tbuckley/cabot-search huggingface dataset:
Correspondence on ‘Characteristics associated with hospitalisation for COVID-19 in people with rheumatic disease: data from the COVID-19 Global Rheumatology Alliance physician-reported registry’ by Gianfrancesco et al. Compassionate use of tocilizumab in severe COVID-19 with hyperinflammation prior to advent of clinical trials – a real-world district general hospital experience
Authors: Asim Khan, Alice Cole, Naveen Bhadauria, Munzir El-Hassan, Daud Abdulla, Thomas Axon, Zozik Fattah, Jessica J Manson, Jeronimo Moreno-Cuesta, Dev Mukerjee
Journal: Annals of the Rheumatic Diseases (2020)

The coronavirus disease 2019 (COVID-19) has resulted in a global pandemic with multiple casualties. Within the UK, specific groups of patients including those with rheumatic diseases requiring significant immunosuppression were advised to shield from the public to protect themselves from COVID-19 during the heart of the pandemic.1 In their important paper, Gianfrancesco et al found lower rates of hospitalisation in patients with rheumatic diseases with COVID-19 who were taking traditional synthetic and biological disease modifying antirheumatic drugs (DMARDs).2 With regard to biologic DMARDs, most of their registry patients were taking tumour necrosis factor inhibitors but did also include other therapies including interleukin-6 (IL-6) antagonists.

They also provide an interesting suggestion of the potential benefit of biologic DMARD therapy in COVID-19 patients particularly in cases associated with a hyperinflammatory response. Indeed, it has been recognised that subsets of COVID-19 patients can develop a cytokine storm involving the uncontrolled production of cytokines such as IL-6.3 4 Moreover, observational studies suggest the potential benefit of IL-6-antagonism using tocilizumab (TOC).5–7 Internationally, TOC has been used in Italy, China and Ireland.8–10

Early during the UK pandemic, there was no access to clinical trials. Moreover, our Trust faced the second highest pressure index in the UK in relation to the number of admissions of COVID-19 patients.11 Our intensive care unit and …
Clinical Impact of PET Imaging in Patients With Metastatic Prostate Cancer
Authors: Murat Tuncel, Meltem Çağlar Tuncalı, Tuğçe Telli, Mustafa Erman
Journal: Clinical Nuclear Medicine (2020)

Abstract Prostate cancer (Pca) is the most common cancer and the second leading cause of death among men. Although conventional bone scans and abdominal CT are preferred in most of the guidelines and clinical trials, PET/CT has already started to become the inevitable part of Pca management because of its higher sensitivity and specificity. Radiotracers used for PET imaging show different molecular aspects of the disease process. Although 68 Ga–prostate-specific membrane antigen offers the highest sensitivity and specificity, other PET radiotracers such as 18 F-FDG and 68 Ga-DOTATATE still have a role in patients with prostate-specific membrane antigen–negative diseases such as Pca with neuroendocrine differentiation. In this pictorial essay, we have presented a series of patients with metastatic Pca who had PET images with different radiotracers and discussed the clinical role of this imaging modality in patient management.
Covid-19: Lack of action on government statistics is unacceptable, says expert
Authors: Shaun Griffin
Journal: BMJ (2020)

A leading expert has strongly criticised the UK government's inertia on accurately reporting the deaths of people with active covid-19 infection.Carl Heneghan, director of the Centre for Evidence Based Medicine at the University of Oxford, expressed his frustration that considerable discrepancies between data from the Office for National Statistics (ONS) and from Public Health England (PHE) on the gov.uk website had not been dealt with despite government commitments to do so.ONS data show that covid-19 was mentioned on 284 death certificates in the week ending 17 July in England, 1 while the gov.uk website reports 442 deaths (56% more) over the same period. 2In Wales the equivalent data show 11 covid-19 deaths in ONS figures and five on gov.uk.Heneghan said, "The inaccuracies in these datasets are unacceptable.Some of the deaths in [the week ending 17 July] have occurred in individuals who may not have an active infection.It has been over 10 days since the government said it was looking into the issue of reporting of deaths, and we have not yet heard an answer."The reasons for this delay are not clear, but it should be straightforward to report the number of deaths of those who died with an active infection in the last 28 days."
Pathogenic <i>ATM</i> Mutations in Cancer and a Genetic Basis for Radiotherapeutic Efficacy
Authors: Kenneth L Pitter, Dana L Casey, Yue C Lu, Margaret Hannum, Zhigang Zhang, Xinmao Song, Isabella Pecorari, Biko McMillan, Jennifer Ma, Robert M Samstein, Isaac X Pei, Atif J Khan, Lior Z Braunstein, Luc G T Morris, Christopher A Barker, Andreas Rimner, Kaled M Alektiar, Paul B Romesser, Christopher H Crane, Joachim Yahalom, Michael J Zelefsky, Howard I Scher, Jonine L Bernstein, Diana L Mandelker, Britta Weigelt, Jorge S Reis-Filho, Nancy Y Lee, Simon N Powell, Timothy A Chan, Nadeem Riaz, Jeremy Setton
Journal: JNCI Journal of the National Cancer Institute (2020)

Abstract Background Radiation therapy is one of the most commonly used cancer therapeutics but genetic determinants of clinical benefit are poorly characterized. Pathogenic germline variants in ATM are known to cause ataxia-telangiectasia, a rare hereditary syndrome notable for marked radiosensitivity. In contrast, somatic inactivation of ATM is a common event in a wide variety of cancers, but its clinical actionability remains obscure. Methods We analyzed 20 107 consecutively treated advanced cancer patients who underwent targeted genomic sequencing as part of an institutional genomic profiling initiative and identified 1085 harboring a somatic or germline ATM mutation, including 357 who received radiotherapy (RT). Outcomes of irradiated tumors harboring ATM loss-of-function (LoF) mutations were compared with those harboring variants of unknown significance. All statistical tests were 2-sided. Results Among 357 pan-cancer patients who received 727 courses of RT, genetic inactivation of ATM was associated with improved radiotherapeutic efficacy. The 2-year cumulative incidence of irradiated tumor progression was 13.2% vs 27.5% for tumors harboring an ATM LoF vs variant of unknown significance allele, respectively (hazard ratio [HR] = 0.51, 95% confidence interval [CI] = 0.34 to 0.77, P = .001). The greatest clinical benefit was seen in tumors harboring biallelic ATM inactivation (HR = 0.19, 95% CI = 0.06 to 0.60, P = .005), with statistically significant benefit also observed in tumors with monoallelic ATM inactivation (HR = 0.57, 95% CI = 0.35 to 0.92, P = .02). Notably, ATM LoF was highly predictive of outcome in TP53 wild-type tumors but not among TP53-mutant tumors. Conclusions We demonstrate that somatic ATM inactivation is associated with markedly improved tumor control following RT. The identification of a radio-sensitive tumor phenotype across multiple cancer types offers potential clinical opportunities for genomically guided RT.
Addressing socioeconomic inequalities in obesity: Democratising access to resources for achieving and maintaining a healthy weight
Authors: Jean Adams
Journal: PLoS Medicine (2020)

In low-income countries, overweight and obesity are more common in more socioeconomically affluent groups [1].This pattern flattens and then reverses as country-level income increases.In high-income countries, those living in less affluent circumstances are more likely to experience overweight and obesity.For example, in England, adults living in the most deprived fifth of neighbourhoods are almost twice as likely to be living with obesity (where the prevalence of obesity is 36%) as those living in the least deprived fifth (where the prevalence of obesity is 20%) [2].These socioeconomic inequalities in unhealthy body weight manifest early in life, with an obvious relationship seen between neighbourhood deprivation and the experience of overweight or obesity in 4-to 5-year-old children in England [3].As more countries experience epidemiological transitions, this inverse association between socioeconomic position and prevalence of unhealthy weight is becoming more common [1].The standard energy balance explanation of unhealthy body weight proposes that weight gain occurs, and unhealthy weight is maintained, when energy intake is greater than energy expenditure.The problem of obesity becomes easily framed within this explanation as one of quantity and personal gluttony and laziness: either energy intake is too high, energy expenditure is too low, or both.Applied to the specific case of socioeconomic inequalities in obesity, this framing leads to the proposal that these personal failings are more common in less affluent groups.The obvious solution that can flow is one of personal restraint and discipline, particularly for those living in less affluent circumstances.A closer look at socioeconomic differences in both dietary and physical activity patterns reveals that these differences may not simply be ones of quantity.Important socioeconomic differences in the quality of both diet and physical activity are becoming clear.For example, there is little evidence of socioeconomic differences in British children's achievement of international recommendations for 60 minutes of moderate-to vigorous-intensity physical activity per day.But more affluent children do accumulate more of the vigorous-intensity activity that is particularly associated with body weight than their less affluent counterparts, and this appears to be via more participation in organised sport [4].Similarly, there is little evidence that total dietary energy varies consistently across socioeconomic groups in the United Kingdom, but dietary quality does.Those living in more affluent households eat more fruit and vegetables than those living in less affluent homes, drink fewer sugar-sweetened beverages, and are more likely to consume diets associated with lower cardiovascular risk [5,6].
The Imaging Features and Clinical Associations of a Novel Tau PET Tracer—18F-APN1607 in Alzheimer Disease
Authors: Jung-Lung Hsu, Kun-Ju Lin, Ing-Tsung Hsiao, Kuo-Lun Huang, Chi-Hung Liu, Hsiu-Chuan Wu, Yi-Ching Weng, Chu-Yun Huang, Chiung-Chih Chang, Tzu-Chen Yen, Makoto Higuchi, Ming-Kuei Jang, Chin-Chang Huang
Journal: Clinical Nuclear Medicine (2020)

Purpose of the Report In vivo tau PET imaging could help clarify the spatial distribution of tau deposition in Alzheimer disease (AD) and aid in the differential diagnosis of tauopathies. To date, there have been no in vivo 18 F-APN1607 tau PET studies in patients with AD. Methods We applied tau tracer in 12 normal controls (NCs) and 10 patients in the mild to moderate stage of probable AD. Detailed clinical information, cognitive measurements, and disease severity were documented. Regional SUV ratios (SUVRs) from 18 F-AV-45 (florbetapir), 18 F-APN1607 PET images, and regional gray matter (GM) atrophic ratios were calculated for further analysis. Results Quantitative analyses showed significantly elevated SUVRs in the frontal, temporal, parietal, occipital lobes, anterior and posterior cingulate gyri, precuneus, and parahippocampal region (all P ’s &lt; 0.01) with medium to large effect sizes (0.44–0.75). The SUVRs from 18 F-APN1607 PET imaging showed significant correlations with the Alzheimer’s Disease Assessment Scale (ADAS-cog) scores (all P ’s &lt; 0.01) and strong correlation coefficients ( R 2 ranged from 0.54 to 0.68), even adjusted for age and sex effects. Finally, the SUVRs from 18 F-APN1607 PET imaging of the parahippocampal region showed rapid saturation as the ADAS-cog scores increased, and the SUVRs of the posterior cingulate gyrus and the temporal, frontal, parietal, and occipital regions slowly increased. The combined SUVRs from amyloid, tau PET, and regional GM atrophic ratio showed regional specific patterns as the ADAS-cog scores increased. Conclusions Our findings suggest that the 18 F-APN1607 tau tracer correlated well with cognitive changes and demonstrated the spatial pattern of amyloid, tau deposition, and GM atrophy in the progression of AD.
Cost-effectiveness of a Stepwise Approach vs Standard Care for Diabetes Prevention in India
Authors: Duygu Islek, Mary Beth Weber, Anjana Ranjit Mohan, Viswanathan Mohan, Lisa R. Staimez, Ranjani Harish, K. M. Venkat Narayan, Michael Laxy, Mohammed K. Ali
Journal: JAMA Network Open (2020)

<h3>Importance</h3> A stepwise approach that includes screening and lifestyle modification followed by the addition of metformin for individuals with high risk of diabetes is recommended to delay progression to diabetes; however, there is scant evidence regarding whether this approach is cost-effective. <h3>Objective</h3> To estimate the cost-effectiveness of a stepwise approach in the Diabetes Community Lifestyle Improvement Program. <h3>Design, Setting, and Participants</h3> This economic evaluation study included 578 adults with impaired glucose tolerance, impaired fasting glucose, or both. Participants were enrolled in the Diabetes Community Lifestyle Improvement Program, a randomized clinical trial with 3-year follow-up conducted at a diabetes care and research center in Chennai, India. <h3>Interventions</h3> The intervention group underwent a 6-month lifestyle modification curriculum plus stepwise addition of metformin; the control group received standard lifestyle advice. <h3>Main Outcomes and Measures</h3> Cost, health benefits, and incremental cost-effectiveness ratios (ICERs) were estimated from multipayer (including direct medical costs) and societal (including direct medical and nonmedical costs) perspectives. Costs and ICERs were reported in 2019 Indian rupees (INR) and purchasing power parity–adjusted international dollars (INT $). <h3>Results</h3> The mean (SD) age of the 578 participants was 44.4 (9.3) years, and 364 (63.2%) were men. Mean (SD) body mass index was 27.9 (3.7), and the mean (SD) glycated hemoglobin level was 6.0% (0.5). Implementing lifestyle modification and metformin was associated with INR 10 549 (95% CI, INR 10 134-10 964) (INT $803 [95% CI, INT $771-834]) higher direct costs; INR 5194 (95% CI, INR 3187-INR 7201) (INT $395; 95% CI, INT $65-147) higher direct nonmedical costs, an absolute diabetes risk reduction of 10.2% (95% CI, 1.9% to 18.5%), and an incremental gain of 0.099 (95% CI, 0.018 to 0.179) quality-adjusted life-years per participant. From a multipayer perspective (including screening costs), mean ICERs were INR 1912 (INT $145) per 1 percentage point diabetes risk reduction, INR 191 090 (INT $14 539) per diabetes case prevented and/or delayed, and INR 196 960 (INT $14 986) per quality-adjusted life-year gained. In the scenario of a 50% increase or decrease in screening and intervention costs, the mean ICERs varied from INR 855 (INT $65) to INR 2968 (INT $226) per 1 percentage point diabetes risk reduction, from INR 85 495 (INT $6505) to INR 296 681 (INT $22 574) per diabetes case prevented, and from INR 88 121 (INT $6705) to INR 305 798 (INT $23 267) per quality-adjusted life-year gained. <h3>Conclusions and Relevance</h3> The findings of this study suggest that a stepwise approach for diabetes prevention is likely to be cost-effective, even if screening costs for identifying high-risk individuals are added.
Identification of a Signaling Mechanism by Which the Microbiome Regulates Th17 Cell-Mediated Depressive-Like Behaviors in Mice
Authors: Eva M. Medina-Rodriguez, Derik Madorma, Gregory O’Connor, Brittany L. Mason, Dongmei Han, Sapna K. Deo, Mark Oppenheimer, Charles B. Nemeroff, Madhukar H. Trivedi, Sylvia Daunert, Eléonore Beurel
Journal: American Journal of Psychiatry (2020)

Objective: Microbiota dysbiosis has been linked to major depressive disorder, but the mechanisms whereby the microbiota modulates mood remain poorly understood. The authors tested whether specific changes in the microbiome modulate depressive-like behaviors. Methods: Stools from learned helpless, non–learned helpless, and non-shocked mice were analyzed by V4 16S RNA sequencing to identify gut bacteria associated with learned helplessness and to quantify the level of the quorum-sensing molecule autoinducer-2 (AI-2). T cells were analyzed by flow cytometry, and serum amyloid proteins (SAA) were analyzed by quantitative real-time polymerase chain reaction. Fecal transfer approach and administration of oleic acid and AI-2 were used to determine the effects of the microbiome and quorum-sensing molecules on depressive-like behaviors. Results: Mice deficient in segmented filamentous bacteria (SFB) were resilient to the induction of depressive-like behavior, and were resensitized when SFB was reintroduced in the gut. SFB produces the quorum-sensing AI-2 and promotes the production of SAA1 and SAA2 by the host, which increases T helper 17 (Th17) cell production. Th17 cells were required to promote depressive-like behaviors by AI-2, as AI-2 administration did not promote susceptibility to depressive-like behaviors or SAA1 and SAA2 production in Th17-deficient mice after stress. Oleic acid, an AI-2 inhibitor, exhibited antidepressant properties, reducing depressive-like behavior, intestinal SAA1 and SAA2 production, and hippocampal Th17 cell accumulation. Stool samples from 10 people with current depressive symptoms and 10 matched healthy control subjects were analyzed as well. Patients with current major depressive disorder exhibited increased fecal interleukin 17A, SAA, and SFB levels. Conclusions: The study results reveal a novel mechanism by which bacteria alter mood.
AB0836 PREVALENCE AND DETERMINANTS OF FATIGUE IN PSORIATIC ARTHRITIS IN AN ASIAN POPULATION
Authors: J. S. Q. Tan, W. Fong, Y. H. Kwan, Y. Y. Leung
Journal: Annals of the Rheumatic Diseases (2020)

Background: Fatigue is one of the core domains to be measured in all clinical trials for psoriatic arthritis (PsA). Studies of fatigue in PsA in Asia are scarce. Objectives: To describe the prevalence and evaluate the factors associated with fatigue in PsA patients within a multi-ethnic Asian population. Methods: We used data from the PRESPOND registry for PsA patients attending an outpatient clinic of a tertiary institution in Singapore. Demographics data and disease characteristics were evaluated. Fatigue was assessed by question 1 of BASDAI (BASDAI-F) and the vitality domain of SF-36 (SF-36 VT). Results: 131 patients (50.4% men, 63.4% Chinese, median PsA duration 1.78 years) with completed data for fatigue were included. The median (IQR) tender and swollen joint count was 2 (5) and 1 (3) respectively. 45 patients (34%) experienced high fatigue (defined by BASDAI-F ≥ 6/10 1,2 ). 5 clusters of factors were identified using principal component analysis that explained 66.2% of the variance of all factors, which mapped to disease activity, disease chronicity, demographics (ethnicity and gender), and BMI (Figure 1). Of these, disease activity and chronicity were significantly associated with BASDAI-F and SF-36 VT. In a multivariate analysis, back pain, peripheral joint pain and patient global assessment were associated with BASDAI-F, whereas peripheral joint pain, HAQ-DI, age and BMI were associated with SF-36 VT (Table 1). Table 1. Multivariable analysis for variables associated with fatigue BASDAI-F SF-36 VT b 95% CI β p b 95% CI β p Back pain (0-10 ) 0.335 (0.180, 0.490) 0.356 &lt;0.001 - - - - Peripheral joint pain (0-10 ) 0.027 (0.012, 0.042) 0.268 0.001 -2.296 (-3.410, -1.182) -0.320 &lt;0.001 PGA (0-100 ) 0.211 (0.061, 0.361) 0.236 0.006 - - - - HAQ-DI (0-3 ) - - - - -12.74 (-17.97, -7.51) -0.386 &lt;0.001 Age, y - - - - 0.260 (0.065, 0.456) 0.179 0.009 BMI, kg/m 2 - - - - -0.644 (-1.183, -0.105) -0.165 0.020 Figure 1. Principal component analysis with 5 components and residuals (in dotted lines). Only factor loadings with magnitudes greater than 0.40 are shown. Conclusion: PsA-associated fatigue is prevalent in this Asian PsA cohort and is associated with disease activity and chronicity. References: [1]Gudu T, Etcheto A, de Wit M, Heiberg T, Maccarone M, Balanescu A, et al. Fatigue in psoriatic arthritis - a cross-sectional study of 246 patients from 13 countries. Joint Bone Spine. 2016;83(4):439-43. [2]Walsh JA, McFadden ML, Morgan MD, Sawitzke AD, Duffin KC, Krueger GG, et al. Work productivity loss and fatigue in psoriatic arthritis. J Rheumatol. 2014;41(8):1670-4. Disclosure of Interests: Joel Shi Quan Tan: None declared, Warren Fong Consultant of: Abbvie, Janssen, Novartis, Speakers bureau: Abbvie, Janssen, Novartis, Yu Heng Kwan: None declared, Ying Ying Leung Speakers bureau: Novartis, Janssen, Eli Lilly
ENaC inhibition in cystic fibrosis: potential role in the new era of CFTR modulator therapies
Authors: Marcus A. Mall
Journal: European Respiratory Journal (2020)

<b>ENaC inhibition with BI 1265162 is a promising strategy to optimise outcomes in patients with CF either eligible, or ineligible, for CFTR modulator therapy. Phase II clinical trials of BI 1265162 must now show this translates into clinical benefit.</b>https://bit.ly/2OQ1IUI
Histopathological features of complete pathological response predict recurrence-free survival following neoadjuvant targeted therapy for metastatic melanoma
Authors: M.T. Tetzlaff, C. Adhikari, S. Lo, R.V. Rawson, R.N. Amaria, A.M. Menzies, J.S. Wilmott, P.M. Ferguson, M.I. Ross, A.J. Spillane, K.A. Vu, J. Ma, J. Ning, L.E. Haydu, R.P.M. Saw, J.A. Wargo, H.A. Tawbi, J.E. Gershenwald, G.V. Long, M.A. Davies, R.A. Scolyer
Journal: Annals of Oncology (2020)
Novel PF74-like small molecules targeting the HIV-1 capsid protein: Balance of potency and metabolic stability
Authors: Lei Wang, Mary C. Casey, Sanjeev Kumar V. Vernekar, Rajkumar Lalji Sahani, Karen A. Kirby, Haijuan Du, Huanchun Zhang, Philip R. Tedbury, Jiashu Xie, Stefan G. Sarafianos, Zhengqiang Wang
Journal: Acta Pharmaceutica Sinica B (2020)

Of all known small molecules targeting human immunodeficiency virus (HIV) capsid protein (CA), PF74 represents by far the best characterized chemotype, due to its ability to confer antiviral phenotypes in both early and late phases of viral replication. However, the prohibitively low metabolic stability renders PF74 a poor antiviral lead. We report herein our medicinal chemistry efforts toward identifying novel and metabolically stable small molecules targeting the PF74 binding site. Specifically, we replaced the inter-domain-interacting, electron-rich indole ring of PF74 with less electron-rich isosteres, including imidazolidine-2,4-dione, pyrimidine-2,4-dione, and benzamide, and identified four potent antiviral compounds (10, 19, 20 and 26) with markedly improved metabolic stability. Compared to PF74, analog 20 exhibited similar submicromolar potency, and much longer (51-fold) half-life in human liver microsomes (HLMs). Molecular docking corroborated that 20 binds to the PF74 binding site, and revealed distinct binding interactions conferred by the benzamide moiety. Collectively, our data support compound 20 as a promising antiviral lead.