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Background: When a journal receives a duplicate publication, the ability to identify the submitted work as previously published, and reject it, is an assay to publication ethics best practices. The aim of this study was to evaluate how three different types of journals, namely open access (OA) journals, subscription-based journals, and presumed predatory journals, responded to receiving a previously published manuscript for review.Methods: We performed a quasi-experimental study in which we submitted a previously published article to a random sample of 602 biomedical journals, roughly 200 journals from each journal type sampled: OA journals, subscription-based journals, and presumed predatory journals. Three hundred and three journals received a Word version in manuscript format, while 299 journals received the formatted publisher's PDF version of the published article. We then recorded responses to the submission received after approximately 1 month. Responses were reviewed, extracted, and coded in duplicate. Our primary outcome was the rate of rejection of the two types of submitted articles (PDF vs Word) within our three journal types.Results: We received correspondence back from 308 (51.1%) journals within our study timeline (32 days); (N = 46 predatory journals, N = 127 OA journals, N = 135 subscription-based journals). Of the journals that responded, 153 received the Word version of the paper, while 155 received the PDF version. Four journals (1.3%) accepted our paper, 291 (94.5%) journals rejected the paper, and 13 (4.2%) requested a revision. A chi-square test looking at journal type, and submission type, was significant (χ2 (4) = 23.50, p < 0.001). All four responses to accept our article came from presumed predatory journals, 3 of which received the Word format and 1 that received the PDF format. Less than half of journals that rejected our submissions did so because they identified ethical issues such as plagiarism with the manuscript (133 (45.7%)).Conclusion: Few journals accepted our submitted paper. However, our findings suggest that all three types of journals may not have adequate safeguards in place to recognize and act on plagiarism or duplicate submissions. [ABSTRACT FROM AUTHOR]

Background: Differences in definitions and methodological approaches have hindered comparison and synthesis of economic evaluation results across multiple health domains, including immunization. At the request of the World Health Organization's (WHO) Immunization and Vaccines-related Implementation Research Advisory Committee (IVIR-AC), WHO convened an ad hoc Vaccine Delivery Costing Working Group, comprising experts from eight organizations working in immunization costing, to address a lack of standardization and gaps in definitions and methodological guidance. The aim of the Working Group was to develop a consensus statement harmonizing terminology and principles and to formulate recommendations for vaccine delivery costing for decision making. This paper discusses the process, findings of the review, and recommendations in the Consensus Statement.Methods: The Working Group conducted several interviews, teleconferences, and one in-person meeting to identify groups working in vaccine delivery costing as well as existing guidance documents and costing tools, focusing on those for low- and middle-income country settings. They then reviewed the costing aims, perspectives, terms, methods, and principles in these documents. Consensus statement principles were drafted to align with the Global Health Cost Consortium costing guide as an agreed normative reference, and consensus definitions were drafted to reflect the predominant view across the documents reviewed.Results: The Working Group identified four major workstreams on vaccine delivery costing as well as nine guidance documents and eleven costing tools for immunization costing. They found that some terms and principles were commonly defined while others were specific to individual workstreams. Based on these findings and extensive consultation, recommendations to harmonize differences in terminology and principles were made.Conclusions: Use of standardized principles and definitions outlined in the Consensus Statement within the immunization delivery costing community of practice can facilitate interpretation of economic evidence by global, regional, and national decision makers. Improving methodological alignment and clarity in program costing of health services such as immunization is important to support evidence-based policies and optimal resource allocation. On the other hand, this review and Consensus Statement development process revealed the limitations of our ability to harmonize given that study designs will vary depending upon the policy question that is being addressed and the country context. [ABSTRACT FROM AUTHOR]

Background: Cardiovascular disease and mental health both hold enormous public health importance, both ranking highly in results of the recent Global Burden of Disease Study 2010 (GBD 2010). For the first time, the GBD 2010 has systematically and quantitatively assessed major depression as an independent risk factor for the development of ischemic heart disease (IHD) using comparative risk assessment methodology. Methods: A pooled relative risk (RR) was calculated from studies identified through a systematic review with strict inclusion criteria designed to provide evidence of independent risk factor status. Accepted case definitions of depression include diagnosis by a clinician or by nonclinician raters adhering to Diagnostic and Statistical Manual of Mental Disorders (DSM) or International Classification of Diseases (ICD) classifications. We therefore refer to the exposure in this paper as major depression as opposed to the DSM-IV category of major depressive disorder (MDD). The population attributable fraction (PAF) was calculated using the pooled RR estimate. Attributable burden was calculated by multiplying the PAF by the underlying burden of IHD estimated as part of GBD 2010. Results: The pooled relative risk of developing IHD in those with major depression was 1.56 (95% CI 1.30 to 1.87). Globally there were almost 4 million estimated IHD disability-adjusted life years (DALYs), which can be attributed to major depression in 2010; 3.5 million years of life lost and 250,000 years of life lived with a disability. These findings highlight a previously underestimated mortality component of the burden of major depression. As a proportion of overall IHD burden, 2.95% (95% CI 1.48 to 4.46%) of IHD DALYs were estimated to be attributable to MDD in 2010. Eastern Europe and North Africa/Middle East demonstrate the highest proportion with Asia Pacific, high income representing the lowest. Conclusions:The present work comprises the most robust systematic review of its kind to date. The key finding that major depression may be responsible for approximately 3% of global IHD DALYs warrants assessment for depression in patients at high risk of developing IHD or at risk of a repeat IHD event. [ABSTRACT FROM AUTHOR]

Background: Globally, an estimated two-thirds of all deaths occur in the community, the majority of which are not attended by a physician and remain unregistered. Identifying and registering these deaths in civil registration and vital statistics (CRVS) systems, and ascertaining the cause of death, is thus a critical challenge to ensure that policy benefits from reliable evidence on mortality levels and patterns in populations. In contrast to traditional processes for registration, death notification can be faster and more efficient at informing responsible government agencies about the event and at triggering a verbal autopsy for ascertaining cause of death. Thus, innovative approaches to death notification, tailored to suit the setting, can improve the availability and quality of information on community deaths in CRVS systems.Improving the Notification Of Community Deaths: Here, we present case studies in four countries (Bangladesh, Colombia, Myanmar and Papua New Guinea) that were part of the initial phases of the Bloomberg Data for Health Initiative at the University of Melbourne, each of which faces unique challenges to community death registration. The approaches taken promote improved notification of community deaths through a combination of interventions, including integration with the health sector, using various notifying agents and methods, and the application of information and communication technologies. One key factor for success has been the smoothing of processes linking notification, registration and initiation of a verbal autopsy interview. The processes implemented champion more active notification systems in relation to the passive systems commonly in place in these countries.Conclusions: The case studies demonstrate the significant potential for improving death reporting through the implementation of notification practices tailored to a country's specific circumstances, including geography, cultural factors, structure of the existing CRVS system, and available human, information and communication technology resources. Strategic deployment of some, or all, of these innovations can result in rapid improvements to death notification systems and should be trialled in other settings. [ABSTRACT FROM AUTHOR]

Keywords: Pancreatic ductal adenocarcinoma; PanNET; Single-cell sequencing; Tumor heterogeneity EN Pancreatic ductal adenocarcinoma PanNET Single-cell sequencing Tumor heterogeneity 1 3 3 07/09/20 20200708 NES 200708 Background Multi-omics sequencing techniques have been applied to dissect inter- and intra-tumoral heterogeneity. Single-cell sequencing is pivotal for exploring tumor heterogeneity and dissecting the tumor-related mechanism in detail. In a recent paper published in I Cell Research i [[1]], Peng et al. applied single-cell RNA sequencing to 24 primary PDAC tumors and 11 control pancreases. [Extracted from the article]

Background: Depression is viewed as a major and increasing public health issue, as it causes high distress in the people experiencing it and considerable financial costs to society. Efforts are being made to reduce this burden by preventing depression. A critical component of this strategy is the ability to assess the individual level and profile of risk for the development of major depression. This paper presents the cost-effectiveness of a personalized intervention based on the risk of developing depression carried out in primary care, compared with usual care.Methods: Cost-effectiveness analyses are nested within a multicentre, clustered, randomized controlled trial of a personalized intervention to prevent depression. The study was carried out in 70 primary care centres from seven cities in Spain. Two general practitioners (GPs) were randomly sampled from those prepared to participate in each centre (i.e. 140 GPs), and 3326 participants consented and were eligible to participate. The intervention included the GP communicating to the patient his/her individual risk for depression and personal risk factors and the construction by both GPs and patients of a psychosocial programme tailored to prevent depression. In addition, GPs carried out measures to activate and empower the patients, who also received a leaflet about preventing depression. GPs were trained in a 10- to 15-h workshop. Costs were measured from a societal and National Health care perspective. Qualityadjustedlife years were assessed using the EuroQOL five dimensions questionnaire. The time horizon was 18 months.Results: With a willingness-to-pay threshold of €10,000 (£8568) the probability of cost-effectiveness oscillated from 83% (societal perspective) to 89% (health perspective). If the threshold was increased to €30,000 (£25,704), the probability of being considered cost-effective was 94% (societal perspective) and 96%, respectively (health perspective). The sensitivity analysis confirmed these results.Conclusions: Compared with usual care, an intervention based on personal predictors of risk of depression implemented by GPs is a cost-effective strategy to prevent depression. This type of personalized intervention in primary care should be further developed and evaluated.Trial Registration: ClinicalTrials.gov, NCT01151982. Registered on June 29, 2010. [ABSTRACT FROM AUTHOR]

Background: Pregnant women with epilepsy frequently experience seizures related to pregnancy complications and are often prescribed anti-epileptic drugs (AEDs) to manage their symptoms. However, less is known about the comparative safety of AED exposure in utero. We aimed to compare the risk of congenital malformations (CMs) and prenatal outcomes of AEDs in infants/children who were exposed to AEDs in utero through a systematic review and Bayesian random-effects network meta-analysis.Methods: MEDLINE, EMBASE, and Cochrane CENTRAL were searched from inception to December 15, 2015. Two reviewers independently screened titles/abstracts and full-text papers for experimental and observational studies comparing mono- or poly-therapy AEDs versus control (no AED exposure) or other AEDs, then abstracted data and appraised the risk of bias. The primary outcome was incidence of major CMs, overall and by specific type (cardiac malformations, hypospadias, cleft lip and/or palate, club foot, inguinal hernia, and undescended testes).Results: After screening 5305 titles and abstracts, 642 potentially relevant full-text articles, and 17 studies from scanning reference lists, 96 studies were eligible (n = 58,461 patients). Across all major CMs, many AEDs were associated with higher risk compared to control. For major CMs, ethosuximide (OR, 3.04; 95% CrI, 1.23-7.07), valproate (OR, 2.93; 95% CrI, 2.36-3.69), topiramate (OR, 1.90; 95% CrI, 1.17-2.97), phenobarbital (OR, 1.83; 95% CrI, 1.35-2.47), phenytoin (OR, 1.67; 95% CrI, 1.30-2.17), carbamazepine (OR, 1.37; 95% CrI, 1.10-1.71), and 11 polytherapies were significantly more harmful than control, but lamotrigine (OR, 0.96; 95% CrI, 0.72-1.25) and levetiracetam (OR, 0.72; 95% CrI, 0.43-1.16) were not.Conclusion: The newer generation AEDs, lamotrigine and levetiracetam, were not associated with significant increased risks of CMs compared to control, and were significantly less likely to be associated with children experiencing cardiac malformations than control. However, this does not mean that these agents are not harmful to infants/children exposed in utero. Counselling is advised concerning teratogenic risks when the prescription is written for a woman of childbearing age and before women continue with these agents when considering pregnancy, such as switching from polytherapy to monotherapy with evidence of lower risk and avoiding AEDs, such as valproate, that are consistently associated with CMs. These decisions must be balanced against the need for seizure control.Systematic Review Registration: PROSPERO CRD42014008925. [ABSTRACT FROM AUTHOR]

Background: Social prescribing is a way of addressing the 'non-medical' needs (e.g. loneliness, debt, housing problems) that can affect people's health and well-being. Connector schemes (e.g. delivered by care navigators or link workers) have become a key component to social prescribing's delivery. Those in this role support patients by either (a) signposting them to relevant local assets (e.g. groups, organisations, charities, activities, events) or (b) taking time to assist them in identifying and prioritising their 'non-medical' needs and connecting them to relevant local assets. To understand how such connector schemes work, for whom, why and in what circumstances, we conducted a realist review.Method: A search of electronic databases was supplemented with Google alerts and reference checking to locate grey literature. In addition, we sent a Freedom of Information request to all Clinical Commissioning Groups in England to identify any further evaluations of social prescribing connector schemes. Included studies were from the UK and focused on connector schemes for adult patients (18+ years) related to primary care.Results: Our searches resulted in 118 included documents, from which data were extracted to produce context-mechanism-outcome configurations (CMOCs). These CMOCs underpinned our emerging programme theory that centred on the essential role of 'buy-in' and connections. This was refined further by turning to existing theories on (a) social capital and (b) patient activation.Conclusion: Our realist review highlights how connector roles, especially link workers, represent a vehicle for accruing social capital (e.g. trust, sense of belonging, practical support). We propose that this then gives patients the confidence, motivation, connections, knowledge and skills to manage their own well-being, thereby reducing their reliance on GPs. We also emphasise within the programme theory situations that could result in unintended consequences (e.g. increased demand on GPs). [ABSTRACT FROM AUTHOR]

Background: Hormonal changes during the menstrual cycle play a key role in shaping immunity in the cervicovaginal tract. Cervicovaginal fluid contains cytokines, chemokines, immunoglobulins, and other immune mediators. Many studies have shown that the concentrations of these immune mediators change throughout the menstrual cycle, but the studies have often shown inconsistent results. Our understanding of immunological correlates of the menstrual cycle remains limited and could be improved by meta-analysis of the available evidence.Methods: We performed a systematic review and meta-analysis of cervicovaginal immune mediator concentrations throughout the menstrual cycle using individual participant data. Study eligibility included strict definitions of the cycle phase (by progesterone or days since the last menstrual period) and no use of hormonal contraception or intrauterine devices. We performed random-effects meta-analyses using inverse-variance pooling to estimate concentration differences between the follicular and luteal phases. In addition, we performed a new laboratory study, measuring select immune mediators in cervicovaginal lavage samples.Results: We screened 1570 abstracts and identified 71 eligible studies. We analyzed data from 31 studies, encompassing 39,589 concentration measurements of 77 immune mediators made on 2112 samples from 871 participants. Meta-analyses were performed on 53 immune mediators. Antibodies, CC-type chemokines, MMPs, IL-6, IL-16, IL-1RA, G-CSF, GNLY, and ICAM1 were lower in the luteal phase than the follicular phase. Only IL-1α, HBD-2, and HBD-3 were elevated in the luteal phase. There was minimal change between the phases for CXCL8, 9, and 10, interferons, TNF, SLPI, elafin, lysozyme, lactoferrin, and interleukins 1β, 2, 10, 12, 13, and 17A. The GRADE strength of evidence was moderate to high for all immune mediators listed here.Conclusions: Despite the variability of cervicovaginal immune mediator measurements, our meta-analyses show clear and consistent changes during the menstrual cycle. Many immune mediators were lower in the luteal phase, including chemokines, antibodies, matrix metalloproteinases, and several interleukins. Only interleukin-1α and beta-defensins were higher in the luteal phase. These cyclical differences may have consequences for immunity, susceptibility to infection, and fertility. Our study emphasizes the need to control for the effect of the menstrual cycle on immune mediators in future studies. [ABSTRACT FROM AUTHOR]

Background: Previous findings on the associations of thiazide use with skin cancers were conflicting. This study aimed to examine the associations of individual thiazide use with skin cancer risk, differentiated by subtypes of skin cancers, geographic regions, and cumulative doses of individual thiazides.Methods: We searched PubMed, Embase, and Cochrane Central Register of Controlled Trials for relevant studies on January 5, 2022, scanned the references of included studies, and consulted experts. We included case-control and cohort studies or randomized trials reporting the associations of individual thiazide or thiazide-like diuretics use with skin cancers. Non-melanoma skin cancer (NMSC) and melanoma were analysed separately. A random-effects model meta-analysis was conducted for pooled odds ratio (OR) and hazard ratio (HR) for skin cancers related to individual thiazide use.Results: We included 15, 5, and 5 case-control or cohort studies reporting the risk for skin cancers associated with hydrochlorothiazide, bendroflumethiazide, and indapamide use, respectively, with 17,848,313 participants. The meta-analysis showed associations of hydrochlorothiazide use with increased risk of NMSC (OR 1.16, 95% CI 1.08-1.24; HR 1.26, 95% CI 1.04-1.54), squamous cell carcinoma (SCC) (OR 1.32, 95% CI 1.06-1.65; HR 1.61, 95% CI 0.97-2.67), and melanoma (OR 1.11, 95% CI 1.02-1.20; HR 1.03, 95% CI 0.93-1.14). The increased risks for SCC were associated with high cumulative doses of hydrochlorothiazide (OR 2.56, 95% CI 1.43-4.57; HR 1.20, 95% CI 1.00-1.45). Hydrochlorothiazide use was associated with different subtypes of melanoma including superficial spreading (OR 1.18, 95% CI 1.05-1.33), nodular (OR 1.23, 95% CI 1.08-1.39), and lentigo maligna melanoma (OR 1.33, 95% CI 1.08-1.65). Various cumulative doses of hydrochlorothiazide were associated with increased odds for melanoma. However, the associations of hydrochlorothiazide use with increased risk of NMSC and melanoma only appeared in non-Asian countries. No meaningful increase in the risk for skin cancers was associated with bendroflumethiazide and indapamide.Conclusions: Hydrochlorothiazide is associated with an increased risk for NMSC (especially SCC) and melanoma in non-Asian countries, whereas bendroflumethiazide and indapamide are not associated with a meaningful risk for skin cancers. Healthcare professionals and patients should be informed of the different risk profiles of skin cancers associated with different thiazides, cumulative doses, and regions.Trial Registration: PROSPERO CRD42021234317 . [ABSTRACT FROM AUTHOR]

Background: Tuberculosis (TB) transmission often occurs within a household or community, leading to heterogeneous spatial patterns. However, apparent spatial clustering of TB could reflect ongoing transmission or co-location of risk factors and can vary considerably depending on the type of data available, the analysis methods employed and the dynamics of the underlying population. Thus, we aimed to review methodological approaches used in the spatial analysis of TB burden.Methods: We conducted a systematic literature search of spatial studies of TB published in English using Medline, Embase, PsycInfo, Scopus and Web of Science databases with no date restriction from inception to 15 February 2017. The protocol for this systematic review was prospectively registered with PROSPERO ( CRD42016036655 ).Results: We identified 168 eligible studies with spatial methods used to describe the spatial distribution (n = 154), spatial clusters (n = 73), predictors of spatial patterns (n = 64), the role of congregate settings (n = 3) and the household (n = 2) on TB transmission. Molecular techniques combined with geospatial methods were used by 25 studies to compare the role of transmission to reactivation as a driver of TB spatial distribution, finding that geospatial hotspots are not necessarily areas of recent transmission. Almost all studies used notification data for spatial analysis (161 of 168), although none accounted for undetected cases. The most common data visualisation technique was notification rate mapping, and the use of smoothing techniques was uncommon. Spatial clusters were identified using a range of methods, with the most commonly employed being Kulldorff's spatial scan statistic followed by local Moran's I and Getis and Ord's local Gi(d) tests. In the 11 papers that compared two such methods using a single dataset, the clustering patterns identified were often inconsistent. Classical regression models that did not account for spatial dependence were commonly used to predict spatial TB risk. In all included studies, TB showed a heterogeneous spatial pattern at each geographic resolution level examined.Conclusions: A range of spatial analysis methodologies has been employed in divergent contexts, with all studies demonstrating significant heterogeneity in spatial TB distribution. Future studies are needed to define the optimal method for each context and should account for unreported cases when using notification data where possible. Future studies combining genotypic and geospatial techniques with epidemiologically linked cases have the potential to provide further insights and improve TB control. [ABSTRACT FROM AUTHOR]

Background: Dietary interventions targeting the gut microbiota have been proposed as innovative strategies to improve obesity-associated metabolic disorders. Increasing physical activity (PA) is considered as a key behavioral change for improving health. We have tested the hypothesis that changing the PA status during a nutritional intervention based on prebiotic supplementation can alter or even change the metabolic response to the prebiotic. We confirm in obese subjects and in high-fat diet fed mice that performing PA in parallel to a prebiotic supplementation is necessary to observe metabolic improvements upon inulin.Methods: A randomized, single-blinded, multicentric, placebo-controlled trial was conducted in obese participants who received 16 g/day native inulin versus maltodextrin, coupled to dietary advice to consume inulin-rich versus -poor vegetables for 3 months, respectively, in addition to dietary caloric restriction. Primary outcomes concern the changes on the gut microbiota composition, and secondary outcomes are related to the measures of anthropometric and metabolic parameters, as well as the evaluation of PA. Among the 106 patients who completed the study, 61 patients filled a questionnaire for PA before and after intervention (placebo: n = 31, prebiotic: n = 30). Except the dietitian (who provided dietary advices and recipes book), all participants and research staff were blinded to the treatments and no advices related to PA were given to participants in order to change their habits. In parallel, a preclinical study was designed combining both inulin supplementation and voluntary exercise in a model of diet-induced obesity in mice.Results: Obese subjects who increased PA during a 3 months intervention with inulin-enriched diet exhibited several clinical improvements such as reduced BMI (- 1.6 kg/m2), decreased liver enzymes and plasma cholesterol, and improved glucose tolerance. Interestingly, the regulations of Bifidobacterium, Dialister, and Catenibacterium genera by inulin were only significant when participants exercised more. In obese mice, we highlighted a greater gut fermentation of inulin and improved glucose homeostasis when PA is combined with prebiotics.Conclusion: We conclude that PA level is an important determinant of the success of a dietary intervention targeting the gut microbiota.Trial Registration: ClinicalTrials.gov, NCT03852069 (February 22, 2019 retrospectively registered). [ABSTRACT FROM AUTHOR]

Background: Faecal immunochemical tests (FITs) are used to triage primary care patients with symptoms that could be caused by colorectal cancer for referral to colonoscopy. The aim of this study was to determine whether combining FIT with routine blood test results could improve the performance of FIT in the primary care setting.Methods: Results of all consecutive FITs requested by primary care providers between March 2017 and December 2020 were retrieved from the Oxford University Hospitals NHS Foundation Trust. Demographic factors (age, sex), reason for referral, and results of blood tests within 90 days were also retrieved. Patients were followed up for incident colorectal cancer in linked hospital records. The sensitivity, specificity, positive and negative predictive values of FIT alone, FIT paired with blood test results, and several multivariable FIT models, were compared.Results: One hundred thirty-nine colorectal cancers were diagnosed (0.8%). Sensitivity and specificity of FIT alone at a threshold of 10 μg Hb/g were 92.1 and 91.5% respectively. Compared to FIT alone, blood test results did not improve the performance of FIT. Pairing blood test results with FIT increased specificity but decreased sensitivity. Multivariable models including blood tests performed similarly to FIT alone.Conclusions: FIT is a highly sensitive tool for identifying higher risk individuals presenting to primary care with lower risk symptoms. Combining blood test results with FIT does not appear to lead to better discrimination for colorectal cancer than using FIT alone. [ABSTRACT FROM AUTHOR]

Background: Plasmodium falciparum malaria is associated with anaemia-related morbidity, attributable to host, parasite and drug factors. We quantified the haematological response following treatment of uncomplicated P. falciparum malaria to identify the factors associated with malarial anaemia.Methods: Individual patient data from eligible antimalarial efficacy studies of uncomplicated P. falciparum malaria, available through the WorldWide Antimalarial Resistance Network data repository prior to August 2015, were pooled using standardised methodology. The haematological response over time was quantified using a multivariable linear mixed effects model with nonlinear terms for time, and the model was then used to estimate the mean haemoglobin at day of nadir and day 7. Multivariable logistic regression quantified risk factors for moderately severe anaemia (haemoglobin < 7 g/dL) at day 0, day 3 and day 7 as well as a fractional fall ≥ 25% at day 3 and day 7.Results: A total of 70,226 patients, recruited into 200 studies between 1991 and 2013, were included in the analysis: 50,859 (72.4%) enrolled in Africa, 18,451 (26.3%) in Asia and 916 (1.3%) in South America. The median haemoglobin concentration at presentation was 9.9 g/dL (range 5.0-19.7 g/dL) in Africa, 11.6 g/dL (range 5.0-20.0 g/dL) in Asia and 12.3 g/dL (range 6.9-17.9 g/dL) in South America. Moderately severe anaemia (Hb < 7g/dl) was present in 8.4% (4284/50,859) of patients from Africa, 3.3% (606/18,451) from Asia and 0.1% (1/916) from South America. The nadir haemoglobin occurred on day 2 post treatment with a mean fall from baseline of 0.57 g/dL in Africa and 1.13 g/dL in Asia. Independent risk factors for moderately severe anaemia on day 7, in both Africa and Asia, included moderately severe anaemia at baseline (adjusted odds ratio (AOR) = 16.10 and AOR = 23.00, respectively), young age (age < 1 compared to ≥ 12 years AOR = 12.81 and AOR = 6.79, respectively), high parasitaemia (AOR = 1.78 and AOR = 1.58, respectively) and delayed parasite clearance (AOR = 2.44 and AOR = 2.59, respectively). In Asia, patients treated with an artemisinin-based regimen were at significantly greater risk of moderately severe anaemia on day 7 compared to those treated with a non-artemisinin-based regimen (AOR = 2.06 [95%CI 1.39-3.05], p < 0.001).Conclusions: In patients with uncomplicated P. falciparum malaria, the nadir haemoglobin occurs 2 days after starting treatment. Although artemisinin-based treatments increase the rate of parasite clearance, in Asia they are associated with a greater risk of anaemia during recovery. [ABSTRACT FROM AUTHOR]

Background: Limitations to accessing delivery care services increase the risks of adverse outcomes during pregnancy and delivery for all pregnant women, particularly among adolescents in LMICs. In order to inform adolescent-specific delivery care initiatives and coverage, we conducted a comprehensive analysis of trends, projections and inequalities in coverage of delivery care services among adolescents at national, urban-rural and socio-economic levels in LMICs.Methods: Using 224 nationally representative cross-sectional survey data between 2000 and 2019, we estimated the coverage of institutional delivery (INSD) and skilled birth attendants (SBA). Bayesian hierarchical regression models were used to estimate trends, projections and determinants of INSD and SBA.Results: Coverage of delivery care services among adolescents increased substantially at the national level, as well as in both urban and rural areas in most countries between 2000 and 2018. Of the 54 LMICs, 24 countries reached 80% coverage of both INSD and SBA in 2018, and predictions for 40 countries are set to exceed 80% by 2030. The trends in coverage of INSD and SBA of adult mothers mostly align with those for adolescent mothers. Our findings show that urban-rural and wealth-based inequalities to delivery care remain persistent by 2030. In 2018, urban settings across 54 countries had higher rates of coverage exceeding 80% compared to rural for both INSD (45 urban, 16 rural) and SBA (50 urban, 19 rural). Several factors such as household head age ≥ 46 years, household head being female, access to mass media, lower parity, higher education, higher ANC visits and higher socio-economic status could increase the coverage of INSD and SBA among adolescents and adult women.Conclusions: More than three-quarters of the LMICs are predicted to achieve 80% coverage of INSD and SBA among adolescent mothers in 2030, although with sustained inequalities. [ABSTRACT FROM AUTHOR]

Background: Heart failure with preserved ejection fraction (HFpEF) is the dominant form of heart failure (HF). We here aimed to investigate the characteristics and prognosis of HFpEF in patients with hypertrophic cardiomyopathy (HCM).Methods: This was a prospective cohort study and patients with HCM with available NT-proBNP results were enrolled. Patients were categorized into HFpEF [defined as LVEF ≥50%, with symptoms or signs of HF, and N-terminal pro-brain natriuretic peptide ≥800 pg/mL according to American Heart Association (AHA) criteria] and without heart failure (non-HF). The outcomes of interest were all-cause death, cardiovascular death, and sudden cardiac death (SCD).Results: Of 1178 included patients with HCM, 513 (43.5%) were identified as having HFpEF according to AHA criteria. Compared with non-HF patients, patients with HFpEF had significantly larger maximal wall thickness (P < 0.001), higher maximal left ventricular outflow tract gradient (P < 0.001), higher proportion of atrial fibrillation (P < 0.001), higher incidence of all-cause death (log-rank test, P = 0.002), and cardiovascular death (log-rank test, P = 0.005). Multivariable Cox analysis showed that patients with HFpEF had a nearly two-fold higher risk of all-cause death (adjusted HR = 1.80, 95% CI 1.11-2.90; P = 0.017) and cardiovascular death (adjusted HR =1.82, 95% CI 1.05-3.18; P = 0.033) than non-HF patients.Conclusions: Patients with HCM have a high prevalence of HFpEF and those with HFpEF present greater disease severity and higher mortality than non-HF patients, and thus may require an appropriate and more aggressive treatment for HF management. Identification of patients with HFpEF using AHA criteria can provide guidance on patient risk stratification for patients with HCM. [ABSTRACT FROM AUTHOR]

Background: Medication review is a core aspect of medicine optimisation, yet existing models of review vary substantially in structure and content and are not necessarily easy to implement in clinical practice. This study aimed to use evidence from the existing literature to identify key medication review components and use this to inform the design of an improved review model.Methods: A systematic review was conducted (PROSPERO: CRD42018109788) to identify randomised control trials of stand-alone medication review in adults (18+ years). The review updated that by Huiskes et al. (BMC Fam Pract. 18:5, 2017), using the same search strategy implemented in MEDLINE and Embase. Studies were assessed using the Cochrane risk of bias tool. Key review components were identified, alongside relevant clinical and health service outcomes. A working group (patients, doctors and pharmacists) developed the model through an iterative consensus process (appraisal of documents plus group discussions), working from the systematic review findings, brief evidence summaries for core review components and examples of previous models, to agree on the main purpose of the review model, overarching model structure, review components and supporting material.Results: We identified 28 unique studies, with moderate bias overall. Consistent medication review components included reconciliation (26 studies), safety assessment (22), suboptimal treatment (19), patient knowledge/preferences (18), adherence (14), over-the-counter therapy (13) and drug monitoring (10). There was limited evidence from studies for improvement in key clinical outcomes. The review structure was underpinned by patient values and preferences, with parallel information gathering and evaluation stages, feeding into the final decision-making and implementation. Most key components identified in the literature were included. The final model was considered to benefit from a patient-centred, holistic approach, which captured both patient-orientated and medication-focused problems, and aligned with traditional consultation methods thus facilitating implementation in practice.Conclusions: The Bristol Medication Review Model provides a framework for standardised delivery of structured reviews. The model has the potential for use by all healthcare professionals with relevant clinical experience and is designed to offer flexibility of implementation not limited to a particular healthcare setting. [ABSTRACT FROM AUTHOR]

Background: Genetic, lifestyle, and environmental factors can lead to perturbations in circulating lipid levels and increase the risk of cardiovascular and metabolic diseases. However, how changes in individual lipid species contribute to disease risk is often unclear. Moreover, little is known about the role of lipids on cardiovascular disease in Pakistan, a population historically underrepresented in cardiovascular studies.Methods: We characterised the genetic architecture of the human blood lipidome in 5662 hospital controls from the Pakistan Risk of Myocardial Infarction Study (PROMIS) and 13,814 healthy British blood donors from the INTERVAL study. We applied a candidate causal gene prioritisation tool to link the genetic variants associated with each lipid to the most likely causal genes, and Gaussian Graphical Modelling network analysis to identify and illustrate relationships between lipids and genetic loci.Results: We identified 253 genetic associations with 181 lipids measured using direct infusion high-resolution mass spectrometry in PROMIS, and 502 genetic associations with 244 lipids in INTERVAL. Our analyses revealed new biological insights at genetic loci associated with cardiometabolic diseases, including novel lipid associations at the LPL, MBOAT7, LIPC, APOE-C1-C2-C4, SGPP1, and SPTLC3 loci.Conclusions: Our findings, generated using a distinctive lipidomics platform in an understudied South Asian population, strengthen and expand the knowledge base of the genetic determinants of lipids and their association with cardiometabolic disease-related loci. [ABSTRACT FROM AUTHOR]

Background: The sustainable development goals aim to improve health for all by 2030. They incorporate ambitious goals regarding tuberculosis (TB), which may be a significant cause of disability, yet to be quantified. Therefore, we aimed to quantify the prevalence and types of TB-related disabilities.Methods: We performed a systematic review of TB-related disabilities. The pooled prevalence of disabilities was calculated using the inverse variance heterogeneity model. The maps of the proportions of common types of disabilities by country income level were created.Results: We included a total of 131 studies (217,475 patients) that were conducted in 49 countries. The most common type of disabilities were mental health disorders (23.1%), respiratory impairment (20.7%), musculoskeletal impairment (17.1%), hearing impairment (14.5%), visual impairment (9.8%), renal impairment (5.7%), and neurological impairment (1.6%). The prevalence of respiratory impairment (61.2%) and mental health disorders (42.0%) was highest in low-income countries while neurological impairment was highest in lower middle-income countries (25.6%). Drug-resistant TB was associated with respiratory (58.7%), neurological (37.2%), and hearing impairments (25.0%) and mental health disorders (26.0%), respectively.Conclusions: TB-related disabilities were frequently reported. More uniform reporting tools for TB-related disability and further research to better quantify and mitigate it are urgently needed.Prospero Registration Number: CRD42019147488. [ABSTRACT FROM AUTHOR]

Background: Glucocorticoids could theoretically decrease breast cancer risk through their anti-inflammatory effects or increase risk through immunosuppression. However, epidemiological evidence is limited regarding the associations between glucocorticoid use and breast cancer risk.Methods: We investigated the association between systemic glucocorticoid use and breast cancer incidence in the E3N cohort, which includes 98,995 women with information on various characteristics collected from repeated questionnaires complemented with drug reimbursement data available from 2004. Women with at least two reimbursements of systemic glucocorticoids in any previous 3-month period since January 1, 2004, were defined as exposed. We considered exposure as a time-varying parameter, and we used multivariable Cox regression models to estimate hazard ratios (HRs) of breast cancer. We performed a competing risk analysis using a cause-specific hazard approach to study the heterogeneity by tumour subtype/stage/grade.Results: Among 62,512 postmenopausal women (median age at inclusion of 63 years old), 2864 developed breast cancer during a median follow-up of 9 years (between years 2004 and 2014). Compared with non-exposure, glucocorticoid exposure was not associated with overall breast cancer risk [HR = 0.94 (0.85-1.05)]; however, it was associated with a higher risk of in situ breast cancer and a lower risk of invasive breast cancer [HRinsitu = 1.34 (1.01-1.78); HRinvasive = 0.86 (0.76-0.97); Phomogeneity = 0.01]. Regarding the risk of invasive breast cancer, glucocorticoid exposure was inversely associated with oestrogen receptor (ER)-positive breast cancer [HRER+ = 0.82 (0.72-0.94); HRER- = 1.21 (0.88-1.66); Phomogeneity = 0.03]; it was also inversely associated with the risk of stage 1 or stage 2 tumours but positively associated with the risk of stage 3/4 breast cancers [HRstage1 = 0.87 (0.75-1.01); HRstage2 = 0.67 (0.52-0.86); HRstage3/4 = 1.49 (1.02-2.20); Phomogeneity = 0.01].Conclusion: This study suggests that the association between systemic glucocorticoid use and breast cancer risk may differ by tumour subtype and stage. [ABSTRACT FROM AUTHOR]

Background: Disparities in health by adult income are well documented, but we know less about the childhood origins of health inequalities, and it remains unclear how the shape of the gradient varies across health conditions. This study examined the association between parental income in childhood and several measures of morbidity in adulthood.Methods: We used administrative data on seven complete Norwegian birth cohorts born in 1967-1973 (N = 429,886) to estimate the association between parental income from birth to age 18, obtained from tax records available from 1967, linked with administrative registries on health. Health measures, observed between ages 39 and 43, were taken from registry data on consultations at primary health care services based on diagnostic codes from the International Classification of Primary Care (ICPC-2) and hospitalizations and outpatient specialist consultations registered in the National Patient Registry (ICD-10).Results: Low parental income during childhood was associated with a higher risk of being diagnosed with several chronic and pain-related disorders, as well as hospitalization, but not overall primary health care use. Absolute differences were largest for disorders related to musculoskeletal pain, injuries, and depression (7-9 percentage point difference). There were also differences for chronic disorders such as hypertension (8%, CI 7.9-8.5 versus 4%, CI 4.1-4.7) and diabetes (3.2%, CI 3.0-3.4 versus 1.4%, CI 1.2-1.6). There was no difference in consultations related to respiratory disorders (20.9%, CI 20.4-21.5 versus 19.7%, CI 19.2-20.3). Childhood characteristics (parental education, low birth weight, and parental marital status) and own adult characteristics (education and income) explained a large share of the association.Conclusions: Children growing up at the bottom of the parental income distribution, compared to children in the top of the income distribution, had a two- to threefold increase in somatic and psychological disorders measured in adulthood. This shows that health inequalities by socioeconomic family background persist in a Scandinavian welfare-state context with universal access to health care. [ABSTRACT FROM AUTHOR]

Background: The mechanisms underlying the obesity-cancer relationship are incompletely understood. This study aimed to characterise metabolic signatures of greater body size and to investigate their association with two obesity-related malignancies, endometrial and colorectal cancers, and with weight loss within the context of an intervention study.Methods: Targeted mass spectrometry metabolomics data from 4326 participants enrolled in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort and 17 individuals from a single-arm pilot weight loss intervention (Intercept) were used in this analysis. Metabolic signatures of body size were first determined in discovery (N = 3029) and replication (N = 1297) sets among EPIC participants by testing the associations between 129 metabolites and body mass index (BMI), waist circumference (WC), and waist-to-hip ratio (WHR) using linear regression models followed by partial least squares analyses. Conditional logistic regression models assessed the associations between the metabolic signatures with endometrial (N = 635 cases and 648 controls) and colorectal (N = 423 cases and 423 controls) cancer risk using nested case-control studies in EPIC. Pearson correlation between changes in the metabolic signatures and weight loss was tested among Intercept participants.Results: After adjustment for multiple comparisons, greater BMI, WC, and WHR were associated with higher levels of valine, isoleucine, glutamate, PC aa C38:3, and PC aa C38:4 and with lower levels of asparagine, glutamine, glycine, serine, lysoPC C17:0, lysoPC C18:1, lysoPC C18:2, PC aa C42:0, PC ae C34:3, PC ae C40:5, and PC ae C42:5. The metabolic signature of BMI (OR1-sd 1.50, 95% CI 1.30-1.74), WC (OR1-sd 1.46, 95% CI 1.27-1.69), and WHR (OR1-sd 1.54, 95% CI 1.33-1.79) were each associated with endometrial cancer risk. Risk of colorectal cancer was positively associated with the metabolic signature of WHR (OR1-sd: 1.26, 95% CI 1.07-1.49). In the Intercept study, a positive correlation was observed between weight loss and changes in the metabolic signatures of BMI (r = 0.5, 95% CI 0.06-0.94, p = 0.03), WC (r = 0.5, 95% CI 0.05-0.94, p = 0.03), and WHR (r = 0.6, 95% CI 0.32-0.87, p = 0.01).Conclusions: Obesity is associated with a distinct metabolic signature comprising changes in levels of specific amino acids and lipids which is positively associated with both colorectal and endometrial cancer and is potentially reversible following weight loss. [ABSTRACT FROM AUTHOR]

Background: Malaria and hypertensive disorders of pregnancy (HDoP) affect millions of pregnancies worldwide, particularly those of young, first-time mothers. Small case-control studies suggest a positive association between falciparum malaria and risk of pre-eclampsia but large prospective analyses are lacking.Methods: We characterized the relationship between malaria in pregnancy and the development of HDoP in a large, prospectively followed cohort. Pregnant women living along the Thailand-Myanmar border, an area of low seasonal malaria transmission, were followed at antenatal clinics between 1986 and 2016. The relationships between falciparum and vivax malaria during pregnancy and the odds of gestational hypertension, pre-eclampsia, or eclampsia were examined using logistic regression amongst all women and then stratified by gravidity.Results: There were 23,262 singleton pregnancies in women who presented during the first trimester and were followed fortnightly. Falciparum malaria was associated with gestational hypertension amongst multigravidae (adjusted odds ratio (AOR) 2.59, 95%CI 1.59-4.23), whereas amongst primigravidae, it was associated with the combined outcome of pre-eclampsia/eclampsia (AOR 2.61, 95%CI 1.01-6.79). In contrast, there was no association between vivax malaria and HDoP.Conclusions: Falciparum but not vivax malaria during pregnancy is associated with hypertensive disorders of pregnancy. [ABSTRACT FROM AUTHOR]

Background: Nutrition and lifestyle have been long established as risk factors for colorectal cancer (CRC). Modifiable lifestyle behaviours bear potential to minimize long-term CRC risk; however, translation of lifestyle information into individualized CRC risk assessment has not been implemented. Lifestyle-based risk models may aid the identification of high-risk individuals, guide referral to screening and motivate behaviour change. We therefore developed and validated a lifestyle-based CRC risk prediction algorithm in an asymptomatic European population.Methods: The model was based on data from 255,482 participants in the European Prospective Investigation into Cancer and Nutrition (EPIC) study aged 19 to 70 years who were free of cancer at study baseline (1992-2000) and were followed up to 31 September 2010. The model was validated in a sample comprising 74,403 participants selected among five EPIC centres. Over a median follow-up time of 15 years, there were 3645 and 981 colorectal cancer cases in the derivation and validation samples, respectively. Variable selection algorithms in Cox proportional hazard regression and random survival forest (RSF) were used to identify the best predictors among plausible predictor variables. Measures of discrimination and calibration were calculated in derivation and validation samples. To facilitate model communication, a nomogram and a web-based application were developed.Results: The final selection model included age, waist circumference, height, smoking, alcohol consumption, physical activity, vegetables, dairy products, processed meat, and sugar and confectionary. The risk score demonstrated good discrimination overall and in sex-specific models. Harrell's C-index was 0.710 in the derivation cohort and 0.714 in the validation cohort. The model was well calibrated and showed strong agreement between predicted and observed risk. Random survival forest analysis suggested high model robustness. Beyond age, lifestyle data led to improved model performance overall (continuous net reclassification improvement = 0.307 (95% CI 0.264-0.352)), and especially for young individuals below 45 years (continuous net reclassification improvement = 0.364 (95% CI 0.084-0.575)).Conclusions: LiFeCRC score based on age and lifestyle data accurately identifies individuals at risk for incident colorectal cancer in European populations and could contribute to improved prevention through motivating lifestyle change at an individual level. [ABSTRACT FROM AUTHOR]

Background: Prostate cancer is the second most frequently diagnosed cancer in men. Metabolomics can potentially provide new insights into the aetiology of prostate cancer by identifying new metabolic risk factors. This study investigated the prospective association between plasma metabolite concentrations and prostate cancer risk, both overall and by stratifying for disease aggressiveness and baseline age.Methods: In a case-control study nested in the Northern Sweden Health and Disease Study, pre-diagnostic concentrations of 148 plasma metabolites were determined using targeted mass spectrometry- and nuclear magnetic resonance-based metabolomics in 777 prostate cancer cases (follow-up ≥ 5 years) and 777 matched controls. Associations between prostate cancer risk and metabolite concentrations were investigated using conditional logistic regression conditioned on matching factors (body mass index, age and sample storage time). Corrections for multiple testing were performed using false discovery rate (20%) and Bonferroni. Metabolomics analyses generated new hypotheses, which were investigated by leveraging food frequency questionnaires (FFQs) and oral glucose tolerance tests performed at baseline.Results: After correcting for multiple testing, two lysophosphatidylcholines (LPCs) were positively associated with risk of overall prostate cancer (all ages and in older subjects). The strongest association was for LPC C17:0 in older subjects (OR = 2.08; 95% CI 1.45-2.98; p < 0.0001, significant also after the Bonferroni correction). Observed associations with risk of overall prostate cancer in younger subjects were positive for glycine and inverse for pyruvate. For aggressive prostate cancer, there were positive associations with six glycerophospholipids (LPC C17:0, LPC C20:3, LPC C20:4, PC ae C38:3, PC ae C38:4 and PC ae C40:2), while there was an inverse association with acylcarnitine C18:2. Moreover, plasma LPC C17:0 concentrations positively correlated with estimated dietary intake of fatty acid C17:0 from the FFQs. The associations between glycerophospholipids and prostate cancer were stronger in case-controls with normal glucose tolerance.Conclusions: Several glycerophospholipids were positively associated with risk of overall and aggressive prostate cancer. The strongest association was observed for LPC C17:0. The associations between glycerophospholipids and prostate cancer risk were stronger in case-controls with normal glucose tolerance, suggesting a link between the glucose metabolism status and risk of prostate cancer. [ABSTRACT FROM AUTHOR]

Background: The prevalence of excess adiposity, as measured by elevated body mass index (BMI) and waist-hip ratio (WHR), is increasing in sub-Saharan African (SSA) populations. This could add a considerable burden of cardiovascular and metabolic diseases for which these populations are currently ill-prepared. Evidence from white, European origin populations shows that higher adiposity leads to an adverse lipid profile; whether these associations are similar in all SSA populations requires further exploration. This study compared the association of BMI and WHR with lipid profile in urban Malawi with a contemporary cohort with contrasting socioeconomic, demographic, and ethnic characteristics in the United Kingdom (UK).Methods: We used data from 1248 adolescents (mean 18.7 years) and 2277 Malawian adults (mean 49.8 years), all urban-dwelling, and from 3201 adolescents (mean 17.8 years) and 6323 adults (mean 49.7 years) resident in the UK. Adiposity measures and fasting lipids were assessed in both settings, and the associations of BMI and WHR with total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C) and triglycerides (TG) were assessed by sex and age groups in both studies.Results: Malawian female adults were more adipose and had more adverse lipid profiles than their UK counterparts. In contrast, Malawian adolescent and adult males were leaner and had more favourable lipid profiles than in the UK. Higher BMI and WHR were associated with increased TC, LDL-C and TG and reduced HDL-C in both settings. The magnitude of the associations of BMI and WHR with lipids was mostly similar or slightly weaker in the Malawian compared with the UK cohort in both adolescents and adults. One exception was the stronger association between increasing adiposity and elevated TC and LDL-C in Malawian compared to UK men.Conclusions: Malawian adult women have greater adiposity and more adverse lipid profiles compared with their UK counterparts. Similar associations of adiposity with adverse lipid profiles were observed for Malawian and UK adults in most age and sex groups studied. Sustained efforts are urgently needed to address the excess adiposity and adverse lipid profiles in Malawi to mitigate a future epidemic of cardio-metabolic disease among the poorest populations. [ABSTRACT FROM AUTHOR]

Background: Since the first cluster of cases was identified in Wuhan City, China, in December 2019, coronavirus disease 2019 (COVID-19) rapidly spreads globally. Scientists have made strides in estimating key transmission and epidemiological parameters. In particular, accumulating evidence points to a substantial fraction of asymptomatic or subclinical infections, which influences our understanding of the transmission potential and severity of this emerging disease. In this study, we derive estimates of the transmissibility and virulence of COVID-19 in Wuhan City, China, by reconstructing the underlying transmission dynamics using multiple data sources.Methods: We employ statistical methods and publicly available epidemiological datasets to jointly derive estimates of transmissibility and severity associated with the novel coronavirus. For this purpose, the daily series of laboratory-confirmed COVID-19 cases and deaths in Wuhan City together with epidemiological data of Japanese repatriated from Wuhan City on board government-chartered flights were integrated into our analysis.Results: Our posterior estimates of basic reproduction number (R) in Wuhan City, China, in 2019-2020 reached values at 3.49 (95% CrI 3.39-3.62) with a mean serial interval of 6.0 days, and the enhanced public health intervention after January 23 in 2020 was associated with a significantly reduced R at 0.84 (95% CrI 0.81-0.88), with the total number of infections (i.e., cumulative infections) estimated at 1,906,634 (95% CrI 1,373,500-2,651,124) in Wuhan City, elevating the overall proportion of infected individuals to 19.1% (95% CrI 13.5-26.6%). We also estimated the most recent crude infection fatality ratio (IFR) and time-delay adjusted IFR at 0.04% (95% CrI 0.03-0.06%) and 0.12% (95% CrI 0.08-0.17%), respectively, estimates that are substantially smaller than the crude CFR estimated at 4.06%.Conclusions: We have estimated key epidemiological parameters of the transmissibility and virulence of COVID-19 in Wuhan, China, during January-February 2020 using an ecological modeling approach that is suitable to infer epidemiological parameters with quantified uncertainty from partial observations collected by surveillance systems. Our estimate of time-delay adjusted IFR falls in the range of the median IFR estimates based on multiple serological studies conducted in several areas of the world. [ABSTRACT FROM AUTHOR]

Background: Hitherto only studies with selected populations have found an increased all-cause mortality of some selected opioids compared to selected non-opioids for chronic non-cancer pain (CNCP). We have examined the all-cause mortality for CNCP associated with all established opioids compared to non-opioid analgesic therapy (anticonvulsants, antidepressants, dipyrone, non-steroidal agents).Methods: The study used the InGef (Institute for Applied Health Research Berlin) database which is an anonymized healthcare claims database including 4,711,668 insured persons who were covered by 61 German statutory health insurances between 2013 and 2017.The health insurance companies are the owners of the database. All-cause mortality was determined from death certificates. Adjusted hazard ratios (HRs) including age, gender, comorbidity index, and propensity score as covariates and risk differences (RD) in incidence of death between patients with long-term opioid therapy (LTOT) and control-drug therapy were calculated.Results: The mean age of participants was 66 years; 55% were women. There were 554 deaths during 10,435 person-years for the LTOT patients, whereas there were 340 deaths during 11,342 person-years in the control group. The HR for all-cause mortality was 1.59 (95% CI, 1.38-1.82) with a risk difference of 148 excess deaths (95% CI 99-198) per 10,000 person-years. The elevated risk of death for LTOT was confined to the out-of-hospital deaths: LTOT patients had 288 out-of-hospital deaths during 10,435 person-years (276 per 10,000 person-years) whereas there were 110 deaths during 11,342 person-years (97 per 10,000 person-years) in the control group. HR was 2.29 (95% CI 1.86, 2.83). Although our propensity score matching model indicated a good classification, residual confounding cannot be fully excluded. The opioid group had a higher prevalence of heart failure and a higher use of anti-thrombotic and antiplatelet agents and of psycholeptics.Conclusions: LTOT for CNCP compared to non-opioid analgesics was associated with an increased risk for all-cause mortality. When considering treatment options for patients with CNCP, the relevant risk of increased all-cause mortality with opioids should be discussed.Trial Registration: ClinicalTrials.gov, NCT03778450, Registered on 7 December 2018. [ABSTRACT FROM AUTHOR]

Background: Many decisions regarding health resource utilization flow through the patient-clinician interaction. Thus, it represents a place where de-implementation interventions may have considerable effect on reducing the use of clinical interventions that lack efficacy, have risks that outweigh benefits, or are not cost-effective (i.e., low-value care). The objective of this systematic review with meta-analysis was to determine the effect of de-implementation interventions that engage patients within the patient-clinician interaction on use of low-value care.Methods: MEDLINE, EMBASE, and CINAHL were searched from inception to November 2019. Gray literature was searched using the CADTH tool. Studies were screened independently by two reviewers and were included if they (1) described an intervention that engaged patients in an initiative to reduce low-value care, (2) reported the use of low-value care with and without the intervention, and (3) were randomized clinical trials (RCTs) or quasi-experimental designs. Studies describing interventions solely focused on clinicians or published in a language other than English were excluded. Data was extracted independently in duplicate and pertained to the low-value clinical intervention of interest, components of the strategy for patient engagement, and study outcomes. Quality of included studies was assessed using the Cochrane Risk of Bias tool for RCTs and a modified Downs and Black checklist for quasi-experimental studies. Random effects meta-analysis (reported as risk ratio, RR) was used to examine the effect of de-implementation interventions on the use of low-value care.Results: From 6736 unique citations, 9 RCTs and 13 quasi-experimental studies were included in the systematic review. Studies mostly originated from the USA (n = 13, 59%), targeted treatments (n = 17, 77%), and took place in primary care (n = 10, 45%). The most common intervention was patient-oriented educational material (n = 18, 82%), followed by tools for shared decision-making (n = 5, 23%). Random effects meta-analysis demonstrated that de-implementation interventions that engage patients within the patient-clinician interaction led to a significant reduction in low-value care in both RCTs (RR 0.74; 95% CI 0.66-0.84) and quasi-experimental studies (RR 0.61; 95% CI 0.43-0.87). There was significant inter-study heterogeneity; however, intervention effects were consistent across subgroups defined by low-value practice and patient-engagement strategy.Conclusions: De-implementation interventions that engage patients within the patient-clinician interaction through patient-targeted educational materials or shared decision-making tools are effective in decreasing the use of low-value care. Clinicians and policymakers should consider engaging patients within initiatives that seek to reduce low-value care.Registration: Open Science Framework (https://osf.io/6fsxm). [ABSTRACT FROM AUTHOR]

Background: The increase in the number of predatory journals puts scholarly communication at risk. In order to guard against publication in predatory journals, authors may use checklists to help detect predatory journals. We believe there are a large number of such checklists yet it is uncertain whether these checklists contain similar content. We conducted a systematic review to identify checklists that help to detect potential predatory journals and examined and compared their content and measurement properties.Methods: We searched MEDLINE, Embase, PsycINFO, ERIC, Web of Science and Library, and Information Science & Technology Abstracts (January 2012 to November 2018); university library websites (January 2019); and YouTube (January 2019). We identified sources with original checklists used to detect potential predatory journals published in English, French or Portuguese. Checklists were defined as having instructions in point form, bullet form, tabular format or listed items. We excluded checklists or guidance on recognizing "legitimate" or "trustworthy" journals. To assess risk of bias, we adapted five questions from A Checklist for Checklists tool a priori as no formal assessment tool exists for the type of review conducted.Results: Of 1528 records screened, 93 met our inclusion criteria. The majority of included checklists to identify predatory journals were in English (n = 90, 97%), could be completed in fewer than five minutes (n = 68, 73%), included a mean of 11 items (range = 3 to 64) which were not weighted (n = 91, 98%), did not include qualitative guidance (n = 78, 84%), or quantitative guidance (n = 91, 98%), were not evidence-based (n = 90, 97%) and covered a mean of four of six thematic categories. Only three met our criteria for being evidence-based, i.e. scored three or more "yes" answers (low risk of bias) on the risk of bias tool.Conclusion: There is a plethora of published checklists that may overwhelm authors looking to efficiently guard against publishing in predatory journals. The continued development of such checklists may be confusing and of limited benefit. The similarity in checklists could lead to the creation of one evidence-based tool serving authors from all disciplines. [ABSTRACT FROM AUTHOR]

Background: The 2018-2019 Ebola virus disease (EVD) outbreak in North Kivu and Ituri provinces in the Democratic Republic of the Congo (DRC) is the largest ever recorded in the DRC. It has been declared a Public Health Emergency of International Concern. The outbreak emerged in a region of chronic conflict and insecurity, and directed attacks against health care workers may have interfered with disease response activities. Our study characterizes and quantifies the broader conflict dynamics over the course of the outbreak by pairing epidemiological and all available spatial conflict data.Methods: We build a set of conflict variables by mapping the spatial locations of all conflict events and their associated deaths in each of the affected health zones in North Kivu and Ituri, eastern DRC, before and during the outbreak. Using these data, we compare patterns of conflict before and during the outbreak in affected health zones and those not affected. We then test whether conflict is correlated with increased EVD transmission at the health zone level.Findings: The incidence of conflict events per capita is ~ 600 times more likely in Ituri and North Kivu than for the rest of the DRC. We identified 15 time periods of substantial uninterrupted transmission across 11 health zones and a total of 120 bi-weeks. We do not find significant short-term associations between the bi-week reproduction numbers and the number of conflicts. However, we do find that the incidence of conflict per capita was correlated with the incidence of EVD per capita at the health zone level for the entire outbreak (Pearson's r = 0.33, 95% CI 0.05-0.57). In the two provinces, the monthly number of conflict events also increased by a factor of 2.7 in Ebola-affected health zones (p value < 0.05) compared to 2.0 where no transmission was reported and 1.3 in the rest of the DRC, in the period between February 2019 and July 2019.Conclusion: We characterized the association between variables documenting broad conflict levels and EVD transmission. Such assessment is important to understand if and how such conflict variables could be used to inform the outbreak response. We found that while these variables can help characterize long-term challenges and susceptibilities of the different regions they provide little insight on the short-term dynamics of EVD transmission. [ABSTRACT FROM AUTHOR]

Background: The recent emergence of strains belonging to the meningococcal serogroup W (MenW) sequence type-11 clonal complex and descending from the South American sub-lineage (MenW:cc11/SA) has caused significant shifts in the epidemiology of meningococcal disease worldwide. Although MenW:cc11/SA is deemed highly transmissible and invasive, its epidemiological characteristics have not yet been quantified.Methods: We designed a mathematical model of MenW transmission, carriage, and infection to analyze the recent epidemiology of invasive disease caused by MenW:cc11/SA strains and by other MenW strains in England and in France. We confronted that model with age-stratified incidence data to estimate the transmissibility and the invasiveness of MenW:cc11/SA in England, using the data in France as a validation cohort.Results: During the epidemiological years 2010/2011-2014/2015 in England, the transmissibility of MenW:cc11/SA relative to that of other MenW strains was estimated at 1.20 (95% confidence interval, 1.15 to 1.26). The relative invasiveness of MenW:cc11/SA was also found to exceed unity and to increase with age, with estimates ranging from 4.0 (1.6 to 9.7) in children aged 0-4 years to 20 (6 to 34) in adults aged ≥ 25 years. In France, the model calibrated in England correctly reproduced the early increase of MenW:cc11/SA disease during 2012/2013-2016/2017. Most recent surveillance data, however, indicated a decline in MenW:cc11/SA disease. In both countries, our results suggested that the transmission of MenW:cc11/SA carriage possibly started several months before the first reported case of MenW:cc11/SA disease.Discussion: Our results confirm earlier suggestions about the transmission and the pathogenic potential of MenW:cc11/SA. The main limitation of our study was the lack of age-specific MenW carriage data to confront our model predictions with. Furthermore, the lesser model fit to the most recent data in France suggests that the predictive accuracy of our model might be limited to 5-6 years.Conclusions: Our study provides the first estimates of the transmissibility and of the invasiveness of MenW:cc11/SA. Such estimates may be useful to anticipate changes in the epidemiology of MenW and to adapt vaccination strategies. Our results also point to silent, prolonged transmission of MenW:cc11/SA carriage, with potentially important implications for epidemic preparedness. [ABSTRACT FROM AUTHOR]

Background: Chronic kidney disease with metabolic acidosis is common in older people, but the effectiveness of oral sodium bicarbonate therapy in this group is unclear. We tested whether oral sodium bicarbonate provides net health benefit for older people with advanced chronic kidney disease and serum bicarbonate concentrations < 22 mmol/L.Methods: Pragmatic multicentre, parallel group, double-blind, placebo-controlled randomised trial. We recruited adults aged ≥ 60 years with estimated glomerular filtration rate of < 30 mL/min/1.73 m2, not receiving dialysis, with serum bicarbonate concentration < 22 mmol/L, from 27 nephrology and geriatric medicine departments in the UK. Participants received oral sodium bicarbonate (up to 3 g/day) or matching placebo given for up to 2 years, randomised in a 1:1 ratio. The primary outcome was between-group difference in the Short Physical Performance Battery (SPPB) at 12 months, adjusted for baseline values, analysed by intention to treat. Secondary outcomes included generic and disease-specific quality of life (EQ-5D and KDQoL tools), anthropometry, renal function, walk distance, blood pressure, bone and vascular health markers, and incremental cost per quality-adjusted life year gained.Results: We randomised 300 participants between May 2013 and February 2017, mean age 74 years, 86 (29%) female. At 12 months, 116/152 (76%) participants allocated to bicarbonate and 104/148 (70%) allocated to placebo were assessed; primary outcome data were available for 187 participants. We found no significant treatment effect for the SPPB: bicarbonate arm 8.3 (SD 2.5) points, placebo arm 8.8 (SD 2.2) and adjusted treatment effect - 0.4 (95% CI - 0.9 to 0.1, p = 0.15). We found no significant treatment effect for glomerular filtration rate (0.6 mL/min/1.73 m2, 95% CI - 0.8 to 2.0, p = 0.39). The bicarbonate arm showed higher costs and lower quality of life as measured by the EQ-5D-3L tool over 1 year (£564 [95% CI £88 to £1154]); placebo dominated bicarbonate under all sensitivity analyses. Adverse events were more frequent in those randomised to bicarbonate (457 versus 400).Conclusions: Oral sodium bicarbonate did not improve physical function or renal function, increased adverse events and is unlikely to be cost-effective for use by the UK NHS for this patient group.Trial Registration: European Clinical Trials Database (2011-005271-16) and ISRCTN09486651; registered 17 February 2012. [ABSTRACT FROM AUTHOR]

Background: The need to monitor the Sustainable Development Goals (SDGs) and to have access to reliable and timely mortality data has created a strong demand in countries for tools that can assist them in this. ANACONDA (Analysis of National Causes of Death for Action) is a new tool developed for this purpose which allows countries to assess how accurate their mortality and cause of death are. Applying ANACONDA will increase confidence and capacity among data custodians in countries about their mortality data and will give them insight into quality problems that will assist the improvement process.Methods: ANACONDA builds on established epidemiological and demographic concepts to operationalise a series of 10 steps and numerous sub-steps to perform data checks. Extensive use is made of comparators to assess the plausibility of national mortality and cause of death statistics. The tool calculates a composite Vital Statistics Performance Index for Quality (VSPI(Q)) to measure how fit for purpose the data are. Extracts from analyses of country data are presented to show the types of outputs.Results: Each of the 10 steps provides insight into how well the current data is describing different aspects of the mortality situation in the country, e.g. who dies of what, the completeness of the reporting, and the amount and types of unusable cause of death codes. It further identifies the exact codes that should not be used by the certifying physicians and their frequency, which makes it possible to institute a focused correction procedure. Finally, the VSPI(Q) allows periodic monitoring of data quality improvements and identifies priorities for action to strengthen the Civil Registration and Vital Statistics (CRVS) system.Conclusions: ANACONDA has demonstrated the potential to dramatically improve knowledge about disease patterns as well as the functioning of CRVS systems and has served as a platform for galvanising wider CRVS reforms in countries. [ABSTRACT FROM AUTHOR]

Background: Improving civil registration and vital statistics (CRVS) systems requires strengthening the capacity of the CRVS workforce. The improvement of data collection and diagnostic practices must be accompanied by efforts to ensure that the workforce has the skills and knowledge to assess the quality of, and analyse, CRVS data using demographic and epidemiological techniques. While longer-term measures to improve data collection practices must continue to be implemented, it is important to build capacity in the cautious use of imperfect data. However, a lack of training programmes, guidelines and tools make capacity shortages a common issue in CRVS systems. As such, any strategy to build capacity should be underpinned by (1) a repository of knowledge and body of evidence on CRVS, and (2) targeted strategies to train the CRVS workforce.Main Text: During the 4 years of the Bloomberg Philanthropies Data for Health (D4H) Initiative at the University of Melbourne, an extensive repository of knowledge and practical tools to support CRVS system improvements was developed for use by various audiences and stakeholders (the 'CRVS Knowledge Gateway'). Complementing this has been a targeted strategy to build CRVS capacity in countries that comprised two approaches - in-country or regional training and a visiting Fellowship Program. These approaches address the need to build competence in countries to collect, analyse and effectively use good quality birth and death data, and a longer-term need to ensure that local staff in countries possess the comprehensive knowledge of CRVS strategies and practices necessary to ensure sustainable CRVS development.Conclusion: The Knowledge Gateway is a dynamic, useful and long-lasting repository of CRVS knowledge for countries and development partners to use to formulate and evaluate CRVS development strategies. Capacity-building through in-country or regional training and the University of Melbourne D4H Fellowship Program will ensure that CRVS capacity and knowledge is developed and maintained, facilitating improvements in CRVS data systems that can be used by policymakers to support better decision-making in health. [ABSTRACT FROM AUTHOR]

Background: Accurate and timely cause of death (COD) data are essential for informed public health policymaking. Medical certification of COD generally provides the majority of COD data in a population and is an essential component of civil registration and vital statistics (CRVS) systems. Accurate completion of the medical certificate of cause of death (MCCOD) should be a relatively straightforward procedure for physicians, but mistakes are common. Here, we present three training strategies implemented in five countries supported by the Bloomberg Philanthropies Data for Health (D4H) Initiative at the University of Melbourne (UoM) and evaluate the impact on the quality of certification.Methods: The three training strategies evaluated were (1) training of trainers (TOT) in the Philippines, Myanmar, and Sri Lanka; (2) direct training of physicians by the UoM D4H in Papua New Guinea (PNG); and (3) the implementation of an online and basic training strategy in Peru. The evaluation involved an assessment of MCCODs before and after training using an assessment tool developed by the University of Melbourne.Results: The TOT strategy led to reductions in incorrectly completed certificates of between 28% in Sri Lanka and 40% in the Philippines. Following direct training of physicians in PNG, the reduction in incorrectly completed certificates was 30%. In Peru, the reduction in incorrect certificates was 30% after implementation and training on an online system only and 43% after training on both the online system and basic medical certification principles.Conclusions: The results of this study indicate that a variety of training strategies can produce benefits in the quality of certification, but further improvements are possible. The experiences of D4H suggest several aspects of the strategies that should be further developed to improve outcomes, particularly key stakeholder engagement from early in the intervention and local committees to oversee activities and support an improved culture in hospitals to support better diagnostic skills and practices. [ABSTRACT FROM AUTHOR]

Background: Even though in situ breast cancer (BCIS) accounts for a large proportion of the breast cancers diagnosed, few studies have investigated potential risk factors for BCIS. Their results suggest that some established risk factors for invasive breast cancer have a similar impact on BCIS risk, but large population-based studies on lifestyle factors and BCIS risk are lacking. Thus, we investigated the association between lifestyle and BCIS risk within the European Prospective Investigation into Cancer and Nutrition cohort.Methods: Lifestyle was operationalized by a score reflecting the adherence to the World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) cancer prevention recommendations. The recommendations utilized in these analyses were the ones pertinent to healthy body weight, physical activity, consumption of plant-based foods, energy-dense foods, red and processed meat, and sugary drinks and alcohol, as well as the recommendation on breastfeeding. Cox proportional hazards regression was used to assess the association between lifestyle score and BCIS risk. The results were presented as hazard ratios (HR) and corresponding 95% confidence intervals (CI).Results: After an overall median follow-up time of 14.9 years, 1277 BCIS cases were diagnosed. Greater adherence to the WCRF/AICR cancer prevention recommendations was not associated with BCIS risk (HR = 0.98, 95% CI 0.93-1.03; per one unit of increase; multivariable model). An inverse association between the lifestyle score and BCIS risk was observed in study centers, where participants were recruited mainly via mammographic screening and attended additional screening throughout follow-up (HR = 0.85, 95% CI 0.73-0.99), but not in the remaining ones (HR = 0.99, 95% CI 0.94-1.05).Conclusions: While we did not observe an overall association between lifestyle and BCIS risk, our results indicate that lifestyle is associated with BCIS risk among women recruited via screening programs and with regular screening participation. This suggests that a true inverse association between lifestyle habits and BCIS risk in the overall cohort may have been masked by a lack of information on screening attendance. The potential inverse association between lifestyle and BCIS risk in our analyses is consistent with the inverse associations between lifestyle scores and breast cancer risk reported from previous studies. [ABSTRACT FROM AUTHOR]

Background: Antidepressants are one of the most commonly prescribed medications in young and middle-aged adults, but there is relatively little information on their safety across a range of adverse outcomes in this age group. This study aimed to assess associations between antidepressant treatment and several adverse outcomes in people aged 20-64 years diagnosed with depression.Methods: We conducted a cohort study in 238,963 patients aged 20-64 years registered with practices across the UK contributing to the QResearch primary care database. Only patients with a first diagnosis of depression were included. Outcomes were falls, fractures, upper gastrointestinal bleed, road traffic accidents, adverse drug reactions and all-cause mortality recorded during follow-up. Cox proportional hazards models were used to estimate hazard ratios associated with antidepressant exposure adjusting for potential confounding variables.Results: During 5 years of follow-up, 4651 patients had experienced a fall, 4796 had fractures, 1066 had upper gastrointestinal bleeds, 3690 had road traffic accidents, 1058 had experienced adverse drug reactions, and 3181 patients died. Fracture rates were significantly increased for selective serotonin reuptake inhibitors (adjusted hazard ratio 1.30, 95% CI 1.21-1.39) and other antidepressants (1.28, 1.11-1.48) compared with periods when antidepressants were not used. All antidepressant drug classes were associated with significantly increased rates of falls. Rates of adverse drug reactions were significantly higher for tricyclic and related antidepressants (1.54, 1.25-1.88) and other antidepressants (1.61, 1.22-2.12) compared with selective serotonin reuptake inhibitors. Trazodone was associated with a significantly increased risk of upper gastrointestinal bleed. All-cause mortality rates were significantly higher for tricyclic and related antidepressants (1.39, 1.22-1.59) and other antidepressants (1.26, 1.08-1.47) than for selective serotonin reuptake inhibitors over 5 years but not 1 year, and were significantly reduced after 85 or more days of treatment with selective serotonin reuptake inhibitors. Mirtazapine was associated with significantly increased mortality rates over 1 and 5 years of follow-up.Conclusions: Selective serotonin reuptake inhibitors had higher rates of fracture than tricyclic and related antidepressants but lower mortality and adverse drug reaction rates than the other antidepressant drug classes. The association between mirtazapine and increased mortality merits further investigation. These risks should be carefully considered and balanced against potential benefits for individual patients when the decision to prescribe an antidepressant is made. [ABSTRACT FROM AUTHOR]

Background: The year 2016 has marked the highest number of displaced people worldwide on record. A large number of these refugees are women, yet little is known about their specific situation and the hurdles they have to face during their journey. Herein, we investigated whether sociodemographic characteristics and traumatic experiences in the home country and during the flight affected the quality of life of refugee women arriving in Germany in 2015-2016.Methods: Six hundred sixty-three women from six countries (Afghanistan, Syria, Iran, Iraq, Somalia, and Eritrea) living in shared reception facilities in five distinct German regions were interviewed by native speakers using a structured questionnaire. Sociodemographic data and information about reasons for fleeing, traumatic experiences, symptoms, quality of life, and expectations towards their future were elicited. All information was stored in a central database in Berlin. Descriptive analyses, correlations, and multivariate analyses were performed.Results: The most frequent reasons cited for fleeing were war, terror, and threat to one's life or the life of a family member. Eighty-seven percent of women resorted to smugglers to make the journey to Europe, and this significantly correlated to residence in a war zone (odds ratio (OR) = 2.5, 95% confidence interval (CI) = 1.4-4.6, p = 0.003) and homelessness prior to fleeing (OR = 2.1, 95% CI = 1-4.3, p = 0.04). Overall the described quality of life by the women was moderate (overall mean = 3.23, range of 1-5) and slightly worse than that of European populations (overall mean = 3.68, p < 0.0001). The main reasons correlating with lower quality of life were older age, having had a near-death experience, having been attacked by a family member, and absence of health care in case of illness.Conclusions: Refugee women experience multiple traumatic experiences before and/or during their journey, some of which are gender-specific. These experiences affect the quality of life in their current country of residence and might impact their integration. We encourage the early investigation of these traumatic experiences to rapidly identify women at higher risk and to improve health care for somatic and mental illness. [ABSTRACT FROM AUTHOR]

Background: National guidance on preventing type 2 diabetes mellitus (T2DM) in the UK recommends low-intensity lifestyle interventions for individuals with intermediate categories of hyperglycaemia defined in terms of impaired fasting glucose (IFG) or 'at-risk' levels of HbA1c. In a recent systematic review of economic evaluations of such interventions, most studies had evaluated intensive trial-based lifestyle programmes in participants with impaired glucose tolerance (IGT). This study examines the costs and effects of different intensity lifestyle programmes and metformin in participants with different categories of intermediate hyperglycaemia.Methods: We developed a decision tree and Markov model (50-year horizon) to compare four approaches, namely (1) a low-intensity lifestyle programme based on current NICE guidance, (2) a high-intensity lifestyle programme based on the US Diabetes Prevention Program, (3) metformin, and (4) no intervention, modelled for three different types of intermediate hyperglycaemia (IFG, IGT and HbA1c). A health system perspective was adopted and incremental analysis undertaken at an individual and population-wide level, taking England as a case study.Results: Low-intensity lifestyle programmes were the most cost-effective (£44/QALY, £195/QALY and £186/QALY compared to no intervention in IGT, IFG and HbA1c, respectively). Intensive lifestyle interventions were also cost-effective compared to no intervention (£2775/QALY, £6820/QALY and £7376/QALY, respectively, in IGT, IFG and HbA1c). Metformin was cost-effective relative to no intervention (£5224/QALY, £6842/QALY and £372/QALY in IGT, IFG and HbA1c, respectively), but was only cost-effective relative to other treatments in participants identified with HbA1c. At a willingness-to-pay threshold of £20,000/QALY, low- and high-intensity lifestyle programmes were cost-effective 98%, 99% and 98% and 81%, 81% and 71% of the time in IGT, IFG and HbA1c, respectively. An England-wide programme for 50-59 year olds could reduce T2DM incidence by < 3.5% over 50 years and would cost 0.2-5.2% of the current diabetes budget for 2-9 years.Discussion: This analysis suggests that current English national policy of low-intensity lifestyle programmes in participants with IFG or HbA1c will be cost-effective and have the most favourable budget impact, but will prevent only a fraction of cases of T2DM. Additional approaches to prevention need to be investigated urgently. [ABSTRACT FROM AUTHOR]

Background: The study aimed to determine the efficacy of melatonin supplementation for sleep disturbances in patients with traumatic brain injury (TBI).Methods: This is a randomised double-blind placebo-controlled two-period two-treatment (melatonin and placebo) crossover study. Outpatients were recruited from Epworth and Austin Hospitals Melbourne, Australia. They had mild to severe TBI (n = 33) reporting sleep disturbances post-injury (mean age 37 years, standard deviation 11 years; 67% men). They were given prolonged-release melatonin formulation (2 mg; Circadin®) and placebo capsules for 4 weeks each in a counterbalanced fashion separated by a 48-hour washout period. Treatment was taken nightly 2 hours before bedtime. Serious adverse events and side-effects were monitored.Results: Melatonin supplementation significantly reduced global Pittsburgh Sleep Quality Index scores relative to placebo, indicating improved sleep quality [melatonin 7.68 vs. placebo 9.47, original score units; difference -1.79; 95% confidence interval (CI), -2.70 to -0.88; p ≤ 0.0001]. Melatonin had no effect on sleep onset latency (melatonin 1.37 vs. placebo 1.42, log units; difference -0.05; 95% CI, -0.14 to 0.03; p = 0.23). With respect to the secondary outcomes, melatonin supplementation increased sleep efficiency on actigraphy, and vitality and mental health on the SF-36 v1 questionnaire (p ≤ 0.05 for each). Melatonin decreased anxiety on the Hospital Anxiety Depression Scale and fatigue on the Fatigue Severity Scale (p ≤ 0.05 for both), but had no significant effect on daytime sleepiness on the Epworth Sleepiness Scale (p = 0.15). No serious adverse events were reported.Conclusions: Melatonin supplementation over a 4-week period is effective and safe in improving subjective sleep quality as well as some aspects of objective sleep quality in patients with TBI.Trial Registration: Identifier: 12611000734965; Prospectively registered on 13 July 2011. [ABSTRACT FROM AUTHOR]

Background: In 2012, the World Health Organization recommended blocking the transmission of Plasmodium falciparum with single low-dose primaquine (SLDPQ, target dose 0.25 mg base/kg body weight), without testing for glucose-6-phosphate dehydrogenase deficiency (G6PDd), when treating patients with uncomplicated falciparum malaria. We sought to develop an age-based SLDPQ regimen that would be suitable for sub-Saharan Africa.Methods: Using data on the anti-infectivity efficacy and tolerability of primaquine (PQ), the epidemiology of anaemia, and the risks of PQ-induced acute haemolytic anaemia (AHA) and clinically significant anaemia (CSA), we prospectively defined therapeutic-dose ranges of 0.15-0.4 mg PQ base/kg for children aged 1-5 years and 0.15-0.5 mg PQ base/kg for individuals aged ≥6 years (therapeutic indices 2.7 and 3.3, respectively). We chose 1.25 mg PQ base for infants aged 6-11 months because they have the highest rate of baseline anaemia and the highest risks of AHA and CSA. We modelled an anthropometric database of 661,979 African individuals aged ≥6 months (549,127 healthy individuals, 28,466 malaria patients and 84,386 individuals with other infections/illnesses) by the Box-Cox transformation power exponential and tested PQ doses of 1-15 mg base, selecting dosing groups based on calculated mg/kg PQ doses.Results: From the Box-Cox transformation power exponential model, five age categories were selected: (i) 6-11 months (n = 39,886, 6.03%), (ii) 1-5 years (n = 261,036, 45.46%), (iii) 6-9 years (n = 20,770, 3.14%), (iv) 10-14 years (n = 12,155, 1.84%) and (v) ≥15 years (n = 328,132, 49.57%) to receive 1.25, 2.5, 5, 7.5 and 15 mg PQ base for corresponding median (1st and 99th centiles) mg/kg PQ base of: (i) 0.16 (0.12-0.25), (ii) 0.21 (0.13-0.37), (iii) 0.25 (0.16-0.38), (iv) 0.26 (0.15-0.38) and (v) 0.27 (0.17-0.40). The proportions of individuals predicted to receive optimal therapeutic PQ doses were: 73.2 (29,180/39,886), 93.7 (244,537/261,036), 99.6 (20,690/20,770), 99.4 (12,086/12,155) and 99.8% (327,620/328,132), respectively.Conclusions: We plan to test the safety of this age-based dosing regimen in a large randomised placebo-controlled trial (ISRCTN11594437) of uncomplicated falciparum malaria in G6PDd African children aged 0.5 - 11 years. If the regimen is safe and demonstrates adequate pharmacokinetics, it should be used to support malaria elimination. [ABSTRACT FROM AUTHOR]

Background: Glucocorticoids are associated with increased fracture risk and are the mainstay of treatment in polymyalgia rheumatica (PMR) and giant cell arteritis (GCA). However, fracture risk in these conditions has not been previously quantified. The aim of this study was to quantify the risk of fracture among patients with PMR and GCA.Methods: A retrospective cohort study was conducted using primary care records from the UK-based Clinical Practice Research Datalink. Individuals aged 40 years and over, with incident diagnoses of PMR or GCA were separately identified from 1990-2004 and followed up until 2015. For each exposed individual, four age-, sex- and practice-matched controls were randomly selected. Incidence rates of fracture per 10,000 person-years were calculated for each disease group and hazard rates were compared to the unexposed using Cox regression models.Results: Overall, 12,136 and 2673 cases of PMR and GCA, respectively, were identified. The incidence rate of fracture was 148.05 (95% CI 141.16-155.28) in PMR and 147.15 (132.91-162.91) in GCA per 10,000 person-years. Risk of fracture was increased by 63% in PMR (adjusted hazard ratio 1.63, 95% CI 1.54-1.73) and 67% in GCA (1.67, 1.49-1.88) compared to the control populations. Fewer than 13% of glucocorticoid-treated cases were prescribed bisphosphonates.Conclusions: This study reports, for the first time, a similar increase in fracture risk for patients with PMR and GCA. More needs to be done to improve adherence to guidelines to co-prescribe bisphosphonates. Further research needs to identify whether lower glucocorticoid starting doses and/or aggressive dose reduction reduces fracture risk. [ABSTRACT FROM AUTHOR]

Background: Interventions in infectious diseases can have both direct effects on individuals who receive the intervention as well as indirect effects in the population. In addition, intervention combinations can have complex interactions at the population level, which are often difficult to adequately assess with standard study designs and analytical methods.Discussion: Herein, we urge the adoption of a new paradigm for the design and interpretation of intervention trials in infectious diseases, particularly with regard to emerging infectious diseases, one that more accurately reflects the dynamics of the transmission process. In an increasingly complex world, simulations can explicitly represent transmission dynamics, which are critical for proper trial design and interpretation. Certain ethical aspects of a trial can also be quantified using simulations. Further, after a trial has been conducted, simulations can be used to explore the possible explanations for the observed effects.Conclusion: Much is to be gained through a multidisciplinary approach that builds collaborations among experts in infectious disease dynamics, epidemiology, statistical science, economics, simulation methods, and the conduct of clinical trials. [ABSTRACT FROM AUTHOR]

To achieve complete polio eradication, the live oral poliovirus vaccine (OPV) currently used must be phased out after the end of wild poliovirus transmission. However, poorly understood threats may arise when OPV use is stopped. To counter these threats, better models than those currently available are needed. Two articles recently published in BMC Medicine address these issues. Mercer et al. (BMC Med 15:180, 2017) developed a statistical model analysis of polio case data and characteristics of cases occurring in several districts in Pakistan to inform resource allocation decisions. Nevertheless, despite having the potential to accelerate the elimination of polio cases, their analyses are unlikely to advance our understanding OPV cessation threats. McCarthy et al. (BMC Med 15:175, 2017) explored one such threat, namely the emergence and transmission of serotype 2 circulating vaccine derived poliovirus (cVDPV2) after OPV2 cessation, and found that the risk of persistent spread of cVDPV2 to new areas increases rapidly 1-5 years after OPV2 cessation. Thus, recently developed models and analysis methods have the potential to guide the required steps to surpass these threats. 'Big data' scientists could help with this; however, datasets covering all eradication efforts should be made readily available.Please see related articles: https://bmcmedicine.biomedcentral.com/articles/10.1186/s12916-017-0937-y and https://bmcmedicine.biomedcentral.com/articles/10.1186/s12916-017-0941-2 . [ABSTRACT FROM AUTHOR]

Background: The UK, like many high-income countries, is experiencing a worsening shortfall of general practitioners (GPs) alongside an increasing demand for their services. At the same time, factors influencing junior doctors' decisions to apply for GP training are only partially understood and research in this area has been hampered by the difficulties in connecting the datasets that map the journey from student to qualified GP. The UK Medical Education Database (UKMED) has been established to ameliorate this problem by linking institutional data across the spectrum of medical education from school to specialty training. Our study aimed to use UKMED to investigate which demographic and educational factors are associated with junior doctors' decisions to apply for GP training.Methods: Study data, provided by the UKMED Development Group and accessed remotely, contained longitudinal educational and sociodemographic information on all doctors who entered UK medical schools in the 2007/2008 academic year and who made first-time specialty training applications in 2015. We used multivariable logistic regression models to investigate two binary outcomes, namely (1) application to GP training, possibly alongside applications to other specialties, and (2) application solely to GP training.Results: Of 7634 doctors in the sample, 43% applied to GP training possibly alongside other specialities and 26% applied solely to GP training. The odds of applying to GP training were associated with particular demographic factors (being female, non-white or secondary educated in the UK increased the odds of application) and educational factors (non-graduate entry, intercalation and above-median academic performance during medical school all decreased the odds of application). After adjusting for these factors, both the medical school and the foundation school attended were independently associated with the odds of applying to GP training.Conclusions: Our findings suggest that the supply and demand imbalance in UK primary care might be improved by (1) efforts to attract greater numbers of female, non-white and UK secondary-educated students into medical schools, and (2) targeting resources at medical and foundation schools that deliver doctors likely to fill significant gaps in the workforce. Further research is required to better understand inter-school differences and to develop strategies to improve recruitment of GP trainees. [ABSTRACT FROM AUTHOR]

Background: Provision of routine iron supplements to prevent anaemia could increase the risk for lower genital tract infections as virulence of some pathogens depends on iron availability. This trial in Burkina Faso assessed whether weekly periconceptional iron supplementation increased the risk of lower genital tract infection in young non-pregnant and pregnant women.Methods: Genital tract infections were assessed within a double blind, controlled, non-inferiority trial of malaria risk among nulliparous women, randomised to receive either iron and folic acid or folic acid alone, weekly, under direct observation for 18 months. Women conceiving during this period entered the pregnancy cohort. End assessment (FIN) for women remaining non-pregnant was at 18 months. For the pregnancy cohort, end assessment was at the first scheduled antenatal visit (ANC1). Infection markers included Nugent scores for abnormal flora and bacterial vaginosis (BV), T. vaginalis PCR, vaginal microbiota, reported signs and symptoms, and antibiotic and anti-fungal prescriptions. Iron biomarkers were assessed at baseline, FIN and ANC1. Analysis compared outcomes by intention to treat and in iron replete/deficient categories.Results: A total of 1954 women (mean 16.8 years) were followed and 478 (24.5%) became pregnant. Median supplement adherence was 79% (IQR 59-90%). Baseline BV prevalence was 12.3%. At FIN and ANC1 prevalence was 12.8% and 7.0%, respectively (P < 0.011). T. vaginalis prevalence was 4.9% at FIN and 12.9% at ANC1 (P < 0.001). BV and T. vaginalis prevalence and microbiota profiles did not differ at trial end-points. Iron-supplemented non-pregnant women received more antibiotic treatments for non-genital infections (P = 0.014; mainly gastrointestinal infections (P = 0.005), anti-fungal treatments for genital infections (P = 0.014) and analgesics (P = 0.008). Weekly iron did not significantly reduce iron deficiency prevalence. At baseline, iron-deficient women were more likely to have normal vaginal flora (P = 0.016).Conclusions: Periconceptional weekly iron supplementation of young women did not increase the risk of lower genital tract infections but did increase general morbidity in the non-pregnant cohort. Unabsorbed gut iron due to malaria could induce enteric infections, accounting for the increased administration of antibiotics and antifungals in the iron-supplemented arm. This finding reinforces concerns about routine iron supplementation in highly malarious areas.Trial Registration: Trial registration number NCT01210040 . Registered with Clinicaltrials.gov on 27 September 2010. [ABSTRACT FROM AUTHOR]

Background: Dietary assessment is complex, and strategies to select the most appropriate dietary assessment tool (DAT) in epidemiological research are needed. The DIETary Assessment Tool NETwork (DIET@NET) aimed to establish expert consensus on Best Practice Guidelines (BPGs) for dietary assessment using self-report.Methods: The BPGs were developed using the Delphi technique. Two Delphi rounds were conducted. A total of 131 experts were invited, and of these 65 accepted, with 48 completing Delphi round I and 51 completing Delphi round II. In all, a total of 57 experts from North America, Europe, Asia and Australia commented on the 47 suggested guidelines.Results: Forty-three guidelines were generated, grouped into the following four stages: Stage I. Define what is to be measured in terms of dietary intake (what? who? and when?); Stage II. Investigate different types of DATs; Stage III. Evaluate existing tools to select the most appropriate DAT by evaluating published validation studies; Stage IV. Think through the implementation of the chosen DAT and consider sources of potential biases.Conclusions: The Delphi technique consolidated expert views on best practice in assessing dietary intake. The BPGs provide a valuable guide for health researchers to choose the most appropriate dietary assessment method for their studies. These guidelines will be accessible through the Nutritools website, www.nutritools.org . [ABSTRACT FROM AUTHOR]

Background: Evidence on immunization costs is a critical input for cost-effectiveness analysis and budgeting, and can describe variation in site-level efficiency. The Expanded Program on Immunization Costing and Financing (EPIC) Project represents the largest investigation of immunization delivery costs, collecting empirical data on routine infant immunization in Benin, Ghana, Honduras, Moldova, Uganda, and Zambia.Methods: We developed a pooled dataset from individual EPIC country studies (316 sites). We regressed log total costs against explanatory variables describing service volume, quality, access, other site characteristics, and income level. We used Bayesian hierarchical regression models to combine data from different countries and account for the multi-stage sample design. We calculated output elasticity as the percentage increase in outputs (service volume) for a 1% increase in inputs (total costs), averaged across the sample in each country, and reported first differences to describe the impact of other predictors. We estimated average and total cost curves for each country as a function of service volume.Results: Across countries, average costs per dose ranged from $2.75 to $13.63. Average costs per child receiving diphtheria, tetanus, and pertussis ranged from $27 to $139. Within countries costs per dose varied widely-on average, sites in the highest quintile were 440% more expensive than those in the lowest quintile. In each country, higher service volume was strongly associated with lower average costs. A doubling of service volume was associated with a 19% (95% interval, 4.0-32) reduction in costs per dose delivered, (range 13% to 32% across countries), and the largest 20% of sites in each country realized costs per dose that were on average 61% lower than those for the smallest 20% of sites, controlling for other factors. Other factors associated with higher costs included hospital status, provision of outreach services, share of effort to management, level of staff training/seniority, distance to vaccine collection, additional days open per week, greater vaccination schedule completion, and per capita gross domestic product.Conclusions: We identified multiple features of sites and their operating environment that were associated with differences in average unit costs, with service volume being the most influential. These findings can inform efforts to improve the efficiency of service delivery and better understand resource needs. [ABSTRACT FROM AUTHOR]