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In follow-up studies over a period of one to two years, the HHV-6 genome persisted in blood mononuclear cells after primary infection in 37 of 56 children (66 percent). Reactivation, sometimes with febrile illnesses, was suggested by subsequent increases in antibody titers in 16 percent (30 of 187) and by PCR in 6 percent (17 of 278). No recurrent viremia was detected. Of 41 healthy newborns studied, 12 (29 percent) had the HHV-6 genome in their blood mononuclear cells; nevertheless, 6 of these newborns subsequently had primary HHV-6 infections. Conclusions: In infants and young children HHV-6 infection is a major . . .

N6-methyladenosine (m⁶A) RNA methylation is the most abundant epitranscriptomic modification of eukaryotic messenger RNAs (mRNAs). Previous reports have found m⁶A on both cellular and viral transcripts and defined its role in regulating numerous biological processes, including viral infection. Here, we show that m⁶A and its associated machinery regulate the life cycle of hepatitis B virus (HBV). HBV is a DNA virus that completes its life cycle via an RNA intermediate, termed pregenomic RNA (pgRNA). Silencing of enzymes that catalyze the addition of m⁶A to RNA resulted in increased HBV protein expression, but overall reduced reverse transcription of the pgRNA. We mapped the m⁶A site in the HBV RNA and found that a conserved m⁶A consensus motif situated within the epsilon stem loop structure, is the site for m⁶A modification. The epsilon stem loop is located in the 3′ terminus of all HBV mRNAs and at both the 5′ and 3′ termini of the pgRNA. Mutational analysis of the identified m⁶A site in the 5′ epsilon stem loop of pgRNA revealed that m⁶A at this site is required for efficient reverse transcription of pgRNA, while m⁶A methylation of the 3′ epsilon stem loop results in destabilization of all HBV transcripts, suggesting that m⁶A has dual regulatory function for HBV RNA. Overall, this study reveals molecular insights into how m⁶A regulates HBV gene expression and reverse transcription, leading to an increased level of understanding of the HBV life cycle.

Bruton's tyrosine kinase (BTK) regulates critical signal transduction pathways involved in the pathobiology of rheumatoid arthritis (RA) and other autoimmune disorders. BMS-986142 is a potent and highly selective reversible small molecule inhibitor of BTK currently being investigated in clinical trials for the treatment of both RA and primary Sjögren's syndrome. In the present report, we detail the in vitro and in vivo pharmacology of BMS-986142 and show this agent provides potent and selective inhibition of BTK (IC50 = 0.5 nM), blocks antigen receptor-dependent signaling and functional endpoints (cytokine production, co-stimulatory molecule expression, and proliferation) in human B cells (IC50 ≤ 5 nM), inhibits Fcγ receptor-dependent cytokine production from peripheral blood mononuclear cells, and blocks RANK-L-induced osteoclastogenesis. Through the benefits of impacting these important drivers of autoimmunity, BMS-986142 demonstrated robust efficacy in murine models of rheumatoid arthritis (RA), including collagen-induced arthritis (CIA) and collagen antibody-induced arthritis (CAIA). In both models, robust efficacy was observed without continuous, complete inhibition of BTK. When a suboptimal dose of BMS-986142 was combined with other agents representing the current standard of care for RA (e.g., methotrexate, the TNFα antagonist etanercept, or the murine form of CTLA4-Ig) in the CIA model, improved efficacy compared to either agent alone was observed. The results suggest BMS-986142 represents a potential therapeutic for clinical investigation in RA, as monotherapy or co-administered with agents with complementary mechanisms of action.

Metallic transition-metal dichalcogenides (TMDCs) are benchmark systems for studying and controlling intertwined electronic orders in solids, with superconductivity developing from a charge-density wave state. The interplay between such phases is thought to play a critical role in the unconventional superconductivity of cuprates, Fe-based and heavy-fermion systems, yet even for the more moderately-correlated TMDCs, their nature and origins have proved controversial. Here, we study a prototypical example, 2H-NbSe 2 , by spin- and angle-resolved photoemission and first-principles theory. We find that the normal state, from which its hallmark collective phases emerge, is characterized by quasiparticles whose spin is locked to their valley pseudospin. This results from a combination of strong spin–orbit interactions and local inversion symmetry breaking, while interlayer coupling further drives a rich three-dimensional momentum dependence of the underlying Fermi-surface spin texture. These findings necessitate a re-investigation of the nature of charge order and superconducting pairing in NbSe 2 and related TMDCs. The origin of intertwined electronic orders in transition-metal dichalcogenides has long been debated. Here, Bawden et al . report that the normal state, from which these phases emerge, is unexpectedly spin-polarized, with spins locked to both valley and layer pseudospins.

In a randomized trial involving patients with subclinical (typically asymptomatic) atrial fibrillation, apixaban led to a lower risk of stroke or systemic embolism than aspirin but a higher risk of major bleeding.

There is limited empiric evidence on the coverage of pneumococcal conjugate vaccines (PCVs) required to generate substantial indirect protection. We investigate the association between population PCV coverage and indirect protection against invasive pneumococcal disease (IPD) and pneumonia hospitalisations among undervaccinated Australian children. Birth and vaccination records, IPD notifications, and hospitalisations were individually linked for children aged <5 years, born between 2001 and 2012 in 2 Australian states (New South Wales and Western Australia; 1.37 million children). Using Poisson regression models, we examined the association between PCV coverage, in small geographical units, and the incidence of (1) 7-valent PCV (PCV7)-type IPD; (2) all-cause pneumonia; and (3) pneumococcal and lobar pneumonia hospitalisation in undervaccinated children. Undervaccinated children received <2 doses of PCV at <12 months of age and no doses at [greater than or equal to]12 months of age. Potential confounding variables were selected for adjustment a priori with the assistance of a directed acyclic graph. In this study, we observed substantial indirect protection at lower levels of PCV coverage than previously described-challenging assumptions that high levels of PCV coverage (i.e., greater than 90%) are required. Understanding the association between PCV coverage and indirect protection is a priority since the control of vaccine-type pneumococcal disease is a prerequisite for reducing the number of PCV doses (from 3 to 2). Reduced dose schedules have the potential to substantially reduce program costs while maintaining vaccine impact.

In Canada, more than 2 million people live with osteoporosis, a disease that increases the risk for fractures, which result in excess mortality and morbidity, decreased quality of life and loss of autonomy. This guideline update is intended to assist Canadian health care professionals in the delivery of care to optimize skeletal health and prevent fractures in postmenopausal females and in males aged 50 years and older. This guideline is an update of the 2010 Osteoporosis Canada clinical practice guideline on the diagnosis and management of osteoporosis in Canada. We followed the Grading of Recommendations Assessment, Development and Evaluation (GRADE) framework and quality assurance as per Appraisal of Guidelines for Research and Evaluation (AGREE II) quality and reporting standards. Primary care physicians and patient partners were represented at all levels of the guideline committees and groups, and participated throughout the entire process to ensure relevance to target users. The process for managing competing interests was developed before and continued throughout the guideline development, informed by the Guideline International Network principles. We considered benefits and harms, patient values and preferences, resources, equity, acceptability and feasibility when developing recommendations; the strength of each recommendation was assigned according to the GRADE framework. The 25 recommendations and 10 good practice statements are grouped under the sections of exercise, nutrition, fracture risk assessment and treatment initiation, pharmacologic interventions, duration and sequence of therapy, and monitoring. The management of osteoporosis should be guided by the patient’s risk of fracture, based on clinical assessment and using a validated fracture risk assessment tool. Exercise, nutrition and pharmacotherapy are key elements of the management strategy for fracture prevention and should be individualized. The aim of this guideline is to empower health care professionals and patients to have meaningful discussions on the importance of skeletal health and fracture risk throughout older adulthood. Identification and appropriate management of skeletal fragility can reduce fractures, and preserve mobility, autonomy and quality of life.

Polygenic risk prediction is a widely investigated topic because of its promising clinical applications. Genetic variants in functional regions of the genome are enriched for complex trait heritability. Here, we introduce a method for polygenic prediction, LDpred-funct, that leverages trait-specific functional priors to increase prediction accuracy. We fit priors using the recently developed baseline-LD model, including coding, conserved, regulatory, and LD-related annotations. We analytically estimate posterior mean causal effect sizes and then use cross-validation to regularize these estimates, improving prediction accuracy for sparse architectures. We applied LDpred-funct to predict 21 highly heritable traits in the UK Biobank (avg N = 373 K as training data). LDpred-funct attained a +4.6% relative improvement in average prediction accuracy (avg prediction R 2 = 0.144; highest R 2 = 0.413 for height) compared to SBayesR (the best method that does not incorporate functional information). For height, meta-analyzing training data from UK Biobank and 23andMe cohorts ( N = 1107 K) increased prediction R 2 to 0.431. Our results show that incorporating functional priors improves polygenic prediction accuracy, consistent with the functional architecture of complex traits. Incorporating functional information has shown promise for improving polygenic risk prediction of complex traits. Here, the authors describe polygenic prediction method LDpred-funct, and demonstrate its utility across 21 heritable traits in the UK Biobank.

People who inject drugs (PWID) in Zambia are an understudied population at high risk for HIV acquisition and transmission. We report here on the progress within the PWID communities of Livingstone, Lusaka, and Ndola, Zambia towards the Joint United Nations Programme on HIV/AIDS (UNAIDS) 95-95-95 targets. A biobehavioral survey used respondent-driven sampling to survey 235 PWID in Livingstone, 349 in Lusaka, and 259 in Ndola in 2021-22. Questions on HIV and injection drug use were administered, and blood was collected for HIV, syphilis, Hepatitis B, and Hepatitis C testing. Weighted prevalence and 95% confidence intervals (CIs) were calculated using Gile's sequential sampling estimator. In Livingstone, Lusaka, and Ndola, HIV prevalence among PWID was 11.9% (95% CI: 7.3, 16.5), 7.3% (95% CI: 4.5, 10.2), and 21.9% (95% CI: 14.5, 29.3), respectively. Among HIV-positive PWID in Livingstone, 70.7% (95% CI: 55.4, 85.0) were aware of their HIV status (95% is 1st UNAIDS target), 100% of those were on antiretroviral therapy (ART) (95% is 2nd UNAIDS target), and 100% of those achieved viral load suppression (VLS) (95% is 3rd UNAIDS target). In Lusaka, 66.0% (95% CI: 49.3, 82.2) were aware, 75.7% (95% CI: 51.1, 99.9) were on ART, and 66.3% (95% CI: 42.1, 90.9) achieved VLS. In Ndola, 60.2% (95% CI: 44.1, 76.0), 100%, and 90.2% (95% CI: 82.2, 98.3) were aware, on ART, and achieved VLS, respectively. Awareness of HIV status was low among PWID living in Livingstone, Lusaka, and Ndola, Zambia. Treatment and VLS progress were lacking in Lusaka and Ndola as well with Lusaka showing the least progress toward all three UNAIDS targets. Our site-level findings highlight critical gaps in PWID-specific HIV awareness, treatment, and VLS status in three major urban areas in Zambia that limit progress toward HIV epidemic control in this hard-to-reach population.

BackgroundThe Monopoint reperfusion system (Monopoint; Route 92 Medical, San Mateo, California, USA) is a large bore (0.088 or 0.070 inch inner diameter) aspiration thrombectomy platform designed to minimize ledge effect and improve neurovascular navigation and embolectomy. We aimed to describe a multicenter, real world experience of the safety and performance of the Monopoint system in first line aspiration thrombectomy for large vessel occlusions (LVOs), outside of the recently completed SUMMIT MAX (A Randomized, Controlled Trial to Evaluate the Safety and Effectiveness of the Route 92 Medical Reperfusion System) clinical trial.MethodsAdults with acute anterior circulation LVO stroke between January 2019 and December 2024 consecutively treated with first line aspiration thrombectomy using the Monopoint at 10 centers were retrospectively reviewed. The primary outcome was first pass effect (FPE, modified Thrombolysis in Cerebral Infarction (mTICI) 2C/3 on first pass) and modified FPE (mFPE, mTICI 2B/2C/3 on first pass). The primary safety outcome was the rate of intraprocedural complications attributed to the Monopoint system.ResultsIn 193 included patients, median age was 67 years (IQR 67–78), and 46.6% (90/193) were women. Successful delivery of the aspiration catheter to the clot site occurred in 96.2% (185/193) of patients. FPE was achieved in 57.5% (111/193) and mFPE was achieved in 68.4% (132/193) of patients. Of 10 (5.2%) total complications, most were vasospasm treated with intra-arterial verapamil (8/193, 4.1%); major complications included one dissection (1/193, 0.5%) and one perforation (1/193, 0.5%).ConclusionThis multicenter study of the Monopoint reperfusion system for LVO thrombectomy outside of the SUMMIT MAX trial demonstrated a high FPE rate and a low rate of major complications.