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Life expectancy is a key indicator of population health and an important guide for health policy1,2. Although Asia represents approximately 60% of the global population, studies of longitudinal trends in life expectancy and their underlying drivers across Asian countries remain limited, with most previous research focused on western or high-income settings3-6. Here we provide a comprehensive analysis of life expectancy, cause-specific mortality and risk factors in 1990-2023 across 34 Asian countries and territories, utilizing data from the Global Burden of Disease Study 20231,7. Life expectancy increased in all countries and territories between 1990 and 2023, with the largest annual gains observed in South Asia and the smallest annual gains in high-income Asia Pacific countries and territories. Reductions in cardiovascular disease mortality were the primary contributors to life expectancy gains in Central Asia, East Asia and high-income Asia Pacific, whereas declines in diarrhoeal diseases and tuberculosis contributed most in South and Southeast Asia. In 2019-2023, life expectancy declined in several Asian regions, largely driven by the COVID-19 pandemic, with a nearly two-year loss in the first year of the pandemic. The causes of changes in life expectancy and the contributing risk factors varied across regions and countries/territories. Therefore, under the principles of proportional universalism, proactive and effective policies at both regional and national levels are essential to reduce premature mortality and reduce life expectancy inequalities across Asia.

Emergency free flap reconstruction (EFFR) involves flap coverage performed during initial operative intervention or within 24 h after traumatic injury. Although EFFR offers notable advantages, standardized criteria for its application are not well established. This manuscript proposes a treatment framework outlining three primary indications for EFFR, including the use of viable tissue from spare parts. We retrospectively analyzed 14 patients (15 flaps) with traumatic limb-threatening injuries treated with EFFR across two academic centers from 2016 to 2024. Data collected included patient demographics, injury patterns, operative details, and clinical outcomes, with results compared to existing literature. Functional recovery was defined as independent ambulation for lower extremity injuries and restoration of range of motion for upper extremity or digital injuries. The cohort (mean age 35 years; 79% male) presented three key indications for 15 EFFR flaps: spare part utilization (47%, n = 7), immediate coverage of exposed critical structures (20%, n = 3), and distal revascularization using flow-through flaps (33%, n = 5). Flap success rate was 87%, with an overall complication rate of 47%. In multiple cases, spare part flaps preserved functional levels of amputation, such as the below-elbow or below-knee level. Functional recovery averaged 5 months (range, 2-11), and mean hospital stay was 15 days (range, 8-39). EFFR is effective for traumatic limb salvage when tailored to specific indications. Our experience-based framework offers structured guidance based on spare part use, timely soft-tissue coverage, and distal revascularization, supporting this acute orthoplastic approach for care of traumatic injuries.

Space-occupying lesions (SOL) other than cysts involving the suprascapular nerve at the suprascapular notch are rare. A 64-year-old female presented with a 6-month history of severe left shoulder pain and restricted motion. The magnetic resonance imaging (MRI) revealed a SOL in the suprascapular notch, which was hyperintense on T2-weighted and isointense on T1-weighted images. Open surgical excision of the mass was performed. Histopathological assessment established the diagnosis of benign schwannoma. At the most recent follow-up at 23 months, the Oxford shoulder score was 43, and the MRI showed no recurrence. Surgeons must appreciate that a suprascapular notch schwannoma is a rare cause of shoulder pain that must be identified by subtle radiological signs. Additionally, it is important to appropriately counsel the patients regarding the prolonged recovery course. The online version contains supplementary material available at 10.1007/s43465-025-01548-6.

Gallbladder carcinoma (GBC) is an aggressive malignancy with a poor prognosis, often diagnosed at a locally advanced stage. Accurate risk stratification is crucial for optimizing treatment, yet conventional imaging and staging systems have limitations. This study aimed to evaluate the prognostic value of metabolic and volumetric parameters from 18 F-fluorodeoxyglucose positron emission tomography/computed tomography ( 18 F-FDG PET/CT) in patients with locally advanced GBC. This retrospective study included 32 patients with biopsy-confirmed, locally advanced GBC who underwent baseline 18 F-FDG PET/CT. The standard uptake values (SUVmax, SUVmean), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) were measured for both primary tumors and nodal metastases. A univariate Cox proportional hazards model was used to assess the association between these volumetric metabolic PET parameters and progression-free survival (PFS) and overall survival (OS). The multivariate Cox model was used to test the independence of significant univariate prognostic factors. In the univariate analysis of volumetric metabolic PET parameters of primary tumors, higher pSUVmean (hazard ratio [HR]: 1.39, p  = 0.04), pTLG2.5 (per 100 units; HR: 1.01, p  = 0.02), pMTV40 (HR: 1.00, p  = 0.02), and pTLG40 (per 100 units; HR: 1.09, p  = 0.01) were all significantly associated with worse OS. Similar significant associations were found for PFS. Notably, the conventional metric of pSUVmax was not a significant predictor of either PFS ( p  = 0.11) or OS ( p  = 0.25). On multivariate analysis, pTLG40 remained an independent predictor of survival. Furthermore, none of the volumetric metabolic PET parameters derived from nodal metastases showed a significant association with survival outcomes. Volumetric metabolic PET parameters, particularly TLG and MTV, which reflect the total metabolic burden of the primary tumor, may offer greater prognostic utility in locally advanced GBC compared with the conventional SUVmax. These parameters should be considered for integration into prognostic models to enhance patient risk stratification and guide personalized therapeutic strategies.

Pediatric sleep disorders are common, underrecognized conditions with significant short-term and long-term consequences for physical health, neurocognitive development, mental well-being, and family functioning. This article provides a comprehensive, clinically focused overview of pediatric sleep disorders, with particular emphasis on Generation Z and Generation Alpha cohorts who are uniquely shaped by pervasive digital exposure, circadian disruption, and contemporary psychosocial stressors. Normal developmental changes in sleep architecture are reviewed to distinguish physiologic variation from pathology. Key sleep disorders including insomnia, circadian rhythm sleep-wake disorders, sleep-disordered breathing, parasomnias, and sleep-related bruxism are discussed.

Synaptic protein interaction networks (PINs) dynamically translate neural activity into biochemical signals that regulate synaptic structure and plasticity. Disruption of these coordinated networks is a common feature of autism spectrum disorder (ASD) risk genes, yet it remains unclear whether the molecular organization of a perturbed network can be restored after development. Here, we examined how post-developmental re-expression of the synaptic Ras GTPase-activating protein SynGAP1 affects network structure and signaling dynamics in a conditional SynGAP1 haploinsufficient mouse. Quantitative multiplex co-immunoprecipitation (QMI) across development revealed that SynGAP haploinsufficiency selectively reduced SynGAP-containing complexes without broadly disrupting NMDA-dependent network responses. Tamoxifen-inducible re-expression of SynGAP at postnatal day 21 fully restored both steady-state and activity-dependent interactions within the SynGAP module in hippocampus, and additionally normalized secondary alterations in Shank-Homer scaffolding complexes in somatosensory cortex. These data demonstrate that biochemical restoration of a disrupted synaptic network is achievable, even after early developmental windows have closed. Our findings suggest that while critical periods may constrain functional recovery, molecular network normalization remains possible through genetic reactivation of haploinsufficient synaptic regulators.

Improved methods to identify therapeutically relevant tumor neoantigens and their cognate T cells would aid the development of precision medicines for cancer. Here, we developed Slide-GoTags, a droplet-based single-nucleus spatial transcriptomics approach that characterizes neoantigen-specific immunity by integrating targeted transcript genotyping and T cell receptor (TCR) sequencing with single-nucleus RNA sequencing from the same slice of frozen tissue. Application of Slide-GoTags to mouse and human tumors revealed colocalization of clonally expanded, neoantigen-specific T cells with tumor cells expressing their cognate neoantigen. We also identified distinct spatial immune landscapes shaped by anti-PD1 or anti-CTLA4 blockade in mouse colorectal tumors. Across human tumor types, Slide-GoTags detected TCR-neoantigen interactions through spatial proximity and identified an enrichment of interferon-driven immunogenicity niches in immunologically 'hot' tumors compared to 'cold' tumors. These niches harbored three T cell clonotypes that colocalized with genotyped neoantigens, highlighting a spatially organized antitumor immune response. Collectively, Slide-GoTags establishes a framework for in situ mapping of T cell-tumor interactions directly from individual tissue.

Symptomatic neuroma formation after peripheral nerve injury poses a major clinical challenge, contributing to chronic neuropathic pain, which is reported by approximately 60% of residual limb patients. Traditional neuroma management approaches, featuring passive techniques such as neurectomy and nerve burial in muscle, have shown limited success with relatively high recurrence rates and fail to address the fundamental pathophysiology of misguided axonal regeneration. The past two decades have witnessed a fundamental transformation toward active nerve reconstruction management strategies, prominently featuring targeted muscle reinnervation (TMR). Originally developed for myoelectric prosthetic control, TMR has had a significant impact on the field of peripheral nerve surgery through its efficacy in preventing and treating neuropathic pain. TMR provides physiologic targets for organized axonal regeneration while potentially interrupting the peripheral-to-central pain cascade that characterizes chronic neuropathic pain. Level I evidence demonstrates superior outcomes compared to traditional treatments, with TMR providing sustained pain relief in 82% of patients. Beyond pain reduction, TMR has demonstrated improvements in quality of life, sleep, and psychosocial well-being, suggesting its effects on inhibiting central sensitization mechanisms. Applications of TMR have expanded beyond amputees to include myriad anatomic locations, representing a transition from experimental prosthetic applications to comprehensive neuropathic pain management. As understanding of peripheral nerve biology and neuropathic pain advances, TMR is positioned to play an increasingly important role in personalized nerve surgery. The growing international adoption offers hope for reducing the global burden of chronic neuropathic pain through focused interventions that address both peripheral and central pain mechanisms.

Out-of-hospital cardiac arrest (OHCA) is a major public health challenge in India. Cardiopulmonary resuscitation (CPR) awareness, training, and bystander response rates remain critically low across the country. This Indian Society of Electrocardiology position statement aims to promote nationwide CPR awareness, strengthen community response to sudden cardiac arrest (SCA) and improve survival in OHCA, with measures adapted to India-specific systems of care and bystander training. The statement highlights the SCA burden, early recognition, rapid response, barriers to community CPR training in India, dispatcher-assisted CPR, and public access defibrillation (PAD). It emphasizes school-based CPR education, corporate social responsibility partnerships, legislative support, and development of a national CPR ecosystem. Role of digital innovations, mobile applications, virtual reality, mobile CPR training units, psychological barriers and the bystander effect are emphasized. The position statement advocates transforming CPR from a medical skill into a societal responsibility and improve OHCA survival in India.

Few data exist on practice trends for cardiovascular magnetic resonance (CMR) in pediatric and congenital heart disease (CHD). The Society for Cardiovascular Magnetic Resonance addressed this gap by conducting an international survey of CMR sites in 2014 and 2018. We now report the most recent survey results from 2024. Surveys with 31 (2014), 33 (2018), and 41 (2024) items were sent to all SCMR members. One response per center was collected. There were 93 centers that responded in 2014, 83 in 2018, and 124 in 2024. The following results are per center and data from 2014, 2018, and 2024 are separated by dashes. The median annual number of pediatric/CHD CMR cases was 183-209-250. The median number of CMR scanners was 2-2-2 (range, 1-8) with 58-63-53% using only 1.5T scanners and 4-4-3% using only 3T. CMR examinations were performed in infants (<1 year old) in 74%-76%-90% and sedation and/or anesthesia was used in 84%-86%-94% of the centers. The mean number of attendings/staff reading CMRs was 3.7-2.6-2.9. Combining attending/staff physicians from all centers, 52-61-62% were pediatric or adult cardiologists, and 47-38-37% were pediatric or adult radiologists. The median annual case volume per physician per center was 54-86-76. The median number of technologists was 4-5-4. The median scanner time allocated for a non-sedated examination was 75-75-75minutes (range, 30-120minutes). Among the 14 centers responding to all 3 surveys, the mean annual case volume was 380-500-588, with 82% of centers experiencing a sequential increase in volume with each survey. All of these 14 centers were in the United States and for them, the mean time for an attending/staff physician to perform a typical CMR examination, including supervision and reporting, was 150-153-154minutes, and the median scanner time allocated per ex per year was 92 in the amination for non-sedation cases remained unchanged at 90-90-90minutes. These survey data provide a unique and comprehensive view of CMR practice in pediatric and CHD across centers worldwide. This information is useful for internal benchmarking, resource allocation, addressing practice variation, quality improvement initiatives, and identifying unmet needs.

Insertion of a compact motif into CARs enables activation-induced receptor shedding, thereby enhancing CAR T cell potency.

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This cross-sectional study seeks to quantify the association between minimum concentration and area under the concentration curve (AUC) measurements of vancomycin.

Brown dwarfs occupy the mass regime between planets and stars. In systems containing both a star and a substellar companion (be it a brown dwarf or an exoplanet), a third object orbiting the companion can be called an exosatellite. Exoplanet satellites can be easily described as exomoons, but it is not clear if satellites of brown dwarf companions can be called the same, as the term lacks a formal definition. Despite more than 6,000 exoplanets being discovered1, no exomoon has ever been confidently detected. Although there are candidates, they lack confirmation and remain controversial2-5. In this work, we present evidence of an exosatellite orbiting the directly imaged brown dwarf companion CD-35 2722 B. Applying radial velocity analysis, the same technique used to discover the first exoplanet around a Solar-type star6, to VLT/CRIRES+ spectra of this brown dwarf, we find what appears to be the periodic signal of at least one orbiting satellite. This is the first time, to our knowledge, this technique has produced evidence of satellites around a companion brown dwarf. Our best-fitting model includes a satellite with a minimum mass of about 0.9 Jupiter masses and a period of around 170&#x2009;days. Although it is uncertain whether this exosatellite will fulfil the presently undefined criteria for qualifying as an exomoon, it is a marked step towards that first uncontroversial detection, as advancing technology will allow the same method to be applied to less massive targets.

Polymorphonuclear (PMN) leukocyte recruitment to activated pulmonary endothelium is a central mechanism in acute respiratory distress syndrome (ARDS). This process is mediated by selectins and their counter-ligand, P-selectin glycoprotein ligand-1 (PSGL-1), encoded by SELPLG. Genetic variation in SELPLG has been associated with ARDS susceptibility, while disruption of PSGL-1/P-selectin interactions attenuates lung injury in preclinical models. Because inflammatory stimuli increase both SELPLG expression and circulating PSGL-1 levels, PSGL-1 represents a promising biomarker and therapeutic target. We sought to define the genetic determinants of plasma PSGL-1 levels and evaluate their causal relationships with key inflammatory and endothelial biomarkers. Genome-wide association study (GWAS) summary statistics for plasma PSGL-1 levels were obtained from the UK Biobank Pharma Proteomics Project (n = 35,571) and the SCALLOP consortium (n = 21,758 across 13 cohorts). Associated variants underwent functional annotation and in silico analyses to identify potential effects on protein structure and gene regulation. Bidirectional Mendelian randomization (MR) was performed using GWAS summary statistics for C-reactive protein (CRP), E-selectin, GlycA, and soluble intercellular adhesion molecule-1 (sICAM-1) to assess potential causal relationships with PSGL-1 levels. Multiple cis- and trans-acting loci were significantly associated with plasma PSGL-1 concentrations. Three coding SELPLG variants (rs201689859, rs74792300, and rs139943851) were predicted to alter PSGL-1 protein structure and were associated with lower circulating PSGL-1 levels. Four promoter variants (rs1420663, rs1833245, rs1420664, and rs8179110) were linked to altered transcriptional activity, including a potential effect of rs1420664 on hypoxia-inducible factor binding. Bidirectional MR demonstrated that genetically predicted CRP, E-selectin, GlycA, and sICAM-1 levels were associated with increased plasma PSGL-1 concentrations. Additional loci implicated pathways related to immune signaling, cell adhesion, and protein stability. Large-scale GWAS and Mendelian randomization analyses identified genetic variants that regulate plasma PSGL-1 levels and demonstrated causal links between inflammatory and endothelial biomarkers and PSGL-1 expression. These findings provide new insights into the genetic regulation of leukocyte trafficking pathways and support a role for PSGL-1 in inflammatory diseases, including ARDS, sepsis, and cardiovascular disorders.

Liquid water exists on the Earth and several other planetary bodies in our solar system. The chemical character of these aqueous reservoirs is central to evaluating their habitability. Here, we synthesize the chemical features of water reservoirs and their biological implications on the modern Earth. We then outline constraints on the evolutionary history of Earth's ocean chemistry and discuss its interplay with the biosphere. Furthermore, we examine the inferred chemical environments of water bodies on early Mars, dwarf planet Ceres, Jupiter's moon Europa and Saturn's moons Enceladus and Titan. We conclude by outlining priority questions for future planetary habitability studies.

Reconstructing 3D molecular volumes from sparsely sampled 2D tissue sections is limited by per-section marker dropout and tissue loss. We present 3D-Omics-Flow, a generative pipeline that jointly repairs damaged sections and interpolates between them at single-cell resolution. Across datasets spanning health and disease, 3D-Omics-Flow expands 3D spatial proteomics to practical sampling regimes, enabling atlas construction and downstream analysis from imperfect 2D section stacks.

We describe the physical processes that affect the formation, trapping, and outgassing of O2 at Europa and Ganymede. Following Voyager measurements of their ambient magnetospheric plasmas, laboratory data indicated that the observed ions, which were mostly ejected from volcanic Io, would in turn impact and sputter their surfaces. This would decompose the ice and produce thin oxygen atmospheres. More than a decade later, Europa's O2 atmosphere was inferred from observations of the O aurora, and "condensed" O2 bands were observed in Ganymede's icy surface at 5773 and 6275 &#xc5;. More than another decade later, their atmospheres were shown to have a dusk/dawn enhancement, confirmed by recent Juno data. Although the incident plasma produces these observables, processes that occur within the topmost surface are still not well understood. Here, we note that the incident plasma particles produce a nonequilibrium defect density locally in the surface ice grains. Defect diffusion within these grains leads to the formation of voids and molecular products, some of which are volatile. Although some volatiles are released into the satellite atmospheres, others are trapped at defect sites or trapped in voids, which create gas bubbles whose lifetimes (in steady state) are limited by the plasma-induced destruction rate. Here, we discuss how trapping competes with the annealing of the radiation damage. We describe the differences observed at Europa and Ganymede and roughly determine the observed trend with latitude of O2 bands observed on Ganymede's trailing hemisphere. This understanding is used to discuss the relative importance of "condensed" O2 and O2 adsorbed on regolith grains as atmospheric sources, accounting for dusk/dawn enhancements and temporal variability reported in "condensed" O2 band depths. Since plasma-induced damage and thermal annealing timescales drive oxidant variability on icy moons (likely also Callisto, Dione, and Rhea), they can help determine volatile downwelling, a potentially metabolic source for their oceans, and upwelling of other trapped oxidants (e.g., CO2), suggestive of ongoing geologic activity.

Background/Objectives: Methamphetamine (meth) use disorder (MUD) continues to pose a significant public health challenge, and there are currently no FDA-approved pharmacological treatments available. Compounds that simultaneously activate nociceptin opioid peptide (NOP) and mu opioid receptors offer a promising therapeutic approach for substance use disorders, including psychostimulant addiction. Methods: We evaluated two mixed NOP/mu receptor agonists for their ability to reduce meth intake using a translational drug-versus-food choice self-administration paradigm in male and female Sprague-Dawley rats. In addition, both compounds were tested in female rats for their effects on cue- and priming-induced reinstatement of meth-seeking behavior, established preclinical models of relapse. Results: PPL-138 and PPL-143 are structurally related bifunctional NOP/mu partial agonists that exhibit greater efficacy at NOP than at mu receptors, with PPL-143 showing the highest NOP efficacy. In behavioral assays, both compounds significantly reduced meth self-administration in male rats and exhibited comparable potency in this effect. In female rats, however, PPL-143 was less effective than PPL-138 in reducing meth intake. In reinstatement models, PPL-138, but not PPL-143, attenuated prime-induced reinstatement of meth seeking, whereas both compounds produced comparable increases in meth seeking in the cue-induced reinstatement paradigm. Additional findings indicated that PPL-138 enhanced meth-induced locomotor activation. Conclusions: The findings support mixed mu/NOP partial agonists as a promising pharmacological strategy for treating MUD, while also indicating a potential for increased drug seeking under certain conditions. Notably, enhancing the NOP component does not appear to meaningfully improve either the safety profile or the anti-meth efficacy of these bifunctional ligands.