tbuckley/cabot-search huggingface dataset:
AB1313-HPR EFFECTS OF N-ACETYLCYSTEINE ON PULMONARY FUNCTIONS IN PATIENTS WITH SYSTEMIC SCLEROSIS: A DOUBLE BLIND, PLACEBO CONTROLLED STUDY
Authors: M. A. Nazarinia, S. Mehrabi, Z. Khodamoradi, M. Mazidi Moradi
Journal: Annals of the Rheumatic Diseases (2020)

Background: Systemic sclerosis (SSc) is a systematic and rare autoimmune disease that affects many organs. N-acetylcysteine (NAC), thiol containing compound, can act both as the precursor of reduced glutathione and direct scavenger of reactive oxygen species. Objectives: We assessed the clinical effect of NAC on pulmonary function test of patients with diffuse scleroderma. Methods: This study is a randomized double blind clinical trial that was done on 25 patients with diffuse SSc without lung involvement on primary chest high-resolution computed tomography. Placebo was administered for 13 patients and 1200 milligram NAC for 12 patients. Body plethysmography parameters were assessed at the beginning of the study and after 24 weeks. Results: Patients in the two groups were matched in the basic demographic data like age, duration of disease, and modified Rodnan skin score. The analysis showed no significant differences in parameters of plethysmography between the two groups. After importing the data of 2 patients in the placebo-treated group, who developed interstitial lung disease, DLCO in the placebo-treated group was 90.69 ± 21.29 milliliter at the end of the study, which significantly decreased compared with the beginning of the study (102.30 ± 13.83 ml). Also, changes of DLCO between the two groups were significantly different. Conclusion: In this trial, sensitivity of DLCO as the first marker in evaluation of pulmonary function in patients with SSc was confirmed. On the other hand, NAC had no effect versus placebo in a period of 24 weeks. We recommend that more studies with larger sample size and longer duration should conduct for further evaluation. References: No reference. Acknowledgments: The present article was extracted from the thesis written by Maryam Mazidi Moradi. The authors would like to thank Shiraz University of Medical Sciences, Shiraz, Iran and also Center for Development of Clinical Research of Nemazee Hospital and Dr. Nasrin Shokrpour for editorial assistance. Disclosure of Interests: None declared
Prescribing by Ethnicity: (Im)precision Medicine?
Authors: Nishi Chaturvedi, Sophie Eastwood
Journal: Diabetes Care (2020)

The right drug, for the right patient, at the right time. Who wouldn’t want this? For diabetologists, after decades of domination by biguanides and sulfonylureas, only briefly punctuated by thiazolidinediones, the choice of early-stage glucose-lowering agents has recently more than doubled, now including glucagon-like peptide 1 (GLP-1) receptor agonists, and dipeptidyl peptidase 4 (DPP-4) and sodium–glucose cotransporter 2 (SGLT2) inhibitors. Armed with this greater choice, can we now fulfill the promise of precision medicine?

Half of the 500 million people in the world with diabetes live in either China or the Indian subcontinent (1). Aside from simple demographics, these huge numbers are largely due to the greater diabetes susceptibility experienced by both populations. In this issue, Gan and associates (2) hypothesize that pathophysiological differences contributing to this greater susceptibility may be associated with different glycemic responses to diabetes medication. This is not unreasonable; 20% of new drug approvals show differences in exposure or response by ethnicity (3). They performed a systematic review and meta-analysis of published randomized clinical trials comparing absolute change in HbA1c from baseline to either 24 or 52 weeks in studies that recruited predominantly (>70%) Asians versus studies that recruited predominantly (>70%) whites. They report that SGLT2 and, possibly, DPP-4 inhibitors are more effective in lowering HbA1c in Asians than in whites. There was no ethnic difference in efficacy of GLP-1 receptor agonists.

Their findings are somewhat at odds with previous work. The most striking observation, of an ∼0.3% lower HbA1c in Asians than in whites in response to SGLT2 inhibitors, contrasts with a previous meta-analysis reporting no ethnic difference (4), though an agent-specific analysis did show modest superiority of dapagliflozin (0.16%) in Asians versus non-Asians. Gan et al. …
Association of Radial Artery Graft vs Saphenous Vein Graft With Long-term Cardiovascular Outcomes Among Patients Undergoing Coronary Artery Bypass Grafting
Authors: Mario Gaudino, Umberto Benedetto, Stephen Fremes, Karla Ballman, Giuseppe Biondi-Zoccai, Art Sedrakyan, Giuseppe Nasso, Jai Raman, Brian Buxton, Philip A. Hayward, Neil Moat, Peter Collins, Carolyn Webb, Miodrag Peric, Ivana Petrovic, Kyung J. Yoo, Irbaz Hameed, Antonino Di Franco, Marco Moscarelli, Giuseppe Speziale, John D. Puskas, Leonard N. Girardi, David L. Hare, David P. Taggart
Journal: JAMA (2020)

<h3>Importance</h3> Observational studies have suggested that the use of radial artery grafts for coronary artery bypass grafting may improve clinical outcomes compared with the use of saphenous vein grafts, but this has not been confirmed in randomized trials. <h3>Objective</h3> To compare clinical outcomes between patients receiving radial artery vs saphenous vein grafts for coronary artery bypass grafting after long-term follow-up. <h3>Design, Setting, and Participants</h3> Patient-level pooled analysis comparing radial artery vs saphenous vein graft in adult patients undergoing isolated coronary artery bypass grafting from 5 countries (Australia, Italy, Serbia, South Korea, and the United Kingdom), with enrollment from 1997 to 2009 and follow-up completed in 2019. <h3>Interventions</h3> Patients were randomized to undergo either radial artery (n = 534) or saphenous vein (n = 502) grafts for coronary artery bypass grafting. <h3>Main Outcomes and Measures</h3> The primary outcome was a composite of death, myocardial infarction, or repeat revascularization and the secondary outcome was a composite of death or myocardial infarction. <h3>Results</h3> A total of 1036 patients were randomized (mean age, 66.6 years in the radial artery group vs 67.1 years in the saphenous vein group; 376 [70.4%] men in the radial artery group vs 351 [69.9%] in the saphenous vein group); 942 (90.9%) of the originally randomized patients completed 10 years of follow-up (510 in the radial artery group). At a median (interquartile range) follow-up of 10 (10-11) years, the use of the radial artery, compared with the saphenous vein, in coronary artery bypass grafting was associated with a statistically significant reduction in the incidence of the composite outcome of death, myocardial infarction, or repeat revascularization (220 vs 237 total events; 41 vs 47 events per 1000 patient-years; hazard ratio, 0.73 [95% CI, 0.61-0.88];<i>P</i> &lt; .001) and of the composite of death or myocardial infarction (188 vs 193 total events; 35 vs 38 events per 1000 patient-years; hazard ratio, 0.77 [95% CI, 0.63-0.94];<i>P</i> = .01). <h3>Conclusions and Relevance</h3> In this individual participant data meta-analysis with a median follow-up of 10 years, among patients undergoing coronary artery bypass grafting, the use of the radial artery compared with the saphenous vein was associated with a lower risk of a composite of cardiovascular outcomes.
A coagulation defect arising from heterozygous premature termination of tissue factor
Authors: Sol Schulman, Emale El-Darzi, Mary H.C. Florido, Max Friesen, Glenn Merrill-Skoloff, Marisa A. Brake, Calvin R. Schuster, Lin Lin, Randal J. Westrick, Chad A. Cowan, Robert Flaumenhaft, Willem H. Ouwehand, Kathelijne Peerlinck, Kathleen Freson, Ernest Turro, Bruce Furie
Journal: Journal of Clinical Investigation (2020)

Tissue factor (TF) is the primary initiator of blood coagulation in vivo and the only blood coagulation factor for which a human genetic defect has not been described. As there are no routine clinical assays that capture the contribution of endogenous TF to coagulation initiation, the extent to which reduced TF activity contributes to unexplained bleeding is unknown. Using whole genome sequencing, we identified a heterozygous frameshift variant (p.Ser117HisfsTer10) in F3, the gene encoding TF, causing premature termination of TF (TFshort) in a woman with unexplained bleeding. Routine hematological laboratory evaluation of the proposita was normal. CRISPR-edited human induced pluripotent stem cells recapitulating the variant were differentiated into vascular smooth muscle and endothelial cells that demonstrated haploinsufficiency of TF. The variant F3 transcript is eliminated by nonsense-mediated decay. Neither overexpression nor addition of exogenous recombinant TFshort inhibited factor Xa or thrombin generation, excluding a dominant-negative mechanism. F3+/- mice provide an animal model of TF haploinsufficiency and exhibited prolonged bleeding times, impaired thrombus formation, and reduced survival following major injury. Heterozygous TF deficiency is present in at least 1 in 25,000 individuals and could limit coagulation initiation in undiagnosed individuals with abnormal bleeding but a normal routine laboratory evaluation.
Predicting and Preventing Myocardial Infarction in the Young
Authors: Sandeep R. Das
Journal: Diabetes Care (2020)

In this issue of Diabetes Care , Divakaran et al. (1) report on patients from the Partners YOUNG-MI registry who suffered a first myocardial infarction (MI) at or before the age of 50 years. They describe diabetes prevalence and long-term cardiovascular outcomes stratified by diabetes status. Diabetes is a well-established risk factor for major adverse cardiovascular events (MACE) such as MI, stroke, or cardiovascular death. However, most existing data are in older patients. Thus, this article offers an opportunity to gain insight into an important and understudied population.

The mean age of this study cohort was 44 years, 19% were women, and 73% were white. Patients were enrolled between 2000 and 2016, and median follow-up was just over 11 years. Of the 2,097 patients in this cohort, 416 (20%) had diabetes, 39 (2%) of whom had type 1 diabetes. In 81 patients (20% of the patients with diabetes, 4% of the overall cohort), this was a new diabetes diagnosis. Although young, the risk factor burden in these patients was substantial. Half the cohort reported current smoking, 9 in 10 carried a diagnosis of hyperlipidemia, and 1 in 4 reported a family history of premature cardiovascular disease. Despite this significant risk factor burden, the median atherosclerotic cardiovascular disease (ASCVD) 10-year risk score was just under 10% in study patients with diabetes.

Despite the young age of this cohort, the cumulative incidence curves shown in Fig. 1 of the article show all-cause mortality >20% at 10 years in patients on insulin and >10% in patients with diabetes not on insulin. Cardiovascular mortality was ∼10% in patients with diabetes, over threefold higher than …
A Phase Ib/II Study of the BRAF Inhibitor Encorafenib Plus the MEK Inhibitor Binimetinib in Patients with <i>BRAFV600E/K</i>-mutant Solid Tumors
Authors: Ryan J. Sullivan, Jeffrey Weber, Sapna Patel, Reinhard Dummer, Matteo S. Carlino, Daniel S.W. Tan, Celeste Lebbé, Salvatore Siena, Elena Elez, Lance Wollenberg, Michael D. Pickard, Victor Sandor, Paolo A. Ascierto
Journal: Clinical Cancer Research (2020)

This open-label, dose-finding phase Ib/II study reports the safety and activity of the first combination use with BRAF inhibitor (BRAFi) encorafenib plus MEK inhibitor (MEKi) binimetinib in patients with BRAF V600E-mutant solid tumors.In phase I, the recommended phase 2 doses (RP2D) were established (primary objective). In phase II, the clinical activity of the combination at the RP2D was assessed (primary objective) in patients with BRAF-mutant metastatic colorectal cancer (mCRC), BRAFi-treated BRAF-mutant melanoma, and BRAFi-naïve BRAF-mutant melanoma.A total of 126 patients with BRAF-mutant solid tumors were enrolled (phase I: 47 patients; phase II: 79 patients). The RP2D was encorafenib 450 mg once daily plus binimetinib 45 mg twice daily and pharmacokinetic data suggest that drug exposures of each agent were similar in combination compared with single-agent studies. In the phase II cohorts, confirmed responses were seen in two of 11 (18%) evaluable patients with mCRC, 11 of 26 (42%) evaluable patients with BRAFi-pretreated melanoma, and 28 of 42 (67%) BRAFi-naïve patients with melanoma. The most common grade 3/4 adverse event in phase II was increased alanine aminotransferase.The combination of encorafenib (450 mg) plus binimetinib (45 mg) showed acceptable tolerability and encouraging activity in patients with BRAF V600-mutant tumors, which led to the dose selection for the melanoma COLUMBUS study. The safety profile of the combination was consistent with other approved BRAFi plus MEKi regimens, with several differences, including lower rates of dose-limiting pyrexia, arthralgia, and photosensitivity.
New combination treatment from ROS-Induced sensitized radiotherapy with nanophototherapeutics to fully eradicate orthotopic breast cancer and inhibit metastasis
Authors: Te-I Liu, Ting-Yu Lu, Ying-Chieh Yang, Siou-Han Chang, Hsin-Hung Chen, I.-Lin Lu, Arjun Sabu, Hsin-Cheng Chiu
Journal: Biomaterials (2020)
Shortened Relative Leukocyte Telomere Length Is Associated With Prevalent and Incident Cardiovascular Complications in Type 2 Diabetes: Analysis From the Hong Kong Diabetes Register
Authors: Feifei Cheng, Andrea O. Luk, Claudia H.T. Tam, Baoqi Fan, Hongjiang Wu, Aimin Yang, Eric S.H. Lau, Alex C.W. Ng, Cadmon K.P. Lim, Heung Man Lee, Elaine Chow, Alice P. Kong, Anthony C. Keech, Mugdha V. Joglekar, Wing Yee So, Alicia J. Jenkins, Juliana C.N. Chan, Anandwardhan A. Hardikar, Ronald C.W. Ma
Journal: Diabetes Care (2020)

OBJECTIVE Several studies support potential links between relative leukocyte telomere length (rLTL), a biomarker of biological aging, and type 2 diabetes. This study investigates relationships between rLTL and incident cardiovascular disease (CVD) in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS Consecutive Chinese patients with type 2 diabetes (N = 5,349) from the Hong Kong Diabetes Register for whom DNA obtained at baseline was stored and follow-up data were available were studied. rLTL was measured by using quantitative PCR. CVD was diagnosed on the basis of ICD-9 code. RESULTS Mean follow-up was 13.4 years (SD 5.5 years). rLTL was correlated inversely with age, diabetes duration, blood pressure, HbA1c, and urine albumin-to-creatinine ratio (ACR), and positively with estimated glomerular filtration rate (eGFR) (all P &amp;lt; 0.001). Subjects with CVD at baseline had a shorter rLTL (4.3 ± 1.2 ΔΔCt) than did subjects without CVD (4.6 ± 1.2 ΔΔCt) (P &amp;lt; 0.001). Of the 4,541 CVD-free subjects at baseline, the 1,140 who developed CVD during follow-up had a shorter rLTL (4.3 ± 1.2 ΔΔCt) than those who remained CVD-free after adjusting for age, sex, smoking, and albuminuria status (4.7 ± 1.2 ΔΔCt) (P &amp;lt; 0.001). In Cox regression models, shorter rLTL was associated with higher risk of incident CVD (for each unit decrease, hazard ratio 1.252 [95% CI 1.195–1.311], P &amp;lt; 0.001), which remained significant after adjusting for age, sex, BMI, systolic blood pressure, LDL cholesterol, HbA1c, eGFR, and ACR (hazard ratio 1.141 [95% CI 1.084–1.200], P &amp;lt; 0.001). CONCLUSIONS rLTL is significantly shorter in patients with type 2 diabetes and CVD, is associated with cardiometabolic risk factors, and is independently associated with incident CVD. Telomere length may be a useful biomarker for CVD risk in patients with type 2 diabetes.
The Paradox of HIV Blood–Brain Barrier Penetrance and Antiretroviral Drug Delivery Deficiencies
Authors: Olivia Osborne, Nadia Peyravian, Madhavan Nair, Sylvia Daunert, Michal Toborek
Journal: Trends in Neurosciences (2020)

HIV attacks the body's immune cells, frequently compromises the integrity of the blood-brain barrier (BBB), and infects the CNS in the early stages of infection. Dysfunction of the BBB further potentiates viral replication within the CNS, which can lead to HIV-associated neuropathology. Antiretroviral therapy (ART) significantly improves HIV patient outcomes and reduces mortality rates. However, there has been limited progress in targeting latent viral reservoirs within the CNS, which may eventually lead to rebound viremia. While ART drugs are shown to be effective in attenuating HIV replication in the periphery, the protection of the brain by the BBB offers an isolated sanctuary to harbor HIV and maintains chronic and persistent replication within the CNS. In this review, we elucidate the pathology of the BBB, its ability to potentiate viral replication, as well as current therapies and insufficiencies in treating HIV-infected individuals.
Prognostic Value of Early 18F-FDG PET/CT Scanner Evaluation in Immunocompetent Primary CNS Lymphoma Patients
Authors: Rudy Birsen, Estelle Blanc, Barbara Burroni, Chloe Broudin, Lise Willems, Marielle Legoff, Emmanuelle Leray, Sylvain Pilorge, Sawsen Salah, Aude Quentin, Bénédicte Deau-Fisher, Patricia Franchi, Marguerite Vignon, Laurence Mabille, Charles Nguyen, Youlia Kirova, Pascale Varlet, Arnault tauziede-Espariat, Myriam Edjlali, Dezamis Edouard, Khe Hoang-xuan, Caroline Houillier, Carole Soussain, Johan Pallud, Diane Damotte, Didier Bouscary, Jerome Tamburini Bonnefoy
Journal: Blood (2017)
Age-specific sequence of colorectal cancer screening options in Germany: A model-based critical evaluation
Authors: Thomas Heisser, Korbinian Weigl, Michael Hoffmeister, Hermann Brenner
Journal: PLoS Medicine (2020)

Background The current organized screening program for colorectal cancer in Germany offers both sexes 5 annual fecal immunochemical tests (FITs) between ages 50 and 54 years, followed by a first screening colonoscopy at age 55 years if all of these FITs were negative. We sought to assess the implications of this approach for key parameters of diagnostic performance. Methods and findings Using a multistate Markov model, we estimated the expected detection rates of advanced neoplasms (advanced adenomas and cancers) and number needed to scope (NNS) to detect 1 advanced neoplasm at a first screening colonoscopy conducted at age 55 after 5 preceding negative FITs and compared them with the corresponding estimates for a first screening colonoscopy at age 55 with no preceding FIT testing. In individuals with 5 consecutive negative FITs undergoing screening colonoscopy at age 55, expected colonoscopy detection rate (NNS) was 3.7% (27) and 0.10% (1,021) for any advanced neoplasm and cancer, respectively, in men, and 2.1% (47) and 0.05% (1,880) for any advanced neoplasm and cancer, respectively, in women. These NNS values for detecting 1 advanced neoplasm are approximately 3-fold higher, and the NNS values for detecting 1 cancer are approximately 8-fold higher, than those for a first screening colonoscopy at age 55 without prior FITs. This study is limited by model simplifying assumptions and uncertainties related to input parameters. Conclusions Screening colonoscopy at age 55 after 5 consecutive negative FITs at ages 50–54, as currently offered in the German cancer early detection program, is expected to have very low positive predictive value. Our results may inform efforts to enhance the design of screening programs.
Hepatocellular Carcinoma in Acute Hepatic Porphyrias: Results from the Longitudinal Study of the U.S. Porphyrias Consortium
Authors: Behnam Saberi, Hetanshi Naik, Jessica R. Overbey, Angelika L. Erwin, Karl E. Anderson, D. Montgomery Bissell, Herbert L. Bonkovsky, John D. Phillips, Bruce Wang, Ashwani K.Singal, Brendan M.McGuire, Robert J. Desnick, Manisha Balwani
Journal: Hepatology (2020)

The risk for hepatocellular carcinoma (HCC) is increased in acute hepatic porphyrias (AHP). The aim of this study was to explore the clinicopathologic characteristics, outcomes, and frequency of HCC in patients with AHP in the United States.This cross-sectional analysis evaluated patients with HCC in a multicenter, longitudinal study of AHP. Among 327 patients with AHP, 5 (1.5%) were diagnosed with HCC. Of the 5 HCC cases, 4 had acute intermittent porphyria and 1 had variegate porphyria, confirmed by biochemical and/or genetic testing. All patients were white females, with a median age of 27 years (range 21-75) at diagnosis. The median age at HCC diagnosis was 69 years (range 61-74). AHP was asymptomatic in 2 patients; 2 reported sporadic attacks; and 1 reported recurrent attacks (>4 attacks/year). All patients had a single HCC lesion on liver imaging that was 1.8-6.5 centimeters in diameter. Serum alpha fetoprotein levels were below 10 ng/mL in all 4 patients with available results. Four patients underwent liver resection, and 1 was treated with radioembolization. No significant inflammation or fibrosis was found in adjacent liver tissues of 3 patients who underwent liver resection. Two patients developed recurrence of HCC at 22 and 26 months following liver resection. All patients are alive with survival times from HCC diagnosis ranging from 26-153 months.In this U.S. study, 1.5% of patients with AHP had HCC. HCC in AHP occurred in the absence of cirrhosis, which contrasts with other chronic liver diseases. Patients with AHP, regardless of clinical attacks, should be screened for HCC, beginning at age 50. The pathogenesis of hepatocarcinogenesis in AHP is unknown and needs further investigation.
DNA damage repair response in mesenchymal stromal cells: From cellular senescence and aging to apoptosis and differentiation ability
Authors: Behnaz banimohamad-shotorbani, Houman Kahroba, Hadi Sadeghzadeh, David M. Wilson, Hamid Maadi, Nasser Samadi, Mohammad Saeid Hejazi, Hekmat Farajpour, Behzad Nemati Onari, Mohammad Reza Sadeghi
Journal: Ageing Research Reviews (2020)
An exosome-like programmable-bioactivating paclitaxel prodrug nanoplatform for enhanced breast cancer metastasis inhibition
Authors: Kaiyuan Wang, Hao Ye, Xuanbo Zhang, Xia Wang, Bin Yang, Cong Luo, Zhiqiang Zhao, Jian Zhao, Qi Lu, Haotian Zhang, Qiming Kan, Yongjun Wang, Zhonggui He, Jin Sun
Journal: Biomaterials (2020)
Liver Injury in COVID-19: Caution and Management
Authors: Jiasheng Cao, Xiujun Cai, Mingyu Chen
Journal: Liver Cancer (2020)

The postmortem biopsies of a COVID-19 patient showed mild lobular and portal activity, and moderate microvascular steatosis, which indicated that liver injury was SARS-CoV-2 infection-related or drug-related [2]. [...]clinicians should concentrate on liver injury and monitoring liver function in COVID-19 patients. [...]considering the immunocompromised status, intensive surveillance and individually tailored therapy are appropriate for the above patients. Even if the COVID-19 RT-PCR test was negative during the treatment, it may be positive later due to the rise of viral load as the dosage of immunosuppression medicine was increased. [...]strict screening guidance and prolonged follow-up should be offered for liver recipients with COVID-19 infection.
Next-generation sequencing in the diagnosis of non-cirrhotic splanchnic vein thrombosis
Authors: Marta Magaz, Alberto Alvarez-Larrán, Dolors Colomer, Mónica López-Guerra, M. Ángeles García-Criado, Gabriel Mezzano, Ernest Belmonte, Pol Olivas, Guillem Soy, Francisco Cervantes, Anna Darnell, José Ferrusquía-Acosta, Anna Baiges, Fanny Turon, Virginia Hernández-Gea, Juan Carlos García-Pagán
Journal: Journal of Hepatology (2020)