tbuckley/cabot-search huggingface dataset:
Comparing vitamin D levels in patients with COVID-19 and tuberculosis infection
Authors: N. Essaji, J. B. Fanshawe, T. Mohajer, L. V. Baker
Journal: Gut (2021)

Introduction Vitamin D is important in innate and adaptive immunity  Deficiency is associated with susceptibility to tuberculosis( TB) and viral respiratory tract infections  Prevalence increases in patients of Black and Asian ethnicity, high BMI, smokers and the elderly  Vitamin D deficiency may have a role in acquisition and severity of COVID-19 infection  Objective To investigate vitamin D status in patients admitted to hospital and critical care with COVID-19, and to compare vitamin D levels to patients with TB infection  Methods Vitamin D levels were measured prospectively in adult patients admitted to three medical wards and HDU/ITU with suspected COVID-19 infection between 6/4/20 and 4/5/ 20  Data was supplemented by retrospectively screening admissions between 1/3/20 and 31/5/20 with PCR confirmed COVID-19 infection or highly suggestive chest radiology with a Vitamin D level within 3 months  Adult patients treated for latent and active TB between 1/1/18 to 30/6/20 had Vitamin D levels measured at treatment start  Patients were stratified as Vitamin D deficient(50 nmol)  Results Vitamin D levels were available for 244/551(44%) patients admitted with confirmed COVID-19, including 62/ 113(55%) ITU/HDU admissions, and for 230/237(97%) TB patients  Overall, 195/244(76%) inpatients with COVID-19 had vitamin D 30 kg/m2  Vitamin D levels were not lower in COVID-19 patients requiring respiratory support or those that died- 76% of discharged patients were insufficient/deficient, compared to 69% requiring respiratory support and 70% that died  There was no significant difference in proportion of insufficient/deficient patients with ethnicity- White 89/120(74%), Black 52/68 (76%), Asian 11/14(78%)  Patients with active TB had lower vitamin D than patients with latent infection, but similar levels to patients with COVID-19(median 28 5 mol, 51% deficient, vs 40 8 nmol, 17% deficient vs 29 nmol, 43% deficient)  Conclusion Three-quarters of patients admitted with COVID- 19 had low Vitamin D levels, proportionately similar to patients with TB infection  There was no correlation with disease severity
Assessment of Methylene Chloride–Related Fatalities in the United States, 1980-2018
Authors: Anh Hoang, Kathleen Fagan, Dawn L. Cannon, Swati D. G. Rayasam, Robert Harrison, Dennis Shusterman, Veena Singla
Journal: JAMA Internal Medicine (2021)

<h3>Importance</h3> Methylene chloride is a halogenated organic solvent widely used in paint strippers, cleaners, adhesives, and sealants. Despite label warnings and occupational standards, methylene chloride–related fatalities continue to occur in the United States. <h3>Objective</h3> To identify and analyze methylene chloride–related fatalities in the US. <h3>Design, Setting, and Participants</h3> For this case series, we conducted systematic searches of sources, including PubMed and government databases, for unintentional fatalities in the US that were associated with exposure to methylene chloride or products containing methylene chloride between 1980 and 2018. We reviewed all available information, including inspection reports, autopsy reports, and medical records; data analyses were conducted from August 2018 to August 2020. Cases were categorized as those occurring in the home (consumer deaths) or at work (occupational deaths). <h3>Exposures</h3> Methylene chloride or products containing methylene chloride. <h3>Main Outcomes and Measures</h3> To determine characteristics of the methylene chloride–related fatalities, we recorded demographic information; the setting; circumstances, including information on safety measures used, if available; and products used. Where medical records were available, we recorded toxicology results and autopsy findings. We also obtained data about nonfatal methylene chloride cases from the American Association of Poison Control Centers. <h3>Results</h3> From 1980 to 2018, 85 methylene chloride–related fatalities were identified in the US, including 74 (87%) in occupational settings; of those who died, 75 (94%) were men, and for the 70 cases with available information, the median (interquartile range) age of the decedents was 31 (24-46) years. Paint strippers were the most common products involved in methylene chloride–related fatalities (n = 60). The proportion of occupational fatalities related to paint stripping increased from 22 (55%) before 2000 to 30 (88%) after 2000. Similarly, occupational fatalities associated with bathtub or paint stripping in bathrooms increased from 2 (5%) before 2000 to 21 (62%) after 2000. From 1985 to 2017, the American Association of Poison Control Centers documented 37 201 nonfatal methylene chloride cases, with a decrease in the annual number of cases starting in the late 1990s. <h3>Conclusions and Relevance</h3> Results of this case series demonstrated that despite regulations to address the toxic effects of methylene chloride use for consumers and workers, there are continuing fatalities in the US, particularly in occupational settings. Prevention of fatalities associated with methylene chloride exposure should emphasize the use of safer substitutes, rather than hazard warnings or reliance on personal protective equipment.
Trajectories of Opioid Use Following First Opioid Prescription in Opioid-Naive Youths and Young Adults
Authors: J. Deanna Wilson, Kaleab Z. Abebe, Kevin Kraemer, Jane Liebschutz, Jessica Merlin, Elizabeth Miller, David Kelley, Julie Donohue
Journal: JAMA Network Open (2021)

Although prescription opioids are the most common way adolescents and young adults initiate opioid use, many studies examine population-level risks following the first opioid prescription. There is currently a lack of understanding regarding how patterns of opioid prescribing following the first opioid exposure may be associated with long-term risks.To identify distinct patterns of opioid prescribing following the first prescription using group-based trajectory modeling and examine the patient-, clinician-, and prescription-level factors that may be associated with trajectory membership during the first year.This cohort study examined Pennsylvania Medicaid enrollees' claims data from 2010 through 2016. Participants were aged 10 to 21 years at time of first opioid prescription. Data analysis was performed in March 2020.This study used group-based trajectory modeling and defined trajectory status by opioid fill.Among the 189 477 youths who received an initial opioid prescription, 107 562 were female (56.8%), 81 915 were non-Latinx White (59.6%), and the median age was 16.9 (interquartile range [IQR], 14.6-18.8) years. During the subsequent year, 47 477 (25.1%) received at least one additional prescription. Among the models considered, the 2-group trajectory model had the best fit. Of those in the high-risk trajectory, 65.3% (n = 901) filled opioid prescriptions at month 12, in contrast to 13.1% (n = 6031) in the low-risk trajectory. Median age among the high-risk trajectory was 19.0 years (IQR, 17.1-20.0 years) compared with the low-risk trajectory (17.8 years [IQR, 15.8-19.4 years]). The high-risk trajectory received more potent prescriptions compared with the low-risk trajectory (median dosage of the index month for high-risk trajectory group: 10.0 MME/d [IQR, 5.0-21.2 MME/d] vs the low-risk trajectory group: 4.7 MME/d [IQR, 2.5-7.8 MME/d]; P < .001). The trajectories showed persistent differences with more youths in the high-risk trajectory going on to receive a diagnosis of opioid use disorder (30.0%; n = 412) compared with the low-risk group (10.1%; n = 4638) (P < .001).This study's results identified 2 trajectories associated with elevated risk for persistent opioid receipt within 12 months following first opioid prescription. The high-risk trajectory was characterized by older age at time of first prescription, and longer and more potent first prescriptions. These findings suggest even short and low-dose opioid prescriptions can be associated with risks of persistent use for youths.
Crosstalk between coagulation and complement activation promotes cardiac dysfunction in arrhythmogenic right ventricular cardiomyopathy
Authors: Jie Ren, Konstantinos Tsilafakis, Liang Chen, Konstantinos Lekkos, Ioanna Kostavasili, Aimilia Varela, Dennis V Cokkinos, Constantinos H Davos, Xiaogang Sun, Jiangping Song, Manolis Mavroidis
Journal: Theranostics (2021)

We previously found that complement components are upregulated in the myocardium of patients with arrhythmogenic right ventricular cardiomyopathy (ARVC), and inhibiting the complement receptor C5aR reduces disease severity in desmin knockout (
Abstract IA-008: Etiology of chromosomal rearrangements, and other DNA double-strand break repair outcomes
Authors: Jeremy M. Stark
Journal: Clinical Cancer Research (2021)

Abstract Defining the factors that influence chromosomal double-strand breaks (DSBs) outcomes important for developing radiosensitization strategies that target the DNA damage response (DDR). In a main project in the lab, we have used Cas9 to study mechanisms of end joining (EJ) repair that affect diverse outcomes, ranging from short insertion/deletion (indels) mutations, to large chromosomal rearrangements. In particular, we have sought to define the relative contributions of canonical non-homologous end joining (C-NHEJ), and alternative end joining (ALT-EJ), on such DSB repair outcomes. For instance, I will present evidence that C-NHEJ is absolutely required for EJ between distal ends of two Cas9-induced chromosomal breaks that are joined without causing insertion/deletion mutations (No Indel EJ). Namely, C-NHEJ does not appear to be intrinsically prone to causing indels, relative to the ALT-EJ pathway. Furthermore, using No Indel EJ as a hallmark of C-NHEJ, I will present our current directions for understanding the mechanism and regulation of C-NHEJ and ALT-EJ, and targeting these pathways by DDR inhibitors. I suggest that establishing how the DDR affects distinct EJ events will reveal the ideal contexts for using DDR inhibitors during cancer therapy and inform the development of biomarkers of response. Citation Format: Jeremy M. Stark. Etiology of chromosomal rearrangements, and other DNA double-strand break repair outcomes [abstract]. In: Proceedings of the AACR Virtual Special Conference on Radiation Science and Medicine; 2021 Mar 2-3. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(8_Suppl):Abstract nr IA-008.
Overcoming spectrum bias for accurate SARS-CoV-2 seroprevalence estimates
Authors: Milo A Puhan, Arnaud Chiolero, Jan Fehr, Stéphane Cullati
Journal: BMJ (2021)

Repeated population based SARS-CoV-2 seroprevalence studies provide evidence on how immunity develops in a population. They are especially relevant now, as we are at a turning point with vaccines that greatly accelerate the development of immunity.

A surprisingly low seroprevalence of 14% was recently reported for the UK.1 The cumulative proportion of confirmed infected people in the UK (6.3%) is very close to that of Switzerland (6.6%).2 Assuming that only around one in 3-4 infected people are …
Wouldn't you like to know: are tertiary lymphoid structures necessary for lung defence?
Authors: Jeffrey L. Curtis
Journal: European Respiratory Journal (2021)

A key principle of emergency management is establishing an incident command centre. That's where information is gathered via integrated communications, plans are formulated, responsibilities assigned, and resources deployed. The immune system deals with microbial threats by this same approach, using organised lymphoid tissues. At the early stages of infections, conventional dendritic cells (cDCs) transmit intelligence on the nature of the threat to regional lymph nodes, which along with the spleen, tonsils and Peyer's patches, constitute the secondary lymphoid organs. Within lymph nodes, immune responses are optimised as large numbers of effector T cells search for their cognate antigens on the surfaces of cDCs, under the supervision of regulatory T cells. However, widespread and chronic threats require additional command centres closer to the action. "Tertiary lymphoid structures" is one name for these de novo frontline assemblages, along with "lymphoid follicles". The process, termed lymphoid neogenesis, occurs within many organs in infectious, autoimmune and inflammatory disorders, and in transplanted organs and malignancies [1]. Because tertiary lymphoid structures (TLSs) develop in multiple lung diseases (table 1), defining their roles in pathogenesis is a crucial unmet goal that experimental models are well-suited to address. Organised lung lymphoid tissues are unnecessary to defend against bacteria in a mouse chronic infection model <https://bit.ly/3adwW3Z>
The PSMD14 inhibitor Thiolutin as a novel therapeutic approach for esophageal squamous cell carcinoma through facilitating SNAIL degradation
Authors: Chao Jing, Xingchen Li, Mengqian Zhou, Shengchi Zhang, Qingchuan Lai, Dandan Liu, Beibei Ye, Linqi Li, Yue Wu, Hong Li, Kai Yue, Peng Chen, Xiaofeng Yao, Yansheng Wu, Yuansheng Duan, Xudong Wang
Journal: Theranostics (2021)

Metastasis and chemoresistance are major causes of poor prognosis in patients with esophageal squamous cell carcinoma (ESCC), manipulated by multiple factors including deubiquitinating enzyme (DUB). DUB PSMD14 is reported to be a promising therapeutic target in various cancers. Here, we explored the antitumor activity of Thiolutin (THL), the PSMD14 inhibitor, as a new therapy strategy in ESCC. Methods: Through 4-NQO-induced murine ESCC model, we investigated the expression of PSMD14 in esophageal tumorigenesis. Ubiquitin-AMC assay was performed to evaluate DUB activity of PSMD14 with THL treatment. The effect of THL on epithelial-to-mesenchymal transition (EMT), invasion, stemness and chemosensitivity was detected by using in vitro and in vivo experiments. Immunoprecipitation and in vivo ubiquitination assay were conducted to examine whether THL could impair the deubiquitination and stability of SNAIL regulated by PSMD14. Results: Compared with normal esophageal epithelium, PSMD14 was upregulated in 4-NQO-induced murine esophageal epithelium dysplasia and ESCC tissues. THL could significantly weaken DUB activity of PSMD14. Furthermore, the results of in vitro and in vivo assays showed that THL efficiently suppressed motility and stemness and increased sensitivity to cisplatin in ESCC. Mechanically, THL impaired the interaction between PSMD14 and SNAIL, then promoted the ubiquitination and degradation of SNAIL to inhibit EMT which plays a crucial role in ESCC metastasis, stemness and chemosensitivity. TCGA database analysis revealed that high concomitant PSMD14/SNAIL expression predicted shorter overall survival in esophageal cancer. Conclusion: Our findings demonstrate for the first time that suppression of PSMD14/SNAIL axis by THL could be a novel and promising therapeutic approach for ESCC clinical therapy.
未治療の慢性リンパ球性白血病に対して,フルダラビンとリツキシマブの導入療法後に実施する皮下アレムツズマブによる地固め療法:CALGB 10101の最終解析
Authors: S Lin Thomas, A Donohue Kathleen, C Byrd John, S Lucas Margaret, E Hoke Eva, M Bengtson Elizabeth, R Rai Kanti, N Atkins James, K Link Brian, A Larson Richard
Journal: Journal of Clinical Oncology (2010)
Targeting the HSP90–CDC37–kinase chaperone cycle: A promising therapeutic strategy for cancer
Authors: Lei Wang, Qiuyue Zhang, Qidong You
Journal: Medicinal Research Reviews (2021)

Abstract Heat shock protein 90 (HSP90) is an indispensable molecular chaperone that facilitates the maturation of numerous oncoproteins in cancer cells, including protein kinases, ribonucleoproteins, steroid hormone receptors, and transcription factors. Although over 30 HSP90 inhibitors have steadily entered clinical trials, further clinical advancement has been restricted by their limited efficacy, inevitable heat shock response, and multiple side‐effects, likely induced via an ATP inhibition mechanism. Since both ATP and various co‐chaperones play essential roles in the HSP90 chaperone cycle to achieve integrated function, optimal therapeutics require an understanding of the dynamic interactions among HSP90, ATP, and cochaperones. To date, continuous research has promoted the exploration of the cochaperone cell division cycle 37 (CDC37) as a kinase‐specific recognizer and has shown that the HSP90–CDC37–kinase complex is particularly relevant in cancers. Indeed, disrupting the HSP90–CDC37–kinase complex, rather than totally blocking the ATP function of HSP90, is emerging as an alternative way to avoid the limitations of current inhibitors. In this review, we first briefly introduce the HSP90–CDC37–kinase cycle and present the currently available approaches for inhibitor development targeting this cycle and provide insights into selective regulation of the kinase clients of HSP90 by more directional ways.
Increased resistance of SARS-CoV-2 variant P.1 to antibody neutralization
Authors: Pengfei Wang, Ryan G. Casner, Manoj S. Nair, Maple Wang, Jian Yu, Gabriele Cerutti, Lihong Liu, Peter D. Kwong, Yaoxing Huang, Lawrence Shapiro, David D. Ho
Journal: Cell Host & Microbe (2021)
Cigarette Smoking Increases the Magnitude of Intracoronary Thrombus Observed During Acute Myocardial Infarction
Authors: Satyendra Giri, Joseph Mitchel, Francis J Kiernan, Jeffrey A Hirst, Jonathan Clive, Daniel B Fram, Daniel Simon, Jeffrey J Popma, Murray A Mittleman
Journal: Circulation (2001)

P60 BACKGROUND: Smoking is a well known modifiable chronic risk factor for coronary disease. However, whether it can trigger acute myocardial infarction (MI) is unknown. To determine whether smoking predicts intracoronary thrombus burden in the infarct artery, we analyzed angiograms of 902 patients undergoing emergent coronary angioplasty for acute MI. METHODS: Patients underwent a structured standardized interview. Smokers (n= 348; 39%) were asked the time of last cigarette smoked prior to symptom onset. Quantitative indices of reference vessel diameter, segmental and cross-sectional intracoronary thrombus area, and ordinal TIMI thrombus grades were analyzed by 2 angiographers using a validated, computer-assisted program. RESULTS: Compared to nonsmokers, smokers were younger (54 ± 12 vs 65 ± 13 years; p &lt; 0.001), more likely to be male (75% vs 65%; p = 0.003), normotensive (68% vs 44%;p &lt; 0.001), physically active (36% vs 29%; p = 0.03), tended to present early (277 ± 91 vs 293 ± 98 minute; p = 0.02), have more single-vessel disease (37 vs 25%;p &lt; 0.001), but with larger thrombus area (16.9 ± 17 vs 13.7 ± 17 mm 2 ; p = 0.009). Intracoronary thrombus burden was larger when symptom onset was closer to the time of last cigarette, however, smokers had a greater chance of achieving complete reperfusion (TIMI grade 3 flow: 96% vs 90%; p=0.01). CONCLUSIONS: Despite less coexistent risk factors among smokers, smoking appears to increase thrombogenicity and is temporally related to the magnitude of intracoronary thrombus in the infarct-related artery. Thus, in addition to chronic effects, smoking may acutely trigger acute MI by enhancing thrombogenecity. Table 1.
Effect of adoption of electric vehicles on public health and air pollution in China: a modelling study
Authors: Daniel E Horton, Jordan L Schnell, Daniel R Peters, David C Wong, Xi Lu, Hao Gao, Hongliang Zhang, Patrick L Kinney
Journal: The Lancet Planetary Health (2021)

BackgroundAdoption of electric vehicles has the potential to reduce air pollutant and greenhouse gas emissions, hence China has implemented policies incentivising use of electric vehicles. However, much is unknown about the potential air quality and public health benefits of electric vehicles, including optimal vehicle type prioritisation and the vehicles' ability to reduce acute health impacts due to extreme air quality events. We aimed to assess the potential climate and acute public health benefits of use of electric vehicles during an extreme winter air pollution event.MethodsIn this modelling study, we used the Weather Research Forecast and Community Multiscale Air Quality Modeling System air quality model to simulate the interplay between weather and atmospheric chemistry. We used this model to examine potential co-benefits of electric vehicle adoption during an extreme pollution episode in China. We simulated heavy-duty and light-duty electric vehicle adoption scenarios, in which 40% of the population adopted a heavy-duty or light-duty passenger electric vehicle, re-mapped battery power needs to energy generation facilities, and characterised differences in public health outcomes using China-specific concentration-response functions.FindingsWe found that widespread adoption of heavy-duty electric vehicles would reduces nitric oxide and fine particulate matter resulting in 562 (95% CI 410–723) fewer premature acute deaths than the non-electrified baseline scenario. However, widespread adoption of heavy-duty electric vehicles does not reduce carbon dioxide emissions without the addition of emission-free electricity generation. By contrast, widespread adoption of light-duty electric vehicles robustly reduces greenhouse gas emissions, but results in lesser air quality improvements and fewer premature deaths avoided (145 [95% CI 38–333]) than the heavy-duty scenario. Economic effects of human health endpoints and carbon dioxide reductions for adoption of light-duty electric vehicles are nearly double those of a heavy-duty electric vehicle scenario (US$155 million vs $87 million).InterpretationAmelioration of severe winter pollution events through adoption of electric vehicles could provide a moderate public health benefit, but continued emission reductions in the power generation sector will have greater human health and economic benefits in China.FundingUbben Program for Carbon and Climate Science at Northwestern University.