Category: Nevin Manimala

N Engl J Med. 2021 Apr 29;384(17):1601-1612. doi: 10.1056/NEJMoa2025956.

ABSTRACT

BACKGROUND: Vadadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor, a class of compounds that stimulate endogenous erythropoietin production.

METHODS: We conducted two randomized, open-label, noninferiority phase 3 trials to evaluate the safety and efficacy of vadadustat, as compared with darbepoetin alfa, in patients with anemia and incident or prevalent dialysis-dependent chronic kidney disease (DD-CKD). The primary safety end point, assessed in a time-to-event analysis, was the first occurrence of a major adverse cardiovascular event (MACE, a composite of death from any cause, a nonfatal myocardial infarction, or a nonfatal stroke), pooled across the trials (noninferiority margin, 1.25). A key secondary safety end point was the first occurrence of a MACE plus hospitalization for either heart failure or a thromboembolic event. The primary and key secondary efficacy end points were the mean change in hemoglobin from baseline to weeks 24 to 36 and from baseline to weeks 40 to 52, respectively, in each trial (noninferiority margin, -0.75 g per deciliter).

RESULTS: A total of 3923 patients were randomly assigned in a 1:1 ratio to receive vadadustat or darbepoetin alfa: 369 in the incident DD-CKD trial and 3554 in the prevalent DD-CKD trial. In the pooled analysis, a first MACE occurred in 355 patients (18.2%) in the vadadustat group and in 377 patients (19.3%) in the darbepoetin alfa group (hazard ratio, 0.96; 95% confidence interval [CI], 0.83 to 1.11). The mean differences between the groups in the change in hemoglobin concentration were -0.31 g per deciliter (95% CI, -0.53 to -0.10) at weeks 24 to 36 and -0.07 g per deciliter (95% CI, -0.34 to 0.19) at weeks 40 to 52 in the incident DD-CKD trial and -0.17 g per deciliter (95% CI, -0.23 to -0.10) and -0.18 g per deciliter (95% CI, -0.25 to -0.12), respectively, in the prevalent DD-CKD trial. The incidence of serious adverse events in the vadadustat group was 49.7% in the incident DD-CKD trial and 55.0% in the prevalent DD-CKD trial, and the incidences in the darbepoetin alfa group were 56.5% and 58.3%, respectively.

CONCLUSIONS: Among patients with anemia and CKD who were undergoing dialysis, vadadustat was noninferior to darbepoetin alfa with respect to cardiovascular safety and correction and maintenance of hemoglobin concentrations. (Funded by Akebia Therapeutics and Otsuka Pharmaceutical; INNO₂VATE ClinicalTrials.gov numbers, NCT02865850 and NCT02892149.).

PMID:33913638 | DOI:10.1056/NEJMoa2025956

N Engl J Med. 2021 Apr 29;384(17):1623-1634. doi: 10.1056/NEJMoa2028788.

ABSTRACT

BACKGROUND: Prophylactic administration of tranexamic acid has been associated with reduced postpartum blood loss after cesarean delivery in several small trials, but evidence of its benefit in this clinical context remains inconclusive.

METHODS: In a multicenter, double-blind, randomized, controlled trial, we assigned women undergoing cesarean delivery before or during labor at 34 or more gestational weeks to receive an intravenously administered prophylactic uterotonic agent and either tranexamic acid (1 g) or placebo. The primary outcome was postpartum hemorrhage, defined as a calculated estimated blood loss greater than 1000 ml or receipt of a red-cell transfusion within 2 days after delivery. Secondary outcomes included gravimetrically estimated blood loss, provider-assessed clinically significant postpartum hemorrhage, use of additional uterotonic agents, and postpartum blood transfusion.

RESULTS: Of the 4551 women who underwent randomization, 4431 underwent cesarean delivery, 4153 (93.7%) of whom had primary outcome data available. The primary outcome occurred in 556 of 2086 women (26.7%) in the tranexamic acid group and in 653 of 2067 (31.6%) in the placebo group (adjusted risk ratio, 0.84; 95% confidence interval [CI], 0.75 to 0.94; P = 0.003). There were no significant between-group differences in mean gravimetrically estimated blood loss or in the percentage of women with provider-assessed clinically significant postpartum hemorrhage, use of additional uterotonic agents, or postpartum blood transfusion. Thromboembolic events in the 3 months after delivery occurred in 0.4% of women (8 of 2049) who received tranexamic acid and in 0.1% of women (2 of 2056) who received placebo (adjusted risk ratio, 4.01; 95% CI, 0.85 to 18.92; P = 0.08).

CONCLUSIONS: Among women who underwent cesarean delivery and received prophylactic uterotonic agents, tranexamic acid treatment resulted in a significantly lower incidence of calculated estimated blood loss greater than 1000 ml or red-cell transfusion by day 2 than placebo, but it did not result in a lower incidence of hemorrhage-related secondary clinical outcomes. (Funded by the French Ministry of Health; TRAAP2 ClinicalTrials.gov number, NCT03431805.).

PMID:33913639 | DOI:10.1056/NEJMoa2028788

Sci Rep. 2021 Apr 28;11(1):9485. doi: 10.1038/s41598-021-88890-5.

NO ABSTRACT

PMID:33911181 | DOI:10.1038/s41598-021-88890-5

NPJ Digit Med. 2021 Apr 28;4(1):76. doi: 10.1038/s41746-021-00435-2.

ABSTRACT

Previous studies of seasonal effects on sleep have yielded unclear results, likely due to methodological differences and limitations in data size and/or quality. We measured the sleep habits of 216 individuals across the U.S. over four seasons for slightly over a year using objective, continuous, and unobtrusive measures of sleep and local weather. In addition, we controlled for demographics and trait-like constructs previously identified to correlate with sleep behavior. We investigated seasonal and weather effects of sleep duration, bedtime, and wake time. We found several small but statistically significant effects of seasonal and weather effects on sleep patterns. We observe the strongest seasonal effects for wake time and sleep duration, especially during the spring season: wake times are earlier, and sleep duration decreases (compared to the reference season winter). Sleep duration also modestly decreases when day lengths get longer (between the winter and summer solstice). Bedtimes and wake times tend to be slightly later as outdoor temperature increases.

PMID:33911176 | DOI:10.1038/s41746-021-00435-2

Sci Rep. 2021 Apr 28;11(1):9218. doi: 10.1038/s41598-021-87534-y.

ABSTRACT

Circular codes represent a form of coding allowing detection/correction of frame-shift errors. Building on recent theoretical advances on circular codes, we provide evidence that protein coding sequences exhibit in-frame circular code marks, that are absent in introns and are intimately linked to the keto-amino transformation of codon bases. These properties strongly correlate with translation speed, codon influence and protein synthesis levels. Strikingly, circular code marks are absent at the beginning of coding sequences, but stably occur 40 codons after the initiator codon, hinting at the translation elongation process. Finally, we use the lens of circular codes to show that codon influence on translation correlates with the strong-weak dichotomy of the first two bases of the codon. The results can lead to defining new universal tools for sequence indicators and sequence optimization for bioinformatics and biotechnological applications, and can shed light on the molecular mechanisms behind the decoding process.

PMID:33911089 | DOI:10.1038/s41598-021-87534-y

Sci Rep. 2021 Apr 28;11(1):9143. doi: 10.1038/s41598-021-88513-z.

ABSTRACT

Mandibular cortical and trabecular bone abnormalities in patients with familial adenomatous polyposis (FAP) were evaluated using dental panoramic radiographs (DPR) radiomorphometric indices and fractal dimension (FD). Sixty DPRs from 15 FAP patients and 45 healthy controls were evaluated. FAP group was composed of 33.3% females and 66.6% males, age_mean = 37.2 years (SD 15.79). The non-FAP group was paired by gender and sex. The parameters analyzed were: FD of the trabecular bone in four regions of interest (ROI), mandibular cortical index (MCI) and width (MCW). FD values were lower for the FAP group. Statistically significance differences were shown by ROI 2 and 3 anteriorly to the mental foramen bilaterally, p = 0.001, and p = 0.006. The ROI 1 and 4, at the mandibular angle trabeculae, indicated statistical significances on the right side (p = 0.036) and no differences on the left side (p = 0.091). There was no significant difference in MCI and MCW when the groups were compared, MCW (L) p = 0.247, and MCW (R) p = 0.070. Fractal values of FAP patients’ mandibular trabecular bone were lower than healthy controls. The radiomorphometric indices MCI and MCW were not useful for analyzing the cortical bone pattern. Therefore, FD is a promising tool for detection of abnormal bone structure in DPRs and for supporting the appropriate referral of FAP patients.

PMID:33911117 | DOI:10.1038/s41598-021-88513-z

Sci Rep. 2021 Apr 28;11(1):9154. doi: 10.1038/s41598-021-88733-3.

ABSTRACT

We investigated the association between body weight variability and the risks of cardiovascular disease and mortality in patients with nonalcoholic fatty liver disease (NAFLD) using large-scale, nationwide cohort data. We included 726,736 individuals with NAFLD who underwent a health examination between 2009 and 2010. NAFLD was defined as a fatty liver index ≥ 60, after excluding significant alcohol intake, viral hepatitis, and liver cirrhosis. Body weight variability was assessed using four indices, including variability independent of the mean (VIM). During a median 8.1-year follow-up, we documented 11,358, 14,714, and 22,164 cases of myocardial infarction (MI), stroke, and all-cause mortality, respectively. Body weight variability was associated with an increased risk of MI, stroke, and mortality after adjusting for confounding variables. The hazard ratios (HRs) (95% confidence intervals) for the highest quartile, compared with the lowest quartile, of VIM for body weight were 1.15 (1.10-1.20), 1.22 (1.18-1.26), and 1.56 (1.53-1.62) for MI, stroke, and all-cause mortality, respectively. Body weight variability was associated with increased risks of MI, stroke, and all-cause mortality in NAFLD patients. Appropriate interventions to maintain a stable weight could positively affect health outcomes in NAFLD patients.

PMID:33911167 | DOI:10.1038/s41598-021-88733-3

J Korean Assoc Oral Maxillofac Surg. 2021 Apr 30;47(2):91-98. doi: 10.5125/jkaoms.2021.47.2.91.

ABSTRACT

OBJECTIVES: Hyaluronoglucosaminidase (hyaluronidase) increases the local intercellular permeability of the peripheral lymphatic channel and capillaries, which may help reduce edema. In the present study, the effects of hyaluronidase on postoperative edema and pain reduction were evaluated.

MATERIALS AND METHODS: The study included 38 patients who underwent guided bone regeneration (GBR) surgery before implantation. Patients were randomly assigned to either the control group (n=20) or the test group (n=18). Hyaluronidase was injected into the GBR site of subjects in the test group. Postoperative edema was evaluated by measuring the distance between specific facial landmarks immediately after surgery (T1) and 2-4 days after surgery (T2). The degree of pain at T2 and at 10-14 days after surgery (T3) was assessed.

RESULTS: In the test group, the degree of swelling was lower than in the control group, however, only two measurements, from the tragus to the mouth corner and from the outer canthus to the mouth corner, showed statistically significant differences (P=0.012 and P=0.001, respectively). The anti-edema effect of hyaluronidase was more effective in the maxilla than in the mandible. In the maxilla, the percentage of facial swelling was significant for three measurements. However, in the mandible, the percentage of facial swelling was significant for only one measurement. Low levels of pain that were similar at T2 and T3 were reported in both groups.

CONCLUSION: The results indicate the degree of swelling was lower in the test group and hyaluronidase appeared to be more effective in the maxilla. The degree of pain reduction was similar between groups. Further in vivo and randomized controlled trials with larger sample sizes are warranted.

PMID:33911041 | DOI:10.5125/jkaoms.2021.47.2.91

Transl Psychiatry. 2021 Apr 29;11(1):252. doi: 10.1038/s41398-021-01367-x.

ABSTRACT

White matter (WM) abnormalities in patients with cocaine use disorder (CUD) have been studied; however, the reported effects on the human brain are heterogenous and most results have been obtained from male participants. In addition, biological data supporting the imaging findings and revealing possible mechanisms underlying the neurotoxic effects of chronic cocaine use (CU) on WM are largely restricted to animal studies. To evaluate the neurotoxic effects of CU in the WM, we performed an in vivo diffusion tensor imaging assessment of male and female cocaine users (n = 75) and healthy controls (HC) (n = 58). Moreover, we performed an ex vivo large-scale proteomic analysis using liquid chromatography-tandem mass spectrometry in postmortem brains of patients with CUD (n = 8) and HC (n = 12). Compared with the HC, the CUD group showed significant reductions in global fractional anisotropy (FA) (p < 0.001), and an increase in global mean (MD) and radial diffusion (RD) (both p < 0.001). The results revealed that FA, RD, and MD alterations in the CUD group were widespread along the major WM tracts, after analysis using the tract-based special statistics approach. Global FA was negatively associated with years of CU (p = 0.0421) and female sex (p < 0.001), but not with years of alcohol or nicotine use. Concerning the fibers connecting the left to the right prefrontal cortex, Brodmann area 9 (BA9), the CUD group presented lower FA (p = 0.006) and higher RD (p < 0.001) values compared with the HC group. A negative association between the duration of CU in life and FA values in this tract was also observed (p = 0.019). Proteomics analyses in BA9 found 11 proteins differentially expressed between cocaine users and controls. Among these, were proteins related to myelination and neuroinflammation. In summary, we demonstrate convergent evidence from in vivo diffusion tensor imaging and ex vivo proteomics analysis of WM disruption in CUD.

PMID:33911068 | DOI:10.1038/s41398-021-01367-x

Nat Commun. 2021 Apr 28;12(1):1935. doi: 10.1038/s41467-020-20536-y.

ABSTRACT

Haplotype-resolved genome assemblies are important for understanding how combinations of variants impact phenotypes. To date, these assemblies have been best created with complex protocols, such as cultured cells that contain a single-haplotype (haploid) genome, single cells where haplotypes are separated, or co-sequencing of parental genomes in a trio-based approach. These approaches are impractical in most situations. To address this issue, we present FALCON-Phase, a phasing tool that uses ultra-long-range Hi-C chromatin interaction data to extend phase blocks of partially-phased diploid assembles to chromosome or scaffold scale. FALCON-Phase uses the inherent phasing information in Hi-C reads, skipping variant calling, and reduces the computational complexity of phasing. Our method is validated on three benchmark datasets generated as part of the Vertebrate Genomes Project (VGP), including human, cow, and zebra finch, for which high-quality, fully haplotype-resolved assemblies are available using the trio-based approach. FALCON-Phase is accurate without having parental data and performance is better in samples with higher heterozygosity. For cow and zebra finch the accuracy is 97% compared to 80-91% for human. FALCON-Phase is applicable to any draft assembly that contains long primary contigs and phased associate contigs.

PMID:33911078 | DOI:10.1038/s41467-020-20536-y