Long-term cardiovascular safety of fenfluramine in patients with Dravet syndrome treated for up to 3 years: findings from serial echocardiographic assessments

© 2022 The Authors. Published by Elsevier Ltd on behalf of European Paediatric Neurology Society. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)Objective: To assess the cardiovascular safety of fenfluramine when used to treat children and young adults with Dravet syndrome. Methods: Patients with Dravet syndrome who completed one of three phase 3 clinical trials of fenfluramine could enroll in the open-label extension (OLE) study (NCT02823145). All patients started fenfluramine treatment at an oral dose of 0.2 mg/kg/day. The dose was titrated based on efficacy and tolerability to a maximum of 0.7 mg/kg/day (absolute maximum 26 mg/day) or 0.4 mg/kg/day (absolute maximum 17 mg/day) in patients concomitantly receiving stiripentol. Serial transthoracic echocardiography was performed using standardized methods and blinded readings at OLE entry, after 4-6 weeks, and every 3 months thereafter. Valvular heart disease (VHD) was defined as ≥ moderate mitral regurgitation or ≥ mild aortic regurgitation combined with physical signs or symptoms attributable to valve dysfunction. Pulmonary artery hypertension (PAH) was defined as systolic pulmonary artery pressure >35 mmHg. Results: A total of 327 patients (median age, 9.0 years; range, 2-19 years) have enrolled in the OLE and received ≥1 dose of fenfluramine. The median duration of treatment was 23.9 months (range, 0.2-42.6 months) and the median dose of fenfluramine was 0.44 mg/kg/day. No patient demonstrated VHD or PAH at any time during the OLE. Significance/interpretation: This study, which represents the largest, longest, and most rigorous examination of cardiovascular safety of fenfluramine yet reported, found no cases of VHD or PAH. These results, combined with fenfluramine's substantial antiseizure efficacy, support a strong positive benefit-risk profile for fenfluramine in the treatment of Dravet syndrome.info:eu-repo/semantics/publishedVersio

Predictors of In-Hospital Mortality Among Older Patients

OBJECTIVE: The objective of this study was to determine predictors of in-hospital mortality among older patients admitted to a geriatric care unit. INTRODUCTION: The growing number of older individuals among hospitalized patients demands a thorough investigation of the factors that contribute to their mortality. METHODS: This was a prospective observational study implemented from February 2004 to October 2007 in a tertiary university hospital. A consecutive sample of 922 patients was evaluated for possible inclusion in this study. Patients hospitalized for palliative care, those who declined to participate, and those with incomplete data were excluded, resulting in a group of 856 patients aged 60 to 104 years. Bivariate and multivariate analyses were performed to determine associations between in-patient mortality and gender, age, length of stay, number of prescribed medications and diagnoses at admission, history of heart failure, neoplastic disease, immobility syndrome, delirium, infectious disease, and laboratory tests at admission (serum albumin and creatinine). RESULTS: The overall mortality rate was 16.4%. The following factors were associated with higher in-hospital mortality: delirium (OR=4.13, CI=2.65-6.44, P<.001), neoplastic disease (OR=3.38, CI=2.11-5.42, P<.001), serum albumin levels at admission <3.3mg/ dL (OR=3.23, CI=2.03-5.13, P<.001), serum creatinine levels at admission >1.3mg/dL (OR=2.39, CI=1.53-3.72, P<.001), history of heart failure (OR=1.97, CI=1.20-3.22, P=.007), immobility (OR=1.84, CI=1.16-2.92, P =.009), and advanced age (OR=1.03, CI=1.01-1.06, P=.019). CONCLUSIONS: This study strengthens the perception of delirium as a mortality predictor among older inpatients. Cancer, immobility, low albumin levels, elevated creatinine levels, history of heart failure and advanced age were also related to higher mortality rates in this population

Gastroesophageal Reflux Symptoms and Comorbid Asthma and Posttraumatic Stress Disorder Following the 9/11 Terrorist Attacks on World Trade Center in New York City

OBJECTIVES: Excess gastroesophageal reflux disease (GERD) was reported in several populations exposed to the September 11 2001 (9/11) terrorist attacks on the World Trade Center (WTC). We examined new onset gastroesophageal reflux symptoms (GERS) since 9/11 and persisting up to 5–6 years in relation to 9/11-related exposures among the WTC Health Registry enrollees, and potential associations with comorbid asthma and posttraumatic stress disorder (PTSD). METHODS: This is a retrospective analysis of 37,118 adult enrollees (i.e., rescue/recovery workers, local residents, area workers, and passersby in lower Manhattan on 9/11) who reported no pre-9/11 GERS and who participated in two Registry surveys 2–3 and 5–6 years after 9/11. Post-9/11 GERS (new onset since 9/11) reported at first survey, and persistent GERS (post-9/11 GERS reported at both surveys) were analyzed using log-binomial regression. RESULTS: Cumulative incidence was 20% for post-9/11 GERS and 13% for persistent GERS. Persistent GERS occurred more often among those with comorbid PTSD (24%), asthma (13%), or both (36%) compared with neither of the comorbid conditions (8%). Among enrollees with neither asthma nor PTSD, the adjusted risk ratio (aRR) for persistent GERS was elevated among: workers arriving at the WTC pile on 9/11 (aRR=1.6; 95% confidence interval (CI) 1.3–2.1) or working at the WTC site > 90 days (aRR=1.6; 1.4–2.0); residents exposed to the intense dust cloud on 9/11 (aRR=1.5; 1.0–2.3), or who did not evacuate their homes (aRR=1.7; 1.2–2.3); and area workers exposed to the intense dust cloud (aRR=1.5; 1.2–1.8). CONCLUSIONS: Disaster-related environmental exposures may contribute to the development of GERS. GERS may be accentuated in the presence of asthma or PTSD

Multiple Gene Variants Linked to Alzheimer\u27s-Type Clinical Dementia via GWAS are Also Associated with Non-Alzheimer\u27s Neuropathologic Entities

The classic pathologic hallmarks of Alzheimer’s disease (AD) are amyloid plaques and neurofibrillary tangles (AD neuropathologic changes, or ADNC). However, brains from individuals clinically diagnosed with “AD-type” (amnestic) dementia usually harbor heterogeneous neuropathologies in addition to, or other than, ADNC. We hypothesized that some AD-type dementia associated genetic single nucleotide variants (SNVs) identified from large genomewide association studies (GWAS) were associated with non-ADNC neuropathologies. To test this hypothesis, we analyzed data from multiple studies with available genotype and neuropathologic phenotype information. Clinical AD/dementia risk alleles of interest were derived from the very large GWAS by Bellenguez et al. (2022) who reported 83 clinical AD/dementia-linked SNVs in addition to the APOE risk alleles. To query the pathologic phenotypes associated with variation of those SNVs, National Alzheimer’s disease Coordinating Center (NACC) neuropathologic data were linked to AD Sequencing Project (ADSP) and AD Genomics Consortium (ADGC) data. Separate data were obtained from the harmonized Religious Orders Study and the Rush Memory and Aging Project (ROSMAP). A total of 4811 European participants had at least ADNC neuropathology data and also genotype data available; data were meta-analyzed across cohorts. As expected, a subset of dementia-associated SNVs were associated with ADNC risk in Europeans—e.g., BIN1, PICALM, CR1, MME, and COX7C. Other gene variants linked to (clinical) AD dementia were associated with non-ADNC pathologies. For example, the associations of GRN and TMEM106B SNVs with limbic-predominant age-related TDP-43 neuropathologic changes (LATE-NC) were replicated. In addition, SNVs in TNIP1 and WNT3 previously reported as ADrelated were instead associated with hippocampal sclerosis pathology. Some genotype/neuropathology association trends were not statistically significant at P \u3c 0.05 after correcting for multiple testing, but were intriguing. For example, variants in SORL1 and TPCN1 showed trends for association with LATE-NC whereas Lewy body pathology trended toward association with USP6NL and BIN1 gene variants. A smaller cohort of non-European subjects (n = 273, approximately one-half of whom were African-Americans) provided the basis for additional exploratory analyses. Overall, these findings were consistent with the hypothesis that some genetic variants linked to AD dementia risk exert their affect by influencing non-ADNC neuropathologies

Point-of-care testing for disasters: needs assessment, strategic planning, and future design.

Objective evidence-based national surveys serve as a first step in identifying suitable point-of-care device designs, effective test clusters, and environmental operating conditions. Preliminary survey results show the need for point-of-care testing (POCT) devices using test clusters that specifically detect pathogens found in disaster scenarios. Hurricane Katrina, the tsunami in southeast Asia, and the current influenza pandemic (H1N1, "swine flu") vividly illustrate lack of national and global preparedness. Gap analysis of current POCT devices versus survey results reveals how POCT needs can be fulfilled. Future thinking will help avoid the worst consequences of disasters on the horizon, such as extensively drug-resistant tuberculosis and pandemic influenzas. A global effort must be made to improve POC technologies to rapidly diagnose and treat patients to improve triaging, on-site decision making, and, ultimately, economic and medical outcomes

9/11-Related Experiences and Tasks of Landfill and Barge Workers: Qualitative Analysis from the World Trade Center Health Registry

<p>Abstract</p> <p>Background</p> <p>Few studies have documented the experiences of individuals who participated in the recovery and cleanup efforts at the World Trade Center Recovery Operation at Fresh Kills Landfill, on debris loading piers, and on transport barges after the September 11, 2001 terrorist attack.</p> <p>Methods</p> <p>Semi-structured telephone interviews were conducted with a purposive sample of workers and volunteers from the World Trade Center Health Registry. Qualitative methods were used to analyze the narratives.</p> <p>Results</p> <p>Twenty workers and volunteers were interviewed. They described the transport of debris to the Landfill via barges, the tasks and responsibilities associated with their post-9/11 work at the Landfill, and their reflections on their post-9/11 experiences. Tasks included sorting through debris, recovering human remains, searching for evidence from the terrorist attacks, and providing food and counseling services. Exposures mentioned included dust, fumes, and odors. Eight years after the World Trade Center disaster, workers expressed frustration about poor risk communication during recovery and cleanup work. Though proud of their contributions in the months after 9/11, some participants were concerned about long-term health outcomes.</p> <p>Conclusions</p> <p>This qualitative study provided unique insight into the experiences, exposures, and concerns of understudied groups of 9/11 recovery and cleanup workers. The findings are being used to inform the development of subsequent World Trade Center Health Registry exposure and health assessments.</p

Mental Health of Those Directly Exposed to the World Trade Center Disaster: Unmet Mental Health Care Need, Mental Health Treatment Service Use, and Quality of Life

Mental health service utilization several years following a man-made or natural disaster can be lower than expected, despite a high prevalence of mental health disorders among those exposed. This study focused on factors associated with subjective unmet mental health care need (UMHCN) and its relationship to a combination of diagnostic history and current mental health symptoms, 5–6 years after the 9-11-01 World Trade Center (WTC) disaster in New York City, USA. Two survey waves of the WTC Health Registry, after exclusions, provided a sample of 36,625 enrollees for this analysis. Important differences were found among enrollees who were categorized according to the presence or absence of a self-reported mental health diagnosis and symptoms indicative of post-traumatic stress disorder or serious psychological distress. Persons with diagnoses and symptoms had the highest levels of UMHCN, poor mental health days, and mental health service use. Those with symptoms only were a vulnerable group much less likely to use mental health services yet reporting UMHCN and poor mental health days. Implications for delivering mental health services include recognizing that many persons with undiagnosed but symptomatic mental health symptoms are not using mental health services, despite having perceived need for mental health care

Ten-year cancer incidence in rescue/recovery workers and civilians exposed to the September 11, 2001 terrorist attacks on the World Trade Center

Background: Cancer incidence in exposed rescue/recovery workers (RRWs) and civilians (non-RRWs) was previously reported through 2008. Methods: We studied occurrence of first primary cancer among World Trade Center Health Registry enrollees through 2011 using adjusted standardized incidence ratios (SIRs), and the WTC-exposure-cancer association, using Cox proportional hazards models. Results: All-cancer SIR was 1.11 (95% confidence interval (CI) 1.03–1.20) in RRWs, and 1.08 (95% CI 1.02–1.15) in non-RRWs. Prostate cancer and skin melanoma were significantly elevated in both populations. Thyroid cancer was significantly elevated only in RRWs while breast cancer and non-Hodgkin's lymphoma were significantly elevated only in non-RRWs. There was a significant exposure dose-response for bladder cancer among RRWs, and for skin melanoma among non-RRWs. Conclusions: We observed excesses of total and specific cancers in both populations, although the strength of the evidence for causal relationships to WTC exposures is somewhat limited. Continued monitoring of this population is indicated