Citations

Abstract Background and Aims Accurate differentiation of cardiac amyloidosis (CA) from phenotypic mimics remains challenging using current clinical and echocardiographic techniques. The accuracy of a novel artificial intelligence (AI) screening algorithm for echocardiography-based CA detection was assessed. Methods Utilizing a multisite, multiethnic dataset (n = 2612, 52% CA), a convolutional neural network was trained to differentiate CA from phenotypic controls using transthoracic apical four-chamber video clips. External validation was conducted globally across 18 sites including 597 CA cases and 2122 controls. Classification accuracy was assessed on the entire external validation dataset, and subgroup analyses were performed both on technetium pyrophosphate scintigraphy referrals, and individuals matched for age, sex, and wall thickness. Model accuracy was also compared with the transthyretin CA score and the increased wall thickness score within a subset of older heart failure with preserved ejection fraction patients with increased wall thickness. Results Cardiac amyloidosis patients and controls displayed similar age, sex, race, and comorbidities. After the removal of uncertain AI predictions (13%), model discrimination and classification were excellent for the entire external validation dataset [area under the receiver operating characteristic curve (AUROC) 0.93, sensitivity 85%, specificity 93%], irrespective of CA subtype (sensitivity: light-chain = 84%, wild-type transthyretin = 85%, and hereditary transthyretin = 86%). Performance was maintained in subgroup analysis in patients clinically referred for technetium pyrophosphate scintigraphy imaging (AUROC 0.86, sensitivity 77%, specificity 86%) and matched patients (AUROC 0.92, sensitivity 84%, specificity 91%). The AI model (AUROC 0.93) also outperformed transthyretin CA score (AUROC 0.73) and increased wall thickness (AUROC 0.80) scores. Conclusions This AI screening model—using only an apical four-chamber view—effectively differentiated CA from other causes of increased left ventricular wall thickness.

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.

Introduction Infectious intracranial aneurysms (IIAs) are rare but serious complications of systemic infections, particularly infective endocarditis. These aneurysms are prone to rupture, leading to significant morbidity and mortality. Management strategies lack consensus due to the rarity of the condition and reliance on small case series. This study examines the clinical management of IIAs using data from a large multicenter cohort. Methods A retrospective registry-based cohort study was conducted across 11 tertiary care centers in the USA between 2018 and 2023. Patients with IIAs were identified based on clinical and radiographic criteria. The primary outcome was treatment failure defined as persistence, growth, or rupture of the aneurysm. Secondary outcomes were mortality and the modified Rankin Scale (mRS) score at 90 days and 1 year. Multivariate logistic regressions were used to identify outcome predictors. Results A total of 104 patients with 166 aneurysms were included, with a median age of 43 years. Medical management was successful in 56% of cases, with failure often within 18 days of initiation. Predictors of failure included younger age, larger aneurysm size, and rupture at presentation. Surgical and endovascular interventions achieved higher success rates with better outcomes. At 90 days, 57% of patients achieved functional independence (mRS 0–2), while the mortality rate was 24%. Conclusion This study highlights the limitations of medical management for IIAs and underscores the need for early surgical or endovascular intervention in high-risk patients. Outcome predictors aid clinical decision-making, optimizing patient management. Further research is needed to standardize management guidelines for IIAs.

Abstract Background Hospital‐at‐home programs (HaH) in the United States have evolved to include a virtual‐hybrid delivery model, where all physician encounters are virtual and partnered with a home care team. Objective To examine whether a virtual hybrid HaH program enabled by technology has similar clinical outcomes to traditional brick‐and‐mortar (B&M) hospital care. Methods We conducted a pragmatic trial at three hospitals, randomizing 1150 acutely ill patients requiring hospital care between July 10, 2023, and October 31, 2023 one‐to‐one into two groups: intervention (HaH) and control (B&M). The primary analysis was an intention‐to‐treat non‐inferiority analysis of the primary outcome, which was a composite of 30‐day all‐cause mortality and unplanned readmissions. Secondary outcomes included 30‐day readmission, all‐cause mortality, and patient experience. Results The mean age was 67.8 (standard deviation [SD] 16.3) years, and 52.2% were female. The primary outcome occurred in 99 (17.3%) HaH patients and 114 (19.8%) B&M patients (odds ratio [OR] 0.85, 95% confidence interval [CI] 0.63–1.14, p = .28), meeting the non‐inferiority criterion. Thirty‐day unplanned readmission occurred in 84 (14.7%) HaH patients and 101 (17.5%) B&M patients (OR 0.81, 95% CI 0.59–1.11, p = .19). Thirty‐day all‐cause mortality occurred in 25 (4.4%) HaH patients and 19 (3.3%) B&M patients (OR 1.34, 95% CI 0.73–2.46, p = .35). No HaH patients died while receiving their hospital care at home. HaH program was associated with a higher likelihood of patients reporting feeling extremely comfortable or very comfortable (84.4% HaH; 60.9% B&M, p = .001). Conclusion A hybrid HaH model is a safe and comfortable alternative to traditional B&M hospital care.

ABSTRACTBackgroundWe aimed to determine the performance of postoperative computed tomography (CT) and upper gastrointestinal series (UGI) in patients who underwent surgery for a perforated peptic ulcer and to assess the yield of routine postoperative studies.MethodsRetrospective, single‐institution, chart‐review study of patients who underwent a repair of a perforated gastric or duodenal ulcer between August 2004 and September 2021 at Mayo Clinic, Rochester, Minnesota.ResultsWe identified a total of 240 patients, 28 (12%) were found to have leaks. When any of the four findings (extraluminal gas or fluid collection adjacent to the repair, worsening pneumoperitoneum, or enteral contrast extravasation) was present on postoperative CT scan (n = 116) it had sensitivity of 76% (95% CI 53%–90%), with a specificity of 90% (95% CI 84%–91%). Upper gastrointestinal series (UGI, n = 150) showed a sensitivity of 57% (95% CI 25%–84%) and a specificity of 99% (95% CI 96%–100%). UGI demonstrated higher specificity compared to CT (p < 0.01); there was no significant difference in sensitivity (p = 0.34). The findings from CT scans led to changes in management for a significantly greater number of patients compared to UGI (20% vs. 4%, p < 0.01). The diagnostic yield for leak identification was 3% for routine postoperative CT (n = 63) and 2% for routine UGI studies (n = 141).ConclusionsPostoperative CT is more likely to change management in patients who underwent repair of a perforated peptic ulcer compared to postoperative upper gastrointestinal series. The yield of routine postoperative studies is low, and their benefit is uncertain.

Abstract Introduction Jazz DUET (Develop hypersomnia Understanding by Evaluating low-sodium oxybate Treatment) is a phase 4, prospective, multicenter, single-arm, multiple-cohort, open-label study (NCT05875974) assessing the effectiveness of low-sodium oxybate (LXB; Xywav®) treatment on daytime and nighttime symptoms in participants with narcolepsy (type 1 [NT1] or 2 [NT2]) or idiopathic hypersomnia. Data presented are from the narcolepsy cohort. Methods DUET included a screening period (with 2-week washout for current oxybate users), 8-day baseline (BL) period, 2- to 8-week LXB titration period, 2-week stable-dose period, 8-day end-of treatment (EOT) period, and 2-week safety follow-up. The primary endpoint was change in Epworth Sleepiness Scale (ESS) score from BL to EOT. Key secondary endpoints for the narcolepsy cohort included change in polysomnography parameters: total shifts from deeper to lighter sleep stages, stage N3 sleep duration (minutes), and number of awakenings. Additional endpoints included Patient Global Impression of Change (PGIc)–overall narcolepsy disease. Primary and key secondary endpoints were controlled for multiplicity with sequential testing; other P-values are considered nominal. Results Fifty-five narcolepsy participants enrolled and were dosed with LXB (NT1, n=26; NT2, n=29); 13 transferred to another cohort and 34 were completers (NT1, n=16; NT2, n=18). Enrolled participants were mostly female (72.7%) and White (80.0%); mean (SD) age was 33.4 (12.9) years (NT1=34.6 [12.6]; NT2=32.4 [13.2]). For completers, least-squares mean (LSM) (SE) changes in ESS score were −7.7 (0.9), P&lt;.0001, overall; NT1=−6.5 (1.4), P&lt;.0001; NT2=−8.8 (1.3), P&lt;.0001. Compared with BL, sleep architecture at EOT showed fewer deeper to lighter sleep stage shifts (LSM [SE]: −13.1 [2.9], P&lt;.0001, overall; NT1=−13.9 [4.3], P=0.0029; NT2=−12.3 [4.1], P=0.0050); increased stage N3 sleep (minutes) (45.0 [8.8], P&lt;.0001, overall; NT1=49.8 [13.0], P=0.0006; NT2=40.8 [12.3], P=0.0023); and fewer awakenings (−3.2 [0.9], P=0.0015, overall; NT1=−4.1 [1.4], P=0.0056; NT2=−2.3 [1.3], P=0.0771). Most participants (93.3%, n=30; NT1, 86.7%, n=15; NT2, 100%, n=15) reported improvement (very much, much, minimally) in overall narcolepsy disease on PGIc. Treatment-emergent adverse events were consistent with the known safety profile of LXB. Conclusion Participants with NT1 and NT2 taking open-label LXB showed improvements in daytime sleepiness (decreased ESS scores) and reduced symptom burden (improved PGIc), which paralleled improvements in sleep architecture and disruption. Support (if any) Jazz Pharmaceuticals

Abstract Introduction Introduction: Jazz DUET (Develop hypersomnia Understanding by Evaluating low-sodium oxybate Treatment) is a phase 4, prospective, multicenter, single-arm, multiple-cohort, open-label study (NCT05875974) evaluating the effectiveness of low-sodium oxybate (LXB, Xywav®) treatment on daytime and nighttime symptoms, including excessive daytime sleepiness (EDS) and polysomnography in participants with idiopathic hypersomnia (IH) or narcolepsy. Data presented are from the IH cohort. Methods DUET included screening (with 2-week washout for oxybate users), 8-day baseline (BL), 2- to 8-week LXB titration, 2-week stable-dose, 8-day end-of-treatment (EOT), and 2-week safety follow-up periods. The primary endpoint was change in Epworth Sleepiness Scale (ESS) score from BL to EOT. Secondary endpoints for the IH cohort included change in Idiopathic Hypersomnia Severity Scale (IHSS) total score, Patient Global Impression of Change (PGIc)−overall IH disease, PGIc−sleep inertia, and Patient Global Impression of Severity (PGIs)−sleep inertia. Exploratory endpoints included IHSS component scores (daytime functioning, sleep inertia). Primary and key secondary (IHSS total score) endpoints were controlled for multiplicity with sequential testing; all other P-values are considered nominal. Results Forty-six people with IH enrolled and were dosed with LXB; 40 were completers. Enrolled participants were mostly female (80.4%) and White (84.8%), with a mean (SD) age of 38.1 (11.8) years. For completers, BL mean (SD) ESS score and IHSS total score were 16.5 (2.7) and 32.9 (7.1), respectively; least-squares mean (LSM) (SE) changes from BL to EOT were −8.4 (0.7), P&lt;.0001 and −15.5 (1.5), P&lt;.0001. BL mean (SD) IHSS component scores for daytime functioning and sleep inertia were 17.7 (4.2) and 10.7 (3.1), respectively; LSM (SE) changes from BL to EOT were −8.8 (1.0), P&lt;.0001 and −4.8 (0.4), P&lt;.0001. At EOT, most participants reported improvement (very much, much, minimally) on PGIc−overall IH disease (94.6%) and PGIc−sleep inertia (81.1%). At BL, 25.0% of participants reported sleep inertia severity as very mild/mild/not present on PGIs–sleep inertia vs 59.0% at EOT. Treatment-emergent adverse events were consistent with the known safety profile of LXB. Conclusion People with IH taking open-label LXB showed improvements in EDS and sleep inertia (decreased ESS and IHSS component scores) and reported reduced multi-symptom burden (decreased IHSS total scores and improved PGIc/PGIs ratings). Support (if any) Jazz Pharmaceuticals

Physicians-in-training experience high rates of mental health, burnout, and well-being concerns, yet face many barriers to accessing care. Burnout is associated with poor self-rated health, sleep disturbances, and other health risks. Unfortunately, residents often face barriers to participating in health-promoting activities due to lack of time, perceived stigma, confidentiality concerns, and low awareness of available services. To improve access to health resources, and specifically mental health support, we developed a pilot opt-out well-being check-in program, offered via videoconferencing, at a large academic medical center. Internal medicine and neurology residents ( N = 93) were protected from clinical duties to meet individually with a psychologist. The 45-minute session consisted of a brief assessment, identification of stressors, discussion of well-being goals, and referral to further services as indicated. The study goals were to establish the feasibility of implementing a program-wide intervention, assess resident satisfaction with the intervention, and reduce barriers to mental health and well-being resources. The study authors developed a brief post-session satisfaction survey. Analysis included participation rates and responses to satisfaction survey questions. 64.5% of residents attended the check-in session. Among the 57% who responded to a post-intervention survey, over 90% agreed that the session was valuable, convenient, and recommended program continuation. This health promotion program successfully offered tailored mental health and well-being support within demanding residency training structures. Opt-out programs that minimize barriers to participation are a valuable part of multifaceted workplace well-being initiatives.

Background: Hidradenitis suppurativa (HS) is a chronic, recurrent inflammatory condition and is associated with significant psychosocial impacts on patient quality of life. Objective: This study aimed to characterize the utilization of patient-reported outcomes (PROs) in HS clinical trials and their concordance with trial primary endpoints. Methods: A systematic review of clinical trials was performed using the publicly available U.S. National Library of Medicine (ClinicalTrials.gov) in June 2023 utilizing the search terms hidradenitis, hidradenitis suppurativa, and suppurativa hidradenitis. Study title, start year, trial status, intervention, design, location, and primary and secondary outcomes were collected. To assess for concordance of patient and provider-reported outcomes, we identified published placebo-controlled trials that included Dermatology Life Quality Index (DLQI) and/or a numeric rating scale (NRS) for pain, the 2 most utilized PROs. Results: One hundred sixty-four HS clinical trials were identified, of which 115 were interventional studies. A total of 65.2% ( n = 107) of HS trials included at least one PRO. Pain NRS (42.7%, n = 70) and DLQI (42.1%, n = 69) were the most frequently used PRO instruments. The use of PROs in clinical trials increased over time, with 50% of trials between 2020 and 2023 utilizing PROs. Of 11 published HS trials, 82% ( n = 9) trials showed concordance of provider-assessed and PROs in at least one treatment arm. Limitations: Significance and standard deviations of PROs were rarely reported, preventing the calculation of significance and is a limitation of this review. Conclusion: While lesion counts provide single snapshots of disease, PROs can capture perceptions of lesions not actively present. PROs are frequently concordant with both achievement and nonachievement of primary endpoints in clinical trials.

Objective Present the rationale for the development of a new, patient-facing vital sign for adult hearing. Study Design Structured A3 process. Setting Fourteen virtual meetings and two in-person meetings held between May 2021 and June 2022. Main Outcome Measure(s) Identification and refinement of a countermeasure to develop and imbed a hearing health vital sign for adult hearing. Results Through a rigorous, structured A3 process, the Hearing Health Collaborative identified and refined the rationale for and the qualities associated with a public-facing vital sign for adult hearing loss. Specifically, such a vital sign must embody five qualities: simple, accessible, stable, inclusive, and meaningful. These qualities together would ensure that a hearing health vital sign would be useful not only as a screening tool but also as an instrument to guide next steps in workup and potentially treatment. Conclusions Successful identification and implementation of a hearing metric or “vital sign” for the presence of adult hearing loss, using precedent convention of other medical diseases, may help reframe public perceptions surrounding hearing loss, improve awareness and literacy regarding the presence of the disease, and prompt action to seek diagnostic assessment.