Citations

Abstract Study Objectives Narcolepsy is a chronic condition affecting the sleep/wake cycle that is challenging to diagnose. Epidemiological data from large US-focused studies remain limited, with no validated claims-based case selection definitions for narcolepsy. We estimated the prevalence/incidence of diagnosed narcolepsy (type 1 [NT1], type 2 [NT2], overall) in an insured US population using validated, claims-based narcolepsy case definitions. Materials and Methods This observational study used HealthVerity administrative claims-linked electronic medical records to develop case definitions identifying individuals with NT1, NT2, and overall narcolepsy from diagnosis, medication, and procedure codes. Claims-based case definition performance (NT1, NT2, overall narcolepsy) was assessed using positive predictive values (PPVs). Prevalence (per 100 000 persons, on December 31, 2023) and annual incidence (per 100 000 person-years [PY], 2020 − 2023) were calculated/adjusted using PPVs for each case definition. Results Unadjusted point prevalence among individuals with ≥12 months of continuous enrollment were 15.5/100 000 (NT1), 51.1/100 000 (NT2), and 67.0/100 000 (overall narcolepsy). Unadjusted incidence rates were stable from 2020 − 2023 for NT1 (range, 2.0 − 2.3/100 000 PY) but declined across years for NT2 (9.1 − 7.6/100 000 PY) and overall narcolepsy (11.3 − 9.6/100 000 PY). PPVs (95% confidence interval) of NT1, NT2, and overall narcolepsy were 0.81 (0.72 − 0.88), 0.84 (0.75 − 0.91), and 0.80 (0.71 − 0.87), contributing to epidemiologic estimates being reduced by ~20% after PPV adjustment. Prevalence and incidence were higher in females than males. Individuals with NT1 were ~ 4 years younger versus NT2. Conclusions Validated definitions for narcolepsy can reduce potential misclassification. Our findings highlight a relatively low NT1 prevalence in the US. In contrast, NT2 prevalence estimates were > 3 times higher than NT1.

Abstract Problem The Association of American Medical Colleges has urged actions to promote inclusivity in medical education for historically underrepresented groups. Studies suggest that underrepresentation may be addressed through structured mentorship and workshops at the premedical level and generate interest in less familiar specialties including physical medicine and rehabilitation (PM&R). Approach The authors implemented a novel half-day multi-institutional workshop in spring 2024 featuring physicians and medical students from New York City medical centers. The workshop included structured mentorship and pertinent PM&R-related topics, including disability health and adaptive sports, to which premedical students often have limited exposure. Participants were invited to complete pre- and postworkshop surveys to evaluate the workshop’s impact. The authors collaborated with prehealth chapters of organizations such as the American Medical Women’s Association and the Minority Association of Pre-Medical Students to distribute surveys. Outcomes The preworkshop survey was completed by 147 premedical students, and 81 registered for the workshop. Ultimately, 55 attended the workshop, with 71% completing the postworkshop survey. Most participants had no previous exposure to PM&R (n = 77, 53.5%) and to adaptive sports (n = 116, 80.6%). Furthermore, although 76 (52.8%) had shadowed a physician, only 6 (4.2%) had experience shadowing a PM&R physician. The authors gathered a diverse representation of responses, including those identifying as female (n = 119, 81.0%) and underrepresented in medicine (n = 84, 57.1%). Pre–post comparative analysis showed a statistically significant rise in students’ motivation to apply to medical school (P = .018), along with a statistically significant increase in the interest and understanding of PM&R and adaptive sports (P < .001). Next Steps Future work will focus on developing longitudinal mentorship, improving accessibility through hybrid formats, and expanding the curriculum through interspecialty collaborations to support broader implementation and evaluation.

Background/Aims: Infections with drug-resistant organisms (DROs) are associated with poor outcomes in cirrhosis. Rifaximin, widely used for hepatic encephalopathy (HE), could promote cross-resistance, but data regarding clinical impact are conflicting. Aim: Determine predictors of DROs in a global cirrhosis inpatient cohort focusing on preadmission rifaximin use.Methods: From the global CLEARED consortium, we focused on cirrhosis inpatients with infections on/during admission. Clinical/demographic/medication, especially rifaximin details were recorded. The primary outcome was DRO development. Multivariable regression for DRO including clinical, medications, and country income was performed.Results: 2,949 infected inpatients (55.3 years, 62.9% male) were included. 12.2% of all and 24.4% of culture-positive infections developed DROs; these patients had higher HE (39 vs. 31%, <i>P</i>=0.003), hepatorenal syndrome (25 vs. 19%, <i>P</i>=0.006), lactulose (55 vs. 47%, <i>P</i>=0.008) and rifaximin use (34 vs. 27%, <i>P</i>=0.006) on crude comparisons but country-income distributions were similar. 29.7% were on pre-admission rifaximin, mostly HE-related; they had more advanced cirrhosis and from low/low-middle-income countries. Daptomycin was used in 1.5%, linked with DROs (5.0 vs. 1.0%, <i>P</i><0.0001) without a difference in rifaximin use (1.4 vs.1.7%, <i>P</i>=0.61). On adjusted analysis, MELD-Na (1.03, 95% CI 1.02–1.04, <i>P</i><0.001) increased, whereas male sex (0.73, 95% CI 0.58–0.92, <i>P</i>=0.008) and hepatitis-B (0.65, 95% CI 0.45–0.92, <i>P</i>=0.020) decreased DRO. Rifaximin was not associated with DROs overall (OR 1.07, 95% CI 0.80–1.43, <i>P</i>=0.65) or within income strata (high: 1.07, 95% CI 0.59–1.92, <i>P</i>=0.82, upper-middle: 1.18, 95% CI 0.74–1.85, <i>P</i>=0.49, low/low-middle: 1.04, 95% CI 0.60–1.81, <i>P</i>=0.90) despite sensitivity analyses.Conclusions: In this large global cohort of hospitalized patients with cirrhosis and infections, 12% developed infections involving DROs. 30% had pre-admission rifaximin use which was not linked with daptomycin use or with DRO development on adjusted analysis overall or across country income groups.

PURPOSE GBM AGILE (ClinicalTrials.gov identifier: NCT03970447 ) is a phase II/III Bayesian adaptive platform registration trial testing multiple arms against a common control; the primary end point is overall survival (OS). Regorafenib, a multikinase inhibitor, showed OS benefit in recurrent (RD) glioblastoma in the phase II REGOMA trial and entered GBM AGILE as the first investigational arm. METHODS Patient subtypes included in the regorafenib arm of GBM AGILE were newly diagnosed unmethylated (NDU) and RD glioblastoma. Prospective defined sets of subtypes, or arm signatures, were NDU, RD, and all (NDU + RD). As the first investigational arm in GBM AGILE, regorafenib was equally randomized to the control arm. Treatment in the control arm is temozolomide + radiotherapy (in newly diagnosed) or lomustine (in RD). Efficacy was assessed by OS hazard ratio (HR), arm/control, and demonstrated when the Bayesian probability of benefit (HR <1.00) was ≥98%. Analysis was performed monthly for limited efficacy, which occurs when the Bayesian predictive power is <25% for all signatures, and determines stopping enrollment. Follow-up continued for 12 months after accrual stopped. RESULTS When the predictive power was <25% in all predefined signatures for regorafenib, accrual stopped for limited efficacy. The final analysis did not demonstrate OS improvement in the regorafenib arm in RD nor NDU glioblastoma. Median HRs were 1.05 (NDU), 1.07 (RD), and 1.07 (all) with final probabilities of benefit (HR <1.00) of 0.421 (NDU), 0.312 (RD), and 0.296 (all). Regorafenib was associated with increased toxicity relative to control. CONCLUSION GBM AGILE did not show superiority of regorafenib over control in RD (lomustine) or NDU (temozolomide + radiotherapy) glioblastoma, yet caused increased toxicities. Regorafenib has been removed from National Comprehensive Cancer Network guidelines as a treatment option for RD.

Emergence of epidemic viruses in new hosts threatens both human and other animal populations, and often involves virus evolution to overcome barriers that normally prevent efficient infection and spread in that host. After transfer the separated viruses will evolve in parallel as they spread within the original and new hosts. Here we examine the details of a virus involved in such a host-jumping event, where we define the natural evolution of feline panleukopenia virus (FPV) over 60 y, clarify the origins of the new pandemic canine parvovirus (CPV) that arose in the 1970s, and compare the separate evolution of those viruses over 47 y in cats or dogs. Several live-attenuated FPV vaccine viruses originated from early-1960s isolates or were a recombinant of an early virus, and many sequences in databases proved to be vaccine-derived. The sequences of wild viruses showed that FPV-like strains evolved at less than one-third the rate observed for CPV in dogs, and the higher rate of CPV evolution has been consistent since 1979, when a genetic variant became widespread. The common ancestor of the CPV lineage was related to FPVs from Europe and contained several unique host-adaptive capsid changes associated with canine transferrin receptor type-1 binding. Although the FPV vaccine strains are around 60 y old, little selection for antigenic variation was observed. The distinct evolutionary patterns of these closely related viruses circulating for decades in different hosts emphasize the complex evolution associated with viral epidemic emergence and spread in endemic and new hosts.

Abstract We evaluated outcomes by management type for patients with stage IA nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) in the Global NLPHL One Working Group retrospective database of 2243 patients with stages I to IV disease diagnosed from 1992 to 2021 at 38 international institutions. A total of 779 patients had stage IA disease with median age of 35 years (range, 3-89) and median follow-up of 6.1 years. The 6-year progression-free survival (PFS) and overall survival were 86.3% and 97.7%, respectively. Outcomes were analyzed for the 2 groups: complete resection and unresected disease. Patients with a complete resection and observation alone (n = 99) had a 6-year PFS of 65.5% vs 90.5% for those who received radiotherapy (RT) (n = 53). Patients with unresected disease (n = 627; 80.5%) had a 6-year PFS of 62.0% for rituximab alone (n = 31), 89.6% for RT alone (n = 325), 76.8% for ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) alone (n = 40), and 94.3% for ABVD plus RT (n = 130). A total of 127 patients relapsed (16.3%), of which 25 (19.7%) had transformation. Our analysis suggests the following: (1) RT improves the PFS in patients with completely resected disease; (2) rituximab or ABVD alone does not appear to achieve a durable response; and (3) chemotherapy was not observed to add additional PFS benefit when used in combination with RT. Thus, for stage IA NLPHL, RT alone is likely sufficient for definitive treatment.

Importance Transcatheter tricuspid valve replacement (TTVR) demonstrated superior outcomes over medical therapy in patients with severe tricuspid regurgitation (TR) in the Edwards EVOQUE Transcatheter Tricuspid Valve Replacement: Pivotal Clinical Investigation of Safety and Clinical Efficacy Using a Novel Device II (TRISCEND II) randomized clinical trial, and received regulatory approval in the US in 2024. Contemporary real-world data on its effectiveness and safety remain limited. Objective To evaluate 30-day clinical, echocardiographic, and health status outcomes of TTVR in real-world use. Design, Setting, and Population Retrospective cohort study of all consecutive patients who underwent TTVR in the US from February 2024 through March 2025 in the Society of Thoracic Surgeons/American College of Cardiology Transcatheter Valve Therapy Registry. Patients had symptomatic, severe TR despite optimal medical therapy and TTVR was deemed appropriate by a heart team. Statistical analysis was conducted from September 2025 to February 2026. Exposure Device-enabled TTVR. Main Outcomes and Measures Thirty-day event rates (all-cause death, stroke, bleeding, new cardiac implantable electronic device [CIED] implantation, heart failure hospitalizations), TR reduction, and changes in health status (New York Heart Association [NYHA] functional class and Kansas City Cardiomyopathy Questionnaire Overall Summary [KCCQ-OS] score) are reported. Subgroup analyses examined the impact of baseline CIED status on outcomes. Results Among 1034 attempted procedures at 82 centers (mean [SD] age, 77.1 [10.6] years; 69.1% female; 73.2% NYHA functional class III/IV), a valve was successfully implanted in 1017 patients (98.4%). Mild or less TR was achieved in 98.4% of patients post procedure and in 97.7% at 30 days. At 30 days, all-cause mortality was 3.1%; stroke, 0.2%; bleeding, 7.9%; new CIED, 15.9% in CIED-naive patients; and heart failure hospitalization, 3.1%. There were significant improvements in NYHA functional class (class I/II, 82.7%; P &amp;lt; .001) and mean KCCQ-OS score (22.4 points; P &amp;lt; .001) from baseline to 30 days. There were no significant differences in 30-day mortality ( P = .47), heart failure hospitalization ( P &amp;gt; .99), and functional outcomes ( P = .55) when patients were stratified by baseline CIED status. Conclusions and Relevance Early US real-world experience with TTVR confirms safety and effectiveness in patients with severe TR. Thirty-day outcomes are consistent with the TRISCEND II pivotal trial, demonstrating acceptable safety, near-complete TR elimination, and significant health status improvements in an older, comorbid population. Rates of new CIED implantation and bleeding were lower than randomized clinical trial experience.

Background: Rib remodeling, particularly targeting ribs 11 and 12, is gaining popularity in aesthetic body contouring to reduce waist circumference. Although rib manipulation techniques have been applied in other surgical fields, their use in plastic surgery has focused on achieving aesthetic goals. This study investigates the complications associated with rib remodeling techniques to enhance waistline contouring. Methods: A global cross-sectional survey was conducted among board-certified plastic surgeons who perform rib remodeling. Data from 2351 patient records (2018–2024) were collected, including demographic details, surgical information, and complications. Rib remodeling techniques assessed included surgical greenstick fracture modification and osteosynthesis. Results: The overall complication rate was 3.7% (86 of 2351 patients). Hyperpigmentation (17.4%), nonconsolidation (15.1%), burns (12.7%), and corset-related pressure ulcers (12.7%) were the most common complications. Major complications such as pneumothorax were rare (0.17%) and occurred only in RibXcar cases. Rib extraction/removal techniques had no reported complications, whereas Riboss had the lowest complication rate (1.96%) due to the use of osteosynthesis material for fracture stabilization. Conclusions: The incidence of complications related to the rib remodeling procedures in our study was 3.7%. However, some procedure-related complications—such as pneumothorax and hemothorax—can pose serious risks to the patient’s life. Nevertheless, when performed by a well-trained surgeon with an adequate learning curve, these procedures can be considered safe.

The brain is a highly recurrent, nonlinear network hypothesized to remain near the edge of chaos for optimal performance. Excitation and inhibition must be balanced precisely within every neuron to ensure a consistent level of dynamical stability and rich dynamics during transition to chaos. However, analysis of biologically realistic synaptic weight matrices suggests that sparsity and low-dimensional structure interact such that there is no known synaptic balancing rule that constrains the stability (i.e., eigenvalues) of the network while also preserving computationally useful, low-dimensional structure. Further, even if a network were well-balanced, external stimuli interact with the nonlinear activation functions to unbalance the network in real time. Therefore, the brain must utilize dynamic, rather than static, mechanisms to actively regulate its level of stability. We propose that two specific adaptation mechanisms, spike frequency adaptation (SFA) and short-term synaptic depression (STD), continuously modulate the effective connectivity, keeping the brain near the edge of chaos and reducing dynamical fluctuations caused by stimuli. This theoretical framework links intrinsic and synaptic negative feedback mechanisms to network-level dynamics. This offers an explanation of why data-driven modeling of human brain signals, an exciting and useful method in epilepsy and anesthesiology research, seems to require linear time-varying (LTV) models which are refit every half second: difficult to observe adaptation processes interact with nonlinearities to make connectivity effectively dynamic at the macroelectrode scale. We suggest that compromised adaptation may underlie neurological conditions characterized by altered excitability, and that targeted brain stimulation could be used to probe the regulatory action of adaptation.