The molecular regulation of human hematopoietic stem cell (HSC) maintenance is therapeutically important, but limitations in experimental systems and interspecies variation have constrained our ...knowledge of this process. Here, we have studied a rare genetic disorder due to MECOM haploinsufficiency, characterized by an early-onset absence of HSCs in vivo. By generating a faithful model of this disorder in primary human HSCs and coupling functional studies with integrative single-cell genomic analyses, we uncover a key transcriptional network involving hundreds of genes that is required for HSC maintenance. Through our analyses, we nominate cooperating transcriptional regulators and identify how MECOM prevents the CTCF-dependent genome reorganization that occurs as HSCs differentiate. We show that this transcriptional network is co-opted in high-risk leukemias, thereby enabling these cancers to acquire stem cell properties. Collectively, we illuminate a regulatory network necessary for HSC self-renewal through the study of a rare experiment of nature.
Clonal hematopoiesis in sickle cell disease Liggett, L Alexander; Cato, Liam D; Weinstock, Joshua S ...
The Journal of clinical investigation,
02/2022, Letnik:
132, Številka:
4
Journal Article
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BACKGROUNDCurative gene therapies for sickle cell disease (SCD) are currently undergoing clinical evaluation. The occurrence of myeloid malignancies in these trials has prompted safety concerns. ...Individuals with SCD are predisposed to myeloid malignancies, but the underlying causes remain undefined. Clonal hematopoiesis (CH) is a premalignant condition that also confers significant predisposition to myeloid cancers. While it has been speculated that CH may play a role in SCD-associated cancer predisposition, limited data addressing this issue have been reported.METHODSHere, we leveraged 74,190 whole-genome sequences to robustly study CH in SCD. Somatic mutation calling methods were used to assess CH in all samples and comparisons between individuals with and without SCD were performed.RESULTSWhile we had sufficient power to detect a greater than 2-fold increased rate of CH, we found no detectable variation in rate or clone properties between individuals affected by SCD and controls. The rate of CH in individuals with SCD was unaltered by hydroxyurea use.CONCLUSIONSWe did not observe an increased risk for acquiring detectable CH in SCD, at least as measured by whole-genome sequencing. These results should help guide ongoing efforts and further studies that seek to better define the risk factors underlying myeloid malignancy predisposition in SCD and help ensure that curative therapies can be more safely applied.FUNDINGNew York Stem Cell Foundation and the NIH.
Clonal hematopoiesis (CH)-age-related expansion of mutated hematopoietic clones-can differ in frequency and cellular fitness by CH type (e.g., mutations in driver genes (CHIP), gains/losses and ...copy-neutral loss of chromosomal segments (mCAs), and loss of sex chromosomes). Co-occurring CH raises questions as to their origin, selection, and impact. We integrate sequence and genotype array data in up to 482,378 UK Biobank participants to demonstrate shared genetic architecture across CH types. Our analysis suggests a cellular evolutionary trade-off between different types of CH, with LOY occurring at lower rates in individuals carrying mutations in established CHIP genes. We observed co-occurrence of CHIP and mCAs with overlap at TET2, DNMT3A, and JAK2, in which CHIP precedes mCA acquisition. Furthermore, individuals carrying overlapping CH had high risk of future lymphoid and myeloid malignancies. Finally, we leverage shared genetic architecture of CH traits to identify 15 novel loci associated with leukemia risk.
Genome-wide association studies in combination with single-cell genomic atlases can provide insights into the mechanisms of disease-causal genetic variation. However, identification of ...disease-relevant or trait-relevant cell types, states and trajectories is often hampered by sparsity and noise, particularly in the analysis of single-cell epigenomic data. To overcome these challenges, we present SCAVENGE, a computational algorithm that uses network propagation to map causal variants to their relevant cellular context at single-cell resolution. We demonstrate how SCAVENGE can help identify key biological mechanisms underlying human genetic variation, applying the method to blood traits at distinct stages of human hematopoiesis, to monocyte subsets that increase the risk for severe Coronavirus Disease 2019 (COVID-19) and to intermediate lymphocyte developmental states that predispose to acute leukemia. Our approach not only provides a framework for enabling variant-to-function insights at single-cell resolution but also suggests a more general strategy for maximizing the inferences that can be made using single-cell genomic data.
Inpatient burden and mortality of heatstroke in the United States Kaewput, Wisit; Thongprayoon, Charat; Petnak, Tananchai ...
International journal of clinical practice (Esher),
April 2021, 2021-Apr, 2021-04-00, 20210401, Letnik:
75, Številka:
4
Journal Article
Recenzirano
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Background
This study aimed to assess inpatient prevalence, characteristics, outcomes, and resource utilisation of hospitalisation for heatstroke in the United States. Additionally, this study aimed ...to explore factors associated with in‐hospital mortalities of heatstroke.
Methods
The 2003‐2014 National Inpatient Sample database was used to identify hospitalised patients with a principal diagnosis of heatstroke. The inpatient prevalence, clinical characteristics, in‐hospital treatments, outcomes, length of hospital stay, and hospitalisation cost were studied. Multivariable logistic regression was performed to identify independent factors associated with in‐hospital mortality.
Results
A total of 3372 patients were primarily admitted for heatstroke, accounting for an overall inpatient prevalence of heatstroke amongst hospitalised patients of 36.3 cases per 1 000 000 admissions in the United States with an increasing trend during the study period (P < .001). Age 40‐59 was the most prevalent age group. During the hospital stay, 20% required mechanical ventilation, and 2% received renal replacement therapy. Rhabdomyolysis was the most common complication. Renal failure was the most common end‐organ failure, followed by neurological, respiratory, metabolic, hematologic, circulatory, and liver systems. The in‐hospital mortality rate of heatstroke hospitalisation was 5% with a decreasing trend during the study period (P < .001). The presence of end‐organ failure was associated with increased in‐hospital mortality, whereas more recent years of hospitalisation was associated with decreased in‐hospital mortality. The median length of hospital stay was 2 days. The median hospitalisation cost was $17 372.
Conclusion
The inpatient prevalence of heatstroke in the United States increased, while the in‐hospital mortality of heatstroke decreased.
Background Abnormal circadian blood pressure (BP) variations during sleep, specifically the non-dipping (<10% fall in nocturnal BP) and reverse-dipping patterns (rise in nocturnal BP), have been ...associated with an increased risk of cardiovascular events and target organ damage. However, the relationship between abnormal sleep BP variations and cerebral small vessel disease markers is poorly established. This study aims to assess the association between non-dipping and reverse-dipping BP patterns with markers of silent cerebral small vessel disease. Methods and Results MEDLINE, Embase, and Cochrane Databases were searched from inception through November 2019. Studies that reported the odds ratios (ORs) for cerebral small vessel disease markers in patients with non-dipping or reverse-dipping BP patterns were included. Effect estimates from the individual studies were extracted and combined using the random-effect, generic inverse variance method of DerSimonian and Laird. Twelve observational studies composed of 3497 patients were included in this analysis. The reverse-dipping compared with normal dipping BP pattern was associated with a higher prevalence of white matter hyperintensity with a pooled adjusted OR of 2.00 (95% CI, 1.13-2.37; I
=36%). Non-dipping BP pattern compared with normal dipping BP pattern was associated with higher prevalence of white matter hyperintensity and asymptomatic lacunar infarction, with pooled ORs of 1.38 (95% CI, 0.95-2.02; I
=52%) and 2.33 (95% CI, 1.30-4.18; I
=73%), respectively. Limiting to only studies with confounder-adjusted analysis resulted in a pooled OR of 1.38 (95% CI, 0.95-2.02; I
=52%) for white matter hyperintensity and 1.44 (95% CI, 0.97-2.13; I
=0%) for asymptomatic lacunar infarction. Conclusions The non-dipping and reverse-dipping BP patterns are associated with neuroimaging cerebral small vessel disease markers.
Currently, the data on independent risk factors for the progression of kidney disease in type 2 diabetes mellitus (T2DM) patients with CKD are limited. This study aimed to investigate CKD progression ...in T2DM patients who have reduced kidney function with baseline estimated glomerular filtration rate (eGFRs) between 15 and 59 mL/min/1.73 m2. This study was composed of a nationwide retrospective cohort of adult T2DM patients from 831 public hospitals in Thailand during the year 2015. T2DM patients with CKD stages 3 and 4 were followed up, until development of CKD stage 5, requirement of chronic dialysis, loss to follow‐up, death, or 31 May 2018, whichever came first. Cox proportional hazard regression was utilized for analysis. A total of 8464 participants were included; 30.4% were male. The mean age was 69 ± 10 years. The mean eGFR was 45 ± 11 mL/min/1.73 m2. The incidence of CKD stage 5 or the need for chronic dialysis was 16.4 per 1000 person‐years. The annual rate of eGFR decline during a mean follow‐up of 29 months was −2.3 mL/min/1.73 m2; 14.4% had a rapid decline in eGFR. The risk factors associated with progression to CKD stage 5 or the need for chronic dialysis were diabetes duration, systolic blood pressure, serum uric acid, albuminuria, and baseline eGFR. Conversely, older age and the use of renin‐angiotensin aldosterone system blockade were associated with decreased risks for rapid CKD progression and incidence CKD stage 5 or dialysis. This study identifies multiple predictive risk factors that support a multifaceted approach to prevent progression of advanced CKD.
Despite advances in defining diverse somatic mutations that cause myeloid malignancies, a significant heritable component for these cancers remains largely unexplained. Here, we perform rare variant ...association studies in a large population cohort to identify inherited predisposition genes for these blood cancers. CTR9, which encodes a key component of the PAF1 transcription elongation complex, is among the significant genes identified. The risk variants found in the cases cause loss of function and result in a ∼10-fold increased odds of acquiring a myeloid malignancy. Partial CTR9 loss of function expands human hematopoietic stem cells (HSCs) by increased super elongation complex-mediated transcriptional activity, which thereby increases the expression of key regulators of HSC self-renewal. By following up on insights from a human genetic study examining inherited predisposition to the myeloid malignancies, we define a previously unknown antagonistic interaction between the PAF1 and super elongation complexes. These insights could enable targeted approaches for blood cancer prevention.
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•Inherited CTR9 loss-of-function variants predispose to the myeloid malignancies•Partial, but not complete, loss of CTR9 expands human HSCs•Partial CTR9 loss expands HSCs through increased transcription elongation•Select PAF1 complex subunits interact with and activate the super elongation complex
Rare inherited CTR9 loss-of-function variants predispose to myeloid malignancies by altering the balance between the PAF1 and super elongation complexes. Specific subunits of the PAF1 complex then act in concert with the super elongation complex to promote transcription elongation of genes that can drive the self-renewal of hematopoietic stem cells.
•Platelet count follows a nadir at days 2–4 and peaks between days 13 and 14.•Time courses for platelet counts are different when split by mortality and sepsis.•Platelet count and rBaux score may aid ...discrimination of survival within 24h.•There is some association between the nadir platelet count and sepsis.
Platelet cells, or thrombocytes, have additional roles to haemostasis. After burn injury, platelet counts drop to a nadir at days 2–5 then rise to a peak between days 10–18. The nadir has previously been associated with mortality but there is currently no thorough investigation of its potential to predict sepsis in adults. The primary objective of this study is to assess whether platelet count can predict survival and sepsis in adults with severe burn injuries.
A retrospective cohort analysis of platelet count and other blood parameters in 145 burn patients with a TBSA greater than 20%. AUROC analysis revealed that the platelet count and rBaux score together produce moderate discrimination for survival at less than 24h after injury (AUROC=0.848, 95%CI 0.765–0.930). Platelet count at day 3 combined with TBSA has a modest association with sepsis (AUROC=0.779, 95%CI 0.697–0.862). Multivariable Cox regression analysis revealed platelet peak was the strongest predictor of mortality.
A reduced peak platelet count is a strong predictor of 50-day mortality. Platelet count nadir may have some association with sepsis.
This study aims to evaluate the risk factors and the association of acute kidney injury with treatments, complications, outcomes, and resource utilization in patients hospitalized for heat stroke in ...the United States. Hospitalized patients from years 2003 to 2014 with a primary diagnosis of heat stroke were identified in the National Inpatient Sample dataset. End stage kidney disease patients were excluded. The occurrence of acute kidney injury during hospitalization was identified using the hospital diagnosis code. The associations between acute kidney injury and clinical characteristics, in-hospital treatments, outcomes, and resource utilization were assessed using multivariable analyses. A total of 3346 hospital admissions were included in the analysis. Acute kidney injury occurred in 1206 (36%) admissions, of which 49 (1.5%) required dialysis. The risk factors for acute kidney injury included age 20–39 years, African American race, obesity, chronic kidney disease, congestive heart failure, and rhabdomyolysis, whereas age <20 or ≥60 years were associated with lower risk of acute kidney injury. The need for mechanical ventilation and blood transfusion was higher when acute kidney injury occurred. Acute kidney injury was associated with electrolyte and acid-base derangements, sepsis, acute myocardial infarction, ventricular arrhythmia or cardiac arrest, respiratory, circulatory, liver, neurological, hematological failure, and in-hospital mortality. Length of hospital stay and hospitalization cost were higher in acute kidney injury patients. Approximately one third of heat stroke patients developed acute kidney injury during hospitalization. Acute kidney injury was associated with several complications, and higher mortality and resource utilization.
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