Citations

Abstract Aims Significant advancements have been made in the management of obstructive hypertrophic cardiomyopathy (oHCM), yet the extent of left ventricular outflow tract (LVOT) gradient reduction achieved with commonly used pharmacological therapies [beta-blockers (BBs), calcium channel blockers (CCBs), disopyramide, and cardiac myosin inhibitors (CMIs)] relative to each other is still unclear. Methods and results PubMed and Scopus were searched up to September 2024. Clinical trials or observational studies that assessed the changes associated with BBs, CCBs, disopyramide, or CMIs in LVOT gradient at rest or with provocation in patients with oHCM were included. Mean changes in LVOT gradients were pooled as mean differences (MD) with 95% confidence intervals (CIs) in a random-effects model. Thirty-seven studies, with 44 arms and 1898 patients, were included in the analysis. At the therapeutic class level, pooled analysis showed that disopyramide was associated with the highest reduction in LVOT gradient at rest [MD: −43.5 (95% CI, −51.6 to −35.3)], followed by CMIs [MD: −34.8 (95% CI, −40.6 to −29.0)], BBs [MD: −20.7 (95% CI, −29.4 to −12.0)], and then CCBs [MD: −14.7 (95% CI, −23.3 to −6.1)], inter-action P < 0.01. Within CMIs, mavacamten had a higher effect than aficamten on gradient reduction; among the included BBs, metoprolol showed the highest gradient reduction, while among CCBs, verapamil was the most effective (inter-action P < 0.01). Similar results were observed for provocable LVOT gradients. Conclusion Pharmacological therapies effectively reduced LVOT gradients in oHCM patients to varying degrees, with disopyramide and CMIs showing the highest effect, followed by BBs and CCBs.

Background: Recurrent Clostridioides difficile infection (rCDI) occurs in up to 35% of patients with CDI, and further recurrence is common. Fecal microbiota, live-jslm (RBL) is safe and effective for preventing rCDI in adults following antibiotic treatment for rCDI when administered rectally. There is clinical interest in alternative routes of administration. Objectives: CDI-SCOPE assessed the safety and clinical effectiveness of RBL when administered via colonoscopy to adults with rCDI. Design: Single-arm, exploratory phase IIIb trial conducted at 12 sites in the United States. Methods: Eligible adults with rCDI received one administration of RBL consisting of one 150-mL dose of RBL, delivered via colonoscopy to the right side of the colon. The primary endpoint assessed RBL-related treatment-emergent adverse events (TEAEs) within 8 weeks of RBL administration or until confirmed treatment failure. Secondary endpoints included treatment success (absence of CDI recurrence for 8 weeks following RBL administration), physician experience administering RBL via colonoscopy, and physician perception of participant benefit. Results: Of 54 participants screened, 41 were enrolled and received RBL via colonoscopy; 39 participants completed the 8-week visit. Five TEAEs in four participants (9.8%) were assessed as related to RBL, all of which were gastrointestinal and mild in severity. Overall, 18 participants (43.9%) experienced 33 TEAEs within 8 weeks, most of which were of mild (25/33; 75.8%) or moderate (5/33; 15.2%) severity. No TEAEs led to intensive care unit admission or death. Overall, 39 participants (95.1%) experienced treatment success; 2 participants (4.9%) withdrew consent and had an indeterminate outcome. Among physicians, 90.2% of investigators indicated a “positive” or “very positive” experience administering RBL by colonoscopy. All physicians assessed participant benefit as “much” or “very much” improved. Conclusion: This single-arm study suggests RBL administered via colonoscopy is practical, safe, and effective for preventing CDI recurrence following antibiotic treatment in adults. Trial registration: ClinicalTrials.gov: NCT05831189.

Abstract Oncogenic translocations involving the MET gene have been reported in several cancer types, but detailed clinicogenomic characterization of these cancers is not well defined. In addition, prospective clinical trials evaluating the antitumor activity of MET inhibitors in MET rearrangement–positive cancers are limited. In this study, in a pan-cancer analysis of >46,000 solid tumors with comprehensive genomic profiling, we identified oncogenic MET rearrangements in ∼0.04% of cancers. Preliminary analysis from a phase II clinical trial of the type I MET tyrosine kinase inhibitor (TKI) vebreltinib in MET fusion–positive solid tumors demonstrated an objective response rate of 50% and disease control rate of 79%, with antitumor activity seen in diverse cancer types, including lung adenocarcinoma and intrahepatic cholangiocarcinoma, among others. Similar to MET exon 14–altered lung cancer, secondary mutations in the kinase domain can confer resistance to MET TKIs in MET fusion–positive cancers. Overall, these data categorize MET rearrangements as actionable targets in solid tumors. Significance: MET rearrangement–positive cancers are not well-characterized, and optimal treatment strategies are yet to be defined. Through comprehensive genomic analysis, preclinical modeling, and preliminary results of a phase II clinical trial, we demonstrate that MET fusions are a unique molecular subtype of cancers targetable with vebreltinib, a TKI in development.

BACKGROUND AND OBJECTIVES: Rising US healthcare costs and the COVID-19 pandemic put increased pressure on hospitals to reduce patient length of stay (LOS) while maintaining high-quality care. We aimed to determine if implementing a pathway for same-day discharge after elective neuroendovascular procedures to a monitored hotel setting is safe, feasible, and cost-effective. METHODS: We evaluated patient outcomes after elective neuroendovascular procedures and same-day discharge to an on-campus Care Hotel. The study enrolled patients aged ≥18 years from October 1, 2020, to February 28, 2023. Exclusion criteria comprised major comorbidities, additional care necessitating hospitalization, absence of a caregiver, insurer-mandated hospitalization, or patient refusal of the Care Hotel model. Primary outcomes were readmission rate or prolonged LOS, new ischemic or hemorrhagic complications rate, and death rate from vascular causes within 6 months. Secondary outcomes included adverse events and deaths related to causes other than vascular complications within 6 months and changes in modified Rankin Scale score by 1 or more points at last follow-up. Healthcare cost savings associated with same-day discharge were analyzed using a control group. RESULTS: The study included 42 patients discharged to the Care Hotel and 84 controls. The average age was 61 years in the Care Hotel group and 64 years in the control group, and aneurysm treatment was the most frequent neuroendovascular procedure (83.3% and 79.8%, respectively). The readmission and extended LOS rates were 4.8% for the Care Hotel group. The rate of new ischemic or hemorrhagic complications was 4.8%. Cost analysis estimated savings of $7730.12 per procedure. CONCLUSION: This study suggests that the Care Hotel model is a safe, feasible, and cost-effective option for carefully selected patients undergoing elective neuroendovascular interventions. Adherence to discharge readiness criteria and meticulous patient selection are critical to minimizing complications and readmissions.

Importance High-quality evidence regarding suppressive valacyclovir treatment in herpes zoster ophthalmicus (HZO) is necessary to guide care. Objective To determine whether suppressive valacyclovir compared with placebo delays the occurrence of new or worsening stromal keratitis (SK), endothelial keratitis (EK), iritis, or dendriform epithelial keratitis (DEK) during 12 months of treatment and if treatment benefit persisted at 18 months (secondary end point). Design, Setting, and Participants The Zoster Eye Disease Study (ZEDS) was a randomized clinical trial conducted in 95 sites from November 2017 to June 2024. Immunocompetent, nonpregnant adults with a history of an HZO rash, documented active keratitis or iritis within 1 year, and an estimated glomerular filtration rate of 45 mL/min/1.73 m 2 or greater were eligible. After determined to be eligible, participants were randomized in 4 strata: age at onset (<60 years vs ≥60 years) and disease duration (<6 months vs ≥6 months). Interventions A total of 12 months of double-masked daily valacyclovir, 1000 mg, or placebo. Main Outcomes and Measures The primary outcome was time to first occurrence within 12 months of new or worsening SK, EK, iritis, or DEK. Results A total of 527 participants (median [IQR] age, 60 [50-68] years; 266 female [50.5%]; 266 in the valacyclovir group; 261 in the placebo group) were randomized in 4 strata; 481 completed 12 months, and 460 completed 18 months. Data were analyzed by intention to treat. At 12 months, primary end points occurred in 86 participants (33%) assigned to placebo and 74 (28%) assigned to valacyclovir, and at 18 months in 104 participants (40%) assigned to placebo and 86 (32%) assigned to valacyclovir. The hazard ratio (HR) of the primary end point at 12 months was 0.77 for participants taking valacyclovir vs placebo (HR, 0.77; adjusted 95% CI, 0.56-1.05; P = .09) and 0.73 at the secondary end point at 18 months (HR, 0.73; adjusted 95% CI, 0.55-0.97; P = .03). There was a reduction of multiple other secondary end points at 12 months (HR, 0.70; 95% CI, 0.52-0.95; P = .02) and 18 months (HR, 0.72; 95% CI, 0.55-0.95; P = .02). Conclusions and Relevance Although the primary outcome did not show a benefit of suppressive valacyclovir treatment, secondary study outcomes showed treatment superiority at the 18-month end point and reduced number of multiple episodes of keratitis or iritis at both 12 and 18 months. These results support consideration of 1 year of suppressive valacyclovir treatment for HZO. Trial Registration ClinicalTrials.gov Identifier: NCT03134196

Importance Evidence regarding suppressive valacyclovir treatment on postherpetic neuralgia is necessary to guide care. Objective To test the hypothesis that suppressive treatment with 1000 mg/d of oral valacyclovir for 12 months reduces the prevalence, severity, and duration of postherpetic neuralgia compared with placebo at 12 and 18 months in participants with herpes zoster ophthalmicus (HZO). Design, Setting, and Participants Multicenter, placebo-controlled randomized clinical trial including 527 immunocompetent, nonpregnant adults with history of HZO rash, documented keratitis, or iritis within 1 year and an estimated glomerular filtration rate of 45 mL/min/1.73 m 2 or greater. The study was conducted at 95 participating sites (in Canada, New Zealand, and the US) from November 2017 to June 2024 and participant visits occurred every 3 months. Intervention Treatment with 1000 mg/d of valacyclovir or placebo for 12 months. Main Outcomes and Measures Prevalence of postherpetic neuralgia, severity as determined by pain score (a score of ≥3 on a scale of 1-10), pain duration (≥3 months after HZO onset), and total daily dose of pain medication. Results Of the 527 participants (490 completed 12 months of treatment and 460 completed 18 months), 73 (14%) had postherpetic neuralgia and were analyzed by age at HZO onset (<60 years or ≥60 years) and disease duration (recent [<6 months] or chronic [≥6 months]). Of the 73 participants with postherpetic neuralgia (34 in the valacyclovir group and 39 in the placebo group), the mean age was 62.4 years (SD, 13.6 years), 59% were female, 5% were Black or African American, and 10% were Hispanic. The prevalence of postherpetic neuralgia at 12 months was not reduced by valacyclovir (12/32 [38%]) compared with placebo (14/35 [40%]) (between-group difference, 2.5% [95% CI, −20.8% to 25.8%]; P >.99). The participants who were younger than 60 years at HZO onset and had a chronic disease duration had lower pain scores in the valacyclovir group (mean score, 0.3 [SD, 0.9]) vs the placebo group (mean score, 0.8 [SD, 1.9]) at 12 months ( P = .045) and at 18 months (mean score, 0.2 [SD, 0.9] vs 1.0 [SD, 2.3], respectively; P = .02). There was a decrease in pain duration in the valacyclovir group at 18 months (mean, 13.6 [SD, 11.4] months) vs the placebo group (mean, 18.7 [SD, 29.5] months) (linear mixed-effects model between-group difference, −3.39 months [95% CI, −6.73 to −0.04 months]; P = .046). The total daily dose of neuropathic pain medication was lower in the valacyclovir group (mean, 271.4 [SD, 593.8] mg/d) vs the placebo group (mean, 363.4 [SD, 592.2] mg/d) at 12 months (linear mixed-effects model P = .006) and at 18 months (mean, 209.0 [SD, 412.8] mg/d vs 286.2 [SD, 577.9] mg/d, respectively; linear mixed-effects model P = .01). Conclusions and Relevance One year of suppressive treatment with valacyclovir was associated with a lower dosage of neuropathic pain medication. Participants in the valacyclovir group, who were younger at HZO onset and had a chronic disease duration, had lower pain scores. These secondary outcomes support consideration of 1 year of suppressive treatment with valacyclovir to reduce dosage of pain medications and pain due to HZO. Trial Registration ClinicalTrials.gov Identifier: NCT03134196

Abstract Aims Atrial fibrillation (AF) is the most common cardiac arrhythmia. Although lipoprotein(a) [Lp(a)] is known to be a well-established risk factor for atherosclerotic cardiovascular disease, its role in the development of AF, independent of this association, remains unclear. Methods and results Adult patients from the three Mayo Clinic sites with a baseline Lp(a) and without AF history were included. Patients were categorized into two groups based on their Lp(a) levels: high Lp(a) (≥50 mg/dL) and low Lp(a) (<50 mg/dL). Survival probabilities free from incident AF were compared between Lp(a) groups, during a follow-up period up to 15 years, using the Kaplan–Meier curve and the log-rank test. Multivariable Cox regression analysis was also conducted. A total of 75 376 patients were included (median age: 55 years, 59% males), with a median follow-up duration of 8.8 (inter-quartile range: 3.4, 14.8) years. Incident AF was detected in 5738 (7.6%) patients. Survival probability free from incident AF was significantly lower in patients with elevated Lp(a) (86%) compared with those with low Lp(a) (88%, log-rank P < 0.001). Multivariable analysis adjusted for potential risk factors of AF showed a statistically significant association of elevated Lp(a) with an 11% increase in AF risk (adjusted hazard ratio: 1.11, 95% confidence interval: 1.05–1.18). Conclusion Our study suggests that elevated Lp(a) (≥50 mg/dL) is an independent risk factor for incident AF. Future prospective studies are warranted to validate our results and to test if reducing Lp(a) could mitigate the burden of AF.

Introduction and Hypothesis: New bleeding in cerebral cavernous malformations (CCM) heralds increased risk of future hemorrhage for several years, yet conventional imaging only detects new bleeding that occurred in the prior weeks. A biomarker of hemorrhage could help identifying high risk lesions. An increase of mean lesional quantitative susceptibility mapping (QSM) ≥6% on MRI has been adjudicated as reflecting new bleeding in CCM during longitudinal follow-up. However, mean lesional QSM from a single acquisition could not diagnose or prognosticate a bleed. We hypothesize that machine learning (ML) may identify diagnostic and prognostic features of bleeding within QSM maps at a single point in time. Material and Methods: Two hundred and sixty-five QSM maps of CCM lesions were acquired in 120 patients enrolled in National Institute of Health (NIH) multisite trial readiness project (NCT03652181). Each map was classified (Yes/No) in association with symptomatic hemorrhage (SH) and/or biomarker event with QSM increase ≥6% in the prior (diagnostic association) and subsequent (prognostic association) year. Twenty-eight features were extracted including 14 texture, 5 first-order statistical, as well as 3 size, shape, and morphological. Five-fold cross-validation was conducted on a support-vector machine (SVM) with linear stepwise kernel for both diagnostic and prognostic associations. Performance of individual features and composite classifiers was evaluated using student t-test ( p <0.05) with Bonferroni-correction and receiver operating characteristic (ROC) analysis, area under the curve (AUC). Results: Lesions with SH in the prior year had lower average values for sum variance (AUC=0.79, p<0.001), variance (AUC=0.79, p<0.001), and correlation (AUC=0.71, p=0.004) as compared to lesions without SH. The SVM classification method tasked with distinguishing lesions with mean QSM increase ≥6% in the prior year included recurrent selection of sum average, mean, sphericity and margin sharpness, yielding an AUC of 0.61 (p=0.02). In the prognostic cohort, no individual feature nor any SVM classification model was able to distinguish cases with a subsequent clinical bleed or biomarker event. Conclusion: This proof-of-concept suggests that ML may assist in deriving features on QSM maps acquired at a single timepoint, which reflect prior hemorrhagic activity in CCM. Further investigation is planned in larger cohorts and in conjunction with clinical trials of bleeding in CCM.

Lipoprotein(a) [Lp(a)] is a well-established causal risk factor for cardiovascular diseases (CVDs), as reported by multiple Mendelian randomization studies and large epidemiological studies. When elevated Lp(a) is combined with other risk factors, most notably elevated low-density lipoprotein cholesterol (LDL-C), a synergistic atherogenic effect has been reported. However, the current literature is conflicting regarding how Lp(a) interacts in the context of controlled LDL-C levels (e.g., <70 mg/dL) and whether reducing LDL-C can modify the atherogenic effect of Lp(a). In some studies, elevated Lp(a) was still significantly associated with a higher risk of cardiovascular events, despite controlled levels of LDL-C. In contrast, multiple studies have reported attenuation of the cardiovascular risk mediated by elevated Lp(a) with lower LDL-C levels. Moreover, the relationship between Lp(a) and triglycerides, high-density lipoprotein, and very low-density lipoprotein remains unclear. In this literature review, we summarize and discuss the current evidence regarding the interactions between Lp(a) and other lipid molecules, how they contribute to the pathogenesis of CVD, and future perspectives, particularly in the current era where promising targeted Lp(a)-lowering therapies are under development.