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Dravet syndrome (DS) is a severe neurodevelopmental disorder characterized by drug-resistant epilepsy, temperature-sensitive seizures, cognitive impairment, and a high incidence of sudden unexpected death in epilepsy (SUDEP). DS is caused by loss-of-function variants in SCN1A, which encodes the α subunit of the voltage-gated sodium channel (Nav1.1). Current approved treatments manage symptoms of DS but do not correct the root cause of the disease. Here, we describe the use of an adenine base editor (ABE) to directly correct SCN1AR613X, a recurrent variant found in patients with DS. We identified ABE strategies to efficiently correct R613X in engineered homozygous SCN1AR613X human embryonic kidney 293T and mouse Neuro-2a cells (72 and 92% correction efficiencies, respectively). We then used a dual-adeno-associated virus serotype 9 (AAV9) approach to deliver an optimized ABE system to Scn1aR613X/+ mice, which recapitulate several key DS pathologies. AAV9-ABE treatment of Scn1aR613X/+ neonates resulted in efficient DNA and mRNA editing (59 and 97%, respectively, in bulk neocortices), restoring parvalbumin-expressing inhibitory neuron excitability and sodium current to wild-type levels. This ameliorated both spontaneous and temperature-induced seizures and led to a 3.3-fold improvement in 45-day survival over vehicle-treated mice (ABE treated, 90%; and vehicle treated, 27%). Last, ABE treatment in 12-day-old mice resulted in a 3.0-fold improvement in 60-day survival over vehicle-treated mice (ABE treated, 82%; and vehicle treated, 27%). In conclusion, these data validate a strategy to correct SCN1A variants with ABE and highlight the potential of precision genome editing treatments for the treatment of DS and possibly other neurodevelopmental disorders.

Older adults account for approximately 60% of new cancer diagnoses and 70% of cancer-related deaths, yet they remain consistently under-represented in clinical trials and are routinely assessed using performance status (PS) tools developed over seven decades ago. The Karnofsky Performance Status and Eastern Cooperative Oncology Group (ECOG) PS scales, while simple and widely adopted, fail to capture the multidimensional vulnerabilities that define physiologic aging. Studies show that 43%-69% of patients with good PS have geriatric assessment (GA)-identified deficits that independently predict treatment toxicity and survival. Comprehensive GA evaluates functional status, cognition, nutrition, comorbidity burden, polypharmacy, and social support-domains that PS entirely misses. Landmark randomized controlled trials, including GAP70+, GAIN, INTEGERATE, COACH, and PERI-OP, provide level 1 evidence that GA-guided interventions reduce grade 3-5 treatment toxicities by 10%-20% without affecting survival. These trials demonstrate two complementary mechanisms of benefit: treatment modification (dose attenuation and regimen selection) and intensive supportive care. Disease-specific evidence further supports GA integration, including colon, pancreatic, and lung cancers, hematologic malignancies, and surgical oncology. Practical screening tools, including the CARG score, CRASH score, Geriatric 8, and VES-13, can be completed in under 30 minutes and are feasible in routine practice. A proposed clinical algorithm integrates GA findings into treatment decision making alongside standard National Comprehensive Cancer Network, ASCO, and ECOG guidelines. Moving beyond chronologic age and PS toward an understanding of functional reserve is both an evidence-based imperative and an ethical obligation to the fastest growing and most vulnerable segment of the cancer population.

Generalized epilepsy with febrile seizures plus (GEFS+) is an inherited epileptic disorder predominantly linked to autosomal-dominant, loss-of-function mutations in the sodium voltage-gated channel α subunit 1 (SCN1A) gene, which encodes the α subunit of the neuronal voltage-gated sodium ion channel type 1 (NaV1.1). Reduced NaV1.1 function in γ-aminobutyric acid (GABA)-ergic interneurons impairs inhibitory signaling and leads to neuronal hyperexcitability. Clinically, GEFS+ is characterized by a spectrum of seizure types, often beginning with febrile seizures in early childhood and progressing to generalized tonic-clonic seizures later in life. Here, we used prime editing to correct the pathogenic SCN1A-K1270T mutation in the Scn1aKT/+ mouse model of GEFS+. Adeno-associated viral (AAV) vectors were used to deliver an intein-split prime editor under the control of a neuron-specific promoter into the cerebral ventricles of neonatal mice. This enabled efficient in vivo editing, achieving 34.7 ± 14.5% correction of the mutant allele in cortical bulk DNA, 81.2 ± 5.9% correction of mRNA, and improved multiple disease-relevant phenotypes. Survival increased from 80% in control-treated animals to 100% in treated mice, cortical inhibitory neuron transmission was improved (frequencies of inhibitory postsynaptic currents were increased from 0.32 to 1.32 hertz), and the frequency of induced febrile seizures decreased from 78.6% to 13.3%, approaching the frequency seen in wild-type mice (8%). These findings suggest the therapeutic potential of prime editing for the treatment of patients with SCN1A-associated GEFS+.

Due to demographic changes, the number of older people is increasing, often accompanied by limitations in mobility, nutrition, and independence. Preventive monitoring is rare, as care systems struggle with staff shortages and limited resources. Technical assistance systems can support older people in self-assessing their health and maintaining independence. We developed the AS-Tra system, which combines an application with a measurement and training station (MuTS), to enable early detection of nutrition and mobility-related deficits and risks. This paper presents the pilot study of the AS-Tra system with the aim of evaluating its usability and testing the feasibility of collecting health-related data from older adults (&#x2265;70 y) with early/mild deficiencies in nutritional state and mobility in preparation for a future randomized controlled trial. The system used in this 4-week pilot study was developed as a complex intervention in accordance with the Medical Research Council framework. Participants (target n=10) were recruited through a participant registry. They completed standardized mobility assessments (grip strength, Timed "Up and Go," and 5-Time Chair Rise) at baseline and after 1, 2, and 4 weeks (T0, T1, and T2, respectively). Mini Nutritional Assessment-Short Form and short physical performance battery were recorded at baseline and at T2. Participants received a tablet app for regularly documenting nutrition and an activity sensor for 7 days of physical activity monitoring and performed weekly training starting at T0. At T2, the System Usability Scale (SUS) and feedback questionnaires (Evaluation Overall System [EOS] questionnaire-the evaluation of all subcomponents on a scale of 1-5, weekly Experience Report) were additionally collected. Data were analyzed descriptively using IBM SPSS Statistics, in which data were shown as total numbers, percentages, and means with SDs, and data from the activity sensor were displayed and analyzed using Python. A total of 9 older adults, with 1 dropout (mean 80, SD 5 y, 50% female), participated in this study. The SUS score was good (mean 79, SD 13.4 points). The MuTS devices had minor technical problems (in <17% of MuTS sessions), while 57% (17/30) of the users experienced instability issues with the food diary in the tablet app. The average overall system ratings were positive, with an EOS score of 2.01 (SD 0.99). The usability of the technical assistance system used in this study was rated as good. The data collection using questionnaires, sensors, and automated assessments proved feasible. The biggest challenge was the tablet-based food diary, which still needs improvement before the effectiveness of the AS-Tra system regarding mobility and nutritional status can be evaluated in a randomized controlled trial.

Objectives. To examine the magnitude of heat-related emergency medical services (EMS) activations across the United States and identify factors that increase the risk of heat exposure illness. Methods. We extracted heat-related EMS activations from April through September for 2020 through 2024 from the National Emergency Medical Services Information System (NEMSIS) database. We linked information from the 2022 Centers for Disease Control and Prevention (CDC) Social Vulnerability Index with heat-related EMS activations using county of residence. Our analysis focused on heat-related illness by patient demographic, geographic, and EMS system factors. Results. Among the 79&#x2009;077&#x2009;804 EMS activations meeting study inclusion criteria, 261&#x2009;687 (0.3%) were heat related. The rate of heat-related EMS activations was 16.46 per 100&#x2009;000 population, with higher rates among older adults, males, African Americans, and Native Hawaiians/Pacific Islanders. Rates were higher in rural counties and in counties characterized by the CDC Social Vulnerability Index as having relatively worse socioeconomic or environmental conditions. Heat-related EMS activations were commonly reported in the afternoon and in indoor locations. Conclusions. The NEMSIS database provides novel information that improves our ability to monitor heat-related adverse health outcomes. Public Health Implications. The timely collection and sharing of data provide critical situational awareness to inform public health response efforts during a heat wave. (Am J Public Health. 2026;116(6):798-805. https://doi.org/10.2105/AJPH.2026.308513).

The impact of pregnancy on the clinical course of myasthenia gravis (MG) remains uncertain, with existing evidence mainly derived from small case series. Using nationwide longitudinal register data, we aimed to assess the risk of MG exacerbation during pregnancy and up to 1 year postpartum. In this population-based cohort study, we included women with MG recorded in the Swedish National MG Register who had singleton pregnancies documented in the Medical Birth Register after MG diagnosis (1987-2019). The exposure was pregnancy, and the outcome was MG exacerbation. The primary outcome measure was hospital admissions with MG during pregnancy and the postpartum year, compared with the year preceding pregnancy. Cox proportional hazards models estimated hazard ratios (HRs), adjusting for disease duration and prior thymectomy. The secondary outcome measure was changes in immunosuppressive MG medications during pregnancy and postpartum. We identified 112 women with MG (median age 30 years) with 176 singleton pregnancies. During pregnancy, women were not more likely to be hospitalized for MG than in the prepregnancy year (HR 0.74, 95% CI 0.39-1.41), and there was no increased risk of longer hospital admissions (HR 0.83, 95% CI 0.36-1.88). The postpartum period was associated with an increased risk of prolonged MG admissions during the first 3 months (HR 5.02, 95% CI 1.66-15.24), with a similar risk observed throughout the first 12 months postpartum (HR 4.52, 95% CI 1.26-16.14). During pregnancy, immunosuppressive MG medications were reduced or discontinued in 13 pregnancies and increased in 6. Postpartum, medications were initiated or escalated in 10 pregnancies and reduced in none. The risk of prolonged MG admissions was higher in periods outside of pregnancy compared with the prepregnancy year (HR 2.95, 95% CI 0.84-10.43), suggesting that women conceive during periods of relative disease stability. Pregnancy was not associated with an increased risk of MG exacerbation. The postpartum period was linked to more severe or prolonged exacerbations in a minority of women, highlighting the importance of close monitoring after delivery. Milder exacerbations not requiring hospitalization or clear medication escalation may have been underestimated, underscoring the need for larger prospective international studies that include detailed clinical data.

Impaired immune clearance of senescent fibroblasts is a putative driver of pulmonary fibrosis. Exhausted natural killer (NK) cells have been implicated in this process, yet the underlying immune evasion mechanisms remain poorly understood. Using single-cell RNA sequencing (scRNA-seq) and spectral flow cytometry, we identified natural killer group 2 member A (NKG2A) as the predominant inhibitory checkpoint receptor expressed on NK cells in fibrotic lung diseases. Mechanistic in vitro coculture studies showed that NK cell suppression was mediated by senescent fibroblasts expressing human leukocyte antigen-E (HLA-E), the high-affinity ligand for NKG2A. scRNA-seq analysis of lungs from patients with idiopathic pulmonary fibrosis (IPF) further identified selective HLA-E expression in senescent HAS1+ fibroblast subsets. Further, spatial transcriptomics and multiplex immunofluorescence of patient lungs demonstrated that HLA-E+ fibroblasts were positioned at the periphery of fibroblast foci adjacent to NKG2A+ NK cells, establishing an immune-privileged niche. In contrast, extracellular matrix-producing myofibroblasts at the core of fibrotic foci lacked HLA-E and exhibited minimal NK engagement. In vivo, therapeutic blockade of NKG2A restored NK cell function, promoted clearance of senescent fibroblasts, and promoted fibrosis resolution in the bleomycin-induced mouse model. Monalizumab, a clinical-grade NKG2A inhibitor, reactivated patient-derived NK cells and enhanced lysis of human senescent fibroblasts in vitro. Together, these findings uncover a spatially restricted immune checkpoint axis that allows senescent fibroblasts to evade immune NK surveillance. Targeting the HLA-E/NKG2A axis represents a promising therapeutic strategy to restore NK cell-mediated immune clearance of senescent fibroblasts and reverse pulmonary fibrosis.

Primary CNS vasculitis (PCNSV) is a heterogeneous condition. This study examines a large cohort with long-term follow-up to identify potential disease subsets. We retrospectively analyzed 216 patients with PCNSV (Mayo Clinic, 1983-2023), using standardized diagnostic criteria, classifying by vessel size, histopathology, and outcomes. Subsets and predictors of functional and therapeutic outcomes were evaluated. Diagnosis was based on cerebral angiography in 142 patients and histologically confirmed in 74. Isolated small vessel involvement was positively associated with mass-lesion presentation (odds ratio [OR] 19.38, p = 0.02), meningeal-enhancing lesions (OR 39.10, p < 0.0001), elevated CSF protein (OR 4.04, p = 0.03), and &#x3b2;-amyloid vascular deposits (OR 23.43, p = 0.0001), but negatively with focal manifestations (OR 0.32, p = 0.04) and cerebral infarcts (OR 0.22, p = 0.003). Lymphocytic vasculitis was linked to younger age at diagnosis (p = 0.006), longer symptom-to-diagnosis interval (p = 0.05), more seizures (p = 0.04), and lower disability (p = 0.003) and mortality (p = 0.008). Necrotizing vasculitis was associated with intracranial hemorrhage (p = 0.008). Two or more relapses occurred in 12.7%, associated with histologic diagnosis (OR 3.15, p = 0.009) and inversely with gadolinium-enhanced lesions (OR 0.33, p = 0.01). Therapy response occurred in 82.9%, long-term remission in 23.6%. Cerebral infarcts, especially multiple, were associated with poor therapy response (OR 0.11, p = 0.03). Histologic diagnosis was inversely associated with long-term remission (OR 0.44, p = 0.03), whereas aspirin use was positively associated (OR 2.8, p = 0.002). A rapidly progressive course occurred in 13.4% of patients and was linked to increasing age (OR 1.34/10 years, p = 0.04), cognitive dysfunction (OR 5.59, p = 0.02), cerebral infarctions (OR 5.02, p = 0.004), and large vessel involvement (OR 3.51, p = 0.02). Gadolinium-enhanced lesions (OR 0.36, p = 0.04) and aspirin (OR 0.42, p = 0.08) were protective. Mortality (21.3%) was associated with older age (HR 1.42, p = 0.002), cognitive dysfunction (HR 3.93, p = 0.006), and cerebral infarctions (HR 1.94, p = 0.03). PCNSV heterogeneity, driven by vessel size and histology, affects presentation and outcomes; our findings offer insights to improve diagnosis and treatment.

Human anatomy is the cornerstone of medicine. Currently, there is a lack of effective learning tools that can establish a correlation between 2D sectional anatomy and 3D stereoscopic anatomy and facilitate the conversion between the two. This study aimed to evaluate the efficacy of the Imaging Anatomy Virtual Simulation Experiment (IAVSE) course in undergraduate education. This nonrandomized controlled trial was conducted with 102 third-year medical students from the 2017 and 2018 cohorts: 50 medical students who elected to take the IAVSE course were assigned to the experimental group, and 52 students who took the traditional laboratory course served as the control group. Primary outcomes assessed by teaching evaluation included the third-year human anatomy theory scores and fourth-year medical imaging theory, practical test, and total scores. The secondary outcome was a 7-item Likert scale questionnaire based on Bloom's Taxonomy of Educational Objectives. Statistical analyses were performed using SPSS (IBM Corp), with the independent samples t test applied for normally distributed continuous data and the Mann-Whitney U test for nonnormally distributed data. A two-tailed P<.05 was considered statistically significant for all tests. The results of the teaching evaluation indicated a statistically significant difference between the experimental group and the control group. The experimental group achieved higher scores in human anatomy theory (experimental group: median 85, IQR 84.25-85.50, control group: median 81.75, IQR 78.13-83.00; P<.001), medical imaging theory (experimental group: median 61.03, IQR 60.41-61.53, control group: median 59.03, IQR 55.66-59.53; P<.001), practical testing (experimental group: median 22.50, IQR 21.50-23.00, control group: median 20.50, IQR 19.00-22.00; P<.001), and total scores (experimental group: mean 83.26, SD 2.58; control group: mean 78.46, SD 3.76; P<.001). Student feedback collected via a Likert questionnaire also revealed significantly higher ratings in the experimental group across multiple domains, including enjoyment, interactivity, participation, satisfaction, learning efficiency, usability, and acceptance (all P values <.001, except for serviceability, P=.02). Furthermore, the experimental group demonstrated a higher level of acceptance toward the virtual simulation course. The IAVSE course effectively bridges the gap between human anatomy and medical imaging. It enhances students' spatial understanding and academic performance and stimulates their learning interest. It thus holds significant potential for broader application in undergraduate medical education.

An important goal of environmental health research is to assess the health risks posed by mixtures of multiple environmental exposures. In these mixtures analyses, flexible models such as Bayesian kernel machine regression and multiple index models are appealing because they allow for arbitrary non-linear exposure-outcome relationships. However, this flexibility comes at the cost of low power, particularly when exposures are highly correlated and the health effects are weak, as is typical in environmental health studies. We propose a multivariate index modeling strategy that borrows strength across exposures and outcomes by exploiting similar mixture component weights and exposure-response relationships. In the special case of distributed lag models, in which exposures are measured repeatedly over time, we jointly encourage co-clustering of lag profiles and exposure-response curves to more efficiently identify critical windows of vulnerability and characterize important exposure effects. We then extend the proposed approach to the multiple index model setting where the true index structure-the number of indices and their composition-is unknown, and introduce variable importance measures to quantify component contributions to mixture effects. Using time series data from the National Morbidity, Mortality and Air Pollution Study, we demonstrate the proposed methods by jointly modeling three mortality outcomes and two cumulative air pollution measurements with a maximum lag of 14 days.

At the 2026 Conference on Retroviruses and Opportunistic Infections (CROI), investigators presented new findings and innovative interventions that may impact HIV service delivery and care cascade metrics. CROI 2026 focused on challenges faced by specific populations and novel interventions that address those challenges. These include the use of machine learning to predict virologic failure or missed clinic visits; individual-level interventions, such as in-person or virtual training and adherence support; clinic-based person-centered care and optimized clinic practices interventions; and a systemwide opt-out HIV screening and linkage program across federally qualified health centers that led to 100% linkage to care for those newly diagnosed with HIV. Point-ofcare testing for HIV-1 RNA viral load and tenofovir adherence were well received by participants but not associated with improved outcomes. Researchers discussed the impact of disruptions in funding for HIV care and research, particularly among countries receiving support from the US Agency for International Development and the President's Emergency Plan for AIDS Relief. Although data continue to emerge on the profound impact of funding cuts, the collaboration of researchers, care delivery experts, and community members led to the restoration of some programs and continued support for National Institutes of Health-funded research.

Real-time monitoring of cerebrospinal fluid (CSF) is critical in intensive care units for the timely management of complications such as infection and mechanical malfunction in patients with external ventricular drainage systems. Current practice relies on intermittent CSF sampling for laboratory-based biomarker analysis and manual inspection, resulting in delayed reporting and intervention. To address these limitations, we developed NeuroSense, a multiplexed sensing platform that integrates with standard external ventricular drainage systems to enable near real-time monitoring of key CSF (bio)markers, including glucose, lactate, pH, and flow rate, that are essential for detecting infection and drain dysfunction. NeuroSense incorporates glucose and lactate aptamer-based electrochemical biosensors, a polydopamine pH sensor, and an impedance-based flow sensor. Validation in simulated conditions demonstrated sensor specificity, stability in human CSF for several days, and ethylene-oxide sterilization compatibility. Evaluation in patients hospitalized in intensive care unit demonstrated strong correlation with clinical reference standards. By providing near real-time bedside assessment, NeuroSense has the potential to improve temporal resolution for detection of biomarker trends and drain malfunction indicators.

In people with multiple sclerosis (pwMS), optical coherence tomography (OCT) quantifies loss of neurons (macular ganglion cell-inner plexiform layer [mGCIPL]) and axons (peripapillary retinal nerve fiber layer [pRNFL]) in the retina. Serum glial fibrillary acidic protein (sGFAP) is a promising astrocytic biomarker to capture disease progression in pwMS. We aimed to investigate the relationship between OCT markers and sGFAP in pwMS and explore their additive value in predicting disability progression. PwMS and healthy controls underwent OCT at baseline (BL), excluding eyes with inter-eye asymmetry. Age, sex, and body mass index-adjusted Z scores of sGFAP were calculated. Cross-sectional and longitudinal associations between sGFAP and retinal layers were estimated using linear regression- and mixed-effects models (LMM). The additive effect of BL-OCT and BL-sGFAP on the trajectory of the Expanded Disability Status Scale (EDSS) was estimated using LMM, whereby pwMS were stratified into: group (1): low sGFAP Z score (<3rd quartile, <Q3) and thick mGCIPL (>Q1); group (2): high sGFAP Z score (&#x2265;Q3) and thick mGCIPL or low sGFAP Z Score and thin mGCIPL (&#x2264;Q1); and group (3): high sGFAP and thin mGCIPL. Two hundred and sixty-one pwMS (mean age: 48 years (y), female: 63%, on disease-modifying treatment: 80%, mean thickness of pRNFL: 94 &#x3bc;m and mGCIPL: 66 &#x3bc;m) and 52 controls (age: 52 years, female: 65%, pRNFL: 101 &#x3bc;m, mGCIPL: 72 &#x3bc;m) were included. At BL, pRNFL (&#x3b2; = -0.01, p = 0.042) and mGCIPL (&#x3b2; = -0.02, p = 0.013) were negatively associated with sGFAP Z scores in pwMS, but not in controls (p = 0.950, p = 0.386). BL-mGCIPL was also associated with sGFAP trajectories (&#x3b2; = -0.003, p = 0.044), over a median follow-up of 2.9 years. Compared with pwMS with good results in both markers (group 1), those with either high sGFAP or thin mGCIPL had a steeper EDSS increase (&#x3b2; = 0.030, p = 0.048), while pwMS with both high sGFAP and thin mGCIPL (group 3) showed the steepest trajectory of the EDSS (&#x3b2; = 0.101, p < 0.001). Our findings show a close relationship between astrocytic activation/injury and neurodegeneration in the CNS, measured at the retinal level. Moreover, they highlight an additive role of mGCIPL and sGFAP for identification of pwMS at higher risk of disability worsening.

Endometriosis is a complex gynecological condition affecting nearly 10% of reproductive-aged women. This report updates a 2017 MSMR report of gynecological conditions, including endometriosis, from 2012 through 2016 among U.S. active component service women. The current report utilized medical encounter data from 2017 through 2024 to assess the incidence of endometriosis and its health care burden among U.S. active component service women. Factors related to co-occurring gynecological conditions, deployment, parity, and contraceptive use were also examined. Crude incidence rates and incidence rate ratios with 95% confidence intervals were calculated. The overall crude rate of endometriosis was 32.8 cases per 10,000 person-years and increased approximately 42.0% from 2017 to 2024. Incidence rates increased with age and were higher among nulliparous and never-deployed service women. Additionally, obese and underweight service women had higher incidence rates. Menorrhagia was the most common co-occurring condition, with oral birth control the most common form of contraceptive among incident cases. Identification of at-risk service women may help formulate targeted policies for earlier diagnosis to improve both quality of life and military readiness. Incidence of endometriosis increased during the surveillance period, from 28.7 cases per 10,000 person-years in 2017 to 40.7 cases per 10,000 person-years in 2024, coincident with a general increase of medical encounters for endometriosis, from 2,740 medical encounters in 2017 to 3,864 medical encounters in 2024. Service women who were older, obese or underweight, nulliparous, and never deployed had higher incidence rates.

Casearia sylvestris Sw. (Salicaceae) is a South American medicinal plant traditionally used for the treatment of inflammatory conditions, pain, and wound healing, with its biological activity mainly attributed to clerodane diterpenes and flavonoids. This study assessed its therapeutic potential in wound repair and pain modulation by integrating patent landscaping with scientific evidence. A systematic search was conducted in the Orbit-Questel database to identify relevant patent families, complemented by a literature review in PubMed, Scopus, and Web of Science. Patents and studies reporting analgesic, anti-inflammatory, or wound-healing activities were included. Of the 41 patent documents retrieved, eight met the inclusion criteria and were classified into three main technological strategies: (i) nanostructured sprays and biofilms containing glycolic extracts of C. sylvestris; (ii) synergistic herbal combinations; and (iii) innovative formulations for oral mucositis. Some patents also described the isolation of clerodane diterpenes with cytomodulatory and antitumor properties. Among 51 screened scientific articles, seven were included, providing generally supportive but heterogeneous evidence. Despite its promising potential, limitations related to chemical standardization, methodological variability, and the lack of clinical and mechanistic studies remain, highlighting the need for further research to enable safe and effective therapeutic applications.

The 2026 Conference on Retroviruses and Opportunistic Infections (CROI) featured numerous studies on tuberculosis and other opportunistic infections in people with HIV. High mortality rate among people with HIV hospitalized with disseminated tuberculosis (TB) and among those treated for drug-resistant TB represents a major clinical challenge. Intensified TB treatment in one trial and adjunctive prednisone in another failed to reduce mortality in hospitalized people with HIV with disseminated TB. In addition, a novel higher-dose linezolid dosing strategy did not improve culture conversion in drug-resistant TB. Recommended options for TB prevention are increasing, and include 1-month daily (1HP) and 3-month weekly (3HP) isoniazid-rifapentine regimens. Two head-to-head trials comparing 1HP and 3HP found comparable efficacy, although 1HP was associated with lower treatment completion rate and greater treatment intolerance. These and other key findings from TB, mpox, and other opportunistic infection-related studies are summarized herein.

At the 2026 Conference on Retroviruses and Opportunistic Infections (CROI), investigators presented updates on the global HIV epidemic. HIV incidence remains high among key populations, including female sex workers, men who have sex with men, people who inject drugs, and transgender women. Testing for recent infections can guide targeted HIV prevention services to interrupt ongoing transmission. In a cohort study of serodifferent couples in Africa, low-level viremia was associated with reduced but nonnegligible risk of HIV transmission. Sociostructural risk factors play a substantial role in driving new HIV transmissions. Several studies described the use of molecular epidemiology to characterize HIV transmission patterns and identify hot spots. Innovative strategies to increase HIV testing are being evaluated. In an oral preexposure prophylaxis (PrEP) study offering choice between daily and on-demand PrEP, HIV incidence was very low with either regimen. Follow-up data from 2 injectable lenacapavir PrEP trials demonstrated continued high efficacy with very rare breakthrough infections. Although awareness of long-acting PrEP is increasing, use remains low across various cohorts. Several studies reported on the use of PrEP in pregnancy, including a pharmacokinetic study showing no dose adjustment needed for long-acting injectable cabotegravir. Interventions to increase PrEP uptake and persistence show promise. A randomized clinical trial of the meningococcal vaccine did not show efficacy in preventing gonorrhea acquisition. Although doxycycline postexposure prophylaxis (doxy-PEP) use is increasing, it remained low among male veterans with a history of a sexually transmitted infection. Several studies reported on the impact of doxy-PEP on antibiotic use.

The 2026 Conference on Retroviruses and Opportunistic Infections in Denver, Colorado, showcased major advances in our understanding of HIV replication, viral persistence, host-virus interactions, and innate immune sensing. Basic science presentations emphasized the remarkable complexity of the HIV replication cycle and highlighted how structural virology, systems biology, and genome-wide screening approaches are transforming the field. A consistent highlight of the conference is the Scott M. Hammer workshop for new investigators and trainees in which scientific experts help orient trainees to thematic areas being covered in the conference. This underscores the conference's dedication to the mentoring and training of early career investigators new to the field of HIV/AIDS research.

It is well known that Dishevelled (DVL) phosphorylation by casein kinase 1 (CK1) relays Wnt signals from Frizzled (FZD) receptors to downstream effectors, yet any mechanistic aspects of DVL function related to phosphorylation remain unresolved. Here, we uncovered a Wnt-induced DVL phospho-switch that is mutually exclusive with FZD association. CK1 multiphosphorylation changes dramatically the bulk electrostatics to promote DVL intramolecular interaction between the DEP domain and the adjacent disordered region. A panel of DVL3 mutants demonstrated a switch-like behavior at the molecular level when a charge threshold was reached. Charge accumulation proximal to DEP proved to be a key functional event required, but not sufficient, for Wnt/&#x3b2;-catenin signaling. Proximity interactomics revealed FZD receptors as the prominent effectors of the DVL phospho-switch function consistent with the molecular competition at the DEP interface. By integrating findings at different levels, we propose a universal mechanism, in which Wnt-induced DVL conformational phospho-switch attenuates coresidence with FZDs as a means for downstream signaling events.