Clonal hematopoiesis of indeterminate potential (CHIP) refers to clonal expansion of hematopoietic stem cells attributable to acquired leukemic mutations in genes such as
or
. In humans, CHIP ...associates with prevalent myocardial infarction. In mice, CHIP accelerates atherosclerosis and increases IL-6/IL-1β expression, raising the hypothesis that IL-6 pathway antagonism in CHIP carriers would decrease cardiovascular disease (CVD) risk.
We analyzed exome sequences from 35 416 individuals in the UK Biobank without prevalent CVD, to identify participants with
or
CHIP. We used the
p.Asp358Ala coding mutation as a genetic proxy for IL-6 inhibition. We tested the association of CHIP status with incident CVD events (myocardial infarction, coronary revascularization, stroke, or death), and whether it was modified by
p.Asp358Ala.
We identified 1079 (3.0%) individuals with CHIP, including 432 (1.2%) with large clones (allele fraction >10%). During 6.9-year median follow-up, CHIP associated with increased incident CVD event risk (hazard ratio, 1.27 95% CI, 1.04-1.56,
=0.019), with greater risk from large CHIP clones (hazard ratio, 1.59 95% CI, 1.21-2.09,
<0.001).
p.Asp358Ala attenuated CVD event risk among participants with large CHIP clones (hazard ratio, 0.46 95% CI, 0.29-0.73,
<0.001) but not in individuals without CHIP (hazard ratio, 0.95 95% CI, 0.89-1.01,
=0.08;
=0.003). In 9951 independent participants, the association of CHIP status with myocardial infarction similarly varied by
p.Asp358Ala (
=0.036).
CHIP is associated with increased risk of incident CVD. Among carriers of large CHIP clones, genetically reduced IL-6 signaling abrogated this risk.
Hirschsprung's disease, or congenital aganglionosis, is a developmental disorder of the enteric nervous system and is the most common cause of intestinal obstruction in neonates and infants. The ...disease has more than 80% heritability, including significant associations with rare and common sequence variants in genes related to the enteric nervous system, as well as with monogenic and chromosomal syndromes.
We genotyped and exome-sequenced samples from 190 patients with Hirschsprung's disease to quantify the genetic burden in patients with this condition. DNA sequence variants, large copy-number variants, and karyotype variants in probands were considered to be pathogenic when they were significantly associated with Hirschsprung's disease or another neurodevelopmental disorder. Novel genes were confirmed by functional studies in the mouse and human embryonic gut and in zebrafish embryos.
The presence of five or more variants in four noncoding elements defined a widespread risk of Hirschsprung's disease (48.4% of patients and 17.1% of controls; odds ratio, 4.54; 95% confidence interval CI, 3.19 to 6.46). Rare coding variants in 24 genes that play roles in enteric neural-crest cell fate, 7 of which were novel, were also common (34.7% of patients and 5.0% of controls) and conferred a much greater risk than noncoding variants (odds ratio, 10.02; 95% CI, 6.45 to 15.58). Large copy-number variants, which were present in fewer patients (11.4%, as compared with 0.2% of controls), conferred the highest risk (odds ratio, 63.07; 95% CI, 36.75 to 108.25). At least one identifiable genetic risk factor was found in 72.1% of the patients, and at least 48.4% of patients had a structural or regulatory deficiency in the gene encoding receptor tyrosine kinase (
). For individual patients, the estimated risk of Hirschsprung's disease ranged from 5.33 cases per 100,000 live births (approximately 1 per 18,800) to 8.38 per 1000 live births (approximately 1 per 120).
Among the patients in our study, Hirschsprung's disease arose from common noncoding variants, rare coding variants, and copy-number variants affecting genes involved in enteric neural-crest cell fate that exacerbate the widespread genetic susceptibility associated with
. For individual patients, the genotype-specific odds ratios varied by a factor of approximately 67, which provides a basis for risk stratification and genetic counseling. (Funded by the National Institutes of Health.).
Abstract Background Familial combined hypolipidemia, a Mendelian condition characterized by substantial reductions in all 3 major lipid fractions, is caused by mutations that inactivate the gene ...angiopoietin-like 3 ( ANGPTL3 ). Whether ANGPTL3 deficiency reduces risk of coronary artery disease (CAD) is unknown. Objectives The study goal was to leverage 3 distinct lines of evidence—a family that included individuals with complete (compound heterozygote) ANGPTL3 deficiency, a population based-study of humans with partial (heterozygote) ANGPTL3 deficiency, and biomarker levels in patients with myocardial infarction (MI)—to test whether ANGPTL3 deficiency is associated with lower risk for CAD. Methods We assessed coronary atherosclerotic burden in 3 individuals with complete ANGPTL3 deficiency and 3 wild-type first-degree relatives using computed tomography angiography. In the population, ANGPTL3 loss-of-function (LOF) mutations were ascertained in up to 21,980 people with CAD and 158,200 control subjects. LOF mutations were defined as nonsense, frameshift, and splice-site variants, along with missense variants resulting in <25% of wild-type ANGPTL3 activity in a mouse model. In a biomarker study, circulating ANGPTL3 concentration was measured in 1,493 people who presented with MI and 3,232 control subjects. Results The 3 individuals with complete ANGPTL3 deficiency showed no evidence of coronary atherosclerotic plaque. ANGPTL3 gene sequencing demonstrated that approximately 1 in 309 people was a heterozygous carrier for an LOF mutation. Compared with those without mutation, heterozygous carriers of ANGPTL3 LOF mutations demonstrated a 17% reduction in circulating triglycerides and a 12% reduction in low-density lipoprotein cholesterol. Carrier status was associated with a 34% reduction in odds of CAD (odds ratio: 0.66; 95% confidence interval: 0.44 to 0.98; p = 0.04). Individuals in the lowest tertile of circulating ANGPTL3 concentrations, compared with the highest, had reduced odds of MI (adjusted odds ratio: 0.65; 95% confidence interval: 0.55 to 0.77; p < 0.001). Conclusions ANGPTL3 deficiency is associated with protection from CAD.
Background
The water supplies are hindered because aquatic resources have constrained with natural and man-made pollution activities in terms of releasing huge amounts of contaminants from different ...point and non-point sources across the globe. The industries like metal plating, batteries, paint, fertilizers, tanneries, textile industries, dyeing industries, mining operations, and paper industries discharge their effluents into the environment directly or indirectly, and hence, they are considered as the key sources of heavy metals contamination in water resources. Heavy metals are inorganic, non-biodegradable, persistent, and having a tendency to get accumulated in biotic and abiotic components of environment as compared to organic pollutants. Some heavy metal cations, for example, mercury, arsenic, cadmium, zinc, lead, nickel, copper, and chromium, are carcinogenic in nature and so, lethal. There are growing health concerns due to toxic impacts of heavy metals on every genre of ecosystem. To deal with the bottleneck situation, it is highly imperative to search a feasible solution for heavy metal remediation in water in context of preventing amalgamation of noxious contaminants in food web. Different methods are exercised for the remediation of such impurities from its solutions. One method, i.e. adsorption is found to be the simplest, economical, efficient, and eco-friendly in this context.
Main body
Geopolymers exhibit heterogeneous amorphous microstructure and wide surface area. The compatibility for depollution and the performance of these materials mainly depend upon their preparation methods, composition, and microstructure. Fly ash-based geopolymer may serve as a better alternate to various cost-effective adsorbents and it will be a proven environmentally viable, waste to money solution by consuming heaps of fly ash waste for the adsorbent modified by using fly ash. The possible utilization of wastes from several industries is a matter of concerned sustainability benefits. This study shows that fly ash-based geopolymers have the potential to cope up with the problems and risk factors associated with the fly ash waste management and it would be the utmost scientific panacea in the field of removing toxins from aqueous medium and maintain environmental health in the future.
Short conclusions
The literature available in different databases is very limited pertaining to heavy metal remediation using fly ash-based geopolymers
.
Keeping all the factors in mind, this article is an attempt to summarize relevant informations related to work done on fly ash-based geopolymers for treating aqueous solutions comprising heavy metals.
This article intends to understand the position of women in science, technology, engineering and mathematics (STEM) in India and to highlight the challenges faced by them through the perspective of ...gender as a social construct. It argues that the social constructionist perspective helps to focus on the specific socio-cultural context, and to deepen our understanding of the barriers in career advancement for women in STEM. Based on the governmental data and research studies, it demonstrates that these constraints occur at the intersection of Indian social, organizational and institutional contexts. This perspective helps to explore solutions unique to the specific national context.
With mutations continually occurring in each protein-coding gene (at a rate of ~1 × 10-5 per gene per generation for nonsynonymous variants)36-39 and fitness losses of less than 1% for most novel ...nonsynonymous mutations29-31,34, almost every gene is expected to harbor functionally important variants that can be tested through sequencing, even if these variants are rare. ...the strong interest in exome sequencing stems from three factors: the potential to identify many genes underlying complex traits, straightforward functional annotation of coding variation and a substantially lower cost (approximately five times lower) than that of whole-genome sequencing. ...as sample size increases, the number of observed variants grows much faster than is predicted by the neutral model with constant population size41,42 (Fig. 1).
Cytokines are classically thought to stimulate downstream signaling pathways through monotonic activation of receptors. We describe a severe anemia resulting from a homozygous mutation (R150Q) in the ...cytokine erythropoietin (EPO). Surprisingly, the EPO R150Q mutant shows only a mild reduction in affinity for its receptor but has altered binding kinetics. The EPO mutant is less effective at stimulating erythroid cell proliferation and differentiation, even at maximally potent concentrations. While the EPO mutant can stimulate effectors such as STAT5 to a similar extent as the wild-type ligand, there is reduced JAK2-mediated phosphorylation of select downstream targets. This impairment in downstream signaling mechanistically arises from altered receptor dimerization dynamics due to extracellular binding changes. These results demonstrate how variation in a single cytokine can lead to biased downstream signaling and can thereby cause human disease. Moreover, we have defined a distinct treatable form of anemia through mutation identification and functional studies.
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•An anemia-associated EPO mutation alters the kinetics of receptor binding•Extracellular binding changes result in biased downstream signaling responses•The EPO variant shows that functional selectivity is possible in cytokine signaling•Exome sequencing and follow-up studies lead to successful therapy for a rare anemia
A disease-causing mutation in erythropoietin surprisingly causes only a mild change in the affinity for its receptor, but alters extracellular binding kinetics, thereby affecting downstream signaling.
Comprehensive sequence characterization across the MHC is important for successful organ transplantation and genetic association studies. To this end, we have developed an automated sample ...preparation, molecular barcoding and multiplexing protocol for the amplification and sequence-determination of class I HLA loci. We have coupled this process to a novel HLA calling algorithm to determine the most likely pair of alleles at each locus.
We have benchmarked our protocol with 270 HapMap individuals from four worldwide populations with 96.4% accuracy at 4-digit resolution. A variation of this initial protocol, more suitable for large sample sizes, in which molecular barcodes are added during PCR rather than library construction, was tested on 95 HapMap individuals with 98.6% accuracy at 4-digit resolution.
Next-generation sequencing on the 454 FLX Titanium platform is a reliable, efficient, and scalable technology for HLA typing.
Short-term hypotension after general anaesthesia can negatively impact surgical outcomes. This study compared the predictive potential of the pleth variability index (PVI), pulse pressure variability ...(PPV), and perfusion index (PI) for anaesthesia-induced hypotension. This study's primary objective was to evaluate the predictive potential of PI, PVI, and PPV for hypotension.
This observational study included 140 adult patients undergoing major abdominal surgery under general anaesthesia. Mean arterial pressure, heart rate, PVI, PPV, and PI were collected at 1-min intervals up to 20 min post anaesthesia induction. Hypotension was assessed at 5-min and 15-min intervals. Receiver operating characteristic (ROC) curves were plotted to determine the diagnostic performance and best cut-off for continuous variables in predicting a dichotomous outcome. Statistical significance was kept at
< 0.05.
Hypotension prevalence within 5 and 15 min of anaesthesia induction was 36.4% and 45%, respectively. A PI cut-off of <3.5 had an area under the ROC curve (AUROC) of 0.647 (
= 0.004) for a 5-min hypotension prediction. The PVI's AUROC was 0.717 (
= 0.001) at cut-off >11.5, while PPV's AUROC was 0.742 (
= 0.001) at cut-off >12.5. At 15 min, PVI's AUROC was 0.615 (95% confidence interval 0.521-0.708,
= 0.020), with 54.9% positive predictive value and 65.2% negative predictive value.
PVI, PPV, and PI predicted hypotension within 5 min after general anaesthesia induction. PVI had comparatively higher accuracy, sensitivity, specificity, and positive predictive value than PI and PPV when predicting hypotension at 15 min.
Background: The quest for an ideal sedoanalgesic-combination exhibiting the triad of efficacy, safety and patient comfort has led to administration of several permutations and combinations of drugs ...(midazolam, fentanyl, remifentanil, dexmedetomidine, propofol, ketamine, pethidine, pentazocine). The ideal sedoanalgesic for CT-guided core-biopsy of spine, radiofrequency/microwave ablation of hepatic/pulmonary lesions, has hitherto been elusive. In the absence of any guidelines, we compared a ketamine-dexmedetomidine combination (Group-K) with fentanyl-dexmedetomidine (Group-F).
Methods: This prospective, interventional, single-centric, parallel-armed, randomized controlled study included 60 patients (ASA physical state I-II, either gender, aged 18-75y, weighing 35-85kg), undergoing CT-guided core biopsy/radiofrequency/microwave ablation in remote location, allocated to Group-K and Group-F. Independent/paired-sample t-tests were utilized and data expressed as box-whisker plots and trendlines, p-value<0.05 being statistically significant.
Results: There was a significant difference in intraprocedural pain-scores between both groups (p-values 0.0001, 0.0011, 0.0092 and 0.0201 at 0-10mins, 10-20mins, 20-30mins and 30-40mins respectively). More patients in Group-F required rescue-analgesic with reduced interventionist-satisfaction score versus Group-K. In Group-K, mean arterial pressure and heart rate (95.1mmHg;79.6/min) increased after initial ketamine bolus, but were maintained/decreased at intervention-initiation (93.2mmHg;79.4/min) and at 10min and 30min thereafter. In Group-F, MAP and HR decreased after initial fentanyl bolus (83.5mHg;71.9/min), increased with intervention-initiation (90.1mmHg;77/min), progressively decreasing at every time-point thereafter. VAS-scores (resting; on coughing) were lower in Group-K.
Conclusion: A ketamine-dexmedetomidine combination technique demonstrated a superior sedoanalgesic effect with reduced intra-procedural bradypnea, bradycardia, rescue-drug requirement and post-procedural complications with enhanced interventionist-satisfaction and may emerge as the ideal procedural sedoanalgesic for patients undergoing CT-guided core-biopsy, radiofrequency/microwave ablation.
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