tbuckley/cabot-search huggingface dataset:
Pruritus secondary to primary biliary cholangitis: a review of the pathophysiology and management with phototherapy
Authors: A.B. Hussain, R. Samuel, V.S. Hegade, D.E. Jones, N.J. Reynolds
Journal: British Journal of Dermatology (2019)

Primary biliary cholangitis (PBC) is an autoimmune hepatobiliary disorder characterized by destruction of liver bile ducts leading to intrahepatic cholestasis. It causes intractable pruritus for which ultraviolet (UV)B phototherapy is an experimental treatment when alternative therapies fail. The pathophysiology of cholestatic itch and the mechanism of action of narrowband UVB in this condition remains poorly understood.To summarize the current literature and propose testable hypotheses for the mechanism of action of phototherapy in attenuating itch.A focused PubMed search for articles relating to the pathogenesis of itch in cholestatic disease was performed. A total of 3855 articles were screened and 50 were found suitable for literature review. Evidence from this literature review was combined with author expertise in the area.Formulated hypotheses focus on the role of bile salts, autotaxin and specific receptors including G-protein-coupled bile acid receptor, Gpbar1 (also known as TGR5) and the nuclear transcription factor farnesoid X receptor.Several testable mechanisms through which phototherapy may exert its effects are discussed in this review. The next steps are to carry out an objective assessment of the efficacy of phototherapy in cholestatic pruritus, gain further knowledge on the underlying pathways, and subsequently trial its use against current licensed therapies. Such studies could lead to increased mechanistic understanding, identification of novel therapeutic targets and the potential to refine phototherapy protocols, leading to improved control of itch and quality of life in patients with PBC. What's already known about this topic? Primary biliary cholangitis (PBC) is frequently associated with intractable pruritus for which current treatment options are often unsuccessful. Phototherapy is used as an experimental treatment for PBC-associated pruritus when alternative better-studied treatments fail. What does this study add? This study reviews the current literature on the pathophysiology and management of cholestatic pruritus, an area which remains poorly understood. We propose testable hypotheses of the mechanisms behind the attenuation of cholestatic pruritus with phototherapy.
Temporal association between hospitalization event and subsequent risk of mortality among patients with stable chronic heart failure with preserved ejection fraction: insights from the TOPCAT trial
Authors: Ambarish Pandey, Kershaw V. Patel, Colby Ayers, W.H. Wilson Tang, James C. Fang, Mark H. Drazner, Jarett Berry, Justin L. Grodin
Journal: European Journal of Heart Failure (2019)
Smokeless tobacco control in 180 countries across the globe: call to action for full implementation of WHO FCTC measures
Authors: Ravi Mehrotra, Amit Yadav, Dhirendra N Sinha, Mark Parascandola, Rijo M John, Olalekan Ayo-Yusuf, Nigar Nargis, Dorothy K Hatsukami, Saman Warnakulasuriya, Kurt Straif, Kamran Siddiqi, Prakash C Gupta
Journal: The Lancet Oncology (2019)
Niraparib monotherapy for late-line treatment of ovarian cancer (QUADRA): a multicentre, open-label, single-arm, phase 2 trial
Authors: Kathleen N Moore, Angeles Alvarez Secord, Melissa A Geller, David Scott Miller, Noelle Cloven, Gini F Fleming, Andrea E Wahner Hendrickson, Masoud Azodi, Paul DiSilvestro, Amit M Oza, Mihaela Cristea, Jonathan S Berek, John K Chan, Bobbie J Rimel, Daniela E Matei, Yong Li, Kaiming Sun, Katarina Luptakova, Ursula A Matulonis, Bradley J Monk
Journal: The Lancet Oncology (2019)
Abstract 5026: Gender Differences In The Effect Of Hemoglobin A1c On Mortality In Adults with Diabetes: Findings From A National Population-based Follow-up Study
Authors: Ankit Parikh, Stuart Lipsitz, Sundareshwaran Natarajan
Journal: Circulation (2008)

Background: Diabetes is associated with a greater relative risk of cardiovascular mortality in women than in men. Further, diabetes may carry a larger cardiovascular mortality risk than established coronary heart disease in women. It is unclear however if increasing glycosylated hemoglobin (HbA1c) levels are more strongly related to increased mortality in women than men. Methods: We examined the relationship between increasing levels of HbA1c and subsequent all-cause and cardiovascular mortality in a cohort of self-reported diabetics using data from the Third National Health and Nutrition Examination Survey. Mortality outcomes were assessed from the national death index. Population hazard ratios (HR) with 95% confidence intervals (CI) for mortality were derived from Cox proportional hazards models adjusting for age, race, education, income, smoking, obesity, hypertension, hyperlipidemia, physical activity, and diabetes duration. The study’s complex survey design was incorporated in all analyses to obtain population estimates by utilizing the appropriate survey weights, strata, and cluster variables. Results: There were a total of 1323 adults with diabetes with a mean follow-up time of 7.7 years. Among the 544 male diabetics, there were 235 all-cause deaths, 124 of which were from cardiovascular causes. Among the 779 female diabetics, there were 235 all-cause deaths, 111 of which were due to cardiovascular causes. In fully adjusted Cox models, a 2 percent increase in hemoglobin A1c was more strongly related to mortality in women (all-cause HR 1.23, 95% CI 1.04 –1.44, p=.02, cardiovascular HR 1.42, 95% CI 1.08 –1.85, p=.01) than in men (all-cause HR 1.17, 95% CI 0.88 –1.56, p=.27, cardiovascular HR 1.02, 95% CI 0.69 –1.54, p=.92). However, we did not find significant gender-Hemoglobin A1c interactions for either all-cause or cardiovascular mortality. Conclusions: Increasing hemoglobin A1c may be more strongly related to increased all-cause and cardiovascular mortality in women than in men.
Asthma paradoxes: time for a new approach across the spectrum of asthma severity
Authors: Luis J. Nannini
Journal: European Respiratory Journal (2019)

I read with interest the editorial from Beasley et al. [1]; in part, because we are proud to declare ourselves the first short-acting β2-agonist (SABA) free asthma department. Short-acting β2-agonist free asthma management and anti-inflammatory rescue therapy <http://ow.ly/us0L30nHmUE>
The Need for Long-term Follow-ups of Delinquency Prevention Experiments
Authors: David P. Farrington, J. David Hawkins
Journal: JAMA Network Open (2019)

The Cambridge-Somerville Youth Study (CSYS) was the first large-scale well-designed delinquency prevention experiment.Boys were matched on delinquency prediction scores and randomly allocated either to receive a treatment program from 1939 onward or to be in a control group who received no treatment.The treatment program was very intensive, offering regular friendly help from counselors in visits every 2 weeks on average, and it lasted over 5 years on average (from when the boys were approximately ages 10-15 years).However, the treatment program proved to be at best ineffective and at worst damaging.In a follow-up when the participants were approximately aged 45 years, McCord 1 concluded that the program had undesirable effects on criminal behavior, health, and employment.This conclusion, and this experiment, had a major impact on criminology in showing that well-intentioned attempts to help children could backfire.
Gut microbiota dysbiosis in a cohort of patients with psoriasis
Authors: C. Hidalgo‐Cantabrana, J. Gómez, S. Delgado, S. Requena‐López, R. Queiro‐Silva, A. Margolles, E. Coto, B. Sánchez, P. Coto‐Segura
Journal: British Journal of Dermatology (2019)

There is increasing evidence of the key role that the gut microbiota plays in inflammatory diseases.To identify differences in the faecal microbial composition of patients with psoriasis compared with healthy individuals in order to unravel the microbiota profiling in this autoimmune disease.16S rRNA gene sequencing and bioinformatic analyses were performed with the total DNA extracted from the faecal microbiota of 19 patients with psoriasis and 20 healthy individuals from the same geographic location.Gut microbiota composition of patients with psoriasis displayed a lower diversity and different relative abundance of certain bacterial taxa compared with healthy individuals.The gut microbiota profile of patients with psoriasis displayed a clear dysbiosis that can be targeted for microbiome-based therapeutic approaches. What's already known about this topic? Psoriasis is a chronic inflammatory immune-mediated skin disease, the aetiology of which remains unclear. The human microbiota is a complex microbial community that inhabits our body and has been related with the maintenance of a healthy status. Several studies have focused on the skin microbiome and its connection with psoriasis although less attention has been focused on the potential role of the gut microbiota in psoriatic disease. What does this study add? This study unravels the gut microbiome dysbiosis present in a cohort of patients with psoriasis, compared with a healthy control group from the same geographical location. This study shows a lower bacterial diversity and different relative abundance of certain bacterial taxa in patients with psoriasis. We gain knowledge and insight into the microbiome alterations in psoriatic disease, opening new avenues for therapeutic approaches to reshape the human microbiome towards a healthy status.
Targeted lipidomics reveal derangement of ceramides in major depression and bipolar disorder
Authors: Nathalie Brunkhorst-Kanaan, Katharina Klatt-Schreiner, Juliane Hackel, Katrin Schröter, Sandra Trautmann, Lisa Hahnefeld, Sabine Wicker, Andreas Reif, Dominique Thomas, Gerd Geisslinger, Sarah Kittel-Schneider, Irmgard Tegeder
Journal: Metabolism (2019)
Correction to: Therapeutic efficacy, pharmacokinetic profiles, and toxicological activities of humanized antibody-drug conjugate Zt/g4-MMAE targeting RON receptor tyrosine kinase for cancer therapy
Authors: Hang-Ping Yao, Liang Feng, Sreedhar Reddy Suthe, Ling-Hui Chen, Tian-Hao Weng, Chen-Yu Hu, Eun Sung Jun, Zhi-Gang Wu, Wei-Lin Wang, Song Cheol Kim, Xiang-Min Tong, Ming-Hai Wang
Journal: Journal for ImmunoTherapy of Cancer (2019)

Following publication of the original article [1], the author reported two errors in the authors affiliations.
Abstract P6-17-39: BAT8001, a potent anti-HER2 antibody-drug conjugate with a novel stable linker for the treatment of HER2-positive breast cancer
Authors: W Tang, X Deng, Z Ou, J Gan, Q Dong, B Tan, L Lu, B Chen, C Bao, S Li, B Thomas, J-C Yu
Journal: Cancer Research (2019)

Abstract Overexpression of HER2 occurs in approximately 20% of breast cancers and is associated with shortened survival. Trastuzumab emtansine (T-DM1), an anti-HER2 ADC, has shown efficacy in HER2-positive breast cancer patients and was approved by the FDA and EMA for advanced HER2-positive breast cancer. However T-DM1 causes grade 3 and 4 thrombocytopenia in up to 14.5% of patients as its major toxicity. The thrombocytopenia is likely caused by one of T-DM1's catabolites and payload, DM1, indicating T-DM1's linker can be cleaved. Here we adopted a novel noncleavable linker and created an anti-HER2 ADC, BAT8001, which is expected be efficacious in HER2-positive breast cancer and have a better side effect profile relative to T-DM1 due to the stability of BAT8001's noncleavable linker. BAT8001 is internalized in HER2-positive cancer cells. It inhibits proliferation of HER2-positive tumor cells with IC50s of ˜0.1 nM, similar to the potency of T-DM1. BAT8001 also induces apoptosis in HER2-positive cancer cells. In both cell-line and patient-derived mouse xenograft (PDX) models, BAT8001 demonstrates strong inhibition activity on tumor growth. For example, in a cell-line model of breast cancer (BT474), BAT8001 demonstrates potent activity with complete responses in all animals tested at the 15mg/kg dose level. Pharmacokinetics studies in monkey reveals BAT8001 has similar Cmax, AUC, and t1/2 as T-DM1. The major catabolite of BAT8001 is the Cys-linker-payload containing product. No free payload is observed. This compares favorably with T-DM1 where free DM1, T-DM1's payload, is one of the major catabolites. In a multiple dose toxicity study, BAT8001 had a NOAEL of 15 mg/kg versus 10 mg/kg for T-DM1. BAT8001 exhibits similar potency to T-DM1 on inhibiting HER2-positive cell proliferation and tumor growth, yet demonstrates better multiple dose toxicity than T-DM1. The improved toxicity profile of BAT8001 suggests that the novel noncleavable linker utilized in BAT8001 is more stable than the linker utilized in T-DM1. BAT8001 is very efficacious in cell-line xenograft models of breast cancer. The preclinical profile of BAT8001 warrants further development for the treatment of breast cancer and other HER2-positive cancers. Citation Format: Tang W, Deng X, Ou Z, Gan J, Dong Q, Tan B, Lu L, Chen B, Bao C, Li S, Thomas B, Yu J-C. BAT8001, a potent anti-HER2 antibody-drug conjugate with a novel stable linker for the treatment of HER2-positive breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-17-39.
Sixty seconds on . . . wine
Authors: Gareth Iacobucci
Journal: BMJ (2019)

Not in France it seems, where health officials have risked civil unrest by launching a campaign to try and encourage people to limit their drinking to no more than two glasses of wine per day.

It’s true. The agency Sante Publique France estimates that around 10.5 million adults—almost a quarter of the country’s adult population—are regularly drinking too much. It says excessive alcohol consumption causes 41 000 deaths a year, and …
Pharmacist-Led Education to Discontinue Inappropriate Prescribing
Authors: Madeline McCrary, Jennifer Goldstein
Journal: JAMA (2019)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Cost-Effectiveness of Defibrotide for the Treatment of Veno-Occlusive Disease/Sinusoidal Obstruction Syndrome (VOD/SOS) with Multi-Organ Dysfunction (MOD) Post-Hematopoietic Stem Cell Transplantation (HSCT) in Canada
Authors: Jonathan Belsey, Eric Ngonga Kemadjou, Maya Isaila, Kathleen F. Villa
Journal: Blood (2018)
Patient preferences for topical treatment of AK
Authors: D. Kopasker, A. Kwiatkowski, R.N. Matin, C.A. Harwood, F. Ismail, J.T. Lear, J. Thomson, Z. Hasan, G.N. Wali, A. Milligan, L. Crawford, I. Ahmed, H. Duffy, C.M. Proby, P.F. Allanson
Journal: British Journal of Dermatology (2019)

Actinic keratoses are rough patches of skin caused by years of sun damage. There is a small risk that AK patches could progress into a form of skin cancer called cutaneous Squamous Cell Carcinoma (cSCC). Treatment of AK might therefore provide an effective strategy for cSCC prevention, although this theory has not been rigorously tested. Also, the patient perspective on potential benefits of AK treatment in terms of skin cancer reduction has received little attention to date. Treatments for AK include freezing with liquid nitrogen (cryotherapy), surgical removal, topical treatments such as creams or gels (5‐fluorouracil, imiquimod, ingenol mebutate gel, diclofenac and retinoic acid), photodynamic (light) therapy, or laser treatment. The aims of this study were (i) to investigate patient preferences for topical treatments for AK using a discrete‐choice experiment (DCE); (ii) to evaluate patient willingness to trade between clinical benefit (i.e. how well it works) and medical burden (e.g. inconvenience and unwanted side effects). 109 patients were presented with a series of choices between two hypothetical topical treatments for AK, and a ‘no treatment’ opt‐out option in each choice set. Different attributes of the hypothetical treatments related to the burden of medication, (intensity and length of treatment, severity of local skin reaction, and occurrence of flu‐like side effects) and the efficacy of treatment (improvement in skin appearance and reduction in skin cancer risk). The analysis of the data is complex, but showed that most patients would be prepared to accept a lower reduction in skin cancer risk (e.g. a 50% reduction in the risk of skin cancer as opposed to a 60% reduction in the risk) and reduced efficacy of treatment (e.g. 50% clearance of AK lesions as opposed to 100% clearance) in order to reduce the length and intensity of the regimen, and side effects including skin inflammation and pain. This highlights the importance for doctors of taking individual patient preferences into account, to improve their views of their AK treatment and the likelihood that they will stick with their treatment.
Functional and Mechanistic Interrogation of BET Bromodomain Degraders for the Treatment of Metastatic Castration-resistant Prostate Cancer
Authors: Steven Kregel, Rohit Malik, Irfan A. Asangani, Kari Wilder-Romans, Thekkelnaycke Rajendiran, Lanbo Xiao, Josh N. Vo, Tanu Soni, Marcin Cieslik, Ester Fernadez-Salas, Bing Zhou, Xuhong Cao, Corey Speers, Shaomeng Wang, Arul M. Chinnaiyan
Journal: Clinical Cancer Research (2019)

Abstract Purpose: The bromodomain and extraterminal (BET)-containing proteins (BRD2/3/4) are essential epigenetic coregulators for prostate cancer growth. BRD inhibitors have shown promise for treatment of metastatic castration-resistant prostate cancer (mCRPC), and have been shown to function even in the context of resistance to next-generation AR-targeted therapies such as enzalutamide and abiraterone. Their clinical translation, however, has been limited by off-target effects, toxicity, and rapid resistance. Experimental Design: We have developed a series of molecules that target BET bromodomain proteins through their proteasomal degradation, improving efficacy and specificity of standard inhibitors. We tested their efficacy by utilizing prostate cancer cell lines and patient-derived xenografts, as well as several techniques including RNA-sequencing, mass spectroscopic proteomics, and lipidomics. Results: BET degraders function in vitro and in vivo to suppress prostate cancer growth. These drugs preferentially affect AR-positive prostate cancer cells (22Rv1, LNCaP, VCaP) over AR-negative cells (PC3 and DU145), and proteomic and genomic mechanistic studies confirm disruption of oncogenic AR and MYC signaling at lower concentrations than BET inhibitors. We also identified increases in polyunsaturated fatty acids (PUFA) and thioredoxin-interacting protein (TXNIP) as potential pharmacodynamics biomarkers for targeting BET proteins. Conclusions: Compounds inducing the pharmacologic degradation of BET proteins effectively target the major oncogenic drivers of prostate cancer, and ultimately present a potential advance in the treatment of mCRPC. In particular, our compound dBET-3, is most suited for further clinical development.
Single, Repeated, and Maintenance Ketamine Infusions for Treatment-Resistant Depression: A Randomized Controlled Trial
Authors: Jennifer L. Phillips, Sandhaya Norris, Jeanne Talbot, Meagan Birmingham, Taylor Hatchard, Abigail Ortiz, Olabisi Owoeye, Lisa A. Batten, Pierre Blier
Journal: American Journal of Psychiatry (2019)

Subanesthetic ketamine doses have been shown to have rapid yet transient antidepressant effects in patients with treatment-resistant depression, which may be prolonged by repeated administration. The purpose of this study was to evaluate the antidepressant effects of a single ketamine infusion, a series of repeated ketamine infusions, and prolongation of response with maintenance infusions.Forty-one participants with treatment-resistant depression completed a single-site randomized double-blind crossover comparison of single infusions of ketamine and midazolam (an active placebo control). After relapse of depressive symptoms, participants received a course of six open-label ketamine infusions administered thrice weekly over 2 weeks. Responders, classified as those participants who had a ≥50% decrease in their scores on the Montgomery-Åsberg Depression Rating Scale (MADRS), received four additional infusions administered once weekly (maintenance phase).Compared with midazolam, a single ketamine infusion elicited a significantly greater reduction in depressive symptoms at the primary efficacy endpoint (24 hours postinfusion). Linear mixed models revealed cumulative antidepressant effects with repeated infusions and doubling of the antidepressant response rate. Fifty-nine percent of participants met response criteria after repeated infusions, with a median of three infusions required before achieving response. Participants had no further change in MADRS scores during weekly maintenance infusions.Repeated ketamine infusions have cumulative and sustained antidepressant effects. Reductions in depressive symptoms were maintained among responders through once-weekly infusions. These findings provide novel data on efficacious administration strategies for ketamine in patients with treatment-resistant depression. Future studies should further expand on optimizing administration to better translate the use of ketamine into clinical settings.
FRI-031-Association between serum immunoglobulin G levels and intrahepatic plasmacytic gene signature in human autoimmune hepatitis
Authors: Atsumasa Komori, Asami Hori, Yuki Kugiyama, Shigemune Bekki, Tomoyuki Suehiro, Satoru Hashimoto, Akira Saeki, Shinya Nagaoka, Kazumi Yamasaki, Seigo Abiru, Masahiro Itoh, Hiroshi Yatsuhashi
Journal: Journal of Hepatology (2019)
FRI-020-Identification of risk factors for histological progression with sequential liver biopsies in primary cholangitis patients
Authors: Yukihisa Fujinaga, Tadashi Namisaki, Takemi Akahane, Kosuke Kaji, Hiroaki Takaya, Shinya Sato, Kei Moriya, Hideto Kawaratani, Yasuhiko Sawada, Masanori Furukawa, Yuki Tsuji, Hitoshi Yoshiji
Journal: Journal of Hepatology (2019)