tbuckley/cabot-search huggingface dataset:
B3GALNT2 mutations associated with non-syndromic autosomal recessive intellectual disability reveal a lack of genotype–phenotype associations in the muscular dystrophy-dystroglycanopathies
Authors: Reza Maroofian, Moniek Riemersma, Lucas T. Jae, Narges Zhianabed, Marjolein H. Willemsen, Willemijn M. Wissink-Lindhout, Michèl A. Willemsen, Arjan P. M. de Brouwer, Mohammad Yahya Vahidi Mehrjardi, Mahmoud Reza Ashrafi, Benno Kusters, Tjitske Kleefstra, Yalda Jamshidi, Mojila Nasseri, Rolph Pfundt, Thijn R. Brummelkamp, Mohammad Reza Abbaszadegan, Dirk J. Lefeber, Hans van Bokhoven
Journal: Genome Medicine (2017)

The phenotypic severity of congenital muscular dystrophy-dystroglycanopathy (MDDG) syndromes associated with aberrant glycosylation of α-dystroglycan ranges from the severe Walker-Warburg syndrome or muscle-eye-brain disease to mild, late-onset, isolated limb-girdle muscular dystrophy without neural involvement. However, muscular dystrophy is invariably found across the spectrum of MDDG patients. Using linkage mapping and whole-exome sequencing in two families with an unexplained neurodevelopmental disorder, we have identified homozygous and compound heterozygous mutations in B3GALNT2. The first family comprises two brothers of Dutch non-consanguineous parents presenting with mild ID and behavioral problems. Immunohistochemical analysis of muscle biopsy revealed no significant aberrations, in line with the absence of a muscular phenotype in the affected siblings. The second family includes five affected individuals from an Iranian consanguineous kindred with mild-to-moderate intellectual disability (ID) and epilepsy without any notable neuroimaging, muscle, or eye abnormalities. Complementation assays of the compound heterozygous mutations identified in the two brothers had a comparable effect on the O-glycosylation of α-dystroglycan as previously reported mutations that are associated with severe muscular phenotypes. In conclusion, we show that mutations in B3GALNT2 can give rise to a novel MDDG syndrome presentation, characterized by ID associated variably with seizure, but without any apparent muscular involvement. Importantly, B3GALNT2 activity does not fully correlate with the severity of the phenotype as assessed by the complementation assay.
Encapsulated Optically Responsive Cell Systems: Toward Smart Implants in Biomedicine
Authors: Christophe Boss, Nicolas Bouche, Umberto De Marchi
Journal: Advanced Healthcare Materials (2017)

Abstract Managing increasingly prevalent chronic diseases will require close continuous monitoring of patients. Cell‐based biosensors may be used for implantable diagnostic systems to monitor health status. Cells are indeed natural sensors in the body. Functional cellular systems can be maintained in the body for long‐term implantation using cell encapsulation technology. By taking advantage of recent progress in miniaturized optoelectronic systems, the genetic engineering of optically responsive cells may be combined with cell encapsulation to generate smart implantable cell‐based sensing systems. In biomedical research, cell‐based biosensors may be used to study cell signaling, therapeutic effects, and dosing of bioactive molecules in preclinical models. Today, a wide variety of genetically encoded fluorescent sensors have been developed for real‐time imaging of living cells. Here, recent developments in genetically encoded sensors, cell encapsulation, and ultrasmall optical systems are highlighted. The integration of these components in a new generation of biosensors is creating innovative smart in vivo cell‐based systems, bringing novel perspectives for biomedical research and ultimately allowing unique health monitoring applications.
Abstract MP12: Comparing Effectiveness of Mass Media Campaigns vs. Price Reductions Targeting Fruit and Vegetable Intake on US Cvd Mortality and Race Disparities
Authors: Jonathan Pearson-Stuttard, Piotr Bandosz, Colin D Rehm, Ashkan Afshin, Jose Penalvo, Laurie Whitsel, Goodarz Danaei, Thomas Gaziano, Helen Bromley, Ffion Lloyd-Williams, Dariush Mozaffarian, Simon Capewell, Martin O’Flaherty
Journal: Circulation (2016)

Introduction: Cardiovascular disease (CVD) accounts for over 800,000 US deaths annually, with substantial disparities by race. Poor diet is a leading CVD risk factor, including low intake of fruit and vegetable (F&amp;V). Few data exist regarding the potential population level impact and effect on race disparities of policies aimed at increasing F&amp;V intake. Aim: To estimate CVD mortality reductions, including by race, potentially achievable by price reduction and mass media campaign interventions in the US population up to 2030. Methods: We developed a US IMPACT Food Policy Model to compare three contrasting policies targeting F&amp;V intake: A - a national mass media campaign (MMC); B and C - a universal F&amp;V price reduction of 10 and 30% respectively. The MMC assumed unequal coverage by age, gender and race, and duration of either 1 or 15 years. Data sources included the National Vital Statistics System, SEER single year population estimates, the US Bureau 2012 National Population projections and NHANES. We used US population and CVD projections to 2030, F&amp;V mortality effect sizes and best evidence effect sizes for each policy. We modelled cumulative deaths prevented or postponed and life years gained (LYG) by age, gender, race and CVD subtype from 2015 to 2030. Results were tested in a probabilistic sensitivity analysis using Monte Carlo simulation. Results: Scenario A (MMC) could result in 27,000 (95% CI: 21,000-33,000) to 85,000 (83,000-89,000) fewer deaths dependent upon media campaign duration (from 1 to 15 years), gaining up to 1,280,000 LYGs (1,250,000-1,320,000) by 2030. Approximately 62% of deaths prevented would be CHD; and 53% would be in men, with 20% being saved in year 1. Scenario B (10% price decrease) could prevent approximately 90,000 deaths (71,000-114,000) and gain 1,450,000 LYGs (1,180,000-1,740,000) by 2030. Scenario C (30% price decrease) could prevent some 270,000 deaths (215,000-338,000) by 2030, representing a 3.9% reduction in expected CVD mortality. Price reduction policies would have equitable effects in non-hispanic whites vs. blacks. In comparison, a MMC would be ~ 35% less effective in preventing CVD deaths in non-Hispanic blacks. Conclusions: Price reduction policies (10 or 30%) and a nationwide MMC would each effectively reduce US CVD mortality. A 30% price reduction policy would save most lives and do so most equitably. Deaths prevented via a MMC might reduce substantially after year 1 and also increase disparities. These results inform potential fiscal and population level strategies to reduce CVD mortality in the US.
Genotypic and phenotypic <i>M. tuberculosis</i> resistance: guiding clinicians to prescribe the correct regimens
Authors: Andrea Maurizio Cabibbe, Giovanni Sotgiu, Santiago Izco, Giovanni Battista Migliori
Journal: European Respiratory Journal (2017)

Treating multidrug-resistant (MDR-) and extensively drug-resistant (XDR-) tuberculosis (TB) is a difficult task for any clinician: there are few therapeutic options, the treatment is very long (up to 2 years), complicated by frequent adverse events, and expensive [1, 2].-Recently, the debate in the scientific community has been focused on the role and contribution of the new (bedaquiline and delamanid) [3–7] and re-purposed anti-TB drugs (in particular, linezolid, clofazimine and carbapenems) [8–11]. Furthermore, the World Health Organization (WHO), in its 2016 revised MDR-TB guidelines, has recommended a 9–12 month "shorter regimen" for patients not previously exposed and with Mycobacterium tuberculosis (MTB) strains susceptible (or likely to be) to the drugs composing the regimen (with the exception of isoniazid) [12]. The regimen is composed of an initial 4–6-month phase of kanamycin, moxifloxacin, prothionamide, clofazimine, pyrazinamide, high dose isoniazid, and ethambutol followed by 5 months of moxifloxacin, clofazimine, pyrazinamide and ethambutol; it benefits from the use of isoniazid at high dose. Interpreting genotypic tests can help clinicians to take right and timely therapeutic decisions <http://ow.ly/jGHH30hcB6U> The authors wish to thank Lia D'Ambrosio and Rosella Centis for the editorial support in finalising the manuscript.
Data Resources for Conducting Health Services and Policy Research
Authors: Lynn A. Blewett, Kathleen Thiede Call, Joanna Turner, Robert Hest
Journal: Annual Review of Public Health (2017)

Rich federal data resources provide essential data inputs for monitoring the health and health care of the US population and are essential for conducting health services policy research. The six household surveys we document in this article cover a broad array of health topics, including health insurance coverage (American Community Survey, Current Population Survey), health conditions and behaviors (National Health Interview Survey, Behavioral Risk Factor Surveillance System), health care utilization and spending (Medical Expenditure Panel Survey), and longitudinal data on public program participation (SIPP). New federal activities are linking federal surveys with administrative data to reduce duplication and response burden. In the private sector, vendors are aggregating data from medical records and claims to enhance our understanding of treatment, quality, and outcomes of medical care. Federal agencies must continue to innovate to meet the continuous challenges of scarce resources, pressures for more granular data, and new multimode data collection methodologies.
Abstract 16480: Factors That Affect Activity Energy Expenditure of Fontan Patients
Authors: Akiko Yana
Journal: Circulation (2016)

Background:  There is a general trend favoring the recommendation of adequate exercise for Fontan patients. However, its effect on hemodynamics and safety have yet to be clarified. It is clearly very important to ascertain how the daily activity amount and activity intensity are associated with hemodynamics in Fontan patients.   Objectives:  This study aimed to measure activity energy expenditure (AEE) and activity intensity in Fontan patients and examine their associations with hemodynamics.   Method:  In total, 41 Fontan patients (3.5 to 42.3 years of age; mean, 9.6 years) were fitted with a high-accuracy portable accelerometer for 2 consecutive weeks and AEE was calculated and compared with the values of hemodynamics parameters obtained by cardiac catheterization.   Results:  AEE in Fontan patients was 237 ± 95 kcal/day, showing a negative correlation with heart rate (HR; 84.7 ± 17.4 bpm, p   Conclusion:  Our results suggest that the amount of daily activity in Fontan patients may be primarily affected by HR and SV. Also, high activity not corresponding to CO may lead to exacerbation of liver dysfunction.
Abstract 17036: Transesophageal Electrophysiology Study as a Tool to Guide Post-natal Management of Fetal Supraventricular Tachycardia
Authors: Claudia Renaud, Jeffrey M. Vinocur, Edgar Jaeggi
Journal: Circulation (2016)

Background:  With advancements in fetal echocardiography, the diagnosis of supraventricular tachycardia (SVT) is now often made antenatally. There is wide variability in the post-natal management and indications to initiate therapy have not been clearly defined. Esophageal recording and pacing is a useful and minimally invasive tool in the assessment and management of SVT. The proximity of the esophagus to the atria in an anatomically normal individual allows for excellent atrial signal recording as well as noninvasive-programmed stimulation to elicit or terminate reentrant SVT. Transesophageal-pacing study (TEPS) has been used to predict clinical recurrence and efficacy of various management strategies in patients with neonatal SVT, but was never used as a tool to guide post-natal management in newborns with a pre-natal diagnosis of SVT.   Hypothesis:  Our primary hypothesis is that TEPS can guide post-natal management in patients with fetal SVT. Secondary objectives were to evaluate if fetal echo accurately diagnoses SVT mechanism and to assess the proportion of fetal SVT that will resolve by the time of birth.   Methods:  A retrospective review of all cases of fetal SVT at the Hospital for Sick Children of Toronto from 1999 to 2015 was performed.   Results:  A total of 66 patients were included. There were 6 intra-uterine demises. Of the liveborns, 41% had spontaneous SVT during the observation period. Of the 59% remaining, half had inducible SVT during the TEPS. Overall, 70% of patients with a fetal diagnosis of SVT had post-natal recurrence, either spontaneous or inducible. None of the “non-inducible patients” had long-term recurrence.   Conclusions:  TEPS is a valid tool to evaluate the need for postnatal therapy in fetal SVT. Based on the results, treatment could be safely avoided in approximately a third of the patients. Futures studies should be done to evaluate long-term spontaneous recurrence of SVT in inducible patients without initiation of treatment.
Comment on Dubois-Laforgue et al. Diabetes, Associated Clinical Spectrum, Long-term Prognosis, and Genotype/Phenotype Correlations in 201 Adult Patients With Hepatocyte Nuclear Factor 1B (<i>HNF1B</i>) Molecular Defects. Diabetes Care 2017;40:1436–1443
Authors: Rhian L. Clissold, Lorna W. Harries, Sian Ellard, Coralie Bingham, Andrew T. Hattersley
Journal: Diabetes Care (2017)

We read with interest the large and impressive study by Dubois-Laforgue et al. (1) describing the phenotype, long-term follow-up, and genotype/phenotype correlations in 201 adults with hepatocyte nuclear factor 1B (HNF1B)-associated disease. They report that patients with an HNF1B mutation have a worse renal prognosis than those with a 17q12 deletion, as they had a higher frequency of chronic kidney disease stages 3–4/end-stage renal disease and a lower median estimated glomerular filtration rate (eGFR) at follow-up (42.5 vs. 75 mL/min/1.73 m2, respectively; P = 0.008). The article did not comment on the fact that similar results have previously been found in two …
Abstract MP78: Effects of Regular Endurance Exercise on GlycA: Results Across Four Exercise Training Studies
Authors: Mark A Sarzynski, Timothy S Church, James M Hagberg, Rian Landers-Ramos, Arthur S Leon, Dabeeru C Rao, Richard L Seip, James S Skinner, Paul D Thompson, Kenneth R Wilund, Claude Bouchard
Journal: Circulation (2016)

Objective: Our goal was to examine the effects of regular endurance exercise on plasma GlycA levels, a novel NMR-derived biomarker of systemic inflammation. Methods: We examined NMR-derived plasma GlycA levels before and after 5-6 months of exercise training in 1,194 adults from four studies: APOE (N=104), DREW (N=298), GERS (N=78), HERITAGE (N=714). We used unadjusted and adjusted general linear models to evaluate changes in GlycA with regular exercise across sex-specific quartiles of baseline GlycA in all studies combined. Results: At baseline, the combined participants (69% white, 66% female) were an average of 42.5 (15.4) years old with a mean BMI of 28.1 (5.8) kg/m 2 . Exercise training resulted in a decrease in GlycA of 5.6 (42.0) μmol/L (P&lt;0.0001) across all studies. In the unadjusted model, only the fourth quartile of baseline GlycA showed a mean decrease in GlycA with exercise training, while a linear decrease across Q2 to Q4 was observed in the adjusted model ( Figure 1 ). In both models, Q4 showed the greatest decrease in GlycA. Conclusions: Regular exercise tended to decrease GlycA levels across four diverse, standardized exercise training studies. Our results suggest that the individuals at highest risk appear to benefit the most from regular exercise in terms of GlycA. Figure 1. Mean change in GlycA after exercise training by baseline GlycA quartile in four exercise studies combined . P&lt;0.0001 for trend in both the unadjusted and adjusted analyses. Unadjusted analysis included three dummy variables representing the four study groups. Adjusted analyses included age, sex, race, baseline BMI, baseline VO 2 max, baseline GlycA quartile, and three study group dummy variables as covariates. Sex-specific baseline GlycA quartiles in combined group (M/F): Q1: &lt;282/&lt;317; Q2: 283-323/317-356; Q3: 324-370/318-395; Q4: &gt;370/&gt;395
Abstract 257: Plasma PBEF Correlates With Cardiac Arrest Outcome in Mice and Humans
Authors: Terry L Vanden Hoek, Jing Li, Joseph P Ornato, Michael W Donnino, Michael N Cocchi, David F Gaieski, Abella Benjamin, Clifton W Callaway, Jon C Rittenberger, Mary A Peberdy
Journal: Circulation (2013)

Introduction: Pre-B-cell colony enhancing factor (PBEF) is a 52 kDa cytokine that has recently been associated with cardiac dysfunction and insulin resistance in heart failure patients. Such cardiac dysfunction and insulin resistance are also seen after clinical cardiac arrest (CA) and are associated with later death and poor neurologic outcome. We hypothesized that elevated plasma PBEF could serve as a marker of tissue injury in both patients and mice after sudden cardiac arrest. Methods: Human plasma samples after CA resuscitation were collected at four centers of excellence in the care of CA patients (Virginia Commonwealth University, Beth Israel Deaconess Medical Center, University of Pennsylvania and University of Pittsburgh). All patients studied received standardized post-CA care that for most patients included therapeutic hypothermia (TH). Blood was collected within 90 min after return of spontaneous circulation (ROSC) and at 12, 24, and 48 h post-ROSC and plasma PBEF measured by ELISA. Mouse plasma samples taken after KCl-induced CA for 8 min in mice treated with TH versus normothermia after CPR, and in Akt1 partial knockout mice that fail to demonstrate TH protection. Results: CA patients who survived to hospital discharge (n=12) had serial PBEF concentrations that dropped by 40% within 12 h post-ROSC. In both human and mouse samples, the highest PBEF concentrations were seen within the first hour after ROSC. In human samples, plasma PBEF exceeded ~240 ng/ml, well above the PBEF concentrations associated with acute decompensation of heart failure and acute myocardial infarction. In CA patients who did not survive to hospital discharge (n=12), the fall-off of plasma PBEF was less than 20% from the initial level seen. After mouse CA, plasma PBEF at 30 min post-ROSC was significantly lower in TH mice compared to normothermic mice (p &lt; 0.05). Conversely, it was higher in Akt1+/- mice (hypothermia non-responders), over 4-fold, compared to wild type responders (p &lt; 0.05). Conclusions: Plasma PBEF is increased early after CA and may be associated with poor outcome. Further work is needed to test PBEF plasma clearance in cardiac arrest survivors versus non-survivors and understand the mechanism of PBEF release after CA.
11Beta‐hydroxysteroid dehydrogenase‐1 deficiency or inhibition enhances hepatic myofibroblast activation in murine liver fibrosis
Authors: Xiantong Zou, Prakash Ramachandran, Timothy J. Kendall, Antonella Pellicoro, Elena Dora, Rebecca L. Aucott, Kajal Manwani, Tak Yung Man, Karen E. Chapman, Neil C. Henderson, Stuart J. Forbes, Scott P. Webster, John P. Iredale, Brian R. Walker, Zoi Michailidou
Journal: Hepatology (2017)

A hallmark of chronic liver injury is fibrosis, with accumulation of extracellular matrix orchestrated by activated hepatic stellate cells (HSCs). Glucocorticoids limit HSC activation in vitro , and tissue glucocorticoid levels are amplified by 11beta‐hydroxysteroid dehydrogenase‐1 (11βHSD1). Although 11βHSD1 inhibitors have been developed for type 2 diabetes mellitus and improve diet‐induced fatty liver in various mouse models, effects on the progression and/or resolution of liver injury and consequent fibrosis have not been characterized. We have used the reversible carbon tetrachloride‐induced model of hepatocyte injury and liver fibrosis to show that in two models of genetic 11βHSD1 deficiency (global, Hsd11b1 –/– , and hepatic myofibroblast‐specific, Hsd11b1 fl/fl /Pdgfrb‐cre) 11βHSD1 pharmacological inhibition in vivo exacerbates hepatic myofibroblast activation and liver fibrosis. In contrast, liver injury and fibrosis in hepatocyte‐specific Hsd11b1 fl/fl /albumin‐cre mice did not differ from that of controls, ruling out 11βHSD1 deficiency in hepatocytes as the cause of the increased fibrosis. In primary HSC culture, glucocorticoids inhibited expression of the key profibrotic genes Acta2 and Col1α1 , an effect attenuated by the 11βHSD1 inhibitor [4‐(2‐chlorophenyl‐4‐fluoro‐1‐piperidinyl][5‐(1H‐pyrazol‐4‐yl)‐3‐thienyl]‐methanone. HSCs from Hsd11b1 –/– and Hsd11b1 fl/fl /Pdgfrb‐cre mice expressed higher levels of Acta2 and Col1α1 and were correspondingly more potently activated. In vivo [4‐(2‐chlorophenyl‐4‐fluoro‐1‐piperidinyl][5‐(1H‐pyrazol‐4‐yl)‐3‐thienyl]‐methanone administration prior to chemical injury recapitulated findings in Hsd11b1 –/– mice, including greater fibrosis. Conclusion: 11βHSD1 deficiency enhances myofibroblast activation and promotes initial fibrosis following chemical liver injury; hence, the effects of 11βHSD1 inhibitors on liver injury and repair are likely to be context‐dependent and deserve careful scrutiny as these compounds are developed for chronic diseases including metabolic syndrome and dementia. (H epatology 2018;67:2167‐2181).
<i>Akkermansia muciniphila</i> induces gut microbiota remodelling and controls islet autoimmunity in NOD mice
Authors: Arno Hänninen, Raine Toivonen, Sakari Pöysti, Clara Belzer, Hubert Plovier, Janneke P Ouwerkerk, Rohini Emani, Patrice D Cani, Willem M De Vos
Journal: Gut (2017)

Objective Intestinal microbiota is implicated in the pathogenesis of autoimmune type 1 diabetes in humans and in non-obese diabetic (NOD) mice, but evidence on its causality and on the role of individual microbiota members is limited. We investigated if different diabetes incidence in two NOD colonies was due to microbiota differences and aimed to identify individual microbiota members with potential significance. Design We profiled intestinal microbiota between two NOD mouse colonies showing high or low diabetes incidence by 16S ribosomal RNA gene sequencing and colonised the high-incidence colony with the microbiota of the low-incidence colony. Based on unaltered incidence, we identified a few taxa which were not effectively transferred and thereafter, transferred experimentally one of these to test its potential significance. Results Although the high-incidence colony adopted most microbial taxa present in the low-incidence colony, diabetes incidence remained unaltered. Among the few taxa which were not transferred, Akkermansia muciniphila was identified. As A. muciniphila abundancy is inversely correlated to the risk of developing type 1 diabetes-related autoantibodies, we transferred A. muciniphila experimentally to the high-incidence colony. A. muciniphila transfer promoted mucus production and increased expression of antimicrobial peptide Reg3γ , outcompeted Ruminococcus torques from the microbiota, lowered serum endotoxin levels and islet toll-like receptor expression, promoted regulatory immunity and delayed diabetes development. Conclusion Transfer of the whole microbiota may not reduce diabetes incidence despite a major change in gut microbiota, but single symbionts such as A. muciniphila with beneficial metabolic and immune signalling effects may reduce diabetes incidence when administered as a probiotic.
Patient-specific design of a soft occluder for the left atrial appendage
Authors: Sanlin S. Robinson, Seyedhamidreza Alaie, Hannah Sidoti, Jordyn Auge, Lohendran Baskaran, Kenneth Avilés-Fernández, Samantha D. Hollenberg, Robert F. Shepherd, James K. Min, Simon N. Dunham, Bobak Mosadegh
Journal: Nature Biomedical Engineering (2017)