Search

Felicity Veal,1 Angus Thompson,1 Samuel Halliday,2 Peter Boyles,2 Chris Orlikowski,3 Luke Bereznicki1 1Unit for Medication Outcomes Research & Education (UMORE), School of Pharmacy and Pharmacology, University of Tasmania, Hobart, Tasmania, Australia; 2Department of Health, Hobart, Tasmania, Australia; 3Federal Pain Clinic, Hobart, Tasmania, AustraliaCorrespondence: Felicity VealUnit for Medication Outcomes Research & Education (UMORE), School of Pharmacy and Pharmacology, University of Tasmania, Private Bag 26, Hobart, Tasmania 7001, AustraliaTel +61 36 226 2312Fax +61 36 226 7627Email Felicity.Veal@utas.edu.auBackground: Acute pain is common following surgery, with opioids frequently employed in its management. Studies indicate that commencing an opioid during a hospital admission increases the likelihood of long-term use. This study aimed to identify the prevalence of opioid persistence amongst opioid-naïve patients following surgery as well as the indication for use.Methods: A retrospective review of patients who underwent a surgical procedure at the Royal Hobart Hospital, Tasmania, Australia, between August and September 2016 was undertaken. Patients were linked to the Tasmanian real-time prescription monitoring database to ascertain if they were subsequently dispensed a Schedule 8 opioid (morphine, codeine oxycodone, buprenorphine, hydromorphone, fentanyl, methadone, or tapentadol) and the indication for use.Results: Of the 3275 hospital admissions, 1015 opioid-naïve patients were eligible for inclusion. Schedule 8 opioids were dispensed at or within 2 days of discharge in 41.7% of admissions. Thirty-nine (3.9%) patients received prescribed opioids 2-months post-discharge; 1.8% of the patients were approved by State Health to be prescribed Schedule 8 opioids regularly for a chronic condition at 6 months, and 1.3% received infrequent or one-off prescriptions for Schedule 8 opioids at 6 months. Thirteen (1.3%) patients continued Schedule 8 opioids for at least 6 months following their surgery, with the indication for treatment either related to the surgery or the condition which surgery was sought for.Conclusion: This study found that there was a low rate of Schedule 8 opioid persistence following surgery, indicating post-surgical pain is not a significant driver for persistent opioid use.Keywords: opioids, post-operative, persistence, prescribing

BackgroundIn low- and middle-income countries, mental health training often includes sending few generalist clinicians to specialist-led programs for several weeks. Our objective is to develop and test a video-assisted training model addressing the shortcomings of traditional programs that affect scalability: failing to train all clinicians, disrupting clinical services, and depending on specialists.MethodsWe implemented the program -video lectures and on-site skills training- for all clinicians at a rural Nepali hospital. We used Wilcoxon signed-rank tests to evaluate pre- and post-test change in knowledge (diagnostic criteria, differential diagnosis, and appropriate treatment). We used a series of 'Yes' or 'No' questions to assess attitudes about mental illness, and utilized exact McNemar's test to analyze the proportions of participants who held a specific belief before and after the training. We assessed acceptability and feasibility through key informant interviews and structured feedback.ResultsFor each topic except depression, there was a statistically significant increase (Δ) in median scores on knowledge questionnaires: Acute Stress Reaction (Δ = 20, p = 0.03), Depression (Δ = 11, p = 0.12), Grief (Δ = 40, p < 0.01), Psychosis (Δ = 22, p = 0.01), and post-traumatic stress disorder (Δ = 20, p = 0.01). The training received high ratings; key informants shared examples and views about the training's positive impact and complementary nature of the program's components.ConclusionVideo lectures and on-site skills training can address the limitations of a conventional training model while being acceptable, feasible, and impactful toward improving knowledge and attitudes of the participants.

BACKGROUND Among critically ill adults undergoing tracheal intubation, hypoxemia increases the risk of cardiac arrest and death. The effect of preoxygenation with noninvasive ventilation, as compared with preoxygenation with an oxygen mask, on the incidence of hypoxemia during tracheal intubation is uncertain. METHODS In a multicenter, randomized trial conducted at 24 emergency departments and intensive care units in the United States, we randomly assigned critically ill adults (age, ≥18 years) undergoing tracheal intubation to receive preoxygenation with either noninvasive ventilation or an oxygen mask. The primary outcome was hypoxemia during intubation, defined by an oxygen saturation of less than 85% during the interval between induction of anesthesia and 2 minutes after tracheal intubation. RESULTS Among the 1301 patients enrolled, hypoxemia occurred in 57 of 624 patients (9.1%) in the noninvasive-ventilation group and in 118 of 637 patients (18.5%) in the oxygen-mask group (difference, -9.4 percentage points; 95% confidence interval [CI], -13.2 to -5.6; P<0.001). Cardiac arrest occurred in 1 patient (0.2%) in the noninvasive-ventilation group and in 7 patients (1.1%) in the oxygen-mask group (difference, -0.9 percentage points; 95% CI, -1.8 to -0.1). Aspiration occurred in 6 patients (0.9%) in the noninvasive-ventilation group and in 9 patients (1.4%) in the oxygen-mask group (difference, -0.4 percentage points; 95% CI, -1.6 to 0.7). CONCLUSIONS Among critically ill adults undergoing tracheal intubation, preoxygenation with noninvasive ventilation resulted in a lower incidence of hypoxemia during intubation than preoxygenation with an oxygen mask. (Funded by the U.S. Department of Defense; PREOXI ClinicalTrials.gov number, NCT05267652.) [ABSTRACT FROM AUTHOR]

Integrated behavioral healthcare interventions have increased access to care for people with behavioral health conditions in primary care settings. However, they have not been widely implemented in low-barrier HIV care settings where undertreated behavioral health needs remain high. We conducted a formative qualitative evaluation, using in-depth interviews with purposively selected stakeholders ( n  = 13) and patients ( n  = 16), to identify anticipated barriers and facilitators to integrating care for depression and opioid use disorder for people with HIV via the Collaborative Care Model at a low-barrier HIV clinic. Patients and stakeholders expressed their enthusiasm for the Collaborative Care Model based on its perceived relative advantage over the standard of care referral system. Availability of resources, practical concerns about perceived fit with low-barrier HIV care, and anticipated suitability given other behavioral health comorbidities and patients' complex socioeconomic needs partially tempered stakeholder perceptions of appropriateness for the Collaborative Care Model. Patients and service delivery stakeholders were receptive to the Collaborative Care Model, but felt it was moderately appropriate in the context of low-barrier HIV care, which necessitated key adaptations to core model components to improve its contextual fit.

Introduction: Plantar flexors play a pivotal role in human locomotion and balance. Several original research studies and systematic reviews have characterised the impact of single-leg disuse on plantar flexor strength and size. However, no meta-analysis has quantified the effects of single-leg disuse on changes in plantar flexor strength and size in uninjured adults., Aim: To quantify changes in plantar flexor strength and size in response to single-leg disuse., Methods: Data were extracted from 19 studies captured in our previous systematic review on studies that employed a unilateral lower limb immobilisation model (cast or brace) and were published up to January 30, 2022. Random-effects meta-analyses were performed on original research studies reporting measures of plantar flexor strength (isometric, isokinetic, or repetition maximum) and size (magnetic resonance imaging or computed tomography) in uninjured adults., Results: Single-leg disuse decreased plantar flexor strength (Hedges g av  = -0.71 [95% confidence interval: -0.93, -0.48], p < 0.001, 7-28 days, N = 16 studies, n = 121 participants including ≥13 females, ages 19-29) and plantar flexor size (-0.33 [-0.50, -0.15], p < 0.001, 14-35 days, N = 6, n = 49, 10 females, ages 22-27) across all durations of disuse., Discussion: Single-leg disuse decreases plantar flexor strength and size in uninjured adults. This work adds to recent meta-analytic findings demonstrating the declines in knee extensors strength and size following single-leg disuse. The paucity of female and participants >30 years old in the single-leg disuse literature examining plantar flexors represents a priority of future work., (© 2024 The Author(s). Clinical Physiology and Functional Imaging published by John Wiley & Sons Ltd on behalf of Scandinavian Society of Clinical Physiology and Nuclear Medicine.)

Reactive oxygen species (ROS) within the retina play a key role in maintaining function and cell survival. However, excessive ROS can lead to oxidative stress, inducing dysregulation of metabolic and inflammatory pathways. The chm ru848 zebrafish models choroideremia (CHM), an X-linked chorioretinal dystrophy, which predominantly affects the photoreceptors, retinal pigment epithelium (RPE), and choroid. In this study, we examined the transcriptomic signature of the chm ru848 zebrafish retina to reveal the upregulation of cytokine pathways and glia migration, upregulation of oxidative, ER stress and apoptosis markers, and the dysregulation of glucose metabolism with the downregulation of glycolysis and the upregulation of the oxidative phase of the pentose phosphate pathway. Glucose uptake was impaired in the chm ru848 retina using the 2-NBDG glucose uptake assay. Following the overexpression of human PFKM , partial rescue was seen with the preservation of photoreceptors and RPE and increased glucose uptake, but without modifying glycolysis and oxidative stress markers. Therapies targeting glucose metabolism in CHM may represent a potential remedial approach.

Purpose: When severe retinal and corneal injury occur together, a temporary keratoprosthesis (TKP) is often a last resort to allow posterior segment visualization to enable vitreoretinal surgery, followed by a penetrating keratoplasty (PKP) which can restore corneal clarity in a single operation. We aimed to assess visual outcomes following combined PKP and vitreoretinal surgery with the use of a TKP for cases of ocular trauma., Design: A systematic literature review was performed following PRISMA guidelines (PROSPERO registration number: CRD42023423518)., Methods: CENTRAL, MEDLINE, Embase, ISRCTN registry, and ClinicalTrials.gov were searched from inception to 27 April 2023. Randomized and nonrandomized studies assessing visual outcomes after combined vitreoretinal surgery and PKP with the use of a TKP after ocular trauma were eligible for inclusion. Outcomes included change in best corrected visual acuity, corneal graft survival and retinal reattachment at final follow up. Proportional meta-analysis was used to estimate the overall rate of the primary outcomes. Risk of bias for nonrandomized studies was assessed using the Joanna Briggs Institute (JBI) critical appraisal checklist for case series., Results: A total of 19 studies met inclusion criteria reporting a total of 352 eyes. All studies were retrospective and nonrandomized with follow up times ranging from 6 to 91 months, with at least 79% of outcomes reported after 6 months. After combined surgery the rate of corneal graft survival was 52% (95% CI 0.41-0.62; I 2 60%) successful retinal attachment was 79% (95% CI 0.73-0.84; I 2 0%). and improved visual acuity, when compared to no change or decrease in visual acuity, was 45% (95% CI 0.32-0.59; I 2 66%)., Conclusion: Patients with severe injury affecting the anterior and posterior segments have very limited treatment options. This systematic review found that when combined vitreoretinal surgery and PKP with a TKP are performed, approximately half of corneal grafts survive, anatomically successful retinal reattachment is likely, and a similar proportion of patients benefit in terms of improved visual acuity, compared to their preoperative function. This systematic review of the available literature may help inform surgeons of the benefits of using a TKP for cases of ocular trauma., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objectives: This is a protocol for a Cochrane Review (intervention). The objectives are as follows: To assess the effects of early versus delayed timing of vitrectomy after open-globe injury on visual outcomes., (Copyright © 2024 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Aims: This evaluation combines clinical and non-clinical collaborative breast referral triage to gain an understanding relating to the value of triage, by identifying 'suspected cancer' and 'cancer not suspected' populations, improve the patient pathway, and facilitate optimised resource availability., Method: An iterative service improvement method was used, with distinct phases of the process outlined to facilitate testing of ideas. The evaluation ran for 13 weeks in 2022. Regular team member meetings were arranged to discuss and agree improvement aims and outcomes., Findings: A triage flowchart was developed collaboratively, and subsequently adopted by the non-clinical booking team. Bespoke clinics were established, demonstrating no evidence of increased risk to patients, and meeting 28-day Faster Diagnosis Standard (FDS) requirements., Conclusion: breast referral triage of 'suspected cancer' and 'cancer not suspected' patients, using a clinical and non-clinical collaborative approach facilitates improved service visibility, prioritisation, management, and measurement. This also supports delivery of the 2019 NHS Long Term Plan to enhance earlier and faster cancer diagnosis by optimising access to diagnostic resources where required.

Self-stigma-the internalization of negative community attitudes and beliefs about a disease or condition-represents an important barrier to improving patient care outcomes for people living with common mental disorders and diabetes. Integrated behavioral healthcare interventions are recognized as evidence-based approaches to improve access to behavioral healthcare and for improving patient outcomes, including for those with comorbid diabetes, yet their impact on addressing self-stigma remains unclear. Using secondary data from the Integrating Depression and Diabetes Treatment (INDEPENDENT) study-a trial that aimed to improve diabetes outcomes for people with undertreated and comorbid depression in four urban Indian cities via the Collaborative Care Model-we longitudinally analyzed self-stigma scores and evaluated whether change in total self-stigma scores on diabetes outcomes is mediated by depressive symptom severity. Self-stigma scores did not differ longitudinally comparing Collaborative Care Model participants to enhanced standard-of-care participants (mean monthly rate of change in Self-Stigma Scale for Chronic Illness-4 Item scores; B = 0.0087; 95% CI: -0.0018, 0.019, P = .10). Decreases in total self-stigma scores over 12 months predicted diabetes outcomes at 12 months (HbA1c, total effect; B = 0.070 95%CI: 0.0032, 0.14; P < .05), however depressive symptoms did not mediate this relationship (average direct effect; B = 0.064; 95% CI: -0.0043, 0.13, P = .069). Considering the local and plural notions of stigma in India, further research is needed on culturally grounded approaches to measure and address stigma in India, and on the role of integrated care delivery models alongside multi-level stigma reduction interventions. Trial registration : ClinicalTrials.gov, NCT02022111. https://clinicaltrials.gov/study/NCT02022111., Competing Interests: SH is a technical adviser for the non-profit organization Possible for which he receives no compensation. The authors have declared that no competing interests exist., (Copyright: © 2024 Halliday et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Topic: Sympathetic ophthalmia (SO) is a sight-threatening granulomatous panuveitis caused by a sensitizing event. Primary enucleation or primary evisceration, versus primary repair, as a risk management strategy after open-globe injury (OGI) remains controversial., Clinical Relevance: This systematic review was conducted to report the incidence of SO after primary repair compared with that of after primary enucleation or primary evisceration. This enabled the reporting of an estimated number needed to treat., Methods: Five journal databases were searched. This review was registered with International Prospective Register of Systematic Reviews (identifier, CRD42021262616). Searches were carried out on June 29, 2021, and were updated on December 10, 2022. Prospective or retrospective studies that reported outcomes (including SO or lack of SO) in a patient population who underwent either primary repair and primary enucleation or primary evisceration were included. A systematic review and meta-analysis were carried out in accordance with Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. Random effects modelling was used to estimate pooled SO rates and absolute risk reduction (ARR)., Results: Eight studies reporting SO as an outcome were included in total. The included studies contained 7500 patients and 7635 OGIs. In total, 7620 OGIs met the criteria for inclusion in this analysis; SO developed in 21 patients with OGI. When all included studies were pooled, the estimated SO rate was 0.12% (95% confidence interval [CI], 0.00%-0.25%) after OGI. Of 779 patients who underwent primary enucleation or primary evisceration, no SO cases were reported, resulting in a pooled SO estimate of 0.05% (95% CI, 0.00%-0.21%). For primary repair, the pooled estimate of SO rate was 0.15% (95% CI, 0.00%-0.33%). The ARR using a random effects model was -0.0010 (in favour of eye removal; 95% CI, -0.0031 [in favor of eye removal] to 0.0011 [in favor of primary repair]). Grading of Recommendations, Assessment, Development, and Evaluations analysis highlighted a low certainty of evidence because the included studies were observational, and a risk of bias resulted from missing data., Discussion: Based on the available data, no evidence exists that primary enucleation or primary evisceration reduce the risk of secondary SO., Financial Disclosure(s): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article., (Copyright © 2023 American Academy of Ophthalmology. All rights reserved.)

Stroke volume is a key determinant of infarct severity and an important metric for evaluating treatments. However, accurate estimation of stroke volume can be challenging, due to the often confined 2-dimensional nature of available data. Here, we introduce a comprehensive semi-automated toolkit to reliably estimate stroke volumes based on (1) whole brains ex-vivo magnetic resonance imaging (MRI) and (2) brain sections that underwent immunofluorescence staining. We located and quantified infarct areas from MRI three days (acute) and 28 days (chronic) after photothrombotic stroke induction in whole mouse brains. MRI results were compared with measures obtained from immunofluorescent histologic sections of the same brains. We found that infarct volume determined by post-mortem MRI was highly correlated with a deviation of only 6.6 % (acute) and 4.9 % (chronic) to the measurements as determined in the histological brain sections indicating that both methods are capable of accurately assessing brain tissue damage (Pearson r > 0.9, p < 0.001). The Dice similarity coefficient (DC) showed a high degree of coherence (DC > 0.8) between MRI-delineated regions of interest (ROIs) and ROIs obtained from histologic sections at four to six pre-defined landmarks, with histology-based delineation demonstrating higher inter-operator similarity compared to MR images. We further investigated stroke-related scarring and post-ischemic angiogenesis in cortical peri‑infarct regions and described a negative correlation between GFAP + fluorescence intensity and MRI-obtained lesion size., Competing Interests: Declaration of competing interest 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., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Breast pain accounts for 20-40% of new referrals to breast units in the UK and these patients have a very low risk of breast cancer. Patients have previously been assessed in resource-intensive, cancer-exclusion, one stop clinics, which are now failing to meet government targets due to excessive demand. UK Breast units are increasingly piloting Breast Pain-only Pathways (BPP) to assess these patients, and there is no consensus for the optimal pathway. The aim of this prospective multicentre study is to assess the safety and patient satisfaction of different BPPs to inform future BPP design and implementation., Methods: All UK breast units will be invited to join the ASPIRE study between January 2023 and December 2023. Units with a BPP are invited to submit their pathway for evaluation; and those without a BPP who see patients with breast pain-only in a one stop clinics setting are also invited to join the study to evaluate the traditional pathway model concurrently. Patient satisfaction assessments will be collected after their initial consultation and patient outcomes, including subsequent cancer diagnosis, will be followed up at 12 months to determine if they have cancer diagnosis after discharge to assess pathway safety., Competing Interests: RIC receives institutional research funding from SECA and Astra Zeneca. The other authors have no conflicts of interest to declare., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

This dataset offers images of mouse brains impacted by photothrombotic stroke in the sensorimotor cortex published by Weber et al. NeuroImage (2024). Data is gathered using two primary techniques: (1) whole-brain ex-vivo magnetic resonance imaging (MRI) and (2) 40 µm thick coronal histological sections that undergo immunofluorescence staining with NeuroTrace. Infarct areas and volumes are assessed through MRI at two distinct time frames-three days (acute) and 28 days (chronic) following photothrombotic stroke induction. Subsequently, the brains are sectioned into 40 µm thick coronal slices, stained with NeuroTrace, and imaged as whole sections. The dataset holds considerable value for reuse, particularly for researchers focused on stroke volume estimation methods as well as those interested in comparing the efficacy of MRI and histological techniques., (© 2024 The Author(s).)

Time plays a fundamental role in abortion regulation. In this article, we compare the regulatory frameworks in England and Wales and the Netherlands as examples of the centrality accorded to viability in the determination of the parameters of non-criminal abortion, demonstrating that the use of viability as a threshold renders the law uncertain. We assess the role played by the concept of viability, analysing its impact upon the continued criminalization of abortion and categorization of abortion as a medical matter, rather than a reproductive choice. We conclude that viability is misconceived in its application to abortion and that neonatal viability (relating to treatment of the premature infant) and fetal viability (related to the capacity to survive birth) must be distinguished to better reflect the social context within which the law and practice of abortion operate. We show how viability thresholds endanger pregnant people., (© The Author(s) 2023. Published by Oxford University Press.)

Objectives: Although the demands and stress of teaching are generally recognized, little is known about the prevalence and nature of insomnia symptoms in teachers. This scoping study investigated the following questions: How prevalent are insomnia symptoms in teachers? What biopsychosocial variables are associated with insomnia symptoms in teachers? What, if any, interventions for insomnia symptoms in teachers have been studied?, Method: We searched Medline, PsycINFO, Embase, CINAHL, Education Source, and ERIC for original peer-reviewed research on school teachers (kindergarten through high school) and insomnia symptoms (self-reported trouble falling or staying asleep)., Results: We identified 33 relevant articles from 15 countries. The literature was heterogeneous and generally of low quality with respect to the measurement of insomnia. Based on studies that met validity and reliability criteria, 36-61% of teachers reported insomnia symptoms. Associated factors included: being female, classroom violence, low job satisfaction, pain, depression, and rumination. One online intervention, which included stimulus control, sleep restriction, and techniques for reducing rumination, provided evidence of efficacy., Conclusion: Despite the importance of teachers and their work, high-quality research on insomnia in teachers is lacking. Research in this area is sorely needed. Studies should investigate insomnia symptoms over the school year, identify antecedents of insomnia, and develop interventions with the ultimate goals of understanding, preventing, and treating insomnia symptoms in teachers.

Background: The collaborative care management (CoCM) model is an evidence-based intervention for integrating behavioral health care into nonpsychiatric settings. CoCM has been extensively studied in primary care clinics, but implementation in nonconventional clinics, such as those tailored to provide care for high-need, complex patients, has not been well described., Method: We adapted CoCM for a low-barrier HIV clinic that provides walk-in medical care for a patient population with high levels of mental illness, substance use, and housing instability. The Exploration, Preparation, Implementation, and Sustainment model guided implementation activities and support through the phases of implementing CoCM. The Framework for Reporting Adaptations and Modifications to Evidence-Based Interventions guided our documentation of adaptations to process-of-care elements and structural elements of CoCM. We used a multicomponent strategy to implement the adapted CoCM model. In this article, we describe our experience through the first 6 months of implementation., Results: The key contextual factors necessitating adaptation of the CoCM model were the clinic team structure, lack of scheduled appointments, high complexity of the patient population, and time constraints with competing priorities for patient care, all of which required substantial flexibility in the model. The process-of-care elements were adapted to improve the fit of the intervention with the context, but the core structural elements of CoCM were maintained., Conclusions: The CoCM model can be adapted for a setting that requires more flexibility than the usual primary care clinic while maintaining the core elements of the intervention., Competing Interests: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2023.)

We aimed to quantify declines from baseline in lower limb skeletal muscle size and strength of uninjured adults following single-leg disuse. We searched EMBASE, Medline, CINAHL, and CCRCT up to 30 January 2022. Studies were included in the systematic review if they (1) recruited uninjured participants; (2) were an original experimental study; (3) employed a single-leg disuse model; and (4) reported muscle strength, size, or power data following a period of single-leg disuse for at least one group without a countermeasure. Studies were excluded if they (1) did not meet all inclusion criteria; (2) were not in English; (3) reported previously published muscle strength, size, or power data; or (4) could not be sourced from two different libraries, repeated online searches, and the authors. We used the Cochrane Risk of Bias Assessment Tool to assess risk of bias. We then performed random-effects meta-analyses on studies reporting measures of leg extension strength and extensor size. Our search revealed 6548 studies, and 86 were included in our systematic review. Data from 35 and 20 studies were then included in the meta-analyses for measures of leg extensor strength and size, respectively (40 different studies). No meta-analysis for muscle power was performed due to insufficient homogenous data. Effect sizes (Hedges' g av ) with 95% confidence intervals for leg extensor strength were all durations = -0.80 [-0.92, -0.68] (n = 429 participants; n = 68 aged 40 years or older; n ≥ 78 females); ≤7 days of disuse = -0.57 [-0.75, -0.40] (n = 151); >7 days and ≤14 days = -0.93 [-1.12, -0.74] (n = 206); and >14 days = -0.95 [-1.20, -0.70] (n = 72). Effect sizes for measures of leg extensor size were all durations = -0.41 [-0.51, -0.31] (n = 233; n = 32 aged 40 years or older; n ≥ 42 females); ≤7 days = -0.26 [-0.36, -0.16] (n = 84); >7 days and ≤14 days = -0.49 [-0.67, -0.30] (n = 102); and >14 days = -0.52 [-0.74, -0.30] (n = 47). Decreases in leg extensor strength (cast: -0.94 [-1.30, -0.59] (n = 73); brace: -0.90 [-1.18, -0.63] (n = 106)) and size (cast: -0.61[-0.87, -0.35] (n = 41); brace: (-0.48 [-1.04, 0.07] (n = 41)) following 14 days of disuse did not differ for cast and brace disuse models. Single-leg disuse in adults resulted in a decline in leg extensor strength and size that reached a nadir beyond 14 days. Bracing and casting led to similar declines in leg extensor strength and size following 14 days of disuse. Studies including females and males and adults over 40 years of age are lacking., (© 2023 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of Society on Sarcopenia, Cachexia and Wasting Disorders.)

Skilled care during pregnancy, childbirth, and postpartum is essential to prevent adverse maternal health outcomes, yet utilization of care remains low in many resource-limited countries, including Nepal. Community health workers (CHWs) can mitigate health system challenges and geographical barriers to achieving universal health coverage. Gaps remain, however, in understanding whether evidence-based interventions delivered by CHWs, closely aligned with WHO recommendations, are effective in Nepal's context. We conducted a type II hybrid effectiveness-implementation, mixed-methods study in two rural districts in Nepal to evaluate the effectiveness and the implementation of an evidence-based integrated maternal and child health intervention delivered by CHWs, using a mobile application. The intervention was implemented stepwise over four years (2014-2018), with 65 CHWs enrolling 30,785 families. We performed a mixed-effects Poisson regression to assess institutional birth rate (IBR) pre-and post-intervention. We used the Reach, Effectiveness, Adoption, Implementation, and Maintenance framework to evaluate the implementation during and after the study completion. There was an average 30% increase in IBR post-intervention, adjusting for confounding variables (p<0.0001). Study enrollment showed 35% of families identified as dalit, janjati, or other castes. About 78-89% of postpartum women received at least one CHW-counseled home visit within 60 days of childbirth. Ten (53% of planned) municipalities adopted the intervention during the study period. Implementation fidelity, measured by median counseled home visits, improved with intervention time. The intervention was institutionalized beyond the study period and expanded to four additional hubs, albeit with adjustments in management and supervision. Mechanisms of intervention impact include increased knowledge, timely referrals, and longitudinal CHW interaction. Full-time, supervised, and trained CHWs delivering evidence-based integrated care appears to be effective in improving maternal healthcare in rural Nepal. This study contributes to the growing body of evidence on the role of community health workers in achieving universal health coverage., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: A. Tiwari and A. Thapa are employed by a US-based non-profit (Possible) and based in Nepal. S. Sapkota and R. Khatri are employed by a Nepal-based non-governmental organization, Possible that operates with support from US-based Possible. VB, BB, HJR, R. Paudel, SG, NM, R. Poudel and LDB are employed by a Nepal-based non-governmental organization (Nyaya Health Nepal) that delivers free healthcare in rural Nepal using funds from the Government of Nepal and other public, philanthropic, and private foundation sources. NC, DM, SM are employed by, and SM, DC, DM, and S. Sapkota are faculty members at a private medical school (Icahn School of Medicine at Mount Sinai). DM is a member on US-based Possible’s Board of Directors, for which he receives no compensation. IB is a board chair of Nepal-based Possible. WW is a faculty member at a private university (Boston University School of Medicine). DC is a faculty member and SH is a graduate student at a public university (University of Washington). R. Schwarz is employed at an academic medical center (Brigham and Women’s Hospital) that receives public sector research funding, as well as revenue through private sector fee-for-service medical transactions and private foundation grants. R. Schwarz is a faculty member at a private medical school (Harvard Medical School) and employed at an academic medical center (Massachusetts General Hospital) that receives public sector research funding, as well as revenue through private sector fee-for-service medical transactions and private foundation grants. SA is a faculty member at a private medical school (NYU School of Medicine). SK is a nursing student at Gandaki Medical College Teaching Hospital and Research Center. IN is a graduate student at a private university (Harvard T.H. Chan School of Public Health). LK is employed by a non-profit (Medic). PT is a graduate student at a public university (University of New South Wales). S. Saud is employed by a government hospital of Nepal (Civil Service Hospital). YKBK is employed by a government hospital of Nepal (COVID Hospital in Shikhar municipality). AB is employed by the local government of Nepal (Amargadhi municipality). R. Shrestha and KRM are employed by a non-profit hospital (Dhulikhel Hospital, Kathmandu University Hospital). R. Kafle is employed by a Nepal-based non-profit (Nick Simons Institute). GNS is a director of the Nursing and Social Security Division under the Government of Nepal Ministry of Health and Population. All authors declare that we have no competing financial interests., (Copyright: © 2023 Tiwari et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

The liquid biopsy has the potential to improve patient care in the diagnostic and therapeutic setting in non-small cell lung cancer (NSCLC). Consented patients with epidermal growth factor receptor (EGFR) positive disease (n = 21) were stratified into two cohorts: those currently receiving EGFR tyrosine kinase inhibitor (TKI) therapy (n = 9) and newly diagnosed EGFR TKI treatment-naïve patients (n = 12). Plasma genotyping of cell-free DNA was carried out using the FDA-approved cobas® EGFR mutation test v2 and compared to next generation sequencing (NGS) cfDNA panels. Circulating tumor cell (CTC) numbers were correlated with treatment response and EGFR exon 20 p.T790M. The prognostic significance of the neutrophil to lymphocyte ratio (NLR) and lactate dehydrogenase (LDH) was also investigated. Patients in cohort 1 with an EGFR exon 20 p.T790M mutation progressed more rapidly than those with an EGFR sensitizing mutation, while patients in cohort 2 had a significantly longer progression-free survival (p = 0.04). EGFR exon 20 p.T790M was detected by liquid biopsy prior to disease progression indicated by computed tomography (CT) imaging. The cobas® EGFR mutation test detected a significantly greater number of exon 20 p.T790M mutations (p = 0.05). High NLR and derived neutrophil to lymphocyte ratio (dNLR) were associated with shorter time to progression and worse survival outcomes (p < 0.05). High LDH levels were significantly associated with shorter time to disease progression (p = 0.03). These data support the use of liquid biopsy for monitoring EGFR mutations and inflammatory markers as prognostic indicators in NSCLC.

Purpose: Complex elective foot and ankle surgeries are often associated with severe pain pre- and postoperatively. When inadequately managed, chronic postsurgical pain and long-term opioid use can result. As no standards currently exist, we aimed to develop best practice pain management guidelines., Methods: A local steering committee (n = 16) surveyed 116 North American foot and ankle surgeons to understand the "current state" of practice. A multidisciplinary expert panel (n = 35) was then formed consisting of orthopedic surgeons, anesthesiologists, chronic pain physicians, primary care physicians, pharmacists, registered nurses, physiotherapists, and clinical psychologists. Each expert provided up to three pain management recommendations for each of the presurgery, intraoperative, inpatient postoperative, and postdischarge periods. These preliminary recommendations were reduced, refined, and sent to the expert panel and "current state" survey respondents to create a consensus document using a Delphi process conducted from September to December 2020., Results: One thousand four hundred and five preliminary statements were summarized into 51 statements. Strong consensus (≥ 80% respondent agreement) was achieved in 53% of statements including the following: postsurgical opioid use risk should be assessed preoperatively; opioid-naïve patients should not start opioids preoperatively unless non-opioid multimodal analgesia fails; and if opioids are prescribed at discharge, patients should receive education regarding importance of tapering opioid use. There was no consensus regarding opioid weaning preoperatively., Conclusions: Using multidisciplinary experts and a Delphi process, strong consensus was achieved in many areas, showing considerable agreement despite limited evidence for standardized pain management in patients undergoing complex elective foot and ankle surgery. No consensus on important issues related to opioid prescribing and cessation highlights the need for research to determine best practice., (© 2022. Canadian Anesthesiologists' Society.)

Background: Timely tracking of health outcomes is difficult in low- and middle-income countries without comprehensive vital registration systems. Community health workers (CHWs) are increasingly collecting vital events data while delivering routine care in low-resource settings. It is necessary, however, to assess whether routine programmatic data collected by CHWs are sufficiently reliable for timely monitoring and evaluation of health interventions. To study this, we assessed the consistency of vital events data recorded by CHWs using two methodologies-routine data collected while delivering an integrated maternal and child health intervention, and data from a birth history census approach at the same site in rural Nepal., Methods: We linked individual records from routine programmatic data from June 2017 to May 2018 with those from census data, both collected by CHWs at the same site using a mobile platform. We categorized each vital event over a one-year period as 'recorded by both methods,' 'census alone,' or 'programmatic alone.' We further assessed whether vital events data recorded by both methods were classified consistently., Results: From June 2017 to May 2018, we identified a total of 713 unique births collectively from the census (birth history) and programmatic maternal 'post-delivery' data. Three-fourths of these births (n = 526) were identified by both. There was high consistency in birth location classification among the 526 births identified by both methods. Upon including additional programmatic 'child registry' data, we identified 746 total births, of which 572 births were identified by both census and programmatic methods. Programmatic data (maternal 'post-delivery' and 'child registry' combined) captured more births than census data (723 vs. 595). Both methods consistently classified most infants as 'living,' while infant deaths and stillbirths were largely classified inconsistently or recorded by only one method. Programmatic data identified five infant deaths and five stillbirths not recorded in census data., Conclusions: Our findings suggest that data collected by CHWs from routinely tracking pregnancies, births, and deaths are promising for timely program monitoring and evaluation. Despite some limitations, programmatic data may be more sensitive in detecting vital events than cross-sectional census surveys asking women to recall these events., (© 2022. The Author(s).)

This article substantially extends the existing constitutional and legal critiques of the use of soft law public health guidance in the UK during the COVID-19 pandemic. Drawing upon the findings of a national survey undertaken during the first wave of the pandemic in June 2020, it shows how the perceived legal status of lockdown rules made a significant difference as to whether the UK public complied with them and that this effect is a product of the legitimacy that law itself enjoys within UK society. Based on this analysis, it argues that the problems with the Government's approach to guidance, that have been subjected to criticism in constitutional and legal terms, may also be open to critique on the basis that they risk undermining the public's loyalty to the law itself., (© 2022 The Authors. The Modern Law Review published by John Wiley & Sons Ltd on behalf of Modern Law Review Limited.)

Background: The DNA-damage immune-response (DDIR) signature is an immune-driven gene expression signature retrospectively validated as predicting response to anthracycline-based therapy. This feasibility study prospectively evaluates the use of this assay to predict neoadjuvant chemotherapy response in early breast cancer., Methods: This feasibility study assessed the integration of a novel biomarker into clinical workflows. Tumour samples were collected from patients receiving standard of care neoadjuvant chemotherapy (FEC + /-taxane and anti-HER2 therapy as appropriate) at baseline, mid- and post-chemotherapy. Baseline DDIR signature scores were correlated with pathological treatment response. RNA sequencing was used to assess chemotherapy/response-related changes in biologically linked gene signatures., Results: DDIR signature reports were available within 14 days for 97.8% of 46 patients (13 TNBC, 16 HER2 + ve, 27 ER + HER2-ve). Positive scores predicted response to treatment (odds ratio 4.67 for RCB 0-1 disease (95% CI 1.13-15.09, P = 0.032)). DDIR positivity correlated with immune infiltration and upregulated immune-checkpoint gene expression., Conclusions: This study validates the DDIR signature as predictive of response to neoadjuvant chemotherapy which can be integrated into clinical workflows, potentially identifying a subgroup with high sensitivity to anthracycline chemotherapy. Transcriptomic data suggest induction with anthracycline-containing regimens in immune restricted, "cold" tumours may be effective for immune priming., Trial Registration: Not applicable (non-interventional study). CRUK Internal Database Number 14232., (© 2021. The Author(s).)

Introduction: Despite carrying a disproportionately high burden of depression, patients in low-income countries lack access to effective care. The collaborative care model (CoCM) has robust evidence for clinical effectiveness in improving mental health outcomes. However, evidence from real-world implementation of CoCM is necessary to inform its expansion in low-resource settings., Methods: We conducted a 2-year mixed-methods study to assess the implementation and clinical impact of CoCM using the WHO Mental Health Gap Action Programme protocols in a primary care clinic in rural Nepal. We used the Capability Opportunity Motivation-Behaviour (COM-B) implementation research framework to adapt and study the intervention. To assess implementation factors, we qualitatively studied the impact on providers' behaviour to screen, diagnose and treat mental illness. To assess clinical impact, we followed a cohort of 201 patients with moderate to severe depression and determined the proportion of patients who had a substantial clinical response (defined as ≥50% decrease from baseline scores of Patient Health Questionnaire (PHQ) to measure depression) by the end of the study period., Results: Providers experienced improved capability (enhanced self-efficacy and knowledge), greater opportunity (via access to counsellors, psychiatrist, medications and diagnostic tests) and increased motivation (developing positive attitudes towards people with mental illness and seeing patients improve) to provide mental healthcare. We observed substantial clinical response in 99 (49%; 95% CI: 42% to 56%) of the 201 cohort patients, with a median seven point (Q1:-9, Q3:-2) decrease in PHQ-9 scores (p<0.0001)., Conclusion: Using the COM-B framework, we successfully adapted and implemented CoCM in rural Nepal, and found that it enhanced providers' positive perceptions of and engagement in delivering mental healthcare. We observed clinical improvement of depression comparable to controlled trials in high-resource settings. We recommend using implementation research to adapt and evaluate CoCM in other resource-constrained settings to help expand access to high-quality mental healthcare., Competing Interests: Competing interests: PR, PA, MB, BB, BG, PG, TKG, BK, RM, SP, JR, SSw and PT were employed by, and NC, DC, SH, DM, AR, DS, RS, SSa, SSh, AT and BA work in partnership with a non-profit healthcare company (Nyaya Health Nepal, with support from the US-based non-profit, Possible) that delivers free healthcare in rural Nepal using funds from the Government of Nepal and other public, philanthropic and private foundation sources. MB is a faculty at BP Koirala Institute of Health Sciences, Dharan, Nepal. NC, SH and DM are employed by, and DC, DM and SSa are faculty members at a private medical school (Icahn School of Medicine at Mount Sinai). DC is a faculty member at, DC and SH are employed part-time by and SH is a graduate student at a public university (University of Washington). SKD is a resident at an academic medical centre (Hurley Medical Center) that receives revenue through private sector fee-for-service medical transactions and a charitable private foundation. TKG is a fellow with a bidirectional fellowship program (HEAL Initiative) that is affiliated with a public university (University of California, San Francisco) that receives funding from public, philanthropic and private foundation sources. DM and BA are members on Possible’s Board of Directors, for which they receive no compensation. VN is employed at a public university (University of California, Los Angeles). DS and RS are employed at an academic medical centre (Brigham and Women’s Hospital) that receives public sector research funding, as well as revenue through private sector fee-for-service medical transactions and private foundation grants. DS and RS are faculty members at a private medical school (Harvard Medical School). DS is employed at an academic research centre (Ariadne Labs) that is jointly supported by an academic medical center (Brigham and Women’s Hospital) and a private university (Harvard TH Chan School of Public Health) via public sector research funding and private philanthropy. RS is employed at an academic medical centre (Massachusetts General Hospital) that receives public sector research funding, as well as revenue through private sector fee-for-service medical transactions and private foundation grants. SSh is a faculty member at a private college (Wheaton College). PT is a graduate student at a public university (University of New South Wales). BA is a faculty member at a public university (University of California, San Francisco). All authors have read and understood BMJ Open’s policy on declaration of interests, and declare that we have no competing financial interests. The authors do, however, believe strongly that healthcare is a public good, not a private commodity., (© 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.)

Adolescent girls in low- and middle-income countries continue to face poor sexual and reproductive health (SRH). In Nepal, early marriage and motherhood, gender-based violence, and unmet need for contraception remain pervasive. Adolescent girls in rural areas bear a disproportionate burden of poor reproductive health outcomes, but there are limited context-specific data. This is a qualitative study to identify factors that impact adolescent girls' utilisation of and access to SRH services in a rural district of Nepal. We conducted 21 individual interviews with adolescent girls aged 15-19 years, and three focus group discussions with community health workers. We used an inductive analytic approach to identify emergent and recurrent themes and present the themes using the social ecological model. Individual-level factors that contribute to low uptake of services among adolescent girls include lack of knowledge, self-perceived lack of need, low decision-making autonomy, and shyness. Interpersonal factors that impact access include unsupportive family norms, absence of open communication, and need for permission from family members to access care. At the community level, disparate gender norms, son preference, and judgment by community members affect adolescent SRH. Inadequate sex education, far travel distance to facilities, lack of female healthcare providers and teachers, and inability to access abortion services were identified as organisational and systems barriers. Stigma was a factor cross-cutting several levels. Our findings suggest the need for multi-level strategies to address these factors to improve adolescent girls' SRH.

Unmet need for postpartum contraception in rural Nepal remains high and expanding access to sexual and reproductive healthcare is essential to achieving universal healthcare. We evaluated the impact of an integrated intervention that employed community health workers aided by mobile technology to deliver patient-centred, home-based antenatal and postnatal counselling on postpartum modern contraceptive use. This was a pre-post-intervention study in seven village wards in a single municipality in rural Nepal. The primary outcome was modern contraceptive use among recently postpartum women. We performed a multivariable logistic regression to examine contraceptive use among postpartum women pre- and one-year post-intervention. We conducted qualitative interviews to explore the implementation process. There were 445 postpartum women in the pre-intervention group and 508 in the post-intervention group. Modern contraceptive use increased from 29% pre-intervention to 46% post-intervention ( p  < 0.0001). Adjusting for age, caste, and household expenditure, time since delivery and sex of child in the index pregnancy, postpartum women one-year post-intervention had twice the odds (OR 2.3; CI 1.7, 3.1; p  < 0.0001) of using a modern contraceptive method as compared to pre-intervention. Factors at the individual, family, and systems level influenced women's contraceptive decisions. The intervention contributed to increasing contraceptive use through knowledge transfer, demand generation, referrals to healthcare facilities, and follow-up. A community-based, patient-centred contraceptive counselling intervention supported by mobile technology and integrated into longitudinal care delivered by community health workers appears to be an effective strategy for improving uptake of modern contraception among postpartum women in rural Nepal.