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Primary amenorrhea reflects disruption along the hypothalamic-pituitary-ovarian-uterine axis; may arise from anatomic, genetic, or functional abnormalities; and may be diagnosed on the basis of US and MRI findings.

C9orf72 encodes a protein that is important for both typical neurodevelopment and homeostatic processes across the lifespan. Pathogenic C9orf72 repeat expansions constitute the most common genetic cause of frontotemporal lobar degeneration (FTLD). Collectively, preclinical models and clinical neuroimaging studies have observed smaller thalamic volumes in C9orf72-associated FTLD, including in asymptomatic young adult C9orf72 repeat expansion carriers across 18 to 30 years old, supportive of potential neurodevelopmental origins. However, it is unknown whether asymptomatic young adult C9orf72 expansion carriers demonstrate volume differences in specific thalamic nuclei, as reported in older asymptomatic carriers and symptomatic patients; if so, normative transcriptomic patterns could reveal relevant neurodevelopmental and/or FTLD-related neurodegenerative processes. This study investigated volumetric MRI differences of the thalamic nuclei in asymptomatic young adult C9orf72 expansion carriers compared to non-carriers, and examined spatial associations with normative thalamic transcriptomics from 8 weeks post-conception through middle age. Young adult C9orf72 expansion carriers (n=72) and non-carriers (n=48) were enrolled in the Frontotemporal Dementia Prevention Initiative across Europe, Canada, and the USA (ages: 18-30 years; sex: 57% female). Spatial associations between young adult thalamic nuclei volumes and normative transcriptomics from the Allen Human Brain Atlas were examined using complementary data-driven and hypothesis-driven approaches. Spatial expression patterns of transcripts of interest were characterized across prenatal and postnatal neurodevelopment using BrainSpan data. Smaller volumes of the pulvinar, mediodorsal, and lateral nuclei were observed in young adult C9orf72 expansion carriers compared to non-carriers. These nuclei showed higher normative expression of transcripts involved concurrently in neurodevelopmental and C9orf72-associated FTLD neurodegenerative processes (including lysosomal, autophagic, and small GTPase functions), and lower normative expression of CALB1, a marker of prenatal human thalamic development. Normative expression of CALB2 (another human thalamic development marker) yielded positive correlations with C9orf72 across prenatal development to adulthood. These findings identify candidate transcripts that may provide insight into the molecular architecture leading to smaller thalamic nuclei volumes in C9orf72-associated FTLD.

Abstract Post-traumatic headache (PTH) is the most common consequence of mild traumatic brain injury (mTBI) and often resembles migraine. In 20% to 30% of migraine patients, headaches are preceded by aura, transient visual or sensory disturbances, which are caused by cortical spreading depression (CSD) that can induce headache pain. However, whether mTBI promotes the development of aura and CSD and their possible contributions to PTH remains unclear. We examined the incidence of new-onset aura in individuals with PTH who had no history of aura. Thirty-two percent (35/108) developed new aura symptoms within 60 days of injury, suggesting that mTBI can sensitize the cortex to the induction of CSD. To test this, we combined electrophysiology, neuroimaging, and behavioral assays in a mouse model of mTBI-induced PTH. After closed-head mTBI, injured mice exhibited a 160% increase in CSD induction probability (ie, lowered threshold) and became sensitized to CSD induction by brief exposure to stress, a common headache trigger. When evoked optogenetically, CSD produced prolonged periorbital and hind paw allodynia, consistent with headache-like pain. Subcutaneous onabotulinumtoxinA administered to the scalp after mTBI did not alter CSD susceptibility but completely abolished optogenetic CSD-induced allodynia. These findings suggest that mTBI elicits sensitization to CSD induction and promotes the emergence of aura in humans, likely contributing to PTH. It is important that, even after mTBI-induced sensitization, onabotulinumtoxinA decoupled CSD from pain behaviors, suggesting efficacy in treating PTH associated with aura.

OBJECTIVE The objective was to synthesize denominator-based evidence on indications, techniques, and postoperative outcomes of cervicomedullary decompression (CMD), spinal canal stenosis surgery, and cerebrospinal fluid (CSF) diversion for hydrocephalus in achondroplasia. METHODS This systematic review followed PRISMA 2020 and was prospectively registered (PROSPERO CRD42025626915). MEDLINE (via PubMed), Embase, Scopus, Web of Science, and the Cochrane Library were searched from inception through November 2025. The authors included observational studies of patients with achondroplasia who underwent CMD, spinal canal stenosis surgery, or CSF diversion for hydrocephalus with extractable outcomes and definable denominators. Two reviewers independently screened studies and extracted data. Risk of bias was assessed using ROBINS-I. Random-effects single-arm meta-analyses were performed for prespecified endpoints (any improvement, complete resolution, and mortality) only in cohorts with fully categorizable symptom status. RESULTS The authors included 38 observational studies (1442 patients): 18 CMD studies with 600 patients, 18 spinal stenosis studies with 686 patients, and 4 hydrocephalus studies with 156 patients. No study was at low risk of bias. For CMD (mean age 3.5 years; mean follow-up 27.8 months), any improvement was observed in 93% (95% CI 84%–97%) of patients and complete resolution in 44% (95% CI 16%–77%), and pooled mortality was 0% (95% CI 0%–5%). For spinal stenosis (mean age 36.6 years; mean follow-up 53.1 months), any improvement was observed in 92% (95% CI 78%–97%) and complete resolution in 30% (95% CI 16%–51%), and pooled mortality was 1% (95% CI 0%–2%). Hydrocephalus management was predominantly ventriculoperitoneal shunting (74.4%), with endoscopic third ventriculostomy in 23.1%, but symptom outcomes were rarely classifiable (9.6%), precluding strategy-level inference. CONCLUSIONS CMD and spinal stenosis surgery were frequently followed by symptom improvement in published series, whereas complete resolution was variably defined and inconsistently reported. Hydrocephalus studies described practice patterns but lacked outcome reporting adequate for comparing diversion strategies. Validated patient-reported outcomes were rarely reported, limiting inference on health-related quality of life.

Background: Normothermic machine perfusion (NMP) may reduce preservation injury in donation-after-circulatory-death (DCD) liver transplantation, but its association with patient-centered recovery and longer-term graft survival remains uncertain. Study Design: We retrospectively analyzed 306 consecutive adult DCD liver transplant recipients at a single center from January 2019 through December 2022, comparing NMP (n=95) with static cold storage (SCS; n=211). The primary endpoint was days alive and out of hospital at 365 days (DAOH365). Quasi-Poisson regression evaluated factors associated with DAOH365, and Cox regression evaluated graft survival. Propensity-matched and calendar-year sensitivity analyses assessed measured confounding. Results: Median DAOH365 was 357.0 (352.0, 360.0) days with NMP versus 353.0 (336.0, 359.0) with SCS (p<0.001), but preservation strategy was not independently associated with DAOH365 (adjusted rate ratio 1.02; p=0.331). NMP recipients had less early allograft dysfunction (35.8% vs 59.7%; p<0.001), ischemic cholangiopathy (4.2% vs 23.7%; p<0.001), and retransplantation within 2 years (0.0% vs 6.6%; p=0.007). Two-year patient survival did not differ significantly. NMP was associated with improved twoF-year graft survival (HR 2.9, 95% CI 1.23–6.87; p=0.015), an association maintained in propensity-matched and calendar-year sensitivity analyses. Adjusted total 1-year costs did not differ (p=0.512). Conclusions: In this single-center DCD cohort, NMP was associated with superior 2-year graft survival but not independently with DAOH365. These hypothesis-generating findings support multicenter prospective evaluation of NMP using both graft survival and patient-centered recovery endpoints.

Odontogenic myxoma (OM) is an uncommon, locally aggressive odontogenic neoplasm with characteristic histologic and clinico-radiographic features but with potential for histologic overlap with other odontogenic and non-odontogenic entities and a non-specific immunoprofile. Widespread loss of heterozygosity (LOH) has been recently described in rare cases of OM. The aim of this study was to determine whether widespread LOH represents a recurrent molecular signature that can be leveraged for clinical decision-making. Allele-specific copy number variation data from chromosomal microarray were generated from 7 OM, comprising a combined prospective and retrospective cohort. Four tumors arose in the mandible and 3 in the maxilla in patients ranging in age from 18 to 94 years (median: 44), with tumor size ranging from 2.2 to 13.0 cm. Variable amounts of fibrous stroma (odontogenic “fibromyxoma”) were present in 4/7 OM, and hypercellularity not typically appreciated in conventional OM was present in 3/7 cases. All OM (7/7) demonstrated widespread LOH, with 5 cases showing a near-haploid/low hypodiploid genomes (multiple monosomies) and 2 cases showing evidence of pseudo-hyperdiploidy due to probable endoreduplication. Both pseudo-hyperdiploid cases were ≥10 cm in size; 1 represented local recurrence. Chromosomes 1 to 3, 6, 9, 11, 13, 15, and 22 demonstrated LOH in ≥75% of cases (chromosomes 1 to 3, 6, and 9 in 100% of cases), while chromosomes 5, 12, 19, and 20 universally retained heterozygosity. Altogether, widespread LOH is a recurrent event in OM and a novel finding in odontogenic pathology, and allele-specific copy number variation analysis can serve as a diagnostic adjunct in challenging cases.

Autosomal dominant polycystic kidney disease (ADPKD), mainly driven by pathogenic variants in PKD1 and PKD2 , is the most common inherited cause of kidney failure. Details of ADPKD pathogenesis are incompletely resolved, but primary cilia are an integral component. There is also evidence for changes to the tubular basement membrane (TBM) in early disease. In this issue of the JCI , Mazloum and colleagues link cilia-dependent, PKD1-mediated regulation of the TBM to ADPKD pathogenesis. Using in vivo, ex vivo, tubule-on-chip, and cellular models of ADPKD, they connect cilia-dependent tubule dilation and TBM thinning to early-stage cystogenesis. Moreover, they identify a cilia-dependent TBM remodeling expression signature in affected tubules and suggest that PC1 loss compromises TBM stiffness. By integrating roles for cilia at the apical membrane and extracellular matrix at the basolateral membrane in cystogenesis, this work highlights the TBM as an additional area for investigation of therapeutic and biomarker discovery in ADPKD.

Whether early antibiotic administration compromises microbiological tissue culture yield in children with suspected osteoarticular infection remains a common clinical concern, yet the underlying evidence has never been pooled. We performed a systematic review and metaanalysis to quantify the association between antibiotic pretreatment and tissue culture yield in pediatric osteomyelitis and septic arthritis. MEDLINE (PubMed) and Embase (Ovid) were searched from inception to December 2025 under a protocol prospectively registered with PROSPERO (CRD420251126960); the review is reported in accordance with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses) 2020 statement. Eligible studies reported tissue culture yield in pediatric patients (0–18 years) with osteoarticular infection stratified by antibiotic exposure prior to culture; all included evidence was observational, and no randomized controlled trials were identified. Risk of bias was assessed using a modified Newcastle-Ottawa Scale, and a Der Simonian-Laird random-effects meta-analysis was performed for the primary outcome of tissue culture positivity from the infection site. Nine studies: 7 retrospective cohort studies and 2 case series, comprising 1,704 tissue culture specimens were included. Antibiotic pretreatment was not associated with reduced tissue culture yield (odds ratio, 1.60; 95% confidence interval, 1.23–2.08; <i>P</i>=0.0004; <i>I</i>²=8.9%), with culture positivity of 71.5% in pretreated versus 60.0% in not-pretreated specimens. Because an odds ratio greater than 1 could be misread as a benefit of antibiotics, we emphasize that this direction most plausibly reflects confounding by indication or disease severity rather than a true effect on yield. No evidence of publication bias was detected (Egger <i>P</i>=0.99). Pooled evidence does not support routinely withholding antibiotics solely to preserve tissue culture yield in pediatric osteoarticular infection. Because the included studies were observational and subject to confounding by indication, these findings should not be taken as a uniform recommendation on antibiotic timing; decisions should remain individualized, with appropriate specimens obtained before antibiotics whenever clinically feasible.

Introduction Advancements in transplant care have led to an increasing number of women with solid organ transplantation (SOT) living through peri- and postmenopause. Menopause can significantly impact quality of life, and the added burden of SOT may exacerbate symptoms. Few studies have evaluated the menopausal experience in this population, and existing data rarely use validated questionnaires. Research Question This study aimed to characterize menopausal symptoms and menopausal hormone therapy (MHT) use in peri- and postmenopausal SOT recipients using validated measures. Design A cross-sectional survey study of female patients ≥18 years who underwent SOT between 2018 and 2023 was conducted at a tertiary transplant center. A reproductive and sexual health questionnaire incorporating validated instruments, including the Menopause Rating Scale (MRS), was administered. Results Among peri- and postmenopausal SOT recipients ( n = 192), 8.9% reported use of MHT. The median MRS total score was 8.0, consistent with mild-to-moderate symptom severity overall. Symptom severity differed by menopausal status for vasomotor symptoms ( P =.03), sleep disturbances ( P = .04), depressive mood ( P = .04), and anxiety ( P <.001), with perimenopausal participants generally reporting more symptoms in these domains than postmenopausal participants. Despite these differences, overall symptom severity remained mild to moderate in both groups. Conclusion Menopausal symptoms among female SOT recipients are common but generally mild to moderate, with low utilization of MHT. The lack of increased vasomotor burden compared to prior literature may reflect under-recognition or misattribution of symptoms to transplant-related factors. Incorporating menopause-specific screening into transplant care may improve symptom recognition, quality of life, and long-term health outcomes.

CD19-directed CAR T-cells (CTL019) can produce durable remissions in chronic lymphocytic leukemia (CLL), but therapeutic success depends on whether autologous T-cells expand, persist, and retain cytotoxic function after manufacturing. Failure of CLL T-cells is often attributed to exhaustion, although many dysfunctional CLL T-cells retain inflammatory cytokine production. We tested whether this paradox reflects immunosenescence, an aging-like program defined by costimulatory loss, DNA damage, inflammatory secretion, repertoire restriction, and proliferative arrest. In response-linked preinfusion CTL019 products, nonresponders and short partial responders had higher senescence and senescence-associated secretory phenotype (SASP) programs than the functional-responder group, comprising complete responders and partial responders with transformed disease. These programs were detectable before infusion and became more prominent during manufacture in susceptible products. They tracked with weak in vivo CAR T-cell expansion and were associated with inferior survival. Serum proteomics revealed a circulating, CLL-associated SASP-like inflammatory milieu in nonresponders. Flow cytometry and T-cell receptor (TCR) profiling showed that poor responders carried CD27⁻CD28⁻ and KLRG1⁺ CD8 T-cells at apheresis, lower product CD27, and reduced product TCR diversity. Research-manufactured CAR T-cells from treatment-naïve CLL samples displayed the same state, most prominently in CD4 CAR T-cells, with SA-β-gal, p16, p53, DNA damage, depletion of less-differentiated states, and senescence-enriched transcriptomes. Under repeated CD19 stimulation, CLL-derived products reached a proliferative ceiling, and p53-high products lost cytotoxic reserve. Ibrutinib improved proliferative fitness, attenuated senescence-associated features and SASP output in paired patient and direct-exposure assays, and enhanced CAR T-cell expansion in an ibrutinib-resistant CLL model. Together, these data identify immunosenescence as a measurable and functionally consequential barrier to CAR T-cell efficacy in CLL and a candidate for therapeutic modulation.