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Introduction: Falls are a global public health problem and the second leading cause of death from unintentional injury. Globally, approximately 30%-50% of people living in nursing or residential care homes fall each year. Falls have an impact on quality of life and morbidity. Prevention of falls is gold standard care. When falls do occur, implementation of safe strategies to help the person rise is required. Structured risk assessment and the use of a 'lifting' cushion are one such strategy., Aims: To evaluate the impact of the lifting cushion on management of falls and assess barriers and facilitators to staff use of the lifting cushion in 18 care homes., Methods: Two-phase study involving (i) capturing quantitative pre- and post-cushion implementation data along with comparison of means testing and (ii) theoretically underpinned qualitative semi-structured interviews to explore barriers and facilitators to cushion implementation with inductive and deductive data analysis., Results: The cushion was used a total of 32 times out of 567 post-implementation recorded falls (6% of all falls). Barriers and facilitators to cushion use aligned to the Theoretical Domains Framework include knowledge, skills and confidence, emotion, beliefs about safety and decision processes, environmental context and resources and social influences., Conclusion: The lifting cushion was poorly adopted. Identified barriers to adoption would not be addressed using routine train and cascade processes. We identified facilitators that could be enhanced to promote uptake. Theoretically underpinned implementation strategies, tailored to assess determinants, are known to be more effective; however, this approach has rarely been used in care homes. We have demonstrated a structured approach to implementation of cushion use; this may be transferable to other care home practices., Implications for Practice: Cae home leaders should be aware that giving information alone will not change practice. Implementation or improvement strategies will be more effective., (© 2024 The Author(s). International Journal of Older People Nursing published by John Wiley & Sons Ltd.)

Wearable sensors for psychophysiological monitoring are becoming increasingly mainstream in safety critical contexts. They offer a novel solution to capturing sub-optimal states and can help identify when workers in safety critical environments are suffering from states such as fatigue and stress. However, sensors can differ widely in their application, design, usability, and measurement and there is a lack of guidance on what should be prioritized or considered when selecting a sensor. The paper aims to highlight which concepts are important when creating or selecting a device regarding the optimization of both measurement and usability. Additionally, the paper discusses how design choices can enhance both the usability and measurement capabilities of wearable sensors. The hopes are that this paper will provide researchers and practitioners in human factors and related fields with a framework to help guide them in building and selecting wearable sensors that are well suited for deployment in safety critical contexts.

Measuring pilot mental workload (MWL) is crucial for enhancing aviation safety. However, MWL is a multi-dimensional construct that could be affected by multiple factors. Particularly, in the context of a more automated cockpit setting, the traditional methods of assessing pilot MWL may face challenges. Heart rate variability (HRV) has emerged as a potential tool for detecting pilot MWL during real-flight operations. This review aims to investigate the relationship between HRV and pilot MWL and to assess the performance of machine-learning-based MWL detection systems using HRV parameters. A total of 29 relevant papers were extracted from three databases for review based on rigorous eligibility criteria. We observed significant variability across the reviewed studies, including study designs and measurement methods, as well as machine-learning techniques. Inconsistent results were observed regarding the differences in HRV measures between pilots under varying levels of MWL. Furthermore, for studies that developed HRV-based MWL detection systems, we examined the diverse model settings and discovered that several advanced techniques could be used to address specific challenges. This review serves as a practical guide for researchers and practitioners who are interested in employing HRV indicators for evaluating MWL and wish to incorporate cutting-edge techniques into their MWL measurement approaches.

Objective: This study proposed a moving average (MA) approach to dynamically process heart rate variability (HRV) and developed aberrant driving behavior (ADB) prediction models by using long short-term memory (LSTM) networks., Background: Fatigue-associated ADBs have traffic safety implications. Numerous models to predict such acts based on physiological responses have been developed but are still in embryonic stages., Method: This study recorded the data of 20 commercial bus drivers during their routine tasks on four consecutive days and subsequently asked them to complete questionnaires, including subjective sleep quality, driver behavior questionnaire and the Karolinska Sleepiness Scale. Driving behaviors and corresponding HRV were determined using a navigational mobile application and a wristwatch. The dynamic-weighted MA (DWMA) and exponential-weighted MA were used to process HRV in 5-min intervals. The data were independently separated for training and testing. Models were trained with 10-fold cross-validation strategy, their accuracies were evaluated, and Shapley additive explanation (SHAP) values were used to determine feature importance., Results: Significant increases in the standard deviation of NN intervals (SDNN), root mean square of successive heartbeat interval differences (RMSSD), and normalized spectrum of high frequency (nHF) were observed in the pre-event stage. The DWMA-based model exhibited the highest accuracy for both driver types (urban: 84.41%; highway: 80.56%). The SDNN, RMSSD, and nHF demonstrated relatively high SHAP values., Conclusion: HRV metrics can serve as indicators of mental fatigue. DWMA-based LSTM could predict the occurrence of the level of fatigue associated with ADBs., Application: The established models can be used in realistic driving scenarios.

There is a lack of a clear and consistent definition of human-centricity in Industry 5.0. This study identified the definition of human-centricity in Industry 5.0 through a systematic literature review and used it to assess the readiness of Ergonomics/Human Factors communities in the UK. The assessment of the communities readiness was conducted by reviewing UK accredited courses and events of three professional bodies; and interviewing practitioners (n = 8). Eleven themes were identified as elements of human-centricity from the thematic analysis of 30 publications. Gaps that had to be addressed to better equip UK practitioners to support the realisation of human-centricity in Industry 5.0 were also identified.

Our mental representation of the passage of time is structured by concepts of spatial motion, including an ego-moving perspective in which the self is perceived as approaching future events and a time-moving perspective in which future events are perceived as approaching the self. While previous research has found that processing spatial information in one's environment can preferentially activate either an ego-moving or time-moving temporal perspective, potential downstream impacts on everyday decision-making have received less empirical attention. Based on the idea people may feel closer to positive events they see themselves as actively approaching rather than passively waiting for, in this pre-registered study we tested the hypothesis that spatial primes corresponding to an ego-moving (vs. time-moving) perspective would attenuate temporal discounting by making future rewards feel more proximal. 599 participants were randomly assigned to one of three spatial prime conditions (ego-moving, time-moving, control) resembling map-based tasks people may engage with on digital devices, before completing measures of temporal perspective, perceived wait time, perceived control over time, and temporal discounting. Partly consistent with previous research, the results indicated that the time-moving prime successfully activated the intended temporal perspective-though the ego-moving prime did not. Contrary to our primary hypotheses, the spatial primes had no effect on either perceived wait time or temporal discounting. Processing spatial information in a map-based task therefore appears to influence how people conceptualise the passage of time, but there was no evidence for downstream effects on intertemporal preferences. Additionally, exploratory analysis indicated that greater perceived control over time was associated with lower temporal discounting, mediated by a reduction in perceived wait time, suggesting a possible area for future research into individual differences and interventions in intertemporal decision-making., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Fletcher et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background Sydney Sexual Health Centre (SSHC) is the largest sexual health clinic in New South Wales (NSW), servicing clients at high risk of sexually transmissible infections and bloodborne viruses. SSHC piloted a direct-to-pathology pathway that facilitated bloodborne virus/sexually transmissible infection testing at one of the ~500 participating pathology collection centres located across NSW. This qualitative study sought to understand SSHC client and provider perspectives of acceptability of the MyCheck intervention. Methods Semi-structured in-depth interviews were conducted with 11 clients who underwent testing via the MyCheck pathway and eight staff members involved in implementing MyCheck. The seven components of Sekhon's Theoretical Framework of Acceptability informed this analysis. Results Participants broadly conveyed 'affective attitude' toward the MyCheck pathway. The telehealth intervention reduced client 'burden' and 'opportunity cost' through enabling greater testing convenience at a location suitable to them and provided timely results. Issues of 'ethicality' were raised by clients and staff as pathology centre staff were, on a few occasions, regarded as being judgmental of SSHC clients. 'Intervention coherence' issues were largely attributed to pathology centre personnel being unfamiliar with the intervention, with billing issues being a recurrent concern. Participants perceived MyCheck as an 'effective' testing pathway. SSHC staff were able to offer the intervention with ease through seamless IT integration ('self-efficacy'). Conclusion The MyCheck intervention was perceived by both SSHC clients and staff as an acceptable bloodborne virus/sexually transmissible infection testing pathway. However, further work is required to address stigma experienced by some clients when attending pathology collection centres.

Background: The timely provision of test results to facilitate early access to treatment is an essential component of sexually transmissible infection (STI) control and contributes to a significant proportion of the workload at sexual health services. We aimed to estimate the time to deliver client results and treatment as well as the health system costs of the nurse-led urgent results management model at the Sydney Sexual Health Centre (SSHC) compared to an alternative 'ordering clinician' model., Methods: We conducted a retrospective analysis of urgent results managed by the results nurse over 2weeks in 2019 and an observational study over 2weeks in 2021, where 10 clinicians managed five of their own urgent results. Additional activity data were gathered to determine the annual health system costs for both models., Results: In the nurse-led model 211 of 280 clients required notification; 156 (73.9%) were notified on the day their results became available, and the median time to treatment (n =137) was 1day. The annual health system cost for the nurse-led model was A$3922143. In the ordering clinician model, 17 (42.5%) clients were notified on the same day, and of the 27 clients treated at SSHC, the median time to treatment increased to 4days. The annual health system cost for the ordering clinician model was A$4043667.28 compared with the nurse-led model, and an additional 33.3h per week of clinician time was required for the same level of service provision., Conclusions: This study highlights the strengths of the nurse-led results model at SSHC, demonstrating improved client outcomes for STI notification and treatment times and health systems savings.

Objectives. Current approaches via physiological features detecting aberrant driving behaviour (ADB), including speeding, abrupt steering, hard braking and aggressive acceleration, are developing. This study proposes using machine learning approaches incorporating heart rate variability (HRV) parameters to predict ADB occurrence. Methods . Naturalistic driving data of 10 highway bus drivers in Taiwan from their daily routes were collected for 4 consecutive days. Their driving behaviours and physiological data during a driving task were determined using a navigation mobile application and heart rate watch. Participants' self-reported data on sleep, driving-related experience, open-source data on weather and the traffic congestion level were obtained. Five machine learning models - logistic regression, random forest, naive Bayes, support vector machine and gated recurrent unit (GRU) - were employed to predict ADBs. Results . Most drivers with ADB had low sleep efficiency (≤80%), with significantly higher scores in driver behaviour questionnaire subcategories of lapses and errors and in the Karolinska sleepiness scale than those without ADBs. Moreover, HRV parameters were significantly different between baseline and pre-ADB event measurements. GRU had the highest accuracy (81.16-84.22%). Conclusions . Sleep deficit may be related to the increased fatigue level and ADB occurrence predicted from HRV-based models among bus drivers.

Background: Huntington's disease (HD) is a rare, neurodegenerative disease and its complex motor, cognitive and psychiatric symptoms exert a lifelong clinical burden on both patients and their families., Objective: To describe the clinical burden and natural history of HD., Methods: This longitudinal cohort study used data from the linked Swedish national registries to describe the occurrence of comorbidities (acute and chronic), symptomatic treatments and mortality in an incident cohort of individuals who either received the first diagnosis of HD above (adult onset HD; AoHD) or below (juvenile-onset HD; JoHD) 20 years of age, compared with a matched cohort without HD from the general population. Disease burden of all individuals alive in Sweden was described during a single calendar year (2018), including the occurrence of key symptoms, treatments and hospitalizations., Results: The prevalence of HD in 2018 was approximately 10.2 per 100,000. Of 1492 individuals with a diagnosis of HD during 2002 and 2018, 1447 had AoHD and 45 had JoHD. Individuals with AoHD suffered a higher incidence of obsessive-compulsive disorder, acute psychotic episodes, pneumonia, constipation and fractures compared with matched controls. Individuals with JoHD had higher incidence rates of epilepsy, constipation and acute respiratory symptoms. Median time to all-cause mortality in AoHD was 12.1 years from diagnosis. Patients alive with HD in Sweden in 2018 displayed a pattern of increased clinical burden for a number of years since diagnosis., Conclusions: This study demonstrates the significant and progressive clinical burden in individuals with HD and presents novel insights into the natural history of JoHD., (© 2022. The Author(s).)

(a) Objective: Obstructive sleep apnea syndrome (OSAS) is typically diagnosed through polysomnography (PSG). However, PSG incurs high medical costs. This study developed new models for screening the risk of moderate-to-severe OSAS (apnea-hypopnea index, AHI ≥15) and severe OSAS (AHI ≥30) in various age groups and sexes by using anthropometric features in the Taiwan population.(b) Participants: Data were derived from 10,391 northern Taiwan patients who underwent PSG.(c) Methods: Patients' characteristics - namely age, sex, body mass index (BMI), neck circumference, and waist circumference - was obtained. To develop an age- and sex-independent model, various approaches - namely logistic regression, k-nearest neighbor, naive Bayes, random forest (RF), and support vector machine - were trained for four groups based on sex and age (men or women; aged <50 or ≥50 years). Dataset was separated independently (training:70%; validation: 10%; testing: 20%) and Cross-validated grid search was applied for model optimization. Models demonstrating the highest overall accuracy in validation outcomes for the four groups were used to predict the testing dataset.(d) Results: The RF models showed the highest overall accuracy. BMI was the most influential parameter in both types of OSAS severity screening models.(e) Conclusion: The established models can be applied to screen OSAS risk in the Taiwan population and those with similar craniofacial features.

Background: Patient and public involvement and engagement (PPIE) with cardiac arrest survivors is an essential component of research to strengthen development, design, delivery and dissemination to ensure research priorities are in the public interest and patient friendly. Cardiac arrest survivors and their relatives were engaged in PPIE to help develop the methods of a research study that aims to reduce individual and care process variation during paramedic-led resuscitation., Methods: This research methodology paper represents the views of seven PPIE representatives and the authors. PPIE representatives included five cardiac arrest survivors and two relatives. Content for the paper was generated by discussion using audio or video call. Notes were taken by the author which included direct quotations generated by the PPIE process., Results: The PPIE representatives considered research surrounding the decisions made by paramedics to be important. From their first-hand experiences, survivors and their relatives felt that a future research study should focus on patient survival. The decision-making of paramedics was identified as most important to explore. Quality of life before the cardiac arrest was considered important as this may help to inform best-interest decisions. The neurologic recovery of patients was important; however, rehabilitation may be extensive and therefore unachievable within the study timeframe. Relatives highlighted that while incorporating their views during resuscitation was important, gaining consent for research participation was not appropriate., Conclusion: PPIE added value and helped to develop a future study to reduce variation in the resuscitation decisions made by paramedics. The group identified what is important to survivors and their relatives and the factors they would like paramedics to consider when making a resuscitation decision. By identifying these factors, the PPIE process has helped to drive the research methods where both quantitative and qualitative designs would be appropriate. Issues in gaining research consent during resuscitation were highlighted., (© 2022 The Author(s).)

Purpose: Obstructive sleep apnea syndrome (OSAS) has mostly been examined using in-laboratory polysomnography (Lab-PSG), which may overestimate severity. This study compared sleep parameters in different environments and investigated the association between the plasma levels of neurochemical biomarkers and sleep parameters., Methods: Thirty Taiwanese participants underwent Lab-PSG while wearing a single-lead electrocardiogram patch. Participants' blood samples were obtained in the morning immediately after the recording. Participants wore the patch for the subsequent three nights at home. Sleep disorder indices were calculated, including the apnea-hypopnea index (AHI), chest effort index, and cyclic variation of heart rate index (CVHRI). The 23 eligible participants' derived data were divided into the normal-to-moderate (N-M) group and the severe group according to American Association of Sleep Medicine (AASM) guidelines (Lab-PSG) and the recommendations of a previous study (Rooti Rx). Spearman's correlation was used to examine the correlations between sleep parameters and neurochemical biomarker levels., Results: The mean T-Tau protein level was positively correlated with the home-based CVHRI (r = 0.53, p < 0.05), whereas no significant correlation was noted between hospital-based CVHRI and the mean T-tau protein level (r = 0.25, p = 0.25). The home-based data revealed that the mean T-Tau protein level in the severe group was significantly higher than that in the N-M group (severe group: 24.75 ± 6.16 pg/mL, N-M group: 19.65 ± 3.90 pg/mL; p < 0.05). Furthermore, the mean in-hospital CVHRI was higher than the mean at-home values (12.16 ± 13.66 events/h)., Conclusion: Severe OSAS patients classified by home-based CVHRI demonstrated the higher T-Tau protein level, and CVHRI varied in different sleep environments., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Previous studies have described reverse-transcription loop-mediated isothermal amplification (RT-LAMP) for the rapid detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in nasopharyngeal/oropharyngeal swab and saliva samples. This multisite clinical evaluation describes the validation of an improved sample preparation method for extraction-free RT-LAMP and reports clinical performance of four RT-LAMP assay formats for SARS-CoV-2 detection. Direct RT-LAMP was performed on 559 swabs and 86,760 saliva samples and RNA RT-LAMP on extracted RNA from 12,619 swabs and 12,521 saliva samples from asymptomatic and symptomatic individuals across health care and community settings. For direct RT-LAMP, overall diagnostic sensitivity (DSe) was 70.35% (95% CI, 63.48%-76.60%) on swabs and 84.62% (95% CI, 79.50%-88.88%) on saliva, with diagnostic specificity of 100% (95% CI, 98.98%-100.00%) on swabs and 100% (95% CI, 99.72%-100.00%) on saliva, compared with quantitative RT-PCR (RT-qPCR); analyzing samples with RT-qPCR ORF1ab C T values of ≤25 and ≤33, DSe values were 100% (95% CI, 96.34%-100%) and 77.78% (95% CI, 70.99%-83.62%) for swabs, and 99.01% (95% CI, 94.61%-99.97%) and 87.61% (95% CI, 82.69%-91.54%) for saliva, respectively. For RNA RT-LAMP, overall DSe and diagnostic specificity were 96.06% (95% CI, 92.88%-98.12%) and 99.99% (95% CI, 99.95%-100%) for swabs, and 80.65% (95% CI, 73.54%-86.54%) and 99.99% (95% CI, 99.95%-100%) for saliva, respectively. These findings demonstrate that RT-LAMP is applicable to a variety of use cases, including frequent, interval-based direct RT-LAMP of saliva from asymptomatic individuals who may otherwise be missed using symptomatic testing alone., (Copyright © 2022 Association for Molecular Pathology and American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

The development of divinylpyrimidine (DVP) reagents for the synthesis of antibody-drug conjugates (ADCs) with in vivo efficacy and tolerability is reported. Detailed structural characterisation of the synthesised ADCs was first conducted followed by in vitro and in vivo evaluation of the ADCs' ability to safely and selectively eradicate target-positive tumours.

Background: Duodenal mucosal resurfacing (DMR) is a novel day-case endoscopic intervention which results in weight loss-independent reductions in HbA1c in patient with type 2 diabetes mellitus (T2DM). We hypothesized that DMR works by increasing insulin sensitivity and we aimed to investigate the mechanism of action of DMR through longitudinal metabolic phenotyping in humans., Methods: Thirty-two insulin-resistant women with polycystic ovary syndrome (PCOS) and obesity were randomised in a double-blinded manner to DMR or sham endoscopy. They underwent measurements of insulin sensitivity using euglycaemic hyperinsulinaemic clamps, insulin secretion using oral glucose tolerance tests and reproductive function using weekly reproductive hormone profiles and ovarian ultrasonography for 6 months post-intervention., Results: A small increase in total body insulin sensitivity measured by the clamp was observed in both groups at week 12. An increase in insulin sensitivity, as measured by HOMA-IR, was observed in both groups at week 24. There was an increase in the number of menses (median 2 DMR, 0.5 sham). There were no significant differences between the two groups in these outcomes or insulin secretion., Conclusions: These findings suggest that DMR does not work by increasing insulin sensitivity in euglycaemic, insulin resistant women with PCOS. The procedure may exert its effects only in the context of hyperglycaemia or pathologically hyperplastic, insulin-desensitised duodenal mucosa., Competing Interests: Declaration of competing interest DSB is a proctor for Apollo Endosurgery and has received funding from Fractyl to attend educational meetings. VK has received funding from Fractyl to attend educational meetings. All other authors do not report any relevant conflicts of interest., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: A low procalcitonin (PCT) concentration facilitates exclusion of bacterial co-infections in COVID-19, but high costs associated with PCT measurements preclude universal adoption. Changes in inflammatory markers, including C-reactive protein (CRP), can be concordant, and predicting low PCT concentrations may avoid costs of redundant tests and support more cost-effective deployment of this diagnostic biomarker., Objectives: To explore whether, in COVID-19, low PCT values could be predicted by the presence of low CRP concentrations., Methods: Unselected cohort of 224 COVID-19 patients admitted to hospital that underwent daily PCT and CRP measurements as standard care. Both 0.25 ng/mL and 0.5 ng/mL were used as cut-offs for positive PCT test results. Geometric mean was used to define high and low CRP values at each timepoint assessed., Results: Admission PCT was <0.25 ng/mL in 160/224 (71.4%), 0.25-0.5 ng/mL in 27 (12.0%) and >0.5 ng/mL in 37 (16.5%). Elevated PCT was associated with increased risk of death ( P =  0.0004) and was more commonly associated with microbiological evidence of bacterial co-infection ( P <  0.0001). For high CRP values, significant heterogeneity in PCT measurements was observed, with maximal positive predictive value of 50% even for a PCT cut-off of 0.25 ng/mL. In contrast, low CRP was strongly predictive of low PCT concentrations, particularly <0.5 ng/mL, with a negative predictive value of 97.6% at time of hospital admission and 100% 48 hours into hospital stay., Conclusions: CRP-guided PCT testing algorithms can reduce unnecessary PCT measurement and costs, supporting antimicrobial stewardship strategies in COVID-19., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy.)

The COVID-19 pandemic has had a significant impact on surgical specialties. COVID-19 carries a significant risk to the surgical patient and the healthcare workers looking after them, with an increased incidence of pulmonary complications and mortality in patients who test positive perioperatively. Appropriate infection prevention and control measures are critical to ensure appropriate care is given and to reduce the risk of onward transmission. This article will discuss the measures that have been instigated and contributed to infection control in surgery, such as testing, patient isolation, personal protective equipment and ventilation. The COVID-19 pandemic has led to healthcare workers across many specialities working together to provide essential clinical care. This collaborative approach is critical to maintain excellent infection prevention and control practices required during this pandemic, which protect patients and preserve surgical services., (© 2021 Published by Elsevier Ltd.)

Background: Trajectories of comorbidities among individuals at risk of Alzheimer's disease (AD) may differ from those aging without AD clinical syndrome. Therefore, characterizing the comorbidity burden and pattern associated with AD risk may facilitate earlier detection, enable timely intervention, and help slow the rate of cognitive and functional decline in AD. This case-control study was performed to compare the prevalence of comorbidities between AD cases and controls during the 5 years prior to diagnosis (or index date for controls); and to identify comorbidities with a differential time-dependent prevalence trajectory during the 5 years prior to AD diagnosis. Methods: Incident AD cases and individually matched controls were identified in a United States claims database between January 1, 2000 and December 31, 2016. AD status and comorbidities were defined based on the presence of diagnosis codes in administrative claims records. Generalized estimating equations were used to assess evidence of changes over time and between AD and controls. A principal component analysis and hierarchical clustering was performed to identify groups of AD-related comorbidities with respect to prevalence changes over time (or trajectory), and differences between AD and controls. Results: Data from 186,064 individuals in the IBM MarketScan Commercial Claims and Medicare Supplementary databases were analyzed (93,032 AD cases and 93,032 non-AD controls). In total, there were 177 comorbidities with a ≥ 5% prevalence. Five main clusters of comorbidities were identified. Clusters differed between AD cases and controls in the overall magnitude of association with AD, in their diverging time trajectories, and in comorbidity prevalence. Three clusters contained comorbidities that notably increased in frequency over time in AD cases but not in controls during the 5-year period before AD diagnosis. Comorbidities in these clusters were related to the early signs and/or symptoms of AD, psychiatric and mood disorders, cerebrovascular disease, history of hazard and injuries, and metabolic, cardiovascular, and respiratory complaints. Conclusion: We demonstrated a greater comorbidity burden among those who later developed AD vs. controls, and identified comorbidity clusters that could distinguish these two groups. Further investigation of comorbidity burden is warranted to facilitate early detection of individuals at risk of developing AD., Competing Interests: LB, RH, and GD-P were full-time employees of F. Hoffmann-La Roche Ltd., AA was a full-time employee of Genesis Research and received funding from F Hoffmann-La Roche Ltd., for work on this study. MV currently consults for Roche, receives research funding from NIH/NIA, and has equity ownership in Abbott Laboratories, Johnson and Johnson, Medtronic, and Amgen. The funders were not involved in the study design, collection, analysis, interpretation of data, the writing of this article or the decision to submit it for publication., (Copyright © 2021 Butler, Houghton, Abraham, Vassilaki and Durán-Pacheco.)

Aim: To investigate how distributed leadership via the Shared Governance programme influences employee engagement, empowerment, job satisfaction and turnover intentions among direct care nursing staff in a large UK hospital., Background: Increasing turnover rates and shortages of health care staff in the UK has called for interventions to improve employee engagement and job satisfaction., Methods: 116 direct care nursing staff were sampled in a mixed-methods explanatory sequential design. A maximum variance sample of 15 participants were subsequently interviewed to gain a deeper understanding of the motivations and attitudes that influenced employee outcomes through distributed leadership., Results: Higher levels of distributed leadership predicted increased employee engagement and job satisfaction, and lower turnover intentions. Staff also felt more empowered and committed to the organisation despite some challenges experienced in implementing the Shared Governance programme., Conclusion: Distributed leadership was found to be beneficial in promoting employee engagement and empowerment, increasing job satisfaction and organisational commitment and reducing turnover intention in the UK health care setting., Implications for Nursing Management: By encouraging the practice of distributed leadership at work, health care staff can become more engaged and empowered, leading to higher rates of job retention, job satisfaction and organisational commitment., (© 2021 The Authors. Journal of Nursing Management published by John Wiley & Sons Ltd.)

Risperidone and aripiprazole, commonly used antipsychotics in children with autism spectrum disorder (ASD), have previously been associated with elevated fracture risk in other populations. The aim of this study was to evaluate and compare the risk of fracture among children with ASD using risperidone or aripiprazole. This was a retrospective, propensity-score matched cohort study, set between January 2013 and December 2018. We used the MarketScan Medicaid insurance data, which covers multiple states of the United States. We included ASD children aged 2-18 years, who were new users of aripiprazole or risperidone and with no prior history of antipsychotic use or fractures. The main exposure was the continued use of aripiprazole or risperidone. The incidence rates of any fracture during follow-up were evaluated, and the risk between aripiprazole and risperidone was compared via Cox-proportional hazard models. Results were stratified by age, sex, duration of exposure and fracture site. In total, 3312 patients (78% male; mean [SD] age 11.0 [3.7] years) were identified for each cohort. Over the full duration of follow-up, fracture incidence rates per 1000 patient-years were 23.2 for risperidone and 38.4 for aripiprazole (hazard ratio and 95% confidence interval: 0.60 [0.44-0.83]). Risks were similar between cohorts throughout the first 180 days on treatment, but significantly higher in the aripiprazole group thereafter. Extremity fractures drove most of the increased risk, with the biggest differences in lower leg and ankle fractures. Differences widened for children aged 10 years or younger (HR [95% CI]: 0.47 [0.30-0.74]). In conclusion, compared to aripiprazole, risperidone was associated with 40% lower risk of fracture. Further analysis on the mechanism and long-term bone health of antipsychotic-treated children with ASD is warranted. LAY SUMMARY: We compared the risk of bone fractures among 6624 children with autism spectrum disorder (ASD), half of whom used risperidone and half of whom used aripiprazole. Taking other factors into account, risks were similar between the two groups throughout the first 180 days on treatment, but significantly higher in the aripiprazole group thereafter. The biggest differences were in lower leg and ankle fractures. Overall, compared with aripiprazole, risperidone was associated with 40% lower risk of fracture., (© 2021 The Authors Autism Research © 2021 International Society for Autism Research and Wiley Periodicals LLC.)

Huntington's disease (HD) is characterised by a triad of cognitive, behavioural, and motor symptoms which lead to functional decline and loss of independence. With potential disease-modifying therapies in development, there is interest in accurately measuring HD progression and characterising prognostic variables to improve efficiency of clinical trials. Using the large, prospective Enroll-HD cohort, we investigated the relative contribution and ranking of potential prognostic variables in patients with manifest HD. A random forest regression model was trained to predict change of clinical outcomes based on the variables, which were ranked based on their contribution to the prediction. The highest-ranked variables included novel predictors of progression-being accompanied at clinical visit, cognitive impairment, age at diagnosis and tetrabenazine or antipsychotics use-in addition to established predictors, cytosine adenine guanine (CAG) repeat length and CAG-age product. The novel prognostic variables improved the ability of the model to predict clinical outcomes and may be candidates for statistical control in HD clinical studies., Competing Interests: NG, RH, SS, and GP are employees of F. Hoffmann-La Roche Ltd. JL is a paid Advisory Board member for F. Hoffmann-La Roche Ltd and uniQure biopharma B.V, and a paid consultant for Vaccinex Inc, Wave Life Sciences USA Inc, Genentech Inc and Triplet Inc. The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The authors declare that this study received funding from F. Hoffmann-La Roche Ltd. The funder was involved in the study design, analysis, interpretation of data and the decision to submit it for publication., (Copyright © 2021 Ghazaleh, Houghton, Palermo, Schobel, Wijeratne and Long.)

We describe the optimisation of a simplified sample preparation method which permits rapid and direct detection of SARS-CoV-2 RNA within saliva, using reverse-transcription loop-mediated isothermal amplification (RT-LAMP). Treatment of saliva samples prior to RT-LAMP by dilution 1:1 in Mucolyse™, followed by dilution in 10 % (w/v) Chelex© 100 Resin and a 98 °C heat step for 2 min enabled detection of SARS-CoV-2 RNA in positive saliva samples. Using RT-LAMP, SARS-CoV-2 RNA was detected in as little as 05:43 min, with no amplification detected in 3097 real-time reverse transcription PCR (rRT-PCR) negative saliva samples from staff tested within a service evaluation study, or for other respiratory pathogens tested (n = 22). Saliva samples can be collected non-invasively, without the need for skilled staff and can be obtained from both healthcare and home settings. Critically, this approach overcomes the requirement for, and validation of, different swabs and the global bottleneck in obtaining access to extraction robots and reagents to enable molecular testing by rRT-PCR. Such testing opens the possibility of public health approaches for effective intervention during the COVID-19 pandemic through regular SARS-CoV-2 testing at a population scale, combined with isolation and contact tracing., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Introduction: Understanding the epidemiology of Huntington's disease (HD) is key to assessing disease burden and the healthcare resources required to meet patients' needs. We aimed to develop and validate a model to estimate the diagnosed prevalence of manifest HD by the Shoulson-Fahn stage., Methods: A literature review identified epidemiological data from Brazil, Canada, France, Germany, Italy, Spain, the UK, and the USA. Data on staging distribution at diagnosis, progression, and mortality were derived from Enroll-HD. Newly diagnosed patients with manifest HD were simulated by applying annual diagnosed incidence rates to the total population in each country, each year from 1950 onwards. The number of diagnosed prevalent patients from the previous year who remained in each stage was estimated in line with the probability of death or progression. Diagnosed prevalence in 2020 was estimated as the sum of simulated patients, from all the incident cohorts, still alive., Results: The model estimates that in 2020, there were 66,787 individuals diagnosed with HD in the 8 included countries, of whom 62-63% were in Shoulson-Fahn stages 1 and 2 (with less severely limited functional capacity than those in stages 3-5). Diagnosed prevalence is estimated to be 8.2-9.0 per 100,000 in the USA, Canada, and the 5 included European countries and 3.5 per 100,000 in Brazil., Conclusion: The modeled estimates generally accord with the previously published data. This analysis contributes to better understanding of the epidemiology of HD and highlights areas of uncertainty., (© 2021 The Author(s) Published by S. Karger AG, Basel.)

The COVID-19 pandemic has illustrated the importance of simple, rapid and accurate diagnostic testing. This study describes the validation of a new rapid SARS-CoV-2 RT-LAMP assay for use on extracted RNA or directly from swab offering an alternative diagnostic pathway that does not rely on traditional reagents that are often in short supply during a pandemic. Analytical specificity (ASp) of this new RT-LAMP assay was 100% and analytical sensitivity (ASe) was between 1 × 10 1 and 1 × 10 2 copies per reaction when using a synthetic DNA target. The overall diagnostic sensitivity (DSe) and specificity (DSp) of RNA RT-LAMP was 97% and 99% respectively, relative to the standard of care rRT-PCR. When a C T cut-off of 33 was employed, above which increasingly evidence suggests there is a low risk of patients shedding infectious virus, the diagnostic sensitivity was 100%. The DSe and DSp of Direct RT-LAMP (that does not require RNA extraction) was 67% and 97%, respectively. When setting C T cut-offs of ≤33 and ≤25, the DSe increased to 75% and 100%, respectively, time from swab-to-result, C T < 25, was < 15 min. We propose that RNA RT-LAMP could replace rRT-PCR where there is a need for increased sample throughput and Direct RT-LAMP as a near-patient screening tool to rapidly identify highly contagious individuals within emergency departments and care homes during times of increased disease prevalence ensuring negative results still get laboratory confirmation., (Crown Copyright © 2020. Published by Elsevier Ltd. All rights reserved.)

The longitudinal dynamics of the most promising biofluid biomarker candidates for Huntington's disease (HD)-mutant huntingtin (mHTT) and neurofilament light (NfL)-are incompletely defined. Characterizing changes in these candidates during disease progression could increase our understanding of disease pathophysiology and help the identification of effective therapies. In an 80-participant cohort over 24 months, mHTT in cerebrospinal fluid (CSF), as well as NfL in CSF and blood, had distinct longitudinal trajectories in HD mutation carriers compared with controls. Baseline analyte values predicted clinical disease status, subsequent clinical progression, and brain atrophy, better than did the rate of change in analytes. Overall, NfL was a stronger monitoring and prognostic biomarker for HD than mHTT. Nonetheless, mHTT has prognostic value and might be a valuable pharmacodynamic marker for huntingtin-lowering trials., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Pre-clinical models have shown that targeting pancreatic stellate cells with all-trans-retinoic-acid (ATRA) reprograms pancreatic stroma to suppress pancreatic ductal adenocarcinoma (PDAC) growth. Here, in a phase Ib, dose escalation and expansion, trial for patients with advanced, unresectable PDAC (n = 27), ATRA is re-purposed as a stromal-targeting agent in combination with gemcitabine-nab-paclitaxel chemotherapy using a two-step adaptive continual re-assessment method trial design. The maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D, primary outcome) is the FDA/EMEA approved dose of gemcitabine-nab-paclitaxel along-with ATRA (45 mg/m 2 orally, days 1-15/cycle). Dose limiting toxicity (DLT) is grade 4 thrombocytopenia (n = 2). Secondary outcomes show no detriment to ATRA pharmacokinetics.. Median overall survival for RP2D treated evaluable population, is 11.7 months (95%CI 8.6-15.7 m, n = 15, locally advanced (2) and metastatic (13)). Exploratory pharmacodynamics studies including changes in diffusion-weighted (DW)-MRI measured apparent diffusion coefficient after one cycle, and, modulation of cycle-specific serum pentraxin 3 levels over various cycles indicate stromal modulation. Baseline stromal-specific retinoid transport protein (FABP5, CRABP2) expression may be predicitve of response. Re-purposing ATRA as a stromal-targeting agent with gemcitabine-nab-paclitaxel is safe and tolerable. This combination will be evaluated in a phase II randomized controlled trial for locally advanced PDAC. Clinical trial numbers: EudraCT: 2015-002662-23; NCT03307148. Trial acronym: STARPAC.

In New South Wales (NSW), Australia, innovative community-based testing models have been implemented to increase HIV testing among populations at risk. The characteristics of patients newly diagnosed with HIV at a community-based testing site and at a traditional clinical service in Sydney, NSW, were compared. Compared with the clinical service, clients diagnosed at the community-based site were more likely to be diagnosed at their first visit and report no prior HIV test. A high proportion of clients at both sites had a preferred language other than English. Innovative HIV testing models are reaching under-tested populations, but could be further improved.

Purpose: Inherited pathogenic variants in genes encoding the metabolic enzymes succinate dehydrogenase (SDH) and fumarate hydratase predispose to tumor development through accumulation of oncometabolites (succinate and fumarate, respectively; ref. 1). Noninvasive in vivo detection of tumor succinate by proton magnetic resonance spectroscopy ( 1 H-MRS) has been reported in SDH-deficient tumors, but the potential utility of this approach in the management of patients with hereditary leiomyomatosis and renal cell cancer syndrome or Reed syndrome is unknown., Experimental Design: Magnetic resonance spectroscopy ( 1 H-MRS) was performed on three cases and correlated with germline genetic results and tumor IHC when available., Results: Here, we have demonstrated a proof of principle that 1 H-MRS can provide a noninvasive diagnosis of hereditary leiomyomatosis and renal cell cancer syndrome or Reed syndrome through detection of fumarate accumulation in vivo ., Conclusions: This study demonstrates that in vivo detection of fumarate could be employed as a functional biomarker., (©2019 American Association for Cancer Research.)

Background: Psychostimulants and atomoxetine have been shown to increase blood pressure, heart rate, and QT interval in children and adolescents; however, based on current literature, it is unclear if these "attention-deficit/hyperactivity disorder (ADHD) medications" are also associated with serious cardiovascular (SCV) events. We addressed this question in commonly exposed groups of children and adolescents with either ADHD or autism spectrum disorder (ASD)., Methods: Using commercial (years 2000-2016) and Medicaid (years 2012-2016) administrative claims data from the United States (US), we conducted two case-control studies, nested within respective cohorts of ADHD and ASD children aged 3-18 years. We defined cases by a composite outcome of stroke, myocardial infarction, or serious cardiac arrhythmia. For each case, we matched ten controls on age, sex, and insurance type. We conducted conditional logistic regression models to test associations between SCV outcomes and a primary exposure definition of current ADHD medication use. Additionally, we controlled for resource use, cardiovascular and psychiatric comorbidities, and use of medications in a variety of sensitivity analyses., Results: We identified 2,240,774 children for the ADHD cohort and 326,221 children for the ASD cohort. For ADHD, 33.9% of cases (63 of 186) versus 32.2% of controls (598 of 1860) were exposed, which yielded an odds ratio (OR) and 95% confidence interval (CI) of 1.08 (0.78-1.49). For ASD, 12.5% of cases (6 of 48) versus 22.1% of controls (106 of 480) were exposed [OR 0.49 (0.20-1.20)]. Covariate-adjusted results and results for individual outcomes and other exposure definitions were consistent with no increased risk of SCV events., Conclusion: Using large US claims data, we found no evidence of increased SCV risk in children and adolescents with ADHD or ASD exposed to ADHD medications.

The Autism impact measure (AIM) is a caregiver-reported questionnaire assessing autism symptom frequency and impact in children, previously shown to have good test-retest reliability, convergent validity and structural validity. This study extended previous work by exploring the AIM's ability to discriminate between 'known-groups' of children, and estimating thresholds for clinically important responses. Data were collected online and electronically on computer and mobile devices; hence, it was also possible to confirm other psychometric properties of the AIM in this format. This study provides confirmatory and additional psychometric validation of the AIM. The AIM offers a valid, quick and inexpensive method for caregivers to report core symptoms of autism spectrum disorder (ASD) including communication deficits, difficulties with social interactions and repetitive behaviors.

Children with autism receive different types of non-drug treatments. We aimed to describe caregiver-reported pattern of care and its variability by geography and healthcare coverage in a US-wide sample of children aged 3-17 years. We recruited caregivers from the Simons Foundation Powering Autism Research for Knowledge (SPARK) cohort. Two online questionnaires (non-drug treatment, Autism Impact Measure) were completed in September/October 2017. Primary outcome measures were caregiver-reported types and intensities of treatments (behavioral, developmental/relationship, speech and language (SLT), occupational, psychological, "other"; parent/caregiver training) in the previous 12 months. Main explanatory variables were geography and type of healthcare coverage. We investigated associations between the type/intensity of treatments and geography (metropolitan/nonmetropolitan) or coverage (Medicaid vs privately insured by employer) using regression analysis. Caregivers (n = 5,122) were mainly mothers (92.1%) with mean (SD) age of 39.0 (7.3) years. Mean child age was 9.1 (3.9) years; mostly males (80.0%). Almost all children received at least one intervention (96.0%). Eighty percent received SLT or occupational therapy, while 52.0% received both. Behavioral therapy and SLT were significantly more frequent and more intense in metropolitan than in nonmetropolitan areas. No consistently significant associations were seen between healthcare coverage and frequency or intensity of interventions. At least one barrier such as "waiting list" and "no coverage" was reported by 44.8%. In conclusion, in children sampled from SPARK, we observed differences between metropolitan and nonmetropolitan areas, while we did not find significant differences between those privately insured versus Medicaid. Autism Res 2019, 12: 517-526 © 2019 The Authors. Autism Research published by International Society for Autism Research published by Wiley Periodicals, Inc. LAY SUMMARY: The American Academy of Child and Adolescent Psychiatry recommends the use of multiple treatment modalities in autism spectrum disorder (ASD). We wanted to understand what types of treatment children (aged 3-17 years) with ASD receive in the United States, how and where the treatments take place and for how long. We invited caregivers from Simons Foundation Powering Autism Research for Knowledge ("SPARK ," https://sparkforautism.org/) to complete the study questions online. Participants reported on utilization of conventional, non-drug treatments for ASD, including behavioral interventions, developmental/relationship interventions, speech and language therapy (SLT), occupational therapy, psychological therapy, and parent/caregiver training. People that completed the study (n = 5,122) were primarily mothers of the child with ASD (92%); most of the children were boys (80%). The ASD care for the child was mostly coordinating by the mother. Almost all children received at least some type of non-drug therapies (96%), most often SLT and/or occupational therapy, mainly provided in school. Behavioral therapy was most often received in public school in rural areas, while at home in urban areas. We saw less use of behavioral therapy and SLT in rural areas, but overall comparable use between children covered by Medicaid and those covered by private insurance. Almost half the caregivers reported at least one barrier to treatment, such as "waiting list" and "no coverage." More than half said that their child benefited "much" or "very much" from the therapies received. While overall non-drug treatment rates for children with ASD were high in the United States in our study, differences existed depending on where the family lives; not only regarding the type of therapy, but also where it takes place., (© 2019 The Authors. Autism Research published by International Society for Autism Research published by Wiley Periodicals, Inc.)

The effect of performing baseline HIV investigations (BLHIVI) at the time of a reactive HIV point-of-care test in the pathway to antiretroviral therapy (ART) in a community setting has not been described. In this study, 67 men newly diagnosed with HIV across three service models were analysed. The median time to ART was 30, 29.5 and 38 days (P=0.29) at a peer-led community testing site intervention group, in a historical control group and in an urban publicly funded sexual health service respectively. In a community setting, the inclusion of BLHIVI has the potential to reduce the time to early ART initiation.

Background Traditional result notification methods, such as telephone calls, return visits and individualised emails or Short Message Service (SMS) texts, can be time consuming and may not align with client preference. We conducted a cross-sectional survey of our clients that showed that many clients prefer negative results by SMS or email, with the option to call or attend in person for positive results. Methods: We developed an innovative result-robot module in the electronic medical record that reads the electronic result and, using predefined algorithms, determines which SMS or email result template to send to the client. Results and Conclusion: Delivering automated negative results resulted in a 41% decrease in the number of clients calling for their results, demonstrating a significant efficiency gain.

Background: Treatment patterns in Parkinson's disease (PD) have not been extensively studied for nearly two decades. Insurance claims are appropriate for such analysis., Objective: To understand the standard of care use of symptomatic treatments in new cases of PD and factors associated with treatment choice., Methods: Retrospective cohort study using claims data from the United States between 2008 and 2016. We used Kaplan-Meier methodology to estimate time to treatment start and switch or add-on therapy and Cox proportional hazards models to identify predictors., Results: We identified 68,532 patients eligible for treatment pattern analyses. Median time from diagnosis until first treatment was 37 days (95% confidence interval: 36-38). Two distinct patterns of treatment initiation were identified: fast initiators and patients with delayed treatment start (or no recorded treatment). Levodopa therapies were the most commonly prescribed treatment class (52.6%). Increased age was associated with shorter time to start of treatment with levodopa. Younger age was associated with shorter time to initiation of dopamine agonists and other symptomatic treatments. Patients that initiated treatment with levodopa/combinations had the fewest switches/add-ons [30.4%; median time 7.29 (6.71, 8.13) years]. Older patients had fewer switch/add-on therapies, but only in the group that started with levodopa/combination therapy., Conclusions: Time from diagnosis to treatment start was relatively short, suggesting that PD diagnosis, as reflected in the database, is closely linked to start of symptomatic treatment. Levodopa treatment remains the most common treatment, especially for older patients. Delayed treatment start was associated with increased age and comorbidity.

Psychiatric comorbidities and use of psychotropic medications are common among patients with autism spectrum disorder (ASD). However, most previous research used data from the United States (US) and few studies have compared medication use in ASD to control groups, making contextualization of results difficult. In the United Kingdom (UK), general practitioners play a key role in the management of ASD. We conducted a retrospective, cross-sectional study over calendar year 2015, using primary care data from the UK. We identified a prevalent cohort of ASD cases (n = 10,856) and matched control groups of (a) general population (n = 21,712) and (b) attention deficit hyperactivity disorder (ADHD; n = 7,058) on age, sex and region. We described psychiatric comorbidities, psychotropic medications, and healthcare utilization in all three cohorts. Within the ASD cohort, we used multivariable logistic regression models to explore associations between patient characteristics and the outcomes of: any psychotropic medication, polypharmacy, and number of primary care visits. We used conditional logistic regression to compare the ASD and control groups. Psychiatric comorbidities were recorded for 41.5% of ASD patients; 32.3% received psychotropic medication and 9.8% received polypharmacy. Increased age and all psychiatric comorbidities (except conduct disorder) were associated with treatment use. Males were less likely to receive a treatment than females [Odds ratio (OR) 0.74 (0.66-0.83)]. ASD patients were more likely to take psychotropic medications than the general population [OR 4.91 (4.46-5.40)], but less likely compared to ADHD patients [OR 0.40 (0.37-0.44)]. Overall, rates of medication use in the UK were lower than those previously reported in the US. Autism Research 2018, 11: 1690-1700. © 2018 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: We used electronic medical records from the UK, to describe the amount of psychiatric comorbidities, psychotropic medication use and healthcare resource use in ASD. Around one in three people with ASD were prescribed a psychotropic medication, which was more than the general population, but less than for those with ADHD. Increased age, psychiatric comorbidities and female gender were all independently associated with psychotropic medication use. Rates of medication use in the UK were lower than those previously reported in the US., (© 2018 International Society for Autism Research, Wiley Periodicals, Inc.)

There is little evidence and no standardised model for nurse-led HIV pre-exposure prophylaxis (PrEP). In 2016, public sexual health clinics in the state of New South Wales (NSW), Australia, participating in the population-scale PrEP access trial Expanded PrEP Implementation In Communities in New South Wales (EPIC-NSW) were authorised to adopt a nurse-led model of PrEP provision in order to facilitate the rapid expansion of PrEP access to more than 8000 participants in under 2 years without additional resources. The model has been implemented successfully in public clinics in 10 of 14 local health districts, with widespread support and no serious safety events reported. With the increasing importance of PrEP as an HIV prevention tool, non-traditional models of care, including nurse-led PrEP, are needed.

Objective: This prospective, open-label study was designed to evaluate the long-term effectiveness of 10-kHz high-frequency spinal cord stimulation (SCS) in the treatment of chronic axial low back pain with no history of spinal surgery., Methods: Patients with chronic low back pain without previous spinal surgery underwent assessment by a multidisciplinary pain and surgical team to confirm eligibility. After a successful temporary trial of 10-kHz HF-SCS therapy, defined by ≥50% back pain reduction, enrolled subjects underwent permanent system implantation and were followed up for 36 months. Outcome measures consisted of a 100-mm visual analog scale (VAS) for pain intensity, the Oswestry Disability Index (ODI), and a standard measure of health-related quality of life., Results: Twenty-one patients satisfied the inclusion/exclusion criteria. Following a temporary trial, 20 of 21 (95%) subjects were implanted with a pulse generator, and 17 of 20 reached the 36-month time point. From baseline to 36 months, the average VAS pain intensity decreased from 79 ± 12 mm to 10 ± 12 mm, the average ODI score decreased from 53 ± 13 to 19.8 ± 13, and use of opioids decreased from 18 subjects to two subjects. One subject was deceased, unrelated to the study, one subject was explanted due to loss of effectiveness, and one subject was lost to follow-up., Conclusions: These results suggest that 10-kHz high-frequency SCS may provide significant, long-term back pain relief, improvement in disability and quality of life, and reduction in opioids for nonsurgical refractory back pain.

This study investigated psychotropic medication usage in two large, cohorts of people with autism spectrum disorder (ASD) throughout the calendar year 2014. The cohorts referred to individuals with commercial (employer-sponsored) and Medicaid insurance in the United States. We aimed to understand prescribing patterns of such medications across a wide age-range and in the presence/absence of other clinical and non-clinical characteristics, including psychiatric comorbidities. We described the prevalence and length of prescriptions by age, psychiatric comorbidity and overall. We also fitted multivariable logistic regression models to describe the relationship between treatments and subject characteristics simultaneously. Eighty percent of the identified population was male, although gender did not impact the odds of receiving medication. Medication use was strongly associated with age, increasing most rapidly before adulthood; generally plateauing thereafter. All psychiatric comorbidities studied also individually increased the chances of medication use, with epilepsy and ADHD having the highest associations in both the commercial (OR > 7) and Medicaid (OR around 12) cohorts. Those in non-capitated insurance plans, in foster care and white individuals also had increased odds of prescriptions. Overall, slightly more Medicaid enrollees received any psychotropic treatment (commercial: 64%, Medicaid: 69%). Nonetheless in both cohorts, a large proportion of individuals received treatment even without a diagnosis of any other psychiatric comorbidity (commercial: 31%, Medicaid: 33%). In summary, this report sheds new light on the latest patterns of psychiatric comorbidity profile and psycho-pharmacological treatment patterns in ASD Autism Res 2017, 10: 2037-2047. © 2017 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: this study identified a large number of children and adults in the US with autism spectrum disorder (autism) from employer-sponsored and government funded (Medicaid) health insurance data. Psychotropic medications were used by over two thirds of people, and four in ten people received two medications at the same time. The chances of receiving medication increased for individuals with other psychiatric conditions (e.g., ADHD), and also increased with age., (© 2017 International Society for Autism Research, Wiley Periodicals, Inc.)

Background: Respiratory virus infection is a common cause of hospitalisation in adults. Rapid point-of-care testing (POCT) for respiratory viruses might improve clinical care by reducing unnecessary antibiotic use, shortening length of hospital stay, improving influenza detection and treatment, and rationalising isolation facility use; however, insufficient evidence exists to support its use over standard clinical care. We aimed to assess the effect of routine POCT on a broad range of clinical outcomes including antibiotic use., Methods: In this pragmatic, parallel-group, open-label, randomised controlled trial, we enrolled adults (aged ≥18 years) within 24 h of presenting to the emergency department or acute medical unit of a large UK hospital with acute respiratory illness or fever higher than 37·5°C (≤7 days duration), or both, over two winter seasons. Patients were randomly assigned (1:1), via an internet-based allocation sequence with random permuted blocks, to have a molecular POC test for respiratory viruses or routine clinical care. The primary outcome was the proportion of patients who received antibiotics while hospitalised (up to 30 days). Secondary outcomes included duration of antibiotics, proportion of patients receiving single doses or brief courses of antibiotics, length of stay, antiviral use, isolation facility use, and safety. Analysis was by modified intention to treat, excluding patients who declined intervention or were withdrawn for protocol violations. This study is registered with ISRCTN, number 90211642, and has been completed., Findings: Between Jan 15, 2015, and April 30, 2015, and between Oct 1, 2015, and April 30, 2016, we enrolled 720 patients (362 assigned to POCT and 358 to routine care). Six patients withdrew or had protocol violations. 301 (84%) of 360 patients in the POCT group received antibiotics compared with 294 (83%) of 354 controls (difference 0·6%, 95% CI -4·9 to 6·0; p=0·84). Mean duration of antibiotics did not differ between groups (7·2 days [SD 5·1] in the POCT group vs 7·7 days [4·9] in the control group; difference -0·4, 95% CI -1·2 to 0·4; p=0·32). 50 (17%) of 301 patients treated with antibiotics in the POCT group received single doses or brief courses of antibiotics (<48 h) compared with 26 (9%) of 294 patients in the control group (difference 7·8%, 95% CI 2·5 to 13·1; p=0·0047; number needed to test=13). Mean length of stay was shorter in the POCT group (5·7 days [SD 6·3]) than in the control group (6·8 days [7·7]; difference -1·1, 95% CI -2·2 to -0·3; p=0·0443). Appropriate antiviral treatment of influenza-positive patients was more common in the POCT group (52 [91%] of 57 patients) than in the control group (24 [65%] of 37 patients; difference 26·4%, 95% CI 9·6 to 43·2; p=0·0026; number needed to test=4). We found no differences in adverse outcomes between the groups (77 [21%] of 360 patients in the POCT group vs 88 [25%] of 354 patients in the control group; -3·5%, -9·7 to 2·7; p=0·29)., Interpretation: Routine use of molecular POCT for respiratory viruses did not reduce the proportion of patients treated with antibiotics. However, the primary outcome measure failed to capture differences in antibiotic use because many patients were started on antibiotics before the results of POCT could be made available. Although POCT was not associated with a reduction in the duration of antibiotics overall, more patients in the POCT group received single doses or brief courses of antibiotics than did patients in the control group. POCT was also associated with a reduced length of stay and improved influenza detection and antiviral use, and appeared to be safe., Funding: University of Southampton., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Objectives: We describe haemagglutinin (HA) and neuraminidase (NA) sequencing in an apparent cross-site influenza A(H1N1) outbreak in renal transplant and haemodialysis patients, confirmed with whole genome sequencing (WGS)., Methods: Isolates were sequenced from influenza positive individuals. Phylogenetic trees were constructed using HA and NA sequencing and subsequently WGS. Sequence data was analysed to determine genetic relatedness of viruses obtained from inpatient and outpatient cohorts and compared with epidemiological outbreak information., Results: There were 6 patient cases of influenza in the inpatient renal ward cohort (associated with 3 deaths) and 9 patient cases in the outpatient haemodialysis unit cohort (no deaths). WGS confirmed clustered transmission of two genetically different influenza A(H1N1)pdm09 strains initially identified by analysis of HA and NA genes. WGS took longer, and in this case was not required to determine whether or not the two seemingly linked outbreaks were related., Conclusion: Rapid sequencing of HA and NA genes may be sufficient to aid early influenza outbreak investigation making it appealing for future outbreak investigation. However, as next generation sequencing becomes cheaper and more widely available and bioinformatics software is now freely accessible next generation whole genome analysis may increasingly become a valuable tool for real-time Influenza outbreak investigation., (Crown Copyright © 2017. Published by Elsevier Ltd. All rights reserved.)

A 25-year-old Caucasian flight attendant with an extensive travel history presented with night sweats, fevers, weight loss and axillary and supraclavicular lymphadenopathy. Apart from surgical breast augmentation, she had no past medical or surgical history. She was anaemic, leucopenic and lymphopenic, and a broad infection screen was negative. Cross-sectional imaging revealed ipsilateral silicone breast implant rupture, with leaking of implant contents into the surrounding tissue. Histological examination of an axillary lymph node core biopsy confirmed the diagnosis of silicone lymphadenopathy. This case illustrates the broad differential for acute painful lymphadenopathy in the context of global travel, and the use of targeted infection testing, early cross-sectional imaging and biopsy to arrive at an unexpected diagnosis.

Objective: To explore the effectiveness of 10 kHz high frequency spinal cord stimulation (HF10 therapy) treatment of chronic low back pain in patients who have not had spinal surgery., Methods: Patients with chronic low back pain without prior spinal surgery were evaluated by a team of spine surgeons to rule out any spinal pathology amenable to surgical interventions and by a multidisciplinary pain team to confirm eligibility for the study. After a successful (>50% back pain reduction) trial of HF10 therapy, enrolled subjects underwent permanent system implantation and were followed-up one year post-implant., Results: About 95% of the enrolled subjects (20/21) received the permanent system. At 12 months post-implant, both back pain VAS score and ODI were significantly reduced compared with baseline values (by 73% and 48%, respectively); an estimated quality-adjusted life year gain of 0.47 and a reduction in opioid use by 64% was observed. Four more patients among those unable to work at baseline due to back pain were employed at 12 months post-implant. There were no serious adverse events., Conclusion: HF10 therapy may provide significant back pain relief, reduction in disability, improvement quality of life, and reduction in opioid use in chronic low back pain not resulting from spinal surgery., (© 2016 The Authors. Neuromodulation: Technology at the Neural Interface published by Wiley Periodicals, Inc. on behalf of International Neuromodulation Society.)

Background: Healthcare-associated infection rates are high in low-income countries and are associated with significant morbidity. There is a paucity of published data on infection control practice, attitudes or resources in these settings, particularly in ophthalmology. The aim of this study is to understand current hand washing practices, barriers to hand washing and facilities available in two Ugandan specialist eye hospitals. This study was undertaken through non-participant observations of healthcare worker hand washing practices, documentation of hand hygiene facilities and semi-strucutured interviews with clinical staff., Results: Eighty percent of the WHO opportunities for hand washing were missed through lack of attempted hand hygiene measures. Facilities for hand hygiene were inadequate with some key clinical areas having no provisions for hand hygiene. Training on effective hand hygiene varied widely with some staff reporting no training at all. The staff did not perceive the lack of facilities to be a barrier to hand washing but reported forgetfulness, lack of time and a belief that they could predict when transmission might occur and therefore did not wash hands as often as recommended., Conclusions: Hand hygiene at the two observed sites did not comply with WHO-recommended standards. The lack of facilities, variable training and staff perceptions were observable barriers to effective hand hygiene. Simple, low-cost interventions to improve hand hygiene could include increased provision of hand towels and running water and improved staff education to challenge their views and perceived barriers to hand hygiene.

Objective: The objectives of our study were to assess the evidence for the diagnostic efficacy of 3-T MRI for meniscal and anterior cruciate ligament (ACL) injuries in the knee using arthroscopy as the reference standard and to compare these results with the results of a previous meta-analysis assessing 1.5-T MRI., Materials and Methods: The online Cochrane Library, MEDLINE, and PubMed databases were searched using the following terms: MRI AND ((3 OR three) AND (Tesla OR T)) AND knee AND arthroscopy AND (menisc* OR ligament). Patient demographics, patient characteristics, MRI scanning details, and diagnostic results were investigated. The methodologic quality of the included studies was assessed using the revised Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) tool. A meta-analysis of studies using 3-T MRI was performed, and the results were compared with a previous meta-analysis of studies using 1.5-T MRI., Results: One hundred one studies were identified by the search strategy, and 13 studies were included in our review. Twelve studies were considered to have level 1b evidence, and one study was considered to have level 2b evidence. All 13 studies had high methodologic integrity and low risk of bias using the QUADAS-2 tool. The studies included 1197 patients with a mean age of 41.9 years. Ten of the 13 studies were eligible for meta-analysis. The mean sensitivity and mean specificity of 3-T MRI for knee injuries by location were as follows: medial meniscus, 0.94 (95% CI, 0.91-0.96) and 0.79 (95% CI, 0.75-0.83), respectively; lateral meniscus, 0.81 (95% CI, 0.75-0.85) and 0.87 (95% CI, 0.84-0.89); and ACL, 0.92 (95% CI, 0.83-0.96) and 0.99 (95% CI, 0.96-1.00). The specificity of 3-T MRI for injuries of the lateral meniscus was significantly lower than that of 1.5-T MRI (p = 0.0013)., Conclusion: This study does not provide evidence that 3-T scanners have superior diagnostic efficacy for meniscal damage and ACL integrity when compared with previous studies of 1.5-T machines.

Objective: To compare the diagnostic accuracy of magnetic resonance imaging (MRI), 2-dimensional magnetic resonance arthrogram (MRA) and 3-dimensional isotropic MRA in the diagnosis of rotator cuff tears when performed exclusively at 3-T., Materials and Methods: A systematic review was undertaken of the Cochrane, MEDLINE and PubMed databases in accordance with the PRISMA guidelines. Studies comparing 3-T MRI or 3-T MRA (index tests) to arthroscopic surgical findings (reference test) were included. Methodological appraisal was performed using QUADAS 2. Pooled sensitivity and specificity were calculated and summary receiver-operating curves generated. Kappa coefficients quantified inter-observer reliability., Results: Fourteen studies comprising 1332 patients were identified for inclusion. Twelve studies were retrospective and there were concerns regarding index test bias and applicability in nine and six studies respectively. Reference test bias was a concern in all studies. Both 3-T MRI and 3-T MRA showed similar excellent diagnostic accuracy for full-thickness supraspinatus tears. Concerning partial-thickness supraspinatus tears, 3-T 2D MRA was significantly more sensitive (86.6 vs. 80.5 %, p = 0.014) but significantly less specific (95.2 vs. 100 %, p < 0.001). There was a trend towards greater accuracy in the diagnosis of subscapularis tears with 3-T MRA. Three-Tesla 3D isotropic MRA showed similar accuracy to 3-T conventional 2D MRA., Conclusion: Three-Tesla MRI appeared equivalent to 3-T MRA in the diagnosis of full- and partial-thickness tears, although there was a trend towards greater accuracy in the diagnosis of subscapularis tears with 3-T MRA. Three-Tesla 3D isotropic MRA appears equivalent to 3-T 2D MRA for all types of tears.

The function of the majority of genes in the mouse and human genomes remains unknown. The mouse embryonic stem cell knockout resource provides a basis for the characterization of relationships between genes and phenotypes. The EUMODIC consortium developed and validated robust methodologies for the broad-based phenotyping of knockouts through a pipeline comprising 20 disease-oriented platforms. We developed new statistical methods for pipeline design and data analysis aimed at detecting reproducible phenotypes with high power. We acquired phenotype data from 449 mutant alleles, representing 320 unique genes, of which half had no previous functional annotation. We captured data from over 27,000 mice, finding that 83% of the mutant lines are phenodeviant, with 65% demonstrating pleiotropy. Surprisingly, we found significant differences in phenotype annotation according to zygosity. New phenotypes were uncovered for many genes with previously unknown function, providing a powerful basis for hypothesis generation and further investigation in diverse systems.