tbuckley/cabot-search huggingface dataset:
Relapse-free cure from multidrug-resistant tuberculosis in Germany
Authors: Jan Heyckendorf, Frank van Leth, Barbara Kalsdorf, Ioana D. Olaru, Gunar Günther, Helmut J.F. Salzer, Elena Terhalle, Thierry Rolling, Georg Glattki, Marius Müller, Maren Schuhmann, Korkut Avsar, Christoph Lange
Journal: European Respiratory Journal (2018)

Multidrug-resistant (MDR) tuberculosis (TB), defined by bacillary resistance against rifampicin and isoniazid, has been identified as a global threat to mankind [1]. According to the latest report by the European Centres for Disease Prevention and Control, and World Health Organization (WHO) regional office for Europe, only approximately 50% of MDR-TB patients in Europe reach favourable treatment outcomes [2]. Successful treatment outcomes are achieved for less than 25% of patients with extensively drug-resistant (XDR)-TB (MDR plus resistance against a least one fluoroquinolone and one second-line injectable drug) in the European Union/European Economic Area Countries [2]. Under optimal conditions we observed similar rates of relapse-free cure in patients with M/XDR-TB and non-M/XDR-TB <http://ow.ly/SRvd30hPu73> We thank Cordula Ehlers, Jessica Hofmeister, Franziska Daduna, Nelleke Smitsmann, and Dagmar Schaub for the study management and data entry.
IMPACT OF STENT DIAMETER ON OUTCOMES FOLLOWING PERCUTANEOUS CORONARY INTERVENTION WITH 2ND GENERATION DRUG ELUTING STENTS: RESULTS FROM A LARGE SINGLE-CENTER REGISTRY
Authors: Anna Plitt, Usman Baber, Jaya Chandrasekhar, Samantha Sartori, Pooja Vijay, Jason Kovacic, Joseph Sweeny, Nitin Barman, Pedro Moreno, Prakash Krishnan, Roxana Mehran, George Dangas, Annapoorna Subhash Kini, Samin K. Sharma
Journal: Journal of the American College of Cardiology (2018)
Switching From Reference Adalimumab to SB5 (Adalimumab Biosimilar) in Patients With Rheumatoid Arthritis
Authors: Michael E. Weinblatt, Asta Baranauskaite, Eva Dokoupilova, Agnieszka Zielinska, Janusz Jaworski, Artur Racewicz, Margarita Pileckyte, Krystyna Jedrychowicz‐Rosiak, Inyoung Baek, Jeehoon Ghil
Journal: Arthritis & Rheumatology (2018)

The 24-week equivalent efficacy and comparable safety results of the biosimilar SB5 and reference adalimumab (ADA) from the phase III randomized study in patients with moderate-to-severe rheumatoid arthritis (RA) have been reported previously. We undertook this transition study to evaluate patients who switched from ADA to SB5 or who continued to receive SB5 or ADA up to 52 weeks.In this phase III study, patients were initially randomized 1:1 to receive SB5 or ADA (40 mg subcutaneously every other week). At 24 weeks, patients receiving ADA were rerandomized 1:1 to continue with ADA (ADA/ADA group) or to switch to SB5 (ADA/SB5 group) up to week 52; patients receiving SB5 continued with SB5 for 52 weeks (SB5 group). Efficacy, safety, and immunogenicity were evaluated up to 52 weeks.The full analysis set population consisted of 542 patients (269 in the SB5 group, 273 in the ADA overall group [patients who were randomized to receive ADA at week 0], 125 in the ADA/SB5 group, and 129 in the ADA/ADA group). The percentages of patients meeting the American College of Rheumatology 20%, 50%, or 70% improvement criteria (achieving an ACR20, ACR50, or ACR70 response) at week 24 were maintained after the transition from ADA to SB5, and these response rates were comparable across treatment groups throughout the study. ACR20 response rates ranged from 73.4% to 78.8% at week 52. Radiographic progression was minimal and comparable across treatment groups. The safety profile and the incidence of antidrug antibodies were comparable across treatment groups after transition.SB5 was well tolerated over 1 year in patients with RA, with efficacy, safety, and immunogenicity comparable to those of ADA. Switching from ADA to SB5 had no treatment-emergent issues such as increased adverse events, increased immunogenicity, or loss of efficacy.
RUSSCO-RSP study of immunohistochemistry (IHC) diagnostic assays for PD-L1 expression in urothelial cancer (UC).
Authors: Ilya Tsimafeyeu, Larisa Zavalishina, Patrisia Povilaitite, Grigory Raskin, Yulia Andreeva, Alexey Petrov, Ekaterina Kharitonova, Inna Pugach, Alexey Rumyantsev, Georgy Frank, Sergei Tjulandin
Journal: Journal of Clinical Oncology (2018)

489 Background: This collaborative Russian Society of Clinical Oncology (RUSSCO) and Russian Society of Pathology (RSP) study assess the extent of concordance between three validated, commercially available PD-L1 IHC assays for UC patients. Methods: Tumors from 100 UC patients were stained with SP142 (Ventana), 22C3 (Dako) and SP263 (Ventana) clones as used in the clinical trials of second-line therapy of atezolizumab, pembrolizumab and durvalumab. Four trained pathologists independently evaluated the percentages of tumor (TC) and tumor infiltrating immune cells (IC) staining positive at any intensity. One test-specific cutoff rule for each assay in this analysis was pre-specified as: IC ≥5% for SP142, TC+IC ≥10% or TC ≥10% for 22C3, and TC ≥25% or IC ≥25% for SP263. Results: 300 IHC slides were scored. Patients were predominantly male (89%) with T1 (45%) and T2 (45%) stages, respectively. The percent of IC staining across 3 assays is shown to be higher than for TC staining (45% vs. 8% for SP142; 55% vs. 24% for 22C3; 72% vs. 27% for SP263). Pearson Correlation Coefficients for IC were: 0.5, 0.69 and 0.85 between SP142/22C3, SP263/22C3 and SP142/SP263, respectively. Pearson Correlation Coefficients for TC were: 0.93, 0.99 and 0.91 for the same pairs. Table indicates the agreement analysis using recommended individual cutoffs for each test. Conclusions: If a patient with UC is classified as negative by one of the three single tests using the corresponding recommended cutoff rule, the patient will be classified as negative by any other test with a high likelihood (91%-100%), and, therefore, repeated testing can be avoided.[Table: see text]
AVAILABILITY AND QUALITY OF CARDIAC REHABILITATION AROUND THE GLOBE: PATIENTS SERVED, PROVIDERS, AND CORE COMPONENTS
Authors: Marta Supervía Pola, Karam Turk-Adawi, Ella Pesah, Francisco Lopez-Jimenez, Ding Rongjing, Raquel Britto, Wayne Derman, Birna Bjarnason-Wehrens, Ana Abreu, Jong Seng Khiong, Karl Andersen, Graciela Gonzalez, Vojislav Giga, Tee Joo Yeo, Dawn Scantlebury, Dusko Vulic, Eleonora Vataman, Lucky Cuenza, Sherry Grace
Journal: Journal of the American College of Cardiology (2018)
Serum miRNA to predict post-chemotherapy viable disease in testicular non-seminomatous germ cell tumor patients.
Authors: Ricardo Romao Nazario Leao, Ton Van Agthoven, Arnaldo Figueiredo, Kamel Fadaak, Pedro Castelo-Branco, Michael A.S. Jewett, Joan Sweet, Ardalan Ahmad, Lynn Anson-Cartwright, Philippe L. Bedard, Peter W. M. Chung, Aaron Richard Hansen, Padraig Richard Warde, Martin O'Malley, Leendert Looijenga, Robert James Hamilton
Journal: Journal of Clinical Oncology (2018)

546 Background: Retroperitoneal lymph node dissection (RPLND) is recommended for residual masses &gt; 1cm post-chemotherapy (pc) for nonseminomatous germ cell tumors (NSGCT). There is no reliable predictor for pcRPLND histology and up to 50% will harbour necrosis/fibrosis only, thus rendering a potentially morbid surgery to be of limited therapeutic value. Objective: To evaluate the ability of defined serum microRNA (miRNA) using the ampTSmiR test to predict residual viable NSGCT after chemotherapy. Methods: Serum miRNA levels (miR-371a-3p, miR-373-3p and miR-367-3p) were measured in 82 patients (cohort A = 39, cohort B = 43) treated with orchiectomy, chemotherapy and pcRPLND to predict viable GCT post-chemotherapy. Outcomes, measurements and statistical analysis: miRNA levels were compared to clinical characteristics, serum tumor markers and correlated with presence of viable GCT (vs. teratoma; vs. necrosis/fibrosis). miRNA-discriminative capacity was determined by receiver operating characteristic (ROC) analysis. Results: Serum miRNA were associated with stage at the time of chemotherapy and declined significantly post-chemotherapy. Patients with fibrosis/necrosis and teratoma had a significant decline in all three miRNA levels after chemotherapy, while those with viable disease had very little change. Patients with necrosis/fibrosis demonstrated similar miRNA levels as patients with residual teratoma. miR-371a-3p demonstrated the highest discriminative capacity [area under the curve (AUC) 0.874, CI 95% 0.774 - 0.974 p &lt; 0.0001] for viable disease post chemotherapy. If considering a more relaxed cut-point of 3cm before consideration of pcRPLND, miR-371a-3p correctly stratified all patients with residual retroperitoneal lesions ≤ 3 cm ( p= 0.02; 100% sensitivity). Conclusions: Our study is the first to explore a miRNA-based serum test to determine histology in post-chemotherapy residual masses and we demonstrated the value of miR-371a-3p to predict presence of viable GCT. Prospective studies are required to confirm its clinical utility.
In-Hospital ST-Segment Elevation Myocardial Infarction
Authors: Glenn N. Levine, Xuming Dai, Timothy D. Henry, Marcella Calfon Press, Ali E. Denktas, Ross F. Garberich, Alice K. Jacobs, Brian E. Jaski, Prashant Kaul, Michael C. Kontos, George A. Stouffer, Sidney C. Smith
Journal: JAMA Cardiology (2018)

In-hospital ST-segment elevation myocardial infarction (STEMI) is a unique clinical entity with epidemiology, incidence, and outcomes distinct from that of out-of-hospital STEMI and has only within the past 10 years begun to receive increased attention and research. Patients with in-hospital STEMI are older, have more comorbidities, and more frequently have coagulopathies and contraindications for anticoagulation and fibrinolytic therapy. A standardized clinical definition of in-hospital STEMI is lacking. The objectives of this special communication are to (1) summarize the knowledge base regarding in-hospital STEMI; (2) review the challenges of diagnosis and treatment of patients with in-hospital STEMI; (3) present a standardized clinical definition for in-hospital STEMI; and (4) provide a quality improvement protocol to improve diagnosis, triage, and treatment of patients with in-hospital STEMI.Patients with in-hospital STEMI less frequently present with typical angina symptoms, and an electrocardiogram is often obtained owing to changes in clinical status, changes on telemetry, or a finding of elevated cardiac biomarker. The frequent nontypical presentations often lead to substantial delays in the diagnosis of STEMI. Only 34% to 71% of patients with in-hospital STEMI undergo diagnostic catheterization, and only 22% to 56% undergo percutaneous coronary intervention. Even in contemporary reports, some studies report in-hospital mortality in the range of 31% to 42%. Three areas of delay in the treatment of patients with in-hospital STEMI that merit particular attention are (1) delays in electrocardiogram acquisition, (2) delays in electrocardiogram interpretation, and (3) delays in activation of existing STEMI systems of care.Treatment of patients with in-hospital STEMI is more complex and challenging than treatment of patients who develop out-of-hospital STEMI, leading to delays in diagnosis and triage and less frequent use of reperfusion therapy. Quality improvement programs targeted at decreasing delays and streamlining treatment of such patients may improve treatment and outcome.
<i>Editor’s Choice</i>Time to improve rotas
Authors: Tom Moberly
Journal: BMJ (2016)

To doctors who have been denied leave for holidays, to attend family events, or to take part in mandatory training the failings of current rota designs are painfully clear. This week Babatunde Oremule and Oluwafikunayo Orekoya look at what a good rota would look like and what some of the barriers to …
Number of older people with four or more diseases will double by 2035, study warns
Authors: Jacqui Wise
Journal: BMJ (2018)

The number of older people with four or more chronic diseases will double within the next 20 years largely because of an increase in obesity and physical inactivity, a large study has found.1 A third of these people will have dementia, depression, or cognitive impairment diagnosed.

The UK healthcare system, which generally remains centred on treating single diseases, needs to be radically restructured to cope with this rise in multimorbidity, said researchers from Newcastle University’s Institute for Ageing.

Published in the British Geriatrics Society’s journal Age and Ageing ,1 the study found that the gain in life expectancy over the next 20 years (predicted as 3.6 years in …
Convection enhanced delivery of tri-block copolymer nano-micelles: a method of direct intraparenchymal water-insoluble drug delivery for the treatment of high-grade glioma
Authors: Will Singleton, Andy Collins, Ali Bienemann, Clare Killick-Cole, Daniel Asby, Harry Haynes, Marcella Wyatt, Lisa Boulter, Steven Gill
Journal: Neuro-Oncology (2018)

Convection enhanced delivery (CED) is a novel neurosurgical method of direct intraparenchymal drug delivery that utilises surgically implanted microcatheters to bypass the blood brain barrier. Drug is infused with the aim to displace the extracellular fluid within a specific volume of brain or tumour and replace it with infusate. In order to enable this, a compound must be water soluble. Many novel targeted compounds that may be useful in glioma treatment do not cross the blood brain barrier and are water insoluble. We describe the use of the triblock co-polymer Poloxamer-407 (P407) in a self-assembling nano-micellar formulation as a vehicle for administering the water insoluble HDAC inhibitor panobinostat for the treatment of high-grade glioma. Drug-loaded P407 micelles were synthesised in artificial CSF using an emulsion-evaporation technique and characterised with dynamic light scattering, zeta potential measurement and 1H Diffusion Ordered Nuclear Magnetic Resonance Spectroscopy. Nano-micelle distribution in rat brain was analysed following acute CED using rhodamine-labelled micelles and toxicity assayed using immunofluorescent microscopy and synaptophysin ELISA. We compared the survival of the bioluminescent syngenic F98/Fischer344 rat glioblastoma model treated by acute CED of panobinostat-loaded nano-micelles, compared to untreated and vehicle-only treated controls. Drug loaded P407 nano-micelles had a mean diameter of 23 nM. CED of fluorescent rhodamine-labelled nano-micelles distribute with a volume of infusion/volume of diffusion (Vi:Vd) ratio of four and five in rat gray and white matter respectively, and was not associated with any toxicity when compared to controls. CED of panobinostat-loaded nano-micelles was associated with significantly improved survival when compared to controls (n=8 per group; Log Rank p<0.001). CED of P407 nano-micelles is a novel method of CNS delivery of water insoluble compounds. CED of nano-micellar panobinostat represents a novel therapeutic option for high-grade glioma therapy and warrants translation into the clinic.
Effect of Liraglutide on Cardiovascular Events in Patients With Type 2 Diabetes Mellitus and Polyvascular Disease
Authors: Subodh Verma, Deepak L. Bhatt, Stephen C. Bain, John B. Buse, Johannes F.E. Mann, Steven P. Marso, Michael A. Nauck, Neil R. Poulter, Richard E. Pratley, Bernard Zinman, Marie M. Michelsen, Tea Monk Fries, Søren Rasmussen, Lawrence A. Leiter
Journal: Circulation (2018)
OBESITY PARADOX STILL EXISTS AFTER PERCUTANEOUS CORONARY INTERVENTION INDEPENDENT METABOLIC STATUS
Authors: Seung Han, Pyung Chun Oh, Kyounghoon Lee, Soon Yong Suh, Woong Chol Kang, Kwang Kon Koh, Tae Hoon Ahn, Eak Kyun Shin
Journal: Journal of the American College of Cardiology (2014)
Only one in 10 sessional GPs involved in commissioning
Authors: Caroline White
Journal: BMJ (2012)

The NHS is missing out on the potential of a large chunk of its general practitioner workforce because of its failure to fully integrate sessional (locum and salaried) doctors, a report from the Royal College of General Practitioners has found.[1]

Only one in 10 (9%) sessional GPs have a role in a clinical commissioning group (CCG), although most (92%) understand what is meant by commissioning. 

A further 27% of sessional GPs are interested in commissioning but said that they were not invited to take part or were unable to apply for roles. This is despite the fact …
Dose-Dependent Prevention of Metabolic and Neurologic Disease in Murine MPS II by ZFN-Mediated In Vivo Genome Editing
Authors: Kanut Laoharawee, Russell C. DeKelver, Kelly M. Podetz-Pedersen, Michelle Rohde, Scott Sproul, Hoang-Oanh Nguyen, Tam Nguyen, Susan J. St. Martin, Li Ou, Susan Tom, Robert Radeke, Kathleen E. Meyer, Michael C. Holmes, Chester B. Whitley, Thomas Wechsler, R. Scott McIvor
Journal: Molecular Therapy (2018)

Mucopolysaccharidosis type II (MPS II) is an X-linked recessive lysosomal disorder caused by deficiency of iduronate 2-sulfatase (IDS), leading to accumulation of glycosaminoglycans (GAGs) in tissues of affected individuals, progressive disease, and shortened lifespan. Currently available enzyme replacement therapy (ERT) requires lifelong infusions and does not provide neurologic benefit. We utilized a zinc finger nuclease (ZFN)-targeting system to mediate genome editing for insertion of the human IDS (hIDS) coding sequence into a "safe harbor" site, intron 1 of the albumin locus in hepatocytes of an MPS II mouse model. Three dose levels of recombinant AAV2/8 vectors encoding a pair of ZFNs and a hIDS cDNA donor were administered systemically in MPS II mice. Supraphysiological, vector dose-dependent levels of IDS enzyme were observed in the circulation and peripheral organs of ZFN+donor-treated mice. GAG contents were markedly reduced in tissues from all ZFN+donor-treated groups. Surprisingly, we also demonstrate that ZFN-mediated genome editing prevented the development of neurocognitive deficit in young MPS II mice (6–9 weeks old) treated at high vector dose levels. We conclude that this ZFN-based platform for expression of therapeutic proteins from the albumin locus is a promising approach for treatment of MPS II and other lysosomal diseases. Mucopolysaccharidosis type II (MPS II) is an X-linked recessive lysosomal disorder caused by deficiency of iduronate 2-sulfatase (IDS), leading to accumulation of glycosaminoglycans (GAGs) in tissues of affected individuals, progressive disease, and shortened lifespan. Currently available enzyme replacement therapy (ERT) requires lifelong infusions and does not provide neurologic benefit. We utilized a zinc finger nuclease (ZFN)-targeting system to mediate genome editing for insertion of the human IDS (hIDS) coding sequence into a "safe harbor" site, intron 1 of the albumin locus in hepatocytes of an MPS II mouse model. Three dose levels of recombinant AAV2/8 vectors encoding a pair of ZFNs and a hIDS cDNA donor were administered systemically in MPS II mice. Supraphysiological, vector dose-dependent levels of IDS enzyme were observed in the circulation and peripheral organs of ZFN+donor-treated mice. GAG contents were markedly reduced in tissues from all ZFN+donor-treated groups. Surprisingly, we also demonstrate that ZFN-mediated genome editing prevented the development of neurocognitive deficit in young MPS II mice (6–9 weeks old) treated at high vector dose levels. We conclude that this ZFN-based platform for expression of therapeutic proteins from the albumin locus is a promising approach for treatment of MPS II and other lysosomal diseases.
The Association of Age With Clinical Presentation and Comorbidities of Pyoderma Gangrenosum
Authors: Hovik J. Ashchyan, Daniel C. Butler, Caroline A. Nelson, Megan H. Noe, William G. Tsiaras, Stephen J. Lockwood, William D. James, Robert G. Micheletti, Misha Rosenbach, Arash Mostaghimi
Journal: JAMA Dermatology (2018)

Pyoderma gangrenosum is an inflammatory neutrophilic dermatosis. Current knowledge of this rare disease is limited owing to a lack of validated diagnostic criteria and large population studies.To evaluate the association of age with the clinical presentation and comorbidities of pyoderma gangrenosum.This was a multicenter retrospective cohort study performed at tertiary academic referral centers in urban settings. Adults (≥18 years) who were evaluated and diagnosed as having pyoderma gangrenosum at the Brigham and Women's and Massachusetts General Hospitals from 2000 to 2015 and the University of Pennsylvania Health System from 2006 to 2016 were included.Patient demographics, clinical features, medical comorbidities, and treatment.Of the 356 validated cases of pyoderma gangrenosum included in the study, 267 (75%) were women and 284 (84.8%) were white. The mean (SD) age at presentation was 51.6 (17.7) years. Pathergy was recorded in 100 patients (28.1%). A total of 238 patients (66.9%) had associated medical comorbidities: inflammatory bowel disease in 146 patients (41.0%); inflammatory arthritis in 73 patients (20.5%); solid organ malignant neoplasms in 23 patients (6.5%); hematologic malignant neoplasms in 21 patients (5.9%); and hematologic disorders, specifically monoclonal gammopathy of undetermined significance, myelodysplastic syndrome, and polycythemia vera in 17 patients (4.8%). When stratified by age, pathergy was more common in patients 65 years or older (36.3% vs 24.3%; P = .02). Inflammatory bowel disease was the only medical comorbidity that was more common in patients younger than 65 years (47.7% vs 26.6%; P < .001), while a number of medical comorbidities were more common in those 65 years or older, including rheumatoid arthritis (13.3% vs 6.2%; P = .03), ankylosing spondylitis (1.8% vs 0%; P = .04), solid organ malignant neoplasms (13.3% vs 3.3%; P < .001), hematologic malignant neoplasms (9.7% vs 4.1%; P = .04), and the aforementioned hematologic disorders (10.6% vs 2.1%; P < .001).Although clinical presentation in this large cohort was similar between different age groups, disease associations varied by age. The findings of this study may allow for a more focused, age-specific evaluation of patients with pyoderma gangrenosum.
Antiphospholipid antibodies induce thrombosis by PP2A activation via apoER2-Dab2-SHC1 complex formation in endothelium
Authors: Anastasia Sacharidou, Ken L. Chambliss, Victoria Ulrich, Jane E. Salmon, Yu-Min Shen, Joachim Herz, David Y. Hui, Lance S. Terada, Philip W. Shaul, Chieko Mineo
Journal: Blood (2018)