SUDEP in adults and children

Sudden unexpected death in epilepsy (SUDEP) represents an important cause of death in patients with epilepsy and it exceeds the expected rate of sudden death in the general population by nearly 24 times. We searched the electronic databases (Cochrane, EMBASE, Scopus, Medline, Pubmed) for studies related to etiology and risk stratification of SUDEP including data on Takotsubo cardiomyopathy (TKC) following seizures resulting in death or near death.: SUDEP is more common among males in the fourth decade of life. Risk for SUDEP is increased by early onset of seizures, low IQ, generalised tonic clonic seizures, nocturnal seizures and seizure frequency. Nonadherance to antiepileptic medications, absence of therapeutic drug level monitoring, presence of neuropathological lesions on imaging and certain subgroups like Dravet syndrome increase its risk. The risk for premature death in patients undergoing temporal lobe resection for drug resistant epilepsy decreased over time but remained above the standard population. Prolonged postictal electroencephalographic suppression was a risk factor for SUDEP in patients with generalised seizures which may indicate a cerebral electrical shutdown. Documented ictal/postictal hypoventilation, laryngeal spasm and cardiac rhythm abnormalities prior to SUDEP may suggest central apnea, neurogenic pulmonary edema, cardiac arrhythmia, or a combination of the above as a cause. Seizure triggered TKC does not seem to play a major role in the pathogenesis of SUDEP.

CARD9 in Neutrophils Protects from Colitis and Controls Mitochondrial Metabolism and Cell Survival

Objectives: Inflammatory bowel disease (IBD) results from a combination of genetic predisposition, dysbiosis of the gut microbiota and environmental factors, leading to alterations in the gastrointestinal immune response and chronic inflammation. Caspase recruitment domain 9 (Card9), one of the IBD susceptibility genes, has been shown to protect against intestinal inflammation and fungal infection. However, the cell types and mechanisms involved in the CARD9 protective role against inflammation remain unknown. Design: We used dextran sulfate sodium (DSS)-induced and adoptive transfer colitis models in total and conditional CARD9 knock-out mice to uncover which cell types play a role in the CARD9 protective phenotype. The impact of Card9 deletion on neutrophil function was assessed by an in vivo model of fungal infection and various functional assays, including endpoint dilution assay, apoptosis assay by flow cytometry, proteomics and real time bioenergetic profile analysis (Seahorse). Results: Lymphocytes are not intrinsically involved in the CARD9 protective role against colitis. CARD9 expression in neutrophils, but not in epithelial or CD11c+ cells, protects against DSS-induced colitis. In the absence of CARD9, mitochondrial dysfunction in neutrophils leads to their premature death through apoptosis, especially in oxidative environment. The decrease of fonctional neutrophils in tissues could explain the impaired containment of fungi and increased susceptibility to intestinal inflammation. Conclusion: These results provide new insight into the role of CARD9 in neutrophil mitochondrial function and its involvement in intestinal inflammation, paving the way for new therapeutic strategies targeting neutrophils.

Lesion Material From Treponema-Associated Hoof Disease of Wild Elk Induces Disease Pathology in the Sheep Digital Dermatitis Model

A hoof disease among wild elk (Cervus elaphus) in the western United States has been reported since 2008. Now present in Washington, Oregon, Idaho, and California, this hoof disease continues to spread among elk herds suggesting an infectious etiology. Causing severe lesions at the hoof-skin junction, lesions can penetrate the hoof-horn structure causing severe lameness, misshapen hooves, and in some cases, sloughed hooves leaving the elk prone to infection, malnutrition, and premature death. Isolated to the feet, this disease has been termed treponeme-associated hoof disease due to the numerous Treponema spp. found within lesions. In addition to the Treponema spp., treponeme-associated hoof disease shares many similarities with digital dermatitis of cattle and livestock including association with several groups of anaerobic bacteria such as Bacteroides, Clostridia, and Fusobacterium, neutrophilic inflammatory infiltrate, and restriction of the disease to the foot and hoof tissues. To determine if there was a transmissible infectious component to this disease syndrome, elk lesion homogenate was used in a sheep model of digital dermatitis. Ten animals were inoculated with lesion material and lesion development was followed over 7 weeks. Most inoculated feet developed moderate to severe lesions at 2- or 4-weeks post-inoculation timepoints, with 16 of 18 feet at 4 weeks also had spirochetes associated within the lesions. Histopathology demonstrated spirochetes at the invading edge of the lesions along with other hallmarks of elk hoof disease, neutrophilic inflammatory infiltrates, and keratinocyte erosion. Treponema-specific PCR demonstrated three phylotypes associated with elk hoof disease and digital dermatitis were present. Serum of infected sheep had increased anti-Treponema IgG when compared to negative control sheep and pre-exposure samples. Analysis of the bacterial microbiome by sequencing of the bacterial 16S rRNA gene showed a community structure in sheep lesions that was highly similar to the elk lesion homogenate used as inoculum. Bacteroidies, Fusobacterium, and Clostridia were among the bacterial taxa overrepresented in infected samples as compared to negative control samples. In conclusion, there is a highly transmissible, infectious bacterial component to elk treponeme-associated hoof disease which includes several species of Treponema as well as other bacteria previously associated with digital dermatitis.

The Public Economics of Changing Longevity

Our societies are witnessing a steady increase in longevity. This demographic evolution is accompanied by some convergence across countries, but at the same time substantial longevity inequalities persist within nations across income classes. This Element aims to survey some crucial implications of changing longevity on the design of optimal public policy. For that purpose, it first focuses on some difficulties raised by risky and varying lifetime for the representation of individual and social preferences. Then, it explore some central implications of changing longevity for optimal policy making, regarding prevention against premature death, pension policies, education, health care and long-term care. The author distinguishes between the case when longevity is partially the responsibility of individuals and the case when longevity is plainly exogenous.

Impact of Cancer Cachexia on Cardiac and Skeletal Muscle: Role of Exercise Training

Cachexia is a multifactorial syndrome that presents with, among other characteristics, progressive loss of muscle mass and anti-cardiac remodeling effect that may lead to heart failure. This condition affects about 80% of patients with advanced cancer and contributes to worsening patients’ tolerance to anticancer treatments and to their premature death. Its pathogenesis involves an imbalance in metabolic homeostasis, with increased catabolism and inflammatory cytokines levels, leading to proteolysis and lipolysis, with insufficient food intake. A multimodal approach is indicated for patients with cachexia, with the aim of reducing the speed of muscle wasting and improving their quality of life, which may include nutritional, physical, pharmacologic, and psychological support. This review aims to outline the mechanisms of muscle loss, as well as to evaluate the current clinical evidence of the use of physical exercise in patients with cachexia.

Cardiac device implantation and device usage in Fabry and hypertrophic cardiomyopathy

Background Fabry disease (FD) is a treatable X-linked condition leading to progressive cardiac disease, arrhythmia and premature death. We aimed to increase awareness of the arrhythmogenicity of Fabry cardiomyopathy, by comparing device usage in patients with Fabry cardiomyopathy and sarcomeric HCM. All Fabry patients with an implantable cardioverter defibrillator (ICD) implanted in the UK over a 17 year period were included. A comparator group of HCM patients, with primary prevention ICD implantation, were captured from a regional registry database. Results Indications for ICD in FD varied with 72% implanted for primary prevention based on multiple potential risk factors. In FD and HCM primary prevention devices, arrhythmia occurred more frequently in FD over shorter follow-up (HR 4.2, p < 0.001). VT requiring therapy was more common in FD (HR 4.5, p = 0.002). Immediate shock therapy for sustained VT was also more common (HR 2.5, p < 0.001). There was a greater burden of AF needing anticoagulation and NSVT in FD (AF: HR 6.2, p = 0.004, NSVT: HR 3.1, p < 0.001). Conclusion This study demonstrates arrhythmia burden and ICD usage in FD is high, suggesting that Fabry cardiomyopathy may be more ‘arrhythmogenic’ than previously thought. Existing risk models cannot be mutually applicable and further research is needed to provide clarity in managing Fabry patients with cardiac involvement.

Burden of Chronic Heart Failure in Romania

Chronic heart failure (CHF) affects millions of people across the world, with increasing trends in prevalence, putting ever increasing pressure on the healthcare system. The aim of this study was to assess the financial burden of CHF hospital care on the public healthcare sector in Romania by estimating the number of inpatient episodes and the associated costs. Additionally, societal costs associated with missed work and premature death of CHF patients were also estimated. The national claims database was analyzed to estimate the number of CHF patients. Cost data was extracted from a pool of nine public hospitals in Romania. In 2019, 375,037 CHF patient episodes were identified on specific wards at the national level. The average cost calculated for the selected nine hospitals was EUR 996. The calculated weighted national average cost per patient episode was EUR 1002, resulting in a total cost of EUR 376 million at the national level. The cost of workdays missed summed up to EUR 122 million, while the annual costs associated with the premature death of CHF patients was EUR 230 million. In conclusion, the prevalence of CHF in Romania is high, accounting for a large proportion of hospitalizations, which translates into large costs for the national payer.

Advance Care Planning Preferences for Adolescents With Cardiac Disease

BACKGROUND AND OBJECTIVES: Adolescents with cardiac disease are at risk for life-changing complications and premature death. The importance of advance care planning (ACP) in adults with congenital heart disease and in pediatric patients with HIV and cancer has been demonstrated. ACP preferences of adolescents with heart disease have not been evaluated. We describe ACP preferences of adolescents with heart disease and compare with those of their caregivers. METHODS: Outpatient adolescents aged 12 to 18 years with heart failure, cardiomyopathy, heart transplantation, or who were at risk for cardiomyopathy, as well as their caregivers, completed self-administered questionnaires which evaluated participants’ opinions regarding content and timing of ACP discussions, preferences for end-of-life communication, and emotional responses to ACP. RESULTS: Seventy-eight adolescents and 69 caregivers participated, forming 62 adolescent-caregiver dyads. Adolescents and caregivers reported that adolescent ACP discussions should occur early in the disease course (75% and 61%, respectively). Adolescents (92%) wanted to be told about terminal prognosis, whereas only 43% of caregivers wanted the doctor to tell their child this information. Most adolescents (72%) and caregivers (67%) anticipated that discussing ACP would make the adolescent feel relieved the medical team knew their wishes. Most caregivers (61%) believed that adolescents would feel stress associated with ACP discussions, whereas only 31% of adolescents anticipated this. CONCLUSIONS: Adolescents and their caregivers agree that ACP should occur early in disease course. There are discrepancies regarding communication of prognosis and perceived adolescent stress related to ACP discussions. Facilitated conversations between patient, caregiver, and providers may align goals of care and communication preferences.

Adeno-Associated Virus (AAV)-Mediated Gene Therapy for Duchenne Muscular Dystrophy: The Issue of Transgene Persistence

Duchenne muscular dystrophy (DMD) is an X-linked recessive, infancy-onset neuromuscular disorder characterized by progressive muscle weakness and atrophy, leading to delay of motor milestones, loss of autonomous ambulation, respiratory failure, cardiomyopathy, and premature death. DMD originates from mutations in the DMD gene that result in a complete absence of dystrophin. Dystrophin is a cytoskeletal protein which belongs to the dystrophin-associated protein complex, involved in cellular signaling and myofiber membrane stabilization. To date, the few available therapeutic options are aimed at lessening disease progression, but persistent loss of muscle tissue and function and premature death are unavoidable. In this scenario, one of the most promising therapeutic strategies for DMD is represented by adeno-associated virus (AAV)-mediated gene therapy. DMD gene therapy relies on the administration of exogenous micro-dystrophin, a miniature version of the dystrophin gene lacking unnecessary domains and encoding a truncated, but functional, dystrophin protein. Limited transgene persistence represents one of the most significant issues that jeopardize the translatability of DMD gene replacement strategies from the bench to the bedside. Here, we critically review preclinical and clinical studies of AAV-mediated gene therapy in DMD, focusing on long-term transgene persistence in transduced tissues, which can deeply affect effectiveness and sustainability of gene replacement in DMD. We also discuss the role played by the overactivation of the immune host system in limiting long-term expression of genetic material. In this perspective, further studies aimed at better elucidating the need for immune suppression in AAV-treated subjects are warranted in order to allow for life-long therapy in DMD patients.

The role of exercise and physical activity on aging-related diseases and geriatric syndromes

Aging is a complex process of physiological and social changes that leads to various diseases. The number of elderly people in the world is increasing dramatically and it should be noted that rapid population aging represents a major public health burden. On the other hand, providing an appropriate and low-cost approach to control and prevent complications such as chronic diseases, physical dysfunction, and the geriatric syndrome is necessary. Also, numerous studies have shown that participation in physical activity and exercise training reduces the incidence of dysfunctional capacity, cardiovascular and metabolic disease, as well as the premature death rate in older adults. After plenty of precise observations about the role of exercise on aging-related diseases and geriatric syndromes articles, the benefits of exercise and physical activity in older adults will be more tangible. Therefore, the first purpose of the present review was to investigate the mechanisms of PA and exercises that are involved in the prevention of aging-related diseases and GS using current evidence (from 2015 onwards). Also, the purpose of this study was to provide an exercise guideline (aerobic and resistance training) based on recent evidence (from 2015 onwards). El envejecimiento es un proceso complejo de cambios fisiológicos y sociales que conduce a diversas enfermedades. El número de personas de edad avanzada en el mundo está aumentando drásticamente y cabe señalar que el rápido envejecimiento de la población representa una importante carga para la salud pública. Por otro lado, es necesario brindar un enfoque adecuado y de bajo costo para controlar y prevenir complicaciones como enfermedades crónicas, disfunción física y síndrome geriátrico. Además, numerosos estudios han demostrado que la participación en la actividad física y el entrenamiento físico reduce la incidencia de disfunciones, enfermedades cardiovasculares y metabólicas, así como la tasa de muerte prematura en los adultos mayores. Después de muchas observaciones precisas sobre el papel del ejercicio en los artículos sobre enfermedades relacionadas con el envejecimiento y síndromes geriátricos, los beneficios del ejercicio y la actividad física en los adultos mayores serán más tangibles. Por lo tanto, el primer propósito de la presente revisión fue investigar los mecanismos de actividad física y ejercicios que están involucrados en la prevención de enfermedades relacionadas con el envejecimiento y síndrome geriátrico utilizando la evidencia actual (de 2015 en adelante). Además, el propósito de este estudio fue proporcionar una guía de ejercicio (entrenamiento aeróbico y de resistencia) basada en evidencia reciente (de 2015 en adelante).