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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 Myeloid phagocytes are essential for antifungal immunity against pulmonary Aspergillus fumigatus and systemic Candida albicans infections. However, the molecular mechanisms underlying fungal clearance by phagocytes remain incompletely understood. In this study, we investigated the role of Perforin-2 (Mpeg1) in antifungal immunity. We found that Mpeg1−/− mice generated on a mixed C57BL/6J-DBA/2 background exhibited enhanced survival, reduced lung fungal burden, and greater neutrophil fungal killing activity compared to wild-type C57BL/6J (B6) mice, suggesting that Perforin-2 may impair antifungal immune responses. However, when we compared Mpeg1−/− mice with co-housed Mpeg+/+ littermate controls, these differences were no longer observed, indicating that initial findings were likely influenced by differences in the murine genetic background or the microbiota composition. Furthermore, Perforin-2 was dispensable for antifungal immunity during C. albicans bloodstream infection. These results suggest that Perforin-2 is not essential for host defense against fungal infections in otherwise immune-competent mice.IMPORTANCEHumans encounter fungal pathogens daily and rely on innate immune cells to clear Aspergillus fumigatus, the leading cause of mold pneumonia worldwide, and Candida albicans, the most common cause of fungal bloodstream infections. The World Health Organization has classified A. fumigatus and C. albicans as critical priority fungal pathogens due to the emergence of drug resistance and the increasing number of susceptible individuals across the globe. The mechanisms by which innate immune cells clear these fungal pathogens remain incompletely defined. In this study, we examined the role of a pore-forming protein called Perforin-2 in host defense against these fungal pathogens, in part because Perforin-2 has been implicated in antibacterial host defense. Our findings reveal that Perforin-2 is dispensable for antifungal immunity against respiratory A. fumigatus and systemic C. albicans infections in mice, suggesting that the antimicrobial activity of Perforin-2 does not extend to these two fungal pathogens.

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.

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.

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.

Colorectal cancer (CRC) screening reduces morbidity and mortality, but screening rates in the USA remain suboptimal. The Colorectal Cancer Control Program (CRCCP) was established in 2009 to increase screening among groups disproportionately affected. The CRCCP utilizes implementation science to support health system change as a strategy to reduce disparities in CRC screening by directing resources to primary care clinics to implement evidence-based interventions (EBIs) proven to increase CRC screening. As COVID-19 continues to impede in-person healthcare visits and compel the unpredictable redirection of clinic priorities, understanding clinics' adoption and implementation of EBIs into routine care is crucial. Mailed fecal testing is an evidence-based screening approach that offers an alternative to in-person screening tests and represents a promising approach to reduce CRC screening disparities. However, little is known about how mailed fecal testing is implemented in real-world settings. In this retrospective, cross-sectional analysis, we assessed practices around mailed fecal testing implementation in 185 clinics across 62 US health systems. We sought to (1) determine whether clinics that do and do not implement mailed fecal testing differ with respect to characteristics (e.g., type, location, and proportion of uninsured patients) and (2) identify implementation practices among clinics that offer mailed fecal testing. Our findings revealed that over half (58%) of clinics implemented mailed fecal testing. These clinics were more likely to have a CRC screening policy than clinics that did not implement mailed fecal testing (p = 0.007) and to serve a larger patient population (p = 0.004), but less likely to have a large proportion of uninsured patients (p = 0.01). Clinics that implemented mailed fecal testing offered it in combination with EBIs, including patient reminders (92%), provider reminders (94%), and other activities to reduce structural barriers (95%). However, fewer clinics reported having the leadership support (58%) or funding stability (29%) to sustain mailed fecal testing. Mailed fecal testing was widely implemented alongside other EBIs in primary care clinics participating in the CRCCP, but multiple opportunities for enhancing its implementation exist. These include increasing the proportion of community health centers/federally qualified health centers offering mailed screening; increasing the proportion that provide pre-paid return mail supplies with the screening kit; increasing the proportion of clinics monitoring both screening kit distribution and return; ensuring patients with abnormal tests can obtain colonoscopy; and increasing sustainability planning and support.

The respiratory tree maintains sterilizing immunity against human fungal pathogens. Humans inhale ubiquitous filamentous molds and geographically restricted dimorphic fungal pathogens that form small airborne conidia. In addition, pathogenic yeasts, exemplified by encapsulated Cryptococcus species, and Pneumocystis pose significant fungal threats to the lung. Classically, fungal pneumonia occurs in immune compromised individuals, specifically in patients with HIV/AIDS, in patients with hematologic malignancies, in organ transplant recipients, and in patients treated with corticosteroids and targeted biologics that impair fungal immune surveillance in the lung. The emergence of fungal co-infections during severe influenza and COVID-19 underscores the impairment of fungus-specific host defense pathways in the lung by respiratory viruses and by medical therapies to treat viral infections. Beyond life-threatening invasive syndromes, fungal antigen exposure can exacerbate allergenic disease in the lung. In this review, we discuss emerging principles of lung-specific antifungal immunity, integrate the contributions and cooperation of lung epithelial, innate immune, and adaptive immune cells to mucosal barrier immunity, and highlight the pathogenesis of fungal-associated allergenic disease. Improved understanding of fungus-specific immunity in the respiratory tree has paved the way to develop improved diagnostic, pre-emptive, therapeutic, and vaccine approaches for fungal diseases of the lung.