Machine Learning (ML) model which makes predictions on real-time data, alert notifications in case of an emergency, and transferring data between the sensor network and the cloud. A web-based application is developed for the depiction of raw data and ML results and to provide a direct communication channel between the patient and the doctor. The ML module achieved an accuracy of 96.26% on the test set using the K-Nearest Neighbors (KNNs) algorithm. This solution aims to address the sense of emergency due to the alarming statistics that highlight the mortality rate of cardiovascular patients. The project will enable a smart option based on IoT and ML to improve standards of living and prove crucial in saving human lives.

Constructing a graphical model of the relationship between physical activity and cognitive function based on a systematic review of prospective evidence Citation: Thomas Campbell, Jessica Whyte, Karl Ferguson, Breda Cullen Background: Elucidating modifiable factors that may confer protection against cognitive decline is an important area of investigation. Physical activity (PA) represents one such factor and has generated substantial evidence regarding its protective benefit. However, in epidemiological research the presence of multiple covariates has posed challenges to obtaining unconfounded estimates of associations between exposure and outcome variables. Causal diagrams, or Directed Acyclic Graphs (DAGs), have emerged as promising tools for addressing these challenges and improving the planning and specification of statistical analyses. This review aims to utilise a recently developed research method for constructing DAGs in a robust and systematic way: Evidence Synthesis for Constructing Directed Acyclic Graphs (ESC-DAGs) (Ferguson, 2019). The method will be applied to observational studies of the relationship between PA and cognitive decline, and the resulting DAG will be used to inform empirical analysis of UK Biobank data (a very large cohort study), in a separate paper. Review Question(s): (a) What clinical and sociodemographic factors, and health behaviours, do the included studies report as being associated with cognitive function/impairment and/or physical activity? (b) How do the studies vary with regard to the covariates included, how these are adjusted for, and the conclusions of the study? Reporting framework: This systematic review will be conducted and reported according to Conducting Systematic Reviews and Meta-analyses of Observational Studies of Etiology (COSMOS-E) (Dekkers et al., 2019). Searches A systematic search of literature will be conducted using the following electronic databases: • Medline on the Ovid platform • Embase on the Ovid platform • PsycINFO on the EBSCOhost (EBSCO) platform In the event that the searches performed on these databases are not sufficiently sensitive (as would be indicated by known relevant papers not being captured), the CINAHL database on EBSCOhost and Web of Science platform may be incorporated to the search strategy. The search terms will incorporate medical subject headings (MeSH terms) which will be adapted for compatibility within each database. The terms used will be based on the following key terms: - Physical activity OR Exercise OR Physical fitness OR Activity level AND - Cognitive Function OR Cognitive Dysfunction OR Cognitive Decline OR Cognitive Aging OR Cognitive Impairment OR Neuropsychological Tests OR Alzheimer’s Disease OR Dementia AND - Longitudinal studies OR Prospective OR Cohort Where applicable the search terms will be modified to include truncation and wildcard characters. Searches will be restricted to English Language publications from 01.01.2005 to 01.07.2020. Additional hand-searching of the reference lists of recent relevant review papers will also be applied. The sensitivity of the search strategy will be tested by checking whether a sample of papers known to be relevant are detected by the search. Types of study to be included Inclusion criteria Longitudinal cohort studies (prospective design). Exclusion criteria Cross-sectional studies, case-control studies, retrospective studies, intervention studies & review papers. Condition or domain being studied Cognitive function as demonstrated by performance on objective cognitive tests. Where the outcome is measured categorically as impaired versus unimpaired, the threshold for impairment will be as defined by study authors but will at a minimum require performance to be one standard deviation below the mean of a healthy comparison group. Population Community dwelling adults, free of cognitive impairment before the period of exposure to physical activity began and aged ≥45

The design of efficient combination therapies is a difficult key challenge in the treatment of complex diseases such as cancers. The large heterogeneity of cancers and the large number of available drugs renders exhaustive in vivo or even in vitro investigation of possible treatments impractical. In recent years, sophisticated mechanistic, ordinary differential equation-based pathways models that can predict treatment responses at a molecular level have been developed. However, surprisingly little effort has been put into leveraging these models to find novel therapies. In this paper we use for the first time, to our knowledge, a large-scale state-of-the-art pan-cancer signaling pathway model to identify candidates for novel combination therapies to treat individual cancer cell lines from various tissues (e.g., minimizing proliferation while keeping dosage low to avoid adverse side effects) and populations of heterogeneous cancer cell lines (e.g., minimizing the maximum or average proliferation across the cell lines while keeping dosage low). We also show how our method can be used to optimize the drug combinations used in sequential treatment plans—that is, optimized sequences of potentially different drug combinations—providing additional benefits. In order to solve the treatment optimization problems, we combine the Covariance Matrix Adaptation Evolution Strategy (CMA-ES) algorithm with a significantly more scalable sampling scheme for truncated Gaussian distributions, based on a Hamiltonian Monte-Carlo method. These optimization techniques are independent of the signaling pathway model, and can thus be adapted to find treatment candidates for other complex diseases than cancers as well, as long as a suitable predictive model is available., Author summary Combination therapies are a promising approach to counter complex diseases such as cancers. Two key difficulties in the design of effective cancer combination therapies are the large number of available drugs and the heterogeneity of cancers which render exhaustive laboratory studies impractical. In recent years, sophisticated signaling pathway models that can predict responses to combination treatments at a molecular level have been developed. This motivates the question of how one can leverage mechanistic models to identify candidates for novel combination treatments. In this paper we propose a combination treatment optimization framework which employs a large-scale pan-cancer pathway model. We formulate treatment optimization problems for single cell lines and heterogeneous populations of cancer cells. We further investigate sequential treatment plans and combine an existing evolutionary algorithm with an efficient Hamiltonian Monte-Carlo based sampling scheme. During extensive simulation studies our approach identified combination therapies which are predicted to be more effective than conventional treatments. We hope that one day in silico experiments will be used to identify a small set of promising treatment candidates which can then form a starting point for laboratory studies, allowing for an efficient use of limited resources and accelerated discovery of effective therapies.

The purpose of our partnership with the UHN OpenLab was to discover the barriers involved with automating the sporadic release of clinical practice guidelines (CPGs) into the Innovate Guidelines Application (IGA). The problem is considered wicked—interlocking challenges cannot be addressed by a single solution. Accordingly, the goal was to explore the barriers of stakeholders and specialization groups, general guideline issues, and the considerations of healthcare professionals and public perception. An initial literature review was conducted to discover unidentified problems before a first draft of the systems map was created. Subsequently, connections were formed across problems and each was categorized based on degree of complexity. A white paper was drafted to complement the systems map, explain the problem clearly, and highlight areas to be further explored. The recommendation brief outlines where further action could be taken. Key findings of the white paper include that guideline standardization and the use of automation were significant complications with the project. The lack of standardization between guidelines makes categorizing them tedious as there are few common elements or formats. This problem is further perpetuated by new guidelines, which continue to be made without commonality between producers. A recommendation for the UHN OpenLab team is the use of automation software to sort pre-existing guidelines efficiently. Additionally, there should be a push for a checklist screen to generate commonality between future guidelines. This list for guideline producers would act as a completion and quality control marker while still allowing freedom in design and format.

The analysis of brain-imaging data requires complex and often non-linear transformations to support findings on brain function or pathologies. And yet, recent work has shown that variability in the choices that one makes when analyzing data can lead to quantitatively and qualitatively different results, endangering the trust in conclusions1–3. Even within a given method or analytical technique, numerical instabilities could compromise findings4–7. We instrumented a structural-connectome estimation pipeline with Monte Carlo Arithmetic8, 9, a technique to introduce random noise in floating-point computations, and evaluated the stability of the derived connectomes, their features10, 11, and the impact on a downstream analysis12, 13. The stability of results was found to be highly dependent upon which features of the connectomes were evaluated, and ranged from perfectly stable (i.e. no observed variability across executions) to highly unstable (i.e. the results contained no trustworthy significant information). While the extreme range and variability in results presented here could severely hamper our understanding of brain organization in brain-imaging studies, it also leads to an increase in the reliability of datasets. This paper highlights the potential of leveraging the induced variance in estimates of brain connectivity to reduce the bias in networks alongside increasing the robustness of their applications in the detection or classification of individual differences. This paper demonstrates that stability evaluations are necessary for understanding error and bias inherent to scientific computing, and that they should be a component of typical analytical workflows.

Background During the Coronavirus Disease 2019 (COVID-19) pandemic, the number of consultations and diagnoses in primary care and referrals to specialist care declined substantially compared to prepandemic levels. Beyond deferral of elective non-COVID-19 care by healthcare providers, it is unclear to what extent healthcare avoidance by community-dwelling individuals contributed to this decline in routine healthcare utilisation. Moreover, it is uncertain which specific symptoms were left unheeded by patients and which determinants predispose to healthcare avoidance in the general population. In this cross-sectional study, we assessed prevalence of healthcare avoidance during the pandemic from a patient perspective, including symptoms that were left unheeded, as well as determinants of healthcare avoidance. Methods and findings On April 20, 2020, a paper COVID-19 survey addressing healthcare utilisation, socioeconomic factors, mental and physical health, medication use, and COVID-19–specific symptoms was sent out to 8,732 participants from the population-based Rotterdam Study (response rate 73%). All questionnaires were returned before July 10, 2020. By hand, prevalence of healthcare avoidance was subsequently verified through free text analysis of medical records of general practitioners. Odds ratios (ORs) for avoidance were determined using logistic regression models, adjusted for age, sex, and history of chronic diseases. We found that 1,142 of 5,656 included participants (20.2%) reported having avoided healthcare. Of those, 414 participants (36.3%) reported symptoms that potentially warranted urgent evaluation, including limb weakness (13.6%), palpitations (10.8%), and chest pain (10.2%). Determinants related to avoidance were older age (adjusted OR 1.14 [95% confidence interval (CI) 1.08 to 1.21]), female sex (1.58 [1.38 to 1.82]), low educational level (primary education versus higher vocational/university 1.21 [1.01 to 1.46), poor self-appreciated health (per level decrease 2.00 [1.80 to 2.22]), unemployment (versus employed 2.29 [1.54 to 3.39]), smoking (1.34 [1.08 to 1.65]), concern about contracting COVID-19 (per level increase 1.28 [1.19 to 1.38]) and symptoms of depression (per point increase 1.13 [1.11 to 1.14]) and anxiety (per point increase 1.16 [1.14 to 1.18]). Study limitations included uncertainty about (perceived) severity of the reported symptoms and potentially limited generalisability given the ethnically homogeneous study population. Conclusions In this population-based cross-sectional study, 1 in 5 individuals avoided healthcare during lockdown in the COVID-19 pandemic, often for potentially urgent symptoms. Healthcare avoidance was strongly associated with female sex, fragile self-appreciated health, and high levels of depression and anxiety. These results emphasise the need for targeted public education urging these vulnerable patients to timely seek medical care for their symptoms to mitigate major health consequences., Marije J. Splinter and colleagues assess the prevalence of healthcare avoidance during the COIVD-19 pandemic and investigate related determinants, Author summary Why was this study done? ➢ During the Coronavirus Disease 2019 (COVID-19) pandemic, consultation rates in both primary and specialist care declined compared to prepandemic levels, which can partially be attributed to the postponement or cancellation of elective and nonurgent medical care. ➢ It is unclear to what extent these declines in consultation rates could be related to healthcare avoidance by patients in the general population. ➢ To evaluate the collateral health damage of the COVID-19 pandemic, it is important to not only assess the prevalence of healthcare avoidance, but also for what symptoms healthcare was avoided and which determinants are associated with this behaviour. What did the researchers do and find? ➢ We sent out a paper questionnaire to 8,732 participants of the population-based Rotterdam Study containing several COVID-19–related subjects, such as healthcare utilisation, work status, mental and physical health, and concerns about contracting COVID-19. ➢ About 6,241 participants (73%) returned the questionnaire, of whom 5,656 participants (90.6%) were included in our analyses. We found that 1,142 of them (20.2%) avoided healthcare during the COVID-19 pandemic, often for symptoms that might have needed urgent medical evaluation, such as limb weakness (13.6%), palpitations (10.8%), and chest pain (10.2%). ➢ Determinants that were most strongly associated with healthcare avoidance were female sex, poor self-appreciated health, and high levels of depression and anxiety. What do these findings mean? ➢ The results of this population-based study suggest that healthcare avoidance contributed to the decline in consultation rates during the COVID-19 pandemic. Importantly, our findings suggest that this behaviour may be associated with certain vulnerable groups within the population. ➢ These findings should be interpreted in light of the limitations of this study, which include that the actual severity of the symptoms that were reported by participants is unknown, since they were not medically evaluated when they experienced these symptoms. ➢ The findings of this study can be used to develop policy interventions targeted to vulnerable individuals who may be more likely to exhibit healthcare avoiding behaviours.

One of the major achievements in tackling violence against women (VAW) is the adoption of the Council of Europe’s Istanbul Convention on VAW and Domestic Violence. The Istanbul Convention (IC) is a legally binding instrument tackling violence from a gender perspective, with a comprehensive set of measures. Although 21 European Union Member States (MS) and Turkey have ratified the Istanbul Convention and the European Union itself signed it, opposition towards gender equality has also risen. This paper reviews a study tendered by the European Parliament (the EP study), which aimed to understand the implementation of the Convention, its added value and arguments against its ratification. The EP Study grouped the 27 European Union MS and Turkey into those that have and have not ratified and implemented the IC. The EP study was based on four strands of data collection: 1) a literature review focusing on the impact of and arguments against ratification; 2) a legal mapping of the legislation to compare the criminal codes and support services of each country with relevant articles of the Convention; 3) national data collection to identify challenges in the implementation of the Convention and good practices; 4) a stakeholder on-line consultation. The study was conducted in 2020. The EP study found that ratification of the Convention triggered amendments to existing legislation and/or the adoption of new legal measures, but that legislative changes are less extensive in countries that have not ratified the Convention. Most European Union MS have adopted gender-neutral approaches to laws and policies, thus failing to acknowledge the gendered nature of violence against women and domestic violence. Seven of the European Union countries (BG, HR, LT, LV, MT, RO, TU) refer to physical, psychological, economic and sexual violence in their definitions of domestic violence, while nine countries (AT, BE, CZ, DK, EE, FI, FR, IE, LU) do not define domestic violence. Remaining challenges in the implementation of the Istanbul Convention include a lack of sustainable national action plans, and insufficient funding for specialist support services. Resistance to the Convention is evident even in countries that have ratified it, in response to proposed legislation on same-sex marriage, adoption or sexuality education in schools. Non-ratifying countries and countries with high resistance to the Convention often display victim-blaming public attitudes to intimate partner violence, stronger gender stereotypes and a stronger resistance to same-sex marriage/rights. The paper concludes by suggesting recommendations. The cut off date for data collection was 16 September 2020 and therefore legal and policy developments after that date were not included in this paper. This includes Poland and Turkey announcing their withdrawal from the IC in respectively July 2020 and March 2021. However, given the focus of this paper is on understanding the reasons behind resistance against the IC and on the differences between countries that ratified and those that did not, this paper contributes to a better understanding of how progress has been made following the IC, and points to the added value of the IC.

Distracted driving behavior is one of the main factors of road accidents. Accurately predicting the risk of driving behavior is of great significance to the active safety of road transportation. The large amount of information collected by the sensors installed on the vehicle can be identified by the algorithm to obtain the distracted driving behavior data, which can be used to predict the driving behavior risk of the vehicle and the area. In this paper, a new neural network named Driving Behavior Risk Prediction Neural Network (DBRPNN) is developed for prediction based on the distracted driving behavior data. The network consists of three modules: the Feature Processing Module, the Memory Module, and the Prediction Module. In this process, attribute data (time in a day, daily driving time, and daily driving mileage) that can reflect external factors and driver statuses, are added to the network to increase the accuracy of the model. We predicted the driving behavior risk of different objects (Vehicle and Area). For the applicability improvement of the model, we further classify the distracted driving behavior categories, and DBRPNN can provide more accurate risk prediction. The results show that compared with traditional models (Classification and Regression Tree, Support Vector Machines, Recurrent Neural Network, and Long Short-Term Memory), DBRPNN has better prediction performance. The method proposed in this paper has been fully verified and may be transplanted into active safety early warning system for more accurate and flexible application.

In their Commentary paper, Villaverde and Massonis (On testing structural identifiability by a simple scaling method: relying on scaling symmetries can be misleading) have commented on our paper in which we proposed a simple scaling method to test structural identifiability. Our scaling invariance method (SIM) tests for scaling symmetries only, and Villaverde and Massonis correctly show the SIM may fail to detect identifiability problems when a model has other types of symmetries. We agree with the limitations raised by these authors but, also, we emphasize that the method is still valuable for its applicability to a wide variety of models, its simplicity, and even as a tool to introduce the problem of identifiability to investigators with little training in mathematics.

Background Medicine quality screening devices hold great promise for post-market surveillance (PMS). However, there is little independent evidence on their field utility and usability to inform policy decisions. This pilot study in the Lao PDR tested six devices’ utility and usability in detecting substandard and falsified (SF) medicines. Methodology/principal findings Observational time and motion studies of the inspections by 16 Lao medicine inspectors of 1) the stock of an Evaluation Pharmacy (EP), constructed to resemble a Lao pharmacy, and 2) a sample set of medicines (SSM); were conducted without and with six devices: four handheld spectrometers (two near infrared: MicroPHAZIR RX, NIR-S-G1 & two Raman: Progeny, Truscan RM); one portable mid-infrared spectrometer (4500a), and single-use paper analytical devices (PAD). User experiences were documented by interviews and focus group discussions. Significantly more samples were wrongly categorised as pass/fail with the PAD compared to the other devices in EP inspections (p, Author summary Substandard and falsified (SF) medicines threaten the lives of millions of people, especially where pharmaceutical legislation and regulation are limited. Screening for SF medicines in supply chains (‘post-market surveillance’) by medicine inspectors is crucial but currently relies only on subjective visual inspection of medicines in most countries. Many innovative portable screening technologies now exist and could be key additional assets to the current practice, but none have been extensively evaluated for medicine quality post-market surveillance. We assessed the utility and usability of six screening devices in the hands of Lao medicines inspectors in a pharmacy constructed to resemble a Lao pharmacy. Five spectrometers showed promising accuracies to identify falsified medicines, but difficulties to correctly set them up before running tests were observed. Reading and interpreting colour barcodes of the ‘paper analytical cards’–a lab-on-a-chip test by inspectors were difficult, leading to lower accuracy than with spectrometers. The study suggests that overconfidence in devices may cause harm by reducing inspectors’ investment in visual inspection—a crucial step to identify falsified medicines. Advantages/limitations of the devices are also documented to inform policy.

In recent years, there has been a surge in the development of mHealth apps. Nevertheless, there are no scoping reviews that analyze the scientific peer-reviewed articles of these tools. This research systematically reviews the scientific literature published on health apps targeting children in peer-reviewed journals. It aims to answer four questions: what is the primary purpose of these apps; for what medical specialties and main topics were they developed; whom do they target; and how they were analyzed. The study followed PRISMA methodology, and the search process used the Web of Science Core Collection. The selected terms for the search were "pediatr*" and "app." The initial search resulted in 303 papers which, after applying filters, excluded 187 papers. In the end, 116 articles were deemed appropriate for addressing our research questions and were thoroughly reviewed. The primary purpose of pediatric health apps is to support clinical decision-making, patient education, and patient self-management. The most frequent topics covered are cancer, obesity, and asthma. Hematological oncology and endocrinology are the most frequent medical specialties addressed. The apps mainly target children, their caregivers, or both groups. Most of the apps were analyzed using observational studies, predominantly conducted in the USA, with an average participant sample size of 842. No analyses of development costs were found. These findings can be helpful for the development of future pediatric health apps. What is Known: • Health care has become increasingly digital due to digital health technologies, which have helped to expand the scope of health care. • Digital health technology can be used to improve the health of children. • The increasing availability of smartphones for children and families may enable the use of apps to deliver, promote, and sustain interventions which could lead to long-term improvements in health. What is New: • The most frequent topics covered were cancer, obesity, and asthma. Hematology-oncology and endocrinology were the most frequent medical specialties addressed. • The principal aims of the pediatric health apps were to facilitate clinical decision support, patient education, and patient self-management. • The apps mainly targeted children, their caregivers, or both groups. • Most of them had been analyzed using observational studies.

Introduction Degenerative Cervical Myelopathy (DCM) is a common and disabling condition, with a relatively modest research capacity. In order to accelerate knowledge discovery, the AO Spine RECODE-DCM project has recently established the top priorities for DCM research. Uptake of these priorities within the research community will require their effective dissemination, which can be supported by identifying key opinion leaders (KOLs). In this paper, we aim to identify KOLs using artificial intelligence. We produce and explore a DCM co-authorship network, to characterise researchers’ impact within the research field. Methods Through a bibliometric analysis of 1674 scientific papers in the DCM field, a co-authorship network was created. For each author, statistics about their connections to the co-authorship network (and so the nature of their collaboration) were generated. Using these connectedness statistics, a neural network was used to predict H-Index for each author (as a proxy for research impact). The neural network was retrospectively validated on an unseen author set. Results DCM research is regionally clustered, with strong collaboration across some international borders (e.g., North America) but not others (e.g., Western Europe). In retrospective validation, the neural network achieves a correlation coefficient of 0.86 (p Discussion Analysis of the neural network shows that the nature of collaboration strongly impacts an author’s research visibility, and therefore suitability as a KOL. This also suggests greater collaboration within the DCM field could help to improve both individual research visibility and global synergy.

In this paper we review the methodological underpinnings of the general pharmacogenetic approach for uncovering genetically-driven treatment effect heterogeneity. This typically utilises only individuals who are treated and relies on fairly strong baseline assumptions to estimate what we term the ‘genetically moderated treatment effect’ (GMTE). When these assumptions are seriously violated, we show that a robust but less efficient estimate of the GMTE that incorporates information on the population of untreated individuals can instead be used. In cases of partial violation, we clarify when Mendelian randomization and a modified confounder adjustment method can also yield consistent estimates for the GMTE. A decision framework is then described to decide when a particular estimation strategy is most appropriate and how specific estimators can be combined to further improve efficiency. Triangulation of evidence from different data sources, each with their inherent biases and limitations, is becoming a well established principle for strengthening causal analysis. We call our framework ‘Triangulation WIthin a STudy’ (TWIST)’ in order to emphasise that an analysis in this spirit is also possible within a single data set, using causal estimates that are approximately uncorrelated, but reliant on different sets of assumptions. We illustrate these approaches by re-analysing primary-care-linked UK Biobank data relating to CYP2C19 genetic variants, Clopidogrel use and stroke risk, and data relating to APOE genetic variants, statin use and Coronary Artery Disease., Author summary Understanding how much a specific treatment’s effect is moderated by common genetic variation is an important public health question. If a person’s genetics means they will experience a much reduced treatment effect, as measured with respect to a particular health outcome, then they could be switched to an alternative therapy. When assessing the impact of such a switch at the population level, it is typical to only use data on those who are treated with the said drug. However, this analysis is compromised if genetic variants exist which moderate the treatment effect and affect the outcome through alternative pathways. In this paper we describe an extended analysis framework to estimating the ‘genetically moderated treatment effect’ (GMTE) that incorporates information on both treated and untreated individuals. With this larger set of information we show that four analysis approaches for estimating the GMTE are possible. Each one relies on a different set of assumptions to work correctly and provides estimates that are largely uncorrelated with one another. Our paper describes a decision framework for triangulating the findings from these four approaches in order to provide a more robust basis for decision making in public health.

Grounding systems are critical in safeguarding people and equipment from power system failures. A grounding system’s principal goal is to offer the lowest impedance path for undesired fault current. Optimization of the grounding grid designs is important in satisfying the minimum cost of the grounding system and safeguarding those people who work in the surrounding area of the grounded installations. Currently, there is no systematic guidance or standard for grounding grid designs that include two-layer soil and its effects on grounding grid systems, particularly vertically layered soil. Furthermore, while numerous studies have been conducted on optimization, relatively limited study has been done on the problem of optimizing the grounding grid in two-layer soil, particularly in vertical soil structures. This paper presents the results of optimization for substation grounding systems using the Simulated Annealing (SA) algorithm in different soil conditions which conforms to the safety requirements of the grounding system. Practical features of grounding grids in various soil conditions discussed in this paper (uniform soil, two-layer horizontal soil, and two-layer vertical soil) are considered during problem formulation and solution algorithm. The proposed algorithm’s results show that the number of grid conductors in the X and Y directions (Nx and Ny), as well as vertical rods (Nr), can be optimized from initial numbers of 35% for uniform soil, 57% for horizontal two-layer soil for ρ1> ρ2, and 33% for horizontal two-layer soil for ρ1< ρ2, and 29% for vertical two-layer soil structure. In other words, the proposed technique would be able to utilize square and rectangle-shaped grounding grids with a number of grid conductors and vertical rods to be implemented in uniform, two-layer horizontal and vertical soil structure, depending on the resistivity of the soil layer.

Mathematical models are powerful tools in HIV epidemiology, producing quantitative projections of key indicators such as HIV incidence and prevalence. In order to improve the accuracy of predictions, such models need to incorporate a number of behavioural and biological heterogeneities, especially those related to the sexual network within which HIV transmission occurs. An individual-based model, which explicitly models sexual partnerships, is thus often the most natural type of model to choose. In this paper we present PopART-IBM, a computationally efficient individual-based model capable of simulating 50 years of an HIV epidemic in a large, high-prevalence community in under a minute. We show how the model calibrates within a Bayesian inference framework to detailed age- and sex-stratified data from multiple sources on HIV prevalence, awareness of HIV status, ART status, and viral suppression for an HPTN 071 (PopART) study community in Zambia, and present future projections of HIV prevalence and incidence for this community in the absence of trial intervention., Author summary In this paper we present PopART-IBM, an individual-based model used to simulate HIV transmission in communities in high prevalence settings. We show that PopART-IBM can simulate transmission over a span of decades in a large community in less than a minute. This computational efficiency allows us to calibrate the model within an inference framework, and we show an illustrative example of calibration using an adaptive population Monte Carlo Approximate Bayesian Computation algorithm for a community in Zambia that was part of the HPTN-071 (PopART) trial. We compare the detailed model output to real-world data collected during the trial from this community. Finally, we project how the HIV epidemic would have changed over time in this community if no intervention from the trial had occurred.

Background and Objectives: Insulin and oral hypoglycemic agents are drugs widely used in the world population due to their therapeutic effects on diabetes mellitus. Despite these benefits, they can also cause accidental or voluntary drug overdose. This review aims to evaluate post-mortem investigations in cases of suspected hypoglycemic drug overdose. Materials and Methods: We performed a comprehensive search using the Preferred Reporting Items for Systematic Review (PRISMA) standards; we systematically searched the PubMed, Science Direct Scopus, Google Scholar, and Excerpta Medica Database (EM-BASE) databases from the point of database inception until August 2022. The following inclusion criteria were used: (1) original research articles, (2) reviews and mini-reviews, (3) case reports/series, (4) and only papers written in English. Results: Thirty-three scientific papers, including original research articles, case reports, and case series, fulfilled the inclusion criteria. A total of 109 cases of insulin or hypoglycemic drug overdose were found. There were 71 cases of suicide (65%), 25 cases of accidental poisoning (23%), and 13 cases of homicide (12%). The most commonly used drug was insulin (95.4%). Autopsy and post-mortem examinations were performed in 84 cases, while toxicological investigations were performed in 79 cases. The most common gross findings in the autopsy were pulmonary edema (55.7%) and congestion (41.8%), while the most common histological finding was neuronal depletion or necrosis (29.1%). Conclusions: In the suspicion of death from insulin or overdose from oral hypoglycemic agents, autopsy findings may be nonspecific, and the search for injection marks can be positive at the external examination. Significant post-mortal alterations can interest biological samples and an early autopsy investigation is recommended.

ObjectiveTo identify strategies and interventions used to improve interprofessional collaboration and integration (IPCI) in primary care.DesignScoping reviewData sourcesSpecific Medical Subject Headings terms were used, and a search strategy was developed for PubMed and afterwards adapted to Medline, Eric and Web of Science.Study selectionIn the first stage of the selection, two researchers screened the article abstracts to select eligible papers. When decisions conflicted, three other researchers joined the decision-making process. The same strategy was used with full-text screening. Articles were included if they: (1) were in English, (2) described an intervention to improve IPCI in primary care involving at least two different healthcare disciplines, (3) originated from a high-income country, (4) were peer-reviewed and (5) were published between 2001 and 2020.Data extraction and synthesisFrom each paper, eligible data were extracted, and the selected papers were analysed inductively. Studying the main focus of the papers, researchers searched for common patterns in answering the research question and exposing research gaps. The identified themes were discussed and adjusted until a consensus was reached among all authors.ResultsThe literature search yielded a total of 1816 papers. After removing duplicates, screening titles and abstracts, and performing full-text readings, 34 papers were incorporated in this scoping review. The identified strategies and interventions were inductively categorised under five main themes: (1) Acceptance and team readiness towards collaboration, (2) acting as a team and not as an individual; (3) communication strategies and shared decision making, (4) coordination in primary care and (5) integration of caregivers and their skills and competences.ConclusionsWe identified a mix of strategies and interventions that can function as ‘building blocks’, for the development of a generic intervention to improve collaboration in different types of primary care settings and organisations.

Over the last decade the availability of SNP-trait associations from genome-wide association studies has led to an array of methods for performing Mendelian randomization studies using only summary statistics. A common feature of these methods, besides their intuitive simplicity, is the ability to combine data from several sources, incorporate multiple variants and account for biases due to weak instruments and pleiotropy. With the advent of large and accessible fully-genotyped cohorts such as UK Biobank, there is now increasing interest in understanding how best to apply these well developed summary data methods to individual level data, and to explore the use of more sophisticated causal methods allowing for non-linearity and effect modification. In this paper we describe a general procedure for optimally applying any two sample summary data method using one sample data. Our procedure first performs a meta-analysis of summary data estimates that are intentionally contaminated by collider bias between the genetic instruments and unmeasured confounders, due to conditioning on the observed exposure. These estimates are then used to correct the standard observational association between an exposure and outcome. Simulations are conducted to demonstrate the method’s performance against naive applications of two sample summary data MR. We apply the approach to the UK Biobank cohort to investigate the causal role of sleep disturbance on HbA1c levels, an important determinant of diabetes. Our approach can be viewed as a generalization of Dudbridge et al. (Nat. Comm. 10: 1561), who developed a technique to adjust for index event bias when uncovering genetic predictors of disease progression based on case-only data. Our work serves to clarify that in any one sample MR analysis, it can be advantageous to estimate causal relationships by artificially inducing and then correcting for collider bias., Author summary Uncovering causal mechanisms between risk factors and disease is challenging with observational data because of unobserved confounding. Mendelian randomization offers a potential solution by replacing an individual’s observed risk factor data with an unconfounded genetic proxy measure. Over the last decade an array of methods for performing Mendelian randomization studies (MR) using publicly available summary statistics gleaned from two separate genome-wide association studies. With the advent of large and accessible fully-genotyped cohorts such as UK Biobank, there is now increasing interest in understanding how best to apply these well-developed summary data methods to individual level data. In this paper we describe a general procedure for optimally applying any summary data MR method using individual level data from one cohort study. Our approach may at first seem nonsensical: we create summary statistics that are intentionally biased by confounding. This bias can, however, be very accurately estimated, and the estimate then used to correct the results of a standard observational analysis. We apply our new way of performing an MR analysis to data from UK Biobank to investigate the causal role of sleep disturbance on HbA1c levels, an important determinant of diabetes.

Deep brain stimulation (DBS) is a well-established treatment option for a variety of neurological disorders, including Parkinson’s disease and essential tremor. The symptoms of these disorders are known to be associated with pathological synchronous neural activity in the basal ganglia and thalamus. It is hypothesised that DBS acts to desynchronise this activity, leading to an overall reduction in symptoms. Electrodes with multiple independently controllable contacts are a recent development in DBS technology which have the potential to target one or more pathological regions with greater precision, reducing side effects and potentially increasing both the efficacy and efficiency of the treatment. The increased complexity of these systems, however, motivates the need to understand the effects of DBS when applied to multiple regions or neural populations within the brain. On the basis of a theoretical model, our paper addresses the question of how to best apply DBS to multiple neural populations to maximally desynchronise brain activity. Central to this are analytical expressions, which we derive, that predict how the symptom severity should change when stimulation is applied. Using these expressions, we construct a closed-loop DBS strategy describing how stimulation should be delivered to individual contacts using the phases and amplitudes of feedback signals. We simulate our method and compare it against two others found in the literature: coordinated reset and phase-locked stimulation. We also investigate the conditions for which our strategy is expected to yield the most benefit., Author summary In this paper we use computer models of brain tissue to derive an optimal control algorithm for a recently developed new generation of deep brain stimulation (DBS) devices. DBS is a treatment for a variety of neurological disorders including Parkinson’s disease, essential tremor, depression and pain. There is a growing amount of evidence to suggest that delivering stimulation according to feedback from patients, or closed-loop, has the potential to improve the efficacy, efficiency and side effects of the treatment. An important recent development in DBS technology are electrodes with multiple independently controllable contacts and this paper is a theoretical study into the effects of using this new technology. On the basis of a theoretical model, we devise a closed-loop strategy and address the question of how to best apply DBS across multiple contacts to maximally desynchronise neural populations. We demonstrate using numerical simulation that, for the systems we consider, our methods are more effective than two well-known alternatives, namely phase-locked stimulation and coordinated reset. We also predict that the benefits of using multiple contacts should depend strongly on the intrinsic neuronal response. The insights from this work should lead to a better understanding of how to implement and optimise closed-loop multi-contact DBS systems which in turn should lead to more effective and efficient DBS treatments.

Depending on the strategy of "Healthy China", more and more people pay attention to health issues. The integration and development of sports industry and health service industry is an inevitable outcome of industrial transformation and upgrading and healthy life in the new era. Through constructing the evaluation index system of the coupling and coordination development degree between sports industry and health service industry, using entropy evaluation method and coupling and coordination degree model, this paper explore the comprehensive level and coupling and coordination development status of sports industry and health service industry in thirty-one provinces, municipality cities and autonomous regions of China from 2013 to 2017. The results of this paper show that the comprehensive China’s sports industry and health service industry both present an incremental development trend year by year, and are characterized by the distribution of "high in the east and low in the west" in space. The government’s policy support provides superior industrial supporting conditions for the development of sports industry. However, it is not conducive to the promotion of industrial economic benefits. In the health service industry, the rapid development of health insurance is beneficial to the integration of industrial resources and the perfection of industrial chain. Whereas as the core content of health service industry, health service has greater space for development; the coupling and coordination degree between the two industries rises from mild maladjustment to basic coordination, which is characterized by the distribution of "high in the east and low in the west" in space; among provinces, with Beijing, the Yangtze River Delta and Guangdong as the three development center points, it shows the spatial evolutionary process from "dispersion-type plaques" to "gathering type scattered surfaces".

Background As the world’s largest coal producer, China was accounted for about 46% of global coal production. Among present coal mining risks, methane gas (called gas in this paper) explosion or ignition in an underground mine remains ever-present. Although many techniques have been used, gas accidents associated with the complex elements of underground gassy mines need more robust monitoring or warning systems to identify risks. This paper aimed to determine which single method between the PCA and Entropy methods better establishes a responsive weighted indexing measurement to improve coal mining safety. Methods Qualitative and quantitative mixed research methodologies were adopted for this research, including analysis of two case studies, correlation analysis, and comparative analysis. The literature reviewed the most-used multi-criteria decision making (MCDM) methods, including subjective methods and objective methods. The advantages and disadvantages of each MCDM method were briefly discussed. One more round literature review was conducted to search publications between 2017 and 2019 in CNKI. Followed two case studies, correlation analysis and comparative analysis were then conducted. Research ethics was approved by the Shanxi Coking Coal Group Research Committee. Results The literature searched a total of 25,831publications and found that the PCA method was the predominant method adopted, and the Entropy method was the second most widely adopted method. Two weighting methods were compared using two case studies. For the comparative analysis of Case Study 1, the PCA method appeared to be more responsive than the Entropy. For Case Study 2, the Entropy method is more responsive than the PCA. As a result, both methods were adopted for different cases in the case study mine and finally deployed for user acceptance testing on 5 November 2020. Conclusions The findings and suggestions were provided as further scopes for further research. This research indicated that no single method could be adopted as the better option for establishing indexing measurement in all cases. The practical implication suggests that comparative analysis should always be conducted on each case and determine the appropriate weighting method to the relevant case. This research recommended that the PCA method was a dimension reduction technique that could be handy for identifying the critical variables or factors and effectively used in hazard, risk, and emergency assessment. The PCA method might also be well-applied for developing predicting and forecasting systems as it was sensitive to outliers. The Entropy method might be suitable for all the cases requiring the MCDM. There is also a need to conduct further research to probe the causal reasons why the PCA and Entropy methods were applied to each case and not the other way round. This research found that the Entropy method provides higher accuracy than the PCA method. This research also found that the Entropy method demonstrated to assess the weights of the higher dimension dataset was higher sensitivity than the lower dimensions. Finally, the comprehensive analysis indicates a need to explore a more responsive method for establishing a weighted indexing measurement for warning applications in hazard, risk, and emergency assessments.

Child Marriage (before the age of 18) affects over 12 million young women globally, annually. Despite acknowledgement of the negative impacts of the practice on reproductive health, mental health consequences are largely overlooked. Given the ability for poor mental health to intensify other health and social challenges, understanding the mental health consequences linked to child marriage is vital. Our study is the first to examine how mental health is approached in current literature on child marriage. Our conceptual framework was informed by a rapid assessment of key issues in the field. Systematic searches of papers published between 2000–2020 were completed on four electronic databases with no language restrictions. Our protocol was registered on Prospero (CRD42019139685). Articles were assessed using PRISMA guidelines, and their quality assessed using the Joanna Briggs Institute Critical Appraisal Tools. Of the 4,457 records identified, 21 papers meeting inclusion criteria were analysed using narrative synthesis. The final sample included 5 qualitative, 1 mixed-methods and 15 quantitative studies (14 cross-sectional and 1 longitudinal study) reporting on data from 12 countries, largely in the global south. Intimate partner violence, poverty, challenges in childbirth and isolation were identified as social factors linked to emotional distress by those married as children. Depression was the most reported mental disorder. Anxiety, phobias, psychological distress, substance misuse, negative well-being and anti-social personality disorder were reported less frequently. Findings highlight that while significant emotional distress and specific mental health conditions are linked to child marriage, gaps in our understanding remain. Future studies are needed to; clarify directionality in these relationships; understand the mental health needs of young men, LGBTQI communities and those in humanitarian settings. Given the well documented cyclical relationship between social determinants and mental health conditions, we outline a series of community-oriented interventions which blend psychological, social and structural support to promote mental health and wellbeing in the contexts of child marriage.

Enterprises acquire heterogeneous knowledge through external knowledge search and adapt to the change of external environment, which is of great significance to enterprise breakthrough innovation. This paper takes the innovation ecosystem as the boundary of the research paradigm. Based on innovation ecosystem theory, knowledge management theory and enterprise innovation theory, this paper constructs a moderated mediation model of the enterprise knowledge search, knowledge integration and breakthrough innovation under the characteristics of innovation ecosystem network. This model is tested on the survey data of 344 technology enterprise and manufacturing industries including R&D departments in the Beijing-Tianjin-Hebei region. The research results show that: knowledge integration plays part of the intermediary role between knowledge search and enterprise breakthrough innovation; the larger the network scale, the stronger the network connection, the stronger the intermediary role of knowledge integration on the relationship between knowledge search and enterprise breakthrough innovation. The research results reveal the important role of the innovation ecosystem in enterprise breakthrough innovation. At the same time, the research on knowledge search and enterprise breakthrough innovation should consider the network characteristics of innovation ecosystem and the ability of enterprise knowledge integration.

Background Pragmatic challenges remain in the monitoring and return to play (RTP) decisions following suspected Sports Related Concussion (SRC). Reliance on traditional approaches (pen and paper) means players readiness for RTP is often based on self-reported symptom recognition as a marker for full physiological recovery. Non-digital approaches also limit opportunity for robust data analysis which may hinder understanding of the interconnected nature and relationships in deficit recovery. Digital approaches may provide more objectivity to measure and monitor impairments in SRC. Crucially, there is dearth of protocols for SRC assessment and digital devices have yet to be tested concurrently (multimodal) in SRC rugby union assessment. Here we propose a multimodal protocol for digital assessment in SRC, which could be used to enhance traditional sports concussion assessment approaches. Methods We aim to use a repeated measures observational study utilising a battery of multimodal assessment tools (symptom, cognitive, visual, motor). We aim to recruit 200 rugby players (male n≈100 and female n≈100) from University Rugby Union teams and local amateur rugby clubs in the North East of England. The multimodal battery assessment used in this study will compare metrics between digital methods and against traditional assessment. Conclusion This paper outlines a protocol for a multimodal approach for the use of digital technologies to augment traditional approaches to SRC, which may better inform RTP in rugby union. Findings may shed light on new ways of working with digital tools in SRC. Multimodal approaches may enhance understanding of the interconnected nature of impairments and provide insightful, more objective assessment and RTP in SRC. Clinical trial registration NCT04938570. https://clinicaltrials.gov/ct2/results?cond=NCT04938570&term=&cntry=&state=&city=&dist=

With the increase of patients with retinopathy, retinopathy recognition has become a research hotspot. In this article, we describe the etiology and symptoms of three kinds of retinal diseases, including drusen(DRUSEN), choroidal neovascularization(CNV) and diabetic macular edema(DME). In addition, we also propose a hybrid attention mechanism to classify and recognize different types of retinopathy images. In particular, the hybrid attention mechanism proposed in this paper includes parallel spatial attention mechanism and channel attention mechanism. It can extract the key features in the channel dimension and spatial dimension of retinopathy images, and reduce the negative impact of background information on classification results. The experimental results show that the hybrid attention mechanism proposed in this paper can better assist the network to focus on extracting thr fetures of the retinopathy area and enhance the adaptability to the differences of different data sets. Finally, the hybrid attention mechanism achieved 96.5% and 99.76% classification accuracy on two public OCT data sets of retinopathy, respectively.

This paper analyzes the dynamics of the labor market in Latin America during the COVID-19 pandemic. After a decade of a virtuous circle of growth with the creation of formal jobs, the pandemic has had an considerable impact on the region’s labor market, generating an unparalleled increase in the proportion of the inactive population, considerable reductions in informality, and, in contrast, smaller fluctuations in formal jobs. In this context, the formal sector, given its lower flexibility, became a "social safety net" that preserved the stability of employment and wages. Based on the findings presented in this paper, it is projected that, starting in 2021, informality will grow to levels higher than those of the pre-COVID-19 era–with 7.56 million additional informal jobs–as a result of the population returning to the labor market to compensate for the declines in incomes. According to the simulations presented, postponing or forgiving income tax payments and social security contributions conditional on the generation of formal jobs could reduce the growth of informality by 50 to 75 percent. Achieving educational improvements has the potential to reduce it by 50 percent.

In this paper, the algebraic topological characteristics of brain networks composed of electroencephalogram(EEG) signals induced by different quality images were studied, and on that basis, a neurophysiological image quality assessment approach was proposed. Our approach acquired quality perception-related neural information via integrating the EEG collection with conventional image assessment procedures, and the physiologically meaningful brain responses to different distortion-level images were obtained by topological data analysis. According to the validation experiment results, statistically significant discrepancies of the algebraic topological characteristics of EEG data evoked by a clear image compared to that of an unclear image are observed in several frequency bands, especially in the beta band. Furthermore, the phase transition difference of brain network caused by JPEG compression is more significant, indicating that humans are more sensitive to JPEG compression other than Gaussian blur. In general, the algebraic topological characteristics of EEG signals evoked by distorted images were investigated in this paper, which contributes to the study of neurophysiological assessment of image quality.

An unbiased, widely accepted estimate of the rate of occurrence of new cases of autism over time would facilitate progress in understanding the causes of autism. The same may also apply to other disorders. While incidence is a widely used measure of occurrence, birth prevalence—the proportion of each birth year cohort with the disorder—is the appropriate measure for disorders and diseases of early childhood. Studies of autism epidemiology commonly speculate that estimates showing strong increases in rate of autism cases result from an increase in diagnosis rates rather than a true increase in cases. Unfortunately, current methods are not sufficient to provide a definitive resolution to this controversy. Prominent experts have written that it is virtually impossible to solve.This paper presents a novel method, time-to-event birth prevalence estimation (TTEPE), to provide accurate estimates of birth prevalence properly adjusted for changing diagnostic factors. It addresses the shortcomings of prior methods. TTEPE is based on well-known time-to-event (survival) analysis techniques. A discrete survival process models the rates of incident diagnoses by birth year and age. Diagnostic factors drive the probability of diagnosis as a function of the year of diagnosis. TTEPE models changes in diagnostic criteria, which can modify the effective birth prevalence when new criteria take effect. TTEPE incorporates the development of diagnosable symptoms with age. General-purpose optimization software estimates all parameters, forming a non-linear regression. The paper specifies all assumptions underlying the analysis and explores potential deviations from assumptions and optional additional analyses.A simulation study shows that TTEPE produces accurate parameter estimates, including trends in both birth prevalence and the probability of diagnosis in the presence of sampling effects from finite populations. TTEPE provides high power to resolve small differences in parameter values by utilizing all available data points.