Microstructure Evolution during Compaction of Powder Blends

Powder compaction is a manufacturing technology used to transform powder particles into a solid material with unique anisotropic microstructure and low porosity. It is widely used by pharmaceutical companies to manufacture tablets with desired properties. These properties are the result of the microstructure obtained during the compaction process. Therefore, it is imperative to understand the mechanics underneath the constituent granular particles that eventually contribute to properties of the manufactured tablets. Computational simulation tools have been developed in the past to study powder compaction for pharmaceutical tablets. However, most of the already existing tools limit their scope to study individual particles and their interactions with adjunct particles or surfaces. Moreover, they treat powder bed as a continuum body. A study of compaction of powder blends with specific particle size distributions would better elucidate evolution of microstructure during compaction in pharmaceutical tablets. In our study, we introduce a new version of nanoHUB powder compaction tool. We use static based algorithm to place binary mixture of polydisperse particles inside a die. We have also included nonlocal approach of contact mechanics to accurately predict interactions between particles. This approach makes our method computationally less challenging and precise. An inclusion of binary mixture of particles of different sizes in the computational tool allows users to study the relationship between particles’ mechanical properties and their microstructure evolution during the compaction process. Users can also validate their experimental/expected results for deformations of binary mixtures of elastic or plastic particles from those obtained from simulation tool

Caffeinated Coffee, Decaffeinated Coffee and Endometrial Cancer Risk: A Prospective Cohort Study among US Postmenopausal Women

There is plausible biological evidence as well as epidemiologic evidence to suggest coffee consumption may lower endometrial cancer risk. We evaluated the associations between self-reported total coffee, caffeinated coffee and decaffeinated coffee, and endometrial cancer risk using the Women’s Health Initiative Observational Study Research Materials obtained from the National Heart, Lung, and Blood Institute Biological Specimen and Data Repository Coordinating Center. Our primary analyses included 45,696 women and 427 incident endometrial cancer cases, diagnosed over a total of 342,927 person-years of follow-up. We used Cox-proportional hazard models to evaluate coffee consumption and endometrial cancer risk. Overall, we did not find an association between coffee consumption and endometrial cancer risk. Compared to non-daily drinkers (none or <1 cup/day), the multivariable adjusted hazard ratios for women who drank ≥4 cups/day were 0.86 (95% confidence interval (CI) 0.63, 1.18) for total coffee, 0.89 (95% CI 0.63, 1.27) for caffeinated coffee, and 0.51 (95% CI 0.25, 1.03) for decaf coffee. In subgroup analyses by body mass index (BMI) there were no associations among normal-weight and overweight women for total coffee and caffeinated coffee. However among obese women, compared to the referent group (none or <1 cup/day), the hazard ratios for women who drank ≥2 cups/day were: 0.72 (95% CI 0.50, 1.04) for total coffee and 0.66 (95% CI 0.45, 0.97) for caffeinated coffee. Hazard ratios for women who drank ≥2 cups/day for decaffeinated coffee drinkers were 0.67 (0.43-1.06), 0.93 (0.55-1.58) and 0.80 (0.49-1.30) for normal, overweight and obese women, respectively. Our study suggests that caffeinated coffee consumption may be associated with lower endometrial cancer risk among obese postmenopausal women, but the association with decaffeinated coffee remains unclear

Palmitate and group B Streptococcus synergistically and differentially induce IL-1β from human gestational membranes

IntroductionRupture of the gestational membranes often precedes major pregnancy complications, including preterm labor and preterm birth. One major cause of inflammation in the gestational membranes, chorioamnionitis (CAM) is often a result of bacterial infection. The commensal bacterium Streptococcus agalactiae, or Group B Streptococcus (GBS) is a leading infectious cause of CAM. Obesity is on the rise worldwide and roughly 1 in 4 pregnancy complications is related to obesity, and individuals with obesity are also more likely to be colonized by GBS. The gestational membranes are comprised of several distinct cell layers which are, from outermost to innermost: maternally-derived decidual stromal cells (DSCs), fetal cytotrophoblasts (CTBs), fetal mesenchymal cells, and fetal amnion epithelial cells (AECs). In addition, the gestational membranes have several immune cell populations; macrophages are the most common phagocyte. Here we characterize the effects of palmitate, the most common long-chain saturated fatty acid, on the inflammatory response of each layer of the gestational membranes when infected with GBS, using human cell lines and primary human tissue.ResultsPalmitate itself slightly but significantly augments GBS proliferation. Palmitate and GBS co-stimulation synergized to induce many inflammatory proteins and cytokines, particularly IL-1β and matrix metalloproteinase 9 from DSCs, CTBs, and macrophages, but not from AECs. Many of these findings are recapitulated when treating cells with palmitate and a TLR2 or TLR4 agonist, suggesting broad applicability of palmitate-pathogen synergy. Co-culture of macrophages with DSCs or CTBs, upon co-stimulation with GBS and palmitate, resulted in increased inflammatory responses, contrary to previous work in the absence of palmitate. In whole gestational membrane biopsies, the amnion layer appeared to dampen immune responses from the DSC and CTB layers (the choriodecidua) to GBS and palmitate co-stimulation. Addition of the monounsaturated fatty acid oleate, the most abundant monounsaturated fatty acid in circulation, dampened the proinflammatory effect of palmitate.DiscussionThese studies reveal a complex interplay between the immunological response of the distinct layers of the gestational membrane to GBS infection and that such responses can be altered by exposure to long-chain saturated fatty acids. These data provide insight into how metabolic syndromes such as obesity might contribute to an increased risk for GBS disease during pregnancy

Genetic epidemiology of pelvic organ prolapse: a systematic review

Given current evidence supporting a genetic predisposition for pelvic organ prolapse (POP), we conducted a systematic review of published literature on the genetic epidemiology of POP. Inclusion criteria were linkage studies, candidate gene association and genome-wide association studies (GWAS) in adult women published in English and indexed in PubMed through December 2012, with no limit on date of publication. Methodology adhered to the PRISMA guidelines. Data were systematically extracted by two reviewers and graded by the Venice criteria for studies of genetic associations. A meta-analysis was performed on all single nucleotide polymorphisms (SNPs) evaluated by two or more studies with similar methodology. The meta-analysis suggests that collagen type 3 alpha 1 (COL3A1) rs1800255 genotype AA is associated with POP, OR 4.79 (95% CI 1.91 to 11.98, p= 0.001) compared to the reference genotype GG in populations of Asian and Dutch women. There was little evidence of heterogeneity for rs1800255 (p-value for heterogeneity= 0.94; proportion of variance due to heterogeneity, I2= 0.00%). There was insufficient evidence to determine whether other SNPs evaluated by two or more papers were associated with POP. An association with POP was seen in individual studies for estrogen receptor alpha (ER-α) rs2228480 GA, COL3A1 exon 31, chromosome 9q21 (HLOD score 3.41) as well as six SNPs identified by a GWAS. Overall, individual studies were of small sample size and often of poor quality. Future studies would benefit from more rigorous study design as outlined in the Venice recommendations

Subclinical Hypothyroidism and Risk for Incident Ischemic Stroke Among Postmenopausal Women

Background: Subclinical hypothyroidism (SCH) is postulated to increase stroke risk via atherogenic changes associated with abnormal thyroid function. However, the direct relationship of SCH with subsequent stroke is poorly studied

Discovery of rare variants associated with blood pressure regulation through meta-analysis of 1.3 million individuals

Genetic studies of blood pressure (BP) to date have mainly analyzed common variants (minor allele frequency > 0.05). In a meta-analysis of up to ~1.3 million participants, we discovered 106 new BP-associated genomic regions and 87 rare (minor allele frequency ≤ 0.01) variant BP associations (P < 5 × 10−8), of which 32 were in new BP-associated loci and 55 were independent BP-associated single-nucleotide variants within known BP-associated regions. Average effects of rare variants (44% coding) were ~8 times larger than common variant effects and indicate potential candidate causal genes at new and known loci (for example, GATA5 and PLCB3). BP-associated variants (including rare and common) were enriched in regions of active chromatin in fetal tissues, potentially linking fetal development with BP regulation in later life. Multivariable Mendelian randomization suggested possible inverse effects of elevated systolic and diastolic BP on large artery stroke. Our study demonstrates the utility of rare-variant analyses for identifying candidate genes and the results highlight potential therapeutic targets. © 2020, The Author(s), under exclusive licence to Springer Nature America, Inc. There are 286 authors of this articles not all are listed in this record

Comprehensive Bayesian analysis of FRB-like bursts from SGR 1935+2154 observed by CHIME/FRB

The bright millisecond-duration radio burst from the Galactic magnetar SGR 1935+2154 in 2020 April was a landmark event, demonstrating that at least some fast radio burst (FRB) sources could be magnetars. The two-component burst was temporally coincident with peaks observed within a contemporaneous short X-ray burst envelope, marking the first instance where FRB-like bursts were observed to coincide with X-ray counterparts. In this study, we detail five new radio burst detections from SGR 1935+2154, observed by the CHIME/FRB instrument between October 2020 and December 2022. We develop a fast and efficient Bayesian inference pipeline that incorporates state-of-the-art Markov chain Monte Carlo techniques and use it to model the intensity data of these bursts under a flexible burst model. We revisit the 2020 April burst and corroborate that both the radio sub-components lead the corresponding peaks in their high-energy counterparts. For a burst observed in 2022 October, we find that our estimated radio pulse arrival time is contemporaneous with a short X-ray burst detected by GECAM and HEBS, and Konus-Wind and is consistent with the arrival time of a radio burst detected by GBT. We present flux and fluence estimates for all five bursts, employing an improved estimator for bursts detected in the side-lobes. We also present upper limits on radio emission for X-ray emission sources which were within CHIME/FRB's field-of-view at trigger time. Finally, we present our exposure and sensitivity analysis and estimate the Poisson rate for FRB-like events from SGR 1935+2154 to be $0.005^{+0.082}_{-0.004}$ events/day above a fluence of $10~\mathrm{kJy~ms}$ during the interval from 28 August 2018 to 1 December 2022, although we note this was measured during a time of great X-ray activity from the source.Comment: 22 pages, 6 figures, 4 tables. To be submitted to Ap

Genome-wide analysis in over 1 million individuals of European ancestry yields improved polygenic risk scores for blood pressure traits

Hypertension affects more than one billion people worldwide. Here we identify 113 novel loci, reporting a total of 2,103 independent genetic signals (P < 5 × 10−8) from the largest single-stage blood pressure (BP) genome-wide association study to date (n = 1,028,980 European individuals). These associations explain more than 60% of single nucleotide polymorphism-based BP heritability. Comparing top versus bottom deciles of polygenic risk scores (PRSs) reveals clinically meaningful differences in BP (16.9 mmHg systolic BP, 95% CI, 15.5–18.2 mmHg, P = 2.22 × 10−126) and more than a sevenfold higher odds of hypertension risk (odds ratio, 7.33; 95% CI, 5.54–9.70; P = 4.13 × 10−44) in an independent dataset. Adding PRS into hypertension-prediction models increased the area under the receiver operating characteristic curve (AUROC) from 0.791 (95% CI, 0.781–0.801) to 0.826 (95% CI, 0.817–0.836, ∆AUROC, 0.035, P = 1.98 × 10−34). We compare the 2,103 loci results in non-European ancestries and show significant PRS associations in a large African-American sample. Secondary analyses implicate 500 genes previously unreported for BP. Our study highlights the role of increasingly large genomic studies for precision health research

Genetic Determinants of Pelvic Organ Prolapse among African American and Hispanic Women in the Women’s Health Initiative

Current evidence suggests a multifactorial etiology to pelvic organ prolapse (POP), including genetic predisposition. We conducted a genome-wide association study of POP in African American (AA) and Hispanic (HP) women from the Women’s Health Initiative Hormone Therapy study. Cases were defined as any POP (grades 1–3) or moderate/severe POP (grades 2–3), while controls had grade 0 POP. We performed race-specific multiple logistic regression analyses between SNPs imputed to 1000 genomes in relation to POP (grade 0 vs 1–3; grade 0 vs 2–3) adjusting for age at diagnosis, body mass index, parity, and genetic ancestry. There were 1274 controls and 1427 cases of any POP and 317 cases of moderate/severe POP. Although none of the analyses reached genome-wide significance (p<5x10-8), we noted variants in several loci that met p<10−6. In race-specific analysis of grade 0 vs 2–3, intronic SNPs in the CPE gene (rs28573326, OR:2.14; 95% CI 1.62–2.83; p = 1.0x10-7) were associated with POP in AAs, and SNPs in the gene AL132709.5 (rs1950626, OR:2.96; 95% CI 1.96–4.48, p = 2.6x10-7) were associated with POP in HPs. Inverse variance fixed-effect meta-analysis of the race-specific results showed suggestive signals for SNPs in the DPP6 gene (rs11243354, OR:1.36; p = 4.2x10-7) in the grade 0 vs 1–3 analyses and for SNPs around PGBD5 (rs740494, OR:2.17; p = 8.6x10-7) and SHC3 (rs2209875, OR:0.60; p = 9.3x10-7) in the grade 0 vs 2–3 analyses. While we did not identify genome-wide significant findings, we document several SNPs reaching suggestive statistical significance. Further interrogation of POP in larger minority samples is warranted

Protein-coding variants implicate novel genes related to lipid homeostasis contributing to body-fat distribution.

Body-fat distribution is a risk factor for adverse cardiovascular health consequences. We analyzed the association of body-fat distribution, assessed by waist-to-hip ratio adjusted for body mass index, with 228,985 predicted coding and splice site variants available on exome arrays in up to 344,369 individuals from five major ancestries (discovery) and 132,177 European-ancestry individuals (validation). We identified 15 common (minor allele frequency, MAF ≥5%) and nine low-frequency or rare (MAF &lt;5%) coding novel variants. Pathway/gene set enrichment analyses identified lipid particle, adiponectin, abnormal white adipose tissue physiology and bone development and morphology as important contributors to fat distribution, while cross-trait associations highlight cardiometabolic traits. In functional follow-up analyses, specifically in Drosophila RNAi-knockdowns, we observed a significant increase in the total body triglyceride levels for two genes (DNAH10 and PLXND1). We implicate novel genes in fat distribution, stressing the importance of interrogating low-frequency and protein-coding variants