tbuckley/cabot-search huggingface dataset:
Abstract 13845: Added Value of Coronary Calcification in Prediction of Long-term Cardiovascular Events in Chronic Kidney Disease With and Without Diabetes Mellitus: Multi-Ethnic Study of Atherosclerosis (MESA)
Authors: Gautam R Shroff, Otto A Sanchez, Michael D Miedema, Holly Kramer, Joachim H Ix, Daniel A Duprez, David R Jacobs
Journal: Circulation (2016)

Introduction: Cardiovascular disease (CVD) is a major cause of morbidity/mortality in chronic kidney disease (CKD). Coronary calcification (CAC) is infrequently used by clinicians for risk prediction in CKD because high values are not felt to be predictive. We analyzed whether CAC can discriminate long-term outcomes in CKD with (CKD-DM) and without (CKD-non-DM) diabetes mellitus. Methods: We analyzed 6780 MESA participants (age 45-84 yrs, 19.3% CKD) without clinical CVD enrolled at 6 clinical sites, followed for adjudicated CVD (coronary heart disease, stroke, heart failure, peripheral arterial disease) for 12.1 years. CKD was defined as eGFR&lt;60 ml/min/1.73 m 2 estimated using creatinine &amp; cystatin C (CKD-EPI equation) or spot urine albumin/creatinine ≥ 17 mg/g in men; 25 mg/g in women. Baseline CAC was assessed by computed tomography. Poisson regression analysis was performed to adjust CVD events for demographic, clinical &amp; inflammatory biomarker variables. Results: CAC increased across CKD and DM categories (neither condition: 56% had no CAC while 9% had &gt;300 Agatston score; CKD only: 33% had no CAC while 21% had score &gt;300; DM only: 42% had no CAC while 17% had score &gt;300; CKD-DM: 31% had no CAC while 26% had score &gt;300. CVD incidence density per 12.1 years varied greatly across CKD and DM categories (Figure). CVD incidence density per 1000 person-years across CAC categories ranged from 5-21 in non-CKD, non-DM; 7-20 in CKD-non-DM; 9-21 in non-CKD-DM; and 16-29 in CKD-DM. With adjustment for demographics and many risk covariates, baseline CAC added to prediction within each CKD and DM category. Conclusion: CKD-DM had the highest incident CVD events and those with CKD or DM alone had intermediate rates compared to those with neither condition. Contribution to risk prediction was as large from CAC category as from CKD or DM category. Despite the common knowledge that CAC increases in both CKD and DM, assessment of CAC would be helpful in risk stratification in all CKD and DM categories.
Adding mirtazapine to ongoing SNRIs or SSRIs did not improve symptoms of treatment-resistant depression
Authors: Gregory E. Simon
Journal: Annals of Internal Medicine (2019)

Source Citation Kessler DS, MacNeill SJ, Tallon D, et al. Mirtazapine added to SSRIs or SNRIs for treatment resistant depression in primary care: phase III randomised placebo controlled trial (MIR). BMJ. 2018;363:k4218. 30381374
Safeguarding LGBT+ adolescents
Authors: Jessica Salkind, Rosanna Bevan, Ginger Drage, Donna Samuels, Gayle Hann
Journal: BMJ (2019)

### What you need to know

A 14 year old girl attends the emergency department after taking a paracetamol overdose at home. She explains she has felt really hopeless since telling her mother she identifies as bisexual and has a girlfriend. Her mother told her “I would rather you were dead” and has organised an exorcism through the local church. 

Recent years have seen political and social progress for people who identify as LGBT+ (lesbian, gay, bisexual, and transgender; the “+” indicating inclusion of other minority sexual and gender identities). Yet international evidence shows ongoing health and social inequalities in this group, many of which emerge during adolescence and represent unique safeguarding risks.1234567 This article offers an overview of these risks, which include increased rates of self harm, suicide, and family rejection or abuse. The article is aimed at all healthcare professionals who care for young people, including within paediatrics, general practice, emergency medical and surgical settings, and child and adolescent mental health services (CAMHS). We suggest a management strategy based on clinical experience and testimony from LGBT+ young people and organisations. Some suggestions assume legal protection and support services for LGBT+ people that …
Mortality and glycemic control among patients with gastric and esophageal cancer and diabetes mellitus.
Authors: Nina J. Karlin, Matthew Buras, Heidi E. Kosiorek, Patricia M. Verona, Curtiss B. Cook
Journal: Journal of Clinical Oncology (2019)

73 Background: This study evaluated the impact of diabetes mellitus (DM) on survival in gastric and esophageal cancer patients, and examined the impact of these cancers on glycemic control in DM. Methods: Patients with newly diagnosed gastric and esophageal cancers with DM (n = 92) were identified from the Institutional Cancer Registry and matched to 92 gastric and esophageal cancer patients without DM according to age, gender and year of cancer diagnosis (2006 to 2016). The electronic medical record provided information on DM and cancer therapies and laboratory results. Overall survival (OS) was estimated with the Kaplan-Meier method and compared by Cox regression analysis using stratification for matched pairs. Mixed models were used to compare hemoglobin A1c (HbA1c) and glucose during the year following cancer diagnosis. Results: Mean age of the entire cohort was 68 years, 91% were white, 78% were men, and 53% had stage III/IV disease. Adenocarcinoma (79%) was the most common histologic type. BMI was significantly different between DM and non-DM patients (p = 0.006). Alcohol use at time of cancer diagnosis was more prevalent in non-DM patients vs. DM (p = 0.018). Among those with DM, mean HbA1c during the year following cancer diagnosis was 6.8%. Mean glucose was significantly different between DM and non-DM patients (149 mg/dL vs. 116 mg/dL, p &lt; 0.001). For glucose, there was a significant interaction effect (p = 0.005) as DM patients demonstrated a decrease in glucose values over time compared to non-DM patients. Median follow-up time was 35 months. Three year OS was estimated at 46% (95% CI: 36-58%) for DM patients versus 52.0% (95% CI: 41-64%) in non-DM (p = 0.25). Hazard ratio (stratification for matched pairs) was 1.95 (95% CI: 1.14 – 3.43; p = 0.02). Three year PFS was estimated at 40% (95% CI: 31-53%) for DM patients versus 50% (95% CI: 40-63%) for non-DM patients (p = 0.12). Hazard ratio (stratification for matched pairs) was 1.74 (95% CI: 1.04-2.90; p = 0.03). Conclusions: Gastric and esophageal cancer and its treatment did not affect glycemic control. Risks of death and progression are greater in DM patients as compared to non-DM.
Prospective, longitudinal comparison of neurocognitive change in pediatric brain tumor patients treated with proton radiotherapy versus surgery only
Authors: Lisa S Kahalley, M Douglas Ris, Anita Mahajan, M Fatih Okcu, Murali Chintagumpala, Arnold C Paulino, William E Whitehead, Charles G Minard, Heather H Stancel, Jessica Orobio, Judy J Xue, Emily A Warren, David R Grosshans
Journal: Neuro-Oncology (2019)

Proton radiotherapy (PRT) reduces the volume of normal tissue receiving radiation dose, which may lead to better neurocognitive outcomes. We examined change in neurocognitive scores over time in pediatric brain tumor patients treated with proton craniospinal irradiation (CSI), proton focal RT, or surgery only.Patients received annual neurocognitive evaluations for up to 6 years. We examined Full Scale IQ (FSIQ), Verbal Comprehension Index (VCI), Perceptual Reasoning Index (PRI), Working Memory Index (WMI), and Processing Speed Index (PSI) scores. General linear mixed models examined change in scores over time by treatment group, adjusting for significant covariates.Scores from 93 patients treated between 2012 and 2017 (22 proton CSI, 31 proton focal, and 40 surgery only) were examined. Treatment groups were similar on gender (51.6% male), age at treatment (median = 9.7 y), and length of follow-up (median = 2.9 y). The surgery only group had proportionately more gliomas (P < 0.001), and the proton CSI group had more infratentorial tumors (P = 0.001) and higher total RT dose (P = 0.004). The proton focal and surgery only groups exhibited stable neurocognitive scores over time across all indexes (all P > 0.05). In the proton CSI group, WMI, PSI, and FSIQ scores declined significantly (P = 0.036, 0.004, and 0.017, respectively), while VCI and PRI scores were stable (all P > 0.05).Focal PRT was associated with stable neurocognitive functioning into survivorship. Outcomes were similar whether patients received focal PRT or no radiotherapy, even in neurocognitive domains known to be particularly radiosensitive. Proton CSI emerged as a neurocognitive risk factor, consistent with photon outcomes research.
Fitness genes of group A streptococci in necrotizing fasciitis and myositis
Authors: Harry R. Hill
Journal: Journal of Clinical Investigation (2019)

Necrotizing fasciitis and myositis caused by group A streptococci (GAS) are among the most fulminating infections, with a mortality rate of 20% to 30%. Although numerous regimens have been utilized in attempts to control these devastating infections, such as combinations of various antimicrobial agents and intravenous immunoglobulin (IVIG) as well as hyperbaric oxygen therapy, none have been the complete answer. Zhu and colleagues have utilized a transposon-directed insertion-site sequencing (TraDIS) protocol to identify 126 genes of M1 and 116 genes of M28 strains of GAS required for myositis, of which 25% encode transporters, which could be used as possible targets for future therapeutic protocols.
JNJ‐4178 (AL‐335, Odalasvir, and Simeprevir) for 6 or 8 Weeks in Hepatitis C Virus‐Infected Patients Without Cirrhosis: OMEGA‐1
Authors: Stefan Zeuzem, Stefan Bourgeois, Susan Greenbloom, Maria Buti, Alessio Aghemo, Pietro Lampertico, Ewa Janczewska, Seng Gee Lim, Christophe Moreno, Peter Buggisch, Edward Tam, Chris Corbett, Wouter Willems, Leen Vijgen, Bart Fevery, Sivi Ouwerkerk‐Mahadevan, Oliver Ackaert, Maria Beumont, Ronald Kalmeijer, Rekha Sinha, Michael Biermer
Journal: Hepatology (2019)

The combination of three direct‐acting antiviral agents (AL‐335, odalasvir, and simeprevir: JNJ‐4178 regimen) for 6 or 8 weeks demonstrated good efficacy and safety in a phase IIa study in chronic hepatitis C virus (HCV) genotype (GT)‐1‐infected patients without cirrhosis and has now been evaluated in a larger phase IIb study, OMEGA‐1. This multicenter, randomized, open‐label study (NCT02765490) enrolled treatment‐naïve and interferon (±ribavirin) treatment‐experienced patients with HCV GT1, 2, 4, 5, or 6 infection. Patients with HCV GT3 infection and/or liver cirrhosis were excluded. Patients received AL‐335 800 mg, odalasvir 25 mg, and simeprevir 75 mg once daily for 6 or 8 weeks. The primary endpoint was sustained virologic response 12 weeks after the end of treatment (SVR12). In total, 365 patients (GT1a, 29.3%; GT1b, 42.5%; GT2, 12.3%; GT4, 14.2%; GT5, 1.4%; GT6, 0%) were randomized to receive 6 weeks (n = 183) or 8 weeks (n = 182) of treatment. SVR12 rates after 6 weeks (98.9%) or 8 weeks (97.8%) of treatment were noninferior to a historical control (98%). Viral relapse occurred in 5 patients (1.4%; 4 with HCV GT2c; 1 with GT1a). With the exception of 4 patients in the 8‐week group, including 3 patients with missing data at the SVR24 timepoint, all patients who achieved SVR12 also achieved SVR24. One GT1a‐infected patient experienced late viral relapse after achieving SVR18. Most adverse events (AEs) were mild with no treatment‐related serious AEs. All randomized patients completed treatment. Conclusion: In HCV‐infected patients, 6 and 8 weeks of treatment with JNJ‐4178 resulted in SVR12 rates of 98.9% and 97.8%, respectively, and was well tolerated.
Excess Deaths Attributable to Influenza-Like Illness in the ESRD Population
Authors: David T. Gilbertson, Kenneth J. Rothman, Glenn M. Chertow, Brian D. Bradbury, M. Alan Brookhart, Jiannong Liu, Wolfgang C. Winkelmayer, Til Stürmer, Keri L. Monda, Charles A. Herzog, Akhtar Ashfaq, Allan J. Collins, James B. Wetmore
Journal: Journal of the American Society of Nephrology (2019)

Significance Statement The seasonality of influenza activity contributes to seasonal patterns in morbidity and mortality, particularly among vulnerable populations such as patients with ESRD. However, the relationship between seasonal fluctuations of influenza-like illness (ILI), which encompasses a wide range of respiratory infections, and seasonal patterns of mortality in patients with ESRD has not been explicitly examined. Using data from a Centers for Disease Control and Prevention (CDC) ILI surveillance network and the Medicare ESRD database, the authors found that community ILI activity is associated with seasonal variation in mortality among patients with ESRD, and likely contributes to &gt;1000 deaths per year. Greater emphasis on surveillance efforts, such as timely reporting to the CDC of ILI activity within dialysis units, and study of treatment and containment strategies during high-risk periods, may be warranted. Background Morbidity and mortality vary seasonally. Timing and severity of influenza seasons contribute to those patterns, especially among vulnerable populations such as patients with ESRD. However, the extent to which influenza-like illness (ILI), a syndrome comprising a range of potentially serious respiratory tract infections, contributes to mortality in patients with ESRD has not been quantified. Methods We used data from the Centers for Disease Control and Prevention (CDC) Outpatient Influenza-like Illness Surveillance Network and Centers for Medicare and Medicaid Services ESRD death data from 2000 to 2013. After addressing the increasing trend in deaths due to the growing prevalent ESRD population, we calculated quarterly relative mortality compared with average third-quarter (summer) death counts. We used linear regression models to assess the relationship between ILI data and mortality, separately for quarters 4 and 1 for each influenza season, and model parameter estimates to predict seasonal mortality counts and calculate excess ILI-associated deaths. Results An estimated 1% absolute increase in quarterly ILI was associated with a 1.5% increase in relative mortality for quarter 4 and a 2.0% increase for quarter 1. The average number of annual deaths potentially attributable to ILI was substantial, about 1100 deaths per year. Conclusions We found an association between community ILI activity and seasonal variation in all-cause mortality in patients with ESRD, with ILI likely contributing to &gt;1000 deaths annually. Surveillance efforts, such as timely reporting to the CDC of ILI activity within dialysis units during influenza season, may help focus attention on high-risk periods for this vulnerable population.
Benefit of adjuvant chemotherapy in patients with high-risk UICC II colon cancer T4N0M0: A ten-year population-based analysis of 3544 cases.
Authors: Andreas Teufel, Alois Fürst, Michael Gerken, Ina Hohenthanner, Monika Klinkhammer-Schalke
Journal: Journal of Clinical Oncology (2019)

628 Background: The benefit of adjuvant chemotherapy in UICC stage III colon carcinoma has been demonstrated in numerous studies. For UICC stage II such an advantage was not shown. However, it remains controversial whether adjuvant chemotherapy might be considered in certain high-risk UICC stage II situations. High-risk factors include T4 tumors, associated with an increased risk of recurrence and poorer prognosis due to their more aggressive biological behavior. Methods: The present population-based, multicenter cohort study investigated the influence of adjuvant chemotherapy on survival and recurrence rates in UICC stage II in the high-risk situation T4N0M0. It is based on an anonymized nationwide ADT dataset and includes 208,030 patients diagnosed with colorectal cancer from 2002 to 2011. A total of 3544 patients with a T4 tumor were identified, of whom 34.3% (1215 patients) received adjuvant chemotherapy and 65.7% (2329 patients) none. Results: Median overall survival was markedly prolonged in subjects who received adjuvant chemotherapy from 4.5 years (SD 0.163, 95% CI 4.1-4.8) to 8.1 years (SD 0.474, 95% CI 7.2 -9.0; p &lt; .001). After 5 years, 69.5% of chemotherapy patients were still alive compared to 45.1% of non-chemotherapy patients. After adjusting for factors in a multivariable Cox regression analysis, the significant benefit of adjuvant chemotherapy for overall survival was maintained (HR = 0.642, 95% CI 0.555-0.743, p &lt; .001). The relative cumulative risk of recurrence in the multivariable analysis was HR = 0.696 (95% CI 0.580-0.843, p &lt; .001) for chemotherapy patients. Furthermore, a highly significant improvement in relapse-free survival through chemotherapy was demonstrated (HR = 0.634, 95% CI 0.555-0.725, p &lt; .001). Conclusions: In this representative study, a significant advantage of adjuvant chemotherapy for UICC stage II colon carcinoma patients with a T4 tumor was demonstrated in terms of overall survival, recurrence rate and relapse-free survival. On the basis of these results, adjuvant chemotherapy is recommended for the high-risk situation T4.
Evaluation of a Fully Human, Hepatitis B Virus-Specific Chimeric Antigen Receptor in an Immunocompetent Mouse Model
Authors: Marvin M. Festag, Julia Festag, Simon P. Fräßle, Theresa Asen, Julia Sacherl, Sophia Schreiber, Martin A. Mück-Häusl, Dirk H. Busch, Karin Wisskirchen, Ulrike Protzer
Journal: Molecular Therapy (2019)

Chimeric antigen receptor (CAR) T cell therapy is a promising novel therapeutic approach for cancer but also for chronic infection. We have developed a fully human, second-generation CAR directed against the envelope protein of hepatitis B virus on the surface of infected cells (S-CAR). The S-CAR contains a human B cell-derived single-chain antibody fragment and human immunoglobulin G (IgG) spacer, CD28- and CD3-signaling domains that may be immunogenic in mice. Because immunosuppression will worsen the clinical course of chronic hepatitis B, we aimed at developing a preclinical mouse model that is immunocompetent and mimics chronic hepatitis B but nevertheless allows evaluating efficacy and safety of a fully human CAR. The S-CAR grafted on T cells triggered antibody responses in immunocompetent animals, and a co-expressed human-derived safeguard, the truncated epidermal growth factor receptor (EGFRt), even induced B and T cell responses, both limiting the survival of S-CAR-grafted T cells. Total body irradiation and transfer of T cells expressing an analogous, signaling-deficient S-CAR decoy and the safeguard induced immune tolerance toward the human-derived structures. S-CAR T cells transferred after immune recovery persisted and showed long-lasting antiviral effector function. The approach we describe herein will enable preclinical studies of efficacy and safety of fully human CARs in the context of a functional immune system.
Landscape of germline mutations in hepatobiliary carcinoma: Unrealized risk, untapped clinical trial opportunities.
Authors: Jewel Samadder, Margaret Rupp, Shan Yang, Scott T. Michalski, Stephen E Lincoln, Robert L. Nussbaum, Mitesh J. Borad, Edward D. Esplin
Journal: Journal of Clinical Oncology (2019)

236 Background: Hepatobiliary cancer (HBC), including cholangiocarcinoma, affects over 40,000 people in the U.S. each year, and results in over 30,000 cancer deaths annually. Despite continuing advances in next-generation sequencing (NGS), the understanding of germline genetic risk as it relates to these malignancies remains limited, and guidelines for the germline testing of these patients are lacking. We report the spectrum of pathogenic/likely pathogenic (P/LP) germline genetic variants observed in patients with HBC, and the clinical utility related to germline genetic test results. Methods: We retrospectively studied a consecutive series of 267 patients referred to Invitae for germline genetic testing based on a personal history of HBC, per an IRB approved protocol. Patients were evaluated with a multigene panel of up to 135 genes chosen by the ordering providers. De-identified clinical and family history information were reviewed as provided by clinicians. Results: Among 267 HBC patients 15% (n = 41) had P/LP variants identified in genes including MUTYH, ATM, CHEK2, BAP1, BRCA1, MLH1, BRCA2, PALB2, TP53, APC, CDH1, MSH6, and PMS2 (12% excluding MUTYH heterozygotes). Amongst patients with a family history (FH) of HBC, P/LP rate was 13%; for patients with a FH of cancers other than HBC, P/LP rate was 16%; for patients with no reported FH, P/LP rate was 13%. Conclusions: In this study, 15% of HBC patients had P/LP variants in cancer-risk genes. The clinical utility of these germline P/LP variants includes 32% of patients who were eligible for ongoing clinical treatment trials based on their germline test results (NCT02286687), 60% with clinical management recommendations per current NCCN guidelines, and cascade testing of at risk family members. These data justify comprehensive germline multigene panel testing in all HBC patients, in view of the potential impact on clinical management for a substantial fraction of positive patients as well as facilitating cascade testing for risk assessment of family members.
Abstract 20214: Ethnic Disparities in Metabolic Syndrome Among Caregivers of Preschool Children in a Community-Based Trial
Authors: Jacqueline M Latina, Rodrigo Fernandez-Jimenez, Sameer Bansilal, Rajesh Vedanthan, Ana V Soto, Risa Jaslow, Maribel Santana, Briana Cortez, Alexa Schulman, Monali Fatterpekar, Roger Hajjar, Andrew Kasarskis, Zahi A Fayad, Valentin Fuster
Journal: Circulation (2017)

Introduction: Obesity and dyslipidemia are increasingly prevalent, disproportionately affecting low-income families. We studied the presence of metabolic syndrome (MetS) by ethnicity among caregivers of preschool children in Harlem, New York. Methods: We analyzed 553 Hispanic and non-Hispanic black caregivers of children in Head Start preschools at their baseline assessment enrolling in a community-based lifestyle intervention. MetS was defined by at least 3 of the following: waist circumference >102/88 cm for men/women respectively, systolic/diastolic blood pressure ≥130/85 mm Hg, serum glucose > 100 mg/dL, triglycerides >150 mg/dL, or HDL < 40/50 mg/dL for men/women. Univariate logistic regression was used to determine significant predictors of MetS, and a multivariable logistic regression model was constructed to predict MetS among participants. Results: The mean age of participants was 37.5±11.3 years old. 34.4% Hispanic and 24.6% non-Hispanic black participants had MetS (p=0.015). This difference in ...