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Professional phagocytes like neutrophils and macrophages tightly control what they consume, how much they consume, and when they move after cargo uptake. We show that plasma membrane abundance is a key arbiter of these cellular behaviors. Neutrophils and macrophages lacking the G protein subunit Gβ4 exhibited profound plasma membrane expansion, accompanied by marked reduction in plasma membrane tension. These biophysical changes promoted the phagocytosis of bacteria, fungus, apoptotic corpses, and cancer cells. We also found that Gβ4-deficient neutrophils are defective in the normal inhibition of migration following cargo uptake. Sphingolipid synthesis played a central role in these phenotypes by driving plasma membrane accumulation in cells lacking Gβ4. In Gβ4 knockout mice, neutrophils not only exhibited enhanced phagocytosis of inhaled fungal conidia in the lung but also increased trafficking of engulfed pathogens to other organs. Together, these results reveal an unexpected, biophysical control mechanism central to myeloid functional decision-making.

Abstract Previous advances have identified immune pathways associated with inflammatory skin diseases, leading to the development of targeted therapies. However, there is a lack of molecular approaches that delineate these pathways at the individual patient level for personalized diagnostic and therapeutic guidance. Here, we conduct a cross-comparison of expression profiles from multiple inflammatory skin diseases to identify gene modules defining relevant immune pathways. Seven modules are identified, representing key immune pathways: Th17, Th2, Th1, Type I IFNs, neutrophilic, macrophagic, and eosinophilic. These modules allow the development of a molecular map with high diagnostic efficacy for inflammatory skin diseases and clinico-pathologically undetermined cases. Aligning dominant modules with treatment targets offers a rational framework for treatment selection, improving response rates in both treatment-naïve patients and non-responders to targeted therapies. Overall, our approach offers precision medicine for inflammatory skin diseases, utilizing transcriptional modules to support diagnosis and guide personalized treatment selection.

Abstract Symptoms of the Post-COVID-19 Condition are often non-specific making it a challenge to distinguish them from symptoms due to other medical conditions. In this study, we compare the proportion of emergency department patients who developed symptoms consistent with the World Health Organization’s Post-COVID-19 Condition clinical case definition between those who tested positive for Severe Acute Respiratory Syndrome Coronavirus-2 infection and time-matched patients who tested negative. Our results show that over one-third of emergency department patients with a proven acute infection meet Post-COVID-19 Condition criteria 3 months post-index visit. However, one in five test-negative patients who claim never having been infected also report symptoms consistent with Post-COVID-19 Condition highlighting the lack of specificity of the clinical case definition. Testing for SARS-CoV-2 during the acute phase of a suspected infection should continue until specific biomarkers of Post-COVID-19 Condition become available for diagnosis and treatment.

Abstract The bacterial tight adherence pilus system (TadPS) assembles surface pili essential for adhesion and colonisation in many human pathogens. Pilus dynamics are powered by the ATPase CpaF (TadA), which drives extension and retraction cycles in Caulobacter crescentus through an unknown mechanism. Here we use cryogenic electron microscopy and cell-based light microscopy to characterise CpaF mechanism. We show that CpaF assembles into a hexamer with C2 symmetry in different nucleotide states. Nucleotide cycling occurs through an intra-subunit clamp-like mechanism that promotes sequential conformational changes between subunits. Moreover, a comparison of the active sites with different nucleotides bound suggests a mechanism for bidirectional motion. Conserved CpaF residues, predicted to interact with platform proteins CpaG (TadB) and CpaH (TadC), are mutated in vivo to establish their role in pilus processing. Our findings provide a model for how CpaF drives TadPS pilus dynamics and have broad implications for how other ancient type 4 filament family members power pilus assembly.

Background: Wearable sensors have been heralded as revolutionary tools for healthcare. However, while data are easily acquired from sensors, users still grapple with questions about how sensors can meaningfully inform everyday clinical practice and research. Summary: We propose a simple, comprehensive framework for utilizing sensor data in healthcare. The framework includes three key processes that are applied together or separately to (1) automate traditional clinical measures, (2) illuminate novel correlates of disease and impairment, and (3) predict current and future outcomes. We demonstrate applications of the Automate-Illuminate-Predict framework using examples from rehabilitation medicine. Key Messages: Automate-Illuminate-Predict provides a universal approach to extract clinically meaningful data from wearable sensors. This framework can be applied across the care continuum to enhance patient care and inform personalized medicine through accessible, noninvasive technology.

ABSTRACT Background Disorders of consciousness (DoC) refers to a group of clinical conditions of altered consciousness. To improve their diagnosis and prognosis, multimodal assessment can be of great importance. Informal caregivers of people with DoC who are confronted with new technologies as such can benefit from interventions to expand their health literacy, i.e., the ability to use information to make health decisions for oneself and others. Methods We developed an information brochure on multimodal assessment for DoC in a participatory process, with decisions made by a steering group. The process was based on a methodological framework for the development of patient decision aids that built on the International Patient Decision Aid Standards (IPDAS). Results On the background of a broad variety of needs, the priority was to focus on the explanation of multimodal testing and provide information about its uncertainty. Its development aimed at enhancing informal caregivers' understanding of implications of results from multimodal assessment and its relevance for prognosis. It should avoid the portrayal of information that could lead to the impression of false hope or suboptimal rehabilitation care. Informal caregivers rated its usability and acceptability highly, though they preferred less technical language. Conclusion The participatory process was crucial to the project. Future studies should investigate the effectiveness of the brochure in fostering informal caregivers' health literacy. Patient or Public Contribution Informal caregivers of people with DoC were deliberately included in the steering group and they participated in a field test of the prototype brochure.

ABSTRACT Pharmacological treatment of obesity is passing through many changes in the last decades; different agents have been approved, and newer options are leaning towards higher efficacy and a more favourable safety profile; however, medications approved for a longer time are still available and useful for many patients. This document is an 2024 Update Position Statement of Specialists from the Brazilian Association for the Study of Obesity and Metabolic Syndrome (Abeso) and the Brazilian Society of Endocrinology and Metabolism (SBEM), with the aim of reviewing all the approved medications for the management of obesity in Brazil (sibutramine, orlistat, liraglutide, semaglutide and bupropion/naltrexone fixed dose), with the addition of tirzepatide, that is approved in other countries and likely approved soon in Brazil. The review is focused on efficacy, safety profile and the impact of drugs (based on existing studies) on different comorbidities.

Aim: To assess the effects of once-weekly subcutaneous retatrutide on weight and metabolic markers and the occurrence of side effects in patients with overweight, obesity and/or type 2 diabetes (T2D). Methods: PubMed, Embase, Cochrane Library, and ClinicalTrials.gov databases were systematically searched for placebo-controlled, randomized clinical trials (RCTs) published up until February 23, 2024. Weighted mean differences (WMDs) for continuous outcomes and risk ratios (RRs) for binary endpoints were computed, with 95 % confidence intervals (CIs). Results: A total of three studies were included, comprising 640 patients, of whom 510 were prescribed retatrutide. Compared with placebo, retatrutide significantly reduced body weight (WMD -10.66 kg; 95 % CI -17.63, −3.69), body mass index (WMD -4.53 kg/m2; 95 % CI -7.51, −1.55), and waist circumference (WMD -6.61 cm; 95 % CI -13.17, −0.05). In addition, retatrutide significantly increased the proportion of patients who achieved a weight reduction of ≥5 % (RR 2.92; 95 % CI 2.17–3.93), ≥10 % (RR 9.32; 95 % CI 4.56–19.06), ≥15 % (RR 18.40; 95 % CI 6.00–56.42), and ≥20 % (RR 16.61; 95 % CI 4.17–66.12). Conclusions: In this meta-analysis, the use of once-weekly subcutaneous retatrutide was associated with a significant reduction in body weight and improvement of metabolic markers in patients with overweight, obesity and/or T2D, compared with placebo, with an increase in non-severe gastrointestinal and hypersensitivity adverse events. Phase 3 RCTs are expected to shed further light on the efficacy and safety of once-weekly subcutaneous retatrutide over the long term.

Objective The objective is to externally validate and assess the opportunity to update the Canadian COVID-19 Mortality Score (CCMS) to predict in-hospital mortality among consecutive non-palliative COVID-19 patients infected with Omicron subvariants at a time when vaccinations were widespread.Design This observational study validated the CCMS in an external cohort at a time when Omicron variants were dominant. We assessed the potential to update the rule and improve its performance by recalibrating and adding vaccination status in a subset of patients from provinces with access to vaccination data and created the adjusted CCMS (CCMSadj). We followed discharged patients for 30 days after their index emergency department visit or for their entire hospital stay if admitted.Setting External validation cohort for CCMS: 36 hospitals participating in the Canadian COVID-19 Emergency Department Rapid Response Network (CCEDRRN). Update cohort for CCMSadj: 14 hospitals in CCEDRRN in provinces with vaccination data.Participants Consecutive non-palliative COVID-19 patients presenting to emergency departments.Main outcome measures In-hospital mortality.Results Of 39 682 eligible patients, 1654 (4.2%) patients died. The CCMS included age, sex, residence type, arrival mode, chest pain, severe liver disease, respiratory rate and level of respiratory support and predicted in-hospital mortality with an area under the curve (AUC) of 0.88 (95% CI 0.87 to 0.88) in external validation. Updating the rule by recalibrating and adding vaccination status to create the CCMSadj changed the weights for age, respiratory status and homelessness, but only marginally improved its performance, while vaccination status did not. The CCMSadj had an AUC of 0.91 (95% CI 0.89 to 0.92) in validation. CCMSadj scores of 15 had observed mortality of >56.8%.Conclusions The CCMS remained highly accurate in predicting mortality from Omicron and improved marginally through recalibration. Adding vaccination status did not improve the performance. The CCMS can be used to inform patient prognosis, goals of care conversations and guide clinical decision-making for emergency department patients with COVID-19.

Candida parapsilosis is one of the most commen causes of life-threatening candidaemia, particularly in premature neonates, individuals with cancer of the haematopoietic system, and recipients of organ transplants. Historically, drug-susceptible strains have been linked to clonal outbreaks. However, worldwide studies started since 2018 have reported severe outbreaks among adults caused by fluconazole-resistant strains. Outbreaks caused by fluconazole-resistant strains are associated with high mortality rates and can persist despite strict infection control strategies. The emergence of resistance threatens the efficacy of azoles, which is the most widely used class of antifungals and the only available oral treatment option for candidaemia. The fact that most patients infected with fluconazole-resistant strains are azole-naive underscores the high potential adaptability of fluconazole-resistant strains to diverse hosts, environmental niches, and reservoirs. Another concern is the multidrug-resistant and echinocandin-tolerant C parapsilosis isolates, which emerged in 2020. Raising awareness, establishing effective clinical interventions, and understanding the biology and pathogenesis of fluconazole-resistant C parapsilosis are urgently needed to improve treatment strategies and outcomes.