Citations

Abstract Donor-derived tuberculosis is a rare complication following solid organ transplantation, and tuberculosis screening is not a current transplant prerequisite for most donors. Donor-derived tuberculosis usually presents sooner than reactivation tuberculosis, and the most common finding is fever. We present 3 cases of donor-derived tuberculosis in the recipients of 2 kidneys and 1 liver from the same donor, who presented with unexplained fevers occurring 4–5 weeks after transplantation. Initial antibacterial therapy failed in all 3 patients, leading to further testing, which identified Mycobacterium tuberculosis by culture and molecular studies. All recipients successfully received tuberculosis therapy but had significant morbidity and prolonged hospital stays. Donor-derived tuberculosis should be among the differential diagnoses of unexplained fever in solid organ transplant recipients in the first few months after transplantation. Screening protocols should be implemented for donors with an epidemiologic risk of tuberculosis, with special emphasis on deceased donors.

ABSTRACT Bipolar disorder’s (BD) clinical heterogeneity has an unresolved genetic basis. We meta-analyzed genome-wide association studies (GWAS) of 16 BD subphenotypes in 226,032 individuals from 57 cohorts (38,022 cases); 10 advanced to multivariate and multi-trait analyses. Four factors (compulsive, psychotic, dysregulated, internalizing) explained 82.8% of shared genetic variance. BD1 and BD2 loaded on distinct factors despite a high genetic correlation; 87.0% of common-factor loci were significant in neither subtype. Unipolar mania aligned with psychosis over internalizing, and was distinguishable from BD1, and rapid cycling showed heritable cross-domain liability. We identified 356 risk loci, 158 novel, including the first univariate-GWAS associations for psychosis, unipolar mania, rapid cycling and schizoaffective disorder—and 249 credible genes (89 high-confidence), 12 with approved-drug or clinical-phase annotations. Cell-type association showed a midbrain dopaminergic–GABAergic gradient along the psychotic factor. BD’s genetic architecture appears hierarchical—a general liability resolving into dimensions of course and comorbidity beyond diagnostic subtypes.

Abstract Objective This study was undertaken to evaluate the response to second treatments for infantile epileptic spasms syndrome (IESS). Methods Infants aged 2–24 months with IESS were prospectively enrolled in the National Infantile Spasms Cohort study at 21 pediatric epilepsy centers in the United States from 2012 to 2018. We analyzed data from infants who initially received standard treatment (hormonal therapy [adrenocorticotropic hormone, high‐dose prednisolone] or vigabatrin), had continued or recurring epileptic spasms, and received a second treatment. We excluded those with tuberous sclerosis. Treatment groups included hormonal therapy followed by vigabatrin (reference), hormonal‐to‐hormonal, hormonal‐to‐nonstandard, vigabatrin‐to‐hormonal, and vigabatrin‐to‐nonstandard. Nonstandard treatments included other antiseizure medications and dietary therapy. Treatment groups were tested for differences in 3‐month clinical remission using a binary logistic regression to estimate odds ratios (ORs). Results There were 153 infants with IESS who received second treatments. The highest rates of 3‐month remission were among infants in the hormonal‐to‐vigabatrin (22/65, 34%) and vigabatrin‐to‐hormonal (9/26, 35%) groups, followed by vigabatrin‐to‐nonstandard (3/10, 30%), hormonal‐to‐hormonal (4/22, 18%), and hormonal‐to‐nonstandard (1/30, 3.3%). Compared to the hormonal‐to‐vigabatrin group (reference), fewer infants had remission in the hormonal‐to‐nonstandard group (OR = .07, 95% confidence interval [CI] = .01–.53), and there was a trend toward fewer infants in the hormonal‐to‐hormonal group (OR = .43, 95% CI = .13–1.4, p = .17). Following initial hormonal treatment, the number needed to treat was three infants for one additional infant to have remission when treated with vigabatrin compared to nonstandard therapy as the second treatment. Significance This updated analysis with an expanded sample size provided power for additional subgroup analysis. Overall response rates were low, and at best only one third had remission after second treatment. Results support a clinical strategy of switching mechanism of action when selecting a second medication for epileptic spasms (i.e., use vigabatrin after hormonal therapy, or hormonal therapy after vigabatrin). Our findings also support the use of standard over nonstandard therapies.

Importance Tau positron emission tomography (PET) allows in vivo detection of neurofibrillary tangles, a core neuropathologic feature of Alzheimer disease (AD). Objective To provide estimates of the frequency of tau PET positivity and its associated risk of clinical outcomes. Design, Setting, and Participants Longitudinal study using data pooled from 21 cohorts, comprising a convenience sample of 6514 participants from 13 countries, collected between January 2013 and June 2024. Cognitively unimpaired individuals and patients with a clinical diagnosis of mild cognitive impairment (MCI), AD dementia, or other neurodegenerative disorders were included. Exposures Tau PET with flortaucipir F 18, amyloid-β (Aβ) PET, and clinical examinations. Tau PET scans were visually rated as positive according to a US Food and Drug Administration– and European Medicines Agency–approved method, designed to indicate the presence of advanced neurofibrillary tangle pathology (Braak stages V-VI). Main Outcomes and Measures Frequency of tau PET positivity and absolute risk of clinical progression (eg, progression to MCI or dementia). Results Among the 6514 participants (mean age, 69.5 years; 50.5% female), median follow-up time ranged from 1.5 to 4.0 years. Of 3487 cognitively unimpaired participants, 349 (9.8%) were tau PET positive; the estimated frequency of tau PET positivity was less than 1% in those aged younger than 50 years, and increased from 3% (95% CI, 2%-4%) at 60 years to 19% (95% CI, 16%-24%) at 90 years. Tau PET positivity frequency estimates increased across MCI and AD dementia clinical diagnoses (43% [95% CI, 41%-46%] and 79% [95% CI, 77%-82%] at 75 years, respectively). Most tau PET–positive individuals (92%) were also Aβ PET positive. Cognitively unimpaired participants who were positive for both Aβ PET and tau PET had a higher absolute risk of progression to MCI or dementia over the following 5 years (57% [95% CI, 45%-71%]) compared with both Aβ PET–positive/tau PET–negative (17% [95% CI, 13%-22%]) and Aβ PET–negative/tau PET–negative (6% [95% CI, 5%-8%]) individuals. Among participants with MCI at the time of the tau PET scan, an Aβ PET–positive/tau PET–positive profile was associated with a 5-year absolute risk of progression to dementia of 70% (95% CI, 59%-81%). Conclusions and Relevance In a large convenience sample, a positive tau PET scan occurred at a nonnegligible rate among cognitively unimpaired individuals, and the combination of Aβ PET positivity and tau PET positivity was associated with a high risk of clinical progression in both preclinical and symptomatic stages of AD. These findings underscore the potential of tau PET as a biomarker for staging AD pathology.

ABSTRACT Premature infants often require supplemental oxygen therapy, however, exposure to supraphysiological oxygen (hyperoxia) can disrupt normal lung development and contribute to bronchopulmonary dysplasia (BPD). Mitochondrial dysfunction is increasingly recognized as a contributor to hyperoxia-induced BPD. However, the effects of hyperoxia on mitochondrial function and mucociliary differentiation in the developing upper airway epithelium remain poorly understood. This study tested the hypothesis that hyperoxia impairs neonatal airway mucociliary differentiation by disrupting mitochondrial bioenergetic function. Neonatal tracheal airway epithelial cells (nTAECs) from term infants (n=5) were cultured in a 3D air-liquid interface (ALI) model and exposed to 60% O₂ during the mid-phase of differentiation (ALI day 7-14). Cellular phenotype was assessed using immunofluorescence staining and gene expression analyses. Mitochondrial function was evaluated through Seahorse metabolic flux analysis, and global protein changes were characterized by quantitative proteomics. Hyperoxia exposure significantly impaired terminal epithelial differentiation, characterized by reductions in ciliated and goblet cells. Seahorse assay revealed a decrease in baseline oxygen consumption and mitochondrial ATP production, accompanied by a compensatory increase in glycolytic ATP production. Quantitative proteomics identified disruption of mitochondrial Complex I as a central feature of the hyperoxic response. Downstream proteomic pathway analyses further confirmed the metabolic shift from mitochondrial to glycolytic ATP production and demonstrated altered epithelial differentiation pathways, including NOTCH and TGF-β signaling. These findings reveal that moderate hyperoxia impairs mitochondrial bioenergetics and alters metabolic programming, leading to disrupted mucociliary differentiation. Future in vivo studies should evaluate mitochondrial oxidative fitness as a therapeutic target in neonatal lung disease. NEW & NOTEWORTHY We report that moderate hyperoxia during a critical window of mucociliary differentiation disrupts terminal maturation in neonatal airway epithelial cells cultured in a 3D model. Hyperoxia induced mitochondrial bioenergetic dysfunction and metabolic reprogramming, with proteomic analysis identifying Complex I disruption as a key driver of impaired differentiation. Overall, these findings reveal a previously underrecognized link between mitochondrial bioenergetics and airway epithelial development, positioning metabolic dysfunction as an early trigger of hyperoxia-induced neonatal airway injury.

Objective To provide a comprehensive analysis of initial suicide attempts, covering incidence, risk factors, outcomes, and healthcare use in the month before and the month after the attempts. Design Comprehensive analysis of the Swedish population that included three designs: a retrospective cohort study to investigate incidence and healthcare use, a nested case-control study to investigate risk factors, and a matched cohort study to examine subsequent suicide attempts and mortality. Setting Comprehensive Swedish national registers that include patient diagnoses from hospitals and specialist outpatient care, and cause of death information updated to the end of 2019. Participants 3.7 million people born in Sweden in 1963-98 and followed from age 10 to 57 years. Main outcome measure First lifetime suicide attempt identified in patient and death registers using ICD (international classification of diseases) codes for intentional self-harm, any self-harm with lethal methods or requiring hospital admission, or any self-harm resulting in death. Results The lifetime risk of an initial suicide attempt in the study population was 4.6%, with greater risk in females and highest risk between ages 18 and 24. One in 10 families in Sweden had at least one family member who attempted suicide. Overdose and poisoning were the most common methods. Previous psychiatric disorders, general medical diseases, and adverse life events were associated with increased risk of initial suicide attempt, while higher socioeconomic status was associated with decreased risk. People with an initial suicide attempt were at substantially increased risk of subsequent attempts (hazard ratio 23.4), death by suicide (16.4), and all cause mortality (7.3). At least 60% of those who made an initial suicide attempt had a healthcare contact in the month before the attempt. Conclusions This study provides comprehensive data on the incidence, risk factors, outcomes, and healthcare use of initial suicide attempts in the Swedish population, highlighting the need for systematic prevention efforts for people who have attempted suicide for the first time.

Abstract Objective To examine the effectiveness of treatment strategies for medication‐overuse headache (MOH) in children and adolescents. Background There are no guidelines for the treatment of adult or pediatric patients with MOH. However, research pertaining to MOH in adults is far outpacing research in children and adolescents. Methods A systematic review of evidence on treatment for MOH in children and adolescents was performed via PubMed, Embase, Web of Science, PsycINFO, and Cochrane from database inception to October 2024 for articles with the subject headings and keywords for MOH and pediatric, children, and/or adolescent. Inclusion criteria were: (i) randomized controlled trials and retrospective and prospective observational studies, (ii) children and adolescents aged <18 years with chronic headaches and with medication overuse (MO) or MOH, and (iii) interventions addressing MO or MOH, including pharmacologic and behavioral interventions. At least two independent reviewers screened citations and full‐text articles independently. Results A total of 16 studies (one randomized control trial, six prospective observational studies and nine retrospective observational studies) were identified as meeting final inclusion criteria, resulting in 7978 total participants with a subset of those having MO, MOH or probable MOH. Participants ranged in mean age from 10 to 14.7 years, with 7.1%–46.2% male participants. All the studies recruited patients from an outpatient setting. Interventions used in the studies included withdrawal of the overused acute medication, initiation of preventive medication, patient education, physiotherapy and psychological treatment, and motivational interviewing. Multimodal therapy was studied more than single therapeutic intervention. There was vast heterogeneity across the studies, including study design, diagnostic criteria, intervention type, and outcomes. Conclusion From the data available, there does not seem to be a singular superior treatment approach. Accordingly, the most appropriate treatment modality will need to be tailored to the patient and their caregivers. Further research is required regarding management of MOH in children and adolescents.

561 Background: Obesity and other lifestyle factors are associated with breast cancer (BC) risk and outcomes. These relationships appear to vary in pre- vs postmenopausal women. Here we explore associations between pathological features, diet quality and physical activity (PA) in patients (pts) with BC enrolled in the BWEL (Alliance for Clinical Trials in Oncology A011401) trial, stratifying for menopausal status. Methods: BWEL is a phase III trial evaluating the impact of a weight loss intervention on disease outcomes in 3180 pts with stage II-III HER2– BC and body mass index ≥27 kg/m 2 . The first 542 BWEL pts underwent assessment of PA (7-Day PA Recall) and diet (24-hour Diet Recall) at enrollment. Healthy Eating Index 2020 (HEI) score (0-100, higher value = healthier diet) and minutes/week (min/wk) of moderate/vigorous PA (MVPA) were calculated. Estrogen receptor (ER) and progesterone receptor (PR) expression level (%) were abstracted from pathology reports. Analyses of links between HEI score, MVPA min/wk, % ER/PR, stratified by menopausal status, were conducted using t-tests; differential associations by menopausal status used linear regression models with interaction term. Results: In 523 pts with available pathology data, 76.5% had ER/PR+ BC, 56.2% were postmenopausal. Median HEI score was 50.1 (range 18.1-96.4), median MVPA min/wk was 0 (range 0-630), median time from diagnosis to enrollment was 10.0 months (range 2.4-13.1). In postmenopausal pts, higher diet quality was linked to increased % ER and PR (HEI above vs below median, mean % ER 78.0 vs 66.1, p=0.012; mean % PR 57.7 vs 43.1, p=0.004). The relationship between HEI score and % ER/PR differed significantly by menopausal status (interaction term of menopausal status and % ER: p=0.006; and % PR: p=0.012); there were no significant associations between HEI scores and % ER/PR in premenopausal pts. There were no significant associations between PA and % ER/PR. Conclusions: Healthier diet was associated with higher % ER and PR in postmenopausal pts with BC, but no relationship was seen in premenopausal pts. These data suggest that lifestyle factors may influence BC pathologic features related to outcomes in older women. Support: U10CA180821, U10CA180882, UG1CA189823, U24CA196171, https://acknowledgments.alliancefound.org . Clinical trial information: NCT02750826 . % ER mean (SD) p value % PR mean (SD) p value Post-Menopausal HEI* score≤50.1 [n=134]>50.1 [n=156] 66.1 (43.3)78.0 (36.8) 0.012 43.1 (41.8)57.7 (41.0) 0.004 MVPA † min/wk0 [n=147]≥1 [n=147] 74.5 (39.3)70.3 (41.2) 0.37 50.0 (41.8)53.0 (42.0) 0.41 Pre-Menopausal HEI* score≤50.1 [n=124]>50.1 [n=103] 70.5 (38.5)65.5 (43.0) 0.15 53.5 (41.1)49.1 (43.0) 0.43 MVPA † min/wk0 [n=112]≥1 [n=113] 66.3 (41.0)66.3 (41.2) 0.99 49.5 (41.4)52.6 (42.7) 0.59 *Healthy Eating Index. † Moderate/Vigorous Physical Activity.