Women’s Representation in State Politics: Linking Descriptive and Substantive Representation to Health and Economic Policy Outcomes

This paper tests whether women’s descriptive representation in American state legislatures explains variance in policies relevant to women. The relationship between women’s representation and policy is estimated, controlling for alternative explanations of policy adoption including learning from neighboring and politically-similar states, internal economic and political conditions, and state demographics. Following prior research, a single equation instrumental variables model is used to link descriptive and substantive representation, but results do not support the use of a model with endogenous covariates. A simpler model specification demonstrates that women’s descriptive representation in state legislatures improves economic policy but not health policy outcomes. Political party confounds the relationship between gender and health policy outcomes. This paper contributes to the literature by: Using a broader measure of policy outcomes rather than dichotomous measures, examining women’s representation in both executive and legislative branches, demonstrating the role of political party, and linking women’s descriptive and substantive representation

Novel computational analysis of protein binding array data identifies direct targets of Nkx2.2 in the pancreas

<p>Abstract</p> <p>Background</p> <p>The creation of a complete genome-wide map of transcription factor binding sites is essential for understanding gene regulatory networks <it>in vivo</it>. However, current prediction methods generally rely on statistical models that imperfectly model transcription factor binding. Generation of new prediction methods that are based on protein binding data, but do not rely on these models may improve prediction sensitivity and specificity.</p> <p>Results</p> <p>We propose a method for predicting transcription factor binding sites in the genome by directly mapping data generated from protein binding microarrays (PBM) to the genome and calculating a moving average of several overlapping octamers. Using this unique algorithm, we predicted binding sites for the essential pancreatic islet transcription factor <it>Nkx2.2 </it>in the mouse genome and confirmed >90% of the tested sites by EMSA and ChIP. Scores generated from this method more accurately predicted relative binding affinity than PWM based methods. We have also identified an alternative core sequence recognized by the <it>Nkx2.2 </it>homeodomain. Furthermore, we have shown that this method correctly identified binding sites in the promoters of two critical pancreatic islet β-cell genes, <it>NeuroD1 </it>and <it>insulin2</it>, that were not predicted by traditional methods. Finally, we show evidence that the algorithm can also be applied to predict binding sites for the nuclear receptor <it>Hnf4α</it>.</p> <p>Conclusions</p> <p>PBM-mapping is an accurate method for predicting Nkx2.2 binding sites and may be widely applicable for the creation of genome-wide maps of transcription factor binding sites.</p

Women undergoing endovascular thoracoabdominal aortic aneurysm repair differ significantly from their male counterparts preoperatively and postoperatively

OBJECTIVE: A rational approach to the management of aortic aneurysm disease relies on weighing the risk of aneurysm rupture against the complications and durability of operative repair. In men, seminal studies of infrarenal aortic aneurysm disease and its endovascular management can provide a reasoned argument for the timing and modality of surgery, which is then extrapolated to the management of thoracoabdominal aortic aneurysms (TAAAs). In contrast, there is less appreciation for the natural history of TAAA disease in women and its response to therapy. METHODS: We used a retrospective cohort design of women, all men, and matched men, fit for complex endovascular thoracoabdominal aneurysm repair at two large aortic centers. We controlled for preoperative anatomic and comorbidity differences, and assessed technical success, postoperative renal dysfunction, spinal ischemia, and early mortality. Women and matched men were reassessed at follow-up for long-term durability and survival. RESULTS: Assessing women and all men undergoing complex endovascular aortic reconstruction, we demonstrate that these groups are dissimilar before the intervention with respect to comorbidities, aneurysm extent, and aneurysm size; women have a higher proportion of proximal Crawford extent 1, 2, and 3 aneurysms. Matching men and women for demographic and anatomic differences, we find persistent elevated perioperative mortality in women (16%) undergoing endovascular thoracoabdominal aneurysm repair compared with matched men (6%); however, at the 3-year follow-up, both groups have the same survival. Furthermore, women demonstrate more favorable anatomic responses to aneurysm exclusion, with good durability and greater aneurysm sac regression at follow-up, compared with matched men. CONCLUSIONS: Women and unmatched men with TAAA disease differ preoperatively with respect to aneurysm extent and comorbidities. Controlling for these differences, after complex endovascular aneurysm repair, there is increased early mortality in women compared with matched men. These observations argue for a careful risk stratification of women undergoing endovascular thoracoabdominal aneurysm treatment, balanced with women's good long-term survival and durability of endovascular aneurysm repair

Accuracy of implementing principles of fusion imaging in the follow up and surveillance of complex aneurysm repair

Fusion imaging is standard for the endovascular treatment of complex aortic aneurysms, but its role in follow up has not been explored. A critical issue is renal function deterioration over time. Renal volume has been used as a marker of renal impairment; however, it is not reproducible and remains a complex and resource-intensive procedure. The aim of this study is to determine the accuracy of a fusion-based software to automatically calculate the renal volume changes during follow up. In this study, computerized tomography (CT) scans of 16 patients who underwent complex aortic endovascular repair were analysed. Preoperative, 1-month and 1-year follow-up CT scans have been analysed using a conventional approach of semi-automatic segmentation, and a second approach with automatic segmentation. For each kidney and at each time point the percentage of change in renal volume was calculated using both techniques. After review, volume assessment was feasible for all CT scans. For the left kidney, the intraclass correlation coefficient (ICC) was 0.794 and 0.877 at 1 month and 1 year, respectively. For the right side, the ICC was 0.817 at 1 month and 0.966 at 1 year. The automated technique reliably detected a decrease in renal volume for the eight patients with occluded renal arteries during follow up. This is the first report of a fusion-based algorithm to detect changes in renal volume during postoperative surveillance using an automated process. Using this technique, the standardized assessment of renal volume could be implemented with greater ease and reproducibility and serve as a warning of potential renal impairment

Proinsulin Secretion Is a Persistent Feature of Type 1 Diabetes

OBJECTIVE: Abnormally elevated proinsulin secretion has been reported in type 2 and early type 1 diabetes when significant C-peptide is present. We questioned whether individuals with long-standing type 1 diabetes and low or absent C-peptide secretory capacity retained the ability to make proinsulin. RESEARCH DESIGN AND METHODS: C-peptide and proinsulin were measured in fasting and stimulated sera from 319 subjects with long-standing type 1 diabetes (≥3 years) and 12 control subjects without diabetes. We considered three categories of stimulated C-peptide: 1) C-peptide positive, with high stimulated values ≥0.2 nmol/L; 2) C-peptide positive, with low stimulated values ≥0.017 but <0.2 nmol/L; and 3) C-peptide <0.017 nmol/L. Longitudinal samples were analyzed from C-peptide-positive subjects with diabetes after 1, 2, and 4 years. RESULTS: Of individuals with long-standing type 1 diabetes, 95.9% had detectable serum proinsulin (>3.1 pmol/L), while 89.9% of participants with stimulated C-peptide values below the limit of detection (<0.017 nmol/L; n = 99) had measurable proinsulin. Proinsulin levels remained stable over 4 years of follow-up, while C-peptide decreased slowly during longitudinal analysis. Correlations between proinsulin with C-peptide and mixed-meal stimulation of proinsulin were found only in subjects with high stimulated C-peptide values (≥0.2 nmol/L). Specifically, increases in proinsulin with mixed-meal stimulation were present only in the group with high stimulated C-peptide values, with no increases observed among subjects with low or undetectable (<0.017 nmol/L) residual C-peptide. CONCLUSIONS: In individuals with long-duration type 1 diabetes, the ability to secrete proinsulin persists, even in those with undetectable serum C-peptide

Mutational and copy number asset of primary sporadic neuroendocrine tumors of the small intestine

Small intestine neuroendocrine tumors (SI-NETs) represent the most common histotype among small intestine neoplasms, and metastatic disease is usually present at diagnosis. A retrospective series of 52 sporadic primary surgically resected SI-NETs, which were metastatic at diagnosis, was analyzed by high-coverage target sequencing (HCTS) for the mutational status of 57 genes and copy number status of 40 genes selected from recently published genome sequencing data. Seven genes were found to be recurrently mutated: CDKN1B (9.6%), APC and CDKN2C (each 7.7%), BRAF, KRAS, PIK3CA, and TP53 (each 3.8%). Copy number analysis showed frequent allelic loss of 4 genes located on chromosome 18 (BCL2, CDH19, DCC, and SMAD4) in 23/52 (44.2%) and losses on chromosomes 11 (38%) and 16 (15%). Other recurrent copy number variations were gains for genes located on chromosomes 4 (31%), 5 (27%), 14 (36%), and 20 (20%). Univariate survival analysis showed that SRC gene copy number gains were associated with a poorer prognosis (p = 0.047). Recurrent copy number variations are important events in SI-NET and SRC may represent a novel prognostic biomarker for this tumor type

The coronary CT angiography vision protocol : a prospective observational imaging cohort study in patients undergoing non-cardiac surgery

INTRODUCTION: At present, physicians have a limited ability to predict major cardiovascular complications after non-cardiac surgery and little is known about the anatomy of coronary arteries associated with perioperative myocardial infarction. We have initiated the Coronary CT Angiography (CTA) VISION Study to (1) establish the predictive value of coronary CTA for perioperative myocardial infarction and death and (2) describe the coronary anatomy of patients that have a perioperative myocardial infarction. METHODS AND ANALYSIS: The Coronary CTA VISION Study is prospective observational study. Preoperative coronary CTA will be performed in 1000–1500 patients with a history of vascular disease or at least three cardiovascular risk factors who are undergoing major elective non-cardiac surgery. Serial troponin will be measured 6–12 h after surgery and daily for the first 3 days after surgery. Major vascular outcomes at 30 days and 1 year after surgery will be independently adjudicated. ETHICS AND DISSEMINATION: Coronary CTA results in a measurable radiation exposure that is similar to a nuclear perfusion scan (10–12 mSV). Treating physicians will be blinded to the CTA results until 30 days after surgery in order to provide the most unbiased assessment of its prognostic capabilities. The only exception will be the presence of a left main stenosis >50%. This approach is supported by best available current evidence that, excluding left main disease, prophylatic revascularisation prior to non-cardiac surgery does not improve outcomes. An external safety and monitoring committee is overseeing the study and will review outcome data at regular intervals. Publications describing the results of the study will be submitted to major peer-reviewed journals and presented at international medical conferences

Deoxyhypusine synthase, an essential enzyme for hypusine biosynthesis, is required for proper exocrine pancreas development

Pancreatic diseases including diabetes and exocrine insufficiency would benefit from therapies that reverse cellular loss and/or restore cellular mass. The identification of molecular pathways that influence cellular growth is therefore critical for future therapeutic generation. Deoxyhypusine synthase (DHPS) is an enzyme that post-translationally modifies and activates the mRNA translation factor eukaryotic initiation factor 5A (eIF5A). Previous work demonstrated that the inhibition of DHPS impairs zebrafish exocrine pancreas development; however, the link between DHPS, eIF5A, and regulation of pancreatic organogenesis remains unknown. Herein we identified that the conditional deletion of either Dhps or Eif5a in the murine pancreas results in the absence of acinar cells. Because DHPS catalyzes the activation of eIF5A, we evaluated and uncovered a defect in mRNA translation concomitant with defective production of proteins that influence cellular development. Our studies reveal a heretofore unappreciated role for DHPS and eIF5A in the synthesis of proteins required for cellular development and function

Lung neuroendocrine tumours: deep sequencing of the four World Health Organization histotypes reveals chromatin-remodelling genes as major players and a prognostic role for TERT, RB1, MEN1 and KMT2D

Next-generation sequencing (NGS) was applied to 148 lung neuroendocrine tumours (LNETs) comprising the four World Health Organization classification categories: 53 typical carcinoid (TCs), 35 atypical carcinoid (ACs), 27 large-cell neuroendocrine carcinomas, and 33 small-cell lung carcinomas. A discovery screen was conducted on 46 samples by the use of whole-exome sequencing and high-coverage targeted sequencing of 418 genes. Eighty-eight recurrently mutated genes from both the discovery screen and current literature were verified in the 46 cases of the discovery screen, and validated on additional 102 LNETs by targeted NGS; their prevalence was then evaluated on the whole series. Thirteen of these 88 genes were also evaluated for copy number alterations (CNAs). Carcinoids and carcinomas shared most of the altered genes but with different prevalence rates. When mutations and copy number changes were combined, MEN1 alterations were almost exclusive to carcinoids, whereas alterations of TP53 and RB1 cell cycle regulation genes and PI3K/AKT/mTOR pathway genes were significantly enriched in carcinomas. Conversely, mutations in chromatin-remodelling genes, including those encoding histone modifiers and members of SWI\u2013SNF complexes, were found at similar rates in carcinoids (45.5%) and carcinomas (55.0%), suggesting a major role in LNET pathogenesis. One AC and one TC showed a hypermutated profile associated with a POLQ damaging mutation. There were fewer CNAs in carcinoids than in carcinomas; however ACs showed a hybrid pattern, whereby gains of TERT, SDHA, RICTOR, PIK3CA, MYCL and SRC were found at rates similar to those in carcinomas, whereas the MEN1 loss rate mirrored that of TCs. Multivariate survival analysis revealed RB1 mutation (p = 0.0005) and TERT copy gain (p = 0.016) as independent predictors of poorer prognosis. MEN1 mutation was associated with poor prognosis in AC (p = 0.0045), whereas KMT2D mutation correlated with longer survival in SCLC (p = 0.0022). In conclusion, molecular profiling may complement histology for better diagnostic definition and prognostic stratification of LNETs. \ua9 2016 The Authors. The Journal of Pathology published by John Wiley &amp; Sons Ltd on behalf of Pathological Society of Great Britain and Ireland