Allogeneic hematopoietic stem cell transplant outcomes in adults with inherited myeloid malignancies

Final version published online 17 February 2023There is increasing recognition that pathogenic germline variants drive the development of hematopoietic cancers in many individuals. Currently, patients with hereditary hematologic malignancies (HHMs) receive similar standard therapies and hematopoietic stem cell transplant (HSCT) approaches as those with sporadic disease. We hypothesize that patients with myeloid malignancies and deleterious germline predisposition variants have different post-transplant outcomes compared to those without such alleles. We studied 472 patients with myeloid neoplasms, of whom 26% had deleterious germline variants (DGVs) and 34% underwent HSCT. DGVs in CHEK2 and DDX41 were most commonly seen in American and Australian cohorts, respectively. Patients with deleterious germline DDX41 variants had a higher incidence of severe (stage 3-4) acute graft versus host disease (GVHD) (38%) compared to recipients with deleterious CHEK2 variants (0%), other HHM variants (12%), or patients without such germline variants (9%) (p= 0.002). Importantly, the use of post-transplant cyclophosphamide reduced the risk of severe acute GVHD in patients receiving HSCT for deleterious germline DDX41-associated myeloid neoplasms (0% vs 53%, p=0.03). Based on these results, we advocate the use of post-transplant cyclophosphamide when individuals with deleterious germline DDX41 variants undergo allogeneic HSCT for myeloid malignancies, even when transplantation has been performed using wild-type donors.Caner Saygin, Gregory Roloff, Christopher N. Hahn, Rakchha Chhetri, Saar Gill, Hany Elmariah, Chetasi Talati, Emma Nunley, Guimin Gao, Aelin Kim, Michael Bishop, Satyajit Kosuri, Soma Das, Deepak Singhal, Parvathy Venugopal, Claire C. Homan, Anna Brown, Hamish S. Scott, Devendra Hiwase, and Lucy A. Godle

Relation of Serum Vitamin D to Risk of Mitral Annular and Aortic Valve Calcium (from the Multi-Ethnic Study of Atherosclerosis)

Serum 25-hydroxyvitamin D [25(OH)D] concentration has been identified as a possible modifiable risk factor for cardiovascular disease (CVD). We hypothesized that serum 25(OH)D concentration would be associated with calcifications of the left-sided heart valves, which are markers of CVD risk. Aortic valve calcium (AVC) and mitral annular calcium (MAC) were quantified from cardiac computed tomography scans performed on 5,530 Multi-Ethnic Study of Atherosclerosis participants at the baseline examination (2000 to 2002) and at a follow-up visit at either Examination 2 (2002 to 2004) or Examination 3 (2004 to 2005). 25(OH)D was measured from serum samples collected at the baseline examination. Using relative risk regression, we evaluated the multivariable-adjusted risk of prevalent and incident AVC and MAC in this ethnically diverse population free of clinical CVD at baseline. The mean age of participants was 62 ± 10 years; 53% were women, 40% white, 26% black, 21% Hispanic, and 12% Chinese. Prevalent AVC and MAC were observed in 12% and 9% of study sample, respectively. There were no significant associations between 25(OH)D and prevalent AVC or MAC. Over a mean follow-up of 2.5 years, 4% developed incident AVC and 5% developed incident MAC. After adjusting for demographic variables, each 10 ng/ml higher serum 25(OH)D was associated with a 15% (relative risk 0.85, 95% confidence interval 0.74 to 0.98) lower risk of incident MAC but not AVC. However, this association was no longer significant after adjusting for lifestyle and CVD risk factors. Results suggest a possible link between serum 25(OH)D and the risk for incident MAC, but future studies with longer follow-up are needed to further test this association

Roles of glial cells in synapse development

Brain function relies on communication among neurons via highly specialized contacts, the synapses, and synaptic dysfunction lies at the heart of age-, disease-, and injury-induced defects of the nervous system. For these reasons, the formation—and repair—of synaptic connections is a major focus of neuroscience research. In this review, I summarize recent evidence that synapse development is not a cell-autonomous process and that its distinct phases depend on assistance from the so-called glial cells. The results supporting this view concern synapses in the central nervous system as well as neuromuscular junctions and originate from experimental models ranging from cell cultures to living flies, worms, and mice. Peeking at the future, I will highlight recent technical advances that are likely to revolutionize our views on synapse–glia interactions in the developing, adult and diseased brain

Hospital Variation in 30‐Day Readmissions Following Transcatheter Aortic Valve Replacement

Background Data on hospital variation in 30-day readmission rates after transcatheter aortic valve replacement (TAVR) are limited. Further, whether such variation is explained by differences in hospital characteristics and hospital practice patterns remains unknown. Methods and Results We used the 2017 Nationwide Readmissions Database to identify hospitals that performed at least 5 TAVRs. Hierarchical logistic regression models were used to examine between-hospital variation in 30-day all-cause risk-standardized readmission rate (RSRR) after TAVR and to explore reasons underlying hospital variation in 30-day RSRR. The study included 27 091 index TAVRs performed across 325 hospitals. The median (interquartile range) hospital-level 30-day RSRR was 11.9% (11.1%-12.8%) ranging from 8.8% to 16.5%. After adjusting for differences in patient characteristics, there was significant between-hospital variation in 30-day RSRR (hospital odds ratio, 1.59; 95% CI, 1.39-1.77). Differences in length of stay and discharge disposition accounted for 15% of the between-hospital variance in RSRRs. There was no significant association between hospital characteristics and 30-day readmission rates after TAVR. There was statistically significant but weak correlation between 30-day RSRR after TAVR and that after surgical aortic valve replacement, percutaneous coronary intervention, acute myocardial infarction, heart failure, and pneumonia (r=0.132-0.298; P<0.001 for all). Causes of 30-day readmission varied across hospitals, with noncardiac readmissions being more common at the bottom 5% hospitals (ie, those with the highest RSRRs). Conclusions There is significant variation in 30-day RSRR after TAVR across hospitals that is not entirely explained by differences in patient or hospital characteristics as well as hospital-wide practice patterns. Noncardiac readmissions are more common in hospitals with the highest RSRRs

Differential left ventricular remodelling and longitudinal function distinguishes low flow from normal-flow preserved ejection fraction low-gradient severe aortic stenosis

AimsThere is uncertainty in identifying patients with severe aortic stenosis (AS) with preserved left ventricular (LV) ejection fraction, low flow, and low gradients (LFLG). Prior studies propose that these patients demonstrate significant concentric remodelling and decreased survival, while others suggest that they have features and survival similar to moderate AS.Methods and resultsWe compared the clinical characteristics, echocardiographic features, and overall survival of LFLG AS patients (n = 38) to those with normal-flow, low-gradient (NFLG) severe AS (n = 75) and moderate AS (n = 70). Low-flow, low-gradient patients had the lowest end-diastolic volume index (43 vs. 54 vs. 54 mL/m², P < 0.001), highest relative wall thickness (RWT) (60 vs. 49 vs. 48%, P < 0.001), and lowest septal mitral annular displacement (1.0 vs. 1.5 vs. 1.5 cm, P < 0.001). New York Heart Association (NYHA) class III/IV symptoms were the most frequent in the LFLG group (29 vs. 11 vs. 3%, P < 0.001). Survival at 3 years was significantly lower in LFLG compared with NFLG (P = 0.006) and moderate AS (P = 0.002), but not different between NFLG and moderate AS (P = 0.49). Higher NYHA classification (HR 1.77, 95% CI 1.22-2.57), RWT > 50% (HR 3.28, 95% CI 1.33-8.1), and septal displacement <1.1 cm (HR 3.93, 95% CI 1.96-7.82) but not low flow were independent predictors of survival in Cox proportional hazards analysis.ConclusionPreserved ejection fraction, LFLG AS patients exhibit marked concentric remodelling and impaired longitudinal functional-features that predict their poor long-term survival. Normal-flow, low-gradient AS patients have outcomes similar to moderate AS

Coronary sinus pacing for the management of right ventricular and atrial infarction with isolated right ventricular pulsus alternans.

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