Recent ucsdsom items

ADVERSE CHILDHOOD EXPERIENCES (ACES): IMPLICATIONS FOR PHYSICAL, COGNITIVE, AND FUNCTIONAL IMPAIRMENT IN A NATIONAL SAMPLE OF OLDER COMMUNITY-DWELLING ADULTS

Thu, 5 Nov 2026 00:00:00 +0000

ADVERSE CHILDHOOD EXPERIENCES (ACES): IMPLICATIONS FOR PHYSICAL, COGNITIVE, AND FUNCTIONAL IMPAIRMENT IN A NATIONAL SAMPLE OF OLDER COMMUNITY-DWELLING ADULTS

Creatine induced Mania? Recurrent mania temporally associated with creatine supplementation - a case report

Thu, 5 Nov 2026 00:00:00 +0000

Mania is a defining feature of bipolar disorder, although its pathophysiology remains incompletely understood. Multiple substances are known to precipitate mania in susceptible individuals. Here we describe the case of a 22-year-old male with no prior psychiatric history, who was hospitalized due to mania three times within four months. Each relapse corresponded to either increasing or restarting creatine supplementation. The patient met DSM-5-TR criteria for bipolar I disorder. However, the full and rapid recovery with each episode, similar symptoms in a first-degree relative that resolved on cessation, and the consistent temporal relationship with creatine supplementation raise the possibility that creatine contributed to precipitating these symptoms. Causality was rated as probable on the Naranjo Adverse Drug Reaction Probability Scale. This case suggests a possible link between creatine supplementation and mania. It also highlights the importance of screening for supplement...

The Evolution of Modern Combat Orthopaedic Care From Clinical Investigation to Battlefield Application: Three Decades of Research to Decrease Morbidity and Mortality.

Thu, 5 Nov 2026 00:00:00 +0000

Over 52,000 US service members were wounded in the wars in Iraq and Afghanistan over two decades of war. These years also witnessed a continued evolution in the treatment of polytraumatized patients, especially those injured in combat. Because most of those wounded in action sustain musculoskeletal injuries, providing skilled treatment as soon as possible after injury has saved the lives of numerous service members and improved the musculoskeletal function of those injured in these conflicts. Orthopaedic surgeons have been crucial members of forward surgical teams that have performed life and limb-saving care under challenging forward-deployed conditions, sometimes under fire. In this setting, military orthopaedic surgery has continued to evolve, building in part on experience gained in smaller conflicts where the United States was not a principal belligerent but where war trauma familiarity was acquired that contributed to improvements in forward orthopaedic care during the recent...

Restoration of PP2A AαB56αC trimer formation by RPT04402 molecular glue in high-grade uterine cancer

Thu, 5 Nov 2026 00:00:00 +0000

The incidence and mortality of high-grade endometrial cancers are increasing, and heterozygous hotspot mutations in PPP2R1A are drivers of the most aggressive forms of uterine cancer. PPP2R1A encodes the Aα scaffolding subunit of the heterotrimeric phosphatase PP2A. These recurrent mutations, specifically at the Pro¹⁷⁹ and Ser²⁵⁶ residues, disrupt the binding of tumor-suppressive substrate-directing B56 and B55 subunits to the PP2A scaffolding subunit while maintaining binding to other regulatory subunits. Here, we identified a series of molecular glues that correct PP2A trimer formation in the context of the P179R (Pro¹⁷⁹→Arg) and S256F (Ser²⁵⁶→Phe) mutants. A small-molecule library was designed to fit into the pocket at the binding interface of the Aα/B56α/C heterotrimer. The lead molecule, RPT04402, promoted B56α heterotrimerization to the Aα^P179R and Aα^S256F mutant scaffolds. In mice, RPT04402...

Editorial: The spectrum of eating behaviours in athletes: health and performance consequences

Thu, 5 Nov 2026 00:00:00 +0000

Editorial: The spectrum of eating behaviours in athletes: health and performance consequences

PB2247 Multicenter Validation of a Pediatric Hospital-Wide Venous Thromboembolism Risk Assessment Model: A Children's Healthcare Advancements in Thrombosis (CHAT) Study

Thu, 5 Nov 2026 00:00:00 +0000

PB2247 Multicenter Validation of a Pediatric Hospital-Wide Venous Thromboembolism Risk Assessment Model: A Children's Healthcare Advancements in Thrombosis (CHAT) Study

The VIVA‐MIND study: Topline Results from Phase 2 RCT of Varoglutamstat in Early AD

Fri, 30 Oct 2026 00:00:00 +0000

AbstractBackground

Varoglutamstat (PQ912) is an oral small molecule inhibitor of glutaminyl cyclases which reduces the pyroglutamate formation of Aβ and CCL2. Preclinical and Ph1 trials support this Ph2 evaluation in early AD. Our objectives included selecting the highest safe and well‐tolerated dose of varoglutamstat with futility analysis at 24 weeks (Ph2A) followed by seamless evaluation of longer‐term safety and efficacy at 72 weeks at this dose (Ph2B).

Method

Participants with biomarker confirmed early AD were randomized to varoglutamstat or placebo. A sequential design tested 3 descending doses (600mg, 300mg, 150mg BID) using a continuous Pocock safety boundary. A Stage Gate futility analysis of the first 180 subjects at 24 weeks was designed to guide the decision from Ph2A‐B (Figure 1). The Ph2B primary endpoint was CDR‐sum‐of‐boxes (CDR‐SB), with secondary endpoints CFC2, ABC score, spectral EEG, FAQ, ADAS‐Cog‐13, and NPI.

Result

Table 1 presents baseline characteristics...

Improving Apheresis Inlet Flow With a Novel Double‐Draw Vascular Access Technique

Thu, 29 Oct 2026 00:00:00 +0000

Peripheral intravenous catheters (PIVCs) are the preferred vascular access for apheresis; however, veins that initially appear suitable may develop venous spasms, resulting in poor inlet flow and frequent pressure alarms. Ports used for apheresis can also experience inlet pressure alarms due to catheter or venous occlusion. When conservative measures failed, we implemented a novel double-draw technique in which a second draw line was connected via a four-way stopcock and male-to-male adapter to the initial draw access (either a PIVC or port) to improve inlet flow. The double-draw technique was performed in 26 procedures (therapeutic plasma exchange [TPE], n = 10 and lipoprotein apheresis [LA], n = 16) in 8 patients. During TPE, median negative inlet pressure improved from -179 mmHg (IQR -218 to -69) with single-draw access to -71 mmHg (IQR -78 to -62) following placement of a second draw line (p = 0.0162). Inlet flow rate during TPE improved from median 47 mL/min (IQR, 40-58 mL/min)...

GZMK⁺CD8⁺ T Cells Induce Acinar Cell Senescence and Salivary Secretion Impairment in Sjögren's Syndrome via Mitochondrial Dysfunction and TMEM16A Chloride Channel Disruption

Tue, 27 Oct 2026 00:00:00 +0000

Immune cell-mediated damage to acinar cells plays a central role in Sjögren's syndrome (SS) pathogenesis, with T-cell recruitment being critical in the early stages. In this study, single-cell RNA sequencing was employed to generate transcriptomic profiles of labial gland tissues from SS patients, focusing on GZMK⁺CD8⁺ T cells and their correlation with SS clinical pathology. The role of GZMK⁺CD8⁺ T cells in inducing acinar cell senescence and secretory dysfunction was investigated by co-culturing SMG-C6 acinar cells with GZMK⁺CD8⁺ T cells and recombinant granzyme K. Mechanistically, GZMK induces oxidative stress and mitochondrial dysfunction, thereby promoting senescent phenotypes in acinar cells. Additionally, GZMK-mediated downregulation of TMEM16A contributes to reduced chloride transport and salivary secretion dysfunction. This study provides novel insights into the immune-epithelial crosstalk in SS progression by revealing the relationship between GZMK⁺CD8⁺ T cells and...

Clinical characteristics, type 2 comorbidities, and treatment responses in pediatric and adult chronic spontaneous urticaria: A multicenter retrospective cohort study.

Mon, 26 Oct 2026 00:00:00 +0000

Background: Chronic spontaneous urticaria (CSU) presents with unpredictable, often debilitating symptoms, yet detailed clinical characterization, particularly in pediatric populations, remains limited. Improved understanding of clinical profiles and comorbidities may guide management strategies. Objective: The objective was to characterize clinical presentation, comorbid type 2 inflammatory diseases, and treatment responses in a large cohort of pediatric and adult patients with CSU across multiple allergy practices. Methods: A retrospective observational cohort study was conducted across four U.S. allergy clinics, including two pediatric- and two adult-focused practices. Medical records of 400 patients with CSU (189 pediatric patients, 211 adults) with ≥ 6 months of follow-up between 2013 and 2023 were reviewed for demographic data, comorbidities, clinical presentation, clinician-documented disease severity, and treatment outcomes. Results: Disease...

Atopic Comorbidities Associated With Chronic Spontaneous Urticaria: A Case‐Control Analysis of the All of Us Research Program

Mon, 26 Oct 2026 00:00:00 +0000

Background: Chronic spontaneous urticaria (CSU) is a mast cell-driven condition defined by recurrent wheals and/or angioedema lasting over 6 weeks without an identifiable trigger. Though CSU is known to co-occur with atopic diseases and share Th2-dominant immunologic pathways, prior studies have not adequately addressed these relationships in diverse populations. Objectives: To examine associations between CSU and atopic comorbidities in the All of Us (AoU) research program, a diverse, nationwide National Institutes of Health cohort focused on increasing enrollment from historically underrepresented groups. Methods: We conducted a matched, case-control study of AoU participants aged ≧ 18 years enrolled between May 6, 2018 and October 1, 2023. CSU cases were identified using SNOMED codes 51611005 and 42265009. Controls were matched 4:1 by age, sex, race, ethnicity, and smoking status. We compared rates of atopic dermatitis, allergic rhinitis, asthma, nasal polyps, food allergy,...

029 Etanercept Monotherapy in Reactive Infectious Mucocutaneous Eruption - A Case Series

Mon, 26 Oct 2026 00:00:00 +0000

Reactive infectious mucocutaneous eruption (RIME) is a mucocutaneous blistering eruption that frequently follows a respiratory infection. Treatment with immunomodulatory therapies have been used, and emerging evidence supports the use of etanercept, a TNF-alpha inhibitor. This multi-center case series evaluates the use of etanercept monotherapy in pediatric RIME. This IRB exempt case-series collected deidentified data across four institutions. Patients ages 0-17 years with a confirmed diagnosis of RIME and treatment with etanercept monotherapy were included. Ten patients met inclusion criteria. Median age was 14 years (10-months to 16-years), and 90% were male. All patients had oral involvement, 80% ocular, 70% genital, and 20% anal with minimal cutaneous involvement (median 0%; 0%-4%). The most common suspected trigger was Mycoplasma pneumoniae (60%). Etanercept was initiated a median of 5-days after mucocutaneous symptoms started and 2-days after admission with 60% receiving...

Scalp-specific outcomes in psoriasis: A review of systemic therapies

Mon, 26 Oct 2026 00:00:00 +0000

Scalp-specific outcomes in psoriasis: A review of systemic therapies

Apalutamide-induced drug reaction with eosinophilia and systemic symptoms and Stevens-Johnson syndrome overlap successfully treated with cyclosporine and benralizumab: a case report and literature review

Mon, 26 Oct 2026 00:00:00 +0000

Apalutamide-induced drug reaction with eosinophilia and systemic symptoms and Stevens-Johnson syndrome overlap successfully treated with cyclosporine and benralizumab: a case report and literature review

Combination of ATLAS and CMS Searches for Higgs Boson Pair Production at s=13 TeV

Mon, 26 Oct 2026 00:00:00 +0000

This Letter presents a combination of searches for Higgs boson pair (HH) production performed by the ATLAS and CMS Collaborations using proton-proton collision datasets recorded at sqrt[s]=13 TeV during the Large Hadron Collider Run 2, corresponding to integrated luminosities ranging between 126 and 140 fb^{-1}. The upper limit at the 95% confidence level on the total HH signal strength, defined as the ratio of the measured cross section to the standard model (SM) prediction, corresponds to 2.5, with an expected value of 1.7 (2.8) assuming the absence (presence) of the SM HH signal. The strength of the HH signal is measured to be 0.8_{-0.7}^{+0.9} relative to the SM prediction. The observed significance is found to be 1.1 standard deviations whereas 1.3 are expected for the SM HH signal. Constraints are set on the Higgs boson trilinear self-coupling and on the couplings of two Higgs bosons to two vector bosons, both normalized to the SM predictions and denoted as κ_{λ} and κ_{2V},...

B cells regulate T cell transfer colitis by partially reconstituting luminal IgA and modulating the colonic microbiota

Thu, 22 Oct 2026 00:00:00 +0000

Loss of immune tolerance to commensal microbial antigens is a central driver of inflammatory bowel disease. While regulatory T cells are well recognized in maintaining intestinal homeostasis, the contribution of B cells-particularly IgA-secreting cells-remains incompletely defined. In the T cell transfer colitis model, cotransfer of splenic B cells attenuates disease, an effect largely attributed to IL-10-producing regulatory B cells (Bregs). However, alternative B cell-dependent mechanisms have not been fully explored. Here, we investigated whether splenic B cells regulate T cell transfer colitis through IgA-dependent mechanisms independent of Breg-associated cytokines. We show that splenic B cells from wild-type C57BL/6 (B6) mice reconstitute bone marrow and peripheral B cell compartments in RAG1⁻/⁻ recipients, undergo class switching, migrate to the colonic lamina propria as sIgA⁺ B lineage cells, and partially restore luminal secretory IgA. B cell cotransfer significantly...

Innovating for Impact: Participant, Clinical, Educational, and Research Lessons Learned From the Course and Outcome of Bipolar Youth (COBY) Study

Thu, 22 Oct 2026 00:00:00 +0000

Innovating for Impact: Participant, Clinical, Educational, and Research Lessons Learned From the Course and Outcome of Bipolar Youth (COBY) Study

Identifying the window of aggressive postpartum breast cancer based on the 21-gene Oncotype DX® test in women with HR+, HER2-negative breast cancer

Thu, 22 Oct 2026 00:00:00 +0000

Postpartum breast cancer (PPBC) is associated with worse outcomes in young women with breast cancer and demonstrates distinct transcriptomic features, yet a temporal definition based on gene expression has not been established. We conducted a single-institution retrospective cohort study to evaluate the impact of postpartum status on the 21-gene Oncotype DX Recurrence Score® (RS) in hormone receptor-positive, HER2-negative young women with breast cancer. Among 385 patients, 153 were nulliparous, 62 were more than 10 years postpartum, and 170 were within 10 years postpartum. Diagnosis within one year of childbirth was associated with a 13.2-point higher RS compared with nulliparous patients (p < 0.001). Defining PPBC as within 3 years postpartum was associated with increased odds of RS category shift (OR 2.83, p = 0.001). In the context of contemporary adjuvant treatment, with patients diagnosed within three years postpartum more likely to receive chemotherapy, ovarian function...

Reln Haploinsufficiency Enhances Fentanyl‐Induced Locomotion and Dorsal Striatal Activity Without Affecting Opioid Reinforcement and Relapse‐Like Behavior

Thu, 22 Oct 2026 00:00:00 +0000

The Reln gene encodes the extracellular glycoprotein Reelin that regulates synaptic plasticity and activity-dependent gene expression with implication in several neuropsychiatric disorders, including substance use disorder. Although reduction of Reln expression has been associated with altered responses to psychostimulants and cannabinoids, its role in opioid-evoked behaviors has not been investigated. Here, we tested whether Reln haploinsufficiency alters behavioral and molecular responses to the synthetic opioid fentanyl. Heterozygous Reeler (Reln+/-) mice and wild-type littermates were assessed using complementary contingent and non-contingent models of fentanyl exposure, including multi-phase fentanyl intravenous self-administration paradigm, conditioned place preference paradigm, locomotor assays, and dorsal striatal immediate early gene expression. Reln haploinsufficiency did not alter acquisition, extinction, or cue-induced fentanyl seeking during self-administration, indicating...

Predicting Oral HIV Pre‐Exposure Prophylaxis Efficacy in Cisgender Women Across Pregnancy and Postpartum

Thu, 22 Oct 2026 00:00:00 +0000

Cisgender women face an increased risk of HIV acquisition during pregnancy and postpartum. Oral pre-exposure prophylaxis (PrEP) with emtricitabine and tenofovir disoproxil fumarate (F/TDF) is recommended in pregnancy despite limited published pharmacokinetic (PK) and efficacy data during pregnancy. Altered PK during pregnancy may reduce prophylactic efficacy and necessitate higher adherence. Tenofovir alafenamide (TAF) is a newer tenofovir prodrug with higher tenofovir diphosphate (TFV-DP) exposure in peripheral blood mononuclear cells (PBMCs), but the prophylactic efficacy of F/TAF across different reproductive stages in women is understudied. We adapted a multiscale modeling framework to predict the prophylactic efficacy of F/TDF and F/TAF across varying adherence levels and during the second trimester, third trimester, and 6-12 weeks postpartum. Clinical trial simulations were conducted utilizing PBMC TFV-DP and emtricitabine triphosphate concentrations as surrogate markers...

Applying a Health Equity Lens to Pediatric Neurology Research: Lessons Learned From an Educational Workshop.

Wed, 21 Oct 2026 00:00:00 +0000

Health disparities are increasingly important considerations in clinical practice and public health initiatives. Health disparities and health equity research methods are under-utilized in research design, analysis, and dissemination in pediatric neurology. This article highlights our collective experience in organizing a 1-hour workshop on "Applying a Health Equity Lens to Pediatric Neurology Research" at the 54th Annual Child Neurology Society Meeting. The topics covered included (1) use of theories, models, and frameworks from dissemination and implementation science for health equity; (2) community engagement and qualitative research methods in health equity research; (3) recruitment of representative populations in research studies; (4) social determinants of health, data collection tools, and indices used in research; and (5) integrating health equity research into a research career. This article describes session content and summarizes participant survey data. It also provides...

Implementing a curriculum for Lifestyle Medicine application activities in a family medicine residency program

Wed, 14 Oct 2026 00:00:00 +0000

Implementing a curriculum for Lifestyle Medicine application activities in a family medicine residency program

Impact of OMT for Migraines After Concussion

Wed, 14 Oct 2026 00:00:00 +0000

Impact of OMT for Migraines After Concussion

Evaluating Efficiency Improvement Initiatives in a Multispecialty Academic Group Practice

Wed, 14 Oct 2026 00:00:00 +0000

Evaluating Efficiency Improvement Initiatives in a Multispecialty Academic Group Practice

Male athlete with right hip pain after fall

Wed, 14 Oct 2026 00:00:00 +0000

Male athlete with right hip pain after fall

Factors Associated with Colorectal Cancer Screening Knowledge and Practices among Primary Care Clinicians in Academic and Community Practices

Tue, 13 Oct 2026 00:00:00 +0000

Factors Associated with Colorectal Cancer Screening Knowledge and Practices among Primary Care Clinicians in Academic and Community Practices

Learning to Pause and Reflect: Contributions of Artificial Intelligence and Standardized Patients in Reflective Dialogue Practice in Primary Care

Tue, 13 Oct 2026 00:00:00 +0000

Learning to Pause and Reflect: Contributions of Artificial Intelligence and Standardized Patients in Reflective Dialogue Practice in Primary Care

Pilot Study: Feasibility of a Whole-Food, Plant-Based Dietary Intervention for Patients with Low-Risk Chronic Lymphocytic Leukemia

Tue, 13 Oct 2026 00:00:00 +0000

Pilot Study: Feasibility of a Whole-Food, Plant-Based Dietary Intervention for Patients with Low-Risk Chronic Lymphocytic Leukemia

Why the Wobble? Cracking the Case of Knee Swelling and Limp in a Young Patient

Tue, 13 Oct 2026 00:00:00 +0000

Why the Wobble? Cracking the Case of Knee Swelling and Limp in a Young Patient

Enhancing Prenatal Care and Resident Learning Through Structured Obstetrics Chart Review

Tue, 13 Oct 2026 00:00:00 +0000

Enhancing Prenatal Care and Resident Learning Through Structured Obstetrics Chart Review

Demographic Changes of Free Clinic Patients After Medi-Cal Older Adult Eligibility Expansion

Tue, 13 Oct 2026 00:00:00 +0000

Demographic Changes of Free Clinic Patients After Medi-Cal Older Adult Eligibility Expansion

Can a Choosing Wisely-based educational intervention improve inpatient medical decision-making confidence and clinical accuracy among family medicine residents?

Tue, 13 Oct 2026 00:00:00 +0000

Can a Choosing Wisely-based educational intervention improve inpatient medical decision-making confidence and clinical accuracy among family medicine residents?

Assessing Efficacy of the Psychiatric Component of a Collaborative Care Program at a Family Medicine Clinic

Tue, 13 Oct 2026 00:00:00 +0000

Assessing Efficacy of the Psychiatric Component of a Collaborative Care Program at a Family Medicine Clinic

An Unusual Case of Mastoiditis Presenting as Pulsatile Tinnitus

Tue, 13 Oct 2026 00:00:00 +0000

An Unusual Case of Mastoiditis Presenting as Pulsatile Tinnitus

Automated Draft Replies for Patient Messages: Learnings After One Year

Tue, 13 Oct 2026 00:00:00 +0000

Automated Draft Replies for Patient Messages: Learnings After One Year

Facilitating End-of-Life Care Decision Making by Summarizing Goals of Care Notes by Large Language Models

Tue, 13 Oct 2026 00:00:00 +0000

Facilitating End-of-Life Care Decision Making by Summarizing Goals of Care Notes by Large Language Models

Improving Substance Use Treatment in Family Medicine Clinics

Tue, 13 Oct 2026 00:00:00 +0000

Improving Substance Use Treatment in Family Medicine Clinics

Cardio-Cognitive Coherence | A Team-Based Clinical Mini-Application

Tue, 13 Oct 2026 00:00:00 +0000

Cardio-Cognitive Coherence | A Team-Based Clinical Mini-Application

Fentanyl knowledge, attitudes, and safer usage strategies among people who use drugs in the San Diego/Tijuana border region

Tue, 13 Oct 2026 00:00:00 +0000

Fentanyl knowledge, attitudes, and safer usage strategies among people who use drugs in the San Diego/Tijuana border region

Pilocytic astrocytoma presenting as unilateral torsional nystagmus

Tue, 13 Oct 2026 00:00:00 +0000

Pilocytic astrocytoma presenting as unilateral torsional nystagmus

Volumetric mapping of total, bound and pore water as well as collagen protons in cortical bone using 3D ultrashort echo time (UTE) MR imaging techniques allows accurate diagnosis of osteopenia and osteoporosis

Sun, 11 Oct 2026 00:00:00 +0000

Volumetric mapping of total, bound and pore water as well as collagen protons in cortical bone using 3D ultrashort echo time (UTE) MR imaging techniques allows accurate diagnosis of osteopenia and osteoporosis

Ultrashort echo time magnetization transfer imaging of myelin in APP knock-in mice

Sun, 11 Oct 2026 00:00:00 +0000

PURPOSE: Myelin integrity is increasingly recognized as a potential factor in Alzheimer's disease (AD) pathology, making accurate quantification of myelin essential for elucidating its role in the progression of the disease. This study aims to evaluate the potential of ultrashort echo time magnetization transfer (UTE-MT) imaging for assessing myelin-related alterations in an APP knock-in mouse model of AD (hereafter referred to as APPKI mice). METHOD: Eighteen APPKI mice (∼14 months; 9 females/9 males) and fourteen age-matched wild-type C57BL/6 (WT) (8 females/6 males) were scanned on a 3T Bruker scanner. Two sets of UTE-MT data (TR=80 ms, TE=0.026 ms) were acquired with an MT pulse power of 1500° (θ=1500°) and frequency offset of 2 kHz (Δf = 2 kHz) (MT_on), and with θ=500° and Δf = 50 kHz (MT_off), respectively. UTE-MT ratio (UTE-MTR) maps, calculated as (MT_off - MT_on)/MT_off, were generated for comparing APPKI and WT mice....

Quantitative ultrashort echo time (UTE) magnetic resonance imaging of femoral trabecular bone in aging and osteoporosis

Sun, 11 Oct 2026 00:00:00 +0000

ObjectiveTo evaluate quantitative ultrashort echo time (UTE) magnetic resonance imaging (MRI) biomarkers, pore-to-matrix ratio (PMR), and matrix index (MI) for assessing trabecular bone in the proximal femur across aging and osteoporosis-related bone status.Materials and methodsIn this prospective study, 92 female subjects (20–83 years) were classified into four groups based on age and DXA-derived T-scores: Young Normal (n = 19), Old Normal (n = 14), Osteopenia (n = 44), and Osteoporosis (n = 15). All participants underwent 3-T hip MRI using 3D dual-echo proton-density-weighted UTE (PD-UTE) and short TR adiabatic inversion recovery UTE (STAIR-UTE) sequences. Measurements were performed in the femoral head and neck by two readers. Interobserver agreement was assessed via intraclass correlation coefficients (ICC). Group differences were analyzed with the Kruskal–Wallis test and Holm-adjusted post hoc tests. Spearman correlation analysis and receiver operating characteristic (ROC)...

Therapeutic Efficacy of NSI-189 against Diabetic Neuropathy and Encephalopathy in Mice

Fri, 9 Oct 2026 00:00:00 +0000

Therapeutic Efficacy of NSI-189 against Diabetic Neuropathy and Encephalopathy in Mice

Murine model and mechanisms of treatment-induced painful diabetic neuropathy

Fri, 9 Oct 2026 00:00:00 +0000

Diabetes mellitus represents a group of metabolic diseases that are characterized by hyperglycemia caused by either lack of insulin production or a reduced ability to respond to insulin. It is estimated that there were 347 million people worldwide who suffered from diabetes in 2008 and incidence is predicted to double by 2050. Neuropathy is the most common complication of long-term diabetes and approximately 30% of these subjects develop chronic neuropathic pain. A distinct acute, severe form of neuropathic pain, called insulin neuritis or treatment-induced painful neuropathy of diabetes (TIND), may also occur shortly after initiation of intensive glycemic control, with an incidence rate of up to 10.9%. The pathological mechanisms leading to TIND, which is mostly unresponsive to analgesics, are not yet understood, impeding the development of therapies. Studies to date have been clinical and with limited cohorts of patients. In the current study, we developed chronic and acute...

Targeting Ribonucleotide Reductase Induces Synthetic Lethality in PP2A-Deficient Uterine Serous CarcinomaTargeting RNR Induces Synthetic Lethality in USC

Fri, 9 Oct 2026 00:00:00 +0000

Uterine serous carcinoma (USC) is a highly aggressive endometrial cancer subtype with limited therapeutic options and a lack of targeted therapies. While mutations to PPP2R1A, which encodes the predominant protein phosphatase 2A (PP2A) scaffolding protein Aα, occur in 30% to 40% of USC cases, the clinical actionability of these mutations has not been studied. Using a high-throughput screening approach, we showed that mutations in Aα results in synthetic lethality following treatment with inhibitors of ribonucleotide reductase (RNR). In vivo, multiple models of Aα mutant uterine serous tumors were sensitive to clofarabine, an RNR inhibitor (RNRi). Aα-mutant cells displayed impaired checkpoint signaling upon RNRi treatment and subsequently accumulated more DNA damage than wild-type (WT) cells. Consistently, inhibition of PP2A activity using LB-100, a catalytic inhibitor, sensitized WT USC cells to RNRi. Analysis of The Cancer Genome Atlas data indicated that inactivation of PP2A,...

Redundant mispair excision mechanisms in eukaryotic DNA mismatch repair.

Fri, 9 Oct 2026 00:00:00 +0000

DNA mismatch repair (MMR) corrects DNA replication errors, some forms of chemical damage to DNA bases, and acts in processes such as heteroduplex rejection, triplet repeat expansion, antibody maturation and cytotoxicity of alkylating agents. During MMR, the newly synthesized DNA strand containing the error must be removed and resynthesized to prevent mutations. In bacteria, this strand is displaced by the UvrD DNA helicase. In eukaryotes, this strand is excised by redundant pathways. In the first excision pathway identified, Saccharomyces cerevisiae Msh2-Msh6 (or Msh2-Msh3) and/or Mlh1-Pms1 (human MLH1-PMS2) recruit Exo1 to 5' nicks, and 5'-to-3' excision by Exo1 excises the daughter strand containing the mispair to generate a single-stranded gap. The Mlh1-Pms1 endonuclease also mediates excision through extensive nicking of the daughter strand to generate single-stranded gaps. In coupled strand-displacement synthesis coordinated by Msh2-Msh6 (or Msh2-Msh3), DNA polymerase delta...

DNA mismatch repair mediated by Mlh1–Pms1 endonuclease-catalyzed mispair excision

Fri, 9 Oct 2026 00:00:00 +0000

Eukaryotic DNA mismatch repair (MMR) involves several excision pathways, including those mediated by exonuclease 1 (Exo1) and by the flap endonuclease Rad27 (human FEN1) coupled with DNA polymerase δ. Simultaneous inactivation of both excision mechanisms causes an MMR defect that is at most 5 to 13% of that caused by complete inactivation of MMR. Here, we reconstituted nicked-strand-specific MMR with the Saccharomyces cerevisiae proteins Msh2-Msh6 or Msh2-Msh3, DNA polymerase ε, RFC, PCNA, RPA, and Mlh1-Pms1 (human Mlh1-Pms2) under conditions lacking Exo1, Rad27, or strand-displacement synthesis by DNA polymerase δ. These reactions required the Mlh1-Pms1 endonuclease activity, its activation by RFC and PCNA, and its recruitment by Msh2-Msh6 or Msh2-Msh3. MMR was mediated by nicked-strand-specific excision by Mlh1-Pms1 through formation of single-strand DNA gaps having a broad range of sizes. This reaction is consistent with genetic data demonstrating redundancy between...

Time-resolved functional genomics using deep learning reveals global hierarchical control of autophagy

Fri, 9 Oct 2026 00:00:00 +0000

Recycling of cellular components through autophagy maintains homeostasis in changing nutrient environments. Although its core mechanisms are extensively studied, understanding of its systems-wide dynamic regulation remains limited, particularly regarding how autophagy is inactivated once nutrients are restored. Here we mapped the genetic network that controls activation and inactivation of autophagy during nitrogen changes by combining time-resolved high-content imaging, deep learning and latent feature analysis. This dataset, termed AutoDRY, categorizes 5,919 mutants based on nutrient response kinetics and their contributions to autophagosome formation and clearance. Integrating these profiles with functional and genetic network data uncovered hierarchical and multilayered control of autophagy and revealed multiple new regulatory pathways. Notably, we identified the retrograde pathway as a pivotal time-varying modulator that tunes the expression of core autophagy genes and plays...

Tumor FAK supports fibrillar collagen expression in ovarian cancer ascites

Fri, 9 Oct 2026 00:00:00 +0000

High-grade serous ovarian cancer (HGSOC) is a lethal malignancy where matrix proteins enhance ascites-associated recurrent tumor growth. Elevated focal adhesion kinase (FAK/PTK2) and collagen protein expression support tumor survival, chemoresistance, and immune evasion. However, the sources and regulation of collagen production within HGSOC tumorspheres is unclear. Using CRISPR-mediated FAK knockout and FAK re-expression in two syngeneic HGSOC models (MOVCAR and KMF), FAK loss impaired tumorsphere growth in vitro and in vivo while reducing collagen expression, as determined by RNA sequencing, quantitative RT-PCR, and protein mass spectrometry. FAK re-expression promoted spontaneous metastatic ovarian tumor dissemination. Integrated bioinformatic analyses of MOVCAR, KMF, and HGSOC patient datasets identified 56 common mRNAs co-elevated with PTK2, including COL3A1 and COL5A2. Single-cell RNA sequencing of murine KMF ascites revealed a subset of tumor cells expressing Col3a1 and...

Disarming cancer resistance: FAK as a therapeutic target

Fri, 9 Oct 2026 00:00:00 +0000

The FDA recently granted accelerated approval of the small-molecule focal adhesion kinase (FAK) inhibitor (FAKi, defactinib) in combination with a RAF-MEK clamp inhibitor (avutometinib) for KRAS-mutated low-grade serous ovarian cancer developed by Verastem Inc. This milestone moment represents a long journey in FAKi development, from initial findings of limited single-agent activity to orally delivered FAKi effects that can sensitize solid tumors to chemotherapy, radiotherapy, and immunotherapy treatments. In this study, we review a short history of FAK, summarize ongoing combinatorial clinical trials, discuss potential mechanisms of action, and highlight studies showing that FAK activation is a chemo- and mechano-sensitive signaling hub driving tumor adaptive changes. Targeting FAK disarms tumor resistance through multiple mechanisms, which supports new biological insights and future clinical combinations.

Pirenzepine Reverses Chemotherapy-Induced Peripheral Neuropathy in Mice

Fri, 9 Oct 2026 00:00:00 +0000

Background/Objectives: Mitochondrial dysfunction is a common feature of many peripheral neuropathies and agents that enhance mitochondrial function have potential as pan-neuropathy therapeutics. M1 receptor (M1R) antagonists enhance mitochondrial function and reverse multiple indices of neuropathy in rodents and humans with diabetic neuropathy. The present studies extend evaluation of the M1R-selective antagonist pirenzepine to mouse models of chemotherapy-induced peripheral neuropathy (CIPN), with a primary focus on pain relief. Results: Oxaliplatin-exposed mice developed allodynia to light touch that persisted for months before resolution. Systemic pirenzepine (1 mg/kg/day) starting prior to chemotherapy did not prevent allodynia but accelerated recovery. Topical delivery (4% pirenzepine in hydrogel) to the paw, beginning after onset of allodynia, also accelerated recovery, with efficacy persisting weeks after treatment cessation and accompanied by normalization of paw responses...

Topical Delivery of Muscarinic Receptor Antagonists Prevents and Reverses Indices of Neuropathy in Mouse Models of Type 1 and Type 2 Diabetes

Fri, 9 Oct 2026 00:00:00 +0000

Topical Delivery of Muscarinic Receptor Antagonists Prevents and Reverses Indices of Neuropathy in Mouse Models of Type 1 and Type 2 Diabetes

Mutant PP2A Induces IGFBP2 Secretion to Promote Development of High-Grade : Uterine Cancer

Fri, 9 Oct 2026 00:00:00 +0000

Uterine serous carcinoma (USC) and uterine carcinosarcoma (UCS) tumors are uniquely aggressive, suggesting that the primary tumor is intrinsically equipped to disseminate and metastasize. Previous work identified mutational hotspots within PPP2R1A, which encodes the Aα scaffolding subunit of protein phosphatase 2A (PP2A), a heterotrimeric serine/threonine phosphatase. Two recurrent heterozygous PPP2R1A mutations, P179R and S256F, occur exclusively within high-grade subtypes of uterine cancer and can drive tumorigenesis and metastasis. Elucidation of the mechanisms by which PP2A Aα mutants promote tumor development and progression could help identify therapeutic opportunities. Here, we showed that expression of these mutants in USC/UCS cell lines enhanced tumor-initiating capacity, drove a hybrid epithelial-to-mesenchymal plasticity phenotype, and elevated secretion of the tumorigenic cytokine insulin growth factor (IGF) binding protein 2 (IGFBP2). Therapeutic targeting of the...

Biased holoenzyme assembly of protein phosphatase 2A (PP2A): From cancer to small molecules

Fri, 9 Oct 2026 00:00:00 +0000

Protein phosphatase 2A (PP2A) is a family of serine threonine phosphatases responsible for regulating protein phosphorylation, thus opposing the activity of cellular kinases. PP2A is composed of a catalytic subunit (PP2A Cα/β) and scaffolding subunit (PP2A Aα/β) and various substrate-directing B regulatory subunits. PP2A biogenesis is regulated at multiple levels. For example, the sequestration of the free catalytic subunit during the process of biogenesis avoids promiscuous phosphatase activity. Posttranslational modifications of PP2A C direct PP2A heterotrimeric formation. Additionally, PP2A functions as a haploinsufficient tumor suppressor, where attenuated PP2A enzymatic activity creates a permissive environment for oncogenic transformation. Recent work studying PP2A in cancer showed that its role in tumorigenesis is more nuanced, with some holoenzymes being tumor suppressive, while others are required for oncogenic transformation. In cancer biology, PP2A function...

Rare variants of DNA ligase 1 show distinct mechanisms of deficiency

Fri, 9 Oct 2026 00:00:00 +0000

Human DNA ligase 1 (LIG1) performs the final step in DNA repair and recombination pathways by sealing DNA breaks, and it functions as the main replicative ligase. Hypomorphic LIG1 variants R771W and R641L cause immune deficiencies in LIG1 Syndrome patients. In vitro these LIG1 variants have decreased catalytic efficiency and increased abortive ligation and it is not known if either biochemical defect is sufficient on its own to cause immune deficiency. We investigated the enzymatic activity of several new candidate LIG1 Syndrome variants chosen based on their structural proximity to known clinical variants, low minor allele frequency (MAF), high level of conservation, and concurrence in patients with similar symptoms as LIG1 Syndrome patients. The R305Q substitution is in the DNA binding domain, R768W is in the OB-fold domain, and R641S is in the nucleotidyltransferase domain. Biochemical characterization confirmed deficiencies in ligase activity for all three variants, but...

Author Correction: DREAM repressive activity links somatic mutation, lifespan and disease

Thu, 8 Oct 2026 00:00:00 +0000

Author Correction: DREAM repressive activity links somatic mutation, lifespan and disease

Divergent effects of hyperandrogenemia on the female reproductive neuroendocrine axis under different physiological conditions

Thu, 8 Oct 2026 00:00:00 +0000

The hypothalamic-pituitary-gonadal (HPG) axis coordinates reproductive function and incorporates gonadal sex steroid feedback to regulate gonadotropin secretion in a homeostatic manner. In females, ovarian estrogens and progestins act as the primary negative feedback signals to suppress luteinizing hormone (LH) release, whereas in males, androgens, such as testosterone (T), typically provide this feedback. However, androgens can also exert feedback effects on the female HPG axis, particularly in conditions where circulating T levels exceed that of the normal female physiological range. Three clinically relevant examples are anabolic substance abuse, testosterone therapy, and polycystic ovary syndrome (PCOS; recently renamed polyendocrine metabolic ovarian syndrome [PMOS]). Despite shared exposure to "androgen excess," these different hyperandrogenic states are associated with strikingly different neuroendocrine phenotypes. In testosterone therapy and anabolic substance abuse,...

TREM2⁺ tumor-associated macrophages in cancer: Context-dependent biology, biomarkers, and precision immunotherapy

Thu, 8 Oct 2026 00:00:00 +0000

Tumor-associated macrophages (TAMs) are abundant and functionally important components of the tumor microenvironment (TME), yet the molecular programs that distinguish pathogenic macrophage states from tissue-adaptive populations remain incompletely defined. Triggering receptor expressed on myeloid cells 2 (TREM2) has emerged as a key marker of specialized immunoregulatory macrophage states across multiple solid tumors. Accumulating evidence links TREM2⁺ macrophages to metabolic adaptation, immune evasion, and impaired antitumor immunity, although their biological functions vary substantially across tumor types, tissue niches, and disease settings. In this review, we synthesize current understanding of TREM2-associated immunobiology, including ligand recognition, signaling architecture, immunometabolic adaptation, and macrophage functional heterogeneity. We critically evaluate conflicting findings across tumor types and discuss how tissue context, macrophage ontogeny, and microenvironmental...

Phantom-based evaluation of time-SLIP MRI for measuring spinal-canal Lagrangian drift

Thu, 8 Oct 2026 00:00:00 +0000

The pulsatile motion of cerebrospinal fluid (CSF) in the spinal canal includes a mean Lagrangian drift, representing the cumulative net displacement experienced by the fluid over each oscillatory cycle. Quantifying this motion in vivo is challenging because the associated velocities ($$\sim $$cm min$$\vphantom{0}^{-1})$$are much smaller than those of the dominant oscillatory flow ($$\sim $$ cm s$$\vphantom{0}^{-1}$$), limiting the applicability of conventional phase-contrast (PC) MRI. Here we assess the suitability of Time-Spatial Labeling Inversion Pulse MRI (Time-SLIP) for characterizing this motion using in vitro experiments in a spinal-canal phantom. The phantom consists of a flexible tube with a rigid insert forming an eccentric annular canal representative of the spinal subarachnoid space, driven by a 1 Hz sinusoidal flow mimicking cardiac-induced CSF pulsations. Oscillatory velocities were measured with PC-MRI, while net fluid displacement over successive...

Combination of inclusive top-quark pair production cross-section measurements using ATLAS and CMS data at s = 7 and 8 TeV

Wed, 30 Sep 2026 00:00:00 +0000

A combination of measurements of the inclusive top-quark pair production cross-section performed by ATLAS and CMS in proton–proton collisions at centre-of-mass energies of 7 and 8 TeV at the LHC is presented. The cross-sections are obtained using top-quark pair decays with an opposite-charge electron–muon pair in the final state and with data corresponding to an integrated luminosity of about 5 fb−1 at s$$ \sqrt{s} $$ = 7 TeV and about 20 fb−1 at s$$ \sqrt{s} $$ = 8 TeV for each experiment. The combined cross-sections are determined to be 178.5 ± 4.7 pb at s$$ \sqrt{s} $$ = 7 TeV and 243.3−5.9+6.0$$ {243.3}_{-5.9}^{+6.0} $$ pb at s$$ \sqrt{s} $$ = 8 TeV with a correlation of 0.41, using a reference top-quark mass value of 172.5 GeV. The ratio of the combined cross-sections is determined to be R8/7 = 1.363 ± 0.032. The combined measured cross-sections and their ratio agree well with theory calculations using several parton distribution function (PDF) sets. The values of the top-quark...

Feasibility and acceptability of remote smartphone cognitive testing in frontotemporal dementia research

Tue, 29 Sep 2026 00:00:00 +0000

Introduction: Remote smartphone assessments of cognition, speech/language, and motor functioning in frontotemporal dementia (FTD) could enable decentralized clinical trials and improve access to research. We studied the feasibility and acceptability of remote smartphone data collection in FTD research using the ALLFTD Mobile App (ALLFTD-mApp). Methods: A diagnostically mixed sample of 214 participants with FTD or from familial FTD kindreds (asymptomatic: CDR®+NACC-FTLD = 0 [N = 101]; prodromal: 0.5 [N = 49]; symptomatic ≥1 [N = 51]; not measured [N = 13]) were asked to complete ALLFTD-mApp tests on their smartphone three times within 12 days. They completed smartphone familiarity and participation experience surveys. Results: It was feasible for participants to complete the ALLFTD-mApp on their own smartphones. Participants reported high smartphone familiarity, completed ∼ 70% of tasks, and considered...

The ENIGMA Consortium: large-scale collaborative analyses of neuroimaging and genetic data

Tue, 29 Sep 2026 00:00:00 +0000

The Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA) Consortium is a collaborative network of researchers working together on a range of large-scale studies that integrate data from 70 institutions worldwide. Organized into Working Groups that tackle questions in neuroscience, genetics, and medicine, ENIGMA studies have analyzed neuroimaging data from over 12,826 subjects. In addition, data from 12,171 individuals were provided by the CHARGE consortium for replication of findings, in a total of 24,997 subjects. By meta-analyzing results from many sites, ENIGMA has detected factors that affect the brain that no individual site could detect on its own, and that require larger numbers of subjects than any individual neuroimaging study has currently collected. ENIGMA’s first project was a genome-wide association study identifying common variants in the genome associated with hippocampal volume or intracranial volume. Continuing work is exploring genetic associations...

Dynamic activity in cis-regulatory elements of leukocytes identifies transcription factor activation and stratifies COVID-19 severity in ICU patients

Tue, 29 Sep 2026 00:00:00 +0000

Transcription factor programs mediating the immune response to coronavirus disease 2019 (COVID-19) are not fully understood. Capturing active transcription initiation from cis-regulatory elements such as enhancers and promoters by capped small RNA sequencing (csRNA-seq), in contrast to capturing steady-state transcripts by conventional RNA-seq, allows unbiased identification of the underlying transcription factor activity and regulatory pathways. Here, we profile transcription initiation in critically ill COVID-19 patients, identifying transcription factor motifs that correlate with clinical lung injury and disease severity. Unbiased clustering reveals distinct subsets of cis-regulatory elements that delineate the cell type, pathway-specific, and combinatorial transcription factor activity. We find evidence of critical roles of regulatory networks, showing that STAT/BCL6 and E2F/MYB regulatory programs from myeloid cell populations are activated in patients with poor disease outcomes...

Longitudinal Metabolic Trajectories in Diabetes Prevention Program Participants Reveal Subgroups With Varying Micro- and Macrovascular Complication Risks.

Thu, 24 Sep 2026 00:00:00 +0000

OBJECTIVE: Type 2 diabetes (T2D) and its associated complications develop heterogeneously over decades, but few studies span the progression from prediabetes to clinical events. We investigated whether long-term metabolic trajectories beginning in prediabetes delineate subgroups with differential complication risk. RESEARCH DESIGN AND METHODS: Clinical data from 1,732 Diabetes Prevention Program/Outcomes Study participants (follow-up 19 years) were analyzed across 12 phenotypes. Tensor decomposition was used to capture longitudinal patterns, and Gaussian mixture modeling was used to define longitudinal clusters. Cluster-specific complications were quantified with Cox and logistic regression. RESULTS: Four clusters emerged. Clusters 1 and 2 (73% of participants) maintained stable glycemia, blood pressure, and lipids. Although 49% and 71%, respectively, developed T2D, cumulative micro- and macrovascular events remained low. Cluster 3 (12%) showed the steepest rise in insulin resistance...

Adapting Research Protocols During War: The ANCHOR (Analysis of Network Composition, Health Outcomes, and Resilience) Study

Thu, 24 Sep 2026 00:00:00 +0000

BackgroundConducting longitudinal infectious disease research during armed conflicts is important for understanding transmission dynamics and preventing outbreaks. War in Ukraine started in 2014, with the escalation to full-scale invasion in 2022, resulting in massive population displacement, infrastructure destruction, mobility restriction for men, and reduced access to healthcare. The ANCHOR (Analysis of Network Composition, Health Outcomes, and Resilience) study, launched in November 2024, examines how war- and displacement-driven changes affect social networks, HIV risks, and HIV care engagement. Here, we report implementation challenges and adaptations as practical lessons that may inform infectious disease surveillance and research in conflict settings.MethodsANCHOR is a cohort study conducted in Kyiv and Lviv in 2024–2026 that enrolled sexual minority men (SMM) using respondent-driven sampling, with 6- and 12-month follow up of participants testing positive for HIV. Data...

Premature Battery Depletion of an Insertable Cardiac Monitor: A Two-Patient Case Series

Thu, 24 Sep 2026 00:00:00 +0000

Premature Battery Depletion of an Insertable Cardiac Monitor: A Two-Patient Case Series

Eating Disorders and Parkinson's Disease—2: Genetic Epidemiology and Shared Genomics

Thu, 24 Sep 2026 00:00:00 +0000

OBJECTIVE: Individuals with anorexia nervosa (AN) share premorbid traits with Parkinson's Disease (PD) (e.g., anxiety) and exhibit a two-fold relative risk of a reported family history of PD. Published estimates of intra- and inter-disorder genetic architecture were extracted and compared prior to conducting novel analyses to provide evidence for cross-disorder genetic risk. METHODS: National register or meta-analytic familial, twin, and common variant genome-wide studies were searched; estimates and findings were extracted and compared. Novel cross-disorder conditional and conjunctional false discovery rate analyses were performed. RESULTS: Sibling relative risks and additive genetic estimates of the two disorders were similar. AN had greater common variant heritability than PD whether measured via infinitesimal model (linkage disequilibrium score regression, LDSC) or causal mixture model (MiXeR). AN had greater polygenicity than PD (mean (SD) 2.50E-03 (1.64E-04) versus...

Harnessing the mental imprints of climate change for collective climate action

Thu, 24 Sep 2026 00:00:00 +0000

Harnessing the mental imprints of climate change for collective climate action

Seventy Seconds of Asystole Delayed Atrioventricular Block Post-TAVR From His-Bundle Injury and Phase 4 Block

Thu, 24 Sep 2026 00:00:00 +0000

BACKGROUND: Conduction system disturbance is a leading complication of transcatheter aortic valve replacement (TAVR). Conventional predictors of post-TAVR pacing include preexisting right bundle branch block, new left bundle branch block, and annular calcification. CASE SUMMARY: A 71-year-old woman with severe aortic stenosis and left bundle branch block (PR: 160 ms, QRS: 138 ms) underwent TAVR. The QRS paradoxically narrowed postprocedure (104 ms), and inpatient telemetry showed no high-grade atrioventricular block before discharge. Five days later, an outpatient real-time monitor captured 71 seconds of asystole due to complete heart block. She presented with syncope and underwent pacemaker implantation. DISCUSSION: The paradoxical QRS narrowing reflects His-bundle injury producing a proximal conduction delay in the His bundle, with recovery of conduction in the left bundle branch indicative of gap phenomenon. The recovery of conduction in the left bundle also highlights the...

Optimizing adolescent brain development

Thu, 24 Sep 2026 00:00:00 +0000

Optimizing adolescent brain development

A PKA-selective inhibitor captures an open but more ordered conformation of the PKA catalytic subunit

Fri, 18 Sep 2026 00:00:00 +0000

The structure of the catalytic subunit of cAMP-dependent protein kinase (PKA-C), a prototype for the protein kinase superfamily, laid the foundation for the development of targeted kinase inhibitors. Here we describe the structure and biophysical characterization of a PKA-C complex with BLU0588, a small PKA-selective inhibitor. The high-resolution crystal structure not only captures the inhibitor's unusual T-shaped geometry, but also shows how the four rings of BLU0588 serve as surrogates for ATP's adenosine and phosphate-organizing sites. Each site contains two subsites. BLU0588's planar azaindole and pyridine rings, which are buried beneath the glycine-rich loop in a hydrophobic shell at the base of the active site cleft, fill the adenine and ribose subsites. In contrast, BLU0588's indane and pyrrolidine rings fill the phosphate-organizing site. The indane ring occupies the α/β-phosphate organizing site while the pyrrolidine ring fills the Mg/γ-phosphate organizing site. The...

Referral Characteristics of an Ambulatory Integrative Medicine Consultation Service at an Academic Health Center

Thu, 17 Sep 2026 00:00:00 +0000

Referral Characteristics of an Ambulatory Integrative Medicine Consultation Service at an Academic Health Center

Osteopathic Manipulative Treatment Reduces Length of Stay and Opioid Use After Vestibular Schwannoma Resection

Thu, 17 Sep 2026 00:00:00 +0000

Osteopathic Manipulative Treatment Reduces Length of Stay and Opioid Use After Vestibular Schwannoma Resection

Development of an Automated Machine Learning Algorithm for Screening of OSA in Primary Care Settings

Thu, 17 Sep 2026 00:00:00 +0000

Development of an Automated Machine Learning Algorithm for Screening of OSA in Primary Care Settings

The effects of transcranial random noise stimulation on excitation/inhibition balance in ADHD.

Fri, 11 Sep 2026 00:00:00 +0000

Background

Children with attention-deficit/hyperactivity disorder (ADHD) often show aberrant neural activity, including excitation/inhibition (E/I) imbalances, atypical event-related potentials (ERPs), and neural network dysfunction. Transcranial Random Noise Stimulation (tRNS) has shown promise in modulating neural activity in ADHD.

Methods

The current study examined differences in behavioral and EEG signals recorded during an inhibitory control task in children with (N = 23) and without (N = 33) ADHD. Changes in these signals were further assessed following a combined tRNS and cognitive training intervention targeting the right inferior frontal gyrus and left dorsolateral prefrontal cortex in a sham-controlled randomized trial within the ADHD group only (n = 11 and 12 for intervention and sham groups, respectively).

Results

At baseline, children with ADHD showed slower reaction times, and higher commission error rates compared...

What Dose of Methamphetamine Do Regular Consumers Use Daily? Estimating Oral Amphetamine Milligram Equivalents

Fri, 11 Sep 2026 00:00:00 +0000

OBJECTIVES: The purity, accessibility, and affordability of illicit methamphetamine have increased in recent decades, which has been linked to rising rates of methamphetamine-involved overdoses, psychosis, cardiovascular events, and other health consequences. Nevertheless, information about the quantity of methamphetamine used by regular consumers has been limited, despite the potential clinical utility of exposure quantification. METHODS: From August 2024 to April 2026, self-reported daily methamphetamine consumption was assessed among n = 94 individuals in Los Angeles County. Methamphetamine samples (n = 256) were analyzed for purity using liquid chromatography-mass spectrometry. Bioavailability by route of administration and stimulant equivalency were obtained from the literature. A simulation model leveraging bootstrapping with 1,000,000 draws was used to estimate oral amphetamine milligram equivalents (AME). RESULTS: The average reported methamphetamine consumption was 1.09...

Efficacy and Safety of Naloxegol in Patients with Chronic Non-Cancer Pain Who Experience Opioid-Induced Constipation: A Pooled Analysis of Two Global, Randomized Controlled Studies

Fri, 11 Sep 2026 00:00:00 +0000

Objective: This study evaluates the onset, magnitude, and consistency of improvement of opioid-induced constipation (OIC) symptoms with naloxegol treatment. Methods: This was a pooled analysis of two Phase 3, double-blind, randomized, placebo-controlled studies (KODIAC-04/05, NCT01309841/NCT01323790) in patients with chronic non-cancer pain and OIC treated with naloxegol 25mg or 12.5mg daily. This analysis assessed improvements in response rates, frequency of spontaneous bowel movement (SBM) and complete SBMs (CSBM), OIC constipation symptoms (straining, stool consistency), time to first post-dose SBM and CSBM, and onset of adverse events over the 12-week period. Subjects: The population of 1337 subjects had a mean age of 52 years and mean duration of opioid use of 3.6 years at baseline. Mean SBM frequency was 1.4/week. Results: Naloxegol 25mg and 12.5mg demonstrated significantly higher response rates vs placebo (PBO) [41.9% (P < 0.001), 37.8% (P = 0.008), 29.4% respectively]....

Corrigendum to: Topical analgesics for neuropathic pain: an evidence-informed guide for the practicing clinician

Fri, 11 Sep 2026 00:00:00 +0000

Corrigendum to: Topical analgesics for neuropathic pain: an evidence-informed guide for the practicing clinician

Update on Treating Painful Diabetic Peripheral Neuropathy: A Review of Current US Guidelines with a Focus on the Most Recently Approved Management Options

Fri, 11 Sep 2026 00:00:00 +0000

Painful diabetic peripheral neuropathy (DPN) is a highly prevalent and disabling complication of diabetes that is often misdiagnosed and undertreated. The management of painful DPN involves treating its underlying cause via lifestyle modifications and intensive glucose control, targeting its pathogenesis, and providing symptomatic pain relief, thereby improving patient function and health-related quality of life. Four pharmacologic options are currently approved by the US Food and Drug Administration (FDA) to treat painful DPN. These include three oral medications (duloxetine, pregabalin, and tapentadol extended release) and one topical agent (capsaicin 8% topical system). More recently, the FDA approved several spinal cord stimulation (SCS) devices to treat refractory painful DPN. Although not FDA-approved specifically to treat painful DPN, tricyclic antidepressants, serotonin/norepinephrine reuptake inhibitors, gabapentinoids, and sodium channel blockers are common first-line...

S497 Naloxegol Accelerates Time to First Spontaneous Bowel Movement (SBM) and Complete SBM (CSBM) With Predictable Efficacy in Patients With Extreme Opioid-Induced Constipation (OIC): A Pooled Analysis of Two Phase 3 Trials

Fri, 11 Sep 2026 00:00:00 +0000

S497 Naloxegol Accelerates Time to First Spontaneous Bowel Movement (SBM) and Complete SBM (CSBM) With Predictable Efficacy in Patients With Extreme Opioid-Induced Constipation (OIC): A Pooled Analysis of Two Phase 3 Trials

Frontline Perspectives on Buprenorphine for the Management of Chronic Pain

Fri, 11 Sep 2026 00:00:00 +0000

Due to the prevalence of chronic pain and high-impact chronic pain in the US, a significant percentage of the population is prescribed opioids for pain management. However, opioid use disorder is associated with reduced quality of life, along with fatal opioid overdoses, and is a significant burden on the US economy. Considering the clinical needs of patients with intractable chronic pain and the potential harms associated with prescribed and illicit opioids in our communities, having a deep understanding of current treatment options, supporting evidence, and clinical practice guidelines is essential for optimizing treatment selections. Buprenorphine is a Schedule III opioid with a unique mechanism of action, allowing effective and long-lasting analgesia at microgram doses with fewer negative side effects and adverse events, including respiratory depression, when compared with other immediate-release, long-acting, and extended-release prescription opioids. Due to its relatively...

Multimodal Therapies for the Treatment of Neuropathic Pain: The Role of Lidocaine Patches in Combination Therapy: A Narrative Review

Fri, 11 Sep 2026 00:00:00 +0000

Neuropathic pain (NP) has a population presence of up to 10%. Both systemic agents and topical agents are recommended as first-line therapy for the treatment of NP but monotherapy provides adequate pain relief only in < 50% of the cases. This has created the need for multimodal combination therapy, a practice that is becoming more common. Combination therapy with multiple systemic agents has a risk for drug–drug interactions and adverse events (AEs), while add-on therapy with a topical agent such as lidocaine patches minimizes such risks. The focus of this review was to find if there is evidence from trials that combination therapy of the topical lidocaine patches with systemic agents will have better efficacy and/or less risk of AEs than the combination of two systemic agents. Since gabapentinoids are one of the most common systemic agents used in first-line NP therapy, the objective of this review was to summarize the safety and efficacy data and evaluate the benefit–risk...

Founding the Pain Medicine Academy of Advanced Practice Providers

Fri, 11 Sep 2026 00:00:00 +0000

Founding the Pain Medicine Academy of Advanced Practice Providers

Topical analgesics for neuropathic pain: an evidence-informed guide for the practicing clinician

Fri, 11 Sep 2026 00:00:00 +0000

OBJECTIVE: To evaluate available evidence for the efficacy and safety of topical analgesics for neuropathic pain and to offer treatment guidance. METHODS: An expert panel searched PubMed (Medline) and reference lists of published articles for available literature assessing 8 categories of topical analgesics used to treat various neuropathic pain conditions. The panel rated the level of analgesic efficacy evidence for each treatment and considered safety, ease of use, and cost. The degree of consensus on the recommendations among the panelists was measured. RESULTS: There was strong evidence and high consensus that capsaicin 8% is effective for diabetic peripheral neuropathy and postherpetic neuralgia and that lidocaine is effective for postherpetic neuralgia. There was strong evidence and moderate consensus that capsaicin 8% could be effective for HIV-induced neuropathy. There was moderate evidence and high consensus that lidocaine is likely effective for diabetic peripheral neuropathy,...

Naloxegol (Movantik®) Provides Rapid and Sustained Improvement of Opioid-Induced Constipation Symptoms Irrespective of Opioid Dose

Fri, 11 Sep 2026 00:00:00 +0000

Aim Naloxegol (Movantik), an oral peripherally acting mu-opioid receptor antagonist has demonstrated rapid relief of opioid-induced constipation (OIC) in patients with chronic non-cancer pain in two phase 3 trials (KODIAC 4/5; NCT01309841/NCT01323790). This analysis aims to characterize the OIC symptom burden and evaluate the efficacy of naloxegol in treating symptoms of OIC based on daily opioid dosages. This is the first naloxegol analysis based on a lower opioid dose cutoff of 100 MEU/day. Methods Data were pooled from the KODIAC 4/5 intent-to-treat populations (N=1337). Subjects treated with placebo (PBO) and naloxegol (12.5mg, 25mg) QD were evaluated based on opioid dose ranges (lower dose, ≤100mg; higher dose, >100mg MEU/day). OIC symptoms assessed include number of spontaneous bowel movements (SBM/wk), complete evacuation (CSBM), straining (scale 1=not at all, 5=extreme) and stool consistency (Bristol Stool Scale: 1=hard, 7=watery). Results Baseline OIC symptom burden...

Characterization of Spirometric Response to Standard-of-care Treatment in Lung Allograft Recipients With Bronchiolitis Obliterans and the Utility of Spirometric Criteria for Rescue Therapy: Implications for the Design of Risk-stratified Clinical Trials

Fri, 11 Sep 2026 00:00:00 +0000

BACKGROUND: The spirometric response to standard-of-care (SOC) immunosuppressive therapy for the management of bronchiolitis obliterans syndrome (BOS) has been sparsely reported in the literature. Data from a Medicare-approved Registry were analyzed to characterize the effectiveness/durability of a wide range of SOC interventions to manage the decline of lung function and to validate the study spirometric criteria for initiation of rescue therapy. METHODS: Lung transplant recipients with refractory BOS at 21 US collaborating centers were enrolled in the Registry. Data included both nonspirometric (eg, demographic, Immunosuppressive Regimens for management of BOS) and spirometric parameters (ie, forced expiratory volume in 1 s [FEV 1 ] measurements and derived indices). The utility of study FEV 1 criteria for treatment (ie, statistically significant rate of FEV 1 decline >30 mL/mo) was evaluated by comparing the spirometric course between participants who met or did not meet...

Rational Urine Drug Monitoring in Patients Receiving Opioids for Chronic Pain: Consensus Recommendations

Fri, 11 Sep 2026 00:00:00 +0000

Objective: To develop consensus recommendations on urine drug monitoring (UDM) in patients with chronic pain who are prescribed opioids. Methods: An interdisciplinary group of clinicians with expertise in pain, substance use disorders, and primary care conducted virtual meetings to review relevant literature and existing guidelines and share their clinical experience in UDM before reaching consensus recommendations. Results: Definitive (e.g., chromatography-based) testing is recommended as most clinically appropriate for UDM because of its accuracy; however, institutional or payer policies may require initial use of presumptive testing (i.e., immunoassay). The rational choice of substances to analyze for UDM involves considerations that are specific to each patient and related to illicit drug availability. Appropriate opioid risk stratification is based on patient history (especially psychiatric conditions or history of opioid or substance use disorder), prescription drug monitoring...

Intrathecal pain management: a team-based approach

Fri, 11 Sep 2026 00:00:00 +0000

OBJECTIVE: Physician assistants (PAs), nurse practitioners (NPs), and registered nurses (RNs) provide professional services on pain management teams. This review provides an overview of the practical management of chronic pain with intrathecal (IT) therapy using an interprofessional approach (eg, physicians and other health care professionals), with a focus on the contributions of PAs, NPs, and RNs. METHODS: Narrative review based on literature searches of the Medline database and treatment guidelines on the use of IT therapy in the management of patients with chronic pain. RESULTS: The specific roles and responsibilities of PAs, NPs, and RNs in the management of patients receiving IT therapy vary by practice. In many pain treatment centers, PAs, NPs, and RNs are responsible for patient education, postimplant maintenance, and ongoing supportive care of patients receiving IT therapy. Topics that we address include patient selection, patient expectations and goal setting, medication...

A rare case report of decompensated cirrhosis from hereditary hemochromatosis following lung transplant in a person with cystic fibrosis

Fri, 11 Sep 2026 00:00:00 +0000

A 33-year-old woman with cystic fibrosis following bilateral sequential cadaveric lung transplantation experienced prolonged intermittent liver enzyme elevation. An abdominal ultrasound revealed increased hepatic echogenicity and cirrhotic features, warranting further investigation with iron studies and liver biopsy, which confirmed hereditary hemochromatosis. This rare case underscores the importance of considering hereditary hemochromatosis post lung transplantation irrespective of not receiving multiple blood products or iron replacement.

An overview of abuse-deterrent opioids and recommendations for practical patient care

Fri, 11 Sep 2026 00:00:00 +0000

Despite advances in the treatment of severe intractable pain, opioids remain a critical and appropriate component of treatment. However, abuse, misuse, and diversion of prescription opioids are significant public health concerns. Opioid abuse-deterrent formulations (ADFs) are one component of an opioid risk management plan to manage patient's pain relief and quality of life while offering some protection against potentially harmful consequences of opioids from misuse and abuse. Opioid ADFs are designed to make manipulation more difficult and administration via non-oral routes less appealing. There are currently nine extended-release and one immediate-release opioid pain medications with US Food and Drug Administration-approved ADF labeling. All use physical/chemical barriers or agonist/antagonist combinations to deter manipulation and abuse. Evidence suggests that opioid ADFs decrease rates of abuse and diversion of opioids in the USA; however, some opioid ADFs are not yet commercially...

Understanding Buprenorphine for Use in Chronic Pain: Expert Opinion

Fri, 11 Sep 2026 00:00:00 +0000

OBJECTIVE: An expert panel convened to reach a consensus on common misconceptions surrounding buprenorphine, a Schedule III partial µ-opioid receptor agonist indicated for chronic pain. The panel also provided clinical recommendations on the appropriate use of buprenorphine and conversion strategies for switching to buprenorphine from a full µ-opioid receptor agonist for chronic pain management. METHODS: The consensus panel met on March 25, 2019, to discuss relevant literature and provide recommendations on interpreting buprenorphine as a partial µ-opioid receptor agonist, prescribing buprenorphine before some Schedule II, III, or IV options, perioperative/trauma management of patients taking buprenorphine, and converting patients from a full µ-opioid receptor agonist to buprenorphine. RESULTS: The panel recommended that buprenorphine's classification as a partial µ-opioid receptor agonist not be clinically translated to mean partial analgesic efficacy. The panel also recommended...

S508 Naloxegol Achieved Rapid and Sustained Improvement of Opioid-Induced Constipation (OIC) Symptoms in Patients With Extreme OIC: A Pooled Analysis of Two Pivotal Phase 3 Trials

Fri, 11 Sep 2026 00:00:00 +0000

S508 Naloxegol Achieved Rapid and Sustained Improvement of Opioid-Induced Constipation (OIC) Symptoms in Patients With Extreme OIC: A Pooled Analysis of Two Pivotal Phase 3 Trials

Is it justified to order an upfront cytomegalovirus immunohistochemical stain in patients with severe inflammatory bowel disease and ulceration?

Thu, 10 Sep 2026 00:00:00 +0000

BACKGROUND: Cytomegalovirus (CMV) infection is common amongst both immunocompetent and immunocompromised patients. Patients with inflammatory bowel disease (IBD) are more prone to suffer from CMV complications. In this study, we investigated the utility of immunohistochemistry to diagnose CMV infection in patients with severe IBD. METHODS: We searched our pathology data system to identify patients with IBD from January 1, 2017 to December 31, 2021. We identified 5782 IBD cases, out of which 784 cases had severe activity with ulceration. CMV immunohistochemical stain (IHC) was performed on all 784 cases. Hematoxylin and eosin (H&E) staining slides were reviewed to evaluate the presence of characteristic nuclear or cytoplasmic CMV inclusions. H&E and IHC results were categorized as "single" if 1 cell stained positive or had characteristic inclusions, "rare" if 2-5 cells stained positive or had characteristic inclusions and "many" if more than 5 cells stained...

Immunoaffinity‐Based Protocol to Enrich Nervous System Cell‐, Lung Alveolar Cell‐, and Hepatocyte‐Derived Extracellular Vesicles From Human Plasma

Thu, 10 Sep 2026 00:00:00 +0000

By preserving molecular information inherited from the source cell, extracellular vesicles (EVs) can serve as biomarkers for tissue health or disease, paving the way for liquid biopsy applications. The enrichment of tissue-specific EVs (TS-EVs) from human biofluids can be challenging due to technical and methodological limitations. Here, we use single and sequential immunoaffinity capture workflows to enrich antigen-specific EVs circulating in human blood. We demonstrate the specificity, efficiency, and consistency of our approach for enriching blood plasma EV subpopulations from the nervous system, alveolar cells and hepatocytes. The enriched subpopulations are characterized by canonical EV features and markers, as well as co-localization of tissue-specific and general markers on the surface. We provide a validated workflow to derive multiple EV subpopulations from circulation, leveraging their promise as informative biomarkers of tissue status and enabling liquid biopsy and...

Rising Incidence With Modest Survival Improvement in Salivary Duct Carcinoma: A Population‐Based Study in the United States, 2000–2022

Thu, 10 Sep 2026 00:00:00 +0000

BACKGROUND: Salivary duct carcinoma (SDC) is a rare and aggressive malignancy with limited population-based data. METHODS: Incidence trends and survival outcomes were analyzed using the Surveillance, Epidemiology, and End Results database. RESULTS: A total of 955 cases were identified. The age-adjusted incidence rate increased from 0.158 in 2000 to 1.18 in 2022 (average annual percent change, 10.38%; p < 0.001), accelerating after 2012. Increases were more pronounced among females, older patients, regional-stage disease, and tumors > 2 cm. The 5-year disease-specific survival (DSS) and overall survival were 60.6% and 51.2%, respectively. Advanced age, non-parotid site, larger tumor size, lymph node metastasis, advanced stage, and non-surgical management were independent predictors of worse DSS. Patients diagnosed in 2013-2022 showed better DSS compared with those in 2004-2012 (64.7% vs. 52.0%, p = 0.048). CONCLUSION: SDC incidence has increased rapidly, possibly reflecting...

Nemtabrutinib in relapsed or refractory chronic lymphocytic leukemia/small lymphocytic lymphoma: Phase 2 BELLWAVE-003 cohort J

Thu, 10 Sep 2026 00:00:00 +0000

Nemtabrutinib in relapsed or refractory chronic lymphocytic leukemia/small lymphocytic lymphoma: Phase 2 BELLWAVE-003 cohort J

Management of coagulopathy among patients with cirrhosis undergoing upper endoscopy and paracentesis: Persistent gaps and areas of consensus in a multispecialty Delphi

Thu, 10 Sep 2026 00:00:00 +0000

Patients with cirrhosis have abnormal coagulation indices such as a high international normalized ratio and low platelet count, but these do not correlate well with periprocedural bleeding risk. We sought to develop a consensus among the multiple stakeholders in cirrhosis care to inform process measures that can help improve the quality of the periprocedural management of coagulopathy in cirrhosis. We identified candidate process measures for periprocedural coagulopathy management in multiple contexts relating to the performance of paracentesis and upper endoscopy. An 11-member panel with content expertise was convened. It included nominees from professional societies for interventional radiology, transfusion medicine, and anesthesia as well as representatives from hematology, emergency medicine, transplant surgery, and community practice. Each measure was evaluated for agreement using a modified Delphi approach (3 rounds of rating) to define the final set of measures. Out of...

Maternal Serum Nitrate and Nitrite Associations With Birth Outcomes: A Case‐Control Study

Thu, 10 Sep 2026 00:00:00 +0000

Nitrate and nitrite contamination of groundwater and surface water is a global public health concern, often linked to the increasing use of nitrogen-based fertilizers. In Jordan's Ghor region, where agriculture is intensive and fertilizer use is widespread, the issue is particularly relevant. This study aimed to investigate the relationship between serum nitrate and nitrite levels with low birth weight and preterm birth. A total of 659 participants were enrolled, comprising 452 controls (normal birth weight and full-term delivery) and 207 cases (low birth weight/preterm delivery). High maternal serum nitrite levels were significantly associated with increased odds of low birth weight delivery in both the unadjusted model (odds ratio [OR] = 1.43, 95% CI: 1.14-1.80, P = 0.002) and the a priori confounder set adjusted model (OR = 1.33, 95% CI: 1.02-1.74, P = 0.038). Nitrite levels were also significantly associated with the combined...

Peripheral blood biomarkers in PD-1/PD-L1 immunotherapy: distinguishing predictive from prognostic biomarkers

Thu, 10 Sep 2026 00:00:00 +0000

Immune checkpoint inhibitors targeting the programmed cell death protein 1 (PD-1) and programmed death ligand 1 (PD-L1) axis have transformed cancer therapy, yet reliable biomarkers for accurately predicting therapeutic benefit remain limited. Peripheral blood biomarkers have emerged as attractive candidates because of their minimally invasive accessibility, feasibility for serial monitoring, and potential to capture dynamic systemic immune responses during treatment. However, their clinical translation has been hindered by inconsistent findings, biological heterogeneity, and the frequent conflation of prognostic associations with true predictive value. Many commonly reported biomarkers, including circulating tumor DNA (ctDNA), blood-based tumor mutational burden (bTMB), inflammatory indices, and conventional serum markers, primarily reflect tumor burden, systemic inflammation, or host physiological status rather than genuine sensitivity to PD-1/PD-L1 blockade. In contrast, immune...