Fibulin-4 is essential for maintaining arterial wall integrity in conduit but not muscular arteries

Homozygous or compound heterozygous mutations in fibulin-4 (FBLN4) lead to autosomal recessive cutis laxa type 1B (ARCL1B), a multisystem disorder characterized by significant cardiovascular abnormalities, including abnormal elastin assembly, arterial tortuosity, and aortic aneurysms. We sought to determine the consequences of a human disease-causing mutation in FBLN4 (E57K) on the cardiovascular system and vascular elastic fibers in a mouse model of ARCL1B. Fbln4E57K/E57K mice were hypertensive and developed arterial elongation, tortuosity, and ascending aortic aneurysms. Smooth muscle cell organization within the arterial wall of large conducting vessels was abnormal, and elastic fibers were fragmented and had a moth-eaten appearance. In contrast, vessel wall structure and elastic fiber integrity were normal in resistance/muscular arteries (renal, mesenteric, and saphenous). Elastin cross-linking and total elastin content were unchanged in large or small arteries, whereas elastic fiber architecture was abnormal in large vessels. While the E57K mutation did not affect Fbln4 mRNA levels, FBLN4 protein was lower in the ascending aorta of mutant animals compared to wild-type arteries but equivalent in mesenteric arteries. We found a differential role of FBLN4 in elastic fiber assembly, where it functions mainly in large conduit arteries. These results suggest that elastin assembly has different requirements depending on vessel type. Normal levels of elastin cross-links in mutant tissue call into question FBLN4\u27s suggested role in mediating lysyl oxidase-elastin interactions. Future studies investigating tissuespecific elastic fiber assembly may lead to novel therapeutic interventions for ARCL1B and other disorders of elastic fiber assembly. 2017 © The Authors, some rights reserved

Metformin treatment in heart failure with preserved ejection fraction: a systematic review and meta-regression analysis

Background: Observational series suggest a mortality benefit from metformin in the heart failure (HF) population. However, the benefit of metformin in HF with preserved ejection fraction (HFpEF) has yet to be explored. We performed a systematic review and meta-analysis to identify whether variation in EF impacts mortality outcomes in HF patients treated with metformin. Methods: MEDLINE and EMBASE were searched up to October 2019. Observational studies and randomised trials reporting mortality in HF patients and the proportion of patients with an EF > 50% at baseline were included. Other baseline variables were used to assess for heterogeneity in treatment outcomes between groups. Regression models were used to determine the interaction between metformin and subgroups on mortality. Results: Four studies reported the proportion of patients with a preserved EF and were analysed. Metformin reduced mortality in both preserved or reduced EF after adjustment with HF therapies such as angiotensin converting enzyme inhibitors (ACEi) and beta-blockers (β = - 0.2 [95% CI - 0.3 to - 0.1], p = 0.02). Significantly greater protective effects were seen with EF > 50% (p = 0.003). Metformin treatment with insulin, ACEi and beta-blocker therapy were also shown to have a reduction in mortality (insulin p = 0.002; ACEi p p = 0.017), whereas female gender was associated with worse outcomes (p Conclusions: Metformin treatment is associated with a reduction in mortality in patients with HFpEF

A PGD-based multiscale formulation for non-linear solid mechanics under small deformations

Model reduction techniques have became an attractive and a promising field to be applied in multiscale methods. The main objective of this work is to formulate a multiscale procedure for non-linear problems based on parametrized microscale models. The novelty of this work relies in the implementation of the model reduction technique known as Proper Generalized Decomposition for solving the high dimensional parametrized problem resulting from the microscale model. The multiscale framework here proposed is formulated to non-linear problems, specifically to material non-linearities, where material response is governed by a strain dependent evolution law. Two strategies to deal with this kind of problem under small deformations are detailed in this work. Both strategies based on parametrized microscale models solved by PGD have been applied to a problem with a rate-dependent isotropic damage model. First, a procedure where the problem is solved by uncoupling the equilibrium equation to the state variable expression has been explored. In order, to alleviate the parametrized microscale problem, a second strategy for problems with material non-linearity has been proposed, incorporating a parametrized microscale problem at each macroscale increment (FE-PGD). The basis of those procedures are described and compared, highlighting the solution accuracy and computer time consumption in comparison to a traditional finite element analysis

Educational Intervention Improves Proton Pump Inhibitor Stewardship in Outpatient Gastroenterology Clinics

Background Improper chronic proton pump inhibitor (PPI) use has risen significantly in the last few decades. In our gastroenterology trainees’ clinics, we aimed to optimize PPI usage. Methods We collected baseline data on patients’ PPI use for 8 weeks. Based on gastroenterology society guidelines, we determined conditions for appropriate PPI use. If the indication could not be determined, it was categorized as “unknown”. Generated from the three most frequent causes for inappropriate PPI use, interventions were developed to correct each issue. Following a brief educational session, trainees implemented these interventions over a subsequent 8-week interval. Results During our pre-intervention period, trainees evaluated 263 patients who were prescribed a PPI. In 49% of the cases, the use of PPI was deemed inappropriate. The most common reasons were: gastroesophageal reflux disease (GERD) which was never titrated to the lowest effective dose, twice daily dosing for Barrett’s esophagus (BE) chemoprevention and unknown indication. During our intervention period, trainees evaluated 145 patients prescribed a PPI for GERD with well-controlled symptoms in 101 cases. PPI had not been titrated to lowest effective dose in 37 cases prompting intervention which was successful in 23 cases. PPI indication was unknown in 17 cases prompting a message to the prescribing provider to review appropriateness. Two cases of BE chemoprevention with twice daily dosing were appropriately reduced to daily dosing. Ultimately, after intervention, PPI use was deemed appropriate after intervention in 172 (77%) cases. Conclusions Improper chronic PPI use was significant. Focusing intervention efforts on PPI use for GERD, BE and unknown indications substantially increased appropriateness of PPI use

Defining adenoma detection rate benchmarks in average-risk male veterans

Background and Aims Veterans have higher prevalence of colorectal neoplasia than non-veterans; however, it is not known whether specific Veterans Affairs (VA) adenoma detection rate (ADR) benchmarks are required. We compared ADRs of a group of endoscopists for colonoscopies performed at a VA to their ADRs at a non-VA academic medical center. Methods This was a retrospective review of screening colonoscopies performed by endoscopists who practice at the Indianapolis VA and Indiana University (IU). Patients were average-risk males aged 50 years or older. ADR, proximal adenoma detection rate, advanced adenoma detection rate, and adenomas per colonoscopy were compared between IU and the VA groups. Results Six endoscopists performed screening colonoscopies at both locations during the study period (470 at IU vs 608 at the VA). The overall ADR was not significantly different between IU and the VA (58% vs 61%; p =0.21). Advanced neoplasia detection rate (13% vs 17%; p=0.46), proximal adenoma detection rate (46% vs 47%; p=0.31), and adenoma per colonoscopy (1.59 vs 1.84; p=0.24) were not significantly different. There were no significant differences in cecal intubation rate (100% vs 99%; p=0.13) or withdrawal time (10.9 vs 11.1 min; p=0.28). In regression analysis, there was significant correlation between the attending-specific ADRs at IU and the VA (p=0.041, r-square=0.69). Conclusions In this study of average-risk males undergoing screening colonoscopies by the same group of endoscopists, the ADRs of VA and non-VA colonoscopies were not significantly different. This suggests that a VA-specific ADR target is not required for endoscopists with high ADR

Understanding early organogenesis using a simplified in situ hybridization protocol in Xenopus

Organogenesis is the study of how organs are specified and then acquire their specific shape and functions during development. The Xenopuslaevis embryo is very useful for studying organogenesis because their large size makes them very suitable for identifying organs at the earliest steps in organogenesis. At this time, the primary method used for identifying a specific organ or primordium is whole mount in situ hybridization with labeled antisense RNA probes specific to a gene that is expressed in the organ of interest. In addition, it is relatively easy to manipulate genes or signaling pathways in Xenopus and in situ hybridization allows one to then assay for changes in the presence or morphology of a target organ. Whole mount in situ hybridization is a multi-day protocol with many steps involved. Here we provide a simplified protocol with reduced numbers of steps and reagents used that works well for routine assays. In situ hybridization robots have greatly facilitated the process and we detail how and when we utilize that technology in the process. Once an in situ hybridization is complete, capturing the best image of the result can be frustrating. We provide advice on how to optimize imaging of in situ hybridization results. Although the protocol describes assessing organogenesis in Xenopus laevis, the same basic protocol can almost certainly be adapted to Xenopus tropicalis and other model systems

Challenges and Opportunities to Updating Prescribing Information for Longstanding Oncology Drugs.

A number of important drugs used to treat cancer-many of which serve as the backbone of modern chemotherapy regimens-have outdated prescribing information in their drug labeling. The Food and Drug Administration is undertaking a pilot project to develop a process and criteria for updating prescribing information for longstanding oncology drugs, based on the breadth of knowledge the cancer community has accumulated with the use of these drugs over time. This article highlights a number of considerations for labeling updates, including selecting priorities for updating; data sources and evidentiary criteria; as well as the risks, challenges, and opportunities for iterative review to ensure prescribing information for oncology drugs remains relevant to current clinical practice