Contemporary Analysis of Malignancies in Women of Child-Bearing Age: An NSQIP Analysis

Background: Recent evidence suggests that cancer incidence among pregnant women is increasing. The pattern of malignancies in pregnant women and how these compare to their nonpregnant counterparts has not been explored. Here we describe the differences in the proportion of resected malignancies in this population. Methods: The American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) database was used to identify women aged 18-49 who underwent an operation for malignancy from 2007-2012. Age-adjusted distribution of specific surgical interventions for malignancy based on ICD-9 codes were compared among pregnant and non-pregnant women using logistic regression analysis. Results: 42,732 subjects with malignancies surgically treated during child-bearing age were identified. 0.33% (n=143) were pregnant. The most common tumors requiring resection were breast (51%), thyroid (17%), and colorectal (9%). The distribution for most cancers was similar between groups. The age-adjusted proportion was significantly increased in breast, major salivary gland and oropharyngeal malignancies (p\u3c0.05). The proportion of resected colorectal cancers was significantly lower in pregnant women (p\u3c0.05; Table 1). Conclusion: This study serves as the first comprehensive and contemporary overview of malignancies resected in women of childbearing age. This study demonstrates that the proportion of resections among pregnant women was significantly greater in breast, major salivary gland and oropharyngeal cancers and lower for colorectal cancers. While these data might represent true differences in cancer incidence, further work is necessary to demonstrate if these are true differences in incidence versus differences in detection and treatment of the pregnant patient

Does the Indication for Breast Surgery Impact Surgical Outcomes? A Contemporary Analysis of the ACS-NSQIP Database

Background. There is limited data about whether perioperative outcomes differ based on the indication for breast surgery. Herein we aim to assess if breast surgery for prophylaxis, compared to that for malignancy, impacts surgical outcomes. Methods. All women who underwent simple or subcutaneous mastectomy were identified from the 2007-2012 ACS-NSQIP database. Patients were identified by their ICD-9 codes and categorized into two groups. Group 1 consisted of patients diagnosed with breast cancer or carcinoma in situ; group 2 consisted of patients diagnosed with a genetic predisposition to malignant neoplasm of the breast (i.e., BRCA mutation). Demographic and preoperative variables were compared between groups and outcome variables. Outcome variables were analyzed using age- and operative time-adjusted logistic regression models. Results. 30,803 patients were identified. Group 1 consisted of 30,644 (99.5%) patients diagnosed with malignancy; group 2 consisted of 159 (0.5%) who underwent prophylactic surgery. In univariate analyses, those undergoing prophylactic surgery were significantly younger (p \u3c 0.01). There were no other preoperative differences between groups. When adjusted, the prophylactic group demonstrated a greater risk of DVT (p = 0.03). There were no differences in mortality, superficial/deep/organ space infections, UTI, wound dehiscence, or MI. Conclusion. In this analysis of a national cohort of breast surgery patients, those undergoing prophylactic surgery due to a genetic predisposition had a greater risk of perioperative DVT, compared to those who underwent surgery for a diagnosis of malignancy. This data may allow for improved perioperative management of patients to prevent DVT development and their devastating consequences

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

Genome-wide association identifies nine common variants associated with fasting proinsulin levels and provides new insights into the pathophysiology of type 2 diabetes.

OBJECTIVE: Proinsulin is a precursor of mature insulin and C-peptide. Higher circulating proinsulin levels are associated with impaired β-cell function, raised glucose levels, insulin resistance, and type 2 diabetes (T2D). Studies of the insulin processing pathway could provide new insights about T2D pathophysiology. RESEARCH DESIGN AND METHODS: We have conducted a meta-analysis of genome-wide association tests of ∼2.5 million genotyped or imputed single nucleotide polymorphisms (SNPs) and fasting proinsulin levels in 10,701 nondiabetic adults of European ancestry, with follow-up of 23 loci in up to 16,378 individuals, using additive genetic models adjusted for age, sex, fasting insulin, and study-specific covariates. RESULTS: Nine SNPs at eight loci were associated with proinsulin levels (P < 5 × 10(-8)). Two loci (LARP6 and SGSM2) have not been previously related to metabolic traits, one (MADD) has been associated with fasting glucose, one (PCSK1) has been implicated in obesity, and four (TCF7L2, SLC30A8, VPS13C/C2CD4A/B, and ARAP1, formerly CENTD2) increase T2D risk. The proinsulin-raising allele of ARAP1 was associated with a lower fasting glucose (P = 1.7 × 10(-4)), improved β-cell function (P = 1.1 × 10(-5)), and lower risk of T2D (odds ratio 0.88; P = 7.8 × 10(-6)). Notably, PCSK1 encodes the protein prohormone convertase 1/3, the first enzyme in the insulin processing pathway. A genotype score composed of the nine proinsulin-raising alleles was not associated with coronary disease in two large case-control datasets. CONCLUSIONS: We have identified nine genetic variants associated with fasting proinsulin. Our findings illuminate the biology underlying glucose homeostasis and T2D development in humans and argue against a direct role of proinsulin in coronary artery disease pathogenesis

Cholecystostomy Treatment in an ICU Population: Complications and Risks

BACKGROUND: Percutaneous cholecystostomy tube placement has widely been used as an alternative treatment to cholecystectomy, especially in advanced disease or critically ill patients. Reported postprocedural complication rates have varied significantly over the last decade. The goal of this study is to evaluate the safety of percutaneous cholecystostomy tube treatment in critically ill patients. STUDY DESIGN: We performed a retrospective chart analysis of 96 critically ill patients who underwent cholecystostomy tube placement during an intensive care unit (ICU) stay between 2005 and 2010 in a tertiary care center in central Massachusetts. Complications within 72 hours of cholecystostomy tube placement and any morbidity or mortality relating to presence of cholecystostomy tube were considered. RESULTS: A total of 65 male and 31 female patients with a mean age of 67.4 years underwent percutaneous cholecystostomy tube placement during an ICU stay. Sixty-six patients experienced a total of 121 complications, resulting in an overall complication rate of 69%. Fifty-four of these complications resulted from the actual procedure or the presence of the cholecystostomy tube; the other 67 complications occurred within 72 hours of the cholecystostomy procedure. Ten patients died. Tube dislodgment was the most common complication with a total of 34 episodes. CONCLUSIONS: Cholecystostomy tube placement is associated with frequent complications, the most common of which is tube dislodgment. Severe complications may contribute to serious morbidity and death in an ICU population. Complication rates may be underreported in the medical literature. The potential impact of cholecystostomy tube placement in critically ill patients should not be underestimated

Comparative coagulation studies in hibernating and summer-active black bears (Ursus americanus)

The aim of this study was to characterize and compare coagulation screening tests, procoagulant and anticoagulant factors between hibernating and summer-active bears. This may identify relevant pathways sustaining blood flow during immobility and subsequently facilitate translational research for potential future human therapies of thromboembolic disease

NMR Metabolomics Reveal Urine Markers of Microbiome Diversity and Identify Benzoate Metabolism as a Mediator between High Microbial Alpha Diversity and Metabolic Health

Microbial metabolites measured using NMR may serve as markers for physiological or pathological host–microbe interactions and possibly mediate the beneficial effects of microbiome diversity. Yet, comprehensive analyses of gut microbiome data and the urine NMR metabolome from large general population cohorts are missing. Here, we report the associations between gut microbiota abundances or metrics of alpha diversity, quantified from stool samples using 16S rRNA gene sequencing, with targeted urine NMR metabolites measures from 951 participants of the Study of Health in Pomerania (SHIP). We detected significant genus–metabolite associations for hippurate, succinate, indoxyl sulfate, and formate. Moreover, while replicating the previously reported association between hippurate and measures of alpha diversity, we identified formate and 4-hydroxyphenylacetate as novel markers of gut microbiome alpha diversity. Next, we predicted the urinary concentrations of each metabolite using genus abundances via an elastic net regression methodology. We found profound associations of the microbiome-based hippurate prediction score with markers of liver injury, inflammation, and metabolic health. Moreover, the microbiome-based prediction score for hippurate completely mediated the clinical association pattern of microbial diversity, hinting at a role of benzoate metabolism underlying the positive associations between high alpha diversity and healthy states. In conclusion, large-scale NMR urine metabolomics delivered novel insights into metabolic host–microbiome interactions, identifying pathways of benzoate metabolism as relevant candidates mediating the beneficial health effects of high microbial alpha diversity

A Translational Model for Venous Thromboembolism: MicroRNA Expression in Hibernating Black Bears.

BACKGROUND: Hibernating American black bears have significantly different clotting parameters than their summer active counterparts, affording them protection against venous thromboembolism during prolonged periods of immobility. We sought to evaluate if significant differences exist between the expression of microRNAs in the plasma of hibernating black bears compared with their summer active counterparts, potentially contributing to differences in hemostasis during hibernation. MATERIALS AND METHODS: MicroRNA sequencing was assessed in plasma from 21 American black bears in summer active (n = 11) and hibernating states (n = 10), and microRNA signatures during hibernating and active state were established using both bear and human genome. MicroRNA targets were predicted using messenger RNA (mRNA) transcripts from black bear kidney cells. In vitro studies were performed to confirm the relationship between identified microRNAs and mRNA expression, using artificial microRNA and human liver cells. RESULTS: Using the bear genome, we identified 15 microRNAs differentially expressed in the plasma of hibernating black bears. Of these microRNAs, three were significantly downregulated (miR-141-3p, miR-200a-3p, and miR-200c-3p), were predicted to target SERPINC1, the gene for antithrombin, and demonstrated regulatory control of the gene mRNA expression in cell studies. CONCLUSIONS: Our findings suggest that the hibernating black bears\u27 ability to maintain hemostasis and achieve protection from venous thromboembolism during prolonged periods of immobility may be due to changes in microRNA signatures and possible upregulation of antithrombin expression

Genetic Risk Score for Intracranial Aneurysms: Prediction of Subarachnoid Hemorrhage and Role in Clinical Heterogeneity

Background: Recently, common genetic risk factors for intracranial aneurysm (IA) and aneurysmal subarachnoid hemorrhage (ASAH) were found to explain a large amount of disease heritability and therefore have potential to be used for genetic risk prediction. We constructed a genetic risk score to (1) predict ASAH incidence and IA presence (combined set of unruptured IA and ASAH) and (2) assess its association with patient characteristics. Methods: A genetic risk score incorporating genetic association data for IA and 17 traits related to IA (so-called metaGRS) was created using 1161 IA cases and 407 392 controls from the UK Biobank population study. The metaGRS was validated in combination with risk factors blood pressure, sex, and smoking in 828 IA cases and 68 568 controls from the Nordic HUNT population study. Furthermore, we assessed association between the metaGRS and patient characteristics in a cohort of 5560 IA patients. Results: Per SD increase of metaGRS, the hazard ratio for ASAH incidence was 1.34 (95% CI, 1.20-1.51) and the odds ratio for IA presence 1.09 (95% CI, 1.01-1.18). Upon including the metaGRS on top of clinical risk factors, the concordance index to predict ASAH hazard increased from 0.63 (95% CI, 0.59-0.67) to 0.65 (95% CI, 0.62-0.69), while prediction of IA presence did not improve. The metaGRS was statistically significantly associated with age at ASAH (β=-4.82×10-3per year [95% CI, -6.49×10-3to -3.14×10-3]; P=1.82×10-8), and location of IA at the internal carotid artery (odds ratio=0.92 [95% CI, 0.86-0.98]; P=0.0041). Conclusions: The metaGRS was predictive of ASAH incidence, although with limited added value over clinical risk factors. The metaGRS was not predictive of IA presence. Therefore, we do not recommend using this metaGRS in daily clinical care. Genetic risk does partly explain the clinical heterogeneity of IA warranting prioritization of clinical heterogeneity in future genetic prediction studies of IA and ASAH