Category: Statistics

J Chem Inf Model. 2021 Apr 29. doi: 10.1021/acs.jcim.0c01387. Online ahead of print.

ABSTRACT

We present a systematic approach for the identification of statistically relevant conformational macrostates of organic molecules from molecular dynamics trajectories. The approach applies to molecules characterized by an arbitrary number of torsional degrees of freedom and enables the transferability of the macrostates definition across different environments. We formulate a dissimilarity measure between molecular configurations that incorporates information on the characteristic energetic cost associated with transitions along all relevant torsional degrees of freedom. Such metric is employed to perform unsupervised clustering of molecular configurations based on the Fast Search and Find of Density Peaks algorithm. We apply this method to investigate the equilibrium conformational ensemble of Sildenafil, a conformationally complex pharmaceutical compound, in different environments including the crystal bulk, the gas phase, and three different solvents (acetonitrile, 1-butanol, and toluene). We demonstrate that while Sildenafil can adopt more than 100 metastable conformational configurations, only 12 are significantly populated across all of the environments investigated. Despite the complexity of the conformational space, we find that the most abundant conformers in solution are the closest to the conformers found in the most common Sildenafil crystal phase.

PMID:33913713 | DOI:10.1021/acs.jcim.0c01387

Minerva Med. 2021 Apr 29. doi: 10.23736/S0026-4806.21.06970-6. Online ahead of print.

ABSTRACT

BACKGROUND: Inflammatory bowel diseases (IBD) may be complicated by extraintestinal manifestations (EIM). Both conditions may be implicated in the overall increase of cardiovascular (CV) risk profile of the patients. The study aimed to assess CV risk in IBD patients with EIMs in relation to the stages of both diseases.

METHODS: A total of 70 (38 men, mean age 51.7±12.4 years) patients with IBD and 22 controls (12 men, mean age 49.2±13.6 years) were enrolled. All patients and controls were screened for extraintestinal manifestations and underwent physical and anthropometric examinations, standard laboratory investigations, ultrasound evaluation of carotid arteries and flow-mediated vasodilatation (FMD). Patients were divided into four groups in relation to their active or remission stage of disease: 1. IBD+ EIM+; 2. IBD+ EIM-; 3. IBD- EIM+; 4. IBD- EIM-.

RESULTS: The groups were homogenous according to their clinical characteristics. Patients with both IBD and EIM in active phase showed significantly lower values in FMD than controls (p=0.024). Carotid intima-media thickness values (cIMT) were similar among groups. Patients with active phases of IBD and/or EIM showed statistically significant lower values in FMD measurements (p=0.0008 and p=0.0011, respectively). Multivariate regression did not reveal any independent predictors for FMD values.

CONCLUSIONS: The active phase of IBD or EIM or both may promote endothelial dysfunction in patients, thus increasing their CV risk profile. Patients in remission phase showed endothelial function similar at controls.

PMID:33913656 | DOI:10.23736/S0026-4806.21.06970-6

Minerva Med. 2021 Apr 29. doi: 10.23736/S0026-4806.21.07187-1. Online ahead of print.

ABSTRACT

BACKGROUND: Cardiovascular comorbidities are a common cause of death in COVID-19 and the aim of this study is to evaluate the effect of comorbidities on mortality in COVID-19 patients.

METHODS: In this retrospective observational study we enrolled 1049 patients hospitalized with confirmed SARS-CoV-2 infection in a single Italian Center from 21 February to 20 March 2020 Evaluated risk factors (RFs) were: advanced age, gender, hypertension, diabetes, atrial fibrillation, hyperlipidemia, chronic kidney disease, thyroid disease, chronic obstructive pulmonary disease, malignancy, stroke, cardiovascular disease, and peripheral vascular disease. Endpoint of the study was death from any cause. A multivariate logistic regression model was built using covariates that showed as statistically significant at univariate regression analysis.

RESULTS: Median age at presentation was 71.1 years (IQR: 59.1-80.5); 244 (72.2%) were males. Primary outcome occurred in 338 patients (32.2%). In decedents, median survival from Hospitalization was 6 (IQR: 3-10) days. 264 decedents had 1 RF, 120 had 2 RFs and 39 had ≥3 RFs. At multivariate logistic regression model, variables associated with primary outcome were: age class (64-69 years) (OR 3.03, CI 1.75-5.31, p<0.001), age class (70-88 years) (OR 10.08, CI 6.67-15.72, p<0.001), age class (≥ 88 years) (OR 23.99, CI 13.21-44.82, p<0.001), male gender (OR 1.88, CI 1.36-2.62, p<0.001), diabetes (OR 1.56, CI 1.07-2.26, p=0.02), stroke (OR 3.41, CI 1.33-9.91, p=0.015).

CONCLUSIONS: Age, male gender, presence of diabetes and stroke appeared as independent predictors of mortality in COVID-19 patients. A table for risk of 30 days-mortality in SARS-CoV-2 infection was built, based on odds ratios derived from multivariate regression analysis.

PMID:33913658 | DOI:10.23736/S0026-4806.21.07187-1

Minerva Med. 2021 Apr 29. doi: 10.23736/S0026-4806.21.07207-4. Online ahead of print.

ABSTRACT

Chronobiology studies the biological rhythms or circadian cycles of living organisms and their adaptation to external changes. Biological rhythms can affect hormone production cycles such as sleep/wake, and nutrition/fasting, but these factors can also alter the circadian rhythm (CR). In recent years, numerous studies have highlighted how feeding times and frequency can influence biological rhythms. Additionally, individuals’ chronotype, working shifts, and food intake can make a deep impact on people’s tendency to develop obesity and metabolic diseases. In this context, a single food and a specific combination of these, can also affect the CR and fasting cycle and consequently body weight and viceversa. The purpose of the review is to propose practical nutritional recommendations to help in resynchronizing the circadian rhythm as a tool in weight control.

PMID:33913659 | DOI:10.23736/S0026-4806.21.07207-4

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

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):9485. doi: 10.1038/s41598-021-88890-5.

NO ABSTRACT

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

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