On-site peer mentorship's effect on personal and professional development, stress reduction, and ease of transition into the medical education system.

CONTEXT: Mentorship aids in the transition into the medical education system, which is a demanding and stressful time for learners. The development of new medical schools to offset the physician shortage has posed a challenge in that the inaugural class of students lacks an upperclassman cohort as a resource for advice and mentorship. Mentorship has proven to have positive impacts on three domains: personal and professional development (PPD), stress reduction (SR), and ease of transition (ET) into medical school. OBJECTIVES: The purpose of this study was to identify sources of mentorship within the medical education system and compare the subjective growth of the inaugural and second classes of a newly established medical school in the three domains. METHODS: The inaugural and second classes at a newly established medical school completed an Institutional Review Board (IRB)-approved anonymous survey with questions pertaining to unidentifiable demographics, sources of mentorship, and a five-point Likert scale assessing characteristics related to the three domains. RESULTS: Twenty-three students responded to the survey. The second class (n=9) rated their growth higher in all three domains compared to the inaugural class (n=14). The inaugural class utilized the faculty mentor the most (11/14, 78.6 %). The second class utilized the on-site peer mentor the most (9/9, 100 %). Qualitative data analysis led to the emergence of three themes: (1) students utilizing their faculty mentor had the greatest growth in PPD and ET; (2) students utilizing on-site peer mentorship reporting the greatest growth in SR; and (3) informal peer mentorship utilization correlating with less growth in the three domains. CONCLUSIONS: Our study demonstrates the profound impact that mentorship has on growth in the three domains regardless of the type of mentorship utilized. The benefits, specifically with regard to SR, of an on-site peer mentorship program may not have been satisfied by other sources of mentorship.

Evaluation of venous thromboembolism risk assessment models for hospital inpatients: the VTEAM evidence synthesis.

Background: Pharmacological prophylaxis during hospital admission can reduce the risk of acquired blood clots (venous thromboembolism) but may cause complications, such as bleeding. Using a risk assessment model to predict the risk of blood clots could facilitate selection of patients for prophylaxis and optimise the balance of benefits, risks and costs. Objectives: We aimed to identify validated risk assessment models and estimate their prognostic accuracy, evaluate the cost-effectiveness of different strategies for selecting hospitalised patients for prophylaxis, assess the feasibility of using efficient research methods and estimate key parameters for future research. Design: We undertook a systematic review, decision-analytic modelling and observational cohort study conducted in accordance with Enhancing the QUAlity and Transparency Of health Research (EQUATOR) guidelines. Setting: NHS hospitals, with primary data collection at four sites. Participants: Medical and surgical hospital inpatients, excluding paediatric, critical care and pregnancy-related admissions. Interventions: Prophylaxis for all patients, none and according to selected risk assessment models. Main outcome measures: Model accuracy for predicting blood clots, lifetime costs and quality-adjusted life-years associated with alternative strategies, accuracy of efficient methods for identifying key outcomes and proportion of inpatients recommended prophylaxis using different models. Results: We identified 24 validated risk assessment models, but low-quality heterogeneous data suggested weak accuracy for prediction of blood clots and generally high risk of bias in all studies. Decision-analytic modelling showed that pharmacological prophylaxis for all eligible is generally more cost-effective than model-based strategies for both medical and surgical inpatients, when valuing a quality-adjusted life-year at £20,000. The findings were more sensitive to uncertainties in the surgical population; strategies using risk assessment models were more cost-effective if the model was assumed to have a very high sensitivity, or the long-term risks of post-thrombotic complications were lower. Efficient methods using routine data did not accurately identify blood clots or bleeding events and several pre-specified feasibility criteria were not met. Theoretical prophylaxis rates across an inpatient cohort based on existing risk assessment models ranged from 13% to 91%. Limitations: Existing studies may underestimate the accuracy of risk assessment models, leading to underestimation of their cost-effectiveness. The cost-effectiveness findings do not apply to patients with an increased risk of bleeding. Mechanical thromboprophylaxis options were excluded from the modelling. Primary data collection was predominately retrospective, risking case ascertainment bias. Conclusions: Thromboprophylaxis for all patients appears to be generally more cost-effective than using a risk assessment model, in hospitalised patients at low risk of bleeding. To be cost-effective, any risk assessment model would need to be highly sensitive. Current evidence on risk assessment models is at high risk of bias and our findings should be interpreted in this context. We were unable to demonstrate the feasibility of using efficient methods to accurately detect relevant outcomes for future research. Future work: Further research should evaluate routine prophylaxis strategies for all eligible hospitalised patients. Models that could accurately identify individuals at very low risk of blood clots (who could discontinue prophylaxis) warrant further evaluation. Study registration: This study is registered as PROSPERO CRD42020165778 and Researchregistry5216. Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: NIHR127454) and will be published in full in Health Technology Assessment; Vol. 28, No. 20. See the NIHR Funding and Awards website for further award information.

People who are admitted to hospital are at risk of blood clots that can cause serious illness or death. Patients are often given low doses of blood-thinning drugs to reduce this risk. However, these drugs can cause side effects, such as bleeding. Hospitals currently use complex risk assessment models (risk scores, which usually include patient, disease, mobility and intervention factors) to determine the individual risk of blood clots and identify people most likely to benefit from blood-thinning drugs. There are a lot of different risk scores and we do not know which one is best. We also do not know how these scores compare to each other or whether using scores to decide who should get blood-thinning drugs provides good value for money to the NHS. We reviewed all previous studies of risk scores. We found that they did not predict blood clots very well and we could not recommend one score over another. We then created a mathematical model to simulate the use of blood-thinning drugs in people admitted to hospital. The model suggested that giving blood-thinning drugs to everyone who could have them would probably provide the best value for money, in medical patients. Our findings were the same, but less certain, for surgical patients. We also collected information from four NHS hospitals to explore possibilities for future research. Our work showed that routinely collected electronic data on blood clots and bleeding events is not very accurate and that using different scores could result in variable use of blood-thinning medications. Our findings suggest that it may be better value to the NHS and better for patients if we were to offer blood-thinning medications to everyone on admission to hospital, without using any risk score. However, this approach needs further research to ensure it is safe and effective. Such research would not be able to rely on routine electronic data to identify blood clots or bleeding events, in isolation.

Bisphosphonate alternative regimens for the prevention of osteoporotic fragility fractures: BLAST-OFF, a mixed-methods study.

Background: Bisphosphonates are a class of medication commonly used to treat osteoporosis. Alendronate is recommended as the first-line treatment; however, long-term adherence (both treatment compliance and persistence) is poor. Alternative bisphosphonates are available, which can be given intravenously and have been shown to improve long-term adherence. However, the most clinically effective and cost-effective alternative bisphosphonate regimen remains unclear. What is the most cost-effective bisphosphonate in clinical trials may not be the most cost-effective or acceptable to patients in everyday clinical practice. Objectives: 1. Explore patient, clinician and stakeholder views, experiences and preferences of alendronate compared to alternative bisphosphonates. 2. Update and refine the 2016 systematic review and cost-effectiveness analysis of bisphosphonates, and estimate the value of further research into their benefits. 3. Undertake stakeholder/consensus engagement to identify important research questions and further rank research priorities. Methods: The study was conducted in two stages, stages 1A and 1B in parallel, followed by stage 2: • Stage 1A - we elicited patient and healthcare experiences to understand their preferences of bisphosphonates for the treatment of osteoporosis. This was undertaken by performing a systematic review and framework synthesis of qualitative studies, followed by semistructured qualitative interviews with participants. • Stage 1B - we updated and expanded the existing Health Technology Assessment systematic review and clinical and cost-effectiveness model, incorporating a more comprehensive review of treatment efficacy, safety, side effects, compliance and long-term persistence. • Stage 2 - we identified and ranked further research questions that need to be answered about the effectiveness and acceptability of bisphosphonates. Results: Patients and healthcare professionals identified a number of challenges in adhering to bisphosphonate medication, balancing the potential for long-term risk reduction against the work involved in adhering to oral alendronate. Intravenous zoledronate treatment was generally more acceptable, with such regimens perceived to be more straightforward to engage in, although a portion of patients taking alendronate were satisfied with their current treatment. Intravenous zoledronate was found to be the most effective, with higher adherence rates compared to the other bisphosphonates, for reducing the risk of fragility fracture. However, oral bisphosphonates are more cost-effective than intravenous zoledronate due to the high cost of zoledronate administration in hospital. The importance of including patients and healthcare professionals when setting research priorities is recognised. Important areas for research were related to patient factors influencing treatment selection and effectiveness, how to optimise long-term care and the cost-effectiveness of delivering zoledronate in an alternative, non-hospital setting. Conclusions: Intravenous zoledronate treatment was generally more acceptable to patients and found to be the most effective bisphosphonate and with greater adherence; however, the cost-effectiveness relative to oral alendronate is limited by its higher zoledronate hospital administration costs. Future work: Further research is needed to support people to make decisions influencing treatment selection, effectiveness and optimal long-term care, together with the clinical and cost-effectiveness of intravenous zoledronate administered in a non-hospital (community) setting. Limitations: Lack of clarity and limitations in the many studies included in the systematic review may have under-interpreted some of the findings relating to effects of bisphosphonates. Trial registration: This trial is registered as ISRCTN10491361. Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: NIHR127550) and is published in full in Health Technology Assessment; Vol. 28, No. 21. See the NIHR Funding and Awards website for further award information.

Bisphosphonates are drug treatments commonly used to treat osteoporosis. Alendronate is the most used and is taken by mouth, weekly at a specific time of the week, which can be challenging. Less than one in four people continue this treatment beyond 2 years. Alternative bisphosphonates are available, which vary in frequency and how they are administered. The most acceptable and best value-for-money regimen is unclear. Our aim was to determine how effective alternative bisphosphonates are compared to alendronate at preventing fractures and whether reduction in fracture risk was achieved at a reasonable financial cost, but acceptable to patients. The study was conducted in two stages, stages 1A and 1B in parallel, followed by stage 2: Stage 1A: a review of the published evidence on patients' and doctors' views, experiences and preferences regarding different bisphosphonate treatment regimens, followed by interviews with patients and healthcare professionals. Stage 1B: an update of an existing study on how effective bisphosphonates are in preventing fragility fractures caused by osteoporosis and whether they are good value for money. Stage 2: identification of questions that need to be answered about the effectiveness and acceptability of bisphosphonate treatments. Taking bisphosphonate medication often involves quite a lot of effort by patients, particularly when taking alendronate tablets. A yearly infusion of zoledronate treatment was more acceptable, easier to engage with and the most effective treatment compared to alendronate. However, the cost of administering zoledronate in hospital made alendronate better value for money. Bisphosphonates are effective in reducing the risk of fracture, but 'continuing with treatment', particularly alendronate tablets, remains a challenge. A yearly infusion of zoledronate offers an acceptable and effective treatment, but further research is needed to support patients and healthcare professionals in making decisions about the various treatments, benefits and cost savings of administering zoledronate outside of hospital and in the community.

Acute Cardiac Events in Hospitalized Older Adults With Respiratory Syncytial Virus Infection.

Importance: Respiratory syncytial virus (RSV) infection can cause severe respiratory illness in older adults. Less is known about the cardiac complications of RSV disease compared with those of influenza and SARS-CoV-2 infection. Objective: To describe the prevalence and severity of acute cardiac events during hospitalizations among adults aged 50 years or older with RSV infection. Design, Setting, and Participants: This cross-sectional study analyzed surveillance data from the RSV Hospitalization Surveillance Network, which conducts detailed medical record abstraction among hospitalized patients with RSV infection detected through clinician-directed laboratory testing. Cases of RSV infection in adults aged 50 years or older within 12 states over 5 RSV seasons (annually from 2014-2015 through 2017-2018 and 2022-2023) were examined to estimate the weighted period prevalence and 95% CIs of acute cardiac events. Exposures: Acute cardiac events, identified by International Classification of Diseases, 9th Revision, Clinical Modification or International Statistical Classification of Diseases, Tenth Revision, Clinical Modification discharge codes, and discharge summary review. Main Outcomes and Measures: Severe disease outcomes, including intensive care unit (ICU) admission, receipt of invasive mechanical ventilation, or in-hospital death. Adjusted risk ratios (ARR) were calculated to compare severe outcomes among patients with and without acute cardiac events. Results: The study included 6248 hospitalized adults (median [IQR] age, 72.7 [63.0-82.3] years; 59.6% female; 56.4% with underlying cardiovascular disease) with laboratory-confirmed RSV infection. The weighted estimated prevalence of experiencing a cardiac event was 22.4% (95% CI, 21.0%-23.7%). The weighted estimated prevalence was 15.8% (95% CI, 14.6%-17.0%) for acute heart failure, 7.5% (95% CI, 6.8%-8.3%) for acute ischemic heart disease, 1.3% (95% CI, 1.0%-1.7%) for hypertensive crisis, 1.1% (95% CI, 0.8%-1.4%) for ventricular tachycardia, and 0.6% (95% CI, 0.4%-0.8%) for cardiogenic shock. Adults with underlying cardiovascular disease had a greater risk of experiencing an acute cardiac event relative to those who did not (33.0% vs 8.5%; ARR, 3.51; 95% CI, 2.85-4.32). Among all hospitalized adults with RSV infection, 18.6% required ICU admission and 4.9% died during hospitalization. Compared with patients without an acute cardiac event, those who experienced an acute cardiac event had a greater risk of ICU admission (25.8% vs 16.5%; ARR, 1.54; 95% CI, 1.23-1.93) and in-hospital death (8.1% vs 4.0%; ARR, 1.77; 95% CI, 1.36-2.31). Conclusions and Relevance: In this cross-sectional study over 5 RSV seasons, nearly one-quarter of hospitalized adults aged 50 years or older with RSV infection experienced an acute cardiac event (most frequently acute heart failure), including 1 in 12 adults (8.5%) with no documented underlying cardiovascular disease. The risk of severe outcomes was nearly twice as high in patients with acute cardiac events compared with patients who did not experience an acute cardiac event. These findings clarify the baseline epidemiology of potential cardiac complications of RSV infection prior to RSV vaccine availability.

Thromboprophylaxis during pregnancy and the puerperium: a systematic review and economic evaluation to estimate the value of future research.

Background: Pharmacological prophylaxis to prevent venous thromboembolism is currently recommended for women assessed as being at high risk of venous thromboembolism during pregnancy or in the 6 weeks after delivery (the puerperium). The decision to provide thromboprophylaxis involves weighing the benefits, harms and costs, which vary according to the individual's venous thromboembolism risk. It is unclear whether the United Kingdom's current risk stratification approach could be improved by further research. Objectives: To quantify the current decision uncertainty associated with selecting women who are pregnant or in the puerperium for thromboprophylaxis and to estimate the value of one or more potential future studies that would reduce that uncertainty, while being feasible and acceptable to patients and clinicians. Methods: A decision-analytic model was developed which was informed by a systematic review of risk assessment models to predict venous thromboembolism in women who are pregnant or in the puerperium. Expected value of perfect information analysis was used to determine which factors are associated with high decision uncertainty and should be the target of future research. To find out whether future studies would be acceptable and feasible, we held workshops with women who have experienced a blood clot or have been offered blood-thinning drugs and surveyed healthcare professionals. Expected value of sample information analysis was used to estimate the value of potential future research studies. Results: The systematic review included 17 studies, comprising 19 unique externally validated risk assessment models and 1 internally validated model. Estimates of sensitivity and specificity were highly variable ranging from 0% to 100% and 5% to 100%, respectively. Most studies had unclear or high risk of bias and applicability concerns. The decision analysis found that there is substantial decision uncertainty regarding the use of risk assessment models to select high-risk women for antepartum prophylaxis and obese postpartum women for postpartum prophylaxis. The main source of decision uncertainty was uncertainty around the effectiveness of thromboprophylaxis for preventing venous thromboembolism in women who are pregnant or in the puerperium. We found that a randomised controlled trial of thromboprophylaxis in obese postpartum women is likely to have substantial value and is more likely to be acceptable and feasible than a trial recruiting women who have had a previous venous thromboembolism. In unselected postpartum women and women following caesarean section, the poor performance of risk assessment models meant that offering prophylaxis based on these models had less favourable cost effectiveness with lower decision uncertainty. Limitations: The performance of the risk assessment model for obese postpartum women has not been externally validated. Conclusions: Future research should focus on estimating the efficacy of pharmacological thromboprophylaxis in pregnancy and the puerperium, and clinical trials would be more acceptable in women who have not had a previous venous thromboembolism. Study registration: This study is registered as PROSPERO CRD42020221094. Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: NIHR131021) and is published in full in Health Technology Assessment; Vol. 28, No. 9. See the NIHR Funding and Awards website for further award information.

Women who are pregnant or who have given birth in the previous 6 weeks are at increased risk of developing blood clots that can cause serious illness or death. Small doses of blood thinners given by injection are safe in pregnancy and can reduce the risk of blood clots, but they can slightly increase the risk of bleeding. Healthcare professionals use risk assessment tools to decide if a woman is at high risk of blood clots and should be offered blood thinners. We wanted to find out what research would be useful to help them make better decisions. We reviewed previous research to establish which risk assessment tools are best at predicting who will have a blood clot. We then created a mathematical model to predict what would happen when using different risk assessment tools to decide who should be offered blood thinners, both during pregnancy and after giving birth. We found that there was a lot of uncertainty about which women should be offered blood thinners. This was mainly because there have only been a few small studies comparing blood thinners to no treatment in pregnant women or women who have recently given birth. We estimated the value of future studies comparing blood thinners to no treatment, in groups of women with different risk factors, by predicting what information we would gain and how this would be used to improve decisions about using blood thinners. To find out whether these studies would be acceptable and feasible, we held workshops with women who have experienced a blood clot or have been offered blood thinners and surveyed healthcare professionals. We found that a study in obese women who have recently given birth would have substantial value and may be more acceptable than a study in pregnant women with a previous blood clot.

Life in the PFAS lane: The impact of perfluoroalkyl substances on photosynthesis, cellular exudates, nutrient cycling, and composition of a marine microbial community.

Perfluoroalkyl substances (PFAS) are of great ecological concern, however, exploration of their impact on bacteria-phytoplankton consortia is limited. This study employed a bioassay approach to investigate the effect of unary exposures of increasing concentrations of PFAS (perfluorooctane sulfonate (PFOS) and 6:2 fluorotelomer sulfonate (6:2 FTS)) on microbial communities from the northwestern Gulf of Mexico. Each community was examined for changes in growth and photophysiology, exudate production and shifts in community structure (16S and 18S rRNA genes). 6:2 FTS did not alter the growth or health of phytoplankton communities, as there were no changes relative to the controls (no PFOS added). On the other hand, PFOS elicited significant phototoxicity (p < 0.05), altering PSII antennae size, lowering PSII connectivity, and decreasing photosynthetic efficiency over the incubation (four days). PFOS induced a cellular protective response, indicated by significant increases (p < 0.001) in the release of transparent exopolymer particles (TEP) compared to the control. Eukaryotic communities (18S rRNA gene) changed substantially (p < 0.05) and to a greater extent than prokaryotic communities (16S rRNA gene) in PFOS treatments. Community shifts were concentration-dependent for eukaryotes, with the low treatment (5 mg/L PFOS) dominated by Coscinodiscophyceae (40 %), and the high treatment (30 mg/L PFOS) marked by a Trebouxiophyceae (50 %) dominance. Prokaryotic community shifts were not concentration dependent, as both treatment levels became depleted in Cyanobacteriia and were dominated by members of the Bacteroidia, Gammaproteobacteria, and Alphaproteobacteria classes. Further, PFOS significantly decreased (p < 0.05) the Shannon diversity and Pielou's evenness across treatments for eukaryotes, and in the low treatment (5 mg/L PFOS) for prokaryotes. These findings show that photophysiology was not impacted by 6:2 FTS but PFOS elicited toxicity that impacted photosynthesis, exudate release, and community composition. This research is crucial in understanding how PFOS impacts microbial communities.

A nine-month repeat-dose intravaginal ring (Ovaprene) irritation study in sheep.

OBJECTIVES: Ovaprene is a novel, investigational, intravaginal hormone-free monthly ring contraceptive designed for use in women of reproductive age to be worn over multiple weeks (one menstrual cycle). The objective of this work was to evaluate the safety of Ovaprene during a nine-month repeat-dose sheep study. STUDY DESIGN: In addition to traditional safety endpoints such as histopathological evaluation of the sheep female reproductive tract, vaginal fluids were collected and tested for released iron over time. Also, the amount of iron in the rings was assessed following removal, and serum iron levels were measured. There were four sheep in each group (Ovaprene group and sham group). RESULTS: There were no macroscopic clinical findings. There was minimal to mild, mixed or mononuclear cell infiltration present in all levels of vagina (cranial, mid, and caudal) from all animals including sham controls based on post-study necropsy. The female reproductive tract from animals treated with the Ovaprene ring was comparable to the sham controls. The concentrations of serum iron in sheep treated with Ovaprene ring were similar compared to a sham treated animal. The average amount of ferrous gluconate released from Ovaprene over the 29-day period of use was 175 mg of the approximately 512 mg nominally loaded into the rings. CONCLUSIONS: Overall, the Ovaprene devices were well-tolerated in female sheep. IMPLICATIONS: This study should support a chronic (e.g., one year) contraceptive efficacy study in women.

Effectiveness and cost effectiveness of pharmacological thromboprophylaxis for medical inpatients: decision analysis modelling study.

Objective: To determine the balance of costs, risks, and benefits for different thromboprophylaxis strategies for medical patients during hospital admission. Design: Decision analysis modelling study. Setting: NHS hospitals in England. Population: Eligible adult medical inpatients, excluding patients in critical care and pregnant women. Interventions: Pharmacological thromboprophylaxis (low molecular weight heparin) for all medical inpatients, thromboprophylaxis for none, and thromboprophylaxis given to higher risk inpatients according to risk assessment models (Padua, Caprini, IMPROVE, Intermountain, Kucher, Geneva, and Rothberg) previously validated in medical cohorts. Main outcome measures: Lifetime costs and quality adjusted life years (QALYs). Costs were assessed from the perspective of the NHS and Personal Social Services in England. Other outcomes assessed were incidence and treatment of venous thromboembolism, major bleeds including intracranial haemorrhage, chronic thromboembolic complications, and overall survival. Results: Offering thromboprophylaxis to all medical inpatients had a high probability (>99%) of being the most cost effective strategy (at a threshold of £20 000 (€23 440; $25 270) per QALY) in the probabilistic sensitivity analysis, when applying performance data from the Padua risk assessment model, which was typical of that observed across several risk assessment models in a medical inpatient cohort. Thromboprophylaxis for all medical inpatients was estimated to result in 0.0552 additional QALYs (95% credible interval 0.0209 to 0.1111) while generating cost savings of £28.44 (-£47 to £105) compared with thromboprophylaxis for none. No other risk assessment model was more cost effective than thromboprophylaxis for all medical inpatients when assessed in deterministic analysis. Risk based thromboprophylaxis was found to have a high (76.6%) probability of being the most cost effective strategy only when assuming a risk assessment model with very high sensitivity is available (sensitivity 99.9% and specificity 23.7% v base case sensitivity 49.3% and specificity 73.0%). Conclusions: Offering pharmacological thromboprophylaxis to all eligible medical inpatients appears to be the most cost effective strategy. To be cost effective, any risk assessment model would need to have a very high sensitivity resulting in widespread thromboprophylaxis in all patients except those at the very lowest risk, who could potentially avoid prophylactic anticoagulation during their hospital stay.

The implications of competing risks and direct treatment disutility in cardiovascular disease and osteoporotic fracture: risk prediction and cost effectiveness analysis.

Background: Clinical guidelines commonly recommend preventative treatments for people above a risk threshold. Therefore, decision-makers must have faith in risk prediction tools and model-based cost-effectiveness analyses for people at different levels of risk. Two problems that arise are inadequate handling of competing risks of death and failing to account for direct treatment disutility (i.e. the hassle of taking treatments). We explored these issues using two case studies: primary prevention of cardiovascular disease using statins and osteoporotic fracture using bisphosphonates. Objectives: Externally validate three risk prediction tools [QRISK®3, QRISK®-Lifetime, QFracture-2012 (ClinRisk Ltd, Leeds, UK)]; derive and internally validate new risk prediction tools for cardiovascular disease [competing mortality risk model with Charlson Comorbidity Index (CRISK-CCI)] and fracture (CFracture), accounting for competing-cause death; quantify direct treatment disutility for statins and bisphosphonates; and examine the effect of competing risks and direct treatment disutility on the cost-effectiveness of preventative treatments. Design, participants, main outcome measures, data sources: Discrimination and calibration of risk prediction models (Clinical Practice Research Datalink participants: aged 25-84 years for cardiovascular disease and aged 30-99 years for fractures); direct treatment disutility was elicited in online stated-preference surveys (people with/people without experience of statins/bisphosphonates); costs and quality-adjusted life-years were determined from decision-analytic modelling (updated models used in National Institute for Health and Care Excellence decision-making). Results: CRISK-CCI has excellent discrimination, similar to that of QRISK3 (Harrell's c = 0.864 vs. 0.865, respectively, for women; and 0.819 vs. 0.834, respectively, for men). CRISK-CCI has systematically better calibration, although both models overpredict in high-risk subgroups. People recommended for treatment (10-year risk of ≥ 10%) are younger when using QRISK-Lifetime than when using QRISK3, and have fewer observed events in a 10-year follow-up (4.0% vs. 11.9%, respectively, for women; and 4.3% vs. 10.8%, respectively, for men). QFracture-2012 underpredicts fractures, owing to under-ascertainment of events in its derivation. However, there is major overprediction among people aged 85-99 years and/or with multiple long-term conditions. CFracture is better calibrated, although it also overpredicts among older people. In a time trade-off exercise (n = 879), statins exhibited direct treatment disutility of 0.034; for bisphosphonates, it was greater, at 0.067. Inconvenience also influenced preferences in best-worst scaling (n = 631). Updated cost-effectiveness analysis generates more quality-adjusted life-years among people with below-average cardiovascular risk and fewer among people with above-average risk. If people experience disutility when taking statins, the cardiovascular risk threshold at which benefits outweigh harms rises with age (≥ 8% 10-year risk at 40 years of age; ≥ 38% 10-year risk at 80 years of age). Assuming that everyone experiences population-average direct treatment disutility with oral bisphosphonates, treatment is net harmful at all levels of risk. Limitations: Treating data as missing at random is a strong assumption in risk prediction model derivation. Disentangling the effect of statins from secular trends in cardiovascular disease in the previous two decades is challenging. Validating lifetime risk prediction is impossible without using very historical data. Respondents to our stated-preference survey may not be representative of the population. There is no consensus on which direct treatment disutilities should be used for cost-effectiveness analyses. Not all the inputs to the cost-effectiveness models could be updated. Conclusions: Ignoring competing mortality in risk prediction overestimates the risk of cardiovascular events and fracture, especially among older people and those with multimorbidity. Adjustment for competing risk does not meaningfully alter cost-effectiveness of these preventative interventions, but direct treatment disutility is measurable and has the potential to alter the balance of benefits and harms. We argue that this is best addressed in individual-level shared decision-making. Study registration: This study is registered as PROSPERO CRD42021249959. Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health and Social Care Delivery Research programme (NIHR award ref: 15/12/22) and is published in full in Health and Social Care Delivery Research; Vol. 12, No. 4. See the NIHR Funding and Awards website for further award information.

Before offering a medicine to prevent disease, prescribers must expect it to do more good than harm. This balance depends on how likely it is that the person will develop the disease we want to prevent. But people might first die for other reasons. We call this a 'competing risk'. In most cases, the mathematical tools we use to estimate the chance of developing a disease do not account for competing risks. Another problem is that, when weighing up the benefits and harms of medicines, we ignore the hassle they cause patients, even when they do not cause side effects. We used two examples: statins to prevent heart disease and bisphosphonates to prevent fractures. First, we assessed if existing tools get predictions wrong by not accounting for competing risks. We found that they exaggerate the chance of heart attacks and strokes. However, the exaggeration is greatest among people who would clearly benefit from preventative treatment. So it may not change treatment decisions much. The fracture prediction tool we studied was very inaccurate, exaggerating risk among older people, but underestimating risk among younger people. We made a new fracture risk prediction tool. It gave better predictions, but it was still inaccurate for people aged > 85 years and those with several health problems. Next, we asked people questions designed to put a number on the hassle that statins and bisphosphonates cause. Most people thought that taking either is inconvenient, but the hassle factor for bisphosphonates is bigger. Finally, we updated the mathematical models that the National Institute for Health and Care Excellence used when recommending statins and bisphosphonates. We worked out if competing risks and the hassle of taking medicines make a difference to results. Statins remain a good idea for almost everyone, unless they really hate the idea of taking them. But bisphosphonates would do more harm than good for anyone who agrees with the hassle factor we found.

An online clinical decision tool to screen for vertebral fragility fractures (Vfrac) in older women presenting with back pain in general practice: protocol for a feasibility study in preparation for a future cluster randomised controlled trial.

This feasibility study for a future definitive randomized trial assesses the use and acceptability of a new clinical decision tool to identify risk of a vertebral fracture and those who should be referred for spinal radiography in women aged 65 or over presenting to primary care with back pain. PURPOSE: Approximately 12% of older adults have vertebral fragility fractures, but currently fewer than one-third are diagnosed, potentially limiting access to bone protection treatment. Vfrac is a vertebral fracture screening tool which classifies individuals into high or low risk of having a vertebral fracture, allowing targeting of spinal radiographs to high-risk individuals. The objective of this study was to investigate the feasibility of conducting a cluster randomized controlled trial to evaluate the use of an online version of Vfrac in primary care. METHODS: The study will run in six general practices, with three given the Vfrac tool for use on older women (> 65 years) consulting with back pain and three using standard clinical processes for managing such back pain. Anonymised data covering a 12-month period will be collected from all sites on consultations by older women with back pain. Focus groups will be undertaken with healthcare professionals and patients on whom the tool was used to understand the acceptability of Vfrac and identify factors that impact its use. These patients will be sent a paper version of the Vfrac questionnaire to self-complete at home. Outputs of the self-completion Vfrac (high versus low risk) will be compared with the face-to-face Vfrac (high versus low risk), and agreement assessed using Cohen's kappa. RESULTS: This study will evaluate the use and acceptability of Vfrac within primary care and determine if data on resource use can be collected accurately and comprehensively. CONCLUSIONS: This article describes the protocol of the Vfrac feasibility study. TRIAL REGISTRATION: ISRCTN18000119 (registered 01/03/2022) and ISRCTN12150779 (registered 10/01/2022).

Estimating the value of future research into thromboprophylaxis for women during pregnancy and after delivery: a value of information analysis.

BACKGROUND: Risk assessment models (RAMs) are used to select women at increased risk of venous thromboembolism (VTE) during pregnancy and the puerperium for thromboprophylaxis. OBJECTIVES: To estimate the value of potential future studies that would reduce the decision uncertainty associated with offering thromboprophylaxis according to available RAMs in the following groups: high-risk antepartum women (eg, prior VTE), unselected postpartum women, and postpartum women with risk factors (obesity or cesarean delivery). METHODS: A decision-analytic model was developed to simulate clinical outcomes, lifetime costs, and quality-adjusted life-years for different thromboprophylaxis strategies, including thromboprophylaxis for all, thromboprophylaxis for none, and RAM-based thromboprophylaxis. The expected value of perfect information analysis was used to determine which factors are associated with high decision uncertainty. The value of future research studies was estimated using expected value of sample information analysis. Costs were assessed from a health and social services perspective. RESULTS: The expected value of perfect information analysis identified high decision uncertainty for high-risk antepartum women (£21.8 million) and obese postpartum women (£13.4 million), which was largely attributable to uncertainty regarding the effectiveness of thromboprophylaxis in reducing VTE. A randomized controlled trial of thromboprophylaxis compared with none in obese postpartum women is likely to have substantial value (£2.8 million; 300 participants per arm). A trial in women with previous VTE would have higher value but would be less acceptable. CONCLUSION: Future research should focus on estimating the effectiveness of thromboprophylaxis in obese postpartum women with additional risk factors who have not had a previous VTE.

Phase 1 trial of navitoclax and sorafenib in patients with relapsed or refractory solid tumors with hepatocellular carcinoma expansion cohort.

Navitoclax (ABT-263) is an oral BCL2 homology-3 mimetic that binds with high affinity to pro-survival BCL2 proteins, resulting in apoptosis. Sorafenib, an oral multi kinase inhibitor also promotes apoptosis and inhibits tumor angiogenesis. The efficacy of either agent alone is limited; however, preclinical studies demonstrate synergy with the combination of navitoclax and sorafenib. In this phase 1 study, we evaluated the combination of navitoclax and sorafenib in a dose escalation cohort of patients with refractory solid tumors, with an expansion cohort in hepatocellular carcinoma (HCC). Maximum tolerated dose (MTD) was determined using the continual reassessment method. Navitoclax and sorafenib were administered continuously on days 1 through 21 of 21-day cycles. Ten patients were enrolled in the dose escalation cohort and 15 HCC patients were enrolled in the expansion cohort. Two dose levels were tested, and the MTD was navitoclax 150 mg daily plus sorafenib 400 mg twice daily. Among all patients, the most common grade 3 toxicity was thrombocytopenia (5 patients, 20%): there were no grade 4 or 5 toxicities. Patients received a median of 2 cycles (range 1-36 cycles) and all patients were off study treatment at data cut off. Six patients in the expansion cohort had stable disease, and there were no partial or complete responses. Drug-drug interaction between navitoclax and sorafenib was not observed. The combination of navitoclax and sorafenib did not increase induction of apoptosis compared with navitoclax alone. Navitoclax plus sorafenib is tolerable but showed limited efficacy in the HCC expansion cohort. These findings do not support further development of this combination for the treatment of advanced HCC. This phase I trial was conducted under ClinicalTrials.gov registry number NCT01364051.

Comparison of two contrast-enhancing staining agents for use in X-ray imaging and digital volume correlation measurements across the cartilage-bone interface.

OBJECTIVE: The pathogenesis of osteoarthritis (OA) is associated with subchondral bone changes, which is linked to abnormal strain distribution in the overlying articular cartilage. This highlights the importance of understanding mechanical interaction at the cartilage-bone interface. The aim of this study is to compare solutions of two contrast-enhancing staining agents (CESA) for combining high-resolution Contrast-Enhanced X-ray microfocus Computed Tomography (CECT) with Digital Volume Correlation (DVC) for full-field strain measurements at the cartilage-bone interface. DESIGN: Bovine osteochondral plugs were stained with phosphotungstic acid (PTA) in 70% ethanol or 1:2 hafnium-substituted Wells-Dawson polyoxometalate (Hf-WD POM) in PBS. Mechanical properties were assessed using micromechanical probing and nanoindentation. Strain uncertainties (from CECT data) were evaluated following two consecutive unloaded scans. Residual strains were computed following unconfined compression (ex situ) testing. RESULTS: PTA and Hf-WD POM enabled the visualisation of structural features in cartilage, allowing DVC computation on the CECT data. Residual strains up to ∼10,000 µÉ› were detected up to the tidemark. Nanoindentation showed that PTA-staining caused an average ∼6-fold increase in articular cartilage stiffness, a ∼19-fold increase in reduced modulus and ∼7-fold increase in hardness, whereas Hf-WD POM-stained specimens had mechanical properties similar to pre-stain tissue. Micromechanical probing showed a 77% increase in cartilage surface stiffness after PTA-staining, in comparison to a 16% increase in stiffness after staining with Hf-WD POM. CONCLUSION: Hf-WD POM is a more suitable CESA solution compared to PTA for CECT imaging combined with DVC as it allowed visualisation of structural features in the cartilage tissue whilst more closely maintaining tissue mechanical properties.

The Professional Quality of Life of Domestic and Sexual Violence Advocates: A Systematic Review of Possible Risk and Protective Factors.

Professionals employed within the field of domestic and sexual violence (DV/SV) are known to experience both positive and negative psychological impacts because of the nature of their work. This review aims to establish which factors influence the professional quality of life (ProQOL) of DV/SV advocates. This group is known to face challenges that are specific to their working practices including scarce resources and frequent exposure to traumatic material. The systematic review protocol was designed based upon Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidance. Following a mixed-methods convergent segregated approach, a systematic search for qualitative and quantitative research within PsycINFO, Academic Search Complete, CINAHL, MEDLINE, Sage, Taylor & Francis, Wiley Online Library, and BASE was undertaken. Peer-reviewed empirical research and relevant gray literature, published in English, were considered for inclusion. Thirty articles were identified (16 quantitative, 13 qualitative, and 1 mixed-methods study), and assessed for methodological quality and risk of bias using established quality appraisal tools. An array of risk and protective factors emerged including communication competence, support from co-workers, office resources, and occupational stigma. A gap in the current evidence base was identified regarding the role that personal strengths may play in the well-being of those employed within the DV/SV sector. The ProQOL of DV/SV advocates is complex and dependent upon a variety of factors specific to their situation at the time. However, the findings of this review provide an important evidence base for future research avenues as well as policies and procedures for this workforce specifically.

Rapid, automated quantification of Haemonchus contortus ova in sheep faecal samples.

Haemonchus contortus is one of the most pathogenic nematodes affecting small ruminants globally and is responsible for large economic losses in the sheep and goat industry. Anthelmintic resistance is rampant in this parasite and thus parasite control programs must account for drug efficacy on individual farms and, sometimes, whether H. contortus is the most prevalent trichostrongylid. Historically, coproculture has been the main way to determine the prevalence of H. contortus in faecal samples due to the inability to morphologically differentiate between trichostrongylid egg types, but this process requires a skilled technician and takes multiple days to complete. Fluoresceinated peanut agglutinin (PNA) has been shown to specifically bind H. contortus and thus differentiate eggs based on whether they fluoresce, but this method has not been widely adopted. The ParasightTM System (PS) fluorescently stains helminth eggs in order to identify and quantify them, and the H. contortus PNA staining method was therefore adapted to this platform using methodology requiring only 20 min to obtain results. In this study, 74 fecal samples were collected from sheep and analyzed for PNA-stained H. contortus, using both PS and manual fluorescence microscopy. The percentage of H. contortus was determined based on standard total strongylid counts with PS or brightfield microscopy. Additionally, 15 samples were processed for coproculture with larval identification, and analyzed with both manual and automated PNA methods. All methods were compared using the coefficient of determination (R2) and the Lin's concordance correlation coefficient (ρc). ParasightTM and manual PNA percent H. contortus results were highly correlated with R2 = 0.8436 and ρc = 0.9100 for all 74 fecal samples. Coproculture versus PS percent H. contortus were also highly correlated with R2 = 0.8245 and ρc = 0.8605. Overall, this system provides a rapid and convenient method for determining the percentage of H. contortus in sheep and goat fecal samples without requiring specialized training.

Residential social vulnerability among healthcare personnel with and without severe acute respiratory coronavirus virus 2 (SARS-CoV-2) infection in Five US states, May-December 2020.

OBJECTIVE: To characterize residential social vulnerability among healthcare personnel (HCP) and evaluate its association with severe acute respiratory coronavirus virus 2 (SARS-CoV-2) infection. DESIGN: Case-control study. SETTING: This study analyzed data collected in May-December 2020 through sentinel and population-based surveillance in healthcare facilities in Colorado, Minnesota, New Mexico, New York, and Oregon. PARTICIPANTS: Data from 2,168 HCP (1,571 cases and 597 controls from the same facilities) were analyzed. METHODS: HCP residential addresses were linked to the social vulnerability index (SVI) at the census tract level, which represents a ranking of community vulnerability to emergencies based on 15 US Census variables. The primary outcome was SARS-CoV-2 infection, confirmed by positive antigen or real-time reverse-transcriptase- polymerase chain reaction (RT-PCR) test on nasopharyngeal swab. Significant differences by SVI in participant characteristics were assessed using the Fisher exact test. Adjusted odds ratios (aOR) with 95% confidence intervals (CIs) for associations between case status and SVI, controlling for HCP role and patient care activities, were estimated using logistic regression. RESULTS: Significantly higher proportions of certified nursing assistants (48.0%) and medical assistants (44.1%) resided in high SVI census tracts, compared to registered nurses (15.9%) and physicians (11.6%). HCP cases were more likely than controls to live in high SVI census tracts (aOR, 1.76; 95% CI, 1.37-2.26). CONCLUSIONS: These findings suggest that residing in more socially vulnerable census tracts may be associated with SARS-CoV-2 infection risk among HCP and that residential vulnerability differs by HCP role. Efforts to safeguard the US healthcare workforce and advance health equity should address the social determinants that drive racial, ethnic, and socioeconomic health disparities.

Further Progress Toward Automating Functional Analysis Interpretation.

It is considered best practice to conduct a functional analysis and visually inspect data collected to determine the function of problem behavior, which then informs the intervention approaches applied. Visual inspection has been described as a "subjective" process that may be affected by factors unrelated to the data. Structured decision-making guidelines have been established to address some of these shortcomings. The current paper is a follow-up to earlier work describing positive outcomes related to the viability of a decision support system based on structured criteria from Roane et al. Here, we demonstrate important improvements in a computer script's interpretation of functional analysis data, including improvement in agreement between the updated computer script version and experienced human raters (89%) compared to our original agreement outcomes (81%). This paper further supports the use of decision support systems for functional analysis interpretation.

Rectus to defect ratio for estimating the complexity of ventral hernia repair: Is it reliable for robotic surgery?

INTRODUCTION: The rectus to defect ratio (RDR) has been previously described as a metric which enables surgeons to estimate the need to perform additional myofascial release (AMR), in addition to open Rives-Stoppa retro-muscular hernia repair. We sought to validate this measurement specifically for patients undergoing robotic totally extraperitoneal (eTEP) hernia repair. METHODS: A retrospective chart review of 188 patients who underwent robotic ventral hernia repair via eTEP approach. RDR on preoperative CT was compared to the final operation rendered. The primary endpoint was the RDR's ability to predict the need for TAR to achieve fascial closure. RESULTS: Of 188 patients, 154 were repaired with rectus myofascial release, while 34 also required TAR. There was a linear decrease in the need for TAR with increasing RDR. RDR 1-1.49 (n â€‹= â€‹12) required TAR in 66.7 â€‹% of cases, RDR 1.5-1.99 (n â€‹= â€‹25) in 43.8 â€‹%, RDR 2-2.49 (n â€‹= â€‹31) in 29 â€‹%, and RDR >2.5 (n â€‹= â€‹151) in just 5.8 â€‹% CONCLUSION: The RDR accurately predicts the need for TAR to achieve fascial closure during robotic eTEP ventral hernia repair. An RDR >2.5 portends fascial closure without TAR 94.2 â€‹% of cases.

The Impact of Neurotransmitters on the Neurobiology of Neurodegenerative Diseases.

Neurodegenerative diseases affect millions of people worldwide. Neurodegenerative diseases result from progressive damage to nerve cells in the brain or peripheral nervous system connections that are essential for cognition, coordination, strength, sensation, and mobility. Dysfunction of these brain and nerve functions is associated with Alzheimer's disease, Parkinson's disease, Huntington's disease, Amyotrophic lateral sclerosis, and motor neuron disease. In addition to these, 50% of people living with HIV develop a spectrum of cognitive, motor, and/or mood problems collectively referred to as HIV-Associated Neurocognitive Disorders (HAND) despite the widespread use of a combination of antiretroviral therapies. Neuroinflammation and neurotransmitter systems have a pathological correlation and play a critical role in developing neurodegenerative diseases. Each of these diseases has a unique pattern of dysregulation of the neurotransmitter system, which has been attributed to different forms of cell-specific neuronal loss. In this review, we will focus on a discussion of the regulation of dopaminergic and cholinergic systems, which are more commonly disturbed in neurodegenerative disorders. Additionally, we will provide evidence for the hypothesis that disturbances in neurotransmission contribute to the neuronal loss observed in neurodegenerative disorders. Further, we will highlight the critical role of dopamine as a mediator of neuronal injury and loss in the context of NeuroHIV. This review will highlight the need to further investigate neurotransmission systems for their role in the etiology of neurodegenerative disorders.