The heart of Rett syndrome: A quantitative analysis of cardiac repolarization

BACKGROUND: Rett syndrome (RTT) is a developmental encephalopathy disorder that is associated with a high incidence of sudden death presumably from cardiorespiratory etiologies. Electrocardiogram (ECG) abnormalities, such as prolonged heart-rate corrected QT (QTc) interval, are markers of cardiac repolarization and are associated with potentially lethal ventricular arrhythmias. This study investigates the cardiac repolarization characteristics of RTT patients, including QTc and T-wave morphology characteristics. METHODS: A retrospective quantitative analysis on 110 RTT patients and 124 age and sex-matched healthy controls was conducted. RESULTS: RTT patients had longer QTc, more abnormal T-wave morphology, and greater heterogeneity of cardiac repolarization parameters compared to controls. Even RTT patients without prolonged QTc had more abnormal ECG and T-wave characteristics than controls. Among RTT patients, CONCLUSIONS: Cardiac repolarization abnormalities are present in RTT patients, even without long QTc. T-wave morphology is related to RTT genotype and may be predictive of mortality. These findings could be used to help the management and monitoring of RTT patients

How the Commonwealth of the Northern Mariana Islands Stalled COVID-19 for 22 Months and Managed its First Significant Community Transmission

OBJECTIVE: The Commonwealth of the Northern Mariana Islands (CNMI) is a remote Pacific island territory with a population of 47 329 that successfully prevented the significant introduction of coronavirus disease (COVID-19) until late 2021. This study documents how the response to the introduction of COVID-19 in CNMI in 2021 was conducted with limited resources without overwhelming local clinical capacity or compromising health service delivery for the population. METHODS: Data from COVID-19 case investigations, contact tracing, the Commonwealth\u27s immunization registry and whole genome sequencing were collated and analysed as part of this study. RESULTS: Between 26 March 2020 and 31 December 2021, 3281 cases and 14 deaths due to COVID-19 were reported in CNMI (case fatality rate, 0.4%). While notification rates were highest among younger age groups, hospitalization and mortality rates were disproportionately greater among those aged \u3e 50 years and among the unvaccinated. The first widespread community transmission in CNMI was detected in October 2021, with genomic epidemiology and contact tracing data indicating a single introduction event involving the AY.25 lineage and subsequent rapid community spread. Vaccination coverage was high before widespread transmission occurred in October 2021 and increased further over the study period. DISCUSSION: Robust preparedness and strong leadership generated resilience within the public health sector such that COVID-19 did not overwhelm CNMI\u27s health system as it did in other jurisdictions and countries around the world. At no point was hospital capacity exceeded, and all patients received adequate care without the need for health-care rationing

Pharmacological treatment of delayed cerebral ischemia and vasospasm in subarachnoid hemorrhage

Subarachnoid hemorrhage after the rupture of a cerebral aneurysm is the cause of 6% to 8% of all cerebrovascular accidents involving 10 of 100,000 people each year. Despite effective treatment of the aneurysm, delayed cerebral ischemia (DCI) is observed in 30% of patients, with a peak on the tenth day, resulting in significant infirmity and mortality. Cerebral vasospasm occurs in more than half of all patients and is recognized as the main cause of delayed cerebral ischemia after subarachnoid hemorrhage. Its treatment comprises hemodynamic management and endovascular procedures. To date, the only drug shown to be efficacious on both the incidence of vasospasm and poor outcome is nimodipine. Given its modest effects, new pharmacological treatments are being developed to prevent and treat DCI. We review the different drugs currently being tested

Effector memory and central memory NY-ESO-1-specific re-directed T cells for treatment of multiple myeloma

The cancer-testis antigen NY-ESO-1 is a potential target antigen for immune therapy expressed in a subset of patients with multiple myeloma. We generated chimeric antigen receptors (CARs) recognizing the immunodominant NY-ESO-1 peptide 157-165 in the context of HLA-A*02:01 to re-direct autologous CD8(+) T cells towards NY-ESO-1(+) myeloma cells. These re-directed T cells specifically lysed NY-ESO-1(157-165)/HLA-A*02:01-positive cells and secreted IFNγ. A total of 40% of CCR7(-) re-directed T cells had an effector memory phenotype and 5% a central memory phenotype. Based on CCR7 cell sorting, effector and memory CAR-positive T cells were separated and CCR7(+) memory cells demonstrated after antigen-specific re-stimulation downregulation of CCR7 as sign of differentiation towards effector cells accompanied by an increased secretion of memory signature cytokines such as IL-2. To evaluate NY-ESO-1 as potential target antigen, we screened 78 bone marrow biopsies of multiple myeloma patients where NY-ESO-1 protein was found to be expressed by immunohistochemistry in 9.7% of samples. Adoptively transferred NY-ESO-1-specific re-directed T cells protected mice against challenge with endogenously NY-ESO-1-positive myeloma cells in a xenograft model. In conclusion, re-directed effector- and central memory T cells specifically recognized NY-ESO-1(157-165)/ HLA-A*02:01-positive cells resulting in antigen-specific functionality in vitro and in vivo