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Neurodegenerative diseases are a large class of neurological disorders characterized by progressive dysfunction and death of neurones. Examples include Alzheimer’s disease, Parkinson’s disease, frontotemporal dementia, and amyotrophic lateral sclerosis. Aging is the primary risk factor for neurodegeneration; individuals over 65 are more likely to suffer from a neurodegenerative disease, with prevalence increasing with age. As the population ages, the social and economic burden caused by these diseases will increase. Therefore, new therapies that address both aging and neurodegeneration are imperative. Ketogenic diets (KDs) are low carbohydrate, high-fat diets developed initially as an alternative treatment for epilepsy. The classic ketogenic diet provides energy via long-chain fatty acids (LCFAs); naturally occurring medium chain fatty acids (MCFAs), on the other hand, are the main components of the medium-chain triglyceride (MCT) ketogenic diet. MCT-based diets are more efficient at generating the ketone bodies that are used as a secondary energy source for neurones and astrocytes. However, ketone levels alone do not closely correlate with improved clinical symptoms. Recent findings suggest an alternative mode of action for the MCFAs, e.g., via improving mitochondrial biogenesis and glutamate receptor inhibition. MCFAs have been linked to the treatment of both aging and neurodegenerative disease via their effects on metabolism. Through action on multiple disease-related pathways, MCFAs are emerging as compounds with notable potential to promote healthy aging and ameliorate neurodegeneration. MCFAs have been shown to stimulate autophagy and restore mitochondrial function, which are found to be disrupted in aging and neurodegeneration. This review aims to provide insight into the metabolic benefits of MCFAs in neurodegenerative disease and healthy aging. We will discuss the use of MCFAs to combat dysregulation of autophagy and mitochondrial function in the context of “normal” aging, Parkinson’s disease, amyotrophic lateral sclerosis and Alzheimer’s disease.

Background: The coronavirus disease 2019 (COVID-19) has resulted in an unprecedented research response, demonstrating exceptional examples of rapid research and collaboration. There has however been an ongoing need for greater coordination, with limited resources for research and the shifting global pandemic. Methods: The UK Collaborative on Development Research (UKCDR) and Global Research Collaboration for Infectious Disease Preparedness (GloPID-R), two funder coordination groups have collaborated to develop a live database of funded research projects across the world relating to COVID-19. Drawing data continually from their members and further global funding bodies, as of 15th October 2022 the database contains 20,006 projects, funded by 351 funders, taking place across 157 countries representing an investment of at least $7.4 billion. To our knowledge it is one of the most comprehensive databases. The database is aligned to the World Health Organisation and GloPID-R Global Research Roadmap: 2019 Novel Coronavirus and the UN Research Roadmap for the COVID-19 Recovery. It is being used by the WHO, governments and further policy makers, research funders and researchers. This living mapping review aims to supplement the database by providing an open, accessible, and frequently updated resource summarising the characteristics of the COVID-19 funded research portfolio. Both descriptive and thematic analyses are presented and updated frequently to aid interpretation of the global COVID-19 funded research portfolio. Results: In this final version ten analysis, we provide an updated detailed descriptive analysis of the database (on data from three months after version nine) and focus our thematic analysis on research gaps, research areas in need of coordination, study populations, and research locations (with a focus on resource-limited countries). Conclusions: As the global research response to COVID-19 plateaus, this living mapping review has helped both funders and researchers to prioritise resources and review investments.

Background: The effects of climate change are seen with a rise of extreme weather and climate events (EWCEs) which lead to the closures of many healthcare facilities, such as community pharmacies. Pharmacists in community pharmacies are seen as the most accessible healthcare professional to the public and are responsible for the continued delivery of care to patients. However, amid closures due to EWCEs and the emergence of pharmacy deserts, there is decreased access to pharmacies and a disruption of care. Objective: It is important to address the preparedness and accessibility of pharmacies post-EWCEs to guide future research and policy. Additionally, to tackle health disparities that arise due to pharmacy deserts, the populations most affected by a decreased access to pharmacies should be identified. We conducted a scoping review to assess the preparedness and accessibility of pharmacies post-EWCEs and to identify populations most affected by pharmacy deserts. Methods: We searched PubMed, Embase, and Web of Science from January 1, 2012 to September 30, 2022 and included all English-language, peer-reviewed primary literature that examined the preparedness and accessibility of community pharmacies in the United States post-EWCEs and addressed disparities within pharmacy deserts. Studies meeting these criteria were screened of their titles and abstracts by the first author and discrepancies were resolved with co-authors. We used Covidence for data extraction. Results: A total of 472 studies were identified (196 duplicates removed) and after screening, 53 studies were assessed for eligibility. The results of included publications (N = 26) showed that pharmacists and pharmacies are not equipped with the necessary emergency protocols which could lead to decreased access of pharmacies in the wake of EWCEs. Pharmacy deserts disproportionately affect residents living in rural, lower income, and Black/African American and Hispanic/Latino neighborhoods. The lack of preparedness of pharmacies post-EWCEs could worsen medication access. Conclusion: This scoping review addresses challenges impacting pharmacies and patients post-EWCEs and within pharmacy deserts. In times of increased need, these challenges implicate the well-being of communities affected by EWCEs by breaking the continuum of care and access to medications. Here we offer suggestions for future research and directions for policy change.

Food waste (FW) is a significant global issue with a carbon footprint of 3.3 billion tonnes (Bt), primarily generated due to improper food supply chain management, storage issues, and transportation problems. Acidogenic processes like dark fermentation, anaerobic digestion, and a combination of DF-AD can produce renewable biofuels (Bio-CH4, Bio-H2) by valorising FW, aligning with the UN SDGs. FW is an ideal substrate for acidogenic processes due to its high moisture content, organic matter, and biodegradability. However, the choice of FW valorisation pathways depends on energy yield, conversion efficiency, and cost effectiveness. Acidogenic processes are not economically viable for industrial scale FW treatment due to reduced energy recovery from stand-alone processes. So, this study reviews comparative studies on biogas, biohydrogen, and biohythane production from FW via acidogenic processes, focusing on energy yield, energy recovery, and environmental and economic impact to provide a clear understanding of energy recovery and yield from all acidogenic processes. Additionally, this review also explores the recent advancements in digestate slurry management and the synergistic effects of AD and HTC processes. Lastly, a futuristic integrated bio-thermo-chemical process is proposed for maximum energy recovery, valuing food waste to energy vectors (Bio-H2, Bio-CH4, and hydro-char) along with digestate management and biofertilizer production.

Insomnia is common in children with autism. Cognitive behavioral treatment for childhood insomnia may improve sleep and functioning in children with autism and their parents, but delivery involving multiple office visits limits accessibility. This single-arm pilot study tested telehealth delivery of eight-session cognitive behavioral treatment for childhood insomnia in 17 children (6-12 years) with autism spectrum disorder and insomnia and their parent(s). Treatment integrity was assessed each session ("delivery," by therapist; "receipt," participant understanding; and "enactment," home practice). Treatment satisfaction was assessed after treatment. Children and parents wore actigraphs and completed electronic diaries for 2 weeks, children completed 5-min Holter Monitoring (assessed heart rate variability, physiological arousal indicator), and parents completed Aberrant Behavior Checklist before and after 1 month. Average integrity scores were high (98%, "delivery"; 93%, "receipt"; and 82%, "enactment"). Parents found cognitive behavioral treatment for childhood insomnia helpful, age-appropriate, and autism-friendly. Paired-samples t-tests (family-wise error controlled) indicated telehealth cognitive behavioral treatment for childhood insomnia improved child and parent sleep ("objective" and "subjective") and functioning (child--decreased irritability, lethargy, stereotypy, hyperactivity; parent--decreased fatigue). At 1 month, inappropriate speech also decreased, but hyperactivity was no longer decreased. Other gains were maintained. Most children demonstrated reduced arousal following treatment. This pilot shows telehealth cognitive behavioral treatment for childhood insomnia is feasible and may improve child and parent sleep, child behavior and arousal, and parent fatigue. A randomized controlled trial of telehealth cognitive behavioral treatment for childhood insomnia for children with autism is needed.

Rationale: Primary treatment of obstructive sleep apnea can be accompanied by a persistence of excessive sleepiness despite adherence. Furthermore, effectiveness of sleep apnea treatment is limited by poor adherence. Currently available pharmacologic options for the treatment of sleepiness in this population are limited. Objectives: To evaluate the efficacy and safety of solriamfetol (JZP-110), a selective dopamine and norepinephrine reuptake inhibitor with robust wake-promoting effects, for the treatment of excessive sleepiness in participants with obstructive sleep apnea with current or prior sleep apnea treatment. Methods: This was a double-blind, randomized, placebo-controlled, parallel-group, 12-week trial comparing solriamfetol, 37.5, 75, 150, and 300 mg, with placebo. Measurements and Main Results: Of 476 randomized participants, 459 were included in the prespecified efficacy analyses. Coprimary endpoints (Maintenance of Wakefulness Test sleep latency and Epworth Sleepiness Scale score) were met at all solriamfetol doses (P

BackgroundRecent findings on emergency department (ED) patient experience surveys and concerns for the low response rates challenge the quality and reliability of the survey reports. We assessed the consistency of an ED patient experience survey report and identified the effects of patient demographics on ED patient experiences.MethodsWe conducted a prospective, cross-sectional study at a university-based ED from July to December 2017. We obtained ED patient experience scores from an institutional version (IS) survey and the Press Ganey Associates-distributed survey (PGA). We compared top box scores from the two reports using frequency analysis and performed multivariable logistic regressions to identify associations between IS patient demographics and scores.ResultsWe obtained 289 PGA and 234 IS responses. The IS reported significant, higher top box scores in doctor-specific patient questions compared to PGA (all four P-values < 0.01). Female, Christian and White patients were more likely to give top box scores (OR 3.07, OR 2.22 and OR 2.41, P-value < 0.05, respectively).ConclusionWe found significant differences in ED patient experience scores between the IS and PGA surveys. We recommend that healthcare providers consider patient demographic variables when interpreting ED experience score reports. Multiple survey techniques and distribution methods may be adopted to best capture ED patient experiences.

Omphaloliths are uncommon benign umbilical lesions caused by the accumulation of sebum and keratin into a stone-like concretion. Recognition of this entity can prevent unnecessary procedures and imaging studies for uncomplicated cases. We present three cases of omphaloliths from our department and review all 26 cases previously reported in the English literature with regard to modes of presentation, potential risk factors, complications, and treatment options to guide clinicians. The mean age at presentation was 48 years. Of the 29 cases, 17 (59%) were asymptomatic. Male patients presented at a younger age and were more likely to present with complications compared to females who presented at an older age with asymptomatic lesions (P=0.006). Features of patients described included dementia, hirsutism, a deep or narrow umbilicus, multiple nevi, obesity, and poor hygiene. Two patients developed overlying pyogenic granulomas. Removal of asymptomatic lesions was uncomplicated and done using forceps or following irrigation, with no recurrence. Complications, including localized abscesses and peritonitis, were associated in 41% of patients who were treated surgically; recurrence was noted in one patient. Removal of omphaloliths is recommended, once identified, to reduce risks of complications and patients should be encouraged to improve their personal hygiene.

Abstract Background The cause of infertility remains unclear in a significant proportion of reproductive-age couples who fail to conceive naturally. Chromosomal aberrations have been identified as one of the main genetic causes of male and female infertility. Structural chromosomal aberrations may disrupt the functioning of various genes, some of which may be important for fertility. The present study aims to identify candidate genes and putative functional interaction networks involved in male and female infertility using cytogenetic data from cultured peripheral blood lymphocytes of infertile patients. Methods Karyotypic analyses was done in 201 infertile patients (100 males and 101 females) and 201 age and gender matched healthy controls (100 males and 101 females) after 72 h peripheral lymphocyte culturing and GTG banding, followed by bioinformatic analysis using Cytoscape v3.8.2 and Metascape. Results Several chromosomal regions with a significantly higher frequency of structural aberrations were identified in the infertile males (5q2, 10q2, and 17q2) and females (6q2, 16q2, and Xq2). Segregation of the patients based on type of infertility (primary v/s secondary infertility) led to the identification of chromosomal regions with a significantly higher frequency of structural aberrations exclusively within the infertile males (5q2, 17q2) and females (16q2) with primary infertility. Cytoscape identified two networks specific to these regions: a male specific network with 99 genes and a female specific network with 109 genes. The top enriched GO terms within the male and female infertility networks were “skeletal system morphogenesis” and “mRNA transport” respectively. PSME3, PSMD3, and CDC27 were the top 3 hub genes identified within the male infertility network. Similarly, UPF3B, IRF8, and PSMB 1 were the top 3 hub genes identified with the female infertility network. Among the hub genes identified in the male- and female-specific networks, PSMB1, PSMD3, and PSME3 are functional components of the proteasome complex. These hub genes have a limited number of reports related to their respective roles in maintenance of fertility in mice model and humans and require validation in further studies. Conclusion The candidate genes predicted in the present study can serve as targets for future research on infertility.

A composite radial filter was designed, fabricated and developed for the removal of agrochemicals particularly N, P, K and bacteriological contaminant in runoff water from rice field for recharging aquifer. Zeolite (Z), activated charcoal (C), coarse sand (CS) and gravel (G) filter materials were placed in annular concentric rings of composite radial filter in different combination of thickness in the ratio of 1:2:4:4, 1:3:4:4, 1:2:2:4, 1:3:2:4 and 0:2:1:2 for five treatments (T1, T2, T3, T4 and T5) respectively. Sodium hypochlorite solution (5%) injected at the rate of 0.1 ml per unit discharge (lps) through chlorination unit at the outlet of the radial filter decreased bacteriological contamination to

BackgroundIncreasing prenatal screening options and limited consultation time have made it difficult for pregnant women to participate in shared decision-making. Interactive digital decision aids (IDDAs) could integrate interactive technology into health care to a facilitate higher-quality decision-making process. ObjectiveThe objective of this study was to assess the effectiveness of IDDAs on pregnant women’s decision-making regarding prenatal screening. MethodsWe searched Cochrane Central Register of Controlled Trials, MEDLINE, Embase, PsycINFO, World Health Organization International Clinical Trials Registry Platform, Google Scholar, and reference lists of included studies until August 2021. We included the randomized controlled trials (RCTs) that compared the use of IDDAs (fulfilling basic criteria of International Patient Decision Aid Standards Collaboration and these were interactive and digital) as an adjunct to standard care with standard care alone and involved pregnant women themselves in prenatal screening decision-making. Data on primary outcomes, that is, knowledge and decisional conflict, and secondary outcomes were extracted, and meta-analyses were conducted based on standardized mean differences (SMDs). Subgroup analysis based on knowledge was performed. The Cochrane risk-of-bias tool was used for risk-of-bias assessment. ResultsEight RCTs were identified from 10,283 references, of which 7 were included in quantitative synthesis. Analyses showed that IDDAs increased knowledge (SMD 0.58, 95% CI 0.26-0.90) and decreased decisional conflict (SMD –0.15, 95% CI –0.25 to –0.05). Substantial heterogeneity in knowledge was identified, which could not be completely resolved through subgroup analysis. ConclusionsIDDAs can improve certain aspects of decision-making in prenatal screening among pregnant women, but the results require cautious interpretation.

Abstract Background Currently the only available therapies for fibrotic Interstitial Lung Disease are administered systemically, often causing significant side effects. Inhaled therapy could avoid these but to date there is no evidence that drug can be effectively delivered to distal, fibrosed lung. We set out to combine mass spectrometry and histopathology with rapid sample acquisition using transbronchial cryobiopsy to determine whether an inhaled drug can be delivered to fibrotic, distal lung parenchyma in participants with Interstitial Lung Disease. Methods Patients with radiologically and multidisciplinary team confirmed fibrotic Interstitial Lung Disease were eligible for this study. Transbronchial cryobiopsies and endobronchial biopsies were taken from five participants, with Interstitial Lung Disease, within 70 min of administration of a single dose of nebulised ipratropium bromide. Thin tissue cryosections were analysed by Matrix Assisted Laser Desorption/Ionization-Mass Spectrometry imaging and correlated with histopathology. The remainder of the cryobiopsies were homogenised and analysed by Liquid Chromatography—tandem Mass Spectrometry. Results Drug was detected in proximal and distal lung samples from all participants. Fibrotic regions were identified in research samples of four of the five participants. Matrix Assisted Laser Desorption/Ionization-Mass Spectrometry imaging showed co-location of ipratropium with fibrotic regions in samples from three participants. Conclusions In this proof of concept study, using mass spectrometry, we demonstrate for the first-time that an inhaled drug can deposit in distal fibrotic lung parenchyma in patients with Interstitial Lung Disease. This suggests that drugs to treat pulmonary fibrosis could potentially be administered by the inhaled route. Trial registration A prospective clinical study approved by London Camden and Kings Cross Research Ethics Committee and registered on clinicaltrials.gov (NCT03136120)

Introduction: Trelegy is a combination inhaler that is often reported to offer benefits over multiple inhalers. We compared Trelegy use with multiple inhalers for adherence, symptoms, medication beliefs, and medication attitudes. Methods: This cross-sectional survey of 58 patients compared the patient’s experience with Trelegy (n = 18) versus any other inhaler (n = 40). Outcome variables consisted of Test of the Adherence to Inhalers scale, the Chronic obstructive pulmonary disease Assessment Test (CAT) scale, attitude items from the St. George’s Respiratory Questionnaire, the Beliefs about Medicines Questionnaire (BMQ)-necessity subscale, and the BMQ-concerns subscale. Results: We found that patients using Trelegy had greater CAT symptoms (M = 19.8, SD = 7.75) in comparison with the any other inhaler group (M = 15.7, SD = 11.10; P = 0.04). We did not find any difference between the groups for adherence or any of the medication attitudes or beliefs. CAT score was positively correlated with the number of months patients were on their current inhaler (rs = 0.29, P < 0.05) and their use of a rescue inhaler (rs = 0.42, P < 0.01). Patients with more concern about their medications were negatively correlated with the use of a rescue inhaler (rs = −0.31, P < 0.05). Discussion: We found that patients using Trelegy had greater symptoms in comparison with the any other inhaler group, but did not differ for adherence, medication attitudes, or medication beliefs. Conclusion: We recommend that clinicians should regularly re-evaluate their Trelegy recommendations, as Trelegy use may not be the best therapy for certain patients. Also, a study with a larger sample size can be beneficial to confirm these findings.

Abstract Recent advances in whole‐slide imaging (WSI) technology have led to the development of a myriad of computer vision and artificial intelligence‐based diagnostic, prognostic, and predictive algorithms. Computational Pathology (CPath) offers an integrated solution to utilise information embedded in pathology WSIs beyond what can be obtained through visual assessment. For automated analysis of WSIs and validation of machine learning (ML) models, annotations at the slide, tissue, and cellular levels are required. The annotation of important visual constructs in pathology images is an important component of CPath projects. Improper annotations can result in algorithms that are hard to interpret and can potentially produce inaccurate and inconsistent results. Despite the crucial role of annotations in CPath projects, there are no well‐defined guidelines or best practices on how annotations should be carried out. In this paper, we address this shortcoming by presenting the experience and best practices acquired during the execution of a large‐scale annotation exercise involving a multidisciplinary team of pathologists, ML experts, and researchers as part of the Pathology image data Lake for Analytics, Knowledge and Education (PathLAKE) consortium. We present a real‐world case study along with examples of different types of annotations, diagnostic algorithm, annotation data dictionary, and annotation constructs. The analyses reported in this work highlight best practice recommendations that can be used as annotation guidelines over the lifecycle of a CPath project.

Abstract Routine antenatal rubella serological testing is adopted in many countries. In a population covered by universal childhood rubella immunization for four decades, we have observed an association between pre-eclampsia with maternal rubella seronegativity among multiparous gravidae. This retrospective cohort study was further performed to elucidate the interaction between parity status and rubella seronegativity on obstetric outcome in singleton pregnancies carried to ≥ 24 weeks gestation managed from 1997 to 2019, with the data retrieved from a computerized database used for annual statistics and auditing. Of the 133,926 singleton pregnancies eligible for the study, the 13,320 (9.9%) rubella seronegative gravidae had higher mean booking weight and body mass index (BMI), but shorter height, and higher incidence of advanced age (≥ 35 years), high BMI, short stature, and lower incidence of nulliparas. Univariate analysis showed that adverse obstetric outcomes were more frequently found among the multiparas. On multivariate analysis, there was increased postdated (> 41 weeks) pregnancy irrespective of parity status, while nulliparas had reduced gestational hypertension (aRR 0.714, 95% CI 0.567–0.899) and gestational diabetes (aRR 0.850, 95% CI 0.762–0.950), and multiparas had increased pre-eclampsia (aRR 1.261, 95% CI 1.005–1.582), neonatal death (aRR 2.796, 95% CI 1.243–6.291), and perinatal death (aRR 2.123, 95% CI 1.257–3.587). In conclusion, in a population covered by universal childhood rubella immunization, antenatal rubella seronegativity is associated with increased pre-eclampsia and perinatal loss only in multiparas, suggesting that the rubella seronegativity in these women served as proxy for some form of altered immune response which increases adverse pregnancy outcome.

Background and objectivesCognitive difficulties in people with sickle cell anemia (SCA) are related to lower processing speed index (PSI) and working memory index (WMI). However, risk factors are poorly understood so preventative strategies have not been explored. Brain volumes, specifically white matter volumes (WMV) which increases through early adulthood, have been associated with better cognition in healthy typically developing individuals. In patients with SCA, the reduced WMV and total subcortical volumes noted could explain cognitive deficits. We therefore examined developmental trajectories for regional brain volumes and cognitive endpoints in patients with SCA.MethodsData from two cohorts, the Sleep and Asthma Cohort and Prevention of Morbidity in SCA, were available. MRI data included T1-weighted axial images, pre-processed before regional volumes were extracted using Free-surfer. PSI and WMI from the Weschler scales of intelligence were used to test neurocognitive performance. Hemoglobin, oxygen saturation, hydroxyurea treatment and socioeconomic status from education deciles were available.ResultsOne hundred and twenty nine patients (66 male) and 50 controls (21 male) aged 8–64 years were included. Brain volumes did not significantly differ between patients and controls. Compared with controls, PSI and WMI were significantly lower in patients with SCA, predicted by increasing age and male sex, with lower hemoglobin in the model for PSI but no effect of hydroxyurea treatment. In male patients with SCA only, WMV, age and socioeconomic status predicted PSI, while total subcortical volumes predicted WMI. Age positively and significantly predicted WMV in the whole group (patients + controls). There was a trend for age to negatively predict PSI in the whole group. For total subcortical volume and WMI, age predicted decrease only in the patient group. Developmental trajectory analysis revealed that PSI only was significantly delayed in patients at 8 years of age; the rate of development for the cognitive and brain volume data did not differ significantly from controls.DiscussionIncreasing age and male sex negatively impact cognition in SCA, with processing speed, also predicted by hemoglobin, delayed by mid childhood. Associations with brain volumes were seen in males with SCA. Brain endpoints, calibrated against large control datasets, should be considered for randomized treatment trials.

Background: The coronavirus disease 2019 (COVID-19) has resulted in an unprecedented research response, demonstrating exceptional examples of rapid research and collaboration. There has however been an ongoing need for greater coordination, with limited resources for research and the shifting global pandemic. Methods: The UK Collaborative on Development Research (UKCDR) and Global Research Collaboration for Infectious Disease Preparedness (GloPID-R), two funder coordination groups have collaborated to develop a live database of funded research projects across the world relating to COVID-19. Drawing data continually from their members and further global funding bodies, as of 15th July 2022 the database contains 17,955 projects, funded by 345 funders, taking place across 157 countries representing an investment of at least $6.5 billion. To our knowledge it is one of the most comprehensive databases. The database is aligned to the World Health Organisation and GloPID-R Global Research Roadmap: 2019 Novel Coronavirus and the UN Research Roadmap for the COVID-19 Recovery. It is being used by the WHO, governments and further policy makers, research funders and researchers. This living mapping review aims to supplement the database by providing an open accessible and frequently updated resource summarising the characteristics of the COVID-19 funded research portfolio. Both descriptive and thematic analysis are presented and updated frequently to aid interpretation of the global COVID-19 funded research portfolio. Results: In this version nine analysis we provide an updated detailed descriptive analysis of the database (on data from three months after version eight) and focus our thematic analysis on research gaps, research areas in need of coordination, study populations and research locations (with a focus on resource-limited countries). Conclusions: As the global funding response to COVID-19 plateaus, this living mapping review helps both funders and researchers to prioritise resources and review investments.

Background and aimApproximately one in four women will experience a miscarriage in their lifetime. Ultrasound-guided manual vacuum aspiration (USG-MVA) is an ideal outpatient surgical treatment alternative to traditional surgical evacuation. We aimed to examine the cost-effectiveness of US-MVA with cervical preparation for treatment of early pregnancy loss from the perspective of public healthcare provider of Hong Kong.MethodsA decision-analytic model was designed to simulate outcomes in a hypothetical cohort of patients with early pregnancy loss on four interventions: (1) US-MVA, (2) misoprostol, (3) surgical evacuation of uterus by dilation and curettage (surgical evacuation), and (4) expectant care. Model inputs were retrieved from published literature and public data. Model outcome measures were total direct medical cost and disutility-adjusted life-year (DALY). Base-case model results were examined by sensitivity analysis.ResultsThe expected DALYs (0.00141) and total direct medical cost (USD736) of US-MVA were the lowest of all interventions in base-case analysis, and US-MVA was the preferred cost-effective option. One-way sensitivity analysis showed that the misoprostol group became less costly than the US-MVA group if the evacuation rate of misoprostol (base-case value 0.832) exceeded 0.920. In probabilistic sensitivity analysis, At the willingness-to-pay (WTP) threshold of 49630 USD/DALY averted (1x gross domestic product per capita of Hong Kong), the US-MVA was cost-effective in 72.9% of the time.ConclusionsUS-MVA appeared to be cost-saving and effective for treatment of early pregnancy loss from the perspective of public healthcare provider of Hong Kong.

Introduction Despite a growing body of research on the risks of SARS-CoV-2 infection during pregnancy, there is continued controversy given heterogeneity in the quality and design of published studies.Methods We screened ongoing studies in our sequential, prospective meta-analysis. We pooled individual participant data to estimate the absolute and relative risk (RR) of adverse outcomes among pregnant women with SARS-CoV-2 infection, compared with confirmed negative pregnancies. We evaluated the risk of bias using a modified Newcastle-Ottawa Scale.Results We screened 137 studies and included 12 studies in 12 countries involving 13 136 pregnant women.Pregnant women with SARS-CoV-2 infection—as compared with uninfected pregnant women—were at significantly increased risk of maternal mortality (10 studies; n=1490; RR 7.68, 95% CI 1.70 to 34.61); admission to intensive care unit (8 studies; n=6660; RR 3.81, 95% CI 2.03 to 7.17); receiving mechanical ventilation (7 studies; n=4887; RR 15.23, 95% CI 4.32 to 53.71); receiving any critical care (7 studies; n=4735; RR 5.48, 95% CI 2.57 to 11.72); and being diagnosed with pneumonia (6 studies; n=4573; RR 23.46, 95% CI 3.03 to 181.39) and thromboembolic disease (8 studies; n=5146; RR 5.50, 95% CI 1.12 to 27.12).Neonates born to women with SARS-CoV-2 infection were more likely to be admitted to a neonatal care unit after birth (7 studies; n=7637; RR 1.86, 95% CI 1.12 to 3.08); be born preterm (7 studies; n=6233; RR 1.71, 95% CI 1.28 to 2.29) or moderately preterm (7 studies; n=6071; RR 2.92, 95% CI 1.88 to 4.54); and to be born low birth weight (12 studies; n=11 930; RR 1.19, 95% CI 1.02 to 1.40). Infection was not linked to stillbirth. Studies were generally at low or moderate risk of bias.Conclusions This analysis indicates that SARS-CoV-2 infection at any time during pregnancy increases the risk of maternal death, severe maternal morbidities and neonatal morbidity, but not stillbirth or intrauterine growth restriction. As more data become available, we will update these findings per the published protocol.

Summary: Background: Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal disorder with a variable disease trajectory. The aim of this study was to assess the potential of neutrophil-to-lymphocyte ratio (NLR) to predict outcomes in IPF. Methods: We adopted a two-stage discovery (n = 71) and validation (n = 134) design using patients from the UCL partners (UCLp) cohort. We then combined discovery and validation cohorts and included an additional 794 people with IPF, using real-life data from 5 other UK centers, to give a combined cohort of 999 patients. Data were collected from patients presenting over a 13-year period (2006–2019) with mean follow up of 3.7 years (censoring: 2018–2020). Findings: In the discovery analysis, we showed that high values of NLR (>/ = 2.9 vs

INTRODUCTION:The opioid drug epidemic is a major public health concern and an economic burden in the United States. The purpose of this systematic review is to assess the reliability and validity of screening instruments used in emergency medicine settings to detect opioid use in patients and to assess psychometric data for each screening instrument. METHODS:PubMed/MEDLINE, PsycINFO, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, Web of Science, Cumulative Index to Nursing and Allied Health Literature and ClinicalTrials.gov were searched for articles published up to May 2018. The extracted articles were independently screened for eligibility by two reviewers. We extracted 1555 articles for initial screening and 95 articles were assessed for full-text eligibility. Six articles were extracted from the full-text assessment. RESULTS:Six instruments were identified from the final article list: Screener and Opioid Assessment for Patients with Pain - Revised; Drug Abuse Screening Test; Opioid Risk Tool; Current Opioid Misuse Measure; an Emergency Medicine Providers Clinician Assessment Questionnaire; and an Emergency Provider Impression Data Collection Form. Screening instrument characteristics, and reliability and validity data were extracted from the six studies. A meta-analysis was not conducted due to heterogeneity between the studies. CONCLUSIONS:There is a lack of validity and reliability evidence in all six articles; and sensitivity, specificity and predictive values varied between the different instruments. These instruments cannot be validated for use in emergency medicine settings. There is no clear evidence to state which screening instruments are appropriate for use in detecting opioid use disorders in emergency medicine patients. There is a need for brief, reliable, valid and feasible opioid use screening instruments in the emergency medicine setting.

ObjectivesThe primary objective of this study was to determine whether consensuses on the definition of emergency physician professionalism exist within and among four different generations. Our secondary objective was to describe the most important characteristic related to emergency physician professionalism that each generation values.MethodsWe performed a cross-sectional survey study, using a card-sorting technique, at the emergency departments of two university-based medical centers in the United States. The study was conducted with 288 participants from February to November 2017. Participants included adult emergency department patients, emergency medicine supervising physicians, emergency medicine residents, emergency department nurses, and fourth- and second-year medical students who independently ranked 39 cards that represent qualities related to emergency physician professionalism. We used descriptive statistics, quantitative cultural consensuses and Spearman's correlation coefficients to analyze the data.ResultsWe found cultural consensuses on emergency physician professionalism in Millennials and Generation X overall, with respect for patients named the most important quality (eigenratio 5.94, negative competency 0%; eigenratio 3.87, negative competency 1.64%, respectively). There were consensuses on emergency physician professionalism in healthcare providers throughout all generations, but no consensuses were found across generations in the patient groups.ConclusionsWhile younger generations and healthcare providers had consensuses on emergency physician professionalism, we found that patients had no consensuses on this matter. Medical professionalism curricula should be designed with an understanding of each generation's values concerning professionalism. Future studies using qualitative methods across specialties, to assess definitions of medical professionalism in each generation, should be pursued.

PurposeProviding feedback to students in the emergency department during their emergency medicine clerkship can be challenging due to time constraints, the logistics of direct observation, and limitations of privacy. The authors aimed to evaluate the effectiveness of first-person video, captured via Google Glass™, to enhance feedback quality in medical student education.Material and methodsAs a clerkship requirement, students asked patients and attending physicians to wear the Google Glass™ device to record patient encounters and patient presentations, respectively. Afterwards, students reviewed the recordings with faculty, who provided formative and summative feedback, during a private, one-on-one session. We introduced the intervention to 45, fourth-year medical students who completed their mandatory emergency medicine clerkships at a United States medical school during the 2015-2016 academic year.ResultsStudents assessed their performances before and after the review sessions using standardized medical school evaluation forms. We compared students' self-assessment scores to faculty assessment scores in 14 categories using descriptive statistics and symmetric tests. The overall mean scores, for each of the 14 categories, ranged between 3 and 4 (out of 5) for the self-assessment forms. When evaluating the propensity of self-assessment scores toward the faculty assessment scores, we found no significant changes in all 14 categories. Although not statistically significant, one fifth of students changed perspectives of their clinical skills (history taking, performing physical exams, presenting cases, and developing differential diagnoses and plans) toward faculty assessments after reviewing the video recordings.ConclusionFirst-person video recording still initiated the feedback process, allocated specific time and space for feedback, and possibly substituted for the direct observation procedure. Additional studies, with different outcomes and larger sample sizes, are needed to understand the effectiveness of first-person video in improving feedback quality.

Abstract Background Transvenous lead extraction (TLE) for implantable cardiac‐devices is traditionally performed under general anesthesia (GA). This can lead to greater risk of exposure to COVID‐19, longer recovery‐times and increased procedural‐costs. We report the feasibility/safety of TLE using conscious‐sedation alone with immediate GA/cardiac‐surgery back‐up if needed. Methods Retrospective case‐series of consecutive TLEs performed using conscious‐sedation alone between March 2016 and December 2019. All were performed in the electrophysiology‐laboratory using intravenous Fentanyl, Midazolam/Diazepam with a stepwise approach using locking‐stylets/cutting‐sheaths, including mechanical‐sheaths. Baseline patient‐characteristics, procedural‐details and TLE outcomes (including procedure‐related complications/death) were recorded. Results A total of 130 leads were targeted in 54 patients, mean age ± SD 74.6 ± 11.8years, 47(87%) males; dual‐chamber pacemakers (n = 26; 48%), cardiac resynchronization therapy‐defibrillators (n = 17; 31%) and defibrillators (n = 8; 15%) were commonest extracted devices. Mean ± SD/median (range) lead‐dwell times were 11.0 ± 8.8/8.3 (0.3‐37) years, respectively. Extraction indications included systemic infection (n = 23; 43%) and lead/pulse‐generator erosion (n = 27; 50%); mean 2.1 ± 2.0 leads were removed per procedure/mean procedure‐time was 100 ± 54 min. Local anesthetic (LA) was used for all (mean‐dose: 33 ± 8 ml 1% lidocaine), IV drug‐doses used (mean ± SD) were: midazolam: 3.95 ± 2.44 mg, diazepam: 4.69 ± 0.89 mg and fentanyl: 57 ± 40 µg. Complete lead‐extraction was achieved in 110 (85%) leads, partial lead‐extraction (

Abstract Background To evaluate the performance of the Fetal Medicine Foundation (FMF) preterm preeclampsia (PE) screening algorithm in an indigenous South Asian population. Methods This was a prospective observational cohort study conducted in a tertiary maternal fetal unit in Delhi, India over 2 years. The study population comprised of 1863 women carrying a singleton pregnancy and of South Asian ethnicity who were screened for preterm pre-eclampsia (PE) between 11 and 14 weeks of gestation using Mean Arterial Pressure (MAP), transvaginal Mean Uterine Artery Pulsatility Index (UtAPI) and biochemical markers - Pregnancy Associated Plasma Protein-A (PAPP-A) and Placental Growth Factor.. Absolutemeasurements of noted biomarkers were converted to multiples of the expected gestational median (MoMS) which were then used to estimate risk for preterm PE

Abstract Background True allergy to metronidazole, a common anti-infective in clinical practice, is rarely reported in the literature. In the case of Trichomonas, there are few alternatives to the nitrimidazole class of drugs, and the alternatives that do exist are associated with worse clinical outcomes. Accordingly, for the rare patients with Type 1 hypersensitivity reactions to metronidazole but compelling need, desensitization protocols have been adapted previously. Reactions during these protocols appear common. Patients in previous regimens have required higher level care for observation, which is costly and resource-intensive. Case presentation We report here on a successful outpatient two-day regimen for metronidazole desensitization. Our patient had compelling indication for metronidazole, but reacted after receiving the very first dose of a previously described desensitization protocol. Accordingly, the protocol was adapted further. Despite this, she went on to develop objective hives prior to reaching the full intended dose. With appropriate symptom management and pre-medication on the second day in clinic, she was successfully desensitized and able to complete a week of full-dose metronidazole. No acute care resources were needed. Conclusion We propose this two-day desensitization regimen for patients who react during the previously described desensitization protocols. This regimen was effective and safe, and did not necessitate the use of acute-care resources. Two-day desensitization protocols while relatively uncommon, can be successful.

Abstract Background Young children with sickle cell anaemia (SCA) often have slowed processing speed associated with reduced brain white matter integrity, low oxygen saturation, and sleep-disordered breathing (SDB), related in part to enlarged adenoids and tonsils. Common treatments for SDB include adenotonsillectomy and nocturnal continuous positive airway pressure (CPAP), but adenotonsillectomy is an invasive surgical procedure, and CPAP is rarely well-tolerated. Further, there is no current consensus on the ability of these treatments to improve cognitive function. Several double-blind, randomised controlled trials (RCTs) have demonstrated the efficacy of montelukast, a safe, well-tolerated anti-inflammatory agent, as a treatment for airway obstruction and reducing adenoid size for children who do not have SCA. However, we do not yet know whether montelukast reduces adenoid size and improves cognition function in young children with SCA. Methods The Study of Montelukast In Children with Sickle Cell Disease (SMILES) is a 12-week multicentre, double-blind, RCT. SMILES aims to recruit 200 paediatric patients with SCA and SDB aged 3–7.99 years to assess the extent to which montelukast can improve cognitive function (i.e. processing speed) and sleep and reduce adenoidal size and white matter damage compared to placebo. Patients will be randomised to either montelukast or placebo for 12 weeks. The primary objective of the SMILES trial is to assess the effect of montelukast on processing speed in young children with SCA. At baseline and post-treatment, we will administer a cognitive evaluation; caregivers will complete questionnaires (e.g. sleep, pain) and measures of demographics. Laboratory values will be obtained from medical records collected as part of standard care. If a family agrees, patients will undergo brain MRIs for adenoid size and other structural and haemodynamic quantitative measures at baseline and post-treatment, and we will obtain overnight oximetry. Discussion Findings from this study will increase our understanding of whether montelukast is an effective treatment for young children with SCA. Using cognitive testing and MRI, the SMILES trial hopes to gain critical knowledge to help develop targeted interventions to improve the outcomes of young children with SCA. Trial registration ClinicalTrials.gov NCT04351698 . Registered on April 17, 2020. European Clinical Trials Database (EudraCT No. 2017-004539-36). Registered on May 19, 2020

Background: The coronavirus disease 2019 (COVID-19) has resulted in an unprecedented research response, demonstrating exceptional examples of rapid research and collaboration. There has however been an ongoing need for greater coordination, with limited resources for research and the shifting global pandemic. Methods: The UK Collaborative on Development Research (UKCDR) and Global Research Collaboration for Infectious Disease Preparedness (GloPID-R), two funder coordination groups have collaborated to develop a live database of funded research projects across the world relating to COVID-19. Drawing data continually from their members and further global funding bodies, as of 15th April 2022 the database contains 16,353 projects, funded by 319 funders, taking place across 157 countries representing an investment of at least $6.2 billion. To our knowledge it is one of the most comprehensive databases. The database is aligned to the World Health Organisation and GloPID-R Global Research Roadmap: 2019 Novel Coronavirus and the UN Research Roadmap for the COVID-19 Recovery. It is being used by the WHO, governments and further policy makers, research funders and researchers. This living mapping review aims to supplement the database by providing an open accessible and frequently updated resource summarising the characteristics of the COVID-19 funded research portfolio. Both descriptive and thematic analysis are presented and updated frequently to aid interpretation of the global COVID-19 funded research portfolio. Results: In this version eight analysis we provide an updated detailed descriptive analysis of the database (on data from three months after version seven) and focus our thematic analysis on research gaps, research areas in need of coordination, study populations and research locations (with a focus on resource-limited countries). Conclusions: As the global funding response to COVID-19 plateaus, this living mapping review helps both funders and researchers to prioritise resources to areas where there is continued unmet research need.

Autonomic dysfunction is a prominent concern following spinal cord injury (SCI). In particular, autonomic dysreflexia (AD; paroxysmal hypertension and concurrent bradycardia in response to sensory stimuli below the level of injury) is common in autonomically-complete injuries at or above T6. AD is currently defined as a >20 mmHg increase in systolic arterial pressure (SAP) from baseline, without heart rate (HR) criteria. Urodynamics testing (UDS) is performed routinely after SCI to monitor urological sequelae, often provoking AD. We, therefore, aimed to assess the cardiovascular and cerebrovascular responses to UDS and their association with autonomic injury in individuals with chronic (>1 year) SCI. Following blood draw (plasma norepinephrine [NE]), continuous SAP, HR, and middle cerebral artery blood flow velocity (MCAv) were recorded at baseline (10-minute supine), during standard clinical UDS, and recovery (10-minute supine) (n = 22, age 41.1 ± 2 years, 15 male). Low frequency variability in systolic arterial pressure (LF SAP; a marker of sympathetic modulation of blood pressure) and cerebral resistance were determined. High-level injury (≥T6) with blunted/absent LF SAP (20 mmHg during UDS. Qualitative autonomic assessment did not discriminate autonomic injury. Maximum SAP was higher in autonomically-complete injuries (207.1 ± 2.3 mmHg) than autonomically-incomplete injuries (165.9 ± 5.3 mmHg) during UDS (p < 0.001). HR during UDS was reduced compared to baseline (p = 0.056) and recovery (p = 0.048) only in autonomically-complete lesions. MCAv was not different between groups or phases (all p > 0.05). Cerebrovascular resistance index was increased during UDS in autonomically-complete injuries compared to baseline (p < 0.001) and recovery (p < 0.001) reflecting intact cerebral autoregulation. Risk for both atrial and ventricular arrhythmia increased during UDS compared to baseline (p < 0.05), particularly in autonomically-complete injuries (p < 0.05). UDS is recommended yearly in chronic SCI but is associated with profound AD and an increased risk of arrhythmia, highlighting the need for continued monitoring during UDS. Our data also highlight the need for HR criteria in the definition of AD and the need for quantitative consideration of autonomic function after SCI.

Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disease characterised by progressive degeneration of the motor neurones. An expanded GGGGCC (G4C2) hexanucleotide repeat in C9orf72 is the most common genetic cause of ALS and frontotemporal dementia (FTD); therefore, the resulting disease is known as C9ALS/FTD. Here, we employ a Drosophila melanogaster model of C9ALS/FTD (C9 model) to investigate a role for specific medium-chain fatty acids (MCFAs) in reversing pathogenic outcomes. Drosophila larvae overexpressing the ALS-associated dipeptide repeats (DPRs) in the nervous system exhibit reduced motor function and neuromuscular junction (NMJ) defects. We show that two MCFAs, nonanoic acid (NA) and 4-methyloctanoic acid (4-MOA), can ameliorate impaired motor function in C9 larvae and improve NMJ degeneration, although their mechanisms of action are not identical. NA modified postsynaptic glutamate receptor density, whereas 4-MOA restored defects in the presynaptic vesicular release. We also demonstrate the effects of NA and 4-MOA on metabolism in C9 larvae and implicate various metabolic pathways as dysregulated in our ALS model. Our findings pave the way to identifying novel therapeutic targets and potential treatments for ALS.