tbuckley/cabot-search huggingface dataset:
Insurance Acceptance, Appointment Wait Time, and Dermatologist Access Across Practice Types in the US
Authors: Andrew Creadore, Sheena Desai, Sara J. Li, Karen J. Lee, Ai-Tram N. Bui, Camila Villa-Ruiz, Kelly Lo, Guohai Zhou, Cara Joyce, Jack S. Resneck, Kira Seiger, Arash Mostaghimi
Journal: JAMA Dermatology (2021)

<h3>Importance</h3> In the 15 years since dermatology access was last investigated on a national scale, the practice landscape has changed with the rise of private equity (PE) investment and increased use of nonphysician clinicians (NPCs). <h3>Objective</h3> To determine appointment success and wait times for patients with various insurance types at clinics with and without PE ownership. <h3>Design, Setting, and Participants</h3> In this study, PE-owned US clinics were randomly selected and matched with 2 geographically proximate clinics without PE ownership. Researchers called each clinic 3 times over a 5-day period to assess appointment/clinician availability for a fictitious patient with a new and changing mole. The 3 calls differed by insurance type specified, which were Blue Cross Blue Shield (BCBS) preferred provider organization, Medicare, or Medicaid. <h3>Main Outcomes and Measures</h3> Appointment success and wait times among insurance types and between PE-owned clinics and control clinics. Secondary outcomes were the provision of accurate referrals to other clinics when appointments were denied and clinician and next-day appointment availability. <h3>Results</h3> A total of 1833 calls were made to 204 PE-owned and 407 control clinics without PE ownership across 28 states. Overall appointment success rates for BCBS, Medicare, and Medicaid were 96%, 94%, and 17%, respectively. Acceptance of BCBS (98.5%; 95% CI, 96%-99%;<i>P</i> = .03) and Medicare (97.5%; 95% CI, 94%-99%;<i>P</i> = .02) were slightly higher at PE-owned clinics (compared with 94.6% [95% CI, 92%-96%] and 92.8% [95% CI, 90%-95%], respectively, at control clinics). Wait times (median days, interquartile range [IQR]) were similar for patients with BCBS (7 days; IQR, 2-22 days) and Medicare (7 days; IQR, 2-25 days;<i>P</i> &gt; .99), whereas Medicaid patients waited significantly longer (13 days; IQR, 4-33 days;<i>P</i> = .002). Clinic ownership did not significantly affect wait times. Private equity–owned clinics were more likely than controls to offer a new patient appointment with an NPC (80% vs 63%;<i>P</i> = .001) and to not have an opening with a dermatologist (16% vs 6%;<i>P</i> &lt; .001). Next-day appointment availability was greater at PE-owned clinics than controls (30% vs 21%;<i>P</i> = .001). <h3>Conclusions and Relevance</h3> Patients with Medicaid had significantly lower success in obtaining appointments and significantly longer wait times regardless of clinic ownership. Although the use of dermatologists and NPCs was similar regardless of clinic ownership, PE-owned clinics were more likely than controls to offer new patient appointments with NPCs.
Reference flow: reducing reference bias using multiple population genomes
Authors: Nae-Chyun Chen, Brad Solomon, Taher Mun, Sheila Iyer, Ben Langmead
Journal: Genome biology (2021)

Most sequencing data analyses start by aligning sequencing reads to a linear reference genome, but failure to account for genetic variation leads to reference bias and confounding of results downstream. Other approaches replace the linear reference with structures like graphs that can include genetic variation, incurring major computational overhead. We propose the reference flow alignment method that uses multiple population reference genomes to improve alignment accuracy and reduce reference bias. Compared to the graph aligner vg, reference flow achieves a similar level of accuracy and bias avoidance but with 14% of the memory footprint and 5.5 times the speed.
Investigating infection management and antimicrobial stewardship in surgery: a qualitative study from India and South Africa
Authors: Sanjeev Singh, Marc Mendelson, Surya Surendran, Candice Bonaconsa, Oluchi Mbamalu, Vrinda Nampoothiri, Adam Boutall, Mark Hampton, Puneet Dhar, Tim Pennel, Carolyn Tarrant, Andy Leather, Alison Holmes, Esmita Charani, Raheelah Ahmad, Enrique Castro-Sanchez, Gabriel Birgand, Jules Ndoli, Franco Sassi, Nick Sevdalis, Ramani Moonesinghe, Reda Lebcir, Ewan Ferlie
Journal: Clinical Microbiology and Infection (2021)
The Sleep Apnea–Specific Pulse-Rate Response Predicts Cardiovascular Morbidity and Mortality
Authors: Ali Azarbarzin, Scott A. Sands, Magdy Younes, Luigi Taranto-Montemurro, Tamar Sofer, Daniel Vena, Raichel M. Alex, Sang-Wook Kim, Daniel J. Gottlieb, David P. White, Susan Redline, Andrew Wellman
Journal: American Journal of Respiratory and Critical Care Medicine (2021)

Rationale: Randomized controlled trials have been unable to detect a cardiovascular benefit of continuous positive airway pressure in unselected patients with obstructive sleep apnea (OSA). We hypothesize that deleterious cardiovascular outcomes are concentrated in a subgroup of patients with a heightened pulse-rate response to apneas and hypopneas (ΔHR). Methods: We measured the ΔHR in the MESA (Multi-Ethnic Study of Atherosclerosis) (N = 1,395) and the SHHS (Sleep Heart Health Study) (N = 4,575). MESA data were used to determine the functional form of the association between the ΔHR and subclinical cardiovascular biomarkers, whereas primary analyses tested the association of the ΔHR with nonfatal or fatal cardiovascular disease (CVD) and all-cause mortality in longitudinal data from the SHHS. Measurements and Main Results: In the MESA, U-shaped relationships were observed between subclinical CVD biomarkers (coronary artery calcium, NT-proBNP [N-terminal prohormone BNP], and Framingham risk score) and the ΔHR; notably, a high ΔHR (upper quartile) was associated with elevated biomarker scores compared with a midrange ΔHR (25th-75th centiles). In the SHHS, individuals with a high ΔHR compared with a midrange ΔHR were at increased risk of nonfatal or fatal CVD and all-cause mortality (nonfatal adjusted hazard ratio [95% confidence interval (CI)], 1.60 [1.28-2.00]; fatal adjusted hazard ratio [95% CI], 1.68 [1.22-2.30]; all-cause adjusted hazard ratio [95% CI], 1.29 [1.07-1.55]). The risk associated with a high ΔHR was particularly high in those with a substantial hypoxic burden (nonfatal, 1.93 [1.36-2.73]; fatal, 3.50 [2.15-5.71]; all-cause, 1.84 [1.40-2.40]) and was exclusively observed in nonsleepy individuals. Conclusions: Individuals with OSA who demonstrate an elevated ΔHR are at increased risk of cardiovascular morbidity and mortality. This study identifies a prognostic biomarker for OSA that appears useful for risk stratification and patient selection for future clinical trials.
KDM6A promotes imatinib resistance through YY1-mediated transcriptional upregulation of TRKA independently of its demethylase activity in chronic myelogenous leukemia
Authors: Chengwan Zhang, Li Shen, Yifu Zhu, Ran Xu, Zhikui Deng, Xiaoning Liu, Yihan Ding, Chunling Wang, Yuye Shi, Liye Bei, Dongping Wei, Rick F. Thorne, Xu Dong Zhang, Liang Yu, Song Chen
Journal: Theranostics (2021)

Rationale: Despite landmark therapy of chronic myelogenous leukemia (CML) with tyrosine kinase inhibitors (TKIs), drug resistance remains problematic. Cancer pathogenesis involves epigenetic dysregulation and in particular, histone lysine demethylases (KDMs) have been implicated in TKI resistance. We sought to identify KDMs with altered expression in CML and define their contribution to imatinib resistance. Methods: Bioinformatics screening compared KDM expression in CML versus normal bone marrow with shRNA knockdown and flow cytometry used to measure effects on imatinib-induced apoptosis in K562 cells. Transcriptomic analyses were performed against KDM6A CRISPR knockout/shRNA knockdown K562 cells along with gene rescue experiments using wildtype and mutant demethylase-dead KDM6A constructs. Co-immunoprecipitation, luciferase reporter and ChIP were employed to elucidate mechanisms of KDM6A-dependent resistance. Results: Amongst five KDMs upregulated in CML, only KDM6A depletion sensitized CML cells to imatinib-induced apoptosis. Re-introduction of demethylase-dead KDM6A as well as wild-type KDM6A restored imatinib resistance. RNA-seq identified NTRK1 gene downregulation after depletion of KDM6A. Moreover, NTRK1 expression positively correlated with KDM6A in a subset of clinical CML samples and KDM6A knockdown in fresh CML isolates decreased NTRK1 encoded protein (TRKA) expression. Mechanistically, KDM6A was recruited to the NTRK1 promoter by the transcription factor YY1 with subsequent TRKA upregulation activating down-stream survival pathways to invoke imatinib resistance. Conclusion: Contrary to its reported role as a tumor suppressor and independent of its demethylase function, KDM6A promotes imatinib-resistance in CML cells. The identification of the KDM6A/YY1/TRKA axis as a novel imatinib-resistance mechanism represents an unexplored avenue to overcome TKI resistance in CML.
Genetic variants shape rheumatoid arthritis-specific transcriptomic features in CD4<sup>+</sup> T cells through differential DNA methylation, explaining a substantial proportion of heritability
Authors: Eunji Ha, So-Young Bang, Jiwoo Lim, Jun Ho Yun, Jeong-Min Kim, Jae-Bum Bae, Hye-Soon Lee, Bong-Jo Kim, Kwangwoo Kim, Sang-Cheol Bae
Journal: Annals of the Rheumatic Diseases (2021)

Objective CD4 + T cells have been suggested as the most disease-relevant cell type in rheumatoid arthritis (RA) in which RA-risk non-coding variants exhibit allele-specific effects on regulation of RA-driving genes. This study aimed to understand RA-specific signatures in CD4 + T cells using multi-omics data, interpreting inter-omics relationships in shaping the RA transcriptomic landscape. Methods We profiled genome-wide variants, gene expression and DNA methylation in CD4 + T cells from 82 patients with RA and 40 healthy controls using high-throughput technologies. We investigated differentially expressed genes (DEGs) and differential methylated regions (DMRs) in RA and localised quantitative trait loci (QTLs) for expression and methylation. We then integrated these based on individual-level correlations to inspect DEG-regulating sources and investigated the potential regulatory roles of RA-risk variants by a partitioned-heritability enrichment analysis with RA genome-wide association summary statistics. Results A large number of RA-specific DEGs were identified (n=2575), highlighting T cell differentiation and activation pathways. RA-specific DMRs, preferentially located in T cell regulatory regions, were correlated with the expression levels of 548 DEGs mostly in the same topologically associating domains. In addition, expressional variances in 771 and 83 DEGs were partially explained by expression QTLs for DEGs and methylation QTLs (meQTLs) for DEG-correlated DMRs, respectively. A large number of RA variants were moderately to strongly correlated with meQTLs. DEG-correlated DMRs, enriched with meQTLs, had strongly enriched heritability of RA. Conclusion Our findings revealed that the methylomic changes, driven by RA heritability-explaining variants, shape the differential expression of a substantial fraction of DEGs in CD4 + T cells in patients with RA, reinforcing the importance of a multidimensional approach in disease-relevant tissues.
BCL6 confers KRAS-mutant non–small-cell lung cancer resistance to BET inhibitors
Authors: Jiawei Guo, Yanan Liu, Jing Lv, Bin Zou, Zhi Chen, Kun Li, Juanjuan Feng, Zhenyu Cai, Lai Wei, Mingyao Liu, Xiufeng Pang
Journal: Journal of Clinical Investigation (2021)

The bromodomain and extra-terminal domain (BET) proteins are promising therapeutic targets to treat refractory solid tumors; however, inherent resistance remains a major challenge in the clinic. Recently, the emerging role of the oncoprotein B cell lymphoma 6 (BCL6) in tumorigenesis and stress response has been unveiled. Here, we demonstrate that BCL6 was upregulated upon BET inhibition in KRAS-mutant cancers, including non–small-cell lung cancer (NSCLC). We further found that BRD3, not BRD2 or BRD4, directly interacted with BCL6 and maintained the negative autoregulatory circuit of BCL6. Disrupting this negative autoregulation by BET inhibitors (BETi) resulted in a striking increase in BCL6 transcription, which further activated the mTOR signaling pathway through repression of the tumor suppressor death-associated protein kinase 2. Importantly, pharmacological inhibition of either BCL6 or mTOR improved the tumor response and enhanced the sensitivity of KRAS-mutant NSCLC to BETi in both in vitro and in vivo settings. Overall, our findings identify a mechanism of BRD3-mediated BCL6 autoregulation and further develop an effective combinatorial strategy to circumvent BETi resistance in KRAS-driven NSCLC.
Maternity services at Bedford Hospital must improve urgently, says regulator
Authors: Clare Dyer
Journal: BMJ (2021)

Bedford Hospital’s maternity services have been rated inadequate by inspectors and served with an urgent warning notice to improve after an unannounced inspection sparked by 14 whistleblower complaints between last August and November.1

The Care Quality Commission (CQC) has placed conditions on the registration of Bedfordshire Hospitals NHS Foundation Trust, which runs the hospital, and told the trust it must make “significant and immediate” improvements. During …
Five-Year Outcomes From the Randomized, Phase III Trials CheckMate 017 and 057: Nivolumab Versus Docetaxel in Previously Treated Non–Small-Cell Lung Cancer
Authors: Hossein Borghaei, Scott Gettinger, Everett E. Vokes, Laura Q. M. Chow, Marco Angelo Burgio, Javier de Castro Carpeno, Adam Pluzanski, Oscar Arrieta, Osvaldo Arén Frontera, Rita Chiari, Charles Butts, Joanna Wójcik-Tomaszewska, Bruno Coudert, Marina Chiara Garassino, Neal Ready, Enriqueta Felip, Miriam Alonso García, David Waterhouse, Manuel Domine, Fabrice Barlesi, Scott Antonia, Markus Wohlleber, David E. Gerber, Grzegorz Czyzewicz, David R. Spigel, Lucio Crino, Wilfried Enst Erich Eberhardt, Ang Li, Sathiya Marimuthu, Julie Brahmer
Journal: Journal of Clinical Oncology (2021)

Immunotherapy has revolutionized the treatment of advanced non-small-cell lung cancer (NSCLC). In two phase III trials (CheckMate 017 and CheckMate 057), nivolumab showed an improvement in overall survival (OS) and favorable safety versus docetaxel in patients with previously treated, advanced squamous and nonsquamous NSCLC, respectively. We report 5-year pooled efficacy and safety from these trials.Patients (N = 854; CheckMate 017/057 pooled) with advanced NSCLC, ECOG PS ≤ 1, and progression during or after first-line platinum-based chemotherapy were randomly assigned 1:1 to nivolumab (3 mg/kg once every 2 weeks) or docetaxel (75 mg/m2 once every 3 weeks) until progression or unacceptable toxicity. The primary end point for both trials was OS; secondary end points included progression-free survival (PFS) and safety. Exploratory landmark analyses were investigated.After the minimum follow-up of 64.2 and 64.5 months for CheckMate 017 and 057, respectively, 50 nivolumab-treated patients and nine docetaxel-treated patients were alive. Five-year pooled OS rates were 13.4% versus 2.6%, respectively; 5-year PFS rates were 8.0% versus 0%, respectively. Nivolumab-treated patients without disease progression at 2 and 3 years had an 82.0% and 93.0% chance of survival, respectively, and a 59.6% and 78.3% chance of remaining progression-free at 5 years, respectively. Treatment-related adverse events (TRAEs) were reported in 8 of 31 (25.8%) nivolumab-treated patients between 3-5 years of follow-up, seven of whom experienced new events; one (3.2%) TRAE was grade 3, and there were no grade 4 TRAEs.At 5 years, nivolumab continued to demonstrate a survival benefit versus docetaxel, exhibiting a five-fold increase in OS rate, with no new safety signals. These data represent the first report of 5-year outcomes from randomized phase III trials of a programmed death-1 inhibitor in previously treated, advanced NSCLC.
Drug–Radiotherapy Combination Trial Developments—Response
Authors: Eric Deutsch, Cyrus Chargari, Ralph R. Weichselbaum, Antonin Levy
Journal: Clinical Cancer Research (2021)

In a recent issue of Clinical Cancer Research , we reviewed and discussed key methodologic basic and clinical research aspects that could inform precision drug–radiotherapy trial optimization ([1][1]). We thank the University of Michigan (Ann Arbor, MI) group for underlining that radiotherapy-
Abstract 700: Left Ventricular Outflow Tract (LVOT) Diameter/Aortic Valve Diameter Ratio is an Accurate Non-invasive Cardiac MRI Marker for Estimation of LVOT Obstruction in Patients With Hypertrophic Cardiomyopathy
Authors: Jens Vogel-Claussen, Miguel Santaularia Tomas, Amit Newatia, Danielle Boyce, Aurélio Pinheiro, Roselle Abraham, Theodore Abraham, David A Bluemke
Journal: Circulation (2009)

Purpose: To evaluate if LVOT diameter/aortic valve (LVOT/AO) ratio measured by cardiac MRI is an accurate marker to estimate LVOT obstruction in patients with hypertrophic cardiomyopathy. Methods: ...
Abstract 15560: Induced Pluripotent Stem Cell (iPSC) Derived Smooth Muscle Cells as a Model to Study Vascular Calcification
Authors: Samantha K Atkins, Romi Brouwhuis, Sasha A Singh, Masanori Aikawa, Elena Aikawa
Journal: Circulation (2020)

Introduction: Vascular calcification is the top cause of mortality worldwide. Vascular smooth muscle cells (SMCs) are major contributors to vascular calcification. There is an urgent need for a large scale and inexhaustible source of functional SMCs to study mechanisms of cardiovascular calcification. Here, we describe a new platform utilizing iPSCs differentiated towards SMCs that can calcify, to model ectopic calcification and identify mechanisms of SMCs’ contribution in this pathological process. Methods: We differentiated human iPSCs towards an induced-SMC (iSMC) phenotype in a 10-day protocol. We verified successful iSMC differentiation through immunofluorescent staining for SMC marker proteins αSMA and MYH11, FACS using CD140b, and proteomics analysis on whole cell lysate at days 0, 3, 5, 7, and 10. A set of 19 canonical SMC proteins were used to generate a Pearson’s correlation over the differentiation time course. After differentiation, we cultured the iSMCs in osteogenic media (OM) for 14 days. Alizarin Red S staining performed on day 14 confirmed the presence of calcification. Three independent experiments were performed for all data analyses. Results: Typical SMC morphology with positive staining for αSMA and MYH11 was detected at day 10 by immunofluorescence (Fig 1A). FACS analysis on markers for iPSCs (TRA-1-60), ECs (CD31), and SMCs (CD140b) demonstrated that 93.9% of cells were positive for CD140b after 10 days of differentiation (Fig 1B, C). Time course proteomics showed a strong Pearson’s correlation with of iSMCs with SMC marker proteins (R = 0.89) by day 10 (Figure 1D). Calcification in osteogenic media was observed by day 14 in culture using Alizarin Red S staining (Fig 1E, F), with 4.8-fold higher calcification in OM as compared to normal media (NM). Conclusions: Investigated iSMCs have promising future applications in cardiovascular research and may serve as an inexhaustible resource for studying vascular SMC calcification.
MUC1 expression modulates epidermal growth factor receptor signaling and trafficking in transgenic mice and human breast cancer cell lines
Authors: Mamata R. Pochampalli, Joyce A. Schroeder
Journal: Cancer Research (2005)

1079  The objective of the present study is to characterize the effects of MUC1 expression on Epidermal Growth Factor Receptor (EGFR) signaling both in transgenic mice as well as in human breast cancer cell lines. MUC1 is a heavily glycosylated transmembrane protein overexpressed in a very high percentage of epithelial cancers, including breast cancer. Previous studies have demonstrated that MUC1 overexpression results in the development of metastatic mammary tumors in transgenic mice. However, the precise mechanism by which MUC1 induces mammary carcinoma remains unresolved. It has been shown that MUC1 can interact with EGFR, a receptor tyrosine kinase frequently upregulated in many cancers and plays multiple roles in various aspects of mammary gland development. While MUCI and EGFR are both over expressed in breast carcinomas, the relationship between MUCI expression and EGFR activation has not been determined. To investigate the interactions between MUCI and EGFR, we utilized mammary gland protein lysates from the mice that either overexpress or lack Muc1. Immunoprecipitation experiments looking for interactions of Muc1 and EGFR and recruitment of downstream signaling molecules revealed the following results: MUC1 interacts with EGFR specifically in the tumor but not in the contralateral mammary gland derived from the same mouse. Overexpression of Muc1 in the mouse models results in EGF-independent recruitment of Grb2 to EGFR. Ablation of MUC1 expression in the breast cancer cell lines utilizing siRNA revealed very interesting results. We found that MUC1 expression affects the duration of EGFR phosphorylation and stability and also regulates the activation of Akt in breast cancer cell lines. Thus, we have demonstrated for the first time that MUC1 is a novel regulator of EGFR signaling and trafficking in breast cancer cell lines. Current studies are focused on deciphering the precise role of Muc1 by utilizing the transgenic mouse models of breast cancer and determine how removal of Muc1 expression affects tumor onset and development.
Trends in life expectancy and healthy life years at birth and age 65 in the UK, 2008–2016, and other countries of the EU28: An observational cross-sectional study
Authors: Claire E. Welsh, Fiona E. Matthews, Carol Jagger
Journal: The Lancet Regional Health - Europe (2021)

As society ages, promoting the health of the extra years of life is of paramount importance for health, social care and pension provision. Increases in life expectancy in the UK and elsewhere have slowed in recent years, but the reasons for this are unclear. No formal comparison of trends in healthy life years between the UK and the other countries of the EU28 in recent times has been published. These countries are geographically proximate, and share many social, cultural and demographic properties, making them interesting and useful comparators, especially as the UK prepared to leave the European Union in 2020.We calculated sex-specific healthy life years (HLY), unhealthy life years (ULY), mild and severe ULY at birth and age 65 using life tables and age-specific prevalence of activity limitation amongst the EU28 between 2008 and 2016 from EuroHex. Trends in life expectancy, HLY, ULY and proportion of life spent healthy (HLY%) were compared. We then decomposed HLY temporal changes into relative effects of changes in healthy life and mortality, by age group.Life expectancy at birth, and age 65, in the UK were increasing rapidly in 2008 but slowed around 2011. Germany, Portugal and France showed evidence of a similar slowing. HLY at birth in the UK decreased, whereas it increased in most EU28 countries. The UK experienced a period of absolute expansion of unhealthy life in both sexes. The reduction in HLY at birth in the UK was mainly attributable to increases in unhealthy life in younger age groups.The UK's performance relative to the other countries of the EU28 was poor after 2011, combining static life expectancy and reductions in healthy life years. These trends suggest that the UK government's Ageing Society Grand Challenge (to increase the healthy life expectancy by five years by 2035) will be difficult to attain.National Institute for Health Research (NIHR) Policy Research Programme conducted through the NIHR Older People and Frailty Policy Research Unit, PR-PRU-1217-21502. The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care.