tbuckley/cabot-search huggingface dataset:
Two-year impact of community-based health screening and parenting groups on child development in Zambia: Follow-up to a cluster-randomized controlled trial
Authors: Peter C. Rockers, Arianna Zanolini, Bowen Banda, Mwaba Moono Chipili, Robert C. Hughes, Davidson H. Hamer, Günther Fink
Journal: PLoS Medicine (2018)

Background Early childhood interventions have potential to offset the negative impact of early adversity. We evaluated the impact of a community-based parenting group intervention on child development in Zambia. Methods and findings We conducted a non-masked cluster-randomized controlled trial in Southern Province, Zambia. Thirty clusters of villages were matched based on population density and distance from the nearest health center, and randomly assigned to intervention (15 clusters, 268 caregiver–child dyads) or control (15 clusters, 258 caregiver–child dyads). Caregivers were eligible if they had a child 6 to 12 months old at baseline. In intervention clusters, caregivers were visited twice per month during the first year of the study by child development agents (CDAs) and were invited to attend fortnightly parenting group meetings. Parenting groups selected "head mothers" from their communities who were trained by CDAs to facilitate meetings and deliver a diverse parenting curriculum. The parenting group intervention, originally designed to run for 1 year, was extended, and households were visited for a follow-up assessment at the end of year 2. The control group did not receive any intervention. Intention-to-treat analysis was performed for primary outcomes measured at the year 2 follow-up: stunting and 5 domains of neurocognitive development measured using the Bayley Scales of Infant and Toddler Development–Third Edition (BSID-III). In order to show Cohen's d estimates, BSID-III composite scores were converted to z-scores by standardizing within the study population. In all, 195/268 children (73%) in the intervention group and 182/258 children (71%) in the control group were assessed at endline after 2 years. The intervention significantly reduced stunting (56/195 versus 72/182; adjusted odds ratio 0.45, 95% CI 0.22 to 0.92; p = 0.028) and had a significant positive impact on language (β 0.14, 95% CI 0.01 to 0.27; p = 0.039). The intervention did not significantly impact cognition (β 0.11, 95% CI −0.06 to 0.29; p = 0.196), motor skills (β −0.01, 95% CI −0.25 to 0.24; p = 0.964), adaptive behavior (β 0.21, 95% CI −0.03 to 0.44; p = 0.088), or social-emotional development (β 0.20, 95% CI −0.04 to 0.44; p = 0.098). Observed impacts may have been due in part to home visits by CDAs during the first year of the intervention. Conclusions The results of this trial suggest that parenting groups hold promise for improving child development, particularly physical growth, in low-resource settings like Zambia. Trial registration ClinicalTrials.gov NCT02234726
Z-PROFILE: Real-world utilization and effectiveness of elbasvir/ grazoprevir in adult patients with chronic hepatitis C in Canada
Authors: B. Conway, E. Tam, J. Tremblay, C. Fraser, A. Ramji, S. Borgia, K. Tsoi, E. Yoshida, B. Rajendran, K. Stewart, G. Macphail, B. Trottier, P. Ghali, J. Halsey-Brandt, J. Trepanier
Journal: Journal of Hepatology (2018)
8Identification of cardiomyocyte-specific lncRNAs as potential regulators of cardiac regeneration
Authors: L Pohjolainen, S Kinnunen, H Ruskoaho, V Talman
Journal: Cardiovascular Research (2018)

Introduction: MicroRNAs (miRNAs) play an important role in the cellular function.They often form families, with members sharing high sequence homology, a property that hampers miRNA research as there is a lack of elegant tools for specific miRNA manipulation.Purpose: To establish a reliable workflow for miRNA inhibition using genome editing.Methods and Results: This study focused on miR-195, a member of the miR-15 family and employed the CRISPR-Cas9 system.To this end we generated mouse vascular smooth muscle cells (VSMCs) stably expressing Cas9 nuclease.Cells were then transfected with an in vitro transcribed single guide RNA targeting the mir-195 gene.T7 endonuclease I assay (T7EI) and Sanger sequencing confirmed efficient editing.QPCR demonstrated effective decrease of miR-195 but not of miR-15a and miR-16, two highly expressed members of the miR-15 family in VSMCs.Surprisingly, we noticed that the expression of miR-497 was also decreased in edited cells.Noteworthy, miR-195 and miR-497 form a miRNA cluster and are co-transcribed as a primary transcript.No gene editing of the mir-497 genomic locus was detected by T7EI and sequencing.Computational simulation predicted that mutations of the miR-195 stem loop led to changes in the three dimensional structure of the primary miR-497195 transcript that could affect its processing to mature miRNAs.Similar findings were obtained for the miR-143145 cluster.MiR-143 and miR-145a, two miRNAs that do not belong to the same family, show no sequence homology and play a pivotal role in vascular biology.Specific targeting of the mir-145a locus effectively inhibited the expression of both miRNAs of the cluster while no genomic editing was observed for the mir-143 locus.On the contrary, gene editing in the miR-1792 and miR-106b25 clusters, two miRNA clusters with a key function in the cardiovascular system, resulted in targeted miRNA inhibition.MiR-18a and miR-25, respectively, were targeted on each cluster.Specific editing only for the intended miRNA locus was observed and qPCR quantification indicated inhibition of the edited miRNA.No effect on the expression of other miRNAs occurred, for either of the two miR-1792 and miR-106b25 clusters.Detailed analysis of the gene editing in the four clusters revealed that the unintended inhibition of expression of clustered miRNAs coincides with disruption of sequence motifs of the terminal loop of the targeted hairpin.These results suggest that these elements are critical for the maturation not only of individual hairpins but the entire primary transcript in miRNA clusters.Conclusions: CRISPR/Cas9 emerged as a powerful tool that can offer novel insights into the maturation process of miRNAs in cardiovascular diseases.
Review: In community-dwelling older adults, calcium and vitamin D, alone or combined, do not reduce fractures
Authors: Douglas P. Kiel
Journal: Annals of Internal Medicine (2018)

Source Citation Zhao JG, Zeng XT, Wang J, Liu L. Association between calcium or vitamin D supplementation and fracture incidence in community-dwelling older adults: a systematic review and meta-analysis. JAMA. 2017;318:2466-82. 29279934
Evaluation of SOMAscan as a discovery platform to identify noninvasive protein biomarkers for diagnosis and monitoring of NASH
Authors: M. Lai, T. Libermann, M. Charlton, A.M. Diehl, L. Ngo, S. Dillon, E. Lawitz, N. Chalasani, B. Hameed, S. Caldwell, M. Rinella, T. Nguyen, A. Billin, S. Djedjos, M. Subramanian, R. Myers, Z. Goodman, R. Loomba, N. Afdhal
Journal: Journal of Hepatology (2018)
P318Phosphoinositide 3-kinase gamma inhibition as a novel strategy to reactivate targeted autophagy and limit Doxorubicin-induced cardiotoxicity
Authors: M Li, V Sala, N Pianca, S Sciarretta, F Morello, M Sandri, M Mongillo, T Zaglia, E Hirsch, A Ghigo
Journal: Cardiovascular Research (2018)

Background: Anthracyclines, like doxorubicin (DOX), are among the most potent antitumor drugs.However, their clinical use is hampered by severe cardiotoxicity.We previously demonstrated that inhibition of phosphoinositide 3-kinase c (PI3Kc) protects against anthracyclineinduced cardiomyopathy (manuscript under revision), but the underlying molecular mechanisms are still unexplored.Purpose: Here, we further test the hypothesis that anthracycline-damaged mitochondria activate Toll-like receptor 9 (TLR9)/PI3Kc signaling, which in turn inhibits protective autophagy, thus exacerbating anthracycline cardiotoxicity.Methods: Neonatal cardiomyocytes (NCMs) were isolated from mice expressing a kinase inactive PI3Kc (PI3Kc kinase-dead; KD) and wild-type (WT) controls, and treated with DOX (1 mM) or TLR9 agonist ODN1826 (1 mg/ml) 6 PI3Kc inhibitor AS605240 (500 nM) or TLR9 antagonist ODN2088 (1 mg/ml), for 1 hour before analyzing Akt/mTOR/Ulk-1 signaling.For in vivo studies, WT and KD mice were treated with 4 mg/kg DOX weekly for 3 weeks.Cardiac function was analyzed with echocardiography 6 weeks after the first injection.Electron microscopy (EM) study of morphology and signaling transduction were studied 3 days after the treatment.To investigate the role of protective autophagy in KD hearts, mice were treated with hydroxychloroquine (HCQ) or AAV9-shATG7, which silences the autophagy regulator ATG7 specifically in cardiomyocytes, together with DOX, as described above.Results: In NCMs, DOX significantly increased the phosphorylation of PI3K downstream targets and autophagy inhibitors, Akt, mTOR and Ulk-1.These effects were completely prevented by the TLR9 antagonist ODN2088, the PI3Kc selective inhibitor AS605240 and genetic PI3Kg inactivation (KD NCMs).Notably, the TLR9 agonist ODN1826, mimicking mitochondrial DNA (mitoDNA), similarly upregulated Akt/mTOR/Ulk-1 signaling in WT but not in KD NCMs.These results suggest that DOX activates PI3Kc through mitoDNA/TLR9.In vivo, EM studies showed more abundance of autolysosomes containing injured mitochondria in KD than WT hearts, highlighting the efficient autophagydependent disposal of DOX-damaged mitochondria in KD mice.Enhanced activation of PI3Kgdependent pathway correlated with a significant blunt of autophagy in DOX-treated hearts, whereas inhibition of PI3Kc promoted autophagy and decreased DOX-induced contractile dysfunction.Finally, inhibition of autophagy by HCQ or AAV9-shATG7 erased the protection in KD mice.Conclusion: Overall, this study demonstrates that PI3Kc prevents autophagic disposal of DOXdamaged mitochondria, resulting in cardiomyopathy.We propose PI3Kc inhibition as a novel strategy to reactivate targeted autophagy and limit cancer therapy-related heart disease.
“Too Female” for Liver Transplantation
Authors: Omobonike O. Oloruntoba, Cynthia A. Moylan
Journal: Hepatology (2018)

Oloruntoba, Omobonike O. M.D.; Moylan, Cynthia A. M.D., M.H.S.Editor(s): Corey, Kathleen E.3; Malhi, Harmeet4 Author Information
P510Anthracycline cardiotoxicity 2.4 or Toll-Like Receptor root of all evil
Authors: M Trofenciuc, M Tomescu, H Branea, A Bordejevic, R M Christodorescu, C Cotoraci, M F Onel, I F Ferent, M Puschita, A Pop-Moldovan
Journal: Cardiovascular Research (2018)

nonsynonymous variants was performed with 3 different algorithms.All the mutations were validated by direct Sanger sequencing.Results: About 1,950,000 reads per sample covering the coding and flanking intronic regions of 67 genes have been produced.The sequencing depth resulted in a median coverage of 267X (ranging from 165X to 351X), with 96.45% covered at 10X.Considering only the variants covered at least 15X, on average, 445 variants per sample have been detected, 409 were SNPs and 36 InDels.Discarding synonymous single-nucleotide variants and excluding TTN gene, we identified a total of 25 exonic mutations (2 nonsense and 23 missense) and 2 splice-site variants.About half of patients resulted to carry a mutation, 12 (30%) showed a single mutation and 6 (15%) showed multiple mutations.In 9 out of 40 probands, one or more mutations have been found in genes associated with ACM and/or with other inherited heart diseases.Among missense and nonsense mutations in candidate genes identified in 9 (22.5%)patients, a nonsense mutation c.796C>T, p. (R266*) was detected in a strong ACM candidate gene encoding for p63, a DNA binding transcriptional factor, involved in cardiomyocyte differentiation and in Wnt signalling regulation.The same patient carried also a novel missense variant in TLN1 gene (c.3707A>G,p.Q1236R), whereas the affected mother resulted to carry only the TP63 mutation.ConclusionS: This targeted gene panel resulted to be a valid approach for both diagnostic and research purposes in patients affected with ACM.Our approach led to the identification of the genetic cause in 9 ACM patients and to the identification of TP63 as a possible disease gene.
A Longitudinal Study Examining Changes in Street Connectivity, Land Use, and Density of Dwellings and Walking for Transport in Brisbane, Australia
Authors: Rebecca Bentley, Tony Blakely, Anne Kavanagh, Zoe Aitken, Tania King, Paul McElwee, Billie Giles-Corti, Gavin Turrell
Journal: Environmental Health Perspectives (2018)

Background: Societies face the challenge of keeping people active as they age. Walkable neighborhoods have been associated with physical activity, but more rigorous analytical approaches are needed. Objectives: We used longitudinal data from adult residents of Brisbane, Australia (40–65 years of age at baseline) to estimate effects of changes in neighborhood characteristics over a 6-y period on the likelihood of walking for transport. Methods: Analyses included 2,789–9,747 How Areas Influence Health and Activity (HABITAT) cohort participants from 200 neighborhoods at baseline (2007) who completed up to three follow-up questionnaires (through 2013). Principal components analysis was used to derive a proxy measure of walkability preference. Environmental predictors were changes in street connectivity, residential density, and land use mix within a one-kilometer network buffer. Associations with any walking and minutes of walking were estimated using logistic and linear regression, including random effects models adjusted for time-varying confounders and a measure of walkability preference, and fixed effects models of changes in individuals to eliminate confounding by time-invariant characteristics. Results: Any walking for transport (vs. none) was increased in association with an increase in street connectivity (+10 intersections, fixed effects OR=1.19; 95% confidence interval (CI): 1.07, 1.32), residential density (+5 dwellings/hectare, OR=1.10; 95% CI: 1.05, 1.15), and land-use mix (10% increase, OR=1.12; 95% CI: 1.00, 1.26). Associations with minutes of walking were positive based on random effects models, but null for fixed effects models. The association between land-use mix and any walking appeared to be limited to participants in the highest tertile of increased street connectivity (fixed effects OR=1.17; 95% CI: 0.99, 1.35 for a 1-unit increase in land-use mix; interaction p-value=0.05). Conclusions: Increases in street connectivity, residential density, and land-use heterogeneity were associated with walking for transport among middle-age residents of Brisbane, Australia. https://doi.org/10.1289/EHP2080
PTU-015 Patient perspective on the tolerance of gastroscopy
Authors: S. A Raju, L Marks, H.-L Ching, ME McAlindon
Journal: Gut (2017)

Introduction  The degree of tolerance patients have for gastroscopy may be less than the endoscopist believes. We therefore present a questionnaire study of patients undergoing oesophagogastroduodenoscopy (OGD) in an endoscopy centre to determine what this difference may be.  Method  A close ended questionnaire was given to patients attending adult outpatient OGD between November 2016 and January 2017. The patients’ Gloucester Comfort Score (GCS), was recorded as was the endoscopist rating score. Doctors were not aware of the GCS given by patients nor that the data was to be collected for comparison. All patients were offered the choice of sedation with fentanyl and midazolam.  Results  Questionnaires were completed by 65 patients: 30 female (median: 60 years±13.5 years), 35 male (median: 60±16.5 years). 18.5% reported no pain, 36.9% minimal discomfort, 23.1% mild discomfort, 18.5% moderate discomfort and 3.1% severe discomfort. Sedation was administered in 39% patients.There was no significant difference in reported scores based on sex (p=0.283), age (p=0.202) or whether they were sedated (p=0.107).  Endoscopists rated 43% of procedures good, 29.2% acceptable, 3% poor and 0% not tolerated. There was a moderate correlation (r s =0.413, p=0.001) between the endoscopist rating and the patients GCS.  Conclusion  Although there was some correlation, a fifth of patients still reported moderate to severe pain during OGD which was not identified by endoscopists. This difference highlights how the tolerability of this routine procedure may be perceived differently by patients and endoscopists.  Disclosure of Interest  None Declared
Automated acute kidney injury alerts
Authors: Kianoush B. Kashani
Journal: Kidney International (2018)

Acute kidney injury (AKI) is one of the most common and probably one of the more consequential complications of critical illnesses. Recent information indicates that it is at least partially preventable; however, progress in its prevention, management, and treatment has been hindered by the scarcity of knowledge for effective interventions, inconsistencies in clinical practices, late identification of patients at risk for or with AKI, and limitations of access to best practices for prevention and management of AKI. Growing use of electronic health records has provided a platform for computer science to engage in data mining and processing, not only for early detection of AKI but also for the development of risk-stratification strategies and computer clinical decision-support (CDS) systems. Despite promising perspectives, the literature regarding the impact of AKI electronic alerts and CDS systems has been conflicting. Some studies have reported improvement in care processes and patient outcomes, whereas others have shown no effect on clinical outcomes and yet demonstrated an increase in the use of resources. These discrepancies are thought to be due to multiple factors that may be related to technology, human factors, modes of delivery of information to clinical providers, and level of expectations regarding the impact on patient outcomes. This review appraises the current body of knowledge and provides some outlines regarding research into and clinical aspects of CDS systems for AKI.
Association of concomitant use of acid reducing agents in full-dose vemurafenib users with risk of progression in BRAF V600 mutation-positive unresectable or metastatic melanoma patients: A retrospective cohort study.
Authors: Lotte Marieke Knapen, Rutger H.T. Koornstra, Johanna H.M. Driessen, Bas Van Vlijmen, Sander Croes, Stein J. Schalkwijk, Angela Colbers, Winald Gerritsen, David Burger, Frank de Vries, Nielka P. Van Erp
Journal: Journal of Clinical Oncology (2017)

9540 Background: Vemurafenib is used for the treatment of adult patients with BRAF V600 mutation-positive unresectable or metastatic melanoma. The approved fixed vemurafenib dose of 960 mg twice daily may result in overexposure. Concomitant use of acid reducing agents (ARAs) may result in underexposure. Both situations are likely to affect treatment outcome. Therefore, the aim of this study was to determine the association between the use of vemurafenib (full-dose versus reduced dose) and/or concomitant ARA use (yes versus no) and the risk of disease progression. Methods: A retrospective cohort study was conducted using data from the electronic health record software of the Radboudumc pharmacy and medical records of the Radboudumc (March 17 th 2012 to March 17 th 2016). Patients (N = 112) using vemurafenib as first line treatment for melanoma were included. Multivariable cox regression estimated adjusted hazard ratios (HRa) and 95% confidence intervals (CI) of progression in vemurafenib users (full-dose N = 67 versus reduced dose N = 45) and/or concomitant ARA users (N = 38). Adjustments were made for age and sex. Results: The mean follow-up time was 3.5 months and 41 patients (36.6%) developed progression on first line vemurafenib. Co-treatment of ARAs in patients using full-dose vemurafenib was associated with a 4.6-fold increased risk of progression (HRa 4.56; 95% CI 1.51-13.75) as compared to full-dose vemurafenib users not co-treated with ARAs. No increased risk was found for users of vemurafenib in a reduced dose, regardless of concomitant ARA use. Conclusions: Concomitant use of ARAs in full-dose vemurafenib users was associated with an increased risk of progression. Physicians should be cautious to prescribe ARAs to patients tolerating full-dose vemurafenib. The presence of considerable confounding by disease severity, the small number of events and the hypothesis generating character of this study emphasize the need to prospective validate these results.
Impact of regorafenib in the clinical practice and identification of second-line treatment orphan patients
Authors: M.S. Zamparelli, V. Sapena, A. Diaz-Gonzalez, A. Darnell, N. Llarch, E. Belmonte, L. Boix, G. Iserte, A. Forner, J. Corominas, L.G. Da Fonseca, C. Ayuso, J. Bruix, M. Reig
Journal: Journal of Hepatology (2018)
Safety, pharmakokinetics and antiviral activity of novel capsid assembly modulator (CAM) JNJ-56136379 (JNJ-6379) in treatmentnaive chronic hepatitis B (CHB) patients without cirrhosis
Authors: F. Zoulim, J.Z. Yogaratnam, J.J. Vandenbossche, O. Lenz, W. Talloen, C. Vistuer, I. Moscalu, A. Streinu-Cercel, S. Bourgeois, M. Buti, J. Crespo, J.M. Pascasio, C. Sarrazin, T. Vanwolleghem, L. Blatt, J. Fry
Journal: Journal of Hepatology (2018)
Association of Hemoglobin A1c and Wound Healing in Diabetic Foot Ulcers
Authors: Betiel K. Fesseha, Christopher J. Abularrage, Kathryn F. Hines, Ronald Sherman, Priscilla Frost, Susan Langan, Joseph Canner, Kendall C. Likes, Sayed M. Hosseini, Gwendolyne Jack, Caitlin W. Hicks, Swaytha Yalamanchi, Nestoras Mathioudakis
Journal: Diabetes Care (2018)

OBJECTIVE This study evaluated the association between hemoglobin A1c (A1C) and wound outcomes in patients with diabetic foot ulcers (DFUs). RESEARCH DESIGN AND METHODS We conducted a retrospective analysis of an ongoing prospective, clinic-based study of patients with DFUs treated at an academic institution during a 4.7-year period. Data from 270 participants and 584 wounds were included in the analysis. Cox proportional hazards regression was used to assess the incidence of wound healing at any follow-up time in relation to categories of baseline A1C and the incidence of long-term (≥90 days) wound healing in relation to tertiles of nadir A1C change and mean A1C change from baseline, adjusted for potential confounders. RESULTS Baseline A1C was not associated with wound healing in univariate or fully adjusted models. Compared with a nadir A1C change from baseline of −0.29 to 0.0 (tertile 2), a nadir A1C change of 0.09 to 2.4 (tertile 3) was positively associated with long-term wound healing in the subset of participants with baseline A1C &amp;lt;7.5% (hazard ratio [HR] 2.07; 95% CI 1.08–4.00), but no association with wound healing was seen with the mean A1C change from baseline in this group. Neither nadir A1C change nor mean A1C change were associated with long-term wound healing in participants with baseline A1C ≥7.5%. CONCLUSIONS There does not appear to be a clinically meaningful association between baseline or prospective A1C and wound healing in patients with DFUs. The paradoxical finding of accelerated wound healing and increase in A1C in participants with better baseline glycemic control requires confirmation in further studies.
Comparision of long-term outcome for single small hepatocellular carcinoma between different treatment modalities by size and tumor marker
Authors: D.H. Sinn, S.-G. Lee, D. Hyun, S.W. Shin, G.-S. Choi, J.M. Kim, T.W. Kang, M.W. Lee, W. Kang, G.-Y. Gwak, Y.-H. Paik, M.S. Choi, J.H. Lee, K.C. Koh, S.W. Paik, B.C. Yoo
Journal: Journal of Hepatology (2018)