tbuckley/cabot-search huggingface dataset:
Targeting ER protein TXNDC5 in hepatic stellate cell mitigates liver fibrosis by repressing non-canonical TGFβ signalling
Authors: Chen-Ting Hung, Tung-Hung Su, Yen-Ting Chen, Yueh-Feng Wu, You-Tzung Chen, Sung-Jan Lin, Shuei-Liong Lin, Kai-Chien Yang
Journal: Gut (2021)

Background and objectives Liver fibrosis (LF) occurs following chronic liver injuries. Currently, there is no effective therapy for LF. Recently, we identified thioredoxin domain containing 5 (TXNDC5), an ER protein disulfide isomerase (PDI), as a critical mediator of cardiac and lung fibrosis. We aimed to determine if TXNDC5 also contributes to LF and its potential as a therapeutic target for LF. Design Histological and transcriptome analyses on human cirrhotic livers were performed. Col1a1-GFP Tg , Alb-Cre;Rosa26-tdTomato and Tie2-Cre/ERT2;Rosa26-tdTomato mice were used to determine the cell type(s) where TXNDC5 was induced following liver injury. In vitro investigations were conducted in human hepatic stellate cells (HSCs). Col1a2-Cre/ERT2;Txndc5 fl/fl ( Txndc5 cKO ) and Alb-Cre;Txndc5 fl/fl ( Txndc5 Hep-cKO ) mice were generated to delete TXNDC5 in HSCs and hepatocytes, respectively. Carbon tetrachloride treatment and bile duct ligation surgery were employed to induce liver injury/fibrosis in mice. The extent of LF was quantified using histological, imaging and biochemical analyses. Results TXNDC5 was upregulated markedly in human and mouse fibrotic livers, particularly in activated HSC at the fibrotic foci. TXNDC5 was induced by transforming growth factor β1 (TGFβ1) in HSCs and it was both required and sufficient for the activation, proliferation, survival and extracellular matrix production of HSC. Mechanistically, TGFβ1 induces TXNDC5 expression through increased ER stress and ATF6-mediated transcriptional regulation. In addition, TXNDC5 promotes LF by redox-dependent JNK and signal transducer and activator of transcription 3 activation in HSCs through its PDI activity, activating HSCs and making them resistant to apoptosis. HSC-specific deletion of Txndc5 reverted established LF in mice. Conclusions ER protein TXNDC5 promotes LF through redox-dependent HSC activation, proliferation and excessive extracellular matrix production. Targeting TXNDC5, therefore, could be a potential novel therapeutic strategy to ameliorate LF.
Noninvasive Identification of Carditis in Acute Rheumatic Fever
Authors: Sarah J. Gutman, Benedict T. Costello, Melissa G. van Leeuwen, Leah M. Wright, Seeba E. Varghese, Jessica O’Brien, Stephen Brady, Christopher X. Wong, Graeme P. Maguire, Thomas H. Marwick, Jagat Narula, Andrew J. Taylor
Journal: JACC. Cardiovascular imaging (2021)
Chilblains and COVID-19—An Update on the Complexities of Interpreting Antibody Test Results, the Role of Interferon α, and COVID-19 Vaccines
Authors: Qisi Sun, Esther E. Freeman
Journal: JAMA Dermatology (2021)

Patrick E. McCleskey, MD; Bree Zimmerman, MD; Amara Lieberman, MD; Liyan Liu, MD, MSc; Cynthia Chen, MD; Farzam Gorouhi, MD; Christine C. Jacobson, MD; David S. Lee, MD; Achyuth Sriram, MD; Amanda Thornton, MD; Arnd M. Herz, MD; Paradi Mirmirani, MD; Lisa J. Herrinton, PhD
Efficacy of biological therapies and small molecules in moderate to severe ulcerative colitis: systematic review and network meta-analysis
Authors: Nicholas E Burr, David J Gracie, Christopher J Black, Alexander C Ford
Journal: Gut (2021)

Objective Biological therapies and small molecules continue to be evaluated in moderate to severely active ulcerative colitis, but are often studied in placebo-controlled trials, meaning their relative efficacy and safety is unknown. We examined this in a network meta-analysis. Design We searched the literature to October 2021 to identify eligible trials. We judged efficacy using clinical remission, endoscopic improvement, or clinical response, and according to previous exposure or non-exposure to antitumour necrosis factor (TNF)-α therapy. We also assessed safety. We used a random effects model and reported data as pooled relative risks (RRs) with 95% CIs. Interventions were ranked according to their P-score. Results We identified 28 trials (12 504 patients). Based on failure to achieve clinical remission, upadacitinib 45 mg once daily ranked first versus placebo (RR 0.73; 95% CI 0.68 to 0.80, P-score 0.98), with infliximab 5 mg/kg and 10 mg/kg second and third, respectively. Upadacitinib ranked first for clinical remission in both patients naïve to anti-TNF-α drugs (RR 0.69; 95% CI 0.61 to 0.78, P-score 0.99) and previously exposed (RR 0.78; 95% CI 0.72 to 0.85, P-score 0.99). Upadacitinib was superior to almost all other drugs in these analyses. Based on failure to achieve endoscopic improvement infliximab 10 mg/kg ranked first (RR 0.61; 95% CI 0.51 to 0.72, P-score 0.97), with upadacitinib 45 mg once daily, second, and infliximab 5 mg/kg third. Upadacitinib was more likely to lead to adverse events, but serious adverse events were no more frequent, and withdrawals due to adverse events were significantly lower than with placebo. Infections were significantly more likely with tofacitinib than placebo (RR 1.41; 95% CI 1.03 to 1.91). Conclusion In a network meta-analysis, upadacitinib 45 mg once daily ranked first for clinical remission in all patients, patients naïve to anti-TNF-α drugs and patients previously exposed. Infliximab 10 mg/kg ranked first for endoscopic improvement. Most drugs were safe and well tolerated.
Assessment of population infection with SARS-CoV-2 in Ontario, Canada, March to June 2020
Authors: Shelly Bolotin, Vanessa Tran, Shelley L Deeks, Adriana Peci, Kevin A Brown, Sarah A Buchan, Katherene Ogbulafor, Tubani Ramoutar, Michelle Nguyen, Rakesh Thakkar, Reynato DelaCruz, Reem Mustfa, Jocelyn Maregmen, Orville Woods, Ted Krasna, Kirby Cronin, Selma Osman, Eugene Joh, Vanessa G Allen
Journal: Eurosurveillance (2021)

Background Serosurveys for SARS-CoV-2 aim to estimate the proportion of the population that has been infected. Aim This observational study assesses the seroprevalence of SARS-CoV-2 antibodies in Ontario, Canada during the first pandemic wave. Methods Using an orthogonal approach, we tested 8,902 residual specimens from the Public Health Ontario laboratory over three time periods during March–June 2020 and stratified results by age group, sex and region. We adjusted for antibody test sensitivity/specificity and compared with reported PCR-confirmed COVID-19 cases. Results Adjusted seroprevalence was 0.5% (95% confidence interval (CI): 0.1–1.5) from 27 March–30 April, 1.5% (95% CI: 0.7–2.2) from 26–31 May, and 1.1% (95% CI: 0.8–1.3) from 5–30 June 2020. Adjusted estimates were highest in individuals aged ≥ 60 years in March–April (1.3%; 95% CI: 0.2–4.6), in those aged 20–59 years in May (2.1%; 95% CI: 0.8–3.4) and in those aged ≥ 60 years in June (1.6%; 95% CI: 1.1–2.1). Regional seroprevalence varied, and was highest for Toronto in March–April (0.9%; 95% CI: 0.1–3.1), for Toronto in May (3.2%; 95% CI: 1.0–5.3) and for Toronto (1.5%; 95% CI: 0.9–2.1) and Central East in June (1.5%; 95% CI: 1.0–2.0). We estimate that COVID-19 cases detected by PCR in Ontario underestimated SARS-CoV-2 infections by a factor of 4.9. Conclusions Our results indicate low population seroprevalence in Ontario, suggesting that public health measures were effective at limiting the spread of SARS-CoV-2 during the first pandemic wave.
Abstract 12069: Long-Term Trends in the Incidence and Outcome of Refractory and Non-Refractory Ventricular Fibrillation Cardiac Arrest
Authors: Ziad Nehme, Emily Andrew, Jocasta Ball, Karen L Smith
Journal: Circulation (2021)

Introduction: Although many developed countries are reporting temporal improvements in out-of-hospital cardiac arrest (OHCA) outcomes from initial shockable rhythms, trends in the incidence and outcome of refractory ventricular fibrillation are not well understood. Methods: Between 2010 and 2019, we performed a retrospective observational study of OHCA from a population-based registry in Victoria, Australia. We included all adult, non-traumatic OHCA with an initial shockable rhythm. Temporal trends in incidence and survival to hospital discharge were compared across non-refractory and refractory OHCA, defined as cases receiving 3 or more consecutive shocks for a persistent shockable rhythm. Risk-adjusted logistic regression models were used to describe the year-on-year change in the likelihood of refractory OHCA and survival to hospital discharge. Results: Of the 7,267 initial shockable OHCA with an attempted resuscitation, 4168 (57.4%) and 3,099 (42.6%) were non-refractory and refractory OHCA, respectively. The proportion of cases with refractory OHCA declined over the study period from 48.4% in 2010 to 40.2% in 2019 (p trend &lt;0.001). Unadjusted survival to hospital discharge was higher in non-refractory OHCA (46.3% vs. 25.8%, p&lt;0.001), although both populations experienced increases in survival over time (p trend &lt;0.05 for both). After adjustment for arrest confounders, the likelihood of refractory VF decreased by 4.4% every year (adjusted odds ratio [AOR]: 0.96, 95% CI: 0.94, 0.97; p&lt;0.001). Factors reducing the likelihood of refractory OHCA were female sex, bystander CPR, arrest witnessed by emergency medical services, and public location. In the survival model, refractory OHCA was independently associated with a reduction in survival to hospital discharge (AOR 0.50, 95% CI: 0.45, 0.56; p&lt;0.001). Temporal improvements in survival were observed year-on-year (AOR 1.03, 95% CI: 1.02, 1.05; p&lt;0.001) and this did not differ between non-refractory and refractory OHCA (group interaction, p = 0.51). Conclusions: The incidence of refractory OHCA is declining in our region and survival outcomes are improving. Further research identifying factors contributing to the decline in refractory OHCA may help to improve outcomes further.
Pregnancy Outcomes in Young Women With Youth-Onset Type 2 Diabetes Followed in the TODAY Study
Authors: Marsha D. Marcus, Rachelle Gandica, Laure El ghormli, Janine Higgins, Bereket Tesfaldet, Dorit Koren, Sarah Macleish, Elia Nila Escaname, Ruth S. Weinstock
Journal: Diabetes Care (2021)

OBJECTIVE To assess pregnancy outcomes in young women with youth-onset type 2 diabetes followed in the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study. RESEARCH DESIGN AND METHODS Pregnancy information (outcome and any maternal or fetal complications) was obtained from the female participants by self-report. Additionally, medical records for the pregnancy and the child’s neonatal course were obtained with data abstracted into standardized forms. RESULTS Over a maximum of 15 years, 260 pregnancies were reported by 141 women (aged 21.5 ± 3.2 years, BMI 35.6 ± 7.2 kg/m2, and diabetes duration 8.1 ± 3.2 years). Contraception use prior to pregnancy was reported by 13.5% of the women. Complications were reported by 65% of the women during their pregnancy. Pregnancy loss was observed in 25.3% and preterm birth in 32.6% of pregnancies. HbA1c ≥8% was observed in 31.9% of the pregnancies, and 35% of the pregnancies were complicated by chronic hypertension. Nephropathy prior to pregnancy was observed in 25% of the women. In the offspring, 7.8% were classified as small for gestational age, 26.8% large for gestational age, and 17.9% in the macrosomic range. CONCLUSIONS Based on observations from the TODAY cohort, young women with pregestational, youth-onset type 2 diabetes had very high rates of maternal complications stemming from significant socioeconomic disadvantage. The substantial maternal and infant complications seen in these young moms could potentially be avoided with improved contraception rates and reproductive planning.
Legalization of Psychedelic Substances
Authors: Michael D. Alpert
Journal: JAMA (2021)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Clinical validation of digital biomarkers for paediatric patients with asthma and cystic fibrosis: potential for clinical trials and clinical care
Authors: Matthijs D. Kruizinga, Esmée Essers, Frederik E. Stuurman, Yalçin Yavuz, Marieke L. de Kam, Ahnjili Zhuparris, Hettie M. Janssens, Iris Groothuis, Arwen J. Sprij, Marianne Nuijsink, Adam F. Cohen, Gertjan J.A. Driessen
Journal: European Respiratory Journal (2021)

Background Digital biomarkers are a promising novel method to capture clinical data in a home setting. However, clinical validation prior to implementation is of vital importance. The aim of this study was to clinically validate physical activity, heart rate, sleep and forced expiratory volume in 1 s (FEV 1 ) as digital biomarkers measured by a smartwatch and portable spirometer in children with asthma and cystic fibrosis (CF). Methods This was a prospective cohort study including 60 children with asthma and 30 children with CF (aged 6–16 years). Participants wore a smartwatch, performed daily spirometry at home and completed a daily symptom questionnaire for 28 days. Physical activity, heart rate, sleep and FEV 1 were considered candidate digital end-points. Data from 128 healthy children were used for comparison. Reported outcomes were compliance, difference between patients and controls, correlation with disease activity, and potential to detect clinical events. Analysis was performed with linear mixed effects models. Results Median compliance was 88%. On average, patients exhibited lower physical activity and FEV 1 compared with healthy children, whereas the heart rate of children with asthma was higher compared with healthy children. Days with a higher symptom score were associated with lower physical activity for children with uncontrolled asthma and CF. Furthermore, FEV 1 was lower and (nocturnal) heart rate was higher for both patient groups on days with more symptoms. Candidate biomarkers appeared able to describe a pulmonary exacerbation. Conclusions Portable spirometer- and smartwatch-derived digital biomarkers show promise as candidate end-points for use in clinical trials or clinical care in paediatric lung disease.
Functional Analysis Identifies Damaging<i>CHEK2</i>Missense Variants Associated with Increased Cancer Risk
Authors: Rick A.C.M. Boonen, Wouter W. Wiegant, Nandi Celosse, Bas Vroling, Stephan Heijl, Zsofia Kote-Jarai, Martina Mijuskovic, Simona Cristea, Nienke Solleveld-Westerink, Tom van Wezel, Niko Beerenwinkel, Rosalind Eeles, Peter Devilee, Maaike P.G. Vreeswijk, Giancarlo Marra, Haico van Attikum
Journal: Cancer Research (2021)

Abstract Heterozygous carriers of germline loss-of-function variants in the tumor suppressor gene checkpoint kinase 2 (CHEK2) are at an increased risk for developing breast and other cancers. While truncating variants in CHEK2 are known to be pathogenic, the interpretation of missense variants of uncertain significance (VUS) is challenging. Consequently, many VUS remain unclassified both functionally and clinically. Here we describe a mouse embryonic stem (mES) cell–based system to quantitatively determine the functional impact of 50 missense VUS in human CHEK2. By assessing the activity of human CHK2 to phosphorylate one of its main targets, Kap1, in Chek2 knockout mES cells, 31 missense VUS in CHEK2 were found to impair protein function to a similar extent as truncating variants, while 9 CHEK2 missense VUS resulted in intermediate functional defects. Mechanistically, most VUS impaired CHK2 kinase function by causing protein instability or by impairing activation through (auto)phosphorylation. Quantitative results showed that the degree of CHK2 kinase dysfunction correlates with an increased risk for breast cancer. Both damaging CHEK2 variants as a group [OR 2.23; 95% confidence interval (CI), 1.62–3.07; P &amp;lt; 0.0001] and intermediate variants (OR 1.63; 95% CI, 1.21–2.20; P = 0.0014) were associated with an increased breast cancer risk, while functional variants did not show this association (OR 1.13; 95% CI, 0.87–1.46; P = 0.378). Finally, a damaging VUS in CHEK2, c.486A&amp;gt;G/p.D162G, was also identified, which cosegregated with familial prostate cancer. Altogether, these functional assays efficiently and reliably identified VUS in CHEK2 that associate with cancer. Significance: Quantitative assessment of the functional consequences of CHEK2 variants of uncertain significance identifies damaging variants associated with increased cancer risk, which may aid in the clinical management of patients and carriers.
Adjuvant Therapy for Stage II Colon Cancer: ASCO Guideline Update
Authors: Nancy N. Baxter, Erin B. Kennedy, Emily Bergsland, Jordan Berlin, Thomas J. George, Sharlene Gill, Philip J. Gold, Alex Hantel, Lee Jones, Christopher Lieu, Najjia Mahmoud, Arden M. Morris, Erika Ruiz-Garcia, Y. Nancy You, Jeffrey A. Meyerhardt
Journal: Journal of Clinical Oncology (2021)

To develop recommendations for adjuvant therapy for patients with resected stage II colon cancer.ASCO convened an Expert Panel to conduct a systematic review of relevant studies and develop recommendations for clinical practice.Twenty-one observational studies and six randomized controlled trials met the systematic review inclusion criteria.Adjuvant chemotherapy (ACT) is not routinely recommended for patients with stage II colon cancer who are not in a high-risk subgroup. Patients with T4 tumors are at higher risk of recurrence and should be offered ACT, whereas patients with other high-risk factors, including sampling of fewer than 12 lymph nodes in the surgical specimen, perineural or lymphovascular invasion, poorly or undifferentiated tumor grade, intestinal obstruction, tumor perforation, or grade BD3 tumor budding, may be offered ACT. The addition of oxaliplatin to fluoropyrimidine-based ACT is not routinely recommended, but may be offered as a result of shared decision making. Patients with mismatch repair deficiency/microsatellite instability tumors should not be routinely offered ACT; if the combination of mismatch repair deficiency/microsatellite instability and high-risk factors results in a decision to offer ACT, oxaliplatin-containing chemotherapy is recommended. Duration of oxaliplatin-containing chemotherapy is also addressed, with recommendations for 3 or 6 months of treatment with capecitabine and oxaliplatin or fluorouracil, leucovorin, and oxaliplatin, with decision making informed by key evidence of 5-year disease-free survival in each treatment subgroup and the rate of adverse events, including peripheral neuropathy.Additional information is available at www.asco.org/gastrointestinal-cancer-guidelines.
Abstract 17228: Not Just Another Knick In The Wall: An Unusual Case Of Multiple Arterial Aneurysms
Authors: Vibha Amblihalli, Ayita Ray, Hafiz Khalid, luigi pacifico
Journal: Circulation (2021)

Case Presentation: 47-year-old Liberian woman with a history of latent TB and no prior cardiac history presented with dyspnea, palpitations, and weight loss. She had fevers, tachycardia, and cervical lymphadenopathy. Cardiac exam showed widened pulse pressure, systolic and diastolic murmur, and features of heart failure. TTE showed dilated left ventricle with preserved ejection fraction, aortic root aneurysm compressing left atrium, severe aortic and mitral regurgitation, and moderate pericardial effusion with no tamponade. CT angiogram of neck, chest and abdomen showed right subclavian artery mycotic aneurysm, large left supraclavicular lymphadenopathy, multiple aortic arch, and descending thoracic aorta mycotic aneurysms. She underwent emergent surgical intervention. Intraoperative TEE revealed rupture of aortic root aneurysm into left ventricular outflow tract causing a fistula, perforated anterior mitral leaflet, and distortion of the left atrial wall. She underwent mitral and aortic tissue valve replacement, aortic root replacement, and a pericardial patch repair of the left atrial wall. Subsequently, she underwent right subclavian artery aneurysm resection, right carotid axillary bypass, and vertebral artery reimplantation. Aortic valve pathology was suggestive of endocarditis with negative cultures. Lymph node biopsy revealed non-necrotizing granulomatous inflammation with no evidence of acid-fast bacilli, fungi, and malignancy. Autoimmune workup was negative. A PET CT showed post-surgical inflammatory changes with no evidence of malignancy. Discussion: We describe an unusual case of multiple large arterial aneurysms causing severe valvular insufficiency requiring emergent surgical intervention. The patient underwent extensive workup which was unrevealing. She was treated for subacute bacterial endocarditis and suspected Bechet’s disease. Thus, the quest for a definitive diagnosis continues to elude us.