tbuckley/cabot-search huggingface dataset:
Abstract 19816: Recipient Body Mass Index and Role of Continuous Flow Mechanical Circulatory Assist Device in Patients Undergoing Heart Transplantation
Authors: Sandip Zalawadiya, Ugochukwu Egolum, Henry Ooi
Journal: Circulation (2015)

Introduction: Extremes of body mass indices (BMI) at the time of heart transplantation (HT) have been associated with adverse post-transplant survival. Data is limited in evaluating the survival impact of continuous flow left mechanical circulatory support (CF-LMCS) devices across categories of BMI. Method: We performed post-hoc analysis of 17,480 patients (age: 53±12 years, 74.5% males, 4.1 years of median follow-up) undergoing HT from the United Network of Organ Sharing (UNOS) registry database. Patients were divided into following BMI categories: underweight (BMI &lt;18.5 kg/m2), normal (BMI 18.5 to 24.9 kg/m2), overweight (BMI 25 to 29.9 kg/m2), mildly obese (BMI 30 to 34.9 kg/m2) and morbidly obese (BMI ≥35 kg/m2); Post-transplant survival was assessed for patients with and without CF-LMCS devices across these categories of BMI using Cox-proportional hazard analysis. Results: See Figure 1 and 2 Conclusion: At extremes of BMI, CF-LMCS devices had statistically non-significant association with post-HT survival. For those with BMI between 18.5 to 35 kg/m2, CF-LMCS devices offered survival advantage, suggesting that optimizing recipients' BMI within this range prior to undergoing HT may help improving their post-transplant survival.
Government considers legal reforms to resolve high cost of clinical negligence claims
Authors: Clare Dyer
Journal: BMJ (2019)

The UK government is considering reforms to the legal process for resolving clinical negligence claims after concluding that making care safer will not be enough to curb the burgeoning costs of compensation.

Dianne Kennard, who heads a cross government working group on how to tackle the rising costs, told a Westminster Forum seminar that there was a “strong case for legal reform.”

Kennard, who works on litigation policy for the Department of Health and Social Care, said the current rise in costs was “unsustainable.” Payouts from the clinical negligence scheme for NHS trusts, which covers hospital …
Abstract 17705: Overestimation by Common Cardiovascular Risk Scores Amongst Primary Prevention Patients in the Cholesterol Treatment Trialists’ Collaboration (CTTC) Database
Authors: Jordan Fulcher, Rachel O'Connell, Anthony Keech
Journal: Circulation (2015)

Introduction: Cardiovascular risk calculators are increasingly used to guide treatment recommendations. We examined the accuracy of popular risk calculators amongst primary prevention, control arm patients of statin trials in the CTTC database Methods: Using individual patient data we compared our previously modelled and highly correlated (r=0.997) five year derived vascular risk of participants in the control arms of 22 randomised statin trials without known vascular disease at baseline with 5 year equivalent Framingham, QRisk2 and Pooled Cohort Equations (PCE) scores for each patient. Results: Data was available for 31050 patients with a CTTC derived median five year absolute risk of 6.2% (IQR 4.0-10.2). There was a similar paired sample correlation between CTTC derived risk and each risk score (Framingham 0.68, QRisk2 0.65, PCE 0.68, all p10%) was 85% for Framingham, 64% for QRisk2 and 55% for PCE scores. Fewer than half of all patients had an absolute difference between predicted and CTTC five year risk of less than 2.5% (Table 2). Conclusions: QRisk2 and Pooled Cohort Equations scores outperform Framingham scores when applied to primary prevention control arm patients in the Cholesterol Treatment Trialists’ database. However for all risk calculators accuracy is limited and risk overestimation occurs in the majority of individuals. This may have implications when predicted risk levels are used to guide recommendations and estimate cost effectiveness for cardiovascular therapies.
Psychosis during Attention Deficit–Hyperactivity Disorder Treatment with Stimulants
Authors: Samuele Cortese
Journal: New England Journal of Medicine (2019)

Attention deficit–hyperactivity disorder (ADHD) is one of the most commonly diagnosed conditions in child and adolescent mental health services. Stimulants, including methylphenidate and amphetamines, are recommended for ADHD treatment.1 Methylphenidate is the most frequently prescribed stimulant in many countries; however, data from private insurance claims show that amphetamines are more commonly prescribed in the United States.2 Despite meta-analyses that show the efficacy of stimulants in reducing ADHD symptoms,3 at least in the short term, the quality of evidence and the safety of these medications continue to be debated. In particular, psychosis can occur during stimulant treatment and can be traumatic . . .
BPI19-016: Evaluation of the Use of a Single Dose Rasburicase in Prophylaxis and Management of Tumor Lysis Syndrome (TLS) Among Cancer Patients in Qatar
Authors: Nancy Kassem, Halima El Omri, Mohamed Yassin, Shereen Elazzazy
Journal: Journal of the National Comprehensive Cancer Network (2019)

Introduction: Rasburicase is a urate oxidase enzyme used for prophylaxis and treatment of hyperuricemia associated with TLS. The recommended dose of rasburicase is 0.2 mg/kg/day for 5 days; however, recent studies have demonstrated the effectiveness of a single rasburicase dose in prophylaxis and management of hyperuricemia associated with TLS. Our institution’s TLS guideline was updated to recommend the use of a single rasburicase dose (0.2 mg/kg). The primary objective of this study was to assess the efficacy of a single rasburicase dose in controlling uric acid (UA); the secondary objective was to evaluate the impact of the institutional TLS guidelines update on consumption and cost of rasburicase. Methods: This is a single center retrospective cohort study including all patients who received rasburicase from August 2012 to March 2016 at the National Center for Cancer Care and Research (NCCCR) in Qatar. Patients were divided into 2 groups based on the prescribed number of rasburicase doses (single dose vs multiple doses). Collected data included patients’ diagnosis, laboratory parameters rasburicase dose, duration, and number of dispensed vials. UA levels within 24 hours and on day 5 of initial rasburicase dose were evaluated. Risk stratification was determined according to institutional guidelines based on disease, white blood cell count, lactate dehydrogenase level, renal function, and UA level. Results: A total of 103 patients who received rasburicase were evaluated retrospectively; rasburicase was prescribed as single dose for 65 patients (63%) and multiple doses for 38 patients (37%). The majority of patients who received rasburicase as single or multiple doses were at high risk of developing TLS, representing 68% and 84%, respectively. Baseline mean UA levels were similar in both groups: 5.4±2.9 mg/dL vs 4.7±3.2 mg/L respectively ( P =.7). Normal or undetectable UA levels were observed within 24 hours in 98% of patients in the single dose group and 100% of patients in the multiple doses group. All patients in both groups had normal UA on day 5 of rasburicase with relatively similar UA levels: 1.5±1.2 mg/dL vs 0.8±1 mg/dL ( P =.18). Rasburicase consumption and cost were reduced by 42.5% after the guidelines update. Conclusion: The single rasburicase dose demonstrated efficacy in controlling serum UA levels. Updating the institutional TLS guidelines had a significant impact on rasburicase consumption and led to significant cost reduction.
Abstract 11729: Stress Computed Tomography Myocardial Perfusion is Superior to Single-Photon Emission Computed Tomography for Detection of Myocardial Ischemia
Authors: Yasushi Ueki
Journal: Circulation (2014)

Introduction: Adenosine stress computed tomography myocardial perfusion imaging (CTP) has been developed to detect myocardial ischemia; however, the diagnostic accuracy has not been fully evaluated...
FoxO3 activation in hypoxic tubules prevents chronic kidney disease
Authors: Ling Li, Huimin Kang, Qing Zhang, Vivette D. D’Agati, Qais Al-Awqati, Fangming Lin
Journal: Journal of Clinical Investigation (2019)

Acute kidney injury (AKI) can lead to chronic kidney disease (CKD) if injury is severe and/or repair is incomplete. However, the pathogenesis of CKD following renal ischemic injury is not fully understood. Capillary rarefaction and tubular hypoxia are common findings during the AKI to CKD transition. We investigated the tubular stress response to hypoxia and demonstrated that a stress responsive transcription factor, FoxO3, was regulated by prolyl hydroxylase. Hypoxia inhibited FoxO3 prolyl hydroxylation and FoxO3 degradation, thus leading to FoxO3 accumulation and activation in tubular cells. Hypoxia-activated Hif-1α contributed to FoxO3 activation and functioned to protect kidneys, as tubular deletion of Hif-1α decreased hypoxia-induced FoxO3 activation, and resulted in more severe tubular injury and interstitial fibrosis following ischemic injury. Strikingly, tubular deletion of FoxO3 during the AKI to CKD transition aggravated renal structural and functional damage leading to a more profound CKD phenotype. We showed that tubular deletion of FoxO3 resulted in decreased autophagic response and increased oxidative injury, which may explain renal protection by FoxO3. Our study indicates that in the hypoxic kidney, stress responsive transcription factors can be activated for adaptions to counteract hypoxic insults, thus attenuating CKD development.
YIA19-004: Collateral Deletion of Glycolysis Genes Generates Selective Vulnerabilities to Inhibitors of Oxidative Phosphorylation
Authors: Florian Muller, Naima Hammoudi
Journal: Journal of the National Comprehensive Cancer Network (2019)

Targeted therapies attacking specific genetic alterations in tumor cells have been an effective strategy in the treatment of many cancers and underlie the concept of “precision medicine.” Successes in various cancers have resulted almost exclusively from targeting activated oncogenes, but this approach has not been proven effective in patients with glioblastoma. We have taken a radically different approach to molecular therapy by targeting genomic deletions, which heretofore have not been considered to be therapeutically actionable. In a chemical biology drug screen of gliomas with passenger deletions in the glycolytic gene Enolase 1 ( ENO1 ), we found that the most cytotoxic agents were those that inhibited mitochondrial oxidative phosphorylation (OxPhos), including a new drug developed at MD Anderson Cancer Center by the Institute of Applied Cancer Science (IACS), which inhibits OxPhos by binding mitochondrial complex I with nM affinity. Exquisite sensitivity to OxPhos inhibition derives from impaired glycolysis, as ENO1 -deleted cells are unable to compensatory upregulate glycolysis in the face of inhibition of OxPhos, and succumb to bioenergetic failure. In addition to ENO1 -deletions, we find that passenger deletion of other metabolic genes, including 6-phosphogluconate dehydrogenase ( PGD ), also exhibit selective sensitivity to OxPhos inhibition by the same underlying biochemical mechanism. The IACS compound was found to penetrate the blood brain-barrier and to eradicate PGD and ENO1 -deleted intracranial xenografts. The lead OxPhos inhibitor, IACS-10759, is currently in phase 1 clinical trial for leukemia, and our data provide a strong rationale for advancing this agent to clinical trials in glioblastoma patients.
HSR19-077: Primary Tumor Location (PTL) and Survival Outcomes in a Real World Cohort of KRAS Wild-Type (WT) Metastatic Colorectal Cancer (mCRC) Patients in the United States
Authors: Himani Aggarwal, Kristin M. Sheffield, Li Li, David Lenis, Rachael Sorg, Rebecca Miksad
Journal: Journal of the National Comprehensive Cancer Network (2019)

Background: PTL is a prognostic factor for mCRC. Recent data suggest PTL is also predictive of survival benefit with cetuximab (CET) and bevacizumab (BEV). This study evaluated the prognostic and predictive effect of PTL in patients with KRAS WT mCRC who initiated first-line (1L) therapy with CET vs BEV in the real world. Methods: This retrospective study selected patients with KRAS WT mCRC who initiated 1L therapy with CET or BEV + FOLFIRI or FOLFOX between January 2013 and April 2017 from Flatiron Health’s electronic health record-derived database. PTL was abstracted from patients’ charts. Left-sided PTL (LPTL): splenic flexure to rectum; right-sided PTL (RPTL): cecum to splenic flexure. Propensity score matching was used to balance treatment cohorts on baseline characteristics. Kaplan Meier and Cox regression methods were used for survival analyses. Results: 1,312 patients met the selection criteria. Of 248 CET + FOLFIRI or FOLFOX patients, 164 had LPTL and 84 had RPTL; of 1,064 BEV + FOLFIRI or FOLFOX patients, 679 had LPTL and 385 had RPTL. CET LPTL and RPTL patients were more likely to receive FOLFIRI vs BEV patients (LPTL: 64.0% vs 24.3%; P &lt;.001; RPTL: 76.2% vs 24.9%; P &lt;.001). Stage at initial diagnosis was different between CET RPTL vs BEV RPTL patients ( P &lt;.001). CET RPTL patients were more likely to be stage III (44.0% vs 22.6%) while BEV RPTL patients were more likely to be stage IV (48.8% vs 65.7%) at initial diagnosis. CET RPTL patients were more likely to have a history of adjuvant chemotherapy vs BEV RPTL patients (47.6% vs 22.3%; P &lt;.001). In the matched sample, median overall survival (OS) was 29.7 months (95% CI, 26.9–35.2) for LPTL patients vs 18.3 months (95% CI, 15.8–21.3) for RPTL patients ( P &lt;.001). Median OS was 29.7 months (95% CI, 27.4–NA) for CET LPTL vs 29.1 months (95% CI, 26.6–35.6) for BEV LPTL patients (HR, 0.87; 95% CI, 0.63–1.19; P =.378), and 17.0 months (95% CI, 12.0–32.6) for CET RPTL vs 18.8 months (95% CI, 15.8–22.3) for BEV RPTL patients (HR, 1.00; 95% CI, 0.68–1.46; P =.996). The interaction of treatment and PTL was not significant in the Cox regression. Conclusions: This study found a prognostic effect of PTL but not a predictive effect. LPTL patients had significantly longer OS vs RPTL patients. However, the treatment effect for CET vs BEV by PTL was not significantly different. Future research is needed to examine differences between real-world and clinical trial populations that may have contributed to divergent results.
Food-seeking behavior has complex evolutionary pressures in songbirds: Linking parental foraging to offspring sexual selection
Authors: Kate T. Snyder, Nicole Creanza
Journal: Behavioral and Brain Sciences (2019)

Abstract The target article addresses increased food-seeking behaviors in times of instability, particularly in passerines. We note that food instability might have intergenerational effects on birds: Nutritional stress during development affects song-learning abilities, associating parental foraging with offspring sexual selection. We explore the implications of these compounding selection pressures on food-seeking motivation during breeding, as well as the hormonal underpinnings of these behaviors.
Preservation of Acyl Coenzyme A Attenuates Pathological and Metabolic Cardiac Remodeling Through Selective Lipid Trafficking
Authors: Joseph R. Goldenberg, Andrew N. Carley, Ruiping Ji, Xiaokan Zhang, Matt Fasano, P. Christian Schulze, E. Douglas Lewandowski
Journal: Circulation (2019)

Background: Metabolic remodeling in heart failure contributes to dysfunctional lipid trafficking and lipotoxicity. Acyl coenzyme A synthetase-1 (ACSL1) facilitates long-chain fatty acid (LCFA) uptake and activation with coenzyme A (CoA), mediating the fate of LCFA. The authors tested whether cardiac ACSL1 overexpression aids LCFA oxidation and reduces lipotoxicity under pathological stress of transverse aortic constriction (TAC). Methods: Mice with cardiac restricted ACSL1 overexpression (MHC-ACSL1) underwent TAC or sham surgery followed by serial in vivo echocardiography for 14 weeks. At the decompensated stage of hypertrophy, isolated hearts were perfused with 13 C LCFA during dynamic-mode 13 C nuclear magnetic resonance followed by in vitro nuclear magnetic resonance and mass spectrometry analysis to assess intramyocardial lipid trafficking. In parallel, acyl CoA was measured in tissue obtained from heart failure patients pre- and postleft ventricular device implantation plus matched controls. Results: TAC-induced cardiac hypertrophy and dysfunction was mitigated in MHC-ACSL1 hearts compared with nontransgenic hearts. At 14 weeks, TAC increased heart weight to tibia length by 46% in nontransgenic mice, but only 26% in MHC-ACSL1 mice, whereas ACSL1 mice retained greater ejection fraction (ACSL1 TAC: 65.8±7.5%; nontransgenic TAC: 45.9±7.3) and improvement in diastolic E/E’. Functional improvements were mediated by ACSL1 changes to cardiac LCFA trafficking. ACSL1 accelerated LCFA uptake, preventing C16 acyl CoA loss post-TAC. Long-chain acyl CoA was similarly reduced in human failing myocardium and restored to control levels by mechanical unloading. ACSL1 trafficked LCFA into ceramides without normalizing the reduced triglyceride storage in TAC. ACSL1 prevented de novo synthesis of cardiotoxic C16- and C24-, and C24:1 ceramides and increased potentially cardioprotective C20- and C22-ceramides post-TAC. ACLS1 overexpression activated AMP activated protein kinase at baseline, but during TAC, prevented the reduced LCFA oxidation in hypertrophic hearts and normalized energy state (phosphocreatine:ATP) and consequently, AMP activated protein kinase activation. Conclusions: This is the first demonstration of reduced acyl CoA in failing hearts of humans and mice, and suggests possible mechanisms for maintaining mitochondrial oxidative energy metabolism by restoring long-chain acyl CoA through ASCL1 activation and mechanical unloading. By mitigating cardiac lipotoxicity, via redirected LCFA trafficking to ceramides, and restoring acyl CoA, ACSL1 delayed progressive cardiac remodeling and failure.
Clinical Impact and Therapeutic Opportunity of Insulin Receptor Substrates 1/2 in Acute Myeloid Leukemia
Authors: Juan Luiz Coelho-Silva, Diego Antonio Pereira-Martins, Josiane Lilian Schiavinato, Eduardo Magalhães Rego, João Agostinho Machado-Neto, Fabiola Traina
Journal: Blood (2018)
RETRACTED ARTICLE: CircPSMC3 suppresses the proliferation and metastasis of gastric cancer by acting as a competitive endogenous RNA through sponging miR-296-5p
Authors: Dawei Rong, Chen Lu, Betty Zhang, Kai Fu, Shuli Zhao, Weiwei Tang, Hongyong Cao
Journal: Molecular Cancer (2019)

Circular RNAs (circRNAs) are a class of non-coding RNAs with a loop structure, but its functions remain largely unknown. Growing evidence has revealed that circRNAs play a striking role as functional RNAs in the progression of malignant disease. However, the precise role of circRNAs in gastric cancer (GC) remains unclear.CircRNAs were determined by human circRNA array analysis and quantitative reverse transcription polymerase reaction. Luciferase reporter, RNA pull down, and fluorescence in situ hybridization assays were employed to test the interaction between circPSMC3 and miR-296-5p. Ectopic over-expression and siRNA-mediated knockdown of circPSMC3, proliferation, migration and invasion in vitro, and in vivo experiment of metastasis were used to evaluate the function of circPSMC3.CircPSMC3 rather than liner PSMC3 mRNA was down-regulated in GC tissues, corresponding plasmas from GC patients as well as GC cell lines compared to normal controls. Lower circPSMC3 expression in GC patients was correlated with higher TNM stage and shorter overall survival. Over-expression of circPSMC3 and miR-296-5p inhibitor could inhibit the tumorigenesis of gastric cancer cells in vivo and vitro whereas co-transfection of circPSMC3 and miRNA-296-5p could counteract this effect. Importantly, we demonstrated that circPSMC3 could act as a sponge of miR-296-5p to regulate the expression of Phosphatase and Tensin Homolog (PTEN), and further suppress the tumorigenesis of gastric cancer cells.Our study reveals that circPSMC3 can serve as a novel potential circulating biomarker for detection of GC. CircPSMC3 participates in progression of gastric cancer by sponging miRNA-296-5p with PTEN, providing a new insight into the treatment of gastric cancer.
Psychosis with Methylphenidate or Amphetamine in Patients with ADHD
Authors: Lauren V. Moran, Dost Ongur, John Hsu, Victor M. Castro, Roy H. Perlis, Sebastian Schneeweiss
Journal: New England Journal of Medicine (2019)

The prescription use of the stimulants methylphenidate and amphetamine for the treatment of attention deficit-hyperactivity disorder (ADHD) has been increasing. In 2007, the Food and Drug Administration mandated changes to drug labels for stimulants on the basis of findings of new-onset psychosis. Whether the risk of psychosis in adolescents and young adults with ADHD differs among various stimulants has not been extensively studied.We used data from two commercial insurance claims databases to assess patients 13 to 25 years of age who had received a diagnosis of ADHD and who started taking methylphenidate or amphetamine between January 1, 2004, and September 30, 2015. The outcome was a new diagnosis of psychosis for which an antipsychotic medication was prescribed during the first 60 days after the date of the onset of psychosis. To estimate hazard ratios for psychosis, we used propensity scores to match patients who received methylphenidate with patients who received amphetamine in each database, compared the incidence of psychosis between the two stimulant groups, and then pooled the results across the two databases.We assessed 337,919 adolescents and young adults who received a prescription for a stimulant for ADHD. The study population consisted of 221,846 patients with 143,286 person-years of follow up; 110,923 patients taking methylphenidate were matched with 110,923 patients taking amphetamines. There were 343 episodes of psychosis (with an episode defined as a new diagnosis code for psychosis and a prescription for an antipsychotic medication) in the matched populations (2.4 per 1000 person-years): 106 episodes (0.10%) in the methylphenidate group and 237 episodes (0.21%) in the amphetamine group (hazard ratio with amphetamine use, 1.65; 95% confidence interval, 1.31 to 2.09).Among adolescents and young adults with ADHD who were receiving prescription stimulants, new-onset psychosis occurred in approximately 1 in 660 patients. Amphetamine use was associated with a greater risk of psychosis than methylphenidate. (Funded by the National Institute of Mental Health and others.).
Mesh Implants for Women: Scandal or Standard of Care?
Authors: Rita Rubin
Journal: JAMA (2019)

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