tbuckley/cabot-search huggingface dataset:
Analysis of Severe Hypoglycemia Among Adults With Type 2 Diabetes and Nonalcoholic Fatty Liver Disease
Authors: Ji-Yeon Lee, Young-eun Kim, Kyungdo Han, Eugene Han, Byung Wan Lee, Eun Seok Kang, Bong-Soo Cha, Seung-Hyun Ko, Yong-ho Lee
Journal: JAMA Network Open (2022)

<h3>Importance</h3> Previous studies have indicated that liver cirrhosis is associated with hypoglycemia, but there have been no studies investigating the association between nonalcoholic fatty liver disease (NAFLD) and hypoglycemia in noncirrhotic populations with type 2 diabetes. <h3>Objective</h3> To explore the association of NAFLD with severe hypoglycemia among patients with type 2 diabetes. <h3>Design, Setting, and Participants</h3> This nationwide population-based retrospective cohort study using the National Health Insurance System of South Korea included individuals aged 20 years or older who had undergone a medical health examination between January 1, 2009, and December 31, 2012, and were diagnosed with type 2 diabetes. Participants were followed up until December 31, 2015. Data analyses were performed between January 1, 2019, and February 2, 2021. <h3>Exposures</h3> The baseline fatty liver index (FLI) was used as a surrogate marker for NAFLD. <h3>Main Outcomes and Measures</h3> The outcome of interest, severe hypoglycemia, was measured using hospital admission and emergency department visit records with a primary diagnosis of hypoglycemia. <h3>Results</h3> Among 1 946 581 individuals with type 2 diabetes, 1 125 187 (57.8%) were male. During a median (IQR) follow-up of 5.2 (4.1-6.1) years, 45 135 (2.3%) experienced 1 or more severe hypoglycemia events. Participants with severe hypoglycemia, vs those without severe hypoglycemia, were older (mean [SD] age, 67.9 [9.9] years vs 57.2 [12.3] years;<i>P</i> &lt; .001) and had lower mean (SD) body mass index (24.2 [3.43] vs 25.1 [3.4];<i>P</i> &lt; .001). Patients with NAFLD tended to have less severe hypoglycemia without consideration of obesity status. However, after adjustment of multiple clinical covariates, including body mass index, there was a J-shaped association between FLI and severe hypoglycemia (5th decile: adjusted hazard ratio [aHR], 0.86; 95% CI, 0.83-0.90; 9th decile: aHR, 1.02; 95% CI, 0.96-1.08; 10th decile: aHR, 1.29; 95% CI, 1.22-1.37), and the estimated risk of hypoglycemia was higher in participants with NAFLD (aHR, 1.26; 95% CI, 1.22-1.30). The association was more prominent in female participants (aHR, 1.29; 95% CI, 1.23-1.36) and those with underweight (aHR, 1.71; 95% CI, 1.02-2.88). <h3>Conclusions and Relevance</h3> In this study, NAFLD was associated with a higher risk of severe hypoglycemia in patients with type 2 diabetes independent of obesity status. Presence of NAFLD should be considered when evaluating vulnerability to hypoglycemia in patients with type 2 diabetes.
Time to raise the bar: Transition rate of phase 1 programs on anticancer drugs
Authors: Shen Zhao, Dong Wang, Hongyun Zhao, Jifang Gong, Jian Zhang, Wenfeng Fang, Fei Ma, Binghe Xu, Jin Li, Xichun Hu, Yi Ba, Xiaoyuan Chen, Zhimin Yang, Lin Shen, Jianhua Jiang, Li Zhang
Journal: Cancer Cell (2022)
Secondary Gastrointestinal Amyloidosis With Increased 18F-FDG Uptake as the Only Presentation in a Patient With Multiple Myeloma
Authors: Jie Ding, Li Huo, Ruixue Cui, Yaping Luo
Journal: Clinical Nuclear Medicine (2022)

Abstract A 63-year-old woman presented with abdominal pain and hematochezia was referred for 18 F-FDG PET/CT for the underlying malignancy. PET/CT detected diffuse thickening of the bowel walls with intense radioactivity in the colons. She was later diagnosed with multiple myeloma and secondary gastrointestinal amyloidosis, and achieved complete response of myeloma and amyloidosis after 9 cycles of chemotherapy. This case highlighted that gastrointestinal abnormality caused by amyloidosis might be the only presenting symptoms and findings in 18 F-FDG PET/CT in patients with multiple myeloma.
PKCα/ZFP64/CSF1 axis resets the tumor microenvironment and fuels anti-PD1 resistance in hepatocellular carcinoma
Authors: Chuan-Yuan Wei, Meng-Xuan Zhu, Peng-Fei Zhang, Xiao-Yong Huang, Jin-Kai Wan, Xiu-Zhong Yao, Ze-Tao Hu, Xiao-Qiang Chai, Rui Peng, Xuan Yang, Chao Gao, Jian Gao, Si-Wei Wang, Yi-Min Zheng, Zheng Tang, Qiang Gao, Jian Zhou, Jia-Bin Fan, Ai-Wu Ke, Jia Fan
Journal: Journal of Hepatology (2022)

Despite remarkable advances in treatment, most patients with hepatocellular carcinoma (HCC) respond poorly to anti-programmed cell death 1 (anti-PD1) therapy. A deeper insight into the tolerance mechanism of HCC against this therapy is urgently needed.We performed next-generation sequencing, multiplex immunofluorescence, and dual-color immunohistochemistry and constructed an orthotopic HCC xenograft tumor model to identify the key gene associated with anti-PD1 tolerance. A spontaneously tumorigenic transgenic mouse model, an in vitro coculture system, mass cytometry, and multiplex immunofluorescence were used to explore the biological function of zinc finger protein 64 (ZFP64) on tumor progression and immune escape. Molecular and biochemical strategies like RNA-sequencing, chromatin immunoprecipitation-sequencing and mass spectrometry were used to gain insight into the underlying mechanisms of ZFP64.We showed that ZFP64 is frequently upregulated in tumor tissues from patients with anti-PD1-resistant HCC. Elevated ZFP64 drives anti-PD1 resistance by shifting macrophage polarization toward an alternative activation phenotype (M2) and fostering an inhibitory tumor microenvironment. Mechanistically, we primarily demonstrated that protein kinase C alpha (PKCα) directly phosphorylates ZFP64 at S226, leading to its nuclear translocation and the transcriptional activation of macrophage colony-stimulating factor (CSF1). HCC-derived CSF1 transforms macrophages to the M2 phenotype to drive immune escape and anti-PD1 tolerance. Notably, Gö6976, a protein kinase inhibitor, and lenvatinib, a multi-kinase inhibitor, reset the tumor microenvironment and restore sensitivity to anti-PD1 by blocking the PKCα/ZFP64/CSF1 axis.We propose that the PKCα/ZFP64/CSF1 axis is critical for triggering immune evasion and anti-PD1 tolerance. Inhibiting this axis with Gö6976 or lenvatinib overcomes anti-PD1 resistance in HCC.Despite remarkable treatment progress, most patients with hepatocellular carcinoma respond poorly to anti-PD1 therapy (a type of immunotherapy). A deeper insight into the tolerance mechanisms to this therapy is urgently needed. Herein, we unravel a previously unexplored mechanism linking tumor progression, macrophage polarization, and anti-PD1 resistance, and offer an attractive novel target for anti-PD1 combination therapy, which may benefit patients with hepatocellular carcinoma.
Dr. J. H. Margerison
Journal: British Journal of Sports Medicine (1970)

event, anticipatory anxiety, if not too severe, seems to mobilise extra physiological resources.(3) Staleness: is the dreaded let down of an athlete who can no longer muster zest and enthusiasm for his event.In conclusion, as world-beating becomes increasingly hard work -though no less admirable a spectacle for the onlookers -let us thank goodness for the existence of so many club athletes who run, like Sir Adolphe Abrahams, simply for the fun of it.
Mortality risk prediction of high-sensitivity C-reactive protein in suspected acute coronary syndrome: A cohort study
Authors: Amit Kaura, Adam Hartley, Vasileios Panoulas, Ben Glampson, Anoop S. V. Shah, Jim Davies, Abdulrahim Mulla, Kerrie Woods, Joe Omigie, Anoop D. Shah, Mark R. Thursz, Paul Elliott, Harry Hemmingway, Bryan Williams, Folkert W. Asselbergs, Michael O’Sullivan, Graham M. Lord, Adam Trickey, Jonathan AC Sterne, Dorian O. Haskard, Narbeh Melikian, Darrel P. Francis, Wolfgang Koenig, Ajay M. Shah, Rajesh Kharbanda, Divaka Perera, Riyaz S. Patel, Keith M. Channon, Jamil Mayet, Ramzi Khamis
Journal: PLoS Medicine (2022)

Background There is limited evidence on the use of high-sensitivity C-reactive protein (hsCRP) as a biomarker for selecting patients for advanced cardiovascular (CV) therapies in the modern era. The prognostic value of mildly elevated hsCRP beyond troponin in a large real-world cohort of unselected patients presenting with suspected acute coronary syndrome (ACS) is unknown. We evaluated whether a mildly elevated hsCRP (up to 15 mg/L) was associated with mortality risk, beyond troponin level, in patients with suspected ACS. Methods and findings We conducted a retrospective cohort study based on the National Institute for Health Research Health Informatics Collaborative data of 257,948 patients with suspected ACS who had a troponin measured at 5 cardiac centres in the United Kingdom between 2010 and 2017. Patients were divided into 4 hsCRP groups (&lt;2, 2 to 4.9, 5 to 9.9, and 10 to 15 mg/L). The main outcome measure was mortality within 3 years of index presentation. The association between hsCRP levels and all-cause mortality was assessed using multivariable Cox regression analysis adjusted for age, sex, haemoglobin, white cell count (WCC), platelet count, creatinine, and troponin. Following the exclusion criteria, there were 102,337 patients included in the analysis (hsCRP &lt;2 mg/L ( n = 38,390), 2 to 4.9 mg/L ( n = 27,397), 5 to 9.9 mg/L ( n = 26,957), and 10 to 15 mg/L ( n = 9,593)). On multivariable Cox regression analysis, there was a positive and graded relationship between hsCRP level and mortality at baseline, which remained at 3 years (hazard ratio (HR) (95% CI) of 1.32 (1.18 to 1.48) for those with hsCRP 2.0 to 4.9 mg/L and 1.40 (1.26 to 1.57) and 2.00 (1.75 to 2.28) for those with hsCRP 5 to 9.9 mg/L and 10 to 15 mg/L, respectively. This relationship was independent of troponin in all suspected ACS patients and was further verified in those who were confirmed to have an ACS diagnosis by clinical coding. The main limitation of our study is that we did not have data on underlying cause of death; however, the exclusion of those with abnormal WCC or hsCRP levels &gt;15 mg/L makes it unlikely that sepsis was a major contributor. Conclusions These multicentre, real-world data from a large cohort of patients with suspected ACS suggest that mildly elevated hsCRP (up to 15 mg/L) may be a clinically meaningful prognostic marker beyond troponin and point to its potential utility in selecting patients for novel treatments targeting inflammation. Trial registration ClinicalTrials.gov - NCT03507309
Baricitinib further enhances disease-modifying effects by uncoupling the link between disease activity and joint structural progression in patients with rheumatoid arthritis
Authors: Pedro Lopez-Romero, Inmaculada de la Torre, Ewa Haladyj, Daniel Aletaha, Josef S Smolen
Journal: Annals of the Rheumatic Diseases (2022)

To evaluate if baricitinib, a Janus kinase inhibitor, further enhances disease-modifying effects by uncoupling the link between disease activity and structural damage progression in patients with rheumatoid arthritis (RA) using two phase III randomised, double-blinded trials.In RA-BEAM, patients with established RA and inadequate response to methotrexate (MTX-IR) received placebo (PBO), baricitinib 4 mg or adalimumab 40 mg on background MTX. In RA-BEGIN, conventional synthetic disease-modifying antirheumatic drug (csDMARD)-naïve patients received MTX, baricitinib 4 mg or baricitinib 4 mg plus MTX. Using linear regression analyses, joint damage progression (assessed by change from baseline in van der Heijde modification of the Total Sharp Score) was compared between treatment groups for patients achieving certain disease activity states by the Clinical Disease Activity Index. Time-averaged postbaseline responses were used to week 24 (RA-BEAM) and week 52 (RA-BEGIN).For MTX-IR patients, structural damage progression was reduced regardless of disease activity states in baricitinib-treated patients (p=0.6), whereas in PBO patients there was a clear dependence on disease activity states, being significantly lower in those who achieved remission/low disease activity (REM/LDA) compared with moderate/high disease activity (MDA/HDA) (p=0.02). Furthermore, the baricitinib MDA/HDA group had less damage progression than the PBO MDA/HDA group (p<0.001). For csDMARD-naïve patients, progression was lower in REM/LDA versus MDA/HDA within the MTX group (p<0.001). However, for baricitinib+MTX (p=0.5) or baricitinib monotherapy (p=0.07), progression was similar regardless of disease activity. In MDA/HDA groups, progression was lower with baricitinib+MTX (p<0.001) and numerically lower with baricitinib monotherapy (p=0.07) versus MTX. C reactive protein (≤5 mg/L and >5 mg/L) sensitivity analyses supported the primary findings.Baricitinib reduces structural damage progression versus PBO with background MTX and/or MTX, even in patients with MDA/HDA, showing a disease-modifying effect across all disease activity states.
Real-life multicentre study of lumen-apposing metal stent for EUS-guided drainage of pancreatic fluid collections
Authors: Arnaldo Amato, Ilaria Tarantino, Antonio Facciorusso, Cecilia Binda, Stefano Francesco Crinò, Alessandro Fugazza, Edoardo Forti, Maria Chiara Petrone, Roberto Di Mitri, Raffaele Macchiarelli, Emanuele Sinagra, Marcello Maida, Alessandro Repici, Andrea Anderloni, Carlo Fabbri
Journal: Gut (2022)
Educational online prevention programme (the SPRINT study) has no effect on the number of running-related injuries in recreational runners: a randomised-controlled trial
Authors: Kyra L A Cloosterman, Tryntsje Fokkema, Robert-Jan de Vos, Edwin Visser, Patrick Krastman, John IJzerman, Bart W Koes, Jan A N Verhaar, Sita M A Bierma-Zeinstra, Marienke van Middelkoop
Journal: British Journal of Sports Medicine (2022)

The aim of this study was to examine the effectiveness of an enhanced online injury prevention programme on the number of running-related injuries (RRIs) in recreational runners.We conducted a randomised-controlled trial in runners who registered for running events (distances: 10-42.195 km) in the Netherlands. Adult runners who provided informed consent were randomised into the intervention or control group. Participants in the intervention group received access to the online prevention programme, which included items to prevent RRIs. Participants in the control group followed their regular preparation for the running event. The primary outcome measure was the number of new RRIs from baseline to 1 month after the running event. To determine differences between injury proportions, univariate and multivariate logistic regression analyses were performed.This study included 4050 recreational runners (63.5% males; mean (SD) age: 42.3 (12.1) years) for analyses. During follow-up, 35.5% (95% CI: 33.5 to 37.6) of the participants in the intervention group sustained a new RRI compared with 35.4% (95% CI: 33.3 to 37.5) of the participants in the control group, with no between-group difference (OR: 1.03; 95% CI: 0.90 to 1.17). There was a positive association between the number of items followed in the injury prevention programme and the number of RRIs (OR: 1.05; 95% CI: 1.00 to 1.11).The enhanced online injury prevention programme had no effect on the number of RRIs in recreational runners, and being compliant with the programme paradoxically was associated with a slightly higher injury rate. Future studies should focus on individual targeted prevention with emphasis on the timing and application of preventive measures.NL7694.
Allergy to Insect Stings
Authors: Guy A. Settipane
Journal: JAMA (1972)

<h3>To the Editor.—</h3> The article says that about 20% of Americans are believed to be hypersensitive to venoms of hymenopteran insects. The only references I can find, four of them, give the frequency of hymenoptera allergy at less than 1% of the general population.
Exercise-induced laryngeal obstruction (EILO) in athletes: a narrative review by a subgroup of the IOC Consensus on ‘acute respiratory illness in the athlete’
Authors: Hege Havstad Clemm, J Tod Olin, Cameron McIntosh, Martin Schwellnus, Nicola Sewry, James H Hull, Thomas Halvorsen
Journal: British Journal of Sports Medicine (2022)

Exercise-induced laryngeal obstruction (EILO) is caused by paradoxical inspiratory adduction of laryngeal structures during exercise. EILO is an important cause of upper airway dysfunction in young individuals and athletes, can impair exercise performance and mimic lower airway dysfunction, such as asthma and/or exercise-induced bronchoconstriction. Over the past two decades, there has been considerable progress in the recognition and assessment of EILO in sports medicine. EILO is a highly prevalent cause of unexplained dyspnoea and wheeze in athletes. The preferred diagnostic approach is continuous visualisation of the larynx (via laryngoscopy) during high-intensity exercise. Recent data suggest that EILO consists of different subtypes, possibly caused via different mechanisms. Several therapeutic interventions for EILO are now in widespread use, but to date, no randomised clinical trials have been performed to assess their efficacy or inform robust management strategies. The aim of this review is to provide a state-of-the-art overview of EILO and guidance for clinicians evaluating and treating suspected cases of EILO in athletes. Specifically, this review examines the pathophysiology of EILO, outlines a diagnostic approach and presents current therapeutic algorithms. The key unmet needs and future priorities for research in this area are also covered.
<i>QuickStats: </i>Age-Adjusted Suicide Rates* for Males and Females, by Race† and Ethnicity — National Vital Statistics System, United States, 2000–2020
Journal: MMWR Morbidity and Mortality Weekly Report (2022)

Deaths per 100,000 standard population White, non-Hispanic males Black, non-Hispanic males Hispanic males White, non-Hispanic females Black, non-Hispanic females Hispanic females * Age-adjusted suicide rates are per 100,000 standard population.Suicides were identified using International Classification of Diseases, Tenth Revision codes U03, X60-X84, and Y87.0.† Rates for 2000-2017 are based on multiple-race mortality data that were bridged to single-race categories based on the 1977 Office of Management and Budget standard for the classification of race and ethnicity.Rates for 2018-2020 were based on the 1997 Office of Management and Budget standards and might differ slightly compared with the 1977 standards.https://dx.doi.org/10.15620/cdc:103476After increasing from 2000 to 2018, age-adjusted suicide rates for non-Hispanic White males and females declined from 2018 to 2020, from 28.6 per 100,000 to 27.2 for males and from 8.0 to 6.9 for females.Rates for non-Hispanic Black males and Hispanic males were lower than that for non-Hispanic White males over the entire period and increased more recently to 13.1 and 12.3, respectively, in 2020.Rates for non-Hispanic Black females and Hispanic females, also lower than rates for non-Hispanic White females over the entire period, generally increased throughout most of the period and then leveled off to 2.9 and 2.8, respectively, in 2020.Rates for all races and ethnic groups were higher for males than for females throughout the period.
Tirzepatide cardiovascular event risk assessment: a pre-specified meta-analysis
Authors: Naveed Sattar, Darren K. McGuire, Imre Pavo, Govinda J. Weerakkody, Hiroshi Nishiyama, Russell J. Wiese, Sophia Zoungas
Journal: Nature Medicine (2022)

Abstract Tirzepatide is a novel, once weekly, dual GIP/GLP-1 receptor agonist and is under development for the treatment of type 2 diabetes (T2D) and obesity. Its association with cardiovascular outcomes requires evaluation. This pre-specified cardiovascular meta-analysis included all seven randomized controlled trials with a duration of at least 26 weeks from the tirzepatide T2D clinical development program, SURPASS. The pre-specified primary objective of this meta-analysis was the comparison of the time to first occurrence of confirmed four-component major adverse cardiovascular events (MACE-4; cardiovascular death, myocardial infarction, stroke and hospitalized unstable angina) between pooled tirzepatide groups and control groups. A stratified Cox proportional hazards model, with treatment as a fixed effect and trial-level cardiovascular risk as the stratification factor, was used for the estimation of hazard ratios (HRs) and confidence intervals (CIs) comparing tirzepatide to control. Data from 4,887 participants treated with tirzepatide and 2,328 control participants were analyzed. Overall, 142 participants, 109 from the trial with high cardiovascular risk and 33 from the six trials with lower cardiovascular risk, had at least one MACE-4 event. The HRs comparing tirzepatide versus controls were 0.80 (95% CI, 0.57–1.11) for MACE-4; 0.90 (95% CI, 0.50–1.61) for cardiovascular death; and 0.80 (95% CI, 0.51–1.25) for all-cause death. No evidence of effect modifications was observed for any subgroups, although the evidence was stronger for participants with high cardiovascular risk. Tirzepatide did not increase the risk of major cardiovascular events in participants with T2D versus controls.
Selumetinib Plus Adjuvant Radioactive Iodine in Patients With High-Risk Differentiated Thyroid Cancer: A Phase III, Randomized, Placebo-Controlled Trial (ASTRA)
Authors: Alan L. Ho, Marek Dedecjus, Lori J. Wirth, R. Michael Tuttle, William B. Inabnet, Jan Tennvall, Fernanda Vaisman, Lars Bastholt, Andrew G. Gianoukakis, Patrice Rodien, Ralf Paschke, Rossella Elisei, David Viola, Karen So, Danielle Carroll, Tina Hovey, Bhavana Thakre, James A. Fagin
Journal: Journal of Clinical Oncology (2022)

Selumetinib can increase radioactive iodine (RAI) avidity in RAI-refractory tumors. We investigated whether selumetinib plus adjuvant RAI improves complete remission (CR) rates in patients with differentiated thyroid cancer (DTC) at high risk of primary treatment failure versus RAI alone.
Microglia modulate blood flow, neurovascular coupling, and hypoperfusion via purinergic actions
Authors: Eszter Császár, Nikolett Lénárt, Csaba Cserép, Zsuzsanna Környei, Rebeka Fekete, Balázs Pósfai, Diána Balázsfi, Balázs Hangya, Anett D. Schwarcz, Eszter Szabadits, Dávid Szöllősi, Krisztián Szigeti, Domokos Máthé, Brian L. West, Katalin Sviatkó, Ana Rita Brás, Jean-Charles Mariani, Andrea Kliewer, Zsolt Lenkei, László Hricisák, Zoltán Benyó, Mária Baranyi, Beáta Sperlágh, Ákos Menyhárt, Eszter Farkas, Ádám Dénes
Journal: The Journal of Experimental Medicine (2022)

Microglia, the main immunocompetent cells of the brain, regulate neuronal function, but their contribution to cerebral blood flow (CBF) regulation has remained elusive. Here, we identify microglia as important modulators of CBF both under physiological conditions and during hypoperfusion. Microglia establish direct, dynamic purinergic contacts with cells in the neurovascular unit that shape CBF in both mice and humans. Surprisingly, the absence of microglia or blockade of microglial P2Y12 receptor (P2Y12R) substantially impairs neurovascular coupling in mice, which is reiterated by chemogenetically induced microglial dysfunction associated with impaired ATP sensitivity. Hypercapnia induces rapid microglial calcium changes, P2Y12R-mediated formation of perivascular phylopodia, and microglial adenosine production, while depletion of microglia reduces brain pH and impairs hypercapnia-induced vasodilation. Microglial actions modulate vascular cyclic GMP levels but are partially independent of nitric oxide. Finally, microglial dysfunction markedly impairs P2Y12R-mediated cerebrovascular adaptation to common carotid artery occlusion resulting in hypoperfusion. Thus, our data reveal a previously unrecognized role for microglia in CBF regulation, with broad implications for common neurological diseases.