Novel Use of a Social-Media-Based Survey to Detect Regional Differences in Management of Monochorionic-Diamniotic Twins.

ObjectiveThis study aims to evaluate the utility of social media to distribute a patient survey on differences in management and outcomes of monochorionic-diamniotic (MCDA) pregnancies.Study designA cross-sectional survey was posted to an English-language MCDA twins patient-centered support group within the social media site, Facebook from April 2, 2018 to June 26, 2018. Subjects were recruited through a technique called "snowballing," whereby individuals shared the survey to assist with recruiting. Patient reported data were analyzed using Chi-square and Kruskal-Wallis's tests to explore characteristics associated with surveillance and outcomes as related to region and provider type.ResultsOver 3 months, the post "reached" 14,288 Facebook users, among which 5,653 (40%) clicked on the post. A total of 2,357 respondents with MCDA pregnancies completed the survey. Total 1,928 (82%) were from the United States (US) and 419 (18%) from other countries. Total 85% of patients had co-management with maternal-fetal medicine (MFM), more in the US compared with the rest of the world (87 vs. 74%, p < 0.01). MFM involvement led to increased adherence to biweekly ultrasounds (91 vs. 65%, p < 0.01), diagnosis of monochorionicity by 12 weeks (74 vs. 69%, p < 0.01) and better education about twin-twin transfusion syndrome (90 vs. 66%, p < 0.01). Pregnancies with MFM involvement had a higher take-home baby rate for both babies (92 vs. 89%, p < 0.01) or for at least one baby (98 vs. 93%, p < 0.01) compared with those without MFM involvement.ConclusionA survey distributed via social media can be effective in evaluating real-life management and outcomes of an uncommon obstetrical diagnosis. This survey elucidates wide international variation in adherence to guidelines, management, and outcomes

Decoupling of evolutionary changes in transcription factor binding and gene expression in mammals

To understand the evolutionary dynamics between transcription factor (TF) binding and gene expression in mammals, we compared transcriptional output and the binding intensities for three tissue-specific TFs in livers from four closely related mouse species. For each transcription factor, TF-dependent genes and the TF binding sites most likely to influence mRNA expression were identified by comparing mRNA expression levels between wild-type and TF knockout mice. Independent evolution was observed genome-wide between the rate of change in TF binding and the rate of change in mRNA expression across taxa, with the exception of a small number of TF-dependent genes. We also found that binding intensities are preferentially conserved near genes whose expression is dependent on the TF, and the conservation is shared among binding peaks in close proximity to each other near the TSS. Expression of TF-dependent genes typically showed an increased sensitivity to changes in binding levels as measured by mRNA abundance. Taken together, these results highlight a significant tolerance to evolutionary changes in TF binding intensity in mammalian transcriptional networks and suggest that some TF-dependent genes may be largely regulated by a single TF across evolution

Chinese family with diffuse oesophageal leiomyomatosis: A new COL4A5/COL4A6 deletion and a case of gonosomal mosaicism

© 2015 Liu et al. Background: Diffuse oesophageal leiomyomatosis (DOL) is a rare disorder characterized by tumorous overgrowth of the muscular wall of the oesophagus. DOL is present in 5 % of Alport syndrome (AS) patients. AS is a rare hereditary disease that involves varying degrees of hearing impairment, ocular changes and progressive glomerulonephritis leading to renal failure. In DOL-AS patients, the genetic defect consists of a deletion involving the COL4A5 and COL4A6 genes on the X chromosome. Case presentation: We report a two-generation family (4 individuals; parents and two children, one male and one female) with two members (mother and son) affected with oesophageal leiomyomatosis. Signs of potential renal failure, which characterizes AS, were only apparent in the index patient (son) 2 years and three months after the initial diagnosis of DOL. Blood DNA from the four family members were submitted to exome sequencing and array genotyping to perform a genome wide screening for disease causal single nucleotide (SN) and copy number (CN) variations. Analyses revealed a new 40kb deletion encompassing from intron 2 of COL4A5 to intron 1 of COL4A6 at Xq22.3. The breakpoints were also identified. Possible confounding pathogenic exonic variants in genes known to be involved in other extracellular matrices disorders were also shared by the two affected individuals. Meticulous analysis of the maternal DNA revealed a case of gonosomal mosaicism. Conclusions: This is the first report of gonadosomal mosaicism associated to DOL-AS.published_or_final_versio

Glycolytic requirement for NK cell cytotoxicity and cytomegalovirus control

NK cell activation has been shown to be metabolically regulated in vitro; however, the role of metabolism during in vivo NK cell responses to infection is unknown. We examined the role of glycolysis in NK cell function during murine cytomegalovirus (MCMV) infection and the ability of IL-15 to prime NK cells during CMV infection. The glucose metabolism inhibitor 2-deoxy-ᴅ-glucose (2DG) impaired both mouse and human NK cell cytotoxicity following priming in vitro. Similarly, MCMV-infected mice treated with 2DG had impaired clearance of NK-specific targets in vivo, which was associated with higher viral burden and susceptibility to infection on the C57BL/6 background. IL-15 priming is known to alter NK cell metabolism and metabolic requirements for activation. Treatment with the IL-15 superagonist ALT-803 rescued mice from otherwise lethal infection in an NK-dependent manner. Consistent with this, treatment of a patient with ALT-803 for recurrent CMV reactivation after hematopoietic cell transplant was associated with clearance of viremia. These studies demonstrate that NK cell-mediated control of viral infection requires glucose metabolism and that IL-15 treatment in vivo can reduce this requirement and may be effective as an antiviral therapy

Outcomes of primary care delivery by nurse practitioners: Utilization, cost, and quality of care

ObjectiveTo examine whether nurse practitioner (NP)- assigned patients exhibited differences in utilization, costs, and clinical outcomes compared to medical doctor (MD)- assigned patients.Data SourcesVeterans Affairs (VA) administrative data capturing characteristics, outcomes, and provider assignments of 806 434 VA patients assigned to an MD primary care provider (PCP) who left VA practice between 2010 and 2012.Study DesignWe applied a difference- in- difference approach comparing outcomes between patients reassigned to MD and NP PCPs, respectively. We examined measures of outpatient (primary care, specialty care, and mental health) and inpatient (total and ambulatory care sensitive hospitalizations) utilization, costs (outpatient, inpatient and total), and clinical outcomes (control of hemoglobin A1c, LDL, and blood pressure) in the year following reassignment.Principal FindingsCompared to MD- assigned patients, NP- assigned patients were less likely to use primary care and specialty care services and incurred fewer total and ambulatory care sensitive hospitalizations. Differences in costs, clinical outcomes, and receipt of diagnostic tests between groups were not statistically significant.ConclusionsPatients reassigned to NPs experienced similar outcomes and incurred less utilization at comparable cost relative to MD patients. NPs may offer a cost- effective approach to addressing anticipated shortages of primary care physicians.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154625/1/hesr13246_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/154625/2/hesr13246-sup-0001-Authormatrix.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/154625/3/hesr13246.pd

Mutational Analysis of the Nitrogenase Carbon Monoxide Protective Protein CowN Reveals That a Conserved C‑Terminal Glutamic Acid Residue Is Necessary for Its Activity

Nitrogenase is the only enzyme that catalyzes the reduction of nitrogen gas into ammonia. Nitrogenase is tightly inhibited by the environmental gas carbon monoxide (CO). Many nitrogen fixing bacteria protect nitrogenase from CO inhibition using the protective protein CowN. This work demonstrates that a conserved glutamic acid residue near the C-terminus of Gluconacetobacter diazotrophicus CowN is necessary for its function. Mutation of the glutamic acid residue abolishes both CowN’s protection against CO inhibition and the ability of CowN to bind to nitrogenase. In contrast, a conserved C-terminal cysteine residue is not important for CO protection by CowN. Overall, this work uncovers structural features in CowN that are required for its function and provides new insights into its nitrogenase binding and CO protection mechanism

Comparable, but distinct: Perceptions of primary care provided by physicians and nurse practitioners in full and restricted practice authority states

AimsTo understand patients- and providers- perceptions of primary care delivered by nurse practitioners (NPs) in the Veterans Affairs Healthcare System.DesignQualitative exploratory study (in convergent mixed- methods design).MethodsSemi- structured interviews in 2016 with primary care providers and patients from facilities in states with full and restricted practice authority for NPs. Patient sample based on reassignment to: (a) a NP; or (b) a different physician following an established physician relationship. Data were analysed using content analysis.ResultsWe interviewed 28 patients, 17 physicians and 14 NPs. We found: (a) NPs provided more holistic care than physicians; (b) patients were satisfied with NPs; and (c) providers- professional experience outweighed provider type.ConclusionsPatients- preferences for NPs (compared with prior physicians) contributed to perceptions of patient centredness. Similarities in providers- perceptions suggest NPs and physicians are both viable providers for primary care.ImpactNurse Practitioners (NPs): practice authorityVeterans Affairs Health care: nurse practitioners will continue to be a viable resource for primary care deliveryUnited States Health care: challenges notions patients may not be satisfied with care provided by NPs and supports expanding their use to provide much- needed access to primary care services; expanding Full Practice Authority would allow states to provide acceptable primary care without diminishing patient or provider experiencesæ è¦ ç ®æ  äº è§£æ £è å å »ç æ ºæ 对é ä¼ å äººå »ç ä¿ å ¥ç³»ç» ä¸­æ ¤ç å¸ æ ä¾ å çº§æ ¤ç ç ç æ³ ã è®¾è®¡æ ¢ç´¢æ §ç å® æ §ç  ç©¶(æ ¶æ æ··å æ ¹æ³ è®¾è®¡)ã æ ¹æ³ 2016å¹´è¿ è¡ ç å ç» æ å è®¿è° ,é è®¿äº å· å æ ¥æ æ ¤ç å¸ ç å ¨ç§ å é å ¨ç§ æ §ä¸ æ ºæ ç å çº§æ ¤ç æ ä¾ è å æ £è ã é æ °å é æ £è æ ·æ ¬:(a) ä¸ å æ ¤ç å¸ ;æ (b)ç¡®ç« å »ç å ³ç³»ç å ¦ä¸ å å »ç ã é ç ¨å 容å æ æ³ å¯¹æ °æ ®è¿ è¡ å æ ã ç» æ æ 们é è®¿äº 28å æ £è ,17å å »ç å 14å æ ¤ç å¸ ã æ 们å ç °:(a)æ ¤ç å¸ æ¯ å »ç æ ä¾ ç æ ¤ç æ ´å ¨é ¢;(b)æ £è å¯¹æ ¤ç å¸ æ å °æ»¡æ ;(c)å »ç æ ºæ ç ä¸ ä¸ ç» éª ç æ é æ¯ å »ç æ ºæ ç±»å ç æ é æ ´å¤§ã ç» è®ºæ £è å¯¹æ ¤ç å¸ ç å 好(ä¸ ä»¥å ç å »ç ç ¸æ¯ )æ å ©äº å»ºç« ä»¥æ £è ä¸ºä¸­å¿ ç è®¤ç ¥ã æ ä¾ è ç è§ å¿µç±»ä¼¼,表æ æ ¤ç å¸ å å »ç é ½æ ¯å ¯è¡ ç å çº§æ ¤ç æ ä¾ è ã å½±å - ¢æ ¤ç å¸ :æ §ä¸ æ ºæ - ¢é ä¼ å äººå »ç ä¿ å ¥ç³»ç» :æ ¤ç å¸ å° ç»§ç»­ä½ ä¸ºæ ä¾ å çº§æ ¤ç æ å ¡ç å ¯ç ¨èµ æº ã - ¢ç¾ å ½å «ç ä¿ å ¥:æ æ è§ å¿µ æ £è å ¯è ½ä¸ æ»¡æ ç ±æ ¤ç å¸ æ ä¾ ç æ ¤ç ,å ¶ä¼ æ ¯æ æ ©å¤§ä½¿ç ¨è å ´,以æ ä¾ æ ¥é ç å çº§ä¿ å ¥æ å ¡;æ ©å¤§å ¨ç§ æ §ä¸ æ ºæ å° ä½¿å å· è ½å¤ æ ä¾ å ¯æ ¥å ç å çº§ä¿ å ¥æ å ¡,è ä¸ ä¼ å å¼±æ £è æ æ ä¾ è ç ä½ éª ãPeer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/163369/2/jan14501.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/163369/1/jan14501_am.pd

Toll-Like Receptor 2 Signaling Protects Mice from Tumor Development in a Mouse Model of Colitis-Induced Cancer

Inflammatory bowel disease (IBD) is a disorder of chronic inflammation with increased susceptibility to colorectal cancer. The etiology of IBD is unclear but thought to result from a dysregulated adaptive and innate immune response to microbial products in a genetically susceptible host. Toll-like receptor (TLR) signaling induced by intestinal commensal bacteria plays a crucial role in maintaining intestinal homeostasis, innate immunity and the enhancement of intestinal epithelial cell (IEC) integrity. However, the role of TLR2 in the development of colorectal cancer has not been studied. We utilized the AOM-DSS model for colitis-associated colorectal cancer (CAC) in wild type (WT) and TLR2−/− mice. Colons harvested from WT and TLR2−/− mice were used for histopathology, immunohistochemistry, immunofluorescence and cytokine analysis. Mice deficient in TLR2 developed significantly more and larger colorectal tumors than their WT controls. We provide evidence that colonic epithelium of TLR2−/− mice have altered immune responses and dysregulated proliferation under steady-state conditions and during colitis, which lead to inflammatory growth signals and predisposition to accelerated neoplastic growth. At the earliest time-points assessed, TLR2−/− colons exhibited a significant increase in aberrant crypt foci (ACF), resulting in tumors that developed earlier and grew larger. In addition, the intestinal microenvironment revealed significantly higher levels of IL-6 and IL-17A concomitant with increased phospho-STAT3 within ACF. These observations indicate that in colitis, TLR2 plays a protective role against the development of CAC

MHCII-mediated dialog between group 2 innate lymphoid cells and CD4+ T cells potentiates type 2 immunity and promotes parasitic helminth expulsion

Group 2 innate lymphoid cells (ILC2s) release interleukin-13 (IL-13) during protective immunity to helminth infection and detrimentally during allergy and asthma. Using two mouse models to deplete ILC2s in vivo, we demonstrate that T helper 2 (Th2) cell responses are impaired in the absence of ILC2s. We show that MHCII-expressing ILC2s interact with antigen-specific T cells to instigate a dialog in which IL-2 production from T cells promotes ILC2 proliferation and IL-13 production. Deletion of MHCII renders IL-13-expressing ILC2s incapable of efficiently inducing Nippostrongylus brasiliensis expulsion. Thus, during transition to adaptive T cell-mediated immunity, the ILC2 and T cell crosstalk contributes to their mutual maintenance, expansion and cytokine production. This interaction appears to augment dendritic-cell-induced T cell activation and identifies a previously unappreciated pathway in the regulation of type-2 immunity