Citations

Abstract We conducted a national survey of current pediatric infectious diseases (PID) fellows and PID fellowship graduates from the past 10 years to assess satisfaction with existing PID initial certifying exam preparatory materials. Satisfaction with existing resources was low. The most desired new resource was additional board-style questions.

AbstractINTRODUCTIONThis study investigated the role of the ubiquitin–proteasome system (UPS) in dominantly inherited Alzheimer's disease (DIAD) by examining cerebrospinal fluid (CSF) levels of UPS proteins.METHODThe SOMAscan assay was used to detect changes in UPS proteins in mutation carriers (MCs) relative to disease progression; imaging and CSF biomarkers of amyloid, tau, and neurodegeneration measures; and Clinical Dementia Rating scale.RESULTSSubtle increases in specific ubiquitin enzymes were detected in MCs up to two decades before symptom onset, with more pronounced elevations in UPS‐activating enzymes near symptom onset. Significant correlations were found between UPS proteins and Alzheimer's disease (AD) biomarkers, especially between autophagy markers and late‐stage tau biomarkers, microglia, and axonal degeneration.DISCUSSIONThe rise in UPS proteins alongside tau‐related markers suggests UPS involvement in tau neurofibrillary tangles. Elevated CSF UPS proteins in DIAD MCs may serve as indicators of disease progression, and may support the UPS as a therapeutic target in AD.Highlights This study investigates the ubiquitin‐proteasome system (UPS) in Dominantly Inherited Alzheimer's Disease (DIAD), highlighting early molecular changes linked to disease progression. Using SOMAscan proteomics, we identified significant UPS protein alterations in cerebrospinal fluid of mutation carriers, notably up to 20 years before clinical symptom onset. Correlations between UPS protein levels and Alzheimer's biomarkers, particularly tau and neurodegeneration markers, suggest a strong association between UPS dysregulation and tau pathology in DIAD. Dynamic UPS changes align with A/T biological staging: UPS proteins were shown to increase across Aβ/tau (A/T) groups, with largest increases in the A+/T+ group, reinforcing their role in late‐stage tau pathology and disease progression. These findings underscore the potential of UPS proteins as early biomarkers for Alzheimer's disease progression and as novel therapeutic targets, especially in tau‐pathology‐driven neurodegeneration. This work contributes to understanding AD pathogenesis, by emphasizing the importance of protein quality control systems and by offering avenues for future biomarker discovery and therapeutic development in Alzheimer's disease.

Importance Nontraumatic subarachnoid hemorrhage (SAH) represents the third most common stroke type with unique etiologies, risk factors, diagnostics, and treatments. Nevertheless, epidemiological studies often cluster SAH with other stroke types leaving its distinct burden estimates obscure. Objective To estimate the worldwide burden of SAH. Design, Setting, and Participants Based on the repeated cross-sectional Global Burden of Disease (GBD) 2021 study, the global burden of SAH in 1990 to 2021 was estimated. Moreover, the SAH burden was compared with other diseases, and its associations with 14 individual risk factors were investigated with available data in the GBD 2021 study. The GBD study included the burden estimates of nontraumatic SAH among all ages in 204 countries and territories between 1990 and 2021. Exposures SAH and 14 modifiable risk factors. Main Outcomes and Measures Absolute numbers and age-standardized rates with 95% uncertainty intervals (UIs) of SAH incidence, prevalence, mortality, and disability-adjusted life-years (DALYs) as well as risk factor–specific population attributable fractions (PAFs). Results In 2021, the global age-standardized SAH incidence was 8.3 (95% UI, 7.3-9.5), prevalence was 92.2 (95% UI, 84.1-100.6), mortality was 4.2 (95% UI, 3.7-4.8), and DALY rate was 125.2 (95% UI, 110.5-142.6) per 100 000 people. The highest burden estimates were found in Latin America, the Caribbean, Oceania, and high-income Asia Pacific. Although the absolute number of SAH cases increased, especially in regions with a low sociodemographic index, all age-standardized burden rates decreased between 1990 and 2021: the incidence by 28.8% (95% UI, 25.7%-31.6%), prevalence by 16.1% (95% UI, 14.8%-17.7%), mortality by 56.1% (95% UI, 40.7%-64.3%), and DALY rate by 54.6% (95% UI, 42.8%-61.9%). Of 300 diseases, SAH ranked as the 36th most common cause of death and 59th most common cause of DALY in the world. Of all worldwide SAH-related DALYs, 71.6% (95% UI, 63.8%-78.6%) were associated with the 14 modeled risk factors of which high systolic blood pressure (population attributable fraction [PAF] = 51.6%; 95% UI, 38.0%-62.6%) and smoking (PAF = 14.4%; 95% UI, 12.4%-16.5%) had the highest attribution. Conclusions and Relevance Although the global age-standardized burden rates of SAH more than halved over the last 3 decades, SAH remained one of the most common cardiovascular and neurological causes of death and disabilities in the world, with increasing absolute case numbers. These findings suggest evidence for the potential health benefits of proactive public health planning and resource allocation toward the prevention of SAH.

Abstract Arthrofibrosis of the knee is a difficult‐to‐manage complication after meniscoligamentous knee injuries, traumatic injuries with articular extension, and surgeries to treat these conditions. Treatment protocols for the management of postoperative arthrofibrosis exhaust nonoperative therapies before proceeding to the operating room for lysis of adhesions (LOA). Although LOA restores range of motion in most cases, a recurrence of arthrofibrosis is possible when postoperative therapy protocols are not strictly followed. Limited treatment options exist in the setting of recalcitrant arthrofibrosis. Revision arthroscopic LOA may be performed in this scenario. This revision procedure places neurovascular anatomy in the posterior compartment at risk. Performing a posterior capsule release in the arthroscopic management of recalcitrant arthrofibrosis is challenging but important to optimize recovery of range of motion. This Technical Note and accompanying video present a stepwise approach to LOA that demonstrates a safe method for performing an arthroscopic posterior capsule release in these challenging cases. Technique Video video See video under supplementary data.

BACKGROUND Treatment of tubo-ovarian high-grade serous carcinoma (HGSC) includes cytoreductive surgery, platinum-based chemotherapy, and often poly(ADP-ribose) polymerase (PARP) inhibitors. While homologous recombination (HR) deficiency is a well-established predictor of therapy sensitivity, over 50% of HR-proficient HGSCs also exhibit sensitivity. Currently, there are no biomarkers to identify which HR-proficient HGSCs will be sensitive to standard-of-care therapy. Replication stress may serve as a key determinant of response. METHODS We evaluated phospho–RPA2-T21 (p-RPA2) foci via immunofluorescence as a biomarker of replication stress in formalin-fixed, paraffin-embedded HGSC samples collected at diagnosis from patients treated with platinum chemotherapy (discovery cohort, n = 31; validation cohort, n = 244) or PARP inhibitors ( n = 63). Recurrent HGSCs ( n = 38) were also analyzed. p-RPA2 score was calculated using automated imaging analysis. RESULTS Samples were defined as p-RPA2-high if more than 16% of cells had ≥2 p-RPA2 foci on automated analysis. In the discovery cohort, HR-proficient, p-RPA2-high HGSCs demonstrated significantly higher rates of a chemotherapy response score of 3 to platinum chemotherapy than HR-proficient, p-RPA2-low HGSCs. In the validation cohort, patients with HR-proficient, p-RPA2-high HGSCs had significantly longer survival after platinum treatment than those with HR-proficient, p-RPA2-low HGSCs. Additionally, the p-RPA2 assay effectively predicted survival outcomes in patients treated with PARP inhibitors and in recurrent HGSC samples. CONCLUSION Our study underscores the importance of considering replication stress markers, such as p-RPA2, alongside HR status in therapeutic planning. This approach has the potential to increase the number of patients receiving effective therapy while reducing unnecessary toxicity. FUNDING The Reproductive Scientist Development Program, GOG Foundation, Pilot Translational and Clinical Studies function of the Washington University Institute of Clinical and Translational Sciences, the Foundation for Barnes-Jewish Hospital, Washington University School of Medicine Dean’s Scholar Program, The Cancer Biology Pathway Training Grant (5T32CA113275-17), The Lucy, Anarcha, and Betsey (L.A.B.) Award from the Department of Obstetrics and Gynecology at Washington University School of Medicine, and Veterans Affairs Office of Research and Development (I01BX006020).

Abstract Introduction Rapid eye movement (REM) sleep behavior disorder (RBD) is the single strongest predictor of Parkinson’s disease (PD) risk. Given neurotrauma and psychiatric morbidity, the aging post-9/11 Veteran cohort is a target population for understanding probable RBD frequency and neuroprotection opportunities. We previously reported over 50% of post-9/11 Veterans screened positive for probable RBD. We aimed to examine frequencies of prodromal PD markers and polysomnography (PSG)-confirmed RBD in post-9/11 Veterans. Methods Veterans with probable RBD based on the single-question RBD screen (n=12) were recruited from the Translational Research Center for Traumatic Brain Injury (TBI) and Stress Disorders (TRACTS) Houston cohort. Participants were assessed for subthreshold parkinsonism (Unified Parkinson’s Disease Rating Scale-III Motor score >3, excluding action tremor), olfactory loss (12-item Sniffin’ Sticks), TBI exposures, autonomic symptoms, orthostasis, excessive daytime sleepiness, post-traumatic stress disorder (PTSD), and psychiatric comorbidities. PSG studies were conducted per American Academy of Sleep Medicine guidelines. A board-certified sleep physician confirmed the presence of REM sleep without atonia. We compared the frequency of prodromal marker positivity between participants with and without subthreshold parkinsonism. Results All 12 participants were male (6 [50%] Black, 3 [25%] Hispanic) with a mean (SD) age of 44.4 ± 6.7 years. PSG data (n=10) revealed REM sleep without atonia in 5 (50%), moderate obstructive sleep apnea (OSA) in 2 (20%), and severe OSA in 2 (20%) participants. Five (41.6%) participants had mild motor dysfunction suggestive of subthreshold parkinsonism on the UPDRS-III (M±SD score of 8.6 ± 5.9), while 7 participants had normal or low UPDRS-III ratings (2.3 ± 1.3; p=0.02). Veterans with subthreshold parkinsonism had lower Sniffin’ Sticks scores than those without (M±SD 9.4 ± 2.07 vs. 11.29 ± 0.76; 95% CI: 0.01–3.76, p=0.049). Conclusion This pilot study suggests that motor and olfactory prodromal PD markers are frequent in post-9/11 Veterans with probable RBD. Larger prospective cohort studies are required to further quantify REM sleep without atonia and assess synuclein-specific biomarkers in this population. Support (if any) Center for Alzheimer’s and Neurodegenerative Diseases at Baylor College of Medicine [MJ]; VA CSR&D (#IK2CX002363-01A1) [MJ]; VA RR&D (B9268-X) [RJ]; NIH/NIA/NINDS (U19-AG071754 & R34-AG056639) [ES]; and AASM [ES].

Abstract Introduction Obstructive sleep apnea (OSA) has been linked to metabolic syndrome, heart failure, atrial fibrillation, and hypertension. Although ethnic differences related to OSA have been reported, no studies have evaluated the impact of OSA among Greek-Americans. Methods This prospective cross-sectional study, in partnership with the Greek-American community, employed a community-based participatory research framework. Individuals who were of Greek descent and ≥18 years of age were recruited. Anthropometric measurements, Mallampati score, BMI, and adiposity (DEXA scan) were determined. All subjects were administered the Epworth Sleepiness Scale (ESS) and underwent home sleep apnea test (WatchPAT ONE), using a desaturation threshold of 4% as diagnostic. Descriptive statistics were computed to describe the study population and data were analyzed using the student t-test and chi-squared test. Results A 76 Greeks, 34 males (44.8%) and 42 females (55.2%), were enrolled in this study with a mean ± SD age and BMI of 42.6±17.5 years (p< 0.01) and 27±6 kg/m2, respectively. A total of 22 (29%; 14 males and 8 females) individuals were diagnosed with OSA, of whom 13 (59.1%) had mild, 5 (22.7%) had moderate and 4 (18.2%) had severe OSA. Subjects with OSA were older (58.8±11.9 vs 36.0±15.1 years, p< 0.01), had higher BMI (32±7 vs 25±4 kg/m2, p< 0.01), larger neck circumference (40±4 vs 35±4 cm, p< 0.01) and higher waist-to-hip ratio (0.94±0.08 vs 0.84±0.07, p< 0.01). Body fat percentage was significantly higher among those with versus without OSA (38.8±9.6 vs 34.0±9.2%; p=0.04) while Mallampati and ESS scores were similar. Conclusion This is the first study to assess sleep metrics of Greek-Americans suffering from OSA. Characteristics of those with OSA are similar to other populations. However, the commonly used ESS screening appears to have limited application in this cohort of subjects. Greek-Americans with elevated body fat percentage when associated with concurrent OSA, may be at higher risk of developing cardiometabolic adverse events. Additional studies are required to further elucidate the effect of sleep physiology, cardiometabolic dysfunction and health outcomes. Support (if any) This work was supported by a grant from Sleep Number Corporation to Mayo Clinic, by WatchPATs provided by Zoll Itamar, and by the National Institutes of Health HL160619.

ABSTRACTA core tenant of the Geriatric Emergency care Applied Research Network 2.0—Advancing Dementia Care (GEAR 2.0‐ADC) is the inclusion of community members during all stages of clinical research. As such, we deliberately integrated and supported patient and public involvement in the evaluation and selection of GEAR 2.0‐ADC Pilot Research Grants by developing and adapting traditional grant application review structures, with input from community members, to create the GEAR 2.0‐ADC Community Review Committee approach. Community members, including persons living with dementia, effectively participated in all three rounds of research grant application review and selection, complementing the traditional scientific review process. The structure and flexibility of the GEAR 2.0‐ADC Community Review Committee approach serve as a model for patient and public grant application review involvement with strong potential for applications across grant reviews in other medical specialties.