Search

Objectives: Publicly funded adult social care (ASC) in England aims to improve quality of life through the provision of services for individuals with care needs due to physical and/or mental impairment or illness. Access to these services, however, is often restricted to contain public expenditure. With a fast-growing care need, information on whether extending eligibility is good value for money becomes policy-relevant., Primary and Secondary Outcome Measures: This study investigates the effect of extending ASC eligibility on user care-related quality of life (CRQoL), a policy-relevant measure of quality of life., Design: We use English cross-sectional survey data from 2017/2018 to 2019/2020 on users receiving publicly funded long-term support including domiciliary and other community-based social care, as well as residential and nursing care from local authorities responsible for ASC. We employ the two-stage least square method to estimate the impact of ASC expenditure on CRQoL at various levels of ASC expenditure in each financial year. This includes the CRQoL effect of increasing expenditure from zero to some level, which captures the effect of extending ASC eligibility to new users., Results: We find that publicly funded ASC improves the CRQoL of both existing and newly eligible users, although the latter are likely to experience greater CRQoL gains. Moreover, from 2017/2018 to 2019/2020, spending as much as an average user for a newly eligible user costs between £54 224 and £77 778 per social care-quality-adjusted life year (SC-QALY) gained. These results are statistically significant at the 5% level. Compared with this finding, increasing expenditure for an existing user has always a higher cost per SC-QALY gained., Conclusions: Extending ASC eligibility to new users is likely to be more cost-effective compared with using the same resources to increase expenditure for existing users., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

An intronic GGGGCC repeat expansion in C9orf72 is a common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia. The repeats are transcribed in both sense and antisense directions to generate distinct dipeptide repeat proteins, of which poly(GA), poly(GR), and poly(PR) have been implicated in contributing to neurodegeneration. Poly(PR) binding to RNA may contribute to toxicity, but analysis of poly(PR)-RNA binding on a transcriptome-wide scale has not yet been carried out. We therefore performed crosslinking and immunoprecipitation (CLIP) analysis in human cells to identify the RNA binding sites of poly(PR). We found that poly(PR) binds to nearly 600 RNAs, with the sequence GAAGA enriched at the binding sites. In vitro experiments showed that poly(GAAGA) RNA binds poly(PR) with higher affinity than control RNA and induces the phase separation of poly(PR) into condensates. These data indicate that poly(PR) preferentially binds to poly(GAAGA)-containing RNAs, which may have physiological consequences., (© 2023 Balendra et al.)

Background: The United States' (U.S.) initiative to End the HIV Epidemic aims to reduce new HIV infections in areas of high HIV prevalence. Despite national efforts to reduce HIV incidence, cisgender women continue to represent approximately one out of every five new HIV diagnoses in the U.S. Taking pre-exposure prophylaxis (PrEP) is an effective HIV prevention strategy; however, PrEP initiation among cisgender women is suboptimal, with only 10% of eligible women receiving PrEP prescriptions in 2019., Methods: We designed a trial to test the effectiveness of interventions to increase PrEP initiation, while evaluating the implementation strategy (hybrid type II trial) in seven obstetrics and gynecology (OB/GYN) clinics (two federally qualified health centers, three community-based, and two academic) in Baltimore, Maryland. A total of 42 OB/GYN providers will be enrolled and randomized (1:1:1) into one of three clinical trial arms (standard of care, patient-level intervention, or multi-level intervention). Eligible patients of enrolled providers will receive a sexual health questionnaire before their appointment through the electronic health record's (EHR) patient portal. The questionnaire will be scored in three tiers (low, moderate, and high) to assess HIV risk. Patients at low risk will be offered an HIV test only, while those who score medium or high risk will be included in the clinical trial and assigned to the clinical trial arm associated with their provider. Differences in PrEP initiation, our primary outcome, across the three arms will be analyzed using generalized linear mixed-effect models with logistic regression. We will adjust results for demographic differences observed between arms and examine PrEP initiation stratified by patient's and provider's race and ethnicity.Additionally, a comprehensive economic analysis for each intervention will be conducted., Discussion: We hypothesize that gathering information on sensitive sexual behaviors electronically, communicating HIV risk in an understandable and relatable format to patients and OB/GYN providers, and deploying EHR alerts will increase PrEP initiation and HIV testing., Trial Registration: The trial is registered with ClinicalTrials.gov (NCT05412433) on 09 June 2022. https://clinicaltrials.gov/ct2/show/NCT05412433?term=NCT05412433&draw=2&rank=1., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Izadi, Mmeje, Drabo, Perin, Martin and Coleman.)

English data from 2003 to 2012 suggests that it costs the NHS £10,000 to generate an additional quality-adjusted life year (QALY).  This estimate relates to all NHS expenditure and no attempt was made to explore possible heterogeneity within this total.  Different types of expenditure - such as secondary care, primary care and specialized commissioning - may have different productivities and estimates of these may help policymakers decide where additional investment is most beneficial.  We use the two-stage least squares estimator and data for 2016 to explore the mortality response to three types of healthcare expenditure.  Three specifications are estimated for each type of expenditure: backward selection and regularized regression are used to identify parsimonious specifications, and a full specification with all covariates is also estimated.  The regression results are combined with information about survival and morbidity disease burden to calculate the marginal cost per QALY for each type of expenditure: the most conservative results suggest that this is about £8,000 for locally (CCG) commissioned services, while estimates for specialized commissioning and primary care are more uncertain.  When this heterogeneity is taken into account, the estimated marginal cost per QALY for all NHS expenditure increases slightly, from about £6,000 to £7,000.  Our results suggest that additional investment is likely to be most productive in primary care and in locally commissioned services., Competing Interests: Declarations of Competing Interest None., (Copyright © 2023. Published by Elsevier B.V.)

Purpose: Gunshot wound (GSW) injuries are an important public health concern in the United States. The study purpose was to measure the association between GSW location and need for operative treatment., Methods: This was a retrospective cohort study. Sample consisted of all patients treated for maxillofacial gunshot wound injuries at Cook County Health from 2008 to 2018. The sample data were collected through a retrospective charts review and review of computed tomography imaging. The predictor variable was the region of the face involved with the GSW and it was divided into 3 levels, upper face (UF), middle face (MF), and lower face (LF). The outcome variable was whether operative intervention was rendered or not (operative vs no intervention). Other variables of interest collected included patient demographics, the type of surgical intervention, disposition (home vs rehab/morgue), rate of intracranial injury, and need for blood transfusion. Data analysis was performed using Chi-square for proportions and relative risk (RR) with 95% confidence interval (CI)., Results: A total of 180 patients were identified to have sustained GSW injuries to the face during abovementioned time frame. Of those, 120 patients had isolated GSW injuries with no other organs involvement. The median age was 25 years. Majority of the patients were males (94%). The involved facial region appeared to influence the need for operative management and this reached statistical significance (Chi-square 22.703, P < .001). GSW injuries to LF were 2.94 times more likely to require operative intervention than injuries to the MF (RR = 2.94, 95% CI = 1.625-5.327). Injuries of the UF were 2 times more likely to require operative intervention than injuries of the MF (RR = 2.03, 95% CI 1.023-4.008). Injuries to the UF were more likely to be associated with intracranial injuries (Chi-square = 20.522, P < .001)., Conclusions: In patients with facial GSW injuries, there is an association between injury location and the need for operative intervention. Injuries to the LF were most likely to require surgical intervention followed by the UF and MF, respectively., (Copyright © 2022 American Association of Oral and Maxillofacial Surgeons. Published by Elsevier Inc. All rights reserved.)

Objective: To determine the influence of radiographic examination on the recommendations made at the time of planned re-evaluation of dogs after medial patellar luxation (MPL) surgery., Study Design: Retrospective multi-institutional case series., Animals: Client-owned dogs (N = 825) that underwent MPL surgery., Methods: Records of 10 referral institutions were searched for dogs that had been treated surgically for unilateral MPL and underwent a planned follow-up visit, including radiographs. The frequency of, and reasons for, changes in further recovery recommendations were investigated., Results: Follow up was performed at a median of 6 (range, 4-20) weeks postoperatively. Isolated radiographic abnormalities were identified in 3.3% (27/825) of dogs following MPL surgery and led to a change in recommendations in 3% (13/432) of dogs that were presented without owner or clinician concerns. Lameness, administration of analgesia at follow up, and history of unplanned visits prior to routine re-examination were associated with a change in postoperative plan (P < .001). In the absence of owner and clinician concerns, the odds of having a change in convalescence plans were not different, whether or not isolated radiographic abnormalities were present (P = .641)., Conclusion: Routine radiographs at follow up did not influence postoperative management of most dogs after MPL surgery in the absence of abnormalities on clinical history or orthopedic examination., Clinical Significance: Dogs that were presented for routine follow up after unilateral MPL surgery without owner concerns, lameness, analgesic treatment or a history of unplanned visits, and for which examination by a surgical specialist was unremarkable, were unlikely to benefit from radiographs., (© 2023 American College of Veterinary Surgeons.)

Gap Junction intercellular communication (GJIC) is often dysregulated in cancers, and this dysregulation has been shown to have pro-tumorigenic effects. Connexins (Cxs) are transmembrane proteins that make up gap junctions. Previous studies have indicated that RNA interference (RNAi)-based suppression of Cx43 increases cellular resistance to the chemotherapeutic agent cisplatin. Interestingly, we found that the loss of Cx43 expression induced by the CRISPR-Cas9 technology sensitizes cells to cisplatin in a KRAS mutant-dependent manner., (Copyright: © 2022 by the authors.)

Background: Research using local English data from 2003 to 2012 suggests that a 1% increase in healthcare expenditure causes a 0.78% reduction in mortality, and that it costs the NHS £10,000 to generate an additional quality-adjusted life year (QALY). In 2013, the existing 151 local health authorities (Primary Care Trusts) were abolished and replaced with 212 Clinical Commissioning Groups (CCGs). CCGs retained responsibility for secondary care and pharmaceuticals, but responsibility for primary care and specialised commissioning returned to central administrators., Objectives: The aim was to extend and apply existing methods to more recent data using a new geography and expenditure base, while improving covariate selection and examining the responsiveness of mortality to expenditure across the mortality distribution., Methods: Instrumental variable regression is used to quantify the relationship between mortality and local expenditure. Backward selection and regularised regression are used to identify parsimonious specifications. These results are combined with information about survival and morbidity disease burden to calculate the marginal cost per QALY. Unconditional quantile regression (UQR) is used to examine the response of mortality to expenditure across the mortality distribution., Results: Backward selection and regularised regression both suggest that the marginal cost per QALY in 2014/15 was about £7000 for locally commissioned services. The UQR results suggest that additional expenditure generates larger health benefits in high-mortality areas and that, if anything, the average size of this heterogeneous response is larger than the response at the mean., Conclusions: The new healthcare geography and expenditure base can be used to update estimates of the health opportunity costs associated with additional expenditure. The variation in the mortality response across the mortality distribution suggests that the use of the response at the mean will, if anything, underestimate the health opportunity costs associated with a national policy or nationally mandated guidance on the use of new technologies. The health opportunity costs of such policies are likely to be greater (lower) in areas of higher (lower) mortality, increasing health inequalities., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Objective: To compare the effect of Healthy for Two/Healthy for You (H42/H4U), a health coaching program, in prenatal care clinics that serve a racially and economically diverse population, on total gestational weight gain (GWG) (vs. usual care). We hypothesize that compared to usual prenatal care, intervention participants will have lower GWG and lower rates of gestational diabetes mellitus (GDM)., Methods: We report the rationale and design of a pragmatic, parallel arm randomized clinical trial with 380 pregnant patients ≤15 weeks gestation with overweight or obesity from one of 6 academic and community-based obstetrics practices, randomized to either H42/H4U or usual prenatal care in a 1:1 ratio. The study duration is early pregnancy to 6 months postpartum. The primary outcome is total GWG, calculated as the difference between first clinic-assessed pregnancy weight and the weight at 37 weeks gestation. Key maternal and infant secondary outcomes include GDM incidence, weight retention at 6 months postpartum, infant weight, maternal health behaviors and wellness., Conclusions: This pragmatic clinical trial embeds a pregnancy health coaching program into prenatal care to allow parallel testing compared to usual prenatal care on the outcome of total GWG. The real-world design provides an approach to enhance its sustainability beyond the trial to ultimately improve maternal/child health outcomes and reduce future obesity., Trial Registration: The study was first registered at clinicaltrials.gov on 1/26/21 (NCT04724330)., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: The endogenous nature of healthcare expenditure means that instruments are often used when estimating the relationship between expenditure and mortality. Previous English studies of this relationship have largely relied on statistical tests to justify their instruments. A recent paper proposed that exogenous components of the resource allocation formula, used to distribute the national healthcare budget to local health authorities, be used as instruments., Objectives: To estimate the relationship between healthcare expenditure and mortality by disease area for England from 2003/4 to 2012/13 using exogenous elements from the resource allocation formula as instruments for expenditure. To use these disease-specific estimates to calculate the marginal cost per quality-adjusted life year (QALY) for English NHS expenditure. To compare these estimates with those that relied on statistical tests to justify their instruments., Methods: The two-stage least squares estimator is used to determine the annual relationship between mortality and healthcare expenditure by disease area across 151 local authorities. These disease-specific outcome elasticities are combined with information about survival and morbidity disease burden in different disease areas to calculate the marginal cost per QALY for English National Health Service (NHS) expenditure., Results: The results suggest an annual marginal cost per QALY of between £5000 and £10,000. This is similar to that reported previously by studies that used statistical tests to justify their instruments., Conclusion: These cost per QALY estimates are much lower than the threshold currently used by the UK's National Institute for Health and Care Excellence (NICE) (£20,000 to £30,000) to assess whether a new pharmaceutical product should be funded by the NHS. Our estimates suggest that guidance issued by NICE is likely to do more harm than good, reducing health outcomes overall for the NHS. There may be legitimate reasons why such harms are deemed appropriate, but it is only through the type of empirical analysis in this paper that the reasons for these 'harms' are likely to be articulated and explicitly justified., (© 2021. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Objectives: The first objective is to estimate the joint impact of social care, public health and healthcare expenditure on mortality in England. The second objective is to use these results to estimate the impact of spending constraints in 2010/2011-2014/2015 on total mortality., Methods: The impact of social care, healthcare and public health expenditure on mortality is analysed by applying the two-stage least squares method to local authority data for 2013/2014. Next, we compare the growth in healthcare and social care expenditure pre-2010 and post-2010. We use the difference between these growth rates and the responsiveness of mortality to changes in expenditure taken from the 2013/2014 cross-sectional analysis to estimate the additional mortality generated by post-2010 spending constraints., Results: Our most conservative results suggest that (1) a 1% increase in healthcare expenditure reduces mortality by 0.532%; (2) a 1% increase in social care expenditure reduces mortality by 0.336%; and (3) a 1% increase in local public health spending reduces mortality by 0.019%. Using the first two of these elasticities and data on the change in spending growth between 2001/2002-2009/2010 and 2010/2011-2014/2015, we find that there were 57 550 (CI 3075 to 111 955) more deaths in the latter period than would have been observed had spending growth during this period matched that in 2001/2002-2009/2010., Conclusions: All three forms of public healthcare-related expenditure save lives and there is evidence that additional social care expenditure is more than twice as productive as additional healthcare expenditure. Our results are consistent with the hypothesis that the slowdown in the rate of improvement in life expectancy in England and Wales since 2010 is attributable to spending constraints in the healthcare and social care sectors., Competing Interests: Competing interests: All authors declared financial support from the National Institute for Health Research Policy Research Programme for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; and no other relationships or activities that could appear to have influenced the submitted work., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Public long-term care (LTC) systems provide services to support people experiencing difficulties with their activities of daily living. This study investigates the marginal effect of changes in public LTC expenditure on care-related quality of life (CRQoL) of existing service users in England. The public LTC program for people aged 18 or older in England is called Adult Social Care (ASC) and it is provided and managed by local authorities. We collect data on the outcomes and characteristics of public ASC users, on public ASC expenditure, and on the characteristics of local authorities across England in 2017/18. We employ an instrumental variable approach using conditionally exogenous elements of the public funding system to estimate the effect of public ASC expenditure on user CRQoL. Our findings show that by increasing public ASC expenditure by £1000 per user, on average, local authorities increase user CRQoL by 0.0030. These results suggest that public ASC is effective in increasing users' quality of life but only to a relatively small extent. When combined with the other potential effects of LTC expenditure (e.g., on informal carers, mortality), this study can inform policy makers in the United Kingdom and internationally about whether social care provides good value for money., (© 2021 John Wiley & Sons Ltd.)

Material extrusion-type fused filament fabrication (FFF) 3-D printing is a valuable tool for education. During FFF 3-D printing, thermal degradation of the polymer releases small particles and chemicals, many of which are hazardous to human health. In this study, particle and chemical emissions from 10 different filaments made from virgin (never printed) and recycled polymers were used to print the same object at the polymer manufacturer's recommended nozzle temperature ("normal") and at a temperature higher than recommended ("hot") to simulate the real-world scenarios of a person intentionally or unknowingly printing on a machine with a changed setting. Emissions were evaluated in a college teaching laboratory using standard sampling and analytical methods. From mobility sizer measurements, particle number-based emission rates were 81 times higher; the proportion of ultrafine particles (diameter <100 nm) were 4% higher, and median particle sizes were a factor of 2 smaller for hot-temperature prints compared with normal-temperature prints (all p -values <0.05). There was no difference in emission characteristics between recycled and virgin acrylonitrile butadiene styrene and polylactic acid polymer filaments. Reducing contaminant release from FFF 3-D printers in educational settings can be achieved using the hierarchy of controls: (1) elimination/substitution (e.g., training students on principles of prevention-through-design, limiting the use of higher emitting polymer when possible); (2) engineering controls (e.g., using local exhaust ventilation to directly remove contaminants at the printer or isolating the printer from students); (3) administrative controls such as password protecting printer settings and establishing and enforcing adherence to a standard operating procedure based on a proper risk assessment for the setup and use (e.g., limiting the use of temperatures higher than those specified for the filaments used); and (4) maintenance of printers., Competing Interests: The authors declare no competing financial interest.

Objectives: The UK government is proposing to cease cutting the local authority public health grant by reallocating part of the treatment budget to preventative activity. This study examines whether this proposal is evidenced based and, in particular, whether these resources are best reallocated to prevention, or whether this expenditure would generate more health gains if used for treatment., Methods: Instrumental variable regression methods are applied to English local authority data on mortality, healthcare and public health expenditure to estimate the responsiveness of mortality to variations in healthcare and public health expenditure in 2013/14. Using a well-established method, these mortality results are converted to a quality-adjusted life year (QALY) basis, and this facilitates the estimation of the cost per QALY for both National Health Service (NHS) healthcare and local public health expenditure., Results: Saving lives and improving the quality of life requires resources. Our estimates suggest that each additional QALY costs about £3800 from the local public health budget, and that each additional QALY from the NHS budget costs about £13 500. These estimates can be used to calculate the number of QALYs generated by a budget boost. If we err on the side of caution and use the most conservative estimates that we have, then an additional £1 billion spent on public health will generate 206 398 QALYs (95% CI 36 591 to 3 76 205 QALYs), and an additional £1 billion spent on healthcare will generate 67 060 QALYs (95% CI 21 487 to 112 633 QALYs)., Conclusions: Additional public health expenditure is very productive of health and is more productive than additional NHS expenditure. However, both types of expenditure are more productive of health than the norms used by National Institute for Health and Care Excellence (£20 000-£30 000 per QALY) to judge whether new therapeutic technologies are suitable for adoption by the NHS., Competing Interests: Competing interests: All authors have completed the Unified Competing Interest form (available on request from the corresponding author) and declare: financial support from the National Institute for Health Research Policy Research Programme for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous 3 years; and no other relationships or activities that could appear to have influenced the submitted work., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Previous attempts to enhance medical nutrition education have typically focussed on students' acquiring nutrition knowledge or skills. Given that medical training uses an apprenticeship model of training, surprisingly few studies have explored the 'hidden curriculum' that students experience regarding expectations of behaviour, roles and responsibilities regarding nutrition. This study explored medical students' perceptions and experiences regarding medical nutrition education, focussing on the context in which nutrition teaching has been provided, the presented place of nutrition within medicine and their subsequent views on their role in providing nutrition care., Methods: Individual semi-structured qualitative interviews were conducted with 14 postgraduate medical students at different stages of their medical degree in Australia. The interviews were conducted using case studies followed by interview questions. Data were audio recorded, transcribed, coded and then underwent inductive thematic analysis., Results: Three themes were discovered (i) Valuing nutrition in the medical management of patients whereby students perceived nutrition to be a foundational and central component of ideal medical management for patients, particularly those with chronic disease; (ii) Fluctuating emphasis on nutrition which showed that students experienced diversity in the importance placed on nutrition by others and (iii) Working with others whereby students expressed their understanding of their role in nutrition and the roles of team members such as dietitians., Conclusion: To enhance medical nutrition education, consideration needs to extend beyond counting dedicated teaching hours and mapping nutrition content, to a more contextual understanding of the situated learning that occurs for medical students., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Protein ubiquitination plays a key role in the regulation of cellular processes, and misregulation of the ubiquitin system is linked to many diseases. So far, development of tool compounds that target enzymes of the ubiquitin system has been slow and only a few specific inhibitors are available. Here, we report the selection of single-domain antibodies (single-dAbs) based on a human scaffold that recognize the catalytic domain of HOIP, a subunit of the multi-component E3 LUBAC and member of the RBR family of E3 ligases. Some of these dAbs affect ligase activity and provide mechanistic insight into the ubiquitin transfer mechanism of different E2-conjugating enzymes. Furthermore, we show that the co-crystal structure of a HOIP RBR/dAb complex serves as a robust platform for soaking of ligands that target the active site cysteine of HOIP, thereby providing easy access to structure-based ligand design for this important class of E3 ligases., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: Estimates of the marginal productivity of the health sector are required for a wide range of resource allocation decisions. Founding these estimates on robust empirical analysis can inform these decisions and improve allocative efficiency. This article estimates the annual marginal productivity of the English NHS over a 10-year period (between 2003 and 2012)., Methods: Data on expenditure and mortality by program budget category are used in conjunction with socioeconomic and demographic variables from the censuses for 2001 and 2011. This article applies an econometric strategy that employs an established instrumental variable approach, which is then subjected to a number of sensitivity analyses. The results of the econometric analysis, along with additional data on the burden of disease, are used to generate an estimate of the marginal productivity for each of the study years., Results: We find that an additional unit of health benefit has cost between £5000 and £15 000 per quality-adjusted life-year from 2003 to 2012. Over this period these estimates (all in current prices) have increased at a faster rate than NHS price inflation, suggesting an increase in real terms., Conclusions: These results are discussed in the context of the existing literature, and the potential policy implications for decisions about resource allocation are explored., (Copyright © 2019 ISPOR–The Professional Society for Health Economics and Outcomes Research. Published by Elsevier Inc. All rights reserved.)

Clathrin-mediated endocytosis (CME) is key to maintaining the transmembrane protein composition of cells' limiting membranes. During mammalian CME, a reversible phosphorylation event occurs on Thr156 of the μ2 subunit of the main endocytic clathrin adaptor, AP2. We show that this phosphorylation event starts during clathrin-coated pit (CCP) initiation and increases throughout CCP lifetime. μ2Thr156 phosphorylation favors a new, cargo-bound conformation of AP2 and simultaneously creates a binding platform for the endocytic NECAP proteins but without significantly altering AP2's cargo affinity in vitro. We describe the structural bases of both. NECAP arrival at CCPs parallels that of clathrin and increases with μ2Thr156 phosphorylation. In turn, NECAP recruits drivers of late stages of CCP formation, including SNX9, via a site distinct from where NECAP binds AP2. Disruption of the different modules of this phosphorylation-based temporal regulatory system results in CCP maturation being delayed and/or stalled, hence impairing global rates of CME., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: To measure the impact of the improvement in hospital survival rates on patients' subsequent utilization of unplanned (emergency) admissions., Data Sources/study Setting: Unplanned admissions occurring in all acute hospitals of the National Health Service in England between 2000 and 2009, including 286,027 hip fractures, 375,880 AMI, 387,761 strokes, and 9,966,246 any cause admissions., Study Design: Population-based retrospective cohort study. Unplanned admissions experienced by patients within 28 days, 1 year, and 2 years of discharge from the index admission are modeled as a function of hospital risk-adjusted survival rates using patient-level probit and negative binomial models. Identification is also supported by an instrumental variable approach and placebo test., Principal Findings: The improvement in hospital survival rates that occurred between 2000 and 2009 explains 37.3 percent of the total increment in unplanned admissions observed over the same period. One extra patient surviving increases the expected number of subsequent admissions occurring within 1 year from discharge by 1.9 admissions for every 100 index admissions (0.019 per admission, 95% CI, 0.016-0.022). Similar results in hip fracture (0.006[0.004-0.007]), AMI (0.006[0.04-0.007]), and stroke (0.004(0.003-0.005))., Conclusions: The success of hospitals in improving survival from unplanned admissions can be an important contributory factor to the increase in subsequent admissions., (© 2017 The Authors. Health Services Research published by Wiley Periodicals, Inc. on behalf of Health Research and Educational Trust.)

Combining the official cholera line list data and outbreak investigation reports from the ministries of health in Uganda and South Sudan with molecular analysis of Vibrio cholerae strains revealed the interrelatedness of the epidemics in both countries in 2014. These results highlight the need for collaboration to control cross-border outbreaks.

The objectives of this survey were to identify the practice patterns of Canadian physicians working in the field of occupational medicine and to determine whether the type of certification influences the nature of the work they perform in the field. An Internet-based survey was conducted in September 2015 of members of the Occupational and Environmental Medicine Association of Canada. Eighty-six Canadian-based occupational medicine physicians completed the survey (response rate 36%). These physicians performed a wide variety of tasks (12 ± 6), with few spending most of their time doing a single task. The most frequently performed tasks were fitness-to-work (78%) and return-to-work evaluations (78%). Specialty-trained physicians were more likely to be involved in teaching and research and less likely to be involved in a variety of ability-to-work evaluations.

Considering whether or not a proposed investment (an intervention, technology, or program of care) is affordable is really asking whether the benefits it offers are greater than its opportunity cost. To say that an investment is cost-effective but not affordable must mean that the (implicit or explicit) "threshold" used to judge cost-effectiveness does not reflect the scale and value of the opportunity costs. Existing empirical estimates of health opportunity costs are based on cross-sectional variation in expenditure and mortality outcomes by program budget categories (PBCs) and do not reflect the likely effect of nonmarginal budget impacts on health opportunity costs. The UK Department of Health regularly updates the needs-based target allocation of resources to local areas of the National Health Service (NHS), creating two subgroups of local areas (those under target allocation and those over). These data provide the opportunity to explore how the effects of changes in health care expenditure differ with available resources. We use 2008-2009 data to evaluate two econometric approaches to estimation and explore a range of criteria for accepting subgroup specific effects for differences in expenditure and outcome elasticities across the 23 PBCs. Our results indicate that health opportunity costs arising from an investment imposing net increases in expenditure are underestimated unless account is taken of likely nonmarginal effects. They also indicate the benefits (reduced health opportunity costs or increased value-based price of a technology) of being able to "smooth" these nonmarginal budget impacts by health care systems borrowing against future budgets or from manufacturers offering "mortgage" type arrangements., (Copyright © 2018 International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc. All rights reserved.)

IscX (or YfhJ) is a protein of unknown function which takes part in the iron-sulfur cluster assembly machinery, a highly specialized and essential metabolic pathway. IscX binds to iron with low affinity and interacts with IscS, the desulfurase central to cluster assembly. Previous studies have suggested a competition between IscX and CyaY, the bacterial ortholog of frataxin, for the same binding surface of IscS. This competition could suggest a link between the two proteins with a functional significance. Using a hybrid approach based on nuclear magnetic resonance, small angle scattering and biochemical methods, we show here that IscX is a modulator of the inhibitory properties of CyaY: by competing for the same site on IscS, the presence of IscX rescues the rates of enzymatic cluster formation which are inhibited by CyaY. The effect is stronger at low iron concentrations, whereas it becomes negligible at high iron concentrations. These results strongly suggest the mechanism of the dual regulation of iron sulfur cluster assembly under the control of iron as the effector.

Displaced persons living in camps are at an increased risk of diarrheal diseases. Subclinical carriage of pathogens may contribute to the spread of disease, especially for microbes that require a low infectious dose. Multiplex real-time polymerase chain reaction was performed to detect a panel of 20 bacterial, viral, and protozoal targets, and we report a high prevalence of enteropathogen carriage, including Shigella spp. or enteroinvasive Escherichia coli in 14%, among a sample of 88 asymptomatic individuals in an internally displaced persons camp in South Sudan. Further studies are needed to determine the contribution of such carriage to the spread of disease.

Varroa destructor, a parasitic mite of honey bees, is also a vector for viral diseases. The mite displays high host specificity and requires access to colonies of Apis spp. to complete its lifecycle. In contrast, the Deformed Wing Virus (DWV), one of the many viruses transmitted by V. destructor, appears to have a much broader host range. Previous studies have detected DWV in a variety of insect groups that are not directly parasitized by the mite. In this study, we take advantage of the discrete distribution of the Varroa mite in the Hawaiian archipelago to compare DWV prevalence on non-Apis flower visitors, and test whether Varroa presence is linked to a "viral spillover". We selected two islands with different viral landscapes: Oahu, where V. destructor has been present since 2007, and Maui, where the mite is absent. We sampled individuals of Apis mellifera, Ceratina smaragdula, Polistes aurifer, and Polistes exclamens, to assess and compare the DWV prevalence in the Hymenoptera community of the two islands. The results indicated that, as expected, honey bee colonies on Oahu have much higher incidence of DWV compared to Maui. Correspondingly, DWV was detected on the Non-Apis Hymenoptera collected from Oahu, but was absent in the species examined on Maui. The study sites selected shared a similar geography, climate, and insect fauna, but differed in the presence of the Varroa mite, suggesting an indirect, but significant, increase on DWV prevalence in the Hymenoptera community on mite-infected islands., (Published by Elsevier Inc.)

Objective: Non-Hodgkin's lymphoma (NHL) is the most common childhood malignancy in sub-Saharan Africa. Survival rates for NHL are higher than 80% in high-income countries.This study explores treatment outcomes of children with NHL in Kenya, a sub-Saharan low-income country, and the association between health insurance status at diagnosis and treatment outcomes., Design: This was a retrospective medical records study. All children diagnosed with NHL in 2010, 2011 and 2012 were included. Data on treatment outcomes and health insurance status at diagnosis were collected., Results: Of all 63 patients with NHL, 35% abandoned treatment, 22% had progressive or relapsed disease, 14% died and 29% had event-free survival. Most patients (73%) had no health insurance at diagnosis. Treatment outcomes in children with or without health insurance at diagnosis differed significantly (p=0.005). The most likely treatment outcome in children with health insurance at diagnosis was event-free survival (53%), whereas in children without health insurance at diagnosis it was abandonment of treatment (44%). Crude HR for treatment failure was 3.1 (95% CI 1.41 to 6.60, p=0.005) for uninsured versus insured children. The event-free survival estimate was significantly higher in children with health insurance at diagnosis than in patients without health insurance at diagnosis (p=0.003). Stage of disease at diagnosis was identified as a confounder of this association (adjusted HR=2.4, 95% CI 0.95 to 6.12, p=0.063)., Conclusions: Survival of children with NHL in Kenya is much lower compared with high-income countries. Abandonment of treatment is the most common cause of treatment failure. Health insurance at diagnosis was associated with better treatment outcomes and survival., Competing Interests: Competing interests: None declared.

Cholera remains an important but neglected public health threat, affecting the health of the poorest populations and imposing substantial costs on public health systems. Cholera can be eliminated where access to clean water, sanitation, and satisfactory hygiene practices are sustained, but major improvements in infrastructure continue to be a distant goal. New developments and trends of cholera disease burden, the creation of affordable oral cholera vaccines (OCVs) for use in developing countries, as well as recent evidence of vaccination impact has created an increased demand for cholera vaccines. The global OCV stockpile was established in 2013 and with support from Gavi, has assisted in achieving rapid access to vaccine in emergencies. Recent WHO prequalification of a second affordable OCV supports the stockpile goals of increased availability and distribution to affected populations. It serves as an essential step toward an integrated cholera control and prevention strategy in emergency and endemic settings.

In the United States, vulnerable populations at highest risk for poor oral health are more likely to visit a physician than a dentist. Patients in acute dental pain often present to hospital emergency departments or primary care offices where only palliative care is available. While numerous measures to improve oral health access in the United States are necessary, the authors propose that physician training incorporate techniques in dental diagnosis and primary dental care, including extraction where indicated, to allow providers to deliver definitive dental measures to patients unable to access the dental health care system. These skills will allow primary care providers to improve oral health, and ultimately strengthen ties to oral health providers that will improve patient care.

Introduction: Chronic pain is often managed using co-prescription of analgesics and adjuvants, with concomitant medication prescribed for comorbidities. Patients may have suboptimal response to some analgesics or be at risk of drug interactions or adverse drug reactions (ADRs) due to polypharmacy affecting CYP2D6 enzyme activity. The aim of the service improvement project was to determine the proportion of patients referred to a specialist pain service in the UK National Health Service (NHS) by general practitioners (GPs) who may be at risk of suboptimal analgesic response or ADRs due to CYP2D6 inhibition through polypharmacy. This was achieved by reviewing clinical prescribing information provided by GPs at time of referral. It was hoped that the findings could be used to aid clinical and prescribing decisions without conducting CYP2D6 genotyping or phenotyping., Methods: A review of letters from 250 patients referred to an NHS hospital pain service from GPs over a 3-month period was undertaken. Information about current and concomitant medications was analysed to identify the potential for CYP2D6 inhibition and adverse events., Results: Letters failed to provide information about current pain medication for 20 (8%) patients or non-pain concomitant medication for 54 (21.6%) patients. Of 176 patients, 52 (29.5%) patients with information about non-pain concomitant medication had been prescribed at least one known CYP2D6 inhibitor. A total of 35 (19.9%) patients were identified as being at risk of an adverse drug reaction and 33 (18.75%) patients at risk of suboptimal analgesic response due to co-administration of CYP2D6 inhibitors., Conclusion: The review revealed the need for improved detail in GP referral letters used to transfer care to UK NHS hospital pain clinics. There is a need to consider an individual's CYP2D6 phenotype when prescribing analgesic prodrugs to manage persistent pain. Caution is needed when patients are co-prescribed codeine or tramadol with selective serotonin reuptake inhibitors (SSRIs)., Competing Interests: The authors declared no potential conflicts of interest with respect to the research, authorship and/or publication of this article.

Despite recent large-scale cholera outbreaks, little is known about the immunogenicity of oral cholera vaccines (OCV) in African populations, particularly among those at highest cholera risk. During a 2015 preemptive OCV campaign among internally displaced persons in South Sudan, a year after a large cholera outbreak, we enrolled 37 young children (1-5 years old), 67 older children (6-17 years old) and 101 adults (≥18 years old), who received two doses of OCV (Shanchol) spaced approximately 3 weeks apart. Cholera-specific antibody responses were determined at days 0, 21 and 35 post-immunization. High baseline vibriocidal titers (>80) were observed in 21% of the participants, suggesting recent cholera exposure or vaccination. Among those with titers ≤80, 90% young children, 73% older children and 72% adults seroconverted (≥4 fold titer rise) after the 1 st OCV dose; with no additional seroconversion after the 2 nd dose. Post-vaccination immunological endpoints did not differ across age groups. Our results indicate Shanchol was immunogenic in this vulnerable population and that a single dose alone may be sufficient to achieve similar short-term immunological responses to the currently licensed two-dose regimen. While we found no evidence of differential response by age, further immunologic and epidemiologic studies are needed.

Oral cholera vaccination (OCV) campaigns were conducted from February to April 2014 among internally displaced persons (IDPs) in the midst of a humanitarian crisis in Juba, South Sudan. IDPs were predominantly members of the Nuer ethnic group who had taken refuge in United Nations bases following the eruption of violence in December 2013. The OCV campaigns, which were conducted by United Nations and non-governmental organizations (NGOs) at the request of the Ministry of Health, reached an estimated 85-96% of the target population. As no previous studies on OCV acceptance have been conducted in the context of an on-going humanitarian crisis, semi-structured interviews were completed with 49 IDPs in the months after the campaigns to better understand perceptions of cholera and reasons for full, partial or non-acceptance of the OCV. Heightened fears of disease and political danger contributed to camp residents' perception of cholera as a serious illness and increased trust in United Nations and NGOs providing the vaccine to IDPs. Reasons for partial and non-acceptance of the vaccination included lack of time and fear of side effects, similar to reasons found in OCV campaigns in non-crisis settings. In addition, distrust in national institutions in a context of fears of ethnic persecution was an important reason for hesitancy and refusal. Other reasons included fear of taking the vaccine alongside other medication or with alcohol. The findings highlight the importance of considering the target populations' perceptions of institutions in the delivery of OCV interventions in humanitarian contexts. They also suggest a need for better communication about the vaccine, its side effects and interactions with other substances., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Following mass population displacements in South Sudan, preventive cholera vaccination campaigns were conducted in displaced persons camps before a 2014 cholera outbreak. We compare cholera transmission in vaccinated and unvaccinated areas and show vaccination likely halted transmission within vaccinated areas, illustrating the potential for oral cholera vaccine to stop cholera transmission in vulnerable populations.

We assess the relationship between changes in hospital length of stay (LoS) and hospital quality, as measured by 28-day emergency readmission. We estimate regression models to analyse LoS and other factors associated with readmission for all those admitted for hip replacement (n=496,334), hernia repair (n=413,712) or following a stroke (n=480,113) in England between 2002/3 and 2007/8. There were reductions in LoS over time while changes in crude readmission rates varied by condition. Given the high mortality rate for stroke, it is critical to account for the probability of surviving the initial admission when evaluating readmissions. Conditional upon survival, the probability of readmission was greater for stroke patients who originally had a shorter LoS and for hernia patients who had an overnight stay but there is no relationship between LoS and readmission for patients who had hip replacement. The evidence does not generally suggest that reductions in LoS were associated with an increased probability of emergency readmission., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Introduction: Prehospital care, including patient transport, is integral in the patient care process during the Ebola response. Transporting ill persons from the community to Ebola care facilities can stop community spread. Vehicles used for patient transport in infectious disease outbreaks should be evaluated for adequate infection prevention and control., Problem: An ambulance driver in Sierra Leone attributed his Ebola infection to exposure to body fluids that leaked from the patient compartment to the driver cabin of the ambulance., Methods: A convenience sample of 14 vehicles used to transport patients with suspected or confirmed Ebola in Sierra Leone were assessed. The walls separating the patient compartment and driver cabin in these vehicles were evaluated for structural integrity and potential pathways for body fluid leakage. Ambulance drivers and other staff were asked to describe their cleaning and decontamination practices. Ambulance construction and design standards from the National Fire Protection Association, US General Services Administration, and European Committee on Standardization (CEN) were reviewed., Results: Many vehicles used by ambulance staff in Sierra Leone were not traditional ambulances, but were pick-up trucks or sport-utility vehicles that had been assembled or modified for patient transport. The wall separating the patient compartment and driver cabin in many vehicles did not have a waterproof seal around the edges. Staff responsible for cleaning and disinfection did not thoroughly clean bulk body fluids with disposable towels before disinfection of the patient compartment. Pressure from chlorine sprayers used in the decontamination process may have pushed body fluids from the patient compartment into the driver cabin through gaps around the wall. Ambulance design standards do not require a waterproof seal between the patient compartment and driver cabin. Sealing the wall by tightening or replacing existing bolts is recommended, followed by caulking of all seams with a sealant., Conclusion: Waterproof separation between the patient compartment and driver cabin may be essential for patient transport vehicles in infectious disease outbreaks, especially when chlorine sprayers are used for decontamination or in resource-limited settings where cleaning supplies may be limited.

Objective: To investigate whether better management of chronic conditions by family practices reduces mortality risk., Data: Two random samples of 5 million patients registered with over 8,000 English family practices followed up for 4 years (2004/5-2007/8). Measures of the quality of disease management for 10 conditions were constructed for each family practice for each year. The outcome measure was an indicator taking the value 1 if the patient died during a specified year, 0 otherwise., Study Design: Cross-section and multilevel panel data multiple logistic regressions were estimated. Covariates included age, gender, morbidity, hospitalizations, attributed socio-economic characteristics, and local health care supply measures., Principal Findings: Although a composite measure of the quality of disease management for all 10 conditions was significantly associated with lower mortality, only the quality of stroke care was significant when all 10 quality measures were entered in the regression., Conclusions: The panel data results suggest that a 1 percent improvement in the quality of stroke care could reduce the annual number of deaths in England by 782 [95 percent CI: 423, 1140]. A longer study period may be necessary to detect any mortality impact of better management of other conditions., (© Health Research and Educational Trust.)

In the yeast Saccharomyces cerevisiae, the essential nuclear helicase Sen1 is required for efficient termination of transcription of short noncoding RNA genes by RNA polymerase II. However, the mechanism by which Sen1 promotes transcription termination is not known. Prior biochemical studies on the Sen1 homolog from Schizosaccharomyces pombe showed that it can bind and unwind both DNA and RNA, but the S. pombe protein is not essential and has not been demonstrated to function in transcription. Furthermore, Sen1 from either yeast has not previously been expressed as a recombinant protein, due to its large molecular mass (252 kDa in S. cerevisiae). Here, we report the purification and characterization of the 89-kDa S. cerevisiae Sen1 helicase domain (Sen1-HD) produced in Escherichia coli. Sen1-HD binds single-stranded RNA and DNA with similar affinity in the absence of ATP, but it binds RNA more stably than DNA in the presence of ATP, apparently due to a slower translocation rate on RNA. Translocation occurs in the 5' to 3' direction, as for the S. pombe protein. When purified from E. coli at a moderate salt concentration, Sen1-HD was associated with short RNAs that are enriched for the trinucleotide repeat (CAN)4. We propose that Sen1 binds to RNAs and prevents their stable pairing with DNA, consistent with in vivo studies by others showing increased R-loop (RNA/DNA hybrid) formation when Sen1 activity is impaired by mutations. Our results are consistent with a model in which Sen1 promotes transcription termination by resolving R-loops., (© 2015 by The American Society for Biochemistry and Molecular Biology, Inc.)

Introduction: Giant cell arteritis (GCA) is an autoimmune disease commonest in Northern Europe and Scandinavia. Previous studies report various associations with HLA-DRB1*04 and HLA-DRB1*01; HLA-DRB1 alleles show a gradient in population prevalence within Europe. Our aims were (1) to determine which amino acid residues within HLA-DRB1 best explained HLA-DRB1 allele susceptibility and protective effects in GCA, seen in UK data combined in meta-analysis with previously published data, and (2) to determine whether the incidence of GCA in different countries is associated with the population prevalence of the HLA-DRB1 alleles that we identified in our meta-analysis., Methods: GCA patients from the UK GCA Consortium were genotyped by using single-strand oligonucleotide polymerization, allele-specific polymerase chain reaction, and direct sequencing. Meta-analysis was used to compare and combine our results with published data, and public databases were used to identify amino acid residues that may explain observed susceptibility/protective effects. Finally, we determined the relationship of HLA-DRB1*04 population carrier frequency and latitude to GCA incidence reported in different countries., Results: In our UK data (225 cases and 1378 controls), HLA-DRB1*04 carriage was associated with GCA susceptibility (odds ratio (OR) = 2.69, P = 1.5×10(-11)), but HLA-DRB1*01 was protective (adjusted OR = 0.55, P = 0.0046). In meta-analysis combined with 14 published studies (an additional 691 cases and 4038 controls), protective effects were seen from HLA-DR2, which comprises HLA-DRB1*15 and HLA-DRB1*16 (OR = 0.65, P = 8.2×10(-6)) and possibly from HLA-DRB1*01 (OR = 0.73, P = 0.037). GCA incidence (n = 17 countries) was associated with population HLA-DRB1*04 allele frequency (P = 0.008; adjusted R(2) = 0.51 on univariable analysis, adjusted R(2) = 0.62 after also including latitude); latitude also made an independent contribution., Conclusions: We confirm that HLA-DRB1*04 is a GCA susceptibility allele. The susceptibility data are best explained by amino acid risk residues V, H, and H at positions 11, 13, and 33, contrary to previous suggestions of amino acids in the second hypervariable region. Worldwide, GCA incidence was independently associated both with population frequency of HLA-DRB1*04 and with latitude itself. We conclude that variation in population HLA-DRB1*04 frequency may partly explain variations in GCA incidence and that HLA-DRB1*04 may warrant investigation as a potential prognostic or predictive biomarker.

Objective: To describe and analyse the characteristics of oral cholera vaccination campaigns; including location, target population, logistics, vaccine coverage and delivery costs., Methods: We searched PubMed, the World Health Organization (WHO) website and the Cochrane database with no date or language restrictions. We contacted public health personnel, experts in the field and in ministries of health and did targeted web searches., Findings: A total of 33 documents were included in the analysis. One country, Viet Nam, incorporates oral cholera vaccination into its public health programme and has administered approximately 10.9 million vaccine doses between 1997 and 2012. In addition, over 3 million doses of the two WHO pre-qualified oral cholera vaccines have been administered in more than 16 campaigns around the world between 1997 and 2014. These campaigns have either been pre-emptive or reactive and have taken place under diverse conditions, such as in refugee camps or natural disasters. Estimated two-dose coverage ranged from 46 to 88% of the target population. Approximate delivery cost per fully immunized person ranged from 0.11-3.99 United States dollars., Conclusion: Experience with oral cholera vaccination campaigns continues to increase. Public health officials may draw on this experience and conduct oral cholera vaccination campaigns more frequently.