tbuckley/cabot-search huggingface dataset:
Abstract 17167: Risk Stratification for Long-term Survival Benefit With Cardiac Resynchronization Therapy in Mild Heart Failure Patients
Authors: Yitschak Biton, Ilan Goldenberg, Wojciech Zareba, Jason Costa, Scott Mcnitt, Bronislava Polonsky, Arthur J Moss, Valentina Kutyifa
Journal: Circulation (2015)

Background: Cardiac resynchronization therapy (CRT) has been shown to reduce heart failure (HF) events or death in mild HF patients with left bundle branch block (LBBB) ECG pattern. However, risk stratification for long-term mortality benefit with CRT in this cohort is currently lacking. Methods: The study population comprised 1266 patients with LBBB enrolled in the Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy (MADIT-CRT). A clinical risk score was developed using best-subset proportional hazards regression analysis in patients randomized to CRT with defibrillator (CRT-D) to predict survival benefit. Cox proportional hazards regression analysis was used to evaluate risk reduction of death by CRT-D versus an implantable cardioverter defibrillator (ICD)-only among the risk score groups. Results: We identified four clinical variables predicting outcome in CRT-D patients: age≥65, creatinine≥1.4 mg/dl, coronary artery bypass graft [CABG] in the patient history, and left ventricular ejection fraction [LVEF] &lt; 26%. Five-year risk of mortality was 4% with no risk factor (low risk, n=357), 6% with 1 risk factor (n=500), 12% with 2 risk factors, and 27% with 3 risk factors (n=123); there were no patients with 4 risk factors. The mortality benefit from CRT-D vs. an ICD-only showed a U-shaped pattern with no significant benefit in patients with no risk factor (HR=0.77, CI 0.32-1.85, p=0.553), 46% reduction with 1 risk factor (HR=0.54, CI 0.32-0.89, p=0.017), 45% reduction with 2 risk factors (HR=0.55, CI 0.34-0.90, p=0.018), and no benefit with 3 risk factors (HR=0.77, CI 0.32-1.85, p=0.553). Conclusions: In MADIT-CRT, mild HF patients with LBBB with an intermediate mortality risk derived long-term survival benefit from CRT-D vs. an ICD-only. However, no survival benefit was observed in patients with low risk or a very-high risk.
GAPVD1 and ANKFY1 Mutations Implicate RAB5 Regulation in Nephrotic Syndrome
Authors: Tobias Hermle, Ronen Schneider, David Schapiro, Daniela A. Braun, Amelie T. van der Ven, Jillian K. Warejko, Ankana Daga, Eugen Widmeier, Makiko Nakayama, Tilman Jobst-Schwan, Amar J. Majmundar, Shazia Ashraf, Jia Rao, Laura S. Finn, Velibor Tasic, Joel D. Hernandez, Arvind Bagga, Sawsan M. Jalalah, Sherif El Desoky, Jameela A. Kari, Kristen M. Laricchia, Monkol Lek, Heidi L. Rehm, Daniel G. MacArthur, Shrikant Mane, Richard P. Lifton, Shirlee Shril, Friedhelm Hildebrandt
Journal: Journal of the American Society of Nephrology (2018)

Background Steroid-resistant nephrotic syndrome (SRNS) is a frequent cause of CKD. The discovery of monogenic causes of SRNS has revealed specific pathogenetic pathways, but these monogenic causes do not explain all cases of SRNS. Methods To identify novel monogenic causes of SRNS, we screened 665 patients by whole-exome sequencing. We then evaluated the in vitro functional significance of two genes and the mutations therein that we discovered through this sequencing and conducted complementary studies in podocyte-like Drosophila nephrocytes. Results We identified conserved, homozygous missense mutations of GAPVD1 in two families with early-onset NS and a homozygous missense mutation of ANKFY1 in two siblings with SRNS. GAPVD1 and ANKFY1 interact with the endosomal regulator RAB5. Coimmunoprecipitation assays indicated interaction between GAPVD1 and ANKFY1 proteins, which also colocalized when expressed in HEK293T cells. Silencing either protein diminished the podocyte migration rate. Compared with wild-type GAPVD1 and ANKFY1, the mutated proteins produced upon ectopic expression of GAPVD1 or ANKFY1 bearing the patient-derived mutations exhibited altered binding affinity for active RAB5 and reduced ability to rescue the knockout-induced defect in podocyte migration. Coimmunoprecipitation assays further demonstrated a physical interaction between nephrin and GAPVD1, and immunofluorescence revealed partial colocalization of these proteins in rat glomeruli. The patient-derived GAPVD1 mutations reduced nephrin-GAPVD1 binding affinity. In Drosophila , silencing Gapvd1 impaired endocytosis and caused mistrafficking of the nephrin ortholog. Conclusions Mutations in GAPVD1 and probably in ANKFY1 are novel monogenic causes of NS. The discovery of these genes implicates RAB5 regulation in the pathogenesis of human NS.
More real-world trials are needed to establish if web-based physical activity interventions are effective
Authors: Corneel Vandelanotte, Mitch J Duncan, Gregory S Kolt, Cristina M Caperchione, Trevor N Savage, Anetta Van Itallie, Christopher Oldmeadow, Stephanie J Alley, Rhys Tague, Anthony J Maeder, Richard R Rosenkranz, W Kerry Mummery
Journal: British Journal of Sports Medicine (2018)

Despite the positive health benefits of physical activity, physical inactivity remains highly prevalent.1 To address this public health issue, population-based interventions that can effectively reach large numbers of people at low cost are needed.2 Numerous randomised controlled trials (RCT) have examined the effectiveness of web-based physical activity interventions, and overall, these intervention studies have found to increase participants’ physical activity levels.3 Few studies, however, have examined how well these interventions work in ‘real world’ or ecologically valid settings, where there are no repeated contacts with research staff, comprehensive assessments or incentives.4 A recent systematic review examined mobile health (mHealth) clinical trial study methodology for trials conducted in 2014 and 2015 and did not identify a single ecological trial, yet RCTs were dominant (80%, 51/71).5

To address this, we conducted two studies using the same web-based physical activity interventions: a RCT and a randomised ecological trial (RET).6 7 For the RCT, 504 inactive participants were randomised into either a control group or intervention group using the existing Australian 10000 Steps website or a new website with social network features that included annotation, messaging and group-publishing, as well as ‘status updates’, inviting ‘friends’ and personalised profile pages (WALK 2.0).7 Outcomes (accelerometer-based activity monitoring, Active Australia Survey questionnaire,8 website usage) were assessed at 0, 3, 12 and 18 months. For the RET, 1328 adults spontaneously signing up for the free 10000 Steps website were randomised into either the 10000 Steps website or the WALK 2.0 website. …
Single-dose oral ciprofloxacin prophylaxis as a response to a meningococcal meningitis epidemic in the African meningitis belt: A 3-arm, open-label, cluster-randomized trial
Authors: Matthew E. Coldiron, Bachir Assao, Anne-Laure Page, Matt D. T. Hitchings, Gabriel Alcoba, Iza Ciglenecki, Céline Langendorf, Christopher Mambula, Eric Adehossi, Fati Sidikou, Elhadji Ibrahim Tassiou, Victoire De Lastours, Rebecca F. Grais
Journal: PLoS Medicine (2018)

Background Antibiotic prophylaxis for contacts of meningitis cases is not recommended during outbreaks in the African meningitis belt. We assessed the effectiveness of single-dose oral ciprofloxacin administered to household contacts and in village-wide distributions on the overall attack rate (AR) in an outbreak of meningococcal meningitis. Methods and findings In this 3-arm, open-label, cluster-randomized trial during a meningococcal meningitis outbreak in Madarounfa District, Niger, villages notifying a suspected case were randomly assigned (1:1:1) to standard care (the control arm), single-dose oral ciprofloxacin for household contacts within 24 hours of case notification, or village-wide distribution of ciprofloxacin within 72 hours of first case notification. The primary outcome was the overall AR of suspected meningitis after inclusion. A random sample of 20 participating villages was enrolled to document any changes in fecal carriage prevalence of ciprofloxacin-resistant and extended-spectrum beta-lactamase (ESBL)–producing Enterobacteriaceae before and after the intervention. Between April 22 and May 18, 2017, 49 villages were included: 17 to the control arm, 17 to household prophylaxis, and 15 to village-wide prophylaxis. A total of 248 cases were notified in the study after the index cases. The AR was 451 per 100,000 persons in the control arm, 386 per 100,000 persons in the household prophylaxis arm (t test versus control p = 0.68), and 190 per 100,000 persons in the village-wide prophylaxis arm (t test versus control p = 0.032). The adjusted AR ratio between the household prophylaxis arm and the control arm was 0.94 (95% CI 0.52–1.73, p = 0.85), and the adjusted AR ratio between the village-wide prophylaxis arm and the control arm was 0.40 (95% CI 0.19‒0.87, p = 0.022). No adverse events were notified. Baseline carriage prevalence of ciprofloxacin-resistant Enterobacteriaceae was 95% and of ESBL-producing Enterobacteriaceae was >90%, and did not change post-intervention. One limitation of the study was the small number of cerebrospinal fluid samples sent for confirmatory testing. Conclusions Village-wide distribution of single-dose oral ciprofloxacin within 72 hours of case notification reduced overall meningitis AR. Distributions of ciprofloxacin could be an effective tool in future meningitis outbreak responses, but further studies investigating length of protection, effectiveness in urban settings, and potential impact on antimicrobial resistance patterns should be carried out. Trial registration ClinicalTrials.gov NCT02724046
Early Pulmonary Vascular Disease in Young Adults Born Preterm
Authors: Kara N. Goss, Arij G. Beshish, Gregory P. Barton, Kristin Haraldsdottir, Taylor S. Levin, Laura H. Tetri, Therese J. Battiola, Ashley M. Mulchrone, David F. Pegelow, Mari Palta, Luke J. Lamers, Andrew M. Watson, Naomi C. Chesler, Marlowe W. Eldridge
Journal: American Journal of Respiratory and Critical Care Medicine (2018)

Rationale: Premature birth affects 10% of live births in the United States and is associated with alveolar simplification and altered pulmonary microvascular development. However, little is known about the long-term impact prematurity has on the pulmonary vasculature.Objectives: Determine the long-term effects of prematurity on right ventricular and pulmonary vascular hemodynamics.Methods: Preterm subjects (n = 11) were recruited from the Newborn Lung Project, a prospectively followed cohort at the University of Wisconsin-Madison, born preterm with very low birth weight (≤1,500 g; average gestational age, 28 wk) between 1988 and 1991. Control subjects (n = 10) from the same birth years were recruited from the general population. All subjects had no known adult cardiopulmonary disease. Right heart catheterization was performed to assess right ventricular and pulmonary vascular hemodynamics at rest and during hypoxic and exercise stress.Measurements and Main Results: Preterm subjects had higher mean pulmonary arterial pressures (mPAPs), with 27% (3 of 11) meeting criteria for borderline pulmonary hypertension (mPAP, 19-24 mm Hg) and 18% (2 of 11) meeting criteria for overt pulmonary hypertension (mPAP ≥ 25 mm Hg). Pulmonary vascular resistance and elastance were higher at rest and during exercise, suggesting a stiffer vascular bed. Preterm subjects were significantly less able to augment cardiac index or right ventricular stroke work during exercise. Among neonatal characteristics, total ventilatory support days was the strongest predictor of adult pulmonary pressure.Conclusions: Young adults born preterm demonstrate early pulmonary vascular disease, characterized by elevated pulmonary pressures, a stiffer pulmonary vascular bed, and right ventricular dysfunction, consistent with an increased risk of developing pulmonary hypertension.
What’s the Best Way to Treat Normal-Weight People With Metabolic Abnormalities?
Authors: Rita Rubin
Journal: JAMA (2018)

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Time-Dependent Molecular Responses Differ between Gastric Bypass and Dieting but Are Conserved Across Species
Authors: Danny Ben-Zvi, Luca Meoli, Wasif M. Abidi, Eirini Nestoridi, Courtney Panciotti, Erick Castillo, Palmenia Pizarro, Eleanor Shirley, William F. Gourash, Christopher C. Thompson, Rodrigo Munoz, Clary B. Clish, Ron C. Anafi, Anita P. Courcoulas, Nicholas Stylopoulos
Journal: Cell Metabolism (2018)
Phase 1B of ibrutinib and high-dose methotrexate for recurrent/refractory CNS lymphoma.
Authors: Christian Grommes, Jacqueline Stone, Craig Nolan, Elina Tsyvkin, Julia Wolfe, Ingo K. Mellinghoff, Lisa Marie DeAngelis
Journal: Journal of Clinical Oncology (2017)

7533 Background: Primary CNS Lymphoma (PCNSL) is an aggressive primary brain tumor. Outcome and treatment options for patients with recurrent/refractory (r/r) disease are poor. We have observed promising efficacy of single agent ibrutinib in r/r PCNSL and secondary CNS lymphoma (SCNSL). In this phase 1B trial, we investigate the toxicity of ibrutinib in combination with high-dose methotrexate (HD-MTX) in r/r PCNSL/SCNSL. Methods: Eligible patients had r/r PCNSL/SCNSL or newly diagnosed SCNSL, age≥18, ECOG≤2, normal end-organ function, and with any number and type of prior therapies. In patients with SCNSL disease, systemic disease needed to be absent. HD-MTX was given at 3.5g/m2 every 2 weeks for a total of 8 doses. To minimize adverse events, ibrutinib was stopped on days of HD-MTX infusion and was restarted 5 days after MTX infusion or after completion of MTX-clearance, if clearance of MTX required more than 5 days. Ibrutinib was continued daily after completion of 8 doses of MTX. Results: Six patients have been enrolled; 3 received 560mg and 3 received 840mg ibrutinib in combination with HD-MTX. Median age was 62 (range 43-74); median ECOG 1 (0:2; 1:3; 2:1). Two had r/r PCNSL and 4 SCNSL. Three had brain disease, one isolated cerebrospinal fluid (CSF) involvement and two parenchymal and CSF involvement. Three patients had recurrent (2 PCNSL; 1 SCNSL), two refractory (both SCNSL), and one newly diagnosed disease (SCNSL). There were no grade 4 adverse events. Grade 3 events were observed in 5 patients (lymphopenia in 3, ALT elevation in 2, diarrhea in 1, electrolyte changes in 1, hypertension in 1). The most common adverse events were hypokalemia, low WBC, hyperglycemia, ALT and AST elevation. There was no dose reduction of methotrexate or ibrutinib in any patient. After a median follow-up of 130 days, all patients were evaluated for response after 4 doses of HD-MTX, with 4/6 (67%) showing a response: 2 CR, 2 PR, and 1 SD, 1 PD; both non-responders were refractory SCNSL. Ibrutinib concentrations were measured in plasma and CSF. Conclusions: Patients with CNS lymphoma tolerate the combination of HD-MTX and Ibrutinib (at 560 and 840mg) well. Continued enrollment into a combination arm that includes rituximab, methotrexate and ibrutinib is ongoing. Clinical trial information: NCT02315326.
Talazoparib Is a Potent Radiosensitizer in Small Cell Lung Cancer Cell Lines and Xenografts
Authors: James H. Laird, Benjamin H. Lok, Jennifer Ma, Andrew Bell, Elisa de Stanchina, John T. Poirier, Charles M. Rudin
Journal: Clinical Cancer Research (2018)

Purpose: Small cell lung cancer (SCLC) is an aggressive malignancy with a critical need for novel therapies. Our goal was to determine whether PARP inhibition could sensitize SCLC cells to ionizing radiation (IR) and if so, to determine the contribution of PARP trapping to radiosensitization.Experimental Design: Short-term viability assays and clonogenic survival assays (CSA) were used to assess radiosensitization in 6 SCLC cell lines. Doses of veliparib and talazoparib with equivalent enzymatic inhibitory activity but differing PARP trapping activity were identified and compared in CSAs. Talazoparib, IR, and their combination were tested in three patient-derived xenograft (PDX) models.Results: Talazoparib radiosensitized 5 of 6 SCLC cell lines in short-term viability assays and confirmed in 3 of 3 cell lines by CSAs. Concentrations of 200 nmol/L talazoparib and 1,600 nmol/L veliparib similarly inhibited PAR polymerization; however, talazoparib exhibited greater PARP trapping activity that was associated with superior radiosensitization. This observation further correlated with an increased number of double-stranded DNA breaks induced by talazoparib as compared with veliparib. Finally, a dose of 0.2 mg/kg talazoparib in vivo caused tumor growth inhibition in combination with IR but not as a single agent in 3 SCLC PDX models.Conclusions: PARP inhibition effectively sensitizes SCLC cell lines and PDXs to IR, and PARP trapping activity enhances this effect. PARP inhibitors, especially those with high PARP trapping activity, may provide a powerful tool to improve the efficacy of radiotherapy in SCLC. Clin Cancer Res; 24(20); 5143-52. ©2018 AACR.
New uses for old drugs
Authors: Pan Pantziarka, Munir Pirmohamed, Nasir Mirza
Journal: BMJ (2018)

Purpose: Culturally competent health care providers understand cultural attitudes, values, beliefs and practices and are able to use this knowledge to guide patient care. Rising oral health disparities among racial and ethnic minorities require that dental educators emphasize the attainment of cultural competence in order to prepare students to effectively care for patients with backgrounds different from their own. This study investigated the role of community rotations on the cultural competence of second-year Texas dental hygiene students.  Methods: A modified version of the validated self-assessing Clinical Cultural Competency Questionnaire (CCCQ) was given to students at twelve Texas dental hygiene programs with a 100% response rate (239/239). Data analysis was performed using the Kendall tau correlation for associations and Kruskal-Wallis and Mann-Whitney U tests for differences among and between groups.  Results: Students scored highest in attitude (86th percentile). Time spent in community rotations (p=0.009), number of community rotations (p=0.028), racial/ethnic diversity of program clinic patients (p=0.042), and training hours (p=0.044) were associated with increased cultural competence scores. Students with over 50 community rotation hours (p=0.006) scored significantly higher than students with less than 50 hours. Generally, those with four rotations (p=0.002) scored highest. Those with public clinic (p=0.049) and school (p=0.044) rotations scored significantly higher than those without these experiences. Those with nursing home (p=0.009) and hospital (p=0.026) experience scored lower than those without these experiences. Students seeing the most racially/ethnically diverse patients in program clinics scored higher (p=0.014) than students seeing less diverse patients. Those with 6-10 training hours scored higher (p=0.013) than those with other training levels. Hispanics scored significantly higher than whites in skill and overall cultural competence (p≤ 0.005).  Conclusion: Dental hygiene programs should invest time in cultural competence training and choose a robust program of community rotations, while considering the diversity of the student body and clinic patient pool to enhance graduates9 cultural competence.
Stop fRETting the Target: Next-Generation RET Inhibitors Have Arrived
Authors: Wade T. Iams, Christine M. Lovly
Journal: Cancer Discovery (2018)

Abstract Summary: BLU-667 is a next-generation RET inhibitor that maximizes on-target and minimizes off-target effects. It is an exemplar of genotype-driven drug development followed by multi-histology basket trial validation that is becoming a paradigm for precision oncology. Cancer Discov; 8(7); 797–9. ©2018 AACR. See related article by Subbiah et al., p. 836.
Abstract 18418: Favorable Cardiovascular Risk Profile is Associated With Lower Out-of-Pocket Health Care Financial Burden: Medical Expenditure Panel Survey (2010-2013)
Authors: Javier Valero-Elizondo, Haider J Warraich, Joseph A Salami, Adnan Younus, Oluseye Ogunmoroti, Erica S Spatz, Nihar Desai, Jamal S Rana, Salim S Virani, Ron Blankstein, Michael J Blaha, Khurram Nasir
Journal: Circulation (2016)

Introduction:  The AHA 2020 Strategic Impact Goals emphasize the importance of preventing atherosclerotic cardiovascular disease (ASCVD) and optimizing CV modifiable risk factors (CRF) to reduce morbidity, mortality and economic burden. We sought to quantify the impact of favorable CRF profile on out of pocket (OOP) medical spending among those with and without ASCVD in US adult population between 18-64 years of age.   Methods:  The study population was derived from 2010-13 Medical Expenditure Panel Survey. ASCVD diagnoses (coronary artery disease, peripheral arterial disease, stroke) and CRF (hypertension, diabetes mellitus, hypercholesterolemia, smoking, physical activity & obesity) were ascertained by ICD9CM codes and self-report. CRF profile was categorized as “Optimal”, “Average” and “Poor”, (0-1, 2-3 & ≥4 CRF respectively). OOP expenditures were self-reported payments for coinsurance, copayments, deductibles, and medically-related items and services not covered by insurance. High financial burden (HFB) was defined as OOP/family income ratio > 10%.   Results:  The final study sample consisted of 73,492 participants (41±10.7 years). After adjusting for cofounding variables, those without ASCVD were noted to have significantly lower OOP costs than those with ASCVD ($733 vs $1033, p    Conclusions:  Favorable CRF profile is associated with significantly lower OOP spending and financial burden among individuals with and without established ASCVD.