Citations

Abstract Everolimus 10 mg daily is the standard dose for advanced neuroendocrine tumors (NETs), but adverse events frequently necessitate dose reduction. As a result, oncologists often adopt a dose‐escalation strategy starting at 5 mg and increasing the dose as tolerated. In this multicenter study, we evaluated the effect of reduced dose (RD) and standard dose (SD) everolimus on survival, progression, and toxicity in patients with advanced NETs. We conducted a multicenter retrospective cohort study of patients with advanced NETs treated with everolimus at Mayo Clinic and University Hospitals (Cleveland, OH). Patients were grouped by starting dose (5 mg vs. 10 mg). Primary endpoints were overall survival (OS), real‐world progression‐free survival (rwPFS), and adverse events. Multivariable Cox models, inverse probability of treatment weighting (IPTW), and time‐varying dose sensitivity analysis were used to account for confounding and dose crossover. Among 170 patients (48 started on 5 mg; 122 on 10 mg), the 5 mg cohort was older, had worse ECOG PS, and was more heavily pretreated. Median OS was 43.7 months (5 mg) versus 81.5 months (10 mg; log‐rank p = .02). However, after multivariable adjustment ( N = 124 G1–G2 patients; 51 events), the association was no longer statistically significant (adjusted HR, 0.59; 95% CI, 0.31–1.12; p = .11). Median rwPFS was 7.0 versus 12.4 months (log‐rank p = .05); the adjusted rwPFS difference was not statistically significant (HR, 0.95; 95% CI, 0.56–1.61; p = .84). Nearly half (46.7%) of 10 mg starters required dose reduction. Any‐grade toxicity was more common with 10 mg (89% vs. 75%; p = .05). The apparent survival advantage of standard‐dose everolimus was substantially attenuated after adjustment. These findings do not establish dose equivalence and should be interpreted in the context of limited statistical power. Given its more favorable observed tolerability profile, RD everolimus warrants prospective evaluation as a starting strategy for patients at increased risk of treatment‐related toxicity who may not tolerate SD.

Abstract Orthopaedic literature often establishes cutoffs when evaluating risk factors for an outcome of interest, whether patellar instability or most any other pathology. Although such cutoffs are intuitively easy to apply to clinical practice and testing situations, they leave much to be desired when it comes to nuanced patient care. As we increasingly recognize patient‐to‐patient differences, our approach to historic cutoffs such as tibial tubercle‐trochlear groove distance merits a revisit. A reasonable first step is to adjust for patient‐specific factors such as height and sex. However, as larger datasets and deeper mechanistic insights become available, we may ultimately move beyond simplistic thresholds altogether, advancing instead toward truly individualized precision medicine.

Purpose: To assess chest computed tomography (CT) manifestations of Legionella pneumonia (LP) in a large, well-characterized immunocompetent and immunocompromised patient cohort. Materials and Methods: This retrospective study identified LP patients across a multicenter hospital system over 84-months. Chest CTs were reviewed for presence and distibution of ground-glass opacity (GGO), consolidation, and numerous other findings. CT findings were categorized into lobar, bronchopneumonia, atypical, and mixed patterns. Evolution on follow-up CT was assessed. Results: 311/346 patients (median age 66.6 y [IQR: 55.9, 74.8]; 178 [57.2%] male) had CT examinations available. GGO (98.1%, 305/311) and consolidation (92%, 286/311) were the most prevalent findings, commonly coexisting. The segmental pattern occurred most frequently. The GGO and reverse halo signs occurred in 6.1% (19/311) and 3.5% (11/311), respectively. Follow-up CT occurred in 58.5% (182/311) (median=47.5 d), demonstrating improvement in 84.1% (153/182), worsening in 10.4% (19/182), stability in 5.5% (10/182), and new CT patterns in 12.6% (23/182). Respiratory co-infection occurred in 27.0% (84/311), commonly bacterial. Cavitation occurred in 7.1% (22/311), more frequently among co-infected patients (14.3%, 12/84) than isolated LP (4.4%, 10/227, P =0.005), even more common among immunocompromised patients (12.0% [18/150] vs. 2.5% [4/161], P =0.001), the highest prevalence among co-infected immunocompromised patients (21.3%, 10/47). Co-infection (odds ratio [OR]=3.26, 95% CI=1.33-8.00; P =0.01) and immunocompromise (OR=4.93, 95% CI=1.61-15.1; P =0.005) were independently associated with cavitation. Conclusions: LP presents nonspecifically with a multilobar segmental pattern of GGO and consolidation. Respiratory co-infection was common, often heralded by cavitation. CT findings improve after LP diagnosis.

The immune tumor microenvironment (iTME) plays a crucial role in disease biology of plasma cell (PC) dyscrasias, but remains poorly characterized in self-identified Black individuals, a population at increased risk. Mass cytometry and scRNA-seq of 128 bone marrow aspirates revealed significant changes in immune cell composition across the disease spectrum, including shifts from naïve to effector T cells with declines in B cells, MAIT, pDCs, and increases in monocytes with disease progression. Self-identified Black patients had higher relative proportions of terminally differentiated T cells and lower monocytes in newly diagnosed and treated multiple myeloma (MM). ScRNA-seq revealed genes overexpressed in self-identified Black individuals were enriched for E2F targets and G2-M checkpoints, while reduced genes were enriched for TNF-α/NF-kB, interferon and inflammatory responses pathways. These findings were supported by genetic ancestry and validated in an independent dataset of 286 patients with MM from the MMRF Immune Atlas. Self-identified race and African genetic similarity are significantly associated with remodeling the MM iTME, with potential implications for disease biology and treatment response.

Importance Rapid whole-genome sequencing (WGS) has advanced inpatient genetic diagnosis, although most evidence comes from neonatal and pediatric intensive care unit (ICU) populations. Its utility for pediatric neurology inpatients across broader acute settings remains insufficiently established. Objective To assess the diagnostic yield, clinical impact, and factors associated with phenotype-concordant rapid WGS diagnoses. Design, Setting, and Participants This was a retrospective cohort study conducted from June 1, 2022, through January 17, 2026, at a tertiary medical center. Pediatric inpatients in the neonatal ICU, pediatric ICU, or general floor with an unexplained neurologic presentation were included. Those with established nongenetic etiology were excluded from analyses. Exposures Trio (77.8%), duo (9.1%), or singleton (13.1%) rapid WGS. Main Outcomes and Measures The primary outcome was the initial phenotype-concordant diagnostic yield at the point of care. Secondary outcomes were reanalysis yield (new diagnoses from reinterpreting nondiagnostic cases prompted by a new unexplained phenotype or family request), cumulative yield, and management change. Associations were assessed by logistic regression (odds ratios [ORs] and 95% CIs). Results Among 175 children (median [IQR] age, 4 months [1 day-4 years]; 93 male [53.1%]) who met inclusion criteria (82 neonates, 93 nonneonates), initial rapid WGS established a phenotype-concordant diagnosis in 79 (45.1%), higher in nonneonates (49 of 93 [52.7%]) than neonates (30 of 82 [36.6%]). Preliminary results returned at mean (SD) 4.0 (1.6) days and final reports at 10.4 (4.5) days. Positive nonconcordant findings occurred in 33 children (18.9%). Reanalysis of 14 nondiagnostic cases yielded 3 additional diagnoses, for a cumulative yield of 82 of 175 children (46.9%). Most diagnoses were monogenic (63 [76.8%]). Management changed in 54 of 82 phenotype-concordant cases (65.9%; 53 at the point of care, 1 after reanalysis) and 8 of 33 (24.2%) positive nonconcordant cases. Family history was most strongly associated with diagnosis (adjusted OR [aOR], 6.46; 95% CI, 3.23-12.93; P < .001), followed by multisystem involvement (aOR, 2.85; 95% CI, 1.24-6.54; P = .01) and congenital anomaly or dysmorphism (aOR, 2.47; 95% CI, 1.07-5.68; P = .03). Hypotonia was most strongly associated in neonates (OR, 20.63; 95% CI, 5.46-77.87; P < .001); ICU admission (OR, 10.25; 95% CI, 2.79-37.67; P < .001) predominated in nonneonates. Conclusions and Relevance Results of this cohort study suggest that rapid WGS diagnosed nearly half of pediatric neurology inpatients and changed management in two-thirds of diagnosed cases, supporting its potential use as early diagnostic testing. Associated features may guide patient selection, and reanalysis extends yield longitudinally.

Abstract Context Menstrual irregularities have been associated with cardiovascular disease (CVD) risk, but underlying etiologies may confer distinct risk profiles. Functional hypothalamic amenorrhea (FHA) has not been evaluated as a separate risk phenotype. Objective To assess the association between FHA phenotype and incident CVD and cardiometabolic risk factors. Design Prospective cohort study with biennial follow-up from 1993 to 2019. Setting Nurses’ Health Study II cohort. Participants The sample included 52,655 premenopausal women free of CVD in 1993. FHA phenotype was defined as irregular or absent cycles without PCOS traits combined with low body mass index and/or high physical activity. Intervention None Main Outcome Measures Incident CVD (coronary heart disease [CHD; myocardial infarction or coronary revascularization] and stroke) and incident elevated cholesterol, hypertension, and type 2 diabetes (T2DM). Results During up to 26 years of follow-up, 1,007 CVD events occurred. Among women who developed CVD, the median time to the first CVD event was 17.0 years (IQR, 11.3-21.0). FHA phenotype in mid-adulthood was associated with a 62% higher risk of CVD (95% confidence interval [CI]: 1.01–2.59), driven by an almost two-fold higher risk of CHD (hazard ratio [HR] = 1.91; 95% CI: 1.11–3.27), compared with women with regular cycles. FHA was also associated with T2DM (HR = 1.86; 95% CI: 1.41–2.47), but not hypertension or elevated cholesterol. Non-FHA menstrual irregularity was associated with elevated cholesterol, hypertension, and T2DM, but not CVD. FHA in early adulthood was not associated with outcomes. Conclusions FHA phenotype in mid-adulthood was associated with increased CHD risk independent of traditional risk factors. Menstrual history may serve as an early marker of cardiometabolic risk.

Environmental conditions experienced early in life have profound consequences for vertebrate health, yet the molecular pathways linking developmental stress to aging and reduced lifespan remain poorly understood. Through a novel highly accurate epigenetic clock, developed from RRBS-based blood DNA methylation profiles, we show that experimental lifespan-reducing early-life stress rapidly accelerates epigenetic age in zebra finch chicks (Taeniopygia guttata). Corticosterone-treated 29-day-old chicks share differentially methylated loci with non-treated aged birds and cluster with 6-month-old birds. The transcriptional repressor ZBTB16 emerges as an epigenetically top age-correlated gene and is strongest affected by corticosterone. Elevated developmental corticosterone causes rapid epigenetic remodelling of metabolic pathways well-established in aging and longevity. Our results demonstrate epigenetic rewiring of the aging trajectory through conserved stress-survival mechanisms immediately following elevated early-life stress exposure.

Background: Many neurological and cognitive disorders have early oculomotor hallmarks. The Oculo-Cognitive Addition Test (OCAT) is a quick, objective screening tool that measures eye movement and time-based biomarkers of cognitive processing during simple mental addition tasks in under two minutes. Normative values for age, sex, education level, and apolipoprotein E Type 4 (APOE ε4) carrier status must be established so cognitively normal populations are not misdiagnosed. Methods: A total of 382 participants completed OCAT, with 350 participants making up the normative cohort from which raw gaze data were processed to derive fixations, saccades, blinks, pupillary dynamics, and time-based features. Separate multiple linear regression models were fitted for each feature with age, sex, education, and APOE ε4 carrier status as predictors to establish demographic-adjusted normative equations. Results: Processing time, fixation time, fixation size and fixation area and their variability increased progressively from the first to the third number within each addition sequence, consistent with increasing cognitive workload. Demographic-adjusted multiple linear regression models generated normative equations for individual OCAT features based on age, sex, education, and APOE ε4 carrier status. These models were used to derive individualized expected values, 95% reference intervals, and z-scores. Conclusions: These demographic-adjusted normative equations enable individualized interpretation of OCAT performance and are necessary steps towards clinical implementation.