Novel Genetic and Phenotypic Expansion in GOSR2-Related Progressive Myoclonus Epilepsy.

Biallelic variants in the Golgi SNAP receptor complex member 2 gene (GOSR2) have been reported in progressive myoclonus epilepsy with neurodegeneration. Typical clinical features include ataxia and areflexia during early childhood, followed by seizures, scoliosis, dysarthria, and myoclonus. Here, we report two novel patients from unrelated families with a GOSR2-related disorder and novel genetic and clinical findings. The first patient, a male compound heterozygous for the GOSR2 splice site variant c.336+1G>A and the novel c.364G>A,p.Glu122Lys missense variant showed global developmental delay and seizures at the age of 2 years, followed by myoclonus at the age of 8 years with partial response to clonazepam. The second patient, a female homozygous for the GOSR2 founder variant p.Gly144Trp, showed only mild fine motor developmental delay and generalized tonic-clonic seizures triggered by infections during adolescence, with seizure remission on levetiracetam. The associated movement disorder progressed atypically slowly during adolescence compared to its usual speed, from initial intention tremor and myoclonus to ataxia, hyporeflexia, dysmetria, and dystonia. These findings expand the genotype-phenotype spectrum of GOSR2-related disorders and suggest that GOSR2 should be included in the consideration of monogenetic causes of dystonia, global developmental delay, and seizures.

Assessment of Health-Related Quality of Life in Patients with Chronic Heart Failure: A Cross-Sectional Study in Vietnam.

Introduction Heart failure is currently a global health issue, imposing a burden on disease prevalence and mortality rates for patients, while simultaneously impacting the quality of life for affected individuals. Data on assessing the health-related quality of life (HRQoL) of patients with chronic heart failure in developing countries, including Vietnam, is still limited. This study was conducted with the aim of describing the quality of life of patients with chronic heart failure in Vietnam. Methods This cross-sectional investigation enrolled 140 chronic heart failure outpatients, utilizing a convenience sample at Hai Duong Province Hospital, Vietnam, spanning from December 2021 to April 2022. Essential patient variables encompassing age, gender, and heart failure duration were gathered. Surveying of patients took place at the outpatient clinic during chronic heart failure follow-up visits using the 36-Item Short Form Health Survey (SF-36) questionnaire. The SF-36 comprises eight dimensions: (1) Physical functioning, (2) Role limitations due to physical health, (3) Bodily pain, (4) General health perceptions, (5) Vitality, (6) Social role functioning, (7) Role limitations due to emotional health, and (8) Mental health. Component analysis of the SF-36 revealed two distinct concepts: a physical component summary (PCS) reflecting the physical aspect and a mental component summary (MCS) reflecting the mental aspect. Results The research involved 140 participants diagnosed with chronic heart failure, having a median age of 59 years (interquartile range (IQR): 52-63). Among them, 61.4% were male, and 50% exhibited reduced left ventricular ejection fraction (LVEF) (≤ 40%). The role limitations due to the physical health domain indicated the lowest score, registering a median value of 0 (IQR 0-25). Domains with median scores below the 25-point threshold encompassed role limitations due to physical health (0 points). Those with scores ranging from 25 to 49 points constituted general health perceptions (25 points), role limitations due to emotional health (33.3 points), vitality (45 points), and mental health (48 points). Bodily pain and social role functioning achieved median scores at a moderate level (50-74 points), scoring 62 and 62.5 points, respectively. The overall HRQoL score on the SF-36 scale was 45.2 (IQR: 32.1-58.7) points. Median scores for the PCS and MCS were 44.3 (IQR: 30.5-52) and 47.0 (IQR: 32.6-65.4), respectively. No statistically significant differences in PCS and MCS scores were observed when subgroup analysis was performed based on variables like age, gender, or LVEF. However, in the vitality domain, female patients exhibited a significantly lower median score than male patients (p-value = 0.046). In the physical functioning domain, individuals aged ≥ 60 had lower median scores than those aged < 60 years (p = 0.022). Additionally, the group with LVEF ≤ 40% had lower median scores compared to the group with LVEF > 40% (p = 0.038) in role limitations due to emotional health domain. Conclusion In Vietnam, the HRQoL in the outpatient population with chronic heart failure was notably low when assessed using the SF-36 questionnaire. Large-scale, multicenter studies are needed to provide stronger, more conclusive evidence.

Engineering CAR-T cells to activate small-molecule drugs in situ.

Chimeric antigen receptor (CAR)-T cells represent a major breakthrough in cancer therapy, wherein a patient's own T cells are engineered to recognize a tumor antigen, resulting in activation of a local cytotoxic immune response. However, CAR-T cell therapies are currently limited to the treatment of B cell cancers and their effectiveness is hindered by resistance from antigen-negative tumor cells, immunosuppression in the tumor microenvironment, eventual exhaustion of T cell immunologic functions and frequent severe toxicities. To overcome these problems, we have developed a novel class of CAR-T cells engineered to express an enzyme that activates a systemically administered small-molecule prodrug in situ at a tumor site. We show that these synthetic enzyme-armed killer (SEAKER) cells exhibit enhanced anticancer activity with small-molecule prodrugs, both in vitro and in vivo in mouse tumor models. This modular platform enables combined targeting of cellular and small-molecule therapies to treat cancers and potentially a variety of other diseases.