tbuckley/cabot-search huggingface dataset:
ADS-5102 (Amantadine) Extended-Release Capsules for Levodopa-Induced Dyskinesia in Parkinson Disease (EASE LID Study)
Authors: Rajesh Pahwa, Caroline M. Tanner, Robert A. Hauser, Stuart H. Isaacson, Paul A. Nausieda, Daniel D. Truong, Pinky Agarwal, Keith L. Hull, Kelly E. Lyons, Reed Johnson, Mary Jean Stempien
Journal: JAMA Neurology (2017)

Medical treatment of levodopa-induced dyskinesia (LID) in Parkinson disease (PD) is an unmet need.To evaluate the efficacy and safety of ADS-5102 (amantadine) extended-release 274-mg capsules for treatment of LID in patients with PD.A randomized, double-blind, placebo-controlled clinical trial was conducted between May 7, 2014, and July 22, 2015, at 44 North American sites among patients with PD treated with levodopa who experienced at least 1 hour of troublesome dyskinesia per day with at least mild functional impact.Patients were randomized to receive placebo or 274 mg of ADS-5102 administered orally at bedtime for up to 25 weeks.The primary efficacy analysis was the change from baseline to week 12 in the Unified Dyskinesia Rating Scale total score for ADS-5102 vs placebo in the modified intent-to-treat population. OFF time (amount of time the PD medication is not controlling motor symptoms) was a key secondary end point. Safety analyses included all patients who received the study drug (ADS-5102 or placebo).A total of 189 patients were screened, and 126 were randomized; the modified intent-to-treat population included 121 patients (51 women and 70 men; mean [SD] age, 64.7 [9.1] years). At week 12, the least-squares mean (SE) change in the Unified Dyskinesia Rating Scale score was -15.9 (1.6) for ADS-5102 (n = 63) and -8.0 (1.6) for placebo (n = 58) (treatment difference, -7.9; 95% CI, -12.5 to -3.3; P < .001). OFF time decreased by a mean (SE) of 0.6 (0.3) hours for ADS-5102 and increased by 0.3 (0.3) hours for placebo (treatment difference, -0.9 hours; 95% CI, -1.6 to -0.2; P = .02). Common adverse events for ADS-5102 vs placebo included visual hallucinations (15 [23.8%] vs 1 [1.7%]), peripheral edema (15 [23.8%] vs 0), and dizziness (14 [22.2%] vs 0). Adverse events led to treatment discontinuation for 13 patients receiving ADS-5102 (20.6%) vs 4 patients receiving placebo (6.9%).ADS-5102, 274 mg at bedtime, may be an effective treatment for LID. An additional benefit is reduced OFF time. To our knowledge, this is the first demonstration of an oral treatment reducing both LID and OFF time in patients with PD with dyskinesia.clinicaltrials.gov Identifier: NCT02136914.
A systematic review of variables associated with sleep paralysis
Authors: Dan Denis, Christopher C. French, Alice M. Gregory
Journal: Sleep Medicine Reviews (2017)

Sleep paralysis is a relatively common but under-researched phenomenon. While the causes are unknown, a number of studies have investigated potential risk factors. In this article, we conducted a systematic review on the available literature regarding variables associated with both the frequency and intensity of sleep paralysis episodes. A total of 42 studies met the inclusion criteria. For each study, sample size, study site, sex and age of participants, sleep paralysis measure, and results of analyses looking at the relationship(s) between sleep paralysis and associated variable(s) were extracted. A large number of variables were associated with sleep paralysis and a number of themes emerged. These were: substance use, stress and trauma, genetic influences, physical illness, personality, intelligence, anomalous beliefs, sleep problems and disorders (both in terms of subjective sleep quality and objective sleep disruption), symptoms of psychiatric illness in non-clinical samples (particularly anxiety symptoms), and psychiatric disorders. Sleep paralysis appears to be particularly prevalent in post-traumatic stress disorder, and to a less degree, panic disorder. Limitations of the current literature, directions for future research, and implications for clinical practice are discussed.
Rome Foundation-Asian working team report: Asian functional gastrointestinal disorder symptom clusters
Authors: Kewin Tien Ho Siah, Xiaorong Gong, Xi Jessie Yang, William E Whitehead, Minhu Chen, Xiaohua Hou, Nitesh Pratap, Uday C Ghoshal, Ari F Syam, Murdani Abdullah, Myung-Gyu Choi, Young-Tae Bak, Ching-Liang Lu, Sutep Gonlachanvit, Chua Seng Boon, Fan Fang, Pui Kuan Cheong, Justin C Y Wu, Kok-Ann Gwee
Journal: Gut (2017)

Objective Functional gastrointestinal disorders (FGIDs) are diagnosed by the presence of a characteristic set of symptoms. However, the current criteria-based diagnostic approach is to some extent subjective and largely derived from observations in English-speaking Western patients. We aimed to identify latent symptom clusters in Asian patients with FGID. Design 1805 consecutive unselected patients with FGID who presented for primary or secondary care to 11 centres across Asia completed a cultural and linguistic adaptation of the Rome III Diagnostic Questionnaire that was translated to the local languages. Principal components factor analysis with varimax rotation was used to identify symptom clusters. Results Nine symptom clusters were identified, consisting of two oesophageal factors (F6: globus, odynophagia and dysphagia; F9: chest pain and heartburn), two gastroduodenal factors (F5: bloating, fullness, belching and flatulence; F8 regurgitation, nausea and vomiting), three bowel factors (F2: abdominal pain and diarrhoea; F3: meal-related bowel symptoms; F7: upper abdominal pain and constipation) and two anorectal factors (F1: anorectal pain and constipation; F4: diarrhoea, urgency and incontinence). Conclusion We found that the broad categorisation used both in clinical practice and in the Rome system, that is, broad anatomical divisions, and certain diagnoses with long historical records, that is, IBS with diarrhoea, and chronic constipation, are still valid in our Asian societies. In addition, we found a bowel symptom cluster with meal trigger and a gas cluster that suggests a different emphasis in our populations. Future studies to compare a non-Asian cohort and to match to putative pathophysiology will help to verify our findings.
A MUC1/IL-18 DNA vaccine induces protective immunity against subcutaneous MUC1+ tumors in MUC1 transgenic mice
Authors: Linda Snyder, Theresa J. Goletz, Frank Shi, George R. Gunn, Tara Dougherty, Patrick J. Branigan, Stephen McCarthy
Journal: Cancer Research (2004)

Proc Amer Assoc Cancer Res, Volume 45, 2004

4845 

MUC1 (mucin 1) is a transmembrane glycoprotein that is normally expressed on the ductal epithelia of pancreas, breast, prostate, colon, and lung. However, in adenocarcinomas of these organs, this self-antigen is over-expressed and aberrantly glycosylated. Thus, a therapy that targets tumor cells expressing this form of MUC1 could have great value in the treatment of these diseases. For the evaluation of MUC1 vaccine candidates, a human MUC1 transgenic mouse (huMUC1 Tg) model was used. These mice express human MUC1 in the appropriate tissue-specific pattern, thereby making MUC1 a self-antigen. Two MUC1+ tumor models were used to test MUC1 vaccine candidates, a subcutaneous tumor model and a lung metastasis model. Using the subcutaneous tumor model, we found that intradermal vaccination with a DNA vaccine encoding MUC1 (pMUC1) alone was insufficient to break tolerance to MUC1 or to induce tumor protection in a subcutaneous tumor model. However, co-administration of pMUC1 with an adjuvant plasmid encoding interleukin-18 (pIL-18) resulted in significant protection from tumor development. This protection was durable in the absence of additional vaccination as demonstrated by protection of vaccinated mice from a second challenge with MUC1+ tumors. Evidence of epitope spreading was also observed when protected mice survived a third tumor challenge in which MUC1- tumor cells were administered. Antibody-mediated depletion of specific lymphocyte subsets suggests that the mechanism of protection is due to the induction of a cellular immune response against MUC1. These results demonstrate that vaccination with pMUC1/pIL-18 can break tolerance to MUC1 and can induce an immune response that mediates decreased tumor burden and increased survival. Furthermore, by mediating tumor regression of MUC1+ tumors, the cellular immune response induced by vaccination with pMUC1/pIL-18 ‘spread’ to other tumor-associated determinants (epitope spreading) leading to the regression of MUC1- tumors. Therefore, it is likely that DNA vaccination could provide clinical benefit in patients with MUC1+ tumors.
Balloon pulmonary angioplasty for inoperable patients with chronic thromboembolic pulmonary hypertension: the initial German experience
Authors: Karen M. Olsson, Christoph B. Wiedenroth, Jan-Christopher Kamp, Andreas Breithecker, Jan Fuge, Gabriele A. Krombach, Moritz Haas, Christian Hamm, Thorsten Kramm, Stefan Guth, Hossein Ardeschir Ghofrani, Jan B. Hinrichs, Serghei Cebotari, Katrin Meyer, Marius M. Hoeper, Eckhard Mayer, Christoph Liebetrau, Bernhard C. Meyer
Journal: European Respiratory Journal (2017)

Balloon pulmonary angioplasty (BPA) is an emerging treatment for patients with inoperable chronic thromboembolic pulmonary hypertension (CTEPH). We report on a prospective series of 56 consecutive patients who underwent 266 BPA interventions (median, five per patient) at two German institutions. All patients underwent a comprehensive diagnostic work-up including right heart catheterisation at baseline and 24 weeks after their last intervention. BPA resulted in improvements in WHO functional class, 6 min walk distance (mean change, +33 m), right ventricular function and haemodynamics, including a decline in mean pulmonary artery pressure by 18% and in pulmonary vascular resistance by 26%. Procedure-related adverse events occurred in 9.4% of the interventions. The most common complications were related to pulmonary vascular injury and consecutive pulmonary bleeding. Most of these events were asymptomatic and self-limiting, but one patient died from pulmonary bleeding, resulting in a mortality rate of 1.8%. BPA resulted in haemodynamic and clinical improvements but was also associated with a considerable number of complications, including one fatal pulmonary bleeding. As the effects of BPA on survival are unknown, randomised controlled outcome trials comparing BPA with approved medical therapies in patients with inoperable CTEPH are required to allow for appropriate risk–benefit assessments.
Systemic Lupus Erythematosus
Authors: Alfred D. Steinberg, Mark F. Gourley, Dennis M. Klinman, George C. Tsokos, Dorothy E. Scott, Arthur M. Krieg
Journal: Annals of Internal Medicine (1991)

Although the cause of systemic lupus erythematosus remains unknown, pathogenic mechanisms are becoming clearer. Both genetic and environmental factors have been implicated in the induction and in the perpetuation of lupus. Implicated environmental triggers include ultraviolet light, chemicals (hydrazines, hair dyes, drugs), some foods, and possibly infectious agents. Lupus is mediated by the immune system. Patients have excess numbers of antibody-forming cells, including those that produce antibodies reactive with self-antigens. Patients also have an increased number of activated T cells, some of which help B cells to produce autoantibodies. A loss of tolerance is a critical immune abnormality in lupus; many of the activated helper T cells may result from a failure in normal tolerance mechanisms. A hematopoietic stem-cell defect could give rise to both B- and T-cell abnormalities. Such a stem-cell abnormality might lead to both a loss of self-tolerance and polyclonal B-cell activation. Antigen-driven, T-cell-dependent expansion of B-cell clones would then give rise to pathogenic autoantibodies, including anti-DNA. We believe that lupus is a syndrome: Patients differ regarding specific inciting factors and immune defects. Some patients have genetically conditioned abnormalities, similar to those found in mice with lupus; others have a combination of genetic and acquired defects. We hope that insights into pathogenesis lead to improved and more individualized therapy.
Learning in practice
Authors: Wai-Ching Leung, Vin Diwakar
Journal: BMJ (2002)

# Competency based medical training: review {#article-title-2}

The competency approach has become prominent at most stages of undergraduate and postgraduate medical training in many countries. In the United Kingdom, for example, it forms part of the performance procedures of the General Medical Council (GMC),1 underpins objectively structured clinical examinations (OSCEs) and records of in-training assessment (RITA), and has been advocated for the selection of registrars in general practice and interviews. 2 3 It has become central to the professional lives of all doctors and is treated as if it were a panacea—but there is little consensus among trainees, trainers, and committees on what this approach entails.

I aim to explore the origins and development of the competency approach, evaluate its current role in medical training, and discuss its strengths and limitations.

#### Summary points

The competency approach did not result directly from recent scandals of incompetent doctors. It originated from parallel developments in vocational training in many countries, such as the national qualifications framework in New Zealand, the national training board in Australia, the national skills standards initiative in the United States, and the national vocational qualifications (NVQs) in the United Kingdom.4 This movement was driven largely by the political perceived need to make the national workforce more competitive in the …
Simultaneous peripheral facial palsies (SPFP) and bilateral foot drops after initiation of eribulin in a patient with triple-negative breast cancer.
Authors: Tara Morrison, Ramona F. Swaby, Paula D. Ryan, Prakash Ambady
Journal: Journal of Clinical Oncology (2012)

e11085 Background: Simultaneous peripheral facial palsy (SPFP) is extremely rare. Unlike Bell’s palsy it is seldom idiopathic. We describe a case of acute SPFP and bilateral foot drops attributed to the novel chemotherapeutic agent, eribulin mesylate (EM), a synthetic microtubule inhibitor. Methods: Utilizing the medical record as well as physical evaluation and assessment, we diagnosed SPFP and bilateral foot drops temporally related to administration of EM for metastatic triple negative (ER neg/PR neg/HER2 neg) breast cancer. Results: A 71-year-old woman initially diagnosed with Stage I, T1N0M0, ER neg/PR neg/HER2 neg invasive ductal carcinoma of the left breast treated with adjuvant radiotherapy recurred 3 years later with liver metastases. Salvage treatment included first-line capecitabine for 6 months followed by paclitaxel for 13 months with residual grade 1 peripheral neuropathy. Fourteen days following last paclitaxel dosing, EM was started. Within 3 weeks of initiation of therapy, the patient presented with bilateral SPFP, as well as bilateral complete foot drops. She was unable to speak or take liquid or solid oral intake and unable to bear weight. Extensive work-up including initial CT of the brain, followed by MRI and LP revealed no metastatic or infectious (i.e. – Lyme disease, ACE, TSH, ANA, SPEP) etiology. After discontinuation of EM, physical and speech therapy were instituted including in-patient rehab. After follow-up of 16 weeks, she has partial resolution of the facial palsy and improved ambulation with bilateral foot braces and walking cane. Conclusions: Unlike unilateral Bell’s palsy, the differential diagnosis for SPFP includes many conditions that can potentially turn fatal within a short period of time if they are not diagnosed and treated promptly. To the best of our knowledge, CIN presenting with SPFP or foot drop due to EM has not been reported. We highlight the need to screen patients for pre-existing neuropathy and continued close monitoring for development of neuropathy to avoid potentially dose-limiting disabilities before initiating eribulin.
Gingival fibroblasts protect against experimental abdominal aortic aneurysm development and rupture through tissue inhibitor of metalloproteinase-1 production
Authors: Andreas Giraud, Lynda Zeboudj, Marie Vandestienne, Jérémie Joffre, Bruno Esposito, Stéphane Potteaux, José Vilar, Daniela Cabuzu, Johannes Kluwe, Sylvie Seguier, Alain Tedgui, Ziad Mallat, Antoine Lafont, Hafid Ait-Oufella
Journal: Cardiovascular Research (2017)

Abdominal aortic aneurysm (AAA), frequently diagnosed in old patients, is characterized by chronic inflammation, vascular cell apoptosis and metalloproteinase-mediated extracellular matrix destruction. Despite improvement in the understanding of the pathophysiology of aortic aneurysm, no pharmacological treatment is yet available to limit dilatation and/or rupture. We previously reported that human gingival fibroblasts (GFs) can reduce carotid artery dilatation in a rabbit model of elastase-induced aneurysm. Here, we sought to investigate the mechanisms of GF-mediated vascular protection in two different models of aortic aneurysm growth and rupture in mice. In vitro, mouse GFs proliferated and produced large amounts of anti-inflammatory cytokines and tissue inhibitor of metalloproteinase-1 (Timp-1). GFs deposited on the adventitia of abdominal aorta survived, proliferated, and organized as a layer structure. Furthermore, GFs locally produced Il-10, TGF-β, and Timp-1. In a mouse elastase-induced AAA model, GFs prevented both macrophage and lymphocyte accumulations, matrix degradation, and aneurysm growth. In an Angiotensin II/anti-TGF-β model of aneurysm rupture, GF cell-based treatment limited the extent of aortic dissection, prevented abdominal aortic rupture, and increased survival. Specific deletion of Timp-1 in GFs abolished the beneficial effect of cell therapy in both AAA mouse models. GF cell-based therapy is a promising approach to inhibit aneurysm progression and rupture through local production of Timp-1.
Nine doctors are elected as MPs
Authors: Abi Rimmer
Journal: BMJ (2017)

Nine doctors have been elected as MPs in the UK general election, with six representing the Conservative Party, two representing Labour, and one representing the Scottish Nationalist Party.

The election ended in a hung parliament after the Conservative Party won 318 seats, eight short of the 326 seats required for an outright victory.

The Labour Party won 261 seats, the Scottish Nationalist Party 35, the Liberal Democrats 12, and, …
Irritable Bowel Syndrome
Authors: Shahnaz Sultan, Ashish Malhotra
Journal: Annals of Internal Medicine (2017)

This issue provides a clinical overview of irritable bowel syndrome, focusing on diagnosis, treatment, and practice improvement. The content of In the Clinic is drawn from the clinical information and education resources of the American College of Physicians (ACP), including MKSAP (Medical Knowledge and Self-Assessment Program). Annals of Internal Medicine editors develop In the Clinic in collaboration with the ACP's Medical Education and Publishing divisions and with the assistance of additional science writers and physician writers.
Palbociclib (PAL) + letrozole (L) as first-line (1L) therapy (tx) in estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2−) advanced breast cancer (ABC): Efficacy and safety across patient (pt) subgroups.
Authors: Richard S. Finn, Veronique Dieras, Hope S. Rugo, Anil A. Joy, Stacy L. Moulder, Janice Maria Walshe, Hirofumi Mukai, Yaroslav V. Shparyk, In Hae Park, Ave Mori, Dongrui (Ray) Lu, Eric Roland Gauthier, Karen A. Gelmon
Journal: Journal of Clinical Oncology (2017)

1039 Background: Hormone tx (HT) is the primary 1L tx for ER+ ABC. In the PALOMA-2 study (NCT01740427), PAL+L as 1L ABC tx prolonged progression-free survival (PFS; hazard ratio [HR] 0.58; P&lt;.001) (Finn et al, NEJM. 2016). Methods: Postmenopausal pts with ER+/HER2– ABC and no prior systemic treatment in the advanced setting were randomized 2:1 to PAL (125 mg/d oral [3 wk on, 1 wk off]) + L (2.5 mg QD) or placebo (P) + L. Key endpoints were investigator-assessed PFS and safety. Results: 666pts (444, PAL+L; 222, P+L) were enrolled. Pts were similarly distributed between arms for visceral (48%) and nonvisceral (52%) disease and prior HT (56%) and no prior HT (44%); more pts had disease-free interval (DFI) &gt;12 mo (40%) than ≤12 mo (22%). Median PFS (mPFS) was improved in all subgroups by adding PAL to L (Table). Adverse events were consistent across subgroups, as described for the full study population. Conclusions: PAL+L improved mPFS vs P+L with manageable toxicity across all subgroups including those with visceral disease. PAL+L provides a 1L option that should be considered for all pts with ER+/HER2- ABC. Sponsor: Pfizer Clinical trial information: NCT01740427. [Table: see text]
Factors in Early Adolescence Associated With a Mole-Prone Phenotype in Late Adolescence
Authors: Haoming Xu, Michael A. Marchetti, Stephen W. Dusza, Esther Chung, Maira Fonseca, Alon Scope, Alan C. Geller, Marilyn Bishop, Ashfaq A. Marghoob, Allan C. Halpern
Journal: JAMA Dermatology (2017)

Nevi are important phenotypic risk factors for melanoma in adults. Few studies have examined the constitutional and behavioral factors associated with a mole-prone phenotype in adolescents.To identify host, behavioral, and dermoscopic factors in early adolescence (age, 14 years) that are associated with a mole-prone phenotype in late adolescence (age, 17 years).A prospective observational cohort study from the Study of Nevi in Children was conducted from January 1, 2009, to December 31, 2014, with a 2- to 3-year follow-up. A total of 569 students from the school system in Framingham, Massachusetts, were enrolled in the 8th or 9th grade (baseline; mean [SD] age, 14.4 [0.7] years). The overall retention rate was 73.3%, and 417 students were reassessed in the 11th grade.Mole-prone phenotype in the 11th grade, defined as total nevus count of the back and 1 randomly selected leg in the top decile of the cohort or having any nevi greater than 5 mm in diameter.Of the 417 students assessed at follow-up in the 11th grade (166 females and 251 males; mean [SD] age, 17.0 [0.4] years), 111 participants (26.6%) demonstrated a mole-prone phenotype: 69 students (62.2%) with 1 nevus greater than 5 mm in diameter, 23 students (20.7%) with total nevus count in the top decile, and 19 students (17.1%) with both characteristics. On multivariate analysis, baseline total nevus count (adjusted odds ratio, 9.08; 95% CI, 4.0-23.7; P < .001) and increased variability of nevus dermoscopic pattern (adjusted odds ratio, 4.24; 95% CI, 1.36-13.25; P = .01) were associated with a mole-prone phenotype.This study found clinically recognizable factors associated with a mole-prone phenotype that may facilitate the identification of individuals at risk for melanoma. These findings could have implications for primary prevention strategies and help target at-risk adolescents for higher-intensity counseling about sun protection and skin self-examination.