tbuckley/cabot-search huggingface dataset:
Predicting Asthma Development in Children Using a New Personalized Asthma Risk Score
Authors: Eric M. Schauberger, Gurjit K. Khurana Hershey, David I. Bernstein, Jocelyn M. Biagini Myers, Hua He, Lisa J. Martin, John Kroner, James E. Lockey, Grace K. LeMasters
Journal: Journal of Allergy and Clinical Immunology (2018)
Control of Humoral Response in Renal Transplantation by Belatacept Depends on a Direct Effect on B Cells and Impaired T Follicular Helper-B Cell Crosstalk
Authors: Claire Leibler, Allan Thiolat, Carole Hénique, Chloé Samson, Caroline Pilon, Marie Tamagne, France Pirenne, Benoit Vingert, José L. Cohen, Philippe Grimbert
Journal: Journal of the American Society of Nephrology (2018)

Generation of de novo donor-specific antibodies ( dn DSAs) after renal transplant is recognized as the leading cause of late transplant failure. Hence, the optimal immunosuppressive strategies to limit dn DSA development need to be defined. Recent clinical trials using the novel costimulatory blockade agent CTLA4-Ig (Belatacept) have shown that kidney transplant recipients (KTRs) treated with Belatacept have better graft survival and function and a lower proportion of dn DSAs than control-treated KTRs. Mechanisms involved in the control of humoral responses by Belatacept remain to be investigated. Here, we analyzed the effect of Belatacept on different steps of the B cell–mediated response in humans. In vitro , Belatacept reduced plasmablast differentiation, Ig production, and the expression of the major transcription factor involved in plasma cell function, Blimp-1, in a T cell–independent manner. Moreover, Belatacept induced activation of the STAT3 transcription factor in stimulated B cells and reduced the expression of CD86. Additionally, Belatacept blocked CD28-mediated activation of T follicular helper cells (Tfhs) in an autologous Tfh-memory B cells model. We then validated these observations in KTRs treated with Belatacept, who had a reduced proportion of blood effector B cells and activated Tfh (PD1 + ICOS + ) compared with control-treated KTRs. Our in vitro and in vivo results suggest that Belatacept modulates B cell function directly and at the level of B cell-Tfh interaction. These mechanisms likely account for the optimal control of humoral responses observed in KTRs treated with Belatacept.
Stress Signaling JNK2 Crosstalk With CaMKII Underlies Enhanced Atrial Arrhythmogenesis
Authors: Jiajie Yan, Weiwei Zhao, Justin K. Thomson, Xianlong Gao, Dominic M. DeMarco, Elena Carrillo, Biyi Chen, Xiaomin Wu, Kenneth S. Ginsburg, Mamdouh Bakhos, Donald M. Bers, Mark E. Anderson, Long-Sheng Song, Michael Fill, Xun Ai
Journal: Circulation Research (2018)

Atrial fibrillation (AF) is the most common arrhythmia, and advanced age is an inevitable and predominant AF risk factor. However, the mechanisms that couple aging and AF propensity remain unclear, making targeted therapeutic interventions unattainable.To explore the functional role of an important stress response JNK (c-Jun N-terminal kinase) in sarcoplasmic reticulum Ca2+ handling and consequently Ca2+-mediated atrial arrhythmias.We used a series of cutting-edge electrophysiological and molecular techniques, exploited the power of transgenic mouse models to detail the molecular mechanism, and verified its clinical applicability in parallel studies on donor human hearts. We discovered that significantly increased activity of the stress response kinase JNK2 (JNK isoform 2) in the aged atria is involved in arrhythmic remodeling. The JNK-driven atrial proarrhythmic mechanism is supported by a pathway linking JNK, CaMKII (Ca2+/calmodulin-dependent kinase II), and sarcoplasmic reticulum Ca2+ release RyR2 (ryanodine receptor) channels. JNK2 activates CaMKII, a critical proarrhythmic molecule in cardiac muscle. In turn, activated CaMKII upregulates diastolic sarcoplasmic reticulum Ca2+ leak mediated by RyR2 channels. This leads to aberrant intracellular Ca2+ waves and enhanced AF propensity. In contrast, this mechanism is absent in young atria. In JNK challenged animal models, this is eliminated by JNK2 ablation or CaMKII inhibition.We have identified JNK2-driven CaMKII activation as a novel mode of kinase crosstalk and a causal factor in atrial arrhythmic remodeling, making JNK2 a compelling new therapeutic target for AF prevention and treatment.
Dermoscopic Patterns of Spitz Nevi
Authors: Jeffrey L. Pollock
Journal: JAMA (2018)

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From macro- to microfactors in health: Social science approaches in research on sexually transmitted infections
Authors: Ruth Kutalek, Elena Jirovsky, Igor Grabovac
Journal: PLoS Medicine (2018)

Perceptions of the body and sexuality are socially and culturally constructed.They are deeply influenced by historical realities, ethnic affiliation, power relations, gender roles, and concepts of morality.In the highly sensitive context of sexually transmitted infections (STIs), social science research that employs qualitative approaches is therefore especially important.It provides critical perspectives on multiple levels and takes into account biological, social, and political issues of STI coinfection or "syndemics" [1].It also uses participatory approaches that empower patients and communities and enable culturally sensitive responses to infectious disease threats.In a Research Article published last month in PLOS Medicine's Collection on prevention, diagnosis, and treatment of STIs, Kipruto Chesang and colleagues [2] report on their qualitative study of healthcare providers (HCPs) working in HIV clinics in Kenya.Their study investigates HCP knowledge of STIs, day-to-day STI-related screening and treatment practices, HCP attitudes about STIs, health-seeking behavior of people living with HIV (PLWHIV), and structural factors affecting the management of STIs in this setting.The results are anticipated to provide input to Kenya's updated national STI guidelines in 2018.The authors conducted 87 in-depth interviews with HCPs in different professional roles, including clinical staff, pharmacy staff, and facility managers.The majority of the responses suggested that screening for STIs was done inconsistently or not at all.Reasons given included high workload, HCPs' discomfort in discussing sexual issues, and HCPs' anticipation of patient nondisclosure due to stigma.HCPs reported a widely held belief that STIs are a punishment for immoral behavior and felt that, fearing stigma, patients were less likely to disclose symptoms.HCPs sometimes blamed patients for acquiring STIs as this meant patients had not adhered to HCPs' advice regarding safe sex practices.Supportive supervision and training on STIs was almost nonexistent, which resulted in a lack of confidence to discuss broader issues of sexuality and STIs with patients.HCPs felt that because of the strictly vertical character of HIV programs, STI and HIV services were not integrated, leading to poor clinical management of STIs.Other barriers to STI care included lack of accessibility and availability of drugs, costly treatment, and worries regarding privacy and patient confidentiality.The article by Chesang and colleagues reveals, from the perspective of HCPs, the multilayered challenges and barriers to STI care that occur in a resource-poor setting.They report on problems on different structural levels, including infrastructure, human resources, and integration of system, that need to be considered holistically.The highlighted problems require a
Abstract P046: Cardiometabolic Risk Liver Transplant Survivors
Authors: Jeanne Salyer, Kyungeh An, Shadab Siddiqui
Journal: Circulation (2017)

Background: Coronary heart disease (CHD) is an important cause of long-term mortality in liver transplant recipients (LTR). LTR are at increased risk for CHD-related mortality due to exposure to chronic immunosuppression contributing to cardiometabolic risk. Physical activity (PA) and nutrition are important lifestyle management tools used in clinical practice to reduce CHD risk, however, little is known about the long-term effects of these strategies in LTR. Objective: The aim of this study was to evaluate PA and diet and correlate findings with the atherogenic lipoprofile, obesity and 10-year risk of CHD. Methods: LTR (≥ 2 years post LT; stable immunosuppression) without documented CHD, diabetes, graft cirrhosis, physical limitations, and malignancy were included. PA was quantitated via International Physical Activity Questionnaire (IPAQ). Anthropometric assessment was used to obtain body mass index (BMI) and waist hip ratio (WHR). NMR Lipoprofile was used to obtain athrogenic lipoprotein concentration and size followed by generic lipid profile. Food preferences were evaluated via Olbrisch Eating Style Questionnaire and Diet History Questionnaire. CHD risk was assessed by Framingham Risk Score (FRS). Results: Of 122 subjects screened, 27 met entry criteria. Most were overweight (N=11) or obese (N=8) with mean BMI 28.5 kg/m 2 ( SD =4.05; range=20.2-37.8) and mean WHR= 0.94 (SD=0.22; range=0.65-1.85). According to IPAQ, 20 patients (75%) were sedentary. Eating style and food preference choices suggested that 23 (85.2%) were unable to control portion sizes and 14 (51.9%) preferred sugar, fat, or starches in their diet. Fasting glucose was 98.8mg/dL ( SD =14.2, range=78-133) suggesting 7 participants were “pre-diabetes” and 2 undiagnosed type 2 diabetes. Four reported smoking; of these, one was highly nicotine dependent. FRS was 7.15% (SD=6.15, ranged 7-23). While the calculated total cholesterol 166.44 (SD=34.15), HDL 55.19 (SD=15.31), LDL 84.56 (SD=26.58), and TG 143.44 (SD=76.29)(all in mg/dL) were within normal range, numbers and sizes of lipoprotein particles indicate that LTRs were at moderate risk of CHD: LDL-C 1221.48 (SD+447.31)&gt;1000 nmol/L as reference), small LDL-P 799.81 (SD=489.95) &gt;527nmol/L), LDL-size 20.89 (SD=1.12)&gt;20.5nm, Large VLDL-P 2.93 (SD=4.35) &gt;2.7 nmol/L, and VLDL size 51.07(SD=9.74) &gt;46.6 nm. PA (more time sitting) was associated with higher BMI (r=.394, P&lt;0.05) and WHR (r=.535, P&lt;0.01) but not with particle number or density. PA (MET minutes/week) was associated with WHR (r=.535, p&lt;0.01). Neither PA nor nutrition (Kcal/day) was associated with FRS. Conclusion: LTR are generally inactive and make poor dietary choices which are reflected by the obesity indices and characterized by the atherogenic lipoprofile.
Blood Eosinophil Beta1-Integrin Activation Correlates with Eosinophilic Esophagitis (EoE) Disease Activity
Authors: Mats W. Johansson, Michael D. Evans, Elizabeth McKernan, Paul S. Fichtinger, Evelyn L. Angulo, Deane F. Mosher, Shelly M. Cook, Eric A. Gaumnitz, Sameer K. Mathur
Journal: Journal of Allergy and Clinical Immunology (2018)
In-Person Health Care as Option B
Authors: Sean Duffy, Thomas H. Lee
Journal: New England Journal of Medicine (2018)

Interview with Sean Duffy on approaches to providing high-quality nonvisit health care. (07:34)Download Face-to-face interactions will certainly always have a central role in health care. But a system focused on high-quality nonvisit care would work better for many patients — and quite possibly for physicians as well.
Recent data from radiofrequency denervation trials further emphasise that treating nociception is not the same as treating pain
Authors: Matthew K Bagg, James H McAuley, G Lorimer Moseley, Benedict Martin Wand
Journal: British Journal of Sports Medicine (2018)

Persistent low back pain (LBP) is the leading cause of disability globally, for which ever-larger increases in healthcare expenditure have not made a difference in terms of prevalence or burden.1 It is unquestionable that current healthcare is failing individuals with chronic LBP, and we contend that recent evidence from the interventional pain medicine field points clearly to what these failings are.

There has been remarkable growth in the use of interventional pain medicine procedures to manage chronic LBP, particularly radiofrequency denervation.2 In this approach, various diagnostic practices are used to identify a peripheral ‘nociceptive driver’, with the presumption that denervation of the peripheral structure will eradicate or significantly reduce pain and improve function.3 The growth in the use of radiofrequency denervation is surprising given that, until recently, the evidence base was equivocal2 and based on conflicting results from a limited number of small trials.

A welcome addition to the field was recently provided by Juch et al ,2 who reported on the outcome of three large clinical trials of neuroablative procedures in chronic LBP. All three trials compared guideline-based physical rehabilitation to rehabilitation with the addition of radiofrequency denervation. Despite employing a …
Adding patent foramen ovale closure to antiplatelet drugs reduced ischemic stroke after cryptogenic stroke
Authors: Mark J. Alberts
Journal: Annals of Internal Medicine (2018)

Source Citation Søndergaard L, Kasner SE, Rhodes JF, et al; Gore REDUCE Clinical Study Investigators. Patent foramen ovale closure or antiplatelet therapy for cryptogenic stroke. N Engl J Med. 2017;377:1033-42. 28902580
Chronic limb threatening ischaemia
Authors: Kevin Barraclough, Andrew Bradbury
Journal: BMJ (2018)

### What you need to know

A 72 year old ex-smoker with diabetes presents to his general practitioner with a 4 week history of increasing pain in his right foot, worse at night. He finds hanging the leg down provides some relief and he now sleeps in a chair. His leg is increasingly swollen. A cut on his foot has failed to heal and is now red and discharging. On examination, there are no pulses below the femoral artery. The right foot is cold and pale on elevation, and hyperaemic upon dependency. The GP diagnoses chronic limb threatening ischaemia (CLTI) and the patient is seen in the vascular clinic on the same day and admitted. He undergoes imaging and vein bypass surgery. He is discharged a week later free of pain with a healing foot wound.

Peripheral arterial disease affects 10%-20% of patients over 60 and presents in several ways123 (table 1). A quarter of patients have symptoms, typically intermittent claudication, of whom 1%-2% progress to CLTI each year.2 However, many patients with CLTI do not have a history of intermittent claudication and present de novo with ischaemic rest (night) pain and/or a non-healing foot wound. This is either because they cannot, or choose not to, walk far enough to bring on …
Liver sampling: a vital window into HBV pathogenesis on the path to functional cure
Authors: Upkar S Gill, Laura J Pallett, Patrick T F Kennedy, Mala K Maini
Journal: Gut (2018)

In order to optimally refine the multiple emerging drug targets for hepatitis B virus (HBV), it is vital to evaluate virological and immunological changes at the site of infection. Traditionally liver biopsy has been the mainstay of HBV disease assessment, but with the emergence of non-invasive markers of liver fibrosis, there has been a move away from tissue sampling. Here we argue that liver biopsy remains an important tool, not only for the clinical assessment of HBV but also for research progress and evaluation of novel agents. The importance of liver sampling has been underscored by recent findings of specialised subsets of tissue-resident immune subsets capable of efficient pathogen surveillance, compartmentalised in the liver and not sampled in the blood. Importantly, the assessment of virological parameters, such as cccDNA quantitation, also requires access to liver tissue. We discuss strategies to maximise information obtained from the site of infection and disease pathology. Fine needle aspirates of the liver may allow longitudinal sampling of the local virus/host landscape. The careful utilisation of liver tissue and aspirates in conjunction with blood will provide critical information in the assessment of new therapeutics for the functional cure of HBV.
How does dose impact on the severity of food‐induced allergic reactions, and can this improve risk assessment for allergenic foods?
Authors: A. E. J. Dubois, P. J. Turner, J. Hourihane, B. Ballmer‐Weber, K. Beyer, C.‐H. Chan, M. H. Gowland, S. O'Hagan, L. Regent, B. Remington, S. Schnadt, T. Stroheker, R. W. R. Crevel
Journal: Allergy (2018)

Quantitative risk assessment (QRA) for food allergens has made considerable progress in recent years, yet acceptability of its outcomes remains stymied because of the limited extent to which it has been possible to incorporate severity as a variable. Reaction severity, particularly following accidental exposure, depends on multiple factors, related to the allergen, the host and any treatments, which might be administered. Some of these factors are plausibly still unknown. Quantitative risk assessment shows that limiting exposure through control of dose reduces the rates of reactions in allergic populations, but its impact on the relative frequency of severe reactions at different doses is unclear. Food challenge studies suggest that the relationship between dose of allergenic food and reaction severity is complex even under relatively controlled conditions. Because of these complexities, epidemiological studies provide very limited insight into this aspect of the dose-response relationship. Emerging data from single-dose challenges suggest that graded food challenges may overestimate the rate of severe reactions. It may be necessary to generate new data (such as those from single-dose challenges) to reliably identify the effect of dose on severity for use in QRA. Success will reduce uncertainty in the susceptible population and improve consumer choice.
Change in viral bronchiolitis management in primary care in the UK after the publication of NICE guideline
Authors: Elliott J Carande, C Ronny Cheung, Andrew J Pollard, Simon B Drysdale
Journal: Thorax (2018)

The aim of this study was to investigate changes in general practitioner (GP) management before and after the publication of the National Institute for Health and Care Excellence bronchiolitis guideline. In March 2015 and May 2016, an electronic questionnaire was sent to GPs. It was completed by 1001 GPs in 2015 and 1009 in 2016. There were small but significant improvements in proportions of GPs using a guideline, measuring oxygen saturations and providing written guidance, and appropriate reductions in those prescribing medications. Thirty-five per cent had read the guideline and 25% changed their practice since guideline publication. There were modest but significant improvements in reported management by GPs after guideline publication.
Ivosidenib (AG-120) in Mutant IDH1 AML and Advanced Hematologic Malignancies: Results of a Phase 1 Dose Escalation and Expansion Study
Authors: Courtney D. DiNardo, Stephane De Botton, Eytan M. Stein, Gail J. Roboz, Alice S. Mims, Daniel A. Pollyea, Ronan T. Swords, Jessica K. Altman, Robert H. Collins, Gabriel N. Mannis, Geoffrey L. Uy, Will Donnellan, Arnaud Pigneux, Amir T. Fathi, Anthony S. Stein, Harry P. Erba, Gabrielle T. Prince, James M. Foran, Elie Traer, Robert K. Stuart, Martha L. Arellano, James L. Slack, Mikkael A. Sekeres, Katharine Yen, Stephanie M. Kapsalis, Hua Liu, Meredith Goldwasser, Sam Agresta, Eyal C. Attar, Martin S. Tallman, Richard M. Stone, Hagop M. Kantarjian
Journal: Blood (2017)
Early and sustained efficacy with apremilast monotherapy in biological-naïve patients with psoriatic arthritis: a phase IIIB, randomised controlled trial (ACTIVE)
Authors: Peter Nash, Kamal Ohson, Jessica Walsh, Nikolay Delev, Dianne Nguyen, Lichen Teng, Juan J Gómez-Reino, Jacob A Aelion
Journal: Annals of the Rheumatic Diseases (2018)

Evaluate apremilast efficacy across various psoriatic arthritis (PsA) manifestations beginning at week 2 in biological-naïve patients with PsA.Patients were randomised (1:1) to apremilast 30 mg twice daily or placebo. At week 16, patients whose swollen and tender joint counts had not improved by ≥10% were eligible for early escape. At week 24, all patients received apremilast through week 52.Among 219 randomised patients (apremilast: n=110; placebo: n=109), a significantly greater American College of Rheumatology 20 response at week 16 (primary outcome) was observed with apremilast versus placebo (38.2% (42/110) vs 20.2% (22/109); P=0.004); response rates at week 2 (first assessment) were 16.4% (18/110) versus 6.4% (7/109) (P=0.025). Improvements in other efficacy outcomes, including 28-joint count Disease Activity Score (DAS-28) using C reactive protein (CRP), swollen joint count, Health Assessment Questionnaire-Disability Index (HAQ-DI), enthesitis and morning stiffness severity, were observed with apremilast at week 2. At week 16, apremilast significantly reduced PsA disease activity versus placebo, with changes in DAS-28 (CRP) (P<0.0001), HAQ-DI (P=0.023) and Gladman Enthesitis Index (P=0.001). Improvements were maintained with continued treatment through week 52. Over 52 weeks, apremilast's safety profile was consistent with prior phase 3 studies in psoriasis and PsA. During weeks 0-24, the incidence of protocol-defined diarrhoea was 11.0% (apremilast) and 8.3% (placebo); serious adverse event rates were 2.8% (apremilast) and 4.6% (placebo).In biological-naïve patients with PsA, onset of effect with apremilast was observed at week 2 and continued through week 52. The safety profile was consistent with previous reports.NCT01925768; Results.
Food Protein-Induced Enterocolitis Syndrome Food Challenges: The Children’s Hospital of Philadelphia Experience
Authors: Kathleen Y. Wang, Juhee Lee, Antonella Cianferoni, Yuran Chi, Katie Cunha, Jerome M. Molleston, Amy Dean, Nicholas A. Pawlowski, Jennifer Heimall, Rushani W. Saltzman, Gita S. Ram, Joel Fiedler, Laura M. Gober, Jonathan M. Spergel, Terri F. Brown-Whitehorn
Journal: Journal of Allergy and Clinical Immunology (2018)
GMC’s push for erasure of paediatrician is questionable
Authors: David J Nicholl
Journal: BMJ (2018)

The General Medical Council’s High Court appeal for the erasure of Hadiza Bawa-Garba,1 is not aimed at improving patient care if it discourages duty of candour. It may also deter trainees from pursuing careers in high risk specialties, such as paediatrics, thus exacerbating the very …