Citations

We present an overview of strategies our institution has taken to understand the state of its inpatient diabetes management. We first describe how we utilized information systems to assess inpatient glycemic control and insulin management in noncritically ill patients and discuss our findings regarding mean bedside glucose levels, the prevalence and frequency hypoglycemic and hyperglycemic events, the patterns of insulin therapy, and evidence of inpatient clinical inertia. We also review the development of a survey to determine practitioner attitudes and beliefs about inpatient diabetes. Results of this survey study found that, in general, practitioners believed in the importance of controlling hyperglycemia but were not comfortable with many aspects of inpatient diabetes care, particularly with the use of insulin. Finally, we suggest steps to follow in developing a quality-improvement program for hospitals.

Abstract A missense single-nucleotide polymorphism (SNP) in the immune modulatory gene IL1A has been associated with ovarian cancer risk (rs17561). Although the exact mechanism through which this SNP alters risk of ovarian cancer is not clearly understood, rs17561 has also been associated with risk of endometriosis, an epidemiologic risk factor for ovarian cancer. Interleukin-1α (IL1A) is both regulated by and able to activate NF-κB, a transcription factor family that induces transcription of many proinflammatory genes and may be an important mediator in carcinogenesis. We therefore tagged SNPs in more than 200 genes in the NF-κB pathway for a total of 2,282 SNPs (including rs17561) for genotype analysis of 15,604 cases of ovarian cancer in patients of European descent, including 6,179 of high-grade serous (HGS), 2,100 endometrioid, 1,591 mucinous, 1,034 clear cell, and 1,016 low-grade serous, including 23,235 control cases spanning 40 studies in the Ovarian Cancer Association Consortium. In this large population, we confirmed the association between rs17561 and clear cell ovarian cancer [OR, 0.84; 95% confidence interval (CI), 0.76–0.93; P = 0.00075], which remained intact even after excluding participants in the prior study (OR, 0.85; 95% CI, 0.75–0.95; P = 0.006). Considering a multiple-testing–corrected significance threshold of P < 2.5 × 10−5, only one other variant, the TNFSF10 SNP rs6785617, was associated significantly with a risk of ovarian cancer (low malignant potential tumors OR, 0.85; 95% CI, 0.79–0.91; P = 0.00002). Our results extend the evidence that borderline tumors may have a distinct genetic etiology. Further investigation of how these SNPs might modify ovarian cancer associations with other inflammation-related risk factors is warranted. Cancer Res; 74(3); 852–61. ©2013 AACR.

Abstract Recently, the term monoclonal gammopathy of renal significance (MGRS) was introduced to distinguish monoclonal gammopathies that result in the development of kidney disease from those that are benign. By definition, patients with MGRS have B-cell clones that do not meet the definition of multiple myeloma or lymphoma. Nevertheless, these clones produce monoclonal proteins that are capable of injuring the kidney resulting in permanent damage. Except for immunoglobulin light chain amyloidosis with heart involvement in which death can be rapid, treatment of MGRS is often indicated more to preserve kidney function and prevent recurrence after kidney transplantation rather than the prolongation of life. Clinical trials are rare for MGRS-related kidney diseases, except in immunoglobulin light chain amyloidosis. Treatment recommendations are therefore based on the clinical data obtained from treatment of the clonal disorder in its malignant state. The establishment of these treatment recommendations is important until data can be obtained by clinical trials of MGRS-related kidney diseases.

Transforming growth factor β (TGFβ) has significant profibrotic activity both in vitro and in vivo . This reflects its capacity to stimulate fibrogenic mediators and induce the expression of other profibrotic cytokines such as platelet‐derived growth factor (PDGF) and epidermal growth factor (EGF/ErbB) ligands. Here we address both the mechanisms by which TGFβ induced ErbB ligands and the physiological significance of inhibiting multiple TGFβ‐regulated processes. The data document that ErbB ligand induction requires PDGF receptor (PDGFR) mediation and engages a positive autocrine/paracrine feedback loop via ErbB receptors. Whereas PDGFRs are essential for TGFβ‐stimulated ErbB ligand up‐regulation, TGFβ‐specific signals are also required for ErbB receptor activation. Subsequent profibrotic responses are shown to involve the cooperative action of PDGF and ErbB signaling. Moreover, using a murine treatment model of bleomycin‐induced pulmonary fibrosis we found that inhibition of TGFβ/PDGF and ErbB pathways with imatinib plus lapatinib, respectively, not only prevented myofibroblast gene expression to a greater extent than either drug alone, but also essentially stabilized gas exchange (oxygen saturation) as an overall measure of lung function. These observations provide important mechanistic insights into profibrotic TGFβ signaling and indicate that targeting multiple cytokines represents a possible strategy to ameliorate organ fibrosis dependent on TGFβ.—Andrianifahanana, M., Wilkes, M. C., Gupta, S. K., Rahimi, R. R., Repellin, C. E., Edens, M., Wittenberger, J., Yin, X., Maidl, E., Becker, J., Leof, E. B. Profibrotic TGFβ responses require the cooperative action of PDGF and ErbB receptor tyrosine kinases. FASEB J . 27, 4444‐4454 (2013). www.fasebj.org

Summary Purpose To review the efficacy and tolerability of stiripentol in the treatment of U . S . children with D ravet syndrome. Methods U . S . clinicians who had prescribed stiripentol for two or more children with D ravet syndrome between March 2005 and 2012 were contacted to request participation in this retrospective study. Data collected included overall seizure frequency, frequency of prolonged seizures, and use of rescue medications and emergency room ( ER )/hospital visits in the year preceding stiripentol initiation, and with stiripentol therapy. We separately assessed efficacy in the following treatment groups: g roup A , stiripentol without clobazam or valproate; g roup B , stiripentol with clobazam but without valproate; g roup C , stiripentol with valproate but without clobazam; and g roup D , stiripentol with clobazam and valproate. In addition, adverse effects were recorded. Key Findings Thirteen of 16 clinicians contacted for study participated and provided data on 82 children. Stiripentol was initiated a median of 6.0 years after seizure onset and 1.2 years after diagnosis of D ravet syndrome. Compared to baseline, overall seizure frequency was reduced in 2/6 in g roup A , 28/35 in g roup B , 8/14 in g roup C , and 30/48 in g roup D . All children with prolonged seizure frequency greater than quarterly during the baseline period experienced a reduction in this frequency on the various treatment arms with stiripentol. Similarly, 2/4 patients in g roup A , 25/25 in g roup B , 5/10 in g roup C , and 26/33 in g roup D experienced reduction in frequency of rescue medication use and 1/1 in g roup A , 12/12 in g roup B , 3/5 in g roup C , and 18/19 in group D had reduction in frequency of ER /hospital visits. Adverse effects were reported in 38, most commonly sedation and reduced appetite. Four patients (5%) discontinued stiripentol for adverse effects and two (2%) for lack of efficacy. Significance Stiripentol is an effective and well‐tolerated therapy that markedly reduced frequency of prolonged seizures in D ravet syndrome.

ABSTRACTBACKGROUNDProstate cancer (PCa) and smoking‐related morbidity disproportionately burdens African American (AA) men. Smoking is associated with high‐grade PCa and incidence, but few studies have focused on AA men. This study aims to determine the effect of tobacco‐use on odds of PCa and of high‐grade PCa in a population of predominantly AA men.METHODSThis is a cross‐sectional study evaluating smoking and PCa status in men with incident PCa and screened healthy controls. Altogether, 1,085 men (527 cases and 558 controls), age ≥ 40 years were enrolled through outpatient urology clinics in two US cities from 2001 to 2012. Validated questionnaires were used to gather clinical and socioeconomic data.RESULTSThe cases and controls were predominantly AA (79.9% and 71.3%, respectively, P = 0.01). AA men smoked more frequently (53.4% vs. 47.9%, P < 0.001) and quit less frequently than European American (EA) men (31.5% vs. 40.4%, P = 0.01). AA heavy smokers had increased odds of PCa diagnosis (OR 2.57, 95% CI 1.09, 6.10) and high‐grade cancer (OR 1.89, 95% CI 1.03, 3.48) relative to never smokers and light smokers. Among AAs, heavy smokers had lower odds of being in the low risk stratification in the National Comprehensive Cancer Network guidelines. AA former smokers had a trend for increased odds of high‐grade cancer compared to never smokers. The associations between smokings, cancer diagnosis and cancer grade did not reach statistical significance in EA men.CONCLUSIONWe found ethnic differences in smoking behavior. Heavy smoking is associated with increased odds of PCa and of higher Gleason grade in AA men. Prostate 73: 1518–1528, 2013. © 2013 Wiley Periodicals, Inc.

BackgroundBreast and pelvic examinations are challenging intimate examinations. Technology‐based simulation may help to overcome these challenges.ObjectiveTo synthesise the evidence regarding the effectiveness of technology‐based simulation training for breast and pelvic examination.Search strategyOur systematic search included MEDLINE, EMBASE, CINAHL, PsychINFO, Scopus, and key journals and review articles; the date of the last search was January 2012.Selection criteriaOriginal research studies evaluating technology‐enhanced simulation of breast and pelvic examination to teach learners, compared with no intervention or with other educational activities.Data collection and analysisThe reviewers evaluated study eligibility and abstracted data on methodological quality, learners, instructional design, and outcomes, and used random‐effects models to pool weighted effect sizes.Main resultsIn total, 11 272 articles were identified for screening, and 22 studies were eligible, enrolling 2036 trainees. In eight studies comparing simulation for breast examination training with no intervention, simulation was associated with a significant improvement in skill, with a pooled effect size of 0.86 (95% CI 0.52–1.19; P < 0.001). Four studies comparing simulation training for pelvic examination with no intervention had a large and significant benefit, with a pooled effect size of 1.18 (95% CI 0.40–1.96; P = 0.003). Among breast examination simulation studies, dynamic models providing feedback were associated with improved outcomes. In pelvic examination simulation studies, the addition of a standardised patient to the simulation model and the use of an electronic model with enhanced feedback improved outcomes.Author's conclusionsIn comparison with no intervention, breast and pelvic examination simulation training is associated with moderate to large effects for skills outcomes. Enhanced feedback appears to improve learning.

Abstract Aims Left ventricular assist devices (LVADs) are implanted to support the circulation of patients with advanced heart failure. Patients approaching death, or their surrogates, may request withdrawal of LVAD support. We sought to study the attitudes and practices of heart failure clinicians regarding withdrawal of LVAD support in patients approaching death. Methods and results Using internet-based and secure methods, we surveyed members of the European Society of Cardiology-Heart Failure Association (ESC-HFA), the International Society for Heart and Lung Transplantation (ISHLT), and the Heart Failure Society of America (HFSA) to assess their attitudes and practices regarding LVAD withdrawal for patients approaching death. The results indicated that clinicians have varied attitudes and practices regarding withdrawing LVAD support in these patients. Furthermore, ESC-HFA clinicians (primarily European) and ISHLT and HFSA clinicians (primarily North American) differed in their attitudes and practices regarding withdrawal of LVAD support, particularly its ethical and legal permissibility. For example, more European clinicians than North American clinicians regarded withdrawing LVAD support as a form of euthanasia. Conclusion Opinions and level of comfort with LVAD withdrawal vary among clinicians. Clinicians should be aware of suggested approaches or guidelines for managing requests for withdrawal of LVAD therapy.