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Many hormones and substances acting through G-protein coupled receptors and protein kinase A (PKA) activation inhibit the salt-inducible kinases (SIKs) by phosphorylation. SIKs tonically phosphorylate CREB-regulated transcriptional coactivators (CRTC1, 2 and 3), sequestering them in the cytoplasm and, thus, preventing their translocation into the nucleus. Once in the nucleus, CRTCs bind CREB family member transcription factors and enhance their activity. We and others have shown that parathyroid hormone (PTH) activation of PKA and resultant SIK2/3 inhibition allows CRTC2/3 nuclear translocation. One of the major actions of CRTC2/3 in the osteoblast lineage is the regulation of transcription of Rankl, as well as other PTH-controlled genes. However, little is known about the role of these co-activators in the osteoblast lineage in vivo. Here, we have investigated whether there are basal effects in vivo on bone examined at 2 different ages of conditional deletion of these two co-activators in the osteoblast lineage using Col2.3-Cre. We found significant increases in body weight, length, bone mineral density, bone volume/total volume, trabecular thickness and number with decreased trabecular separation in young (2 months old) male mice, all of which dissipated by 6 months of age. Female mice showed minimal changes in the bone phenotype at either age. Nevertheless, there were gene expression changes in bones of both sexes at both ages, and in particular decreases in Rankl, Runx2 and Sost, and accompanying changes in Wnt pathway genes. These effects may explain the changes in the bone phenotype in the young male mice, but it is notable that there is a sexual dimorphism in the action of CRTC2 and CRTC3. Overall, the work supports the data from research in vitro and forms a basis for investigation of the role of these co-activators in PTH action in vivo.

BACKGROUND Anterior placental location has been cited as an independent risk factor for adverse obstetric outcomes, including need for induction of labor, postpartum hemorrhage (PPH), retained placenta, intrapartum Cesarean delivery, and pre-eclampsia diagnosis. (1-4) However, robust evidence to support this association is limited. OBJECTIVE To evaluate the relationship between placental location and subsequent maternal and neonatal outcomes. STUDY DESIGN We conducted a retrospective cohort study of patients who delivered at the Mayo Clinic (Rochester, MN) between May 2018 and May 2023. Patients with singleton pregnancies and ultrasound-confirmed placental location between 16-22 weeks were included. Patients with low-lying placenta, placenta previa, abnormal placentation, uterine anomalies or scheduled Cesarean delivery were excluded. Placental location was categorized as anterior, posterior, lateral, or fundal. Maternal outcomes included postpartum hemorrhage (PPH), prelabor rupture of membranes (PROM), mode of delivery, induction of labor, third-stage duration, and diagnosis of a hypertensive disorder of pregnancy or gestational diabetes. Neonatal outcomes included Apgar scores, birth weight, small for gestational age (SGA), large for gestational age (LGA), and NICU admission. Continuous variables were compared by one-way ANOVA; categorical variables by χ² or Fisher’s exact test. Bonferroni correction was applied for multiple comparisons. RESULTS A total of 4,145 patients were included (placental location: anterior n=2,039; posterior n=1,866; lateral = 158; fundal = 82). Demographic characteristics did not differ significantly across groups. The only maternal outcome achieving statistical significance after Bonferroni correction was PROM [including term or preterm rupture of membranes] (p=0.0003): rates were highest in fundal (18.3%) and lateral (11.4%) groups compared to anterior (7.3%) and posterior (6.8%) placentas. Rates of PPH, induction of labor, delivery modality, third-stage duration, and hypertensive disorders of pregnancy did not differ according to placental location. No neonatal outcomes met the Bonferroni-corrected significance threshold, though a trend toward higher rates of SGA neonates was noted in the lateral group (11.4% vs 5.9% posterior, overall unadjusted p=0.024). CONCLUSIONS Contrary to prevailing clinical assumptions, anterior placentation was not associated with increased rates of PPH, labor induction, or operative delivery in this cohort. Fundal placental location was associated with higher rates of PROM. These findings suggest clinical counselling about placenta-related obstetric risk may need to be reassessed, with particular attention to fundal placental location and PROM risk.

Abstract Purpose Bibliometric indicators are widely used to evaluate faculty productivity, yet these metrics change with career stage, evolving authorship practices, and technological shifts in how science is produced. This study examines patterns of scholarly output among radiation therapy medical physics faculty at leading cancer centers and provides a framework and quantitative metrics for managing career age‐ and era‐based effects. Methods Peer‐reviewed articles (1969–2025) were collected from Scopus for 397 Ph.D. medical physics faculty at the 20 U.S. cancer centers most highly ranked by US News and World Report in 2025. The bibliometric measures included annual rates of authorships (), first/last authorships (), monograph‐equivalents (), as well as the cumulative h‐index and contribution‐normalized ha‐index. Career age was defined by year of first publication. Productivity distributions were evaluated by career age using empirical cumulative distribution functions derived from 2016–2025 data. Era‐dependent fluctuations (1990–2025) were examined using age‐normalized metrics and trends in authorship team size. Tabulated bibliometrics as a function of career age are provided for evaluation of individual performance. Results Productivity increased substantially with career age, peaking in late career. Senior faculty produced approximately two‐fold higher annual output than early‐career peers. At career ages of 1, 10, 20, 30, and 40 years, the median bibliometric rates were = (1.2, 1.6, 2.5, 2.5,1.8) year −1 , = (0.4, 0.4, 0.5, 0.5,0.2) year −1 , = (0.2, 0.2, 0.3, 0.3,0.3) year −1 , h‐index = (0, 7, 15, 23,43), and ha‐index = (0, 3.3, 6.0, 9.4,15.0). Era‐based effects were substantial. Between 1990 and 2025, median authors per paper increased from 4 to 10, inflating authorship‐based metrics. In contrast, contribution‐weighted measures (FL, ME, ha‐index) demonstrated greater temporal stability. Conclusions Scholarly productivity in radiation therapy medical physics is strongly dependent on career age, with peak output occurring near the end of a typical career before declining modestly near retirement. Career‐age‐based percentile benchmarks provide a more balanced framework for evaluating academic performance than unadjusted bibliometric comparisons, especially for early‐career investigators. Due to changes in authorship norms over time, first/last authorships, monograph equivalents, and ha‐index may provide more accurate and equitable assessments of research performance than authorships or h‐index.

Abstract Context Salivary cortisol and cortisone provide non-invasive measures of biologically active cortisol, but their performance during dynamic testing remains incompletely defined. The utility of salivary dexamethasone to confirm exposure during dexamethasone suppression testing (DST) is unknown. Objective To compare salivary cortisol, cortisone, and dexamethasone with serum measurements during dynamic adrenal testing and to derive salivary cortisol and cortisone thresholds corresponding to clinically relevant serum cortisol concentrations. Design and Setting Cross-sectional study at a tertiary referral center. Participants Adults undergoing DST (n = 473), cosyntropin stimulation testing (CST; n = 163), or overnight metyrapone testing (OMT; n = 11). Measurements Serum cortisol was measured by immunoassay. Serum and salivary dexamethasone, salivary cortisol and cortisone were quantified by liquid chromatography–tandem mass spectrometry. Results Among 640 participants, 815 paired serum and salivary samples were analyzed. Salivary cortisol and cortisone correlated well with serum cortisol across dynamic testing, with the greatest difference following 1-mg DST (r = 0.86 vs 0.53 for cortisone and cortisol, respectively; both P < 0.001). During CST, correlations ranged from r = 0.75–0.87 for both analytes (all P < 0.001). Salivary dexamethasone correlated with serum dexamethasone (r = 0.61, P < 0.001). Salivary cortisone thresholds corresponding to prespecified clinically relevant serum cortisol concentrations of 1.8, 5, 10, and 18 µg/dL (50, 138, 276, and 497 nmol/L) were 117, 329, 585, and 1262 ng/dL (3.25, 9.13, 16.23, and 35.01 nmol/L), respectively; corresponding salivary cortisol thresholds were 16.5, 38, 80, and 278 ng/dL (0.46, 1.05, 2.21, and 7.67 nmol/L). Conclusions These findings support saliva-based dynamic adrenal testing and identify clinically relevant salivary thresholds.

Traditional home-call managing after-hours pager communications remains a common component of hematology-oncology fellowship and modern practice. Little is known about these patient-related interactions and implications. This project aimed to characterize after-hours pager volumes and evaluate perceived impacts on care, physician wellbeing, and trainee education. We performed a mixed-methods study at a tertiary academic center, analyzing after-hours pager activity from 2020-2024 across Hematology Consult (HCP), Hematology Outpatient (HOP), and Medical Oncology (MOP) pagers. A survey of hematology-oncology fellows evaluated perceptions and attitudes toward the home-call experience using free-text responses and a 5-point Likert scale. After-hours pager burden was substantial and sustained. The MOP received >3,000 pages annually, with medians of 5-6 per weekday and 15-15.5 per weekend day. The HOP volume nearly doubled over the study period (960 to 1,721 annually) with median pager volumes of 1-3 per weekday and 2-7 per weekend day. The HCP volume ranged from 594-768 pages annually. Survey response rate was 58% (19/33). Only 16% of fellows endorsed educational value from patient calls on MOP or HOP, and ≤5% agreed that call tasks required physician-level expertise. Respondents reported that the pager resulted in fatigue, anxiety, and social disruptions. Free text responses revealed themes of low educational value, high non-urgent call volume, and system inefficiencies. Contemporary home-call had substantial pager burdens with limited actionability, adverse effects on wellbeing, and low educational value. Systems engineering, including triage processes and augmented patient education, could help optimize patient care, physician wellbeing, and trainee education.

Abstract Varlilumab is a monoclonal antibody with agonistic activity on CD27. The efficacy of single-agent PD-1 inhibitors on aggressive B-cell non-Hodkin lymphoma is limited. Preclinical and phase 1 data suggest that Varlilumab is safe and may have synergistic activity with PD-1 inhibitors. In the DIAL study, we explored whether dual immunomodulatory therapy with Varlilumab and Nivolumab in patients with relapsed/refractory aggressive B-NHL was safe and effective. We conducted a randomized phase II clinical trial on adult patients with relapsed/refractory aggressive B-NHL. Patients were randomized to receive Nivolumab monotherapy in the control group and Varlilumab combined with Nivolumab in the experimental group. Crossover to the experimental group was allowed upon progression in the control group. The primary endpoint was the overall response rate based on the Lymphoma Response to Immunomodulatory Therapy Criteria (LYRIC). 54 patients underwent randomization, and 51 received assigned intervention and were included in the intention-to-treat analysis. Objective response was observed in 6 out of 51 patients (ORR 12%). There were 4 responders (ORR 16%) in the Nivolumab group and 2 responders (ORR 7.6%) in the Nivolumab and Varlilumab combination group (p = 0.3). None of the 7 patients that crossed over to the experimental group responded to the addition of Varlilumab. The ORR of patients who were previously exposed to CAR-T cell therapy was 13% (5 out of 39) compared to 8.3% (1 out of 12) in the unexposed patients (p > 0.99). The rate of treatment emergent adverse events was similar between groups, and there was no fatal TEAE in the study. The addition of Varlilumab to Nivolumb did not improve outcomes in patients with aggressive B-NHL. Even though this trial was not designed to evaluate immunotherapy as a rescue therapy after CAR-T failure, most patients (76%) had previously received CAR-T therapy, and their outcomes were equally poor.

Background/Objectives: Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome and hemophagocytic lymphohistiocytosis (HLH) are life-threatening conditions characterized by immune dysregulation. Several reports have identified an overlap between these entities; however, clinical characteristics, triggers, and outcomes remain poorly defined. The objective of this study was to characterize the clinical features and outcomes of DRESS/HLH overlap syndrome. Methods: We conducted a PRISMA-guided systematic review of PubMed, Embase, and MEDLINE. Studies were included if they reported cases meeting criteria for DRESS syndrome and HLH. Results: Thirty-six patients were included, 75% female and 27.8% pediatric. Initial misdiagnosis occurred in 30.6% and was associated with higher mortality (45.5% vs. 20.0%). Antibiotics were the most frequent triggers (36.1%) and 11.1% of patients had no trigger identified. Mean latency was 27.9 days for DRESS syndrome and 35 days for HLH, with shorter latency in antibiotic-associated cases. DRESS syndrome and HLH most commonly occurred sequentially (n = 22, 61.1%) and in 52.8% of cases DRESS preceded HLH. Fever and rash were present in 88.9%. Laboratory abnormalities included hyperferritinemia (91.7%), eosinophilia (77.8%), anemia (75.0%), and thrombocytopenia (75.0%). Hepatic involvement was nearly universal (94.4%), followed by renal involvement (36.1%). Viral reactivation was observed in 38.9%, multiorgan failure in 36.1%, and ICU admission in 19.4% of cases. Mortality was 27.8% and higher in steroid-refractory cases and those with multiorgan failure. Treatment included corticosteroids (97.2%), with IVIG (33.3%), etoposide (13.9%), and cyclosporine (5.6%) used in severe cases. Conclusions: DRESS-HLH overlap represents a severe hyperinflammatory syndrome with high mortality. Early recognition and escalation of therapy are essential to improve outcomes. This is the largest and most uniformly characterized cohort of DRESS/HLH overlap reported to date, and the first to stratify mortality by diagnostic accuracy, temporal pattern, corticosteroid responsiveness, and multiorgan failure. Because the syndrome is rare and the evidence base consists almost entirely of single-case reports, multicenter collaboration and a prospective registry are needed to define incidence and optimal therapy.

ABSTRACT Objectives Lasers are integral to contemporary endourologic stone surgery; however, reported institutional practices regarding laser access, personnel requirements, and safety protocols vary. We sought to characterize respondent‐reported laser access models, operational requirements, safety practices, and perceived barriers to care. Materials and Methods A cross‐sectional, web‐based 25‐item survey was distributed between October 2024 and March 2025 through social media, professional organizations, and departmental contacts. The survey assessed practice characteristics, laser access, physician and technician responsibilities, institutional safety requirements, and perceived barriers to care. Responses were self‐reported, collected anonymously, and summarized using descriptive statistics. Results A total of 187 respondents completed the survey; 85.6% identified as endourologists and 61.5% practiced in academic settings. Most respondents reported institution‐owned laser equipment (70.1%), while 9.6% reported contracted equipment and 20.3% combination models. Among respondents addressing contracted equipment availability ( n = 58), 55.2% reported ready access after regular business hours and 46.6% on weekends. Among 182 evaluable responses, 65.4% reported that physicians could operate lasers without a technician present. Fifty‐two respondents perceived that technician availability could affect patient care; among these, 40 reported potential delays in definitive treatment and 33 reported potential multiple or staged procedures. Staff laser safety goggles could be deferred according to 78.4% of evaluable responses, and 18.3% reported a prior institutional laser safety incident. Conclusion This survey identified substantial respondent‐reported variation in laser access, staffing requirements, and safety practices. The findings describe perceived institutional practices and barriers and do not establish effects on treatment delays, workflow efficiency, patient outcomes, or comparative safety. Future studies should directly compare institutional models using objective measures of access, workflow, treatment delays, and safety outcomes.

Background: A growing body of research has connected electronic health record (EHR) workload to physician burnout. In orthopedic surgery, burn-out rates are rising. This study analyzed orthopedic surgeons' EHR use by sex and practice experience. Materials and Methods: EHR activity was analyzed among attending orthopedic surgeons at a single institution from May 2022 to May 2023. Demographic information included self-reported sex and practice years. Outcomes included time spent in notes, orders, clinical review, and in-basket daily; time spent outside of scheduled clinical responsibilities; volume of in-basket messages received daily; and proportion of orders with team contributions. Multivariable linear regression compared outcomes by sex and practice years. Results: A total of 105 orthopedic surgeons were included (91% male; mean 15.5 ± 9.8 practice years). Female surgeons logged 31% more time in the EHR overall (62.2 vs 47.4 minutes daily; P = .05) and on unscheduled days (10.1 additional daily minutes; P = .03), and received more messages from patients (2.4 vs 1.0 messages daily; P = .002) compared to male surgeons. Senior surgeons spent significantly less time on documentation and orders ( P ≤ .048) and on unscheduled days (3.3 less minutes daily per practice decade; P = .013), and had more support with placing orders ( P < .001). Conclusion: Female sex and fewer practice years were associated with increased EHR use. Female orthopedic surgeons tended to have higher patient message volumes, whereas junior surgeons tended to have less team support, spending more time on orders and documentation. Given known factors contributing to burnout, these findings warrant further investigation into targeted interventions to improve physician EHR use.

Introduction: Large language models (LLMs) match or exceed physician accuracy on benchmark diagnostic tasks. Whether higher accuracy reflects human-like diagnostic behavior, which bears on how safely clinicians can supervise these systems, is rarely assessed. Objectives: To determine whether diagnostic accuracy and alignment with human reader responses move together across widely accessible LLMs under default, point-of-care conditions. Methods: This cross-sectional evaluation submitted the 29 most recent New England Journal of Medicine (NEJM) case challenges to 5 publicly accessible LLMs (GPT-5, Claude, Google Gemini, DeepSeek, and Grok) through each model’s web interface (November 5-8, 2025) at default settings, one query per case, no system prompt. Each case offered a clinical vignette and 6 candidate diagnoses; published human reader response distributions (4386-17 714 per case; median, 7732) were the comparator. Diagnostic accuracy against the published gold-standard diagnosis, compared with the human reader majority by the exact McNemar test; agreement by Cohen κ; alignment by a human-error similarity index (the share of model errors on cases the reader majority also missed) and by the Jensen-Shannon divergence (JSD) between each model’s response and the reader distribution; and ordinary least squares regression of per-case JSD on normalized reader-disagreement entropy. Results: Reader majority accuracy was 48.3% (95% CI, 31.4-65.6). All 5 reached or exceeded this value, from 51.7% for DeepSeek (95% CI, 34.4-68.6) to 82.8% for Grok (95% CI, 65.5-92.4); Grok (P = .02), GPT-5 (P = .004), and Gemini (P = .04) significantly exceeded the reader majority, whereas Claude and DeepSeek did not. Grok, the most accurate model, showed the weakest alignment (similarity index, 0.40; mean JSD, 0.50 bits), with 3 of 5 errors on cases readers answered correctly. GPT-5 showed the strongest alignment (index, 1.000), failing only on cases that also challenged readers. For 4 of 5 models, divergence rose with reader-disagreement entropy; DeepSeek was the exception. Conclusions and Relevance: In this evaluation, diagnostic accuracy and alignment with human reader responses diverged across LLMs. Because a model can outperform clinicians in aggregate yet fail where oversight is least likely to detect it, evaluation of clinical AI should weigh error structure alongside accuracy.