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PubMed2026

Alternative genetic codes in bacteria and archaea identified with a fast k-mer-based algorithm.

The genetic code is conserved across all domains of life and is often described as universal. Nevertheless, many exceptions to the "universal" code have now been documented, most of these through manual or semiautomated inspection of highly conserved genes. Modern bioinformatics tools improved our ability to find alternative genetic codes but remain computationally expensive, preventing widespread use on thousands of new species identified by sequencing environmental samples. Here, I report a >100-fold accelerated method for inferring the genetic code directly from assembled genomes and apply it to thousands of previously uncharacterized assemblies from archaea and bacteria. I describe three candidate genetic code variations, one of which, an alternative genetic code used by a family of Asgard archaea, is a unique example of sense codon reassignments for this domain. Identifying genetic code variations is important for understanding evolution of the standard code and improving accuracy of protein databases and open reading frame identification.

Genetic Code↗

PubMed2026

Feasibility of Prone Positioning in Patients With Obesity and Acute Respiratory Distress Syndrome.

BACKGROUND: Prone positioning in patients with obesity remains uncommon because of concerns about feasibility, safety, and efficacy. OBJECTIVE: To evaluate the feasibility, safety, and clinical outcomes of manual prone positioning in patients with acute respiratory distress syndrome (ARDS) across different classes of obesity. METHODS: This was a retrospective cohort study involving patients with ARDS who underwent manual prone positioning across 15 hospitals between April 2014 and July 2024. Patients were stratified into 5 groups based on body mass index. Standardized prone positioning protocols were followed across institutions. RESULTS: A total of 1448 patients with ARDS underwent prone positioning. Across all obesity categories, prone positioning was associated with shorter intensive care unit and hospital stays, improved oxygenation, and better clinical outcomes. Notably, patients with class III obesity showed the greatest increase in gas exchange efficiency, with a 37% improvement in ratio of Pao2 to fraction of inspired oxygen, compared with 28% in patients with normal weight (P < .05). Complication rates were low across all groups. CONCLUSIONS: Prone positioning is feasible and safe in patients with ARDS across all obesity classes. Patients with class III obesity showed the greatest improvements in oxygenation. Future prospective studies should further explore the long-term impact of prone positioning in patients with class III obesity to refine clinical guidelines and optimize care.

Humans↗

PubMed2026

Sugar rationing during the first 1000 days and early onset cancer: a natural experiment.

BACKGROUND: The "first 1000 days" of life is a critical window for metabolic programming, while the long-term oncological consequences of nutritional exposures during this period remain understudied. OBJECTIVES: We aimed to evaluate whether restricted sugar intake in utero and during early childhood reduces risk of early onset cancer diagnosis and mortality in adulthood, utilizing a natural experiment. METHODS: We analyzed 63,819 United Kingdom Biobank participants born between October 1951 and March 1956, spanning the end of United Kingdom sugar rationing (September 1953). Leveraging a quasi-experimental birth cohort design, we compared participants exposed to sugar rationing in utero and during infancy with those unexposed. Early onset cancer incidence (≤50 y) and mortality were ascertained via integrated national Cancer Registry and hospital inpatient records. Multivariable Cox proportional hazards models (including Gompertz distribution) were used to estimate hazard ratios (HRs), with exploratory site-specific analyses. RESULTS: Among 63,819 participants (56.3% female), 40,397 were exposed to rationing and 23,422 were unexposed. Early life sugar restriction significantly reduced early onset cancer risk (HR: 0.66; 95% confidence interval: 0.53, 0.81; P < 0.001). A dose-response relationship was observed, with peak protection in individuals exposed for ≤24 mo postnatally. This protection was observed systemically across solid tumors, independent of specific cancer sites. Specificity was corroborated by null associations with negative controls (herpes zoster and cataract). No significant difference was found for cancer-specific mortality. CONCLUSIONS: Restricting sugar intake during the first 1000 days is associated with a reduced risk of early onset cancer, extending the disease-free lifespan. The divergence between reduced incidence and unchanged mortality suggests early life metabolic environments primarily influence tumor latency rather than biological aggressiveness. These findings highlight the potential long-term public health implications of early life dietary guidelines against the rising burden of early onset cancer.

Humans↗

PubMed2026

The effects of fitspiration TikTok content on body image and mood among young adult women in the U.S.

Fitspiration is an appearance-based form of media that promotes physical fitness and dieting. While not true of all fitspiration media, some forms promote these ideals through visuals of toned, athletic bodies that have become increasingly prevalent on the short-form video platform, TikTok. Although often framed as health-promoting, fitspiration exposure has been associated with upward appearance comparison (i.e., comparison with people perceived as more attractive) and negative effects on body image and mood. The present study investigated the effects of short-form video-based fitspiration on social comparison, appearance importance, appearance anxiety, body dissatisfaction, and negative affect. Using an experimental design, 150 undergraduate women (Mage = 19.28) in the United States were randomly assigned to view a five-minute TikTok compilation of either animal (n = 75) or fitspiration videos (n = 75). Participants completed baseline measures prior to viewing and state-level measures after completing their video set. Results indicated that, relative to control, viewing fitspiration content led to greater social comparison, appearance concerns, feelings of being fat, and sadness. Baseline appearance concerns and depressive symptoms significantly moderated group differences in responses, such that negative fitspiration effects on state-level appearance concerns were found among individuals high but not low in baseline appearance concerns and among individuals low but not high in baseline depressive symptoms. These findings contribute to the growing literature on fitspiration by demonstrating the immediate psychological effects of this content in short-form videos and highlighting the importance of considering individual differences in vulnerability.

Humans↗

PubMed2026

Impact of kangaroo care on circadian rhythm, growth, physiological stability in premature infants, and cortisol and melatonin levels in maternal breast milk: A randomized controlled trial.

PURPOSE: This study aimed to examine the effects of regular kangaroo care (KC) on sleep-wake cycles, growth, physiological stability, and maternal breast milk cortisol and melatonin levels in premature infants. DESIGN: This study was a parallel group, single-blind, pre-test-post-test, randomised controlled trial (RCT). METHODS: This randomized controlled study was conducted in a neonatal intensive care unit (NICU) in Türkiye between September 2024 and September 2025 Thirty-six premature infants were randomized to intervention (n = 28) or control (n = 28). Infants in the intervention group received KC for three consecutive days, twice daily (10:00 a.m. and 10:00 p.m.) for 60 min per session. Data were collected using the Infant Information Form, Physiological Parameters Monitoring Chart, and Premature Infant Sleep-Wake Cycles Tracking Chart. Sleep-wake cycles were monitored using a Bispectral Index device. Breast milk cortisol and melatonin levels were measured at baseline and on day three using the competitive ELISA method. The study was registered at ClinicalTrials.gov (NCT06589349). RESULTS: Regular KC had a statistically significant effect on BIS values, heart rate, respiratory rate, oxygen saturation, and body temperature (p < 0.05). No statistically significant effects were observed on infant body weight or on maternal breast milk cortisol and melatonin levels (p > 0.05). CONCLUSION: The findings indicate that regular KC is associated with improved regulation of the sleep-wake cycle and enhanced physiological stability in premature infants. No significant changes were observed in maternal breast milk cortisol or melatonin levels following KC.

Humans↗

PubMed2026

Unacknowledged Burdens and Clinical Assets of BIPOC Genetic Counseling Students: Qualitative Evidence to Inform Supervision.

As the genetic counseling profession works to diversify its predominantly white workforce, understanding the experiences of Black, Indigenous, and People of Color (BIPOC) students is central to equity efforts. While BIPOC students bring invaluable cultural and linguistic diversity that improves patient care, they often navigate clinical training environments that lack diversity and psychological safety. This article draws on data from a longitudinal constructivist qualitative study to examine how racial and ethnic concordance (or lack thereof) with patients and clinical supervisors influenced the clinical training, professional development, and well-being of BIPOC genetic counseling students. Semi-structured interviews were conducted with 25 BIPOC genetic counseling students in the United States and Canada. Interviews were recorded using Zoom.us, transcribed using Rev.com, and analyzed in NVivo using reflexive thematic analysis. The analysis led to the construction of three themes: (1)Shared identity with patients is a clinical advantage: Participants leveraged their cultural and linguistic intuition to establish trust and rapport with patients; (2) Identity navigation involves cognitive and emotional labor: Participants shouldered an unacknowledged burden in managing stereotype threat, overcoming feelings of exclusion, and educating supervisors; and (3) Racial/ethnic identity shapes supervisory dynamics: Participants described BIPOC supervisors as providing identity-affirming support, while some white supervisors avoided discussions about identity or committed microaggressions. These results suggest that BIPOC genetic counseling students have clinical assets rooted in biculturalism, yet carry a burden that often goes unacknowledged of managing power imbalances and pressure to assimilate in predominantly white clinical supervision spaces. To promote equitable training, programs should implement supervisor training on culturally responsive identity broaching, establish independent, transparent mechanisms for students to report biases they encounter in clinic, and expand mentorship networks to provide additional support.

Humans↗

PubMed2026

Portable metagenomics for preventive surveillance and outbreak control in livestock and poultry: Pathogen detection, resistome profiling, and antimicrobial stewardship.

Conventional diagnostics for livestock and poultry outbreaks commonly rely on culture or targeted PCR panels, which may be too slow or too narrow to guide early control decisions. Portable metagenomics, particularly real-time nanopore sequencing, offers a route to broad pathogen detection, antimicrobial-resistance gene profiling, and outbreak investigation within an integrated workflow. This implementation-focused review evaluates how near-point-of-care metagenomics may support preventive veterinary medicine through earlier detection, surveillance, cohorting, biosecurity decisions, and antimicrobial stewardship. We synthesize sample-to-answer workflows for enteric and respiratory disease in food-producing animals, including sampling, nucleic-acid extraction, host depletion or target enrichment, library preparation, sequencing, bioinformatics, quality control, and interpretation. Applications in calf diarrhea, bovine respiratory disease, poultry outbreaks, mastitis, and resistome monitoring are considered alongside the central limitation that detection alone does not establish causation. Pathogen and resistance-gene signals must therefore be interpreted with clinical signs, lesions, epidemiology, controls, and confirmatory testing. We also propose a minimum reporting checklist, intended as a practical framework rather than a validated consensus standard. Portable metagenomics is not a replacement for conventional diagnostics, but appropriately validated workflows can reduce uncertainty during time-sensitive outbreaks and support more judicious antimicrobial use.

Animals↗

PubMed2026

In vivo genome-wide CRISPR screens identify FOXR1 as a suppressor of CD8+ T cell antitumor immunity.

T cell dysfunction critically limits the efficacy of T cell-based immunotherapies in solid tumors, yet the intrinsic regulators of T cell dysfunction remain incompletely understood. Through an in vivo genome-wide CRISPR screen in tumor-infiltrating CD8+ T cells, we identified Forkhead Box R1 (FOXR1) as a potent transcriptional suppressor of CD8+ T cell effector functions. Genetic ablation of FOXR1 significantly enhanced cytokine production and cytotoxic capacity in both murine and human CD8+ T cells, whereas its overexpression impaired T cell activation and effector molecule expression. Mechanistically, multiomics integration of RNA-seq, CUT&Tag-seq, and ATAC-seq revealed that FOXR1 binds directly to promoter regions of key effector genes, including IL2, GZMB, and PRF1, and represses their expression. Importantly, FOXR1 deletion in human anti-CD19 CAR T cells improved their efficacy against solid tumors, demonstrating that FOXR1 is a checkpoint of T cell effector function and targeting FOXR1 is a promising strategy to enhance CAR T cell efficacy against solid tumors.

Animals↗

PubMed2026

Associations Between Routine Vaccinations and the Risk of New-Onset Idiopathic Uveitis.

OBJECTIVE: To evaluate the association between vaccination and the risk of new-onset idiopathic uveitis (NIU). DESIGN: Retrospective cohort study of aggregated electronic health records from multiple health systems across the United States. SUBJECTS: Subjects who received the coronavirus disease 2019 (COVID-19), human papillomavirus (HPV), varicella, recombinant herpes zoster, or live herpes zoster vaccinations from 2006 to 2025 and propensity-score matched controls. INTERVENTION: Vaccines against COVID-19, HPV, varicella, recombinant herpes zoster, or live herpes zoster. MAIN OUTCOMES AND MEASURES: The main outcome was the incidence of NIU at 3, 6, and 12 months following vaccination. Vaccinated patients were compared with matched controls who did not receive the respective vaccines. Analyses were repeated, excluding patients with previous diagnosis of the respective viral infection. Risk ratios (RR) with 95% confidence intervals (CIs) were calculated for overall NIU and constituent subtypes (anterior, intermediate, posterior, and panuveitis). RESULTS: All tested vaccinations were associated with reduced risk of NIU through 12 months compared with matched controls. Relative risk reductions were 65% for COVID-19 (RR, 0.35; CI, 0.33-0.37), 56% for HPV (RR, 0.44; CI, 0.35-0.54), 71% for varicella (RR, 0.29; CI, 0.25-0.33), 68% for live zoster (RR, 0.32; CI, 0.23-0.43), and 69% for recombinant zoster vaccination (RR, 0.31; CI, 0.26-0.37). Similar reductions were observed after excluding patients with prior diagnoses of the respective viral infections. CONCLUSIONS: Vaccination was associated with a lower risk of idiopathic uveitis, representing the complex interplay between immune modulation and the development of NIU.

Humans↗

PubMed2026

Workplace Safety Champions: Strengthening safety culture through nurse engagement.

Workplace violence is a growing concern in health care, disproportionately affecting frontline nurses and nursing assistants. Despite high prevalence, underreporting remains a barrier to effective prevention and response. This article describes the development, implementation, and outcomes of a Workplace Safety Champion program designed to increase reporting of violent incidents and strengthen a culture of safety. A multidisciplinary task force developed an evidence-based Workplace Safety Champion course that emphasizes de-escalation strategies, reporting processes, and staff support. Champions were appointed across inpatient and emergency units and integrated into a hospital-wide Workplace Safety Champion Council. Program evaluation used course completion data and posttraining surveys. The organizational goal of having at least one trained champion in 90% of inpatient and emergency units was exceeded, with 98% of units represented (N = 93 champions). More than 85% of learners reported intent to change their response to workplace violence, and 90% endorsed improved knowledge of resources and de-escalation strategies. The Workplace Safety Champion program successfully improved staff awareness, reporting, and engagement in workplace violence prevention. Embedding champions across units can serve as a sustainable strategy to strengthen safety culture and support frontline health care workers.

Humans↗

PubMed2026

Effect of brewers' yeast or beta-glucan derived from Saccharomyces cerevisiae on breast milk supply following preterm birth: the BLOOM randomised controlled trial.

OBJECTIVE: Breast milk is the optimal source of nutrition for preterm infants; however, low breast milk production is common following a preterm birth. This study aimed to determine if taking brewers' yeast or beta-glucan improves daily expressed breast milk volume. DESIGN: Randomised, blinded, parallel, placebo-controlled trial. SETTING: Three Australian tertiary-level neonatal units. PATIENTS: Mothers with a singleton or twin pregnancy who gave birth at <34 weeks' gestation. INTERVENTIONS: Mothers were randomised within 72 hours of birth into three parallel groups in a 1:1:1 ratio to receive either brewers' yeast, beta-glucan or placebo capsules for 7 days. MAIN OUTCOME MEASURE: Total expressed breast milk volume over a 24-hour period on day 7 of intervention. RESULTS: A total of 105 mothers underwent randomisation between August 2022 and April 2024 (36 brewers' yeast, 35 beta-glucan and 34 placebo). The adjusted mean difference in daily expressed breast milk volume was 94 mL/day (95% CI -51 mL/day to 239 mL/day) between the brewers' yeast and placebo groups and -25 mL/day (95% CI -173 mL/day to 123 mL/day) between the beta-glucan and placebo groups. Maternal side effects were similar across groups. CONCLUSION: We found no clear effect of short-term administration of brewers' yeast or beta-glucan on breast-milk production following preterm birth; both interventions were well tolerated. Given the small sample size, these findings do not rule out the possibility of a clinically meaningful benefit of brewers' yeast and suggest further research with a larger sample size may be warranted to clarify the potential clinical impact. TRIAL REGISTRATION NUMBER: ACTRN12622000968774.

Intensive Care Units, Neonatal↗

PubMed2026

A hybrid effectiveness-implementation trial to integrate precision skin cancer risk feedback in federally qualified health centers.

BACKGROUND: Skin cancers are the most common type of cancer in the United States, occur in all segments of the population, and are preventable. Our previous research with primary care patients' demonstrated interest in and efficacy of a precision prevention intervention providing feedback on MC1R risk level (higher versus average) in combination with prevention education materials relative to a standard educational intervention. Our current study is a hybrid type 1 effectiveness-implementation trial deployed at six federally-qualified health centers. This paper presents the study protocol. METHODS: A community advisory panel will guide development of study materials and measures. Staff training at each clinic will be completed in-person. Patients will be approached and screened in-person. Those completing genetic testing and the baseline survey will be randomized to the precision versus standard intervention for each risk level with a target sample size of 286 for each combination. Primary outcomes of effectiveness, assessed at 6 and 12 months, include a tanning score (5 items assessing intentional and unintentional tanning), number of sunburns, conduct of a skin self-examination, and electronic health record documentation of clinician-patient communication about skin cancer prevention. Effectiveness comparisons will focus on the precision relative to the standard intervention among higher risk participants. Implementation data will be collected to identify barriers and facilitators. RESULTS: Effectiveness and implementation outcomes will be evaluated following study completion. CONCLUSIONS: Results will guide subsequent scale-up of the precision intervention, including modifications of the intervention as well as methods for implementation. CLINICAL TRIALS IDENTIFIER: NCT07222995.

Humans↗

PubMed2026

Efficacy and Safety of Mechanical Insufflation-Exsufflation in Invasively Ventilated Critically Ill Adults: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

BACKGROUND: Mechanical insufflation-exsufflation (MI-E) is increasingly used in invasively ventilated adults in the intensive care unit (ICU), yet its therapeutic efficacy and safety remain uncertain due to inconsistent evidence. AIM: To synthesize evidence on the clinical efficacy and safety of MI-E in this population and to examine methodological and clinical heterogeneity underlying reported outcomes. STUDY DESIGN: A systematic review and meta-analysis of randomized studies (including RCTs and randomized crossover trials), conducted following PRISMA guidelines, with risk of bias assessed using the Cochrane risk-of-bias tool. RESULTS: Five randomized controlled trials involving 310 patients were included. Meta-analysis showed that mechanical insufflation-exsufflation (MI-E) significantly increased sputum clearance (SMD = 0.63, 95% CI, 0.32-0.93; p < 0.00011; I2 = 38%) without affecting oxygenation (MD = 0.28, 95% CI, -0.53 to 1.09; p = 0.50; I2 = 9%). Data on respiratory mechanics, ventilation duration and ICU stay could not be pooled. No serious adverse events were reported. CONCLUSIONS: MI-E significantly improves sputum clearance in invasively ventilated critically ill adults, with no severe adverse events reported in the included studies. Its effects on other outcomes remain inconclusive due to limited data and heterogeneity. Standardized protocols and larger trials are needed. RELEVANCE TO CLINICAL PRACTICE: Clinicians may consider MI-E as an adjunct for respiratory secretion management. Application should be guided by structured patient assessment and individualized parameter adjustment. Future research should standardize interventions and target well-defined patient subgroups to inform clear practice guidelines. TRIAL REGISTRATION: The review protocol was registered in the International Prospective Register of Systematic Reviews, with registration number CRD42023403299.

Humans↗

PubMed2026

Risk factors of venous thromboembolism in ICU patients: a systematic review and meta-analysis.

OBJECTIVE: This study aimed to identify risk factors associated with the development of VTE in patients admitted to the intensive care unit (ICU). METHODS: A systematic literature search was conducted via PubMed, Embase, Web of Science, and Cochrane databases up to 25 April 2025, to identify studies examining the association between risk factors and the occurrence of venous thromboembolism (VTE) in ICU patients. Data were pooled using odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: A total of 2465 relevant studies were identified through the systematic search, of which 30 were included in the meta-analysis. The pooled data showed that the following were significant risk factors for venous thromboembolism (VTE) in ICU patients: central venous catheterization (OR = 2.67, 95% CI: 1.67-4.28; I2 = 28%), invasive mechanical ventilation (OR = 2.08, 95% CI: 1.46-2.96; I2 = 0%), advanced age (OR = 2.06, 95% CI: 1.28-3.31; I2 = 86%), length of ICU stay (OR = 4.24, 95% CI: 1.43-12.57; I2 = 98%), malignancy (OR = 2.30, 95% CI: 1.03-5.12; I2 = 67%), elevated D-dimer levels (OR = 2.46, 95% CI: 1.37-4.40; I2 = 34%), and a history of VTE (OR = 2.84, 95% CI: 1.45-5.55; I2 = 51%). According to the GRADE assessment, the quality of evidence was rated as moderate for invasive mechanical ventilation, low for central venous catheterization and D-dimer levels, and very low for the remaining factors. CONCLUSION: Invasive mechanical ventilation, central venous catheterization, and elevated D-dimer levels are associated with VTE risk, supported by relatively high-quality evidence. These findings may help identify ICU patients at higher risk of VTE, inform the development of risk assessment models for patient stratification, and ultimately contribute to improved prognosis through optimal screening and management strategies.

Humans↗

PubMed2026

Pictographs: feasibility and acceptability of a novel method of newborn identification to reduce wrong-patient errors in the NICU.

Wrong-patient errors cause serious harm in newborns. These errors involve ordering and administering tests, procedures, medications, and breast milk to an unintended patient. Newborns receiving care in neonatal intensive care units (NICUs) are at particularly high risk. Although more distinct newborn naming conventions as recommended by the Joint Commission significantly reduce wrong-patient orders, name similarities among multiple-birth infants and truncation of differentiating information in some electronic health record (EHR) systems contribute to this persistent increased risk. Accordingly, novel newborn identifiers are urgently needed. We propose Pictographs - images that are appealing, recognizable, and appropriate - to serve as visual identifiers for newborns in NICUs. Pictographs are selected by caregivers, uploaded into the EHR, and displayed at bedside. As part of a multicenter randomized controlled trial assessing effectiveness of Pictographs to prevent wrong-patient order errors, we initially evaluated feasibility and acceptability of Pictographs at two study sites. Pictographs as novel visual identifiers for newborns in the NICU were generally well received by caregivers and clinicians, and the vast majority of caregivers selected a Pictograph for their infant(s), which was posted at the bedside and uploaded into the EHR. Ordering clinicians - the primary target of the intervention to prevent wrong-patient errors - recognized the potential for Pictographs to provide a visual cue when placing orders, particularly for multiple-birth infants. Here, we describe the rationale, implementation, framework, feasibility, usefulness, and acceptability of Pictographs among key stakeholders. If found effective for preventing wrong-patient errors, Pictographs could be adopted as a patient safety solution in hospitals worldwide.

Female↗

PubMed2026

Effects of Cognitive Behavioral Couple Therapy With Integrated Mindfulness on Mindful Attention, Depressive Symptoms, and Dyadic Adjustment in Low-Income Couples: A Pilot Randomized Clinical Trial.

Psychosocial distress can exacerbate marital conflict, maladjustment, and mental health vulnerability. This pilot randomized clinical trial examined cognitive-behavioral couple therapy (CBCT) integrated with mindfulness in low-income Brazilian couples (per-capita household income up to one minimum wage). Thirty-four participants (17 heterosexual couples) were randomized (independent computer-generated sequence) to an experimental (n = 16) or waitlist control group (n = 18). We assessed dyadic adjustment, mindful attention, marital social skills, and depressive symptoms (R-DAS, MAAS, IHSC, BDI-II) at baseline, post-treatment, and 3-month follow-up. The intervention was eight 80-min conjoint sessions plus daily home exercises. Time × group effects favored the experimental group for dyadic adjustment, mindful attention, and depressive symptoms (all p < 0.001, = 0.20-0.37), but not marital social skills (p = 0.14). Because two outcomes differed at baseline, effects were confirmed with baseline- and dependence-adjusted sensitivity analyses. These findings provide preliminary evidence that CBCT with mindfulness may benefit disadvantaged couples.

Adult↗

PubMed2026

Cryo-EM structure of TGFBIp fibrils driven by a corneal dystrophy-linked mutation enables design of peptide inhibitors of aggregation.

Corneal dystrophy is a heterogeneous group of diseases which manifests clinically by progressive corneal opacity and diminishing visual acuity. A group of corneal dystrophies are linked to autosomal dominant mutations in transforming growth factor β-induced protein (TGFBIp) and characterized by extracellular amyloid-positive deposits of unknown molecular structure. Here, we determined the cryogenic-electron microscopy (cryo-EM) structure of amyloid fibrils formed by the TGFBIp FAS1-4 domain with corneal dystrophy-linked mutation V624M. The L569 to N609 fibril core, which includes the Y571-R588 segment enriched in patient corneal deposits, forms symmetrical protofilaments with internal solvent channels. Leveraging this structure, we designed peptide inhibitors intended to bind onto fibril ends to block elongation, targeting the unequal growth of symmetrical protofilaments. Our G1 and H4 inhibitors exhibit concentration-dependent reduction of TGFBIp FAS1-4 aggregation as assessed by Thioflavin T, solubility fractionation, and electron microscopy. Our work illustrates how fibril structures can guide rational inhibitor design and suggests the targeting of protein aggregates as a therapeutic approach for corneal and ocular diseases.

betaIG-H3 Protein↗

PubMed2026

Transdermal 17β-Estradiol for the Treatment of COVID-19: Protocol of an Early Terminated Phase 2 Randomized Controlled Trial.

BACKGROUND: Early epidemiological studies suggested that pre- and postmenopausal women receiving estrogen therapy were less likely to develop severe disease or die from COVID-19 infection. Potential mechanisms include estrogen-mediated immunomodulation and 17β-estradiol-induced downregulation of angiotensin-converting enzyme type 2 (ACE2), the cellular receptor for SARS-CoV-2. OBJECTIVE: This study aimed to evaluate the feasibility, safety, and preliminary efficacy of transdermal 17β-estradiol as an adjunctive treatment for COVID-19 in men and postmenopausal women. METHODS: We designed and conducted a randomized controlled trial comparing 17β-estradiol transdermal gel plus standard care with standard care alone in adults with confirmed COVID-19. Initial ethics and funding approvals were obtained in March 2021. Owing to changes in the epidemiology of COVID-19 in Qatar and revisions to national quarantine policies, protocol amendments were required before recruitment commenced in February 2022. The treatment duration was reduced from 10 to 7 days due to changes in national quarantine guidelines. Recruitment and follow-up were conducted between February 2022 and June 2022. RESULTS: Recruitment was substantially lower than anticipated because widespread COVID-19 vaccination, declining disease severity, and revised national quarantine policies markedly reduced the number of eligible hospitalized patients. Consequently, the planned sample size was not achieved, and the study was terminated in June 2022. A total of 29 men with mild COVID-19 were enrolled, with 44.8% (n=13) randomized to standard care and 55.2% (n=16) to transdermal 17β-estradiol plus standard care. The intervention was well tolerated, with no adverse safety signals or thromboembolic events reported. CONCLUSIONS: Although the study was underpowered to assess efficacy because recruitment targets were not achieved, it showed that transdermal 17β-estradiol was well tolerated, with no major safety concerns among enrolled participants. The experience also provided important operational lessons for conducting clinical trials during rapidly evolving pandemics. Adequately powered studies are required to determine whether transdermal estrogen has therapeutic potential against COVID-19, other ACE2-mediated coronavirus infections, or potentially other severe viral illnesses.

Humans↗