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Abstract Background It is a requirement that medical students are educated in emergencies and feel well prepared for practice as a doctor, yet national surveys show that many students feel underprepared. Virtual reality (VR), combined with 360-degree filming, provides an immersive, realistic, and interactive simulation experience. Unlike conventional in-person simulation, it is scalable with reduced workforce demands. We sought to compare students’ engagement and enjoyment of VR simulation to desktop computer-based simulation. Methods We conducted a prospective, interventional, evaluation study. The study was carried out on final year medical students undertaking their Pre-Foundation Assistantship (n = 116) at Imperial College School of Medicine (ICSM) in London. We compared objective engagement, subjective engagement, and subjective enjoyment of VR simulation to desktop computer-based simulation using cardiac arrest and life-threatening asthma scenarios. Engagement was measured objectively using students’ physiological parameters, including heart rate and eye tracking, and facilitator observations using the validated ‘Behavioural Engagement Related to Instruction’ (BERI) protocol. Students’ subjective engagement and enjoyment levels were measured using a post-session survey. Results Students’ maximum heart rates were significantly higher during VR simulation with a mean difference of 4.2 beats per minute (3.2 to 5.2, p

ABSTRACT: Background: Successful treatments for intractable chronic low back pain (CLBP) in patients who are not eligible for surgical interventions are scarce. The superior efficacy of differential target multiplexed spinal cord stimulation (DTM SCS) to conventional SCS (Conv-SCS) on the treatment of CLBP in patients with persistent spinal pain syndrome (PSPS) who have failed surgical interventions (PSPS-T2) motivated the evaluation of DTM SCS versus Conv-SCS on PSPS patients who are non-surgical candidates (PSPS-T1). Methods: This is a prospective, open label, crossover, post-market randomized controlled trial in 20 centers across the United States. Eligible patients were randomized to either DTM SCS or Conv-SCS in a 1:1 ratio. Primary endpoint was CLBP responder rate (percentage of subjects with ≥50% CLBP relief) at 3-month in randomized subjects who completed trialing (modified intention-to-treat population). Patients were followed up to 12 months. Secondary endpoints included change of CLBP and leg pain, responder rates, changes in disability, quality of life, patient satisfaction and global impression of change, and safety profile. An optional crossover was available at 6-month to all patients. Results: About 121 PSPS-T1 subjects with CLBP and leg pain mostly associated with degenerative disc disease and radiculopathy and who were not eligible for spine surgery were randomized. CLBP responder rate with DTM SCS (93.5%) was superior to Conv-SCS (36.4%) at the primary endpoint. Superior CLBP responder rates (88.1%–90.5%) were obtained with DTM SCS at all other timepoints. Mean CLBP reduction with DTM SCS (6.52 cm) was superior to that with Conv-SCS (3.01 cm) at the primary endpoint. Similar CLBP reductions (6.23–6.43 cm) were obtained with DTM SCS at other timepoints. DTM SCS provided significantly better leg pain reduction and responder rate, improvement of disability and quality of life, and better patient satisfaction and global impression of change. 90.9% of Conv-SCS subjects who crossed over were CLBP responders at completion of the study. Similar safety profiles were observed between the two groups. Conclusion: DTM SCS for chronic CLBP in nonsurgical candidates is superior to Conv-SCS. Improvements were sustained and provided significant benefits on the management of these patients.

Background and Aims: Eosinophilic esophagitis (EoE) is an antigen-mediated inflammatory esophageal disease that is commonly treated with high-dose proton-pump inhibitors (PPIs), topical corticosteroids, or food elimination diet (FED) monotherapy. Combination treatment has not been well studied in the management of EoE. We aimed to determine if PPI and FED combination therapy was able to induce histologic remission in patients with EoE refractory to monotherapy. Methods: We conducted a retrospective cohort study identifying patients with EoE that was refractory to PPI monotherapy and FED monotherapy but histologically responsive to PPI and FED combination therapy. We also identified symptom changes through chart review. Results: Out of 405 EoE patients, 12 patients were identified with EoE that was refractory to PPI monotherapy and FED monotherapy but histologically responsive to PPI and FED combination therapy. Out of 12 patients, 11 (91.67%) noted resolution of symptoms while on combination therapy. Comparative analysis of peak eosinophil counts showed that patients achieved a median of 4.5 eos/hpf (interquartile range [IQR], 2–6.5), which was significantly decreased compared to baseline (median, 45; IQR, 35.5–50; Wilcoxon signed-rank test, P < .001), PPI monotherapy (median, 41; IQR, 26–50; Wilcoxon signed-rank test, P < .001), and FED monotherapy (median, 45; IQR, 17–67.5; Wilcoxon signed-rank test, P < .001). Conclusion: Our work shows that patients with EoE refractory to PPI monotherapy and FED monotherapy can successfully achieve histologic remission and symptom benefit with PPI and FED combination therapy. Therefore, combination therapy should be considered a viable option for patients with EoE who fail treatment with first-line monotherapies.

Schizophrenia is often a severe and debilitating mental illness, frequently associated with impairments in social cognition that hinder individuals' abilities to relate to others and integrate effectively in society. Oxytocin has emerged as a putative therapeutic agent for treating social deficits in schizophrenia, but the mode of action remains unclear. This placebo-controlled crossover study aimed to elucidate the neural underpinnings of oxytocin administration in patients with schizophrenia. 20 patients with schizophrenia were examined using functional magnetic resonance imaging under oxytocin (40 IU) or placebo nasal spray. Participants performed a stochastically rewarded decision-making task that incorporated elements of social valence provided by different facial expressions, i.e. happy, angry and neutral. Oxytocin attenuated the normal bias in selecting the happy face accompanied by reduced activation in a network of brain regions that support mentalising, processing of facial emotion, salience, aversion, uncertainty and ambiguity in social stimuli, including amygdala, temporo-parietal junction, posterior cingulate cortex, precuneus and insula. These pro-social effects may contribute to the facilitation of social engagement and social interactions in patients with schizophrenia and warrant further investigation in future clinical trials for social cognitive impairments in schizophrenia.

More effective treatments are needed for human papilloma virus (HPV)-induced cancers despite HPV virus vaccination. The oncogenic HPV protein targets are currently undruggable and intracellular and therefore there are no antibodies to these targets. Here we report the discovery of TCR mimic monoclonal antibodies (TCRm mAb) specific for the HPV E7 protein p11-19, YMLDLQPET, when presented on the cell surface in the context of HLA-A*02:01 by use of human phage display libraries. One of the mAbs, 3F8, was able to specifically mediate T cell- redirected cytotoxicity, in a bispecific T cell engager (BiTE) form. While further studies are required to assess the therapeutic potential of this approach, the study provided the proof of concept that TCRm mAb could be a therapeutic strategy for HPV-induced human cancers.

Abstract Background Evidence on the association between sitting for extended periods (i.e. prolonged sedentary time (PST)) and cardio-metabolic health is inconsistent in children. We aimed to estimate the differences in cardio-metabolic health associated with substituting PST with non-prolonged sedentary time (non-PST), light (LIPA) or moderate-to-vigorous physical activity (MVPA) in children. Methods Cross-sectional data from 14 studies (7 countries) in the International Children’s Accelerometry Database (ICAD, 1998–2009) was included. Accelerometry in 19,502 participants aged 3–18 years, together with covariate and outcome data, was pooled and harmonized. Iso-temporal substitution in linear regression models provided beta coefficients (95%CI) for substitution of 1 h/day PST (sedentary time accumulated in bouts > 15 min) with non-PST, LIPA or MVPA, for each study, which were meta-analysed. Results Modelling substitution of 1 h/day of PST with non-PST suggested reductions in standardized BMI, but estimates were > 7-fold greater for substitution with MVPA (− 0.44 (− 0.62; − 0.26) SD units). Only reallocation by MVPA was beneficial for waist circumference (− 3.07 (− 4.47; − 1.68) cm), systolic blood pressure (− 1.53 (− 2.42; − 0.65) mmHg) and clustered cardio-metabolic risk (− 0.18 (− 0.3; − 0.1) SD units). For HDL-cholesterol and diastolic blood pressure, substitution with LIPA was beneficial; however, substitution with MVPA showed 5-fold stronger effect estimates (HDL-cholesterol: 0.05 (0.01; 0.10) mmol/l); diastolic blood pressure: − 0.81 (− 1.38; − 0.24) mmHg). Conclusions Replacement of PST with MVPA may be the preferred scenario for behaviour change, given beneficial associations with a wide range of cardio-metabolic risk factors (including adiposity, HDL-cholesterol, blood pressure and clustered cardio-metabolic risk). Effect estimates are clinically relevant (e.g. an estimated reduction in waist circumference of ≈1.5 cm for 30 min/day replacement). Replacement with LIPA could be beneficial for some of these risk factors, however with substantially lower effect estimates.

Lateral flow devices (LFDs) are quickly being implemented for use in large-scale population surveillance programs for SARS-CoV-2 infection in the United Kingdom. These programs have been piloted in city-wide screening in the city of Liverpool and are now being rolled out to support care home visits and the return home of University students for the Christmas break. Here, we present data on the performance of LFDs to test almost 8,000 students at the University of Birmingham between December 2 and December 9, 2020. The performance is validated against almost 800 samples using PCR performed in the University Pillar 2 testing lab and theoretically validated on thousands of Pillar 2 PCR testing results performed on low-prevalence care home testing samples. Our data show that LFDs do not detect infections presenting with PCR Ct values over 29 to 30 as determined using the Thermo Fisher TaqPath asssay. This may be of particular importance in detecting individuals that are either at the early, or late stages of infection, and reinforces the need for frequent, recurrent testing.

Abstract Increasing exploitation of marine natural resources and expansion of energy infrastructure, shipping, and aquaculture across the oceans are placing increased pressure on marine life. Biodiversity offsets, as the last stage of the mitigation hierarchy, provide an opportunity to promote a more sustainable basis for development by addressing residual impacts and achieving “no net loss” for biodiversity. Despite debate around their effectiveness, biodiversity offsets are seeing increasing application on land but remain a rarely used tool in the marine environment. We assess how offsets can be applied in the marine environment to achieve better biodiversity outcomes, and identify implications for conservation policy and practice. For instance, spatial conservation planning provides opportunities to move away from a siloed, project‐by‐project, approach by pooling offsets on a regional scale. There are real differences between marine and terrestrial environments in relation to ecology, connectivity, data availability, management options, and impact perception, and marine offsets are therefore often regarded as challenging. However, fundamental offset principles, types, and approaches apply equally on land and at sea. Marine biodiversity offset approaches can build on the experience of terrestrial offsets but can also innovate to help achieve biodiversity gains and contribute toward global and national biodiversity targets.

Abstract Background When a patient in a provider network seeks services outside of their community, the community experiences a leakage. Leakage is undesirable as it typically leads to higher out-of-network cost for patient and increases barrier for care coordination, which is particularly problematic for Accountable Care Organization (ACO) as the in-network providers are financially responsible for quality of care and outcome. We aim to design a data-driven method to identify naturally occurring provider networks driven by diabetic patient choices, and understand the relationship among provider composition, patient composition, and service leakage pattern. By doing so, we learn the features of low service leakage provider networks that can be generalized to different patient population. Methods Data used for this study include de-identified healthcare insurance administrative data acquired from Capital District Physicians’ Health Plan (CDPHP) for diabetic patients who resided in four New York state counties (Albany, Rensselaer, Saratoga, and Schenectady) in 2014. We construct a healthcare provider network based on patients’ historical medical insurance claims. A community detection algorithm is used to identify naturally occurring communities of collaborating providers. For each detected community, a profile is built using several new key measures to elucidate stakeholders of our findings. Finally, import-export analysis is conducted to benchmark their leakage pattern and identify further leakage reduction opportunity. Results The design yields six major provider communities with diverse profiles. Some communities are geographically concentrated, while others tend to draw patients with certain diabetic co-morbidities. Providers from the same healthcare institution are likely to be assigned to the same community. While most communities have high within-community utilization and spending, at 85% and 86% respectively, leakage still persists. Hence, we utilize a metric from import-export analysis to detect leakage, gaining insight on how to minimize leakage. Conclusions We identify patient-driven provider organization by surfacing providers who share a large number of patients. By analyzing the import-export behavior of each identified community using a novel approach and profiling community patient and provider composition we understand the key features of having a balanced number of PCP and specialists and provider heterogeneity.

Nayan Kulkarni’s Blade, Lucy and Jorge Orta’s Raft of the Medusa, and Nikolaj Bendix Skyum Larsen’s Quicksand were exhibited in Hull during its year as the 2017 UK City of Culture. These artworks provide the impetus for an article that moves between the local, national, and global, in order to connect visual culture, climate politics, and questions of citizenship and borders in a warming world. In the first section, I discuss how Blade—a wind turbine rotor blade repurposed as a public art installation—provides the opportunity to examine the role of large-scale renewable energy transition in addressing the deep regional economic inequalities in the UK. In the second section, I consider how artworks displayed as part of the ‘Somewhere Becoming Sea’ exhibition linked Hull’s recent history to a global context of displacement and precarity, in the wake of the ongoing ‘refugee crisis’ within Europe and at its borders. In the final section, I seek to bring together a number of threads from the preceding discussion, in order to outline some alternative political horizons. I turn initially to Sean McAllister’s documentary A Northern Soul (2018) and its powerful examination of how personal debt, the toxic fuel of neoliberalism, forecloses the future. In opposition to a future of deepening inequality and climate breakdown, I trace a renewed politics of public ownership and expanded social welfare in the UK, and its place in a prospective global renewable energy transition. This is a hopeful vision, given the current political climate, I argue, but it is also an eminently feasible one.

Mix-and-inject serial crystallography (MISC) is a technique designed to image enzyme catalyzed reactions in which small protein crystals are mixed with a substrate just prior to being probed by an X-ray pulse. This approach offers several advantages over flow cell studies. It provides (i) room temperature structures at near atomic resolution, (ii) time resolution ranging from microseconds to seconds, and (iii) convenient reaction initiation. It outruns radiation damage by using femtosecond X-ray pulses allowing damage and chemistry to be separated. Here, we demonstrate that MISC is feasible at an X-ray free electron laser by studying the reaction of M. tuberculosis ß-lactamase microcrystals with ceftriaxone antibiotic solution. Electron density maps of the apo-ß-lactamase and of the ceftriaxone bound form were obtained at 2.8 Å and 2.4 Å resolution, respectively. These results pave the way to study cyclic and non-cyclic reactions and represent a new field of time-resolved structural dynamics for numerous substrate-triggered biological reactions.

Urobiome research has the potential to advance the understanding of a wide range of diseases, including lower urinary tract symptoms and kidney disease. Many scientific areas have benefited from early research method consensus to facilitate the greater, common good. This consensus document, developed by a group of expert investigators currently engaged in urobiome research (UROBIOME 2020 conference participants), aims to promote standardization and advances in this field by the adoption of common core research practices. We propose a standardized nomenclature as well as considerations for specimen collection, preservation, storage, and processing. Best practices for urobiome study design include our proposal for standard metadata elements as part of core metadata collection. Although it is impractical to follow fixed analytical procedures when analyzing urobiome data, we propose guidelines to document and report data originating from urobiome studies. We offer this first consensus document with every expectation of subsequent revision as our field progresses.

BackgroundFemale urinary microbiota are associated with urgency urinary incontinence and response to medication. The urinary microbiota of women with stress urinary incontinence has not been described.ObjectiveWe sought to study the cross-sectional relationships between urinary microbiota features and demographic and clinical characteristics of women undergoing stress urinary incontinence surgery.Study designPreoperative urine specimens were collected from women without urinary tract infection and were available from 197 women (174 voided, 23 catheterized) enrolled in a multicenter prospective randomized trial, the Value of Urodynamic Evaluation study. Demographic and clinical variables were obtained including stress and urgency urinary incontinence symptoms, menopausal status, and hormone use. The bacterial composition of the urine was qualitatively assessed by sequencing the bacterial 16S ribosomal RNA gene. Phylogenetic relatedness and microbial alpha diversity were compared to demographics and symptoms using generalized estimating equation models.ResultsThe majority of 197 urine samples (86%) had detectable bacterial DNA. Bacterial diversity was significantly associated with higher body mass index (P = .02); increased Medical, Epidemiologic, and Social Aspects of Aging urge index score (P = .04); and hormonal status (P < .001). No associations were detected with stress urinary incontinence symptoms. Increased diversity was also associated with a concomitant lower frequency of Lactobacillus in hormone-negative women.ConclusionWomen undergoing stress urinary incontinence surgery have detectable urinary microbiota. This cross-sectional analysis revealed that increased diversity of the microbiota was associated with urgency urinary incontinence symptoms, hormonal status, and body mass index. In contrast, the female urinary microbiota were not associated with stress urinary incontinence symptoms.

Vaginitis is a widespread issue for women worldwide, yet current diagnostic tools are lacking. Bacterial vaginosis (BV) is the most prevalent type of vaginitis, found in 10–50% of reproductive-aged women. Current diagnostic methods for BV rely on clinical criteria, microscopy, or the detection of a few microbes by qPCR. However, many vaginal infections lack a single etiological agent and are characterized by changes in the vaginal microbiome community structure (e.g., BV is defined as a loss of protective lactobacilli resulting in an overgrowth of anaerobic bacteria). Shotgun metagenomic sequencing provides a comprehensive view of all the organisms present in the vaginal microbiome (VMB), allowing for a better understanding of all potential etiologies. Here, we describe a robust VMB metagenomics sequencing test with a sensitivity of 93.1%, a specificity of 90%, a negative predictive value of 93.4%, and a positive predictive value of 89.6% certified by Clinical Laboratory Improvement Amendments (CLIA), the College of American Pathologist (CAP), and the Clinical Laboratory Evaluation Program (CLEP). We sequenced over 7000 human vaginal samples with this pipeline and described general findings and comparisons to US census data. [ABSTRACT FROM AUTHOR]

Recurrent urogenital infections such as bacterial vaginosis, vulvovaginal candidiasis, and urinary tract infections have a high prevalence and pronounced psychosocial impact. However, no review has compared the psychosocial impacts across infection types. This narrative review discusses the impact of common recurrent urogenital infections on psychosocial aspects, including quality of life, stress, mental health, sexual health, work productivity, race and ethnicity, and satisfaction of medical care. Validated questionnaires show that women with recurrent vulvovaginal candidiasis and urinary tract infections have decreased scores on all aspects of quality of life. Those with recurrent vulvovaginal candidiasis and urinary tract infections show lower mental health scores compared to the general population, with increased risk of anxiety and depression. Recurrent urogenital infections affect sexual relationships and intimacy, including avoidance due to symptoms or as a method of prevention. Recurrent infections also increase medical cost and negatively affect work productivity, leading to a combined estimated cost of over US$13 billion per year. There are clear effects of racial inequality involving minority populations that affect diagnosis, treatment, prevalence, and reporting of recurrent urogenital infections. Satisfactory medical treatment improves quality of life and mental health in those suffering from these conditions. Research evaluating psychosocial aspects of recurrent urogenital infections is variable and is not comparable across vulvovaginal conditions. Even so, psychosocial factors are important in understanding contribution and consequence of urogenital infections. Education, awareness, normalization, community support, and access to care can help to alleviate the negative implications of recurrent urogenital infections. Plain language summary: A narrative review discussing the psychosocial impact of common recurrent urogenital infections and highlights areas where further research is needed to improve clinical care. [ABSTRACT FROM AUTHOR]