Notes

Densification of your NASICON-Type LATP Electrolyte Page by the Cold-Sintering Procedure.
Chimeric antigen receptor (CAR) tonic signaling, defined as spontaneous activation and release of proinflammatory cytokines by CAR-T cells, is considered a negative attribute because it leads to impaired antitumor effects. Here, we report that CAR tonic signaling is caused by the intrinsic instability of the mAb single-chain variable fragment (scFv) to promote self-aggregation and signaling via the CD3ζ chain incorporated into the CAR construct. This phenomenon was detected in a CAR encoding either CD28 or 4-1BB costimulatory endodomains. Instability of the scFv was caused by specific amino acids within the framework regions (FWR) that can be identified by computational modeling. Substitutions of the amino acids causing instability, or humanization of the FWRs, corrected tonic signaling of the CAR, without modifying antigen specificity, and enhanced the antitumor effects of CAR-T cells. Overall, we demonstrated that tonic signaling of CAR-T cells is determined by the molecular instability of the scFv and that computational analyses of the scFv can be implemented to correct the scFv instability in CAR-T cells with either CD28 or 4-1BB costimulation.
Early recognition of individuals with increased risk of sudden cardiac arrest (SCA) remains challenging. SCA research so far has used data from cardiologist care, but missed most SCA victims, since they were only in general practitioner (GP) care prior to SCA. Studying individuals with type 2 diabetes (T2D) in GP care may help solve this problem, as they have increased risk for SCA, and rich clinical datasets, since they regularly visit their GP for check-up measurements. This information can be further enriched with extensive genetic and metabolic information.

To describe the study protocol of the REcognition of Sudden Cardiac arrest vUlnErability in Diabetes (RESCUED) project, which aims at identifying clinical, genetic and metabolic factors contributing to SCA risk in individuals with T2D, and to develop a prognostic model for the risk of SCA.

The RESCUED project combines data from dedicated SCA and T2D cohorts, and GP data, from the same region in the Netherlands. Clinical data, genetic data (common and rare variant analysis) and metabolic data (metabolomics) will be analysed (using classical analysis techniques and machine learning methods) and combined into a prognostic model for risk of SCA.

The RESCUED project is designed to increase our ability at early recognition of elevated SCA risk through an innovative strategy of focusing on GP data and a multidimensional methodology including clinical, genetic and metabolic analyses.
The RESCUED project is designed to increase our ability at early recognition of elevated SCA risk through an innovative strategy of focusing on GP data and a multidimensional methodology including clinical, genetic and metabolic analyses.
Recently, a simple ECG score (DETERMINE score) has been proposed for estimating myocardial scar in patients with ischaemic cardiomyopathy. We sought to evaluate the usefulness of the DETERMINE score for the assessment of myocardial infarct size (IS) as well as microvascular obstruction (MVO), in the setting of ST-elevation myocardial infarction (STEMI).

This observational study enrolled 423 patients with STEMI (median age 56, 17% women), revascularised by primary percutaneous coronary intervention (PCI). For evaluation of the DETERMINE and Selvester scoring system (an established but complex ECG score for IS estimation), ECG was conducted before discharge (median 4 (IQR 2-6) days). Cardiac magnetic resonance (CMR) was conducted within a week after infarction for determination of IS and MVO.

Median DETERMINE score of the overall cohort was 8 points (IQR 5-11). A higher DETERMINE score was significantly associated with a larger IS (21% vs 11% of left ventricular myocardial mass (LVMM), p<0.001) as well as larger MVO (1.2% vs 0.0% of LVMM, p<0.001). In linear and binary multivariable logistic regression analysis, the DETERMINE score remained independently associated with IS (OR 1.09, 95% CI 1.02 to 1.17, p=0.014) and MVO (OR 1.12, 95% CI 1.04 to 1.21, p=0.003), after adjustment for Selvester score and clinical indicators of IS (high-sensitivity cardiac troponin T, high-sensitivity C reactive protein, N-terminal pro-B-type natriuretic peptide, TIMI flow pre-interventional and post-interventional PCI, anterior infarct localisation).

In patients undergoing PCI for STEMI, the DETERMINE score provides an easy and inexpensive tool for appropriate estimation of infarct severity as determined by CMR.
In patients undergoing PCI for STEMI, the DETERMINE score provides an easy and inexpensive tool for appropriate estimation of infarct severity as determined by CMR.
Brugada syndrome (BrS) is an ion channelopathy that predisposes affected patients to spontaneous ventricular tachycardia/fibrillation (VT/VF) and sudden cardiac death. The aim of this study is to examine the predictive factors of spontaneous VT/VF.

This was a territory-wide retrospective cohort study of patients diagnosed with BrS between 1997 and 2019. The primary outcome was spontaneous VT/VF. Cox regression was used to identify significant risk predictors. Non-linear interactions between variables (latent patterns) were extracted using non-negative matrix factorisation (NMF) and used as inputs into the random survival forest (RSF) model.

This study included 516 consecutive BrS patients (mean age of initial presentation=50±16 years, male=92%) with a median follow-up of 86 (IQR 45-118) months. The cohort was divided into subgroups based on initial disease manifestation asymptomatic (n=314), syncope (n=159) or VT/VF (n=41). Annualised event rates per person-year were 1.70%, 0.05% and 0.01% for the VT/VF, syncope and asymptomatic subgroups, respectively. Multivariate Cox regression analysis revealed initial presentation of VT/VF (HR=24.0, 95% CI=1.21 to 479, p=0.037) and SD of P-wave duration (HR=1.07, 95% CI=1.00 to 1.13, p=0.044) were significant predictors. The NMF-RSF showed the best predictive performance compared with RSF and Cox regression models (precision 0.87 vs 0.83 vs. 0.76, recall 0.89 vs. 0.85 vs 0.73, F1-score 0.88 vs 0.84 vs 0.74).

Clinical history, electrocardiographic markers and investigation results provide important information for risk stratification. Machine learning techniques using NMF and RSF significantly improves overall risk stratification performance.
Clinical history, electrocardiographic markers and investigation results provide important information for risk stratification. Machine learning techniques using NMF and RSF significantly improves overall risk stratification performance.
Although there are regional reports that the COVID-19 pandemic is associated with a reduction in acute myocardial infarction presentations and primary percutaneous coronary intervention (PCI) procedures, little is known about the impact of the COVID-19 pandemic on mechanical complications resulting from ST-segment elevation myocardial infarction (STEMI) and mortality.

This single-centre retrospective cohort study analysed presentations, incidence of mechanical complications, and mortality in patients with STEMI before and after a state of emergency was declared due to the COVID-19 pandemic by the Japanese government on 7 April 2020.

We analysed 359 patients with STEMI hospitalised before the declaration and 63 patients hospitalised after the declaration. The proportion of patients with late presentation was significantly higher after the declaration than before (25.4% vs 14.2%, p=0.03). The incidence of late presentation was significantly higher during the COVID-19 pandemic than before (incidence rate rediately seek medical attention when suffering symptoms of a heart attack, may worsen outcomes in patients with STEMI.
Evidence on heterogeneity in outcomes of surgical quality interventions in low-income and middle-income countries is limited. We explored factors driving performance in the Safe Surgery 2020 intervention in Tanzania's Lake Zone to distil implementation lessons for low-resource settings.

We identified higher (n=3) and lower (n=3) performers from quantitative data on improvement from 14 safety and teamwork and communication indicators at 0 and 12 months from 10 intervention facilities, using a positive deviance framework. From 72 key informant interviews with surgical providers across facilities at 1, 6 and 12 months, we used a grounded theory approach to identify practices of higher and lower performers.

Performance experiences of higher and lower performers differed on the following themes (1) preintervention context, (2) engagement with Safe Surgery 2020 interventions, (3) teamwork and communication orientation, (4) collective learning orientation, (5) role of leadership, and (6) perceived impact of Safe Surgery 2020 and beyond. Higher performers had a culture of teamwork which helped them capitalise on Safe Surgery 2020 to improve surgical ecosystems holistically on safety practices, teamwork and communication. Lower performers prioritised overhauling safety practices and began considering organisational cultural changes much later. Thus, while also improving, lower performers prioritised different goals and trailed higher performers on the change continuum.

Future interventions should be tailored to facility context and invest in strengthening teamwork, communication and collective learning and facilitate leadership engagement to build a receptive climate for successful implementation of safe surgery interventions.
Future interventions should be tailored to facility context and invest in strengthening teamwork, communication and collective learning and facilitate leadership engagement to build a receptive climate for successful implementation of safe surgery interventions.
In patients on maintenance dialysis, cardiovascular mortality risk is remarkably high, which can be partly explained by severe coronary artery calcification (CAC). Hyperphosphatemia has been reported to be associated with the severity of CAC. However, the optimal phosphate range in patients on dialysis remains unknown. This study was planned to compare the effects on CAC progression of two types of noncalcium-based phosphate binders and of two different phosphate target ranges.

We conducted a randomized, open-label, multicenter, interventional trial with a two by two factorial design. A total of 160 adults on dialysis were enrolled and randomized to the sucroferric oxyhydroxide or lanthanum carbonate group, with the aim of reducing serum phosphate to two target levels (3.5-4.5 mg/dl in the strict group and 5.0-6.0 mg/dl in the standard group). The primary end point was percentage change in CAC scores during the 12-month treatment.

The full analysis set included 115 patients. We observed no significant dng the Practice of EBM (EPISODE), jRCTs051180048.
Patients with advanced CKD experience increased intestinal potassium excretion. This compensatory mechanism may be enhanced by laxative use; however, little is known about the association of laxative use with risk of dyskalemia in advanced CKD.

Our study population encompassed 36,116 United States veterans transitioning to ESKD from 2007 to 2015 with greater than or equal to one plasma potassium measurement during the last 1-year period before ESKD transition. Using generalized estimating equations with adjustment for potential confounders, we examined the association of time-varying laxative use with risk of dyskalemia (
., hypokalemia [potassium <3.5 mEq/L] or hyperkalemia [>5.5 mEq/L]) versus normokalemia (3.5-5.5 mEq/L) over the 1-year pre-ESKD period. 8-OH-DPAT mw To avoid potential overestimation of dyskalemia risk, potassium measurements within 7 days following a dyskalemia event were disregarded in the analyses.

Over the last 1-year pre-ESKD period, there were 319,219 repeated potassium measurements in the cohort.
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