tbuckley/cabot-search huggingface dataset:
Tocilizumab did not reduce hypoxemic respiratory failure or death in hospitalized patients with COVID-19
Authors: Sameer Sharif, Bram Rochwerg
Journal: Annals of Internal Medicine (2021)

ACP Journal Club2 February 2021Tocilizumab did not reduce hypoxemic respiratory failure or death in hospitalized patients with COVID-19Sameer Sharif, MD, Bram Rochwerg, MD, MScSameer Sharif, MDMcMaster University, Hamilton, Ontario, Canada (S.S., B.R.)Search for more papers by this author, Bram Rochwerg, MD, MScMcMaster University, Hamilton, Ontario, Canada (S.S., B.R.)Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/ACPJ202102160-016 SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail Source CitationStone JH, Frigault MJ, Serling-Boyd NJ, et al. Efficacy of tocilizumab in patients hospitalized with Covid-19. N Engl J Med. 2020;383:2333-44. https://pubmed.ncbi.nlm.nih.gov/33085857Clinical Impact RatingsHospitalists: Infectious Disease: Critical Care: Pulmonology: References1 Le RQ, Li L, Yuan W, et al. FDA approval summary: tocilizumab for treatment of chimeric antigen receptor T cell-induced severe or life-threatening cytokine release syndrome. Oncologist. 2018;23:943-7. [PMID: 29622697] Google Scholar2 Wise J. Covid-19: critically ill patients treated with arthritis drug tocilizumab show improved outcomes, researchers report. BMJ. 2020;371:m4530. [PMID: 33214134] Google Scholar3 Pierrakos C, Vincent JL. Sepsis biomarkers: a review. Crit Care. 2010;14:R15. [PMID: 20144219] Google Scholar4 The WHO Rapid Evidence Appraisal for COVID19 Therapies (REACT) Working Group; Sterne JA, Murthy S, Diaz JV, et al. Association between administration of systemic corticosteroids and mortality among critically ill patients with COVID-19: a meta-analysis. JAMA. 2020;324:1330-41. [PMID: 32876694] Google Scholar Author, Article, and Disclosure InformationAuthors: Sameer Sharif, MD; Bram Rochwerg, MD, MScAffiliations: McMaster University, Hamilton, Ontario, Canada (S.S., B.R.)Disclosures: The commentators have disclosed no conflicts of interest. The forms can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M20-7313.This article was published at Annals.org on 2 February 2021. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics February 2021Volume 174, Issue 2 Page: JC16 Keywords Confidence intervals COVID-19 Cytokines Hazard ratio Immunosuppressives Intensive care units Intent to treat analysis Oxygen Respiratory failure Ventilators ePublished: 2 February 2021 Issue Published: February 2021 Copyright & PermissionsCopyright © 2021 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
Primary Tumor Resection Plus Chemotherapy Versus Chemotherapy Alone for Colorectal Cancer Patients With Asymptomatic, Synchronous Unresectable Metastases (JCOG1007; iPACS): A Randomized Clinical Trial
Authors: Yukihide Kanemitsu, Kohei Shitara, Junki Mizusawa, Tetsuya Hamaguchi, Dai Shida, Koji Komori, Satoshi Ikeda, Hitoshi Ojima, Hideyuki Ike, Akio Shiomi, Jun Watanabe, Yasumasa Takii, Takashi Yamaguchi, Kenji Katsumata, Masaaki Ito, Junji Okuda, Ryoji Hyakudomi, Yasuhiro Shimada, Hiroshi Katayama, Haruhiko Fukuda
Journal: Journal of Clinical Oncology (2021)

It remains controversial whether primary tumor resection (PTR) before chemotherapy improves survival in patients with colorectal cancer (CRC) with asymptomatic primary tumor and synchronous unresectable metastases.This randomized phase III study investigated the superiority of PTR followed by chemotherapy versus chemotherapy alone in relation to overall survival (OS) in patients with unresectable stage IV asymptomatic CRC and three or fewer unresectable metastatic diseases confined to the liver, lungs, distant lymph nodes, or peritoneum. Chemotherapy regimens of either mFOLFOX6 plus bevacizumab or CapeOX plus bevacizumab were decided before study entry. The primary end point was OS, which was analyzed by intention-to-treat.Between June 2012 and September 2019, a total of 165 patients were randomly assigned to either chemotherapy alone (84 patients) or PTR plus chemotherapy (81 patients). When the first interim analysis was performed in September 2019 with 50% (114/227) of the expected events observed among 160 patients at the data cutoff date of June 5, 2019, the Data and Safety Monitoring Committee recommended early termination of the trial because of futility. With a median follow-up of 22.0 months, median OS was 25.9 months (95% CI, 19.9 to 31.5) in the PTR plus chemotherapy arm and 26.7 (95% CI, 21.9 to 32.5) in the chemotherapy-alone arm (hazard ratio, 1.10; 95% CI, 0.76 to 1.59; one-sided P = .69). Three postoperative deaths occurred in the PTR plus chemotherapy arm.Given that PTR followed by chemotherapy showed no survival benefit over chemotherapy alone, PTR should no longer be considered a standard of care for patients with CRC with asymptomatic primary tumors and synchronous unresectable metastases.
Effects of the TNFRSF11B Mutation Associated With Calcium Pyrophosphate Deposition Disease in Osteoclastogenesis in a Murine Model
Authors: Elizabeth Mitton‐Fitzgerald, Claudia M. Gohr, Charlene J. Williams, Amaryllis Ortiz, Gabriel Mbalaviele, Ann K. Rosenthal
Journal: Arthritis & Rheumatology (2021)

The gene TNFRSF11B encodes for osteoprotegerin (OPG) and was recently identified as the CCAL1 locus associated with familial calcium pyrophosphate deposition disease (CPDD). While the CCAL1 OPG mutation (OPG-XL) was originally believed to be a gain-of-function mutation, loss of OPG activity causes arthritis-associated osteolysis in mice, which is likely related to excess subchondral osteoclast formation and/or activity. The purpose of the present study was to further explore the effect of OPG-XL in osteoclastogenesis.The effects of recombinant OPG-XL and wild-type (WT) OPG were determined in monoculture and coculture models of RANKL-induced osteoclastogenesis. The effects of OPG-XL on osteoclast survival as well as on TRAIL-induced apoptosis were determined using standard in vitro assays and compared to WT OPG. The ability of OPG-XL and WT OPG to bind to osteoblasts was measured with enzyme-linked immunosorbent assay and flow cytometry using the osteoblastic MC3T3-E1 cell line.OPG-XL was less effective than WT OPG at blocking RANKL-induced osteoclastogenesis in monoculture and coculture models. Osteoclast survival and inhibition of TRAIL-induced apoptosis were similar in the presence of OPG-XL and WT OPG. Compared to WT OPG, considerably less OPG-XL bound to cells.These findings indicate that OPG-XL is a loss-of-function mutation as it relates to RANKL-mediated osteoclastogenesis, and thus may permit increased osteoclast numbers and heightened bone turnover. Further studies are necessary to demonstrate how this mutation contributes to arthritis in individuals carrying this mutation.
Efficacy of Endocrine Therapy for the Treatment of Breast Cancer in Men
Authors: Mattea Reinisch, Sabine Seiler, Tanja Hauzenberger, Axel Kamischke, Sabine Schmatloch, Hans-Joachim Strittmatter, Dirk-Michael Zahm, Christian Thode, Jenny Furlanetto, Dominika Strik, Volker Möbus, Toralf Reimer, Bruno Valentin Sinn, Elmar Stickeler, Frederik Marmé, Wolfgang Janni, Marcus Schmidt, Christian Rudlowski, Michael Untch, Valentina Nekljudova, Sibylle Loibl
Journal: JAMA Oncology (2021)

<h3>Importance</h3> The extent of changes in estradiol levels in male patients with hormone receptor–positive breast cancer receiving standard endocrine therapies is unknown. The sexual function and quality of life related to those changes have not been adequately evaluated. <h3>Objective</h3> To assess the changes in estradiol levels in male patients with breast cancer after 3 months of therapy. <h3>Design, Setting, and Participants</h3> This multicenter, phase 2 randomized clinical trial assessed 56 male patients with hormone receptor–positive breast cancer. Patients were recruited from 24 breast units across Germany between October 2012 and May 2017. The last patient completed 6 months of treatment in December 2017. The analysis data set was locked on August 24, 2018, and analysis was completed on December 19, 2018. <h3>Interventions</h3> Patients were randomized to 1 of 3 arms: tamoxifen alone or tamoxifen plus gonadotropin-releasing hormone analogue (GnRHa) or aromatase inhibitor (AI) plus GnRHa for 6 months. <h3>Main Outcomes and Measures</h3> The primary end point was the change in estradiol levels from baseline to 3 months. Secondary end points were changes of estradiol levels after 6 months, changes of additional hormonal parameters, adverse effects, sexual function, and quality of life after 3 and 6 months. <h3>Results</h3> In this phase 2 randomized clinical trial, a total of 52 of 56 male patients with a median (range) age of 61.5 (37-83) years started treatment. A total of 3 patients discontinued study treatment prematurely, 1 in each arm. A total of 50 patients were evaluable for the primary end point. After 3 months the patients’ median estradiol levels increased by 67% (a change of +17.0 ng/L) with tamoxifen, decreased by 85% (−23.0 ng/L) with tamoxifen plus GnRHa, and decreased by 72% (−18.5 ng/L) with AI plus GnRHa (<i>P</i> &lt; .001). After 6 months, median estradiol levels increased by 41% (a change of +12 ng/L) with tamoxifen, decreased by 61% (−19.5 ng/L) with tamoxifen plus GnRHa, and decreased by 64% (−17.0 ng/L) with AI plus GnRHa (<i>P</i> &lt; .001). Sexual function and quality of life decreased when GnRHa was added but were unchanged with tamoxifen alone. <h3>Conclusions and Relevance</h3> This phase 2 randomized clinical trial found that AI or tamoxifen plus GnRHa vs tamoxifen alone led to a sustained decrease of estradiol levels. The decreased hormonal parameters were associated with impaired sexual function and quality of life. <h3>Trial Registration</h3> ClinicalTrials.gov Identifier:NCT01638247
Importance of Myocardial Fibrosis in Functional Mitral Regurgitation
Authors: Bernardo B.C. Lopes, Deborah H. Kwon, Dipan J. Shah, John R. Lesser, Vinayak Bapat, Maurice Enriquez-Sarano, Paul Sorajja, João L. Cavalcante
Journal: JACC. Cardiovascular imaging (2021)
Comparing Machine Learning Models for Identifying Chronic Cough Using Diagnosis and Medication in the Electronic Health Records
Authors: Vishal Bali, Xiao Luo, Priyanka Gandhi, Zuoyi Zhang, Wei Shao, Zhi Han, Vasu Chandrasekaran, Vladimir Turzhitsky, Anna Roberts, Megan Metzger, Jarod Baker, Carmen La Rosa, Jessica Weaver, Paul Dexter, Kun Huang
Journal: Journal of Allergy and Clinical Immunology (2021)
Transcriptional and Metabolic Control of Memory B Cells and Plasma Cells
Authors: Tyler J. Ripperger, Deepta Bhattacharya
Journal: Annual Review of Immunology (2021)

For many infections and almost all vaccines, neutralizing-antibody-mediated immunity is the primary basis and best functional correlate of immunological protection. Durable long-term humoral immunity is mediated by antibodies secreted by plasma cells that preexist subsequent exposures and by memory B cells that rapidly respond to infections once they have occurred. In the midst of the current pandemic of coronavirus disease 2019, it is important to define our current understanding of the unique roles of memory B cells and plasma cells in immunity and the factors that control the formation and persistence of these cell types. This fundamental knowledge is the basis to interpret findings from natural infections and vaccines. Here, we review transcriptional and metabolic programs that promote and support B cell fates and functions, suggesting points at which these pathways do and do not intersect.
Ustekinumab for Refractory Colitis Associated with Immune Checkpoint Inhibitors
Authors: Anusha S. Thomas, Weijie Ma, Yinghong Wang
Journal: New England Journal of Medicine (2021)

Ustekinumab for Refractory Colitis Associated with Immune Checkpoint InhibitorsTo the Editor: Immune-mediated colitis, an adverse effect of therapy with immune checkpoint inhibitors that block the production of cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death 1 (PD-1), 1 is managed with glucocorticoids, followed by the administration of infliximab or vedolizumab.Recently, tofacitinib was reported to be effective in one refractory case, although data are lacking with respect to evaluation and management. 2 Transplantation of fecal microbiota has shown favorable results in aggressive cases. 3 Here, we present two cases of refractory immune-mediated colitis that were managed with ustekinumab, a human monoclonal antibody against interleukin-12/23 that is routinely used in patients with severe Crohn's disease. 4 Patient 1, a 56-year-old man with stage III right axillary malignant melanoma, was treated with surgical resection, adjuvant radiation, and nivolumab.The treatment was complicated by the development of grade 3 diarrhea (according to the Common Terminology Criteria for Adverse Events), and nivolumab therapy was withheld.Colonoscopy in which biopsy specimens were obtained showed lymphocytic colitis.The patient had clinical remission of the diarrhea after three infusions of vedolizumab, but the colitis returned and did not respond to glucocorticoids or additional vedolizumab.After induction and three maintenance doses of ustekinumab, the patient had clinical remission from immune-mediated colitis and was cancer-free (Fig. 1A).Patient 2, a 61-year-old woman with stage IV left midback melanoma, underwent surgical excision and was treated with PD-1-directed nivolumab and radiation.Immunotherapy was withheld owing to the development of immune-mediated hepatitis.Consequent metastases to the lungs,
Microsatellite Instability and KRAS Mutation in Stage IV Colorectal Cancer: Prevalence, Geographic Discrepancies, and Outcomes From the National Cancer Database
Authors: Johannes Uhlig, Michael Cecchini, Amar Sheth, Stacey Stein, Jill Lacy, Hyun S. Kim
Journal: Journal of the National Comprehensive Cancer Network (2021)

This study sought to assess microsatellite and KRAS status, prevalence, and impact on outcome in stage IV colorectal cancer (CRC).The 2010 to 2016 US National Cancer Database was queried for adult patients with stage IV CRC. Prevalence of microsatellite status (microsatellite instability-high [MSI-H] or microsatellite stable [MSS]) and KRAS status (KRAS mutation or wild-type) of the primary CRC was assessed. Overall survival (OS) was evaluated using multivariable Cox proportional hazards models in patients with complete data on both microsatellite and KRAS status and information on follow-up.Information on microsatellite and KRAS status was available for 10,844 and 25,712 patients, respectively, and OS data were available for 5,904 patients. The overall prevalence of MSI-H status and KRAS mutation was 3.1% and 42.4%, respectively. Prevalence of MSI-H ranged between 1.6% (rectosigmoid junction) and 5.2% (transverse colon), and between 34.7% (sigmoid colon) and 58.2% (cecum) for KRAS mutation. MSI-H rates were highest in East North Central US states (4.1%), and KRAS mutation rates were highest in West South Central US states (44.1%). Multivariable analyses revealed longer OS for patients with KRAS wild-type versus mutation status (hazard ratio [HR], 0.91; 95% CI, 0.85-0.97; P=.004), those with MSS versus MSI-H status (HR, 0.75; 95% CI, 0.62-0.9; P=.003), and those with left-sided versus right-sided CRC (multivariable HR, 0.65; 95% CI, 0.6-0.7; P<.001). The effect of KRAS mutation further varied with CRC site and microsatellite status (P=.002 for interaction).Depending on the primary site and US geography, stage IV CRC shows distinct mutational behavior. KRAS mutation, MSI-H, and primary CRC sidedness independently affect OS and interact with distinct prognostic profiles. Generically classifying adenocarcinomas at different sites as CRC might deprecate this diversity.
Examining the Relationship Between Delay Discounting, Delay Aversion, Diabetes Self-care Behaviors, and Diabetes Outcomes in U.S. Adults With Type 2 Diabetes
Authors: Jennifer A. Campbell, Joni S. Williams, Leonard E. Egede
Journal: Diabetes Care (2021)

OBJECTIVE Delay discounting and delay aversion are emerging areas for understanding diabetes management; however, few data exist on their relationship with multiple diabetes self-care behaviors and diabetes outcomes. RESEARCH DESIGN AND METHODS This cross-sectional study included 356 adults with type 2 diabetes across three racial/ethnic groups receiving care from two primary care clinics. The primary predictors were delay discounting and delay aversion. Outcomes included self-care behaviors, quality of life (QOL; mental health component score [MCS], physical component score), and A1C. Multiple linear regression models were run to examine the association between predictors and the outcomes, A1C, QOL, and each self-care behavior. RESULTS Higher delay discounting was associated with lower engagement in self-care behaviors for general diet (B = −0.06; 95% CI −0.12; −0.01), specific diet (B = −0.07; 95% CI −0.12; −0.03), and foot care (B = −0.10; 95% CI −0.17; −0.02). Higher delay aversion was associated with lower engagement in self-care behaviors for general diet (B = −0.06; 95% CI −0.10; −0.01), specific diet (B = −0.03; 95% CI −0.07; −0.01), foot care (B = −0.11; 95% CI −0.17; −0.05), and lower MCS (B = −0.38; 95% CI −0.71; −0.06). CONCLUSIONS In a diverse sample of adults with type 2 diabetes, higher delay discounting and higher delay aversion were significantly related to lower engagement in self-care behaviors. High delay aversion was specifically related to lower QOL. These findings offer new knowledge by highlighting the role that delay-related behaviors may have in the performance of self-care behaviors and the impact on QOL. Work is needed to further elucidate these relationships. Specifically, these results highlight the importance of targeting value and decision-making for diabetes self-management.
Prenatal Exposure to Nitrate from Drinking Water and Markers of Fetal Growth Restriction: A Population-Based Study of Nearly One Million Danish-Born Children
Authors: Vanessa R. Coffman, Anja Søndergaard Jensen, Betina B. Trabjerg, Carsten B. Pedersen, Birgitte Hansen, Torben Sigsgaard, Jørn Olsen, Inger Schaumburg, Jörg Schullehner, Marie Pedersen, Leslie T. Stayner
Journal: Environmental Health Perspectives (2021)

BACKGROUND: High levels of nitrate (NO - 3 ) in drinking water cause methemoglobinemia in infants; however, few studies have examined the potential effects of low-level exposure on fetal growth, and the results have been inconsistent.OBJECTIVES: We sought to assess the association between maternal exposure to nitrate in drinking water during pregnancy and offspring size at birth in a nationwide study of full-term (≥37 wk gestation) live-born singletons.METHODS: We estimated maternal nitrate exposure for 898,206 births in Denmark during 1991-2011 by linkage of individual home address(es) with nitrate data from the national monitoring database.Maternal address during pregnancy, infant size at birth [i.e., birth weight, low birth weight (LBW), body length, and birth head circumference] and covariates were compiled from the Danish Civil Registration System, the Danish Medical Birth Register, and The Integrated Database for Longitudinal Labor Market Research.Linear and logistic models with generalized estimating equations were used to account for multiple births to an individual.Nitrate exposure was modeled using five categories and as a log-transformed continuous variable.RESULTS: There was evidence of a decreasing trend in models for term birth weight using categorical or continuous measures of exposure.Modeling exposure continuously, a difference of -9:71 g (95% confidence interval: -14:60, -4:81) was predicted at 25 mg=L (half the value of the European Union drinking water standard) compared with 0 mg=L NO - 3 .Body length also decreased as nitrate concentrations increased in categorical and continuous models.There was little evidence of an association between NO - 3 and head circumference or LBW.DISCUSSION: Although the estimated effects were small, our findings for live singleton births to Danish-born parents suggest that maternal intake of nitrate from drinking water may reduce term birth weight and length, which are markers of intrauterine growth.However, there was little evidence for an association between nitrate and head circumference or LBW.Future studies in other populations and with data on dietary sources of nitrate are encouraged to confirm or refute these findings.
Maintenance therapy with infliximab or vedolizumab in IBD is not associated with increased SARS-CoV-2 seroprevalence: UK experience in the 2020 pandemic
Authors: Colleen GC McGregor, Alex Adams, Ross Sadler, Carolina V Arancibia-Cárcamo, Rebecca Palmer, Tim Ambrose, Oliver Brain, Alissa Walsh, Paul Klenerman, Simon PL Travis, Nicholas M Croft, James O Lindsay, Jack Satsangi
Journal: Gut (2021)

We read with great interest the recent publication from Ungaro and colleagues,1 reporting the latest data from the Surveillance Epidemiology of Coronavirus Under Research Exclusion (SECURE-IBD) registry. These data, while raising concerns regarding the use of thiopurine and corticosteroid therapy in the SARS-CoV-2 pandemic, also provide valuable reassurance that monotherapy with anticytokine therapies, in particular those directed against tumour necrosis factor (TNF), are not associated with adverse outcomes in patients with IBD developing COVID-19. It has been postulated that anticytokine therapies may ameliorate or abrogate the ‘cytokine storm’ associated with severe COVID-19,2 with anti-IL6 strategies now approved for use.3

We have assessed the SARS-CoV-2 antibody seroprevalence in patients with IBD, receiving either intravenous anti-TNF therapy, or anti-integrin therapy, during the first wave of the pandemic in the UK.

Sera from 640 patients attending for maintenance infliximab or vedolizumab infusions between April and June 2020 at the John Radcliffe Hospital (Oxford, UK) and Royal London Hospital (London, UK) were tested using the Abbott SARS-CoV-2 IgG assay. Adults (180) and paediatric (56) patients were included from London. Demographic and clinical data are summarised (online supplemental tables 1, 2). Key differences between the Oxford and London adult cohorts included ethnicity, smoking, comorbidities, disease type, concomitant thiopurines and biologic; in our data set, patients attending Royal London Hospital had significantly greater evidence for deprivation than Oxford (deprivation score 4 (3–6.3) vs 8 (6–9.3), p<0.001). Seroprevalence data were compared with available data from a contemporaneous healthy healthcare worker (HCW) …
Targeted immunotherapy for HER2-low breast cancer with 17p loss
Authors: Yujing Li, Yifan Sun, Michael Kulke, Torsten Hechler, Kevin Van der Jeught, Tianhan Dong, Bin He, Kathy D. Miller, Milan Radovich, Bryan P. Schneider, Andreas Pahl, Xinna Zhang, Xiongbin Lu
Journal: Science Translational Medicine (2021)

Trastuzumab conjugated to α-amanitin kills HER2-low breast cancer cells with loss of chromosome 17p and enhances checkpoint blockade therapy.