Citations

PURPOSE Survival for patients with melanoma has recently improved. The propensity of melanoma to metastasize to the brain remains a common and serious feature of this disease. The purposes of this study were to evaluate prognostic factors for patients with newly diagnosed melanoma brain metastases (MBMs) in a large cohort treated with modern multimodal therapies, compare those results with those in prior eras, and update the Melanoma Graded Prognostic Assessment (GPA). METHODS Univariable and multivariable (MVA) analyses of prognostic factors and treatments associated with survival were performed on 1,796 patients with newly diagnosed MBM treated between January 01, 2015, and December 31, 2021, using a multi-institutional retrospective database. Multiple imputation was used to address missingness of potential predictors. Significant variables in combined MVA were used to update the Melanoma GPA. Comparisons were made with legacy cohorts. RESULTS Median survivals for cohorts A (1985-2007, n = 481), B (2006-2015, n = 823), and C (2015-2021, n = 1,796) were 6.7, 9.8, and 16.6 months and median follow-up times were 40.1, 43.6, and 48.8 months, respectively. In combined MVA, significant prognostic factors for survival were higher Karnofsky Performance Status, fewer MBMs, absence of extracranial metastases, lower serum lactate dehydrogenase, and no immunotherapy before MBM. These factors were incorporated into the updated Melanoma GPA. The combined median and 3-year survivals for patients with GPA 0-1, 1.5-2, and 2.5-4.0 were 5.4, 13.2, and 43.2 months and 12.4%, 28.8%, and 51.6%, respectively. CONCLUSION Prognostic factors have changed and survival has improved for patients with MBM but varies widely by GPA. The updated Melanoma GPA calculator (BrainMetGPA), available free online, can be used to estimate survival, individualize treatment, stratify clinical trials, guide surveillance, and augment clinical trial eligibility. Multidisciplinary treatment is essential. Trials are needed to elucidate the optimal sequencing of various therapeutic modalities.

Abstract Objective The objective was to determine if migraine is independently associated with a greater odds of spontaneous coronary artery dissection (SCAD) in a case–control study. Background There is growing evidence that migraine is associated with SCAD, a non‐atherosclerotic, non‐traumatic cause of myocardial infarction. However, few studies have examined the independent association between migraine and SCAD. Methods A total of 1295 SCAD cases and 1291 (1:1) age, sex, and race/ethnicity matched controls presenting to the Boston, Massachusetts area, using the International Classification of Diseases ninth revision and 10th revision codes from our Research Patient Data Registry, were identified between the years 1990 and 2022. Adjusted odds ratios (aORs) and 95% confidence intervals (CIs) were calculated. For mediation, total effects, natural direct, and indirect effects were estimated using causal inference. Receiver operating characteristic (ROC) curves and area under the curve (AUC) was used to determine predictive power. Statistical significance was defined as p < 0.05. Results Adjusting for age, sex, and race/ethnicity, the data demonstrated an almost two‐fold increased odds of SCAD in patients with migraine (aOR 1.96, 95% CI 1.48–2.6; p < 0.001). There was no effect of aura phenotype on this association. Fibromuscular dysplasia (FMD) was found only in patients with SCAD ( n = 133). After accounting for vascular risk factors, there was no longer an independent association between migraine and SCAD (aOR 0.90, 95% CI 0.63–1.29; p = 0.568). Using a model that adjusted for only demographic variables produced a ROC curve with the lowest predictive power (AUC 0.55) for SCAD, while the vascular risk factor‐adjusted model had a higher predictive power (AUC 0.83). Hypertension appeared to mediate some of the effect of migraine on SCAD (proportion of effect mediated 0.70). FMD was highly associated with an increased risk of SCAD. There remained no independent association between SCAD and migraine when FMD was included in the model. Conclusions The migraine–SCAD association can be partially attributed to the connection between migraine and vascular comorbidities including hypertension and FMD.

Abstract Leucine-rich repeat kinase 2 (LRRK2) phosphorylates a subset of Rab GTPases that regulate receptor trafficking; activating mutations in LRRK2 are linked to Parkinson’s disease. Rab phosphorylation is a transient event that can be reversed by phosphatases, including PPM1H, that acts on phosphoRab8A and phosphoRab10. Here we report a phosphatome-wide siRNA screen that identified PPM1M as a phosphoRab12-preferring phosphatase that also acts on phosphoRab8A and phosphoRab10. Upon knockout from cells or mice, PPM1M displays selectivity for phosphoRab12. As shown previously for mice harboring LRRK2 pathway mutations, knockout of Ppm1m leads to primary cilia loss in striatal cholinergic interneurons. We have also identified a rare PPM1M mutation in patients with Parkinson’s disease that is catalytically inactive when tested in vitro and in cells. These findings identify PPM1M as a key player in the LRRK2 signaling pathway and provide a new therapeutic target for the possible benefit of patients with Parkinson’s disease. Teaser Parkinson’s linked Rab phosphorylation is reversed by PPM1M; the inactive D440N variant is implicated in rare patient cases.

Abstract Background With progressive accumulation of knowledge on SARS-CoV-2 infection clinical management, treatment guidelines recommended several options including remdesivir, a broad-spectrum antiviral. Given the evolving nature of coronavirus disease 2019, capturing the totality of scientific evidence from clinical trials and observational studies is critical to inform clinical decision making. We conducted a systematic literature review with meta-analysis to summarize the effectiveness of remdesivir among hospitalized adults. Methods We systematically searched MEDLINE, Embase and Cochrane Library databases for interventional and observational studies examining remdesivir efficacy. A rigorous double-reviewer approach was used for source identification, screening, data extraction and risk of bias assessment. A hierarchical random-effects model meta-analysis was used, with subgroup analyses for randomized controlled trials (RCTs) and real-world (RW) studies. Results From January 2019 to December 2023 &gt;18 000 sources were screened, and 122 unique studies were identified, reporting on 25 174 participants in RCTs and 1 279 859 in RW studies. Remdesivir significantly increased survival in the overall population (odds ratio, 0.69 [95% confidence interval, .55–.86]; P = .001] across SARS-CoV-2 variants and disease severity levels: no supplemental oxygen (0.81 [.75–.88]), low-flow oxygen (0.71 [.64–.79]), high-flow oxygen (0.87 [.83–.91]), and invasive mechanical ventilation (0.78 [.68–.90]). Rehospitalization risk was significantly reduced in patients receiving remdesivir (odds ratio, 0.72 [95% confidence interval, .64–.81]). Conclusions Our comprehensive systematic literature review, capturing the totality of evidence, showed a significant survival benefit among patients hospitalized for SARS-CoV-2 infection and receiving remdesivir, across all disease severity levels. To assure that healthcare providers are aware of and deploy evidence-based optimal care, recommendations should rely on both RCT and RW data.

Backgrounds and Aims: HBV-related liver disease ranks as the seventh leading cause of mortality. Despite advances in prevention and treatment, global disparities in the burden of primary liver cancer (PLC) persist. We evaluate global trends in the prevalence, incidence, and death of HBV-related liver disease. Approach and Results: Data from the Global Burden of Disease Study 2021 evaluated acute HBV infection, HBV-related cirrhosis, and HBV-related liver cancer prevalence, incidence, and death. In 2021, there were 7.30 million cases of acute HBV, 283.64 million cases of HBV-related cirrhosis, and 288,110 cases of HBV-related PLC. HBV-related PLC accounted for 39% of the global incidence of PLC; Western Pacific had the highest rates for HBV-related PLC, with an incidence of 5.24 and a death rate of 4.38 per 100,000 population. Between 2000 and 2021, age-standardized incidence, prevalence, and death rates from HBV-related liver disease decreased; however, the incidence of HBV-related PLC rose in 65 countries from 2000 to 2021. In parallel, age-standardized prevalent rates from HBV-related PLC increased in Europe (annual percent change: 0.77%, 95% CI: 0.72%–0.81%) and the Americas (annual percent change: 1.05%, 95% CI: 1.00%–1.10%). Conclusions: From 2000 to 2021, decreases in HBV-related liver disease incidence and prevalence were observed; however, more than one-third of countries showed an increase in the incidence of HBV-related PLC. These findings highlight the need for strengthened HBV treatment efforts to reduce the risk of liver cancer.

Migraine with aura(MwA) is associated with an increased risk of stroke and adverse vascular outcomes compared to those with migraine without aura (MwoA). AI-ECG prediction models developed at our institution can evaluate the probability of atrial fibrillation (AF) and estimate a patient’s age based on a normal sinus rhythm (NSR) ECG. Delta age, AI-ECG estimated age minus chronological age, indicates endothelial dysfunction and is associated with cardiovascular mortality. We aim to assess how AI-ECG prediction model outputs, specifically the AF probability and delta age, are associated with adverse vascular outcomes in patients with migraine. Adult patients diagnosed with MwA and MwoA from 2000-2020 with at least one digital, standard 12-lead ECG were identified. The first ECG that showed NSR is used as the index ECG. Patients with any adverse vascular outcomes before the index ECG were excluded. Adverse vascular outcomes used as endpoints include acute ischemic stroke, acute myocardial infarction, deep vein thrombosis/pulmonary embolism, AF, and carotid artery dissection. A total of 31301 patients (13783 MwA, 17518 MwoA) were included in our analysis. The mean age at the time of the index ECG was 44.3 (14.5), and the average follow-up time was 71.6 (69.8) months. Based on the index ECG, the mean AF probability was significantly higher in MwA compared to MwoA (2.39 vs 2.06, p< 0.001), while the delta age was lower in MwA compared to MwoA (3.7 vs 4.2, p <.001). The prevalences of all vascular outcomes are summarized in Table 1. Multivariate Cox regression models showed that a higher AF prediction model output (every 10% increase), as well as a higher delta age (every 10-year increase), are associated with an increased risk of composite vascular outcomes (HR1.20, 95%CI 1.17-1.23, p<.001, and HR1.19, 95%CI 1.14-1.23, p < .001) [Table 2]. The Kaplan-Meier curve of adverse vascular outcome-free survival by AF prediction model output, using 1% as the cutoff (HR 1.49, 95% CI 1.41, 1.57, p<.001), and by delta age, using 2-year as the cutoff (HR 1.14, 95% CI 1.08, 1.21, p <. 001) are presented in Figure 1. Having aura, older age, male, coronary artery disease, congestive heart failure, diabetes, hypertension, and tobacco use were also associated with a higher risk of adverse vascular outcomes. Our results demonstrated the potential of using AI-ECG AF prediction model output and delta age to identify migraine patients at risk for adverse vascular outcomes.