The inflammasome pathway is activated by dengue virus non-structural protein 1 and is protective during dengue virus infection.

Dengue virus (DENV) is a medically important flavivirus causing an estimated 50-100 million dengue cases annually, some of whom progress to severe disease. DENV non-structural protein 1 (NS1) is secreted from infected cells and has been implicated as a major driver of dengue pathogenesis by inducing endothelial barrier dysfunction. However, less is known about how DENV NS1 interacts with immune cells and what role these interactions play. Here we report that DENV NS1 can trigger activation of inflammasomes, a family of cytosolic innate immune sensors that respond to infectious and noxious stimuli, in mouse and human macrophages. DENV NS1 induces the release of IL-1ß in a caspase-1 dependent manner. Additionally, we find that DENV NS1-induced inflammasome activation is independent of the NLRP3, Pyrin, and AIM2 inflammasome pathways, but requires CD14. Intriguingly, DENV NS1-induced inflammasome activation does not induce pyroptosis and rapid cell death; instead, macrophages maintain cellular viability while releasing IL-1ß. Lastly, we show that caspase-1/11-deficient, but not NLRP3-deficient, mice are more susceptible to lethal DENV infection. Together, these results indicate that the inflammasome pathway acts as a sensor of DENV NS1 and plays a protective role during infection.

Phase 1/dose expansion trial of brentuximab vedotin and lenalidomide in relapsed or refractory diffuse large B-cell lymphoma.

New therapies are needed for patients with relapsed/refractory (rel/ref) diffuse large B-cell lymphoma (DLBCL) who do not benefit from or are ineligible for stem cell transplant and chimeric antigen receptor therapy. The CD30-targeted, antibody-drug conjugate brentuximab vedotin (BV) and the immunomodulator lenalidomide (Len) have demonstrated promising activity as single agents in this population. We report the results of a phase 1/dose expansion trial evaluating the combination of BV/Len in rel/ref DLBCL. Thirty-seven patients received BV every 21 days, with Len administered continuously for a maximum of 16 cycles. The maximum tolerated dose of the combination was 1.2 mg/kg BV with 20 mg/d Len. BV/Len was well tolerated with a toxicity profile consistent with their use as single agents. Most patients required granulocyte colony-stimulating factor support because of neutropenia. The overall response rate was 57% (95% CI, 39.6-72.5), complete response rate, 35% (95% CI, 20.7-52.6); median duration of response, 13.1 months; median progression-free survival, 10.2 months (95% CI, 5.5-13.7); and median overall survival, 14.3 months (95% CI, 10.2-35.6). Response rates were highest in patients with CD30+ DLBCL (73%), but they did not differ according to cell of origin (P = .96). NK cell expansion and phenotypic changes in CD8+ T-cell subsets in nonresponders were identified by mass cytometry. BV/Len represents a potential treatment option for patients with rel/ref DLBCL. This combination is being further explored in a phase 3 study (registered on https://clinicaltrials.org as NCT04404283). This trial was registered on https://clinicaltrials.gov as NCT02086604.

Melanopsin elevates locomotor activity during the wake state of the diurnal zebrafish.

Mammalian and fish pineals play a key role in adapting behaviour to the ambient light conditions through the release of melatonin. In mice, light inhibits nocturnal locomotor activity via the non-visual photoreceptor Melanopsin. In contrast to the extensively studied function of Melanopsin in the indirect regulation of the rodent pineal, its role in the intrinsically photosensitive zebrafish pineal has not been elucidated. Therefore, it is not evident if the light signalling mechanism is conserved between distant vertebrates, and how Melanopsin could affect diurnal behaviour. A double knockout of melanopsins (opn4.1-opn4xb) was generated in the diurnal zebrafish, which manifests attenuated locomotor activity during the wake state. Transcriptome sequencing gave insight into pathways downstream of Melanopsin, implying that sustained repression of the melatonin pathway is required to elevate locomotor activity during the diurnal wake state. Moreover, we show that light induces locomotor activity during the diurnal wake state in an intensity-dependent manner. These observations suggest a common Melanopsin-driven mechanism between zebrafish and mammals, while the diurnal and nocturnal chronotypes are inversely regulated downstream of melatonin.

On the multiphoton ionisation photoelectron spectra of phenol.

The phenol molecule is a prototype for non-adiabatic dynamics and the excited-state photochemistry of biomolecules. In this article, we report a joint theoretical and experimental investigation on the resonance enhanced multiphoton ionisation photoelectron (REMPI) spectra of the two lowest ionisation bands of phenol. The focus is on the theoretical interpretation of the measured spectra using quantum dynamics simulations. These were performed by numerically solving the time-dependent Schrödinger equation using the multi-layer variant of the multiconfiguration time-dependent Hartree algorithm together with a vibronic coupling Hamiltonian model. The ionising laser pulse is modelled explicitly within the ionisation continuum model to simulate experimental femtosecond 1+1 REMPI photoelectron spectra. These measured spectra are sensitive to very short lived electronically excited states, providing a rigorous benchmark for our theoretical methods. The match between experiment and theory allows for an interpretation of the features of the spectra at different wavelengths and shows that there are features due to both 'direct' and 'indirect' ionisation, resulting from non-resonant and resonant excitation by the pump pulse.

Organophosphate pesticide exposure and risk of SARS-CoV-2 infection.

Several studies have reported immune modulation by organophosphate (OP) pesticides, but the relationship between OP exposure and SARS-CoV-2 infection is yet to be studied. We used two different measures of OP pesticide exposure (urinary biomarkers (N = 154) and residential proximity to OP applications (N = 292)) to examine the association of early-childhood and lifetime exposure to OPs and risk of infection of SARS-CoV-2 using antibody data. Our study population consisted of young adults (ages 18-21 years) from the Center for the Health Assessment of Mothers and Children of Salinas (CHAMACOS) Study, a longitudinal cohort of families from a California agricultural region. Urinary biomarkers reflected exposure from in utero to age 5 years. Residential proximity reflected exposures between in utero and age 16 years. SARS-CoV-2 antibodies in blood samples collected between June 2022 and January 2023 were detected via two enzyme linked immunosorbent assays, each designed to bind to different SARS-CoV-2 antigens. We performed logistic regression for each measure of pesticide exposure, adjusting for covariates from demographic data and self-reported questionnaire data. We found increased odds of SARS-CoV-2 infection among participants with higher urinary biomarkers of OPs in utero (OR = 1.94, 95% CI: 0.71, 5,58) and from age 0-5 (OR = 1.90, 95% CI: 0.54, 6.95).

Idiopathic Pulmonary Fibrosis Is Associated with Common Genetic Variants and Limited Rare Variants.

Rationale: Idiopathic pulmonary fibrosis (IPF) is a rare, irreversible, and progressive disease of the lungs. Common genetic variants, in addition to nongenetic factors, have been consistently associated with IPF. Rare variants identified by candidate gene, family-based, and exome studies have also been reported to associate with IPF. However, the extent to which rare variants, genome-wide, may contribute to the risk of IPF remains unknown. Objectives: We used whole-genome sequencing to investigate the role of rare variants, genome-wide, on IPF risk. Methods: As part of the Trans-Omics for Precision Medicine Program, we sequenced 2,180 cases of IPF. Association testing focused on the aggregated effect of rare variants (minor allele frequency ⩽0.01) within genes or regions. We also identified individual rare variants that are influential within genes and estimated the heritability of IPF on the basis of rare and common variants. Measurements and Main Results: Rare variants in both TERT and RTEL1 were significantly associated with IPF. A single rare variant in each of the TERT and RTEL1 genes was found to consistently influence the aggregated test statistics. There was no significant evidence of association with other previously reported rare variants. The SNP heritability of IPF was estimated to be 32% (SE = 3%). Conclusions: Rare variants within the TERT and RTEL1 genes and well-established common variants have the largest contribution to IPF risk overall. Efforts in risk profiling or the development of therapies for IPF that focus on TERT, RTEL1, common variants, and environmental risk factors are likely to have the largest impact on this complex disease.

Training with reduced carbohydrate availability affects markers of bone resorption and formation in male academy soccer players from the English Premier League.

PURPOSE: To test the hypothesis that training with reduced carbohydrate (CHO) availability increases bone resorption in adolescent soccer players. METHODS: In a randomised crossover design, ten male players (age: 17.4 ± 0.8 years) from an English Premier League academy completed an acute 90-min field-based training session (occurring between 10:30-12:00) in conditions of high (TRAIN HIGH; 1.5 g.kg-1, 60 g, 1.5 g.kg-1 and 1.5 g.kg-1 consumed at 08:00, during training, 12:30 and 13:30, respectively) or low CHO availability (TRAIN LOW; 0 g.kg-1). Participants also completed a non-exercise trial (REST) under identical dietary conditions to TRAIN LOW. Venous blood samples were obtained at 08:30, 10:30, 12:30 and 14:30 for assessment of bone resorption (ßCTX), bone formation (PINP) and calcium metabolism (PTH and ACa). RESULTS: External training load did not differ (all P > 0.05) between TRAIN HIGH and TRAIN LOW, as evident for total distance (5.6 ± 0.8; 5.5 ± 0.1 km), average speed (81 ± 9; 85 ± 12 m.min-1) and high-speed running (350 ± 239; 270 ± 89 m). Area under the curve for both ßCTX and PINP was significantly greater (P < 0.01 and P = 0.03) in TRAIN LOW versus TRAIN HIGH, whilst no differences in PTH or ACa (P = 0.11 and P = 0.89) were observed between all three trials. CONCLUSION: CHO restriction before, during and after an acute soccer training session increased bone (re)modelling markers in academy players. Despite acute anabolic effects of bone formation, the long-term consequence of bone resorption may impair skeletal development and increase injury risk during growth and maturation.

Perspectives on the role of nutrition in influencing academy soccer player development and performance: A qualitative case study of key stakeholders from an English category one soccer academy.

This study aimed to explore player and stakeholder perceptions of the role of nutrition in influencing the development of male academy soccer players. Semi-structured interviews (28 ± 13 mins in length) were conducted with 31 participants from an English category one academy, including players (Youth Development Phase, YDP: n = 6; Professional Development Phase, PDP: n = 4), parents/guardians (n = 10), coaches (n = 3), sport scientists (n = 3), physiotherapists (n = 3), and catering (n = 2). Via reflexive thematic analysis, data demonstrate an apparent lack of understanding and awareness on the role of nutrition in influencing player development, especially in relation to growth, maturation and reducing injury risk. Players highlighted the influence of their parents on their dietary behaviours, whilst parents also called for education to better support their sons. Notably, players and stakeholders perceived that the daily schedule of an academy soccer player presents as "too busy to eat", especially in relation to before school, and before and after training. The results demonstrate the necessity for the co-creation of player and stakeholder specific nutrition education programmes as an initial step towards positively impacting the nutrition culture associated with the academy soccer environment.

Molecular Determinants of Tissue Specificity of Flavivirus Nonstructural Protein 1 Interaction with Endothelial Cells.

Members of the mosquito-borne flavivirus genus such as dengue (DENV), West Nile (WNV), and Zika (ZIKV) viruses cause distinct diseases and affect different tissues. We previously found that the secreted flaviviral nonstructural protein 1 (NS1) interacts with endothelial cells and disrupts endothelial barrier function in a tissue-specific manner consistent with the disease tropism of the respective viruses. However, the underlying molecular mechanism of this tissue-specific NS1-endothelial cell interaction is not well understood. To elucidate the distinct role(s) that the wing and ß-ladder domains of NS1 play in NS1 interactions with endothelial cells, we constructed flavivirus NS1 chimeras that exchanged the wing and ß-ladder domains in a pairwise manner between DENV, WNV, and ZIKV NS1. We found that both the NS1 wing and ß-ladder domains conferred NS1 tissue-specific endothelial dysfunction, with the wing conferring cell binding and the ß-ladder involved in inducing endothelial hyperpermeability as measured by transendothelial electrical resistance. To narrow down the amino acids dictating cell binding specificity, we utilized the DENV-WNV NS1 chimera and identified residues 91 to 93 (GDI) of DENV NS1 as a molecular motif determining binding specificity. Further, using an in vivo mouse model of localized leak, we found that the GDI motif of the wing domain was essential for triggering DENV NS1-induced vascular leak in mouse dermis. Taken together, we identify molecular determinants of flavivirus NS1 that confer NS1 binding and vascular leak and highlight the importance of the NS1 wing domain for flavivirus pathogenesis. IMPORTANCE Flavivirus NS1 is secreted into the bloodstream from infected cells during a viral infection. Dengue virus NS1 contributes to severe dengue pathology such as endothelial dysfunction and vascular leak independently of the virus. We have shown that multiple flavivirus NS1 proteins result in endothelial dysfunction in a tissue-specific manner consistent with their respective viral tropism. Here, we aimed to identify the molecular determinants that make some, but not other, flavivirus NS1 proteins bind to select endothelial cells in vitro and cause vascular leak in a mouse model. We identified the wing domain of NS1 as a primary determinant conferring differential endothelial dysfunction and vascular leak and narrowed the contributing amino acid residues to a three-residue motif within the wing domain. The insights from this study pave the way for future studies on the effects of flavivirus NS1 on viral dissemination and pathogenesis and offer potential new avenues for antiviral therapies.

Direct Exchange of PerfluoroCarbon Liquid for Silicone Oil: A Surgical Technique to Control Pressure and Avoid Retinal Slippage.

BACKGROUND/PURPOSE: Perfluorocarbon heavy liquid (PFCL) is used in vitreoretinal surgery to flatten the unsupported detached retina before insertion of silicone oil in cases of giant retinal tear or relaxing retinectomy. Direct exchange of PFCL for silicone oil is recommended to reduce retinal slippage when compared with fluid-air exchange, but it is commonly regarded as a difficult procedure. We describe our technique for direct PFCL-silicone oil exchange using a 20-gauge drainage cannula, reliably avoiding the complications of retinal slippage and high intraoperative intraocular pressure. METHODS: We present a consecutive case series of patients undergoing PFCL-oil exchange and explain, using Poiseuille's equation for laminar fluid flow through a cannula, the rationale for using a 20-gauge drainage cannula rather than smaller gauges to avoid high intraocular pressure. RESULTS: Twenty-six patients underwent PFCL-oil exchange from February 1, 2019, to September 30, 2019. There was no intraoperative retinal slippage or pressure-related complications. Postoperatively 20 patients underwent oil removal. Six suffered retinal redetachment, and 14 remained attached. The vision postoil removal ranged from 6/6 to hand movements. CONCLUSION: We are confident that the PFCL-oil exchange technique described here is reliable and safe. The use of a 20-gauge drainage cannula is recommended regardless of vitrectomy gauge.

Daily energy requirements of male academy soccer players are greater than age-matched non-academy soccer players: A doubly labelled water investigation.

This study aimed to test the hypothesis that the total daily energy expenditure (TDEE) of male academy soccer players is greater than players not enrolled on a formalised academy programme. English Premier League academy (ACAD: n = 8, 13 years, 50 ± 6 kg, 88 ± 3% predicted adult stature, PAS) and non-academy players (NON-ACAD: n = 6, 13 years, 53 ± 12 kg, 89 ± 3% PAS) were assessed for TDEE (via doubly labelled water) during a 14-day in-season period. External loading was evaluated during training (ACAD: 8 sessions, NON-ACAD: 2 sessions) and games (2 games for both ACAD and NON-ACAD) via GPS, and daily physical activity was evaluated using triaxial accelerometry. Accumulative duration of soccer activity (ACAD: 975 ± 23 min, NON-ACAD: 397 ± 2 min; p < 0.01), distance covered (ACAD: 54.2 ± 8.3 km, NON-ACAD: 21.6 ± 4.7 km; p < 0.05) and time engaged in daily moderate-to-vigorous (ACAD: 124 ± 17 min, NON-ACAD: 79 ± 18 min; p < 0.01) activity was greater in academy players. Academy players displayed greater absolute (ACAD: 3380 ± 517 kcal · d-1, NON-ACAD: 2641 ± 308 kcal · d-1; p < 0.05) and relative TDEE (ACAD: 66 ± 6 kcal · kg · d-1, NON-ACAD: 52 ± 10 kcal · kg · d-1; p < 0.05) versus non-academy players. Given the injury risk associated with high training volumes during growth and maturation, data demonstrate the requirement for academy players to consume sufficient energy (and carbohydrate) intake to support the enhanced energy cost of academy programmes.

Bacterial biofilm formation on vaginal ring pessaries used for pelvic organ prolapse.

INTRODUCTION AND HYPOTHESIS: The objective of this study was to characterize the bacterial biofilm on vaginal ring pessaries used to treat pelvic organ prolapse and investigate the relationship between biofilm phenotype and patient symptoms and clinical signs that are suggestive of inflammation. METHODS: This was a cross-sectional observational study of 40 women wearing a ring-shaped pessary continuously for at least 12 weeks. Participants underwent a clinical examination, and the pessary was removed. Clinical signs were recorded. A swab from the pessary surface and a high vaginal swab were collected from each woman. Participants completed a questionnaire on symptoms. Pessary biofilm presence and phenotype were determined by scanning electron microscopy (SEM). Vaginal and pessary bacterial composition was determined by 16S rRNA gene sequencing. The relationship between biofilm phenotype and symptoms and clinical signs was assessed using logistic regression. RESULTS: SEM confirmed biofilm formation on all 40 pessaries. Microbiota data were available for 25 pessary swabs. The pessary biofilm microbiota was composed of bacteria typically found in the vagina and was categorized into Lactobacillus-dominated (n = 10/25 pessaries, 40%) communities and Lactobacillus-deficient communities with high relative abundance of anaerobic/facultative anaerobes (n = 15/25 pessaries, 60%). While increasing age was associated with presence of a Lactobacillus-deficient pessary biofilm (odds ratio = 3.60, 95% CI [1.16-11.22], p = 0.04), no associations between biofilm microbiota composition and symptoms or clinical signs were observed. CONCLUSIONS: Lactobacillus-deficient biofilms commonly form on pessaries following long-term use. However, the contribution of biofilm phenotype to symptoms and clinical signs remains to be determined.

Meta-Analysis on Utility of Bronchoscopy in Addition to Computed Tomography Thorax in the Investigation of Lung Cancer in Patients with Haemoptysis.

BACKGROUND: In patients with haemoptysis, many healthcare systems support bronchoscopy regardless of computed tomography (CT) findings. OBJECTIVE: This meta-analysis aimed to address whether a normal CT alone is sufficient to out-rule lung cancer in patients with haemoptysis. METHODS: A search was performed of the following databases: EBSCO (Medline), PubMed, Academic Search Complete, CINAHL, Cochrane Library, and Embase. Meta-Disc 1.4 and RevMan software were used to test for heterogeneity, risk of bias, and to summarize the test performance characteristics using forest plots and summary receiver operating characteristic (SROC) curves. SPSS was used to compare the diagnostic accuracy of CT and bronchoscopy. RESULTS: A total of 14 studies (2,960 patients) were included. The pooled sensitivities for detection of lung cancer using CT scan and bronchoscopy were 0.99 (95% CI: 0.97-1.00) and 0.84 (95% CI: 0.78-0.88), respectively. The sensitivity of CT was higher than that of bronchoscopy (p < 0.001). The pooled specificities for CT scan and bronchoscopy were 0.99 (95% CI: 0.99-1.00) and 1.00 (95% CI: 0.99-1.00), respectively. Of 2,960 patients, 257 had lung cancer (8.7%) at initial investigation. 254 of these had a CT thorax, and the CT scan was false negative in 4/255 (1.6%), with bronchoscopy only identifying one cancer with a normal CT (0.4%). CONCLUSION: CT scan showed a higher diagnostic accuracy than bronchoscopy. This study indicated that bronchoscopy offers an insignificant additional value in the investigation of lung cancer in patients with haemoptysis and a negative CT scan.

Single-Use or Disposable Flexible Bronchoscopy in Advanced Bronchoscopy Procedures: Experience in a Quaternary Referral Centre.

BACKGROUND: The development of single-use flexible or disposable bronchoscopes (SUFBs) has accelerated in recent years, with the reduced risk of infectious transmission and reduced need for endoscopy staffing particularly advantageous in the COVID-19 pandemic era. OBJECTIVE: The objective of this study was to assess the performance of a novel single-use bronchoscope in an academic quaternary referral centre with on-site interventional pulmonology programme. METHODS: With ethical approval in a quaternary referral centre, we prospectively collected data on sequential bronchoscopy procedures using The Surgical Company Broncoflex© range of SUFBs. Data collected included demographic, procedural, scope performance, user satisfaction, and complication parameters in a tertiary bronchoscopy service. RESULTS: 139 procedures were performed by five pulmonology faculty from January to July 2021. The majority were carried out for infection (45%) and malignancy (32%). Most were performed in the endoscopy suite and 8% were COVID positive or suspected. Most procedures reported the highest score in satisfaction (85%) with technical limitations reported in 15% (predominately related to scope suction or inadequate image quality) reverting to a reusable scope in 2.8 %. CONCLUSION: In our subset of patients in a bronchoscopy unit, SUFBs are safe, and both routine and advanced bronchoscopy procedures can be performed with high satisfaction reported.

Examining Tweet Content and Engagement of Users With Tweets About Hikikomori in Japanese: Mixed Methods Study of Social Withdrawal.

BACKGROUND: Hikikomori is a form of severe social withdrawal that is particularly prevalent in Japan. Social media posts offer insight into public perceptions of mental health conditions and may also inform strategies to identify, engage, and support hard-to-reach patient populations such as individuals affected by hikikomori. OBJECTIVE: In this study, we seek to identify the types of content on Twitter related to hikikomori in the Japanese language and to assess Twitter users' engagement with that content. METHODS: We conducted a mixed methods analysis of a random sample of 4940 Japanese tweets from February to August 2018 using a hashtag (#hikikomori). Qualitative content analysis included examination of the text of each tweet, development of a codebook, and categorization of tweets into relevant codes. For quantitative analysis (n=4859 tweets), we used bivariate and multivariate logistic regression models, adjusted for multiple comparisons, and estimated the predicted probabilities of tweets receiving engagement (likes or retweets). RESULTS: Our content analysis identified 9 codes relevant to tweets about hikikomori: personal anecdotes, social support, marketing, advice, stigma, educational opportunities, refuge (ibasho), employment opportunities, and medicine and science. Tweets about personal anecdotes were the most common (present in 2747/4859, 56.53% of the tweets), followed by social support (902/4859, 18.56%) and marketing (624/4859, 12.84%). In the adjusted models, tweets coded as stigma had a lower predicted probability of likes (-33 percentage points, 95% CI -42 to -23 percentage points; P<.001) and retweets (-11 percentage points, 95% CI -18 to -4 percentage points; P<.001), personal anecdotes had a lower predicted probability of retweets (-8 percentage points, 95% CI -14 to -3 percentage points; P=.002), marketing had a lower predicted probability of likes (-13 percentage points, 95% CI -21 to -6 percentage points; P<.001), and social support had a higher predicted probability of retweets (+15 percentage points, 95% CI 6-24 percentage points; P=.001), compared with all tweets without each of these codes. CONCLUSIONS: Japanese tweets about hikikomori reflect a unique array of topics, many of which have not been identified in prior research and vary in their likelihood of receiving engagement. Tweets often contain personal stories of hikikomori, suggesting the potential to identify individuals with hikikomori through Twitter.

A model for abolitionist narrative medicine pedagogy.

To use narrative medicine as a means for action towards social justice in medical education, we need a renewal of our pedagogical methods that grapples not just with the worlds concocted within a text, but also our own world beyond the text. We propose a model for narrative medicine pedagogy that is oriented towards abolition. First, the composition of the classroom and syllabus must employ radical inclusion through recruitment of diverse voices and selection of diverse texts. After a traditional close reading is initiated, conscious expansion should take place through introduction of a text's context and current social structures. Whenever internal and external conflicts arise, active self-interrogation should be encouraged through José Esteban Muñoz's 'disidentification'.We present relevant critiques of narrative medicine, case studies from workshop experiences, and close readings of selected narrative medicine texts to unmask limitations in the standard narrative medicine workshop format and illustrate the utility of our abolitionist model. The model we propose offers methods for disrupting long-standing patterns of inclusion (and exclusion) and radically transforming the structure of spaces and ideas produced within them. When new texts are added to the syllabus, they should be accompanied by hermeneutics that can adequately attend to them. Abolitionist narrative medicine pedagogy should stimulate practitioners to examine their own role in social structures that surround the text and the setting of close reading and, ultimately, to dismantle harmful structures. We offer strategies for confronting discomfort without requiring an abandonment of identity, context or content. Instead, holding complexity works towards the long-term aim of transforming practitioners to think critically about structural violence that prevents universal and equitable access to compassionate healthcare. Using this model for abolition, we hope practitioners of narrative medicine will be equipped with more dynamic tools to engage with texts and patients within and beyond the scope of the narrative medicine workshop.

Prevalence and Clinical Profile of Severe Acute Respiratory Syndrome Coronavirus 2 Infection among Farmworkers, California, USA, June-November 2020.

During the ongoing coronavirus disease (COVID-19) pandemic, farmworkers in the United States are considered essential personnel and continue in-person work. We conducted prospective surveillance for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and antibody prevalence among farmworkers in Salinas Valley, California, during June 15-November 30, 2020. We observed 22.1% (1,514/6,864) positivity for SARS-CoV-2 infection among farmworkers compared with 17.2% (1,255/7,305) among other adults from the same communities (risk ratio 1.29, 95% CI 1.20-1.37). In a nested study enrolling 1,115 farmworkers, prevalence of current infection was 27.7% among farmworkers reporting >1 COVID-19 symptom and 7.2% among farmworkers without symptoms (adjusted odds ratio 4.16, 95% CI 2.85-6.06). Prevalence of SARS-CoV-2 antibodies increased from 10.5% (95% CI 6.0%-18.4%) during July 16-August 31 to 21.2% (95% CI 16.6%-27.4%) during November 1-30. High SARS-CoV-2 infection prevalence among farmworkers underscores the need for vaccination and other preventive interventions.

Safety, pharmacokinetics and pharmacodynamics of SBT-020 in patients with early stage Huntington's disease, a 2-part study.

AIMS: Huntington's disease (HD) is a neurodegenerative disease with cognitive, motor and psychiatric symptoms. Toxic accumulation of misfolded mutant huntingtin protein induces mitochondrial dysfunction, leading to a bioenergetic insufficiency in neuronal and muscle cells. We evaluated the safety, pharmacokinetics and pharmacodynamics of SBT-020, a novel compound to improve mitochondrial function, in a 2-part study in early stage HD patients. METHODS: Part 1 consisted of 7-day multiple ascending dose study to select the highest tolerable dose for Part 2, a 28-day multiple dose study. Mitochondrial function was measured in the visual cortex and calf muscle, using phosphorous magnetic resonance spectroscopy, and in circulating peripheral blood mononuclear cells. RESULTS: Treatment-emergent adverse events were mild and more present in the SBT-020 group. Injection site reactions occurred in 91% in Part 1 and 97% in Part 2. Mitochondrial function in calf muscle, peripheral blood mononuclear cells or visual cortex was not changed overall due to treatment with SBT-020. In a posthoc analysis, patients with a higher degree of mitochondrial dysfunction (below the median [∆Ψm < 3412 and τPCr > 42.5 s]) showed more improvement than patients with a relatively lower level of mitochondrial dysfunction. CONCLUSION: SBT-020 was safe at all doses, but no significant differences in any of the pharmacodynamic measurements between the treatment groups and placebo group could be demonstrated. The data suggest that the better than expected mitochondrial function in our patient population at baseline might explain the lack of effect of SBT-020.

Physics-informed machine learning: case studies for weather and climate modelling.

Machine learning (ML) provides novel and powerful ways of accurately and efficiently recognizing complex patterns, emulating nonlinear dynamics, and predicting the spatio-temporal evolution of weather and climate processes. Off-the-shelf ML models, however, do not necessarily obey the fundamental governing laws of physical systems, nor do they generalize well to scenarios on which they have not been trained. We survey systematic approaches to incorporating physics and domain knowledge into ML models and distill these approaches into broad categories. Through 10 case studies, we show how these approaches have been used successfully for emulating, downscaling, and forecasting weather and climate processes. The accomplishments of these studies include greater physical consistency, reduced training time, improved data efficiency, and better generalization. Finally, we synthesize the lessons learned and identify scientific, diagnostic, computational, and resource challenges for developing truly robust and reliable physics-informed ML models for weather and climate processes. This article is part of the theme issue 'Machine learning for weather and climate modelling'.

Thinking with two brains: Student perspectives on the presentation of race in pre-clinical medical education.

CONTEXT: There is growing concern that during their education medical students come to believe that 'race' is a biological construct and that differential treatment of patients based on 'race' is clinically beneficial. How 'race' is presented to medical students may influence both their implicit biases and future clinical practices, potentially widening racial disparities in care. METHODS: We conducted in-depth interviews with twenty-two pre-clinical mostly non-White medical students attending a public medical school in a major metropolitan area in the northeastern United States. Interview content focused on how medical students experience the presentation of race in medical education, use race in their learning experiences, and envision using race as physicians in future clinical encounters. Transcripts were analysed using the framework method and emergent themes were identified. RESULTS: Participants described being most aware of the presentation of race in board-style questions and least aware of the presentation of race during lectures. They described being aware of race in problem-based learning (PBL) modules if the case revolved around a likely race-disease association. They identified imprecision in how race was presented during lectures and insufficient explanations of causes of racial disparities in health. Participants described feeling ill-prepared to obtain racial self-identification and receiving mixed messages around the utility of race in diagnosing a patient. Participants reported experiences of cognitive dissonance around the presentation of race in board-style questions and lectures. CONCLUSIONS: Critical evaluation of the presentation of and instruction around 'race' is needed to address whether it is presented as a biological vs. social construct, the level of precision of racial categorisation in curricular content, and the causes of and mechanisms behind race-disease associations. This has the potential to minimise false beliefs about race as a biological construct and the resultant negative impacts on clinical care. Future research could evaluate whether problem-based or experiential (OSCE) learning, in contrast to board-style questions and didactic lectures, are the most effective way to educate students around race in health and illness. Additionally, future research can investigate if the mission (ie social) and composition (Predominantly White Institution or Historically Black College/University) of the faculty impacts student experiences of the presentation of race.