tbuckley/cabot-search huggingface dataset:
Availability of Investigational Medicines Through the US Food and Drug Administration’s Expanded Access and Compassionate Use Programs
Authors: Jeremy Puthumana, Jennifer E. Miller, Jeanie Kim, Joseph S. Ross
Journal: JAMA Network Open (2018)

<h3>Importance</h3> The Right to Try Act of 2017 allows patients with life-threatening conditions to access investigational medicines outside clinical trials without oversight from the US Food and Drug Administration (FDA). A better understanding of existing expanded access programs can inform the consideration and implementation of both the federal Right to Try Act and state right-to-try laws. <h3>Objective</h3> To determine the timing and duration of expanded access programs for investigational medicines initiated prior to FDA approval. <h3>Design and Setting</h3> This cross-sectional study examined expanded access and compassionate use programs registered through August 1, 2017, identified from ClinicalTrials.gov and publicly available FDA documents. <h3>Main Outcomes and Measures</h3> Start date of each program and 3 key regulatory dates (investigational new drug application activation, initial new drug application submission, and FDA approval), and timing and duration of expanded access availability in relation to new drug application submission and FDA approval. <h3>Results</h3> Through ClinicalTrials.gov, 92 FDA-approved drugs and biologics with associated expanded access programs initiated prior to FDA approval were identified. These programs were initiated between September 1996 and June 2017 for medicines that were most commonly used to treat cancer (n = 46 [50.0%]); metabolic, endocrine, and genetic diseases (n = 16 [17.4%]); and infectious diseases (n = 14 [15.2%]). The median (interquartile range) premarket expanded access availability was 10.0 (6.0-19.5) months, constituting a median (interquartile range) of 14% (7%-25%) of the premarket clinical development period (investigational new drug application activation to FDA approval). Of 92 expanded access programs, 64 (69.6%) were initiated just before or after new drug application submission: 24 (26.1%) were initiated during the 6-month period before, and 40 (43.5%) in the 6 months after. <h3>Conclusions and Relevance</h3> Over the past 2 decades, expanded access programs have provided access to investigational medicines for which evidence of safety and effectiveness was established. For medicines that ultimately receive FDA approval, these findings suggest that the FDA and pharmaceutical industry have established a balance between investigational new drug access and protection of patients from therapies without established safety. This balance may be compromised by policy makers seeking to speed access to investigational medicines through the Right to Try Act.
Overseas doctors must not be used just to fill rota gaps, says leading consultant
Authors: Abi Rimmer
Journal: BMJ (2018)

Foreign doctors who come to work in the NHS must be treated fairly and should not just be used to fill gaps in hospitals’ rotas, a leading consultant has said.

Partha Kar, a consultant endocrinologist at Portsmouth Hospitals NHS Trust who came to the UK from India in the 1990s, said that the NHS needed to learn from past mistakes. “In the 1990s it was quite common to encourage people from the Indian subcontinent to come to the UK with the suggestion of excellent pay and training,” he said. “And people came …
Visa cap on overseas doctors coming to UK is expected to be removed
Authors: Abi Rimmer
Journal: BMJ (2018)

The Home Office is expected to announce that it will exempt doctors and nurses from the cap on tier 2 skilled worker visas.

The BBC, which reported the news, said that an announcement was expected on Friday 15 June.1 A Home Office spokesman said that the information came from a leaked document and that it would not confirm or deny the claims.

The news comes after the Times reported on 12 June that the prime minister …
Oral pemetrexed facilitates low-dose metronomic therapy and enhances antitumor efficacy in lung cancer
Authors: Foyez Mahmud, Ok-Cheol Jeon, Farzana Alam, Ruby Maharjan, Jeong Uk Choi, Jooho Park, Sojung Lee, Jin Woo Park, Dong Soo Lee, Youngro Byun
Journal: Journal of Controlled Release (2018)
Early Changes in Myocardial Mechanics Detected by 3-Dimensional Speckle Tracking Echocardiography in Patients Treated With Low Doses of Anthracyclines
Authors: Rafael B. Piveta, Ana Clara T. Rodrigues, Marcelo L.C. Vieira, Cláudio H. Fischer, Tania R. Afonso, Edgar Daminello, Felipe M. Cruz, Tatiana F.G. Galvão, Marcelo Katz, Samira S. Morhy
Journal: JACC. Cardiovascular imaging (2018)
Implications of Placebo and Nocebo Effects for Clinical Practice: Expert Consensus
Authors: Andrea W.M. Evers, Luana Colloca, Charlotte Blease, Marco Annoni, Lauren Y. Atlas, Fabrizio Benedetti, Ulrike Bingel, Christian Büchel, Claudia Carvalho, Ben Colagiuri, Alia J. Crum, Paul Enck, Jens Gaab, Andrew L. Geers, Jeremy Howick, Karin B. Jensen, Irving Kirsch, Karin Meissner, Vitaly Napadow, Kaya J. Peerdeman, Amir Raz, Winfried Rief, Lene Vase, Tor D. Wager, Bruce E. Wampold, Katja Weimer, Katja Wiech, Ted J. Kaptchuk, Regine Klinger, John M. Kelley
Journal: Psychotherapy and Psychosomatics (2018)

Placebo and nocebo effects occur in clinical or laboratory medical contexts after administration of an inert treatment or as part of active treatments and are due to psychobiological mechanisms such as expectancies of the patient. Placebo and nocebo studies have evolved from predominantly methodological research into a far-reaching interdisciplinary field that is unravelling the neurobiological, behavioural and clinical underpinnings of these phenomena in a broad variety of medical conditions. As a consequence, there is an increasing demand from health professionals to develop expert recommendations about evidence-based and ethical use of placebo and nocebo effects for clinical practice.A survey and interdisciplinary expert meeting by invitation was organized as part of the 1st Society for Interdisciplinary Placebo Studies (SIPS) conference in 2017. Twenty-nine internationally recognized placebo researchers participated.There was consensus that maximizing placebo effects and minimizing nocebo effects should lead to better treatment outcomes with fewer side effects. Experts particularly agreed on the importance of informing patients about placebo and nocebo effects and training health professionals in patient-clinician communication to maximize placebo and minimize nocebo effects.The current paper forms a first step towards developing evidence-based and ethical recommendations about the implications of placebo and nocebo research for medical practice, based on the current state of evidence and the consensus of experts. Future research might focus on how to implement these recommendations, including how to optimize conditions for educating patients about placebo and nocebo effects and providing training for the implementation in clinical practice.
Douglas G Altman: statistician, researcher, and driving force behind global initiatives to improve the reliability of health research
Authors: Robert Matthews, Iain Chalmers, Peter Rothwell
Journal: BMJ (2018)

With the passing of Doug Altman, professor of statistics in medicine at the University of Oxford, the health research community has lost one of its most distinguished members and constructive critics. From the 1970s he conducted original research in fields ranging from neonatal growth to cancer, provided statistical expertise to countless clinical trials and journals, and served as The BMJ ’s chief statistical adviser for more than 20 years. 

He was also an indefatigable critic of shoddy research practices and did more than anyone else to eliminate them. He sought to drive up standards by every means at his disposal, from lucid lectures and educational papers to global initiatives and research guidelines. Doug consequently became one of the most highly cited researchers in any scientific discipline, with more than 360 000 Google Scholar citations and an h-index of 208, but more importantly, his work helped prevent the unnecessary deaths and suffering of countless patients.



Anyone who knew Doug can imagine him looking down at this point, wishing the encomium would cease. Modest about his abilities and achievements (“All that citation index stuff is complete bollocks, of course”), quick to credit others, and always approachable, he was not typical of the academic establishment. Indeed, he had little time for the establishment, regarding it as complicit in the persistence of poor research.

Born in London into a middle class family of Jewish descent in 1948, Doug had a largely solitary childhood. …
Circulating Vitamin D and Colorectal Cancer Risk: An International Pooling Project of 17 Cohorts
Authors: Marjorie L McCullough, Emilie S Zoltick, Stephanie J Weinstein, Veronika Fedirko, Molin Wang, Nancy R Cook, A Heather Eliassen, Anne Zeleniuch-Jacquotte, Claudia Agnoli, Demetrius Albanes, Matthew J Barnett, Julie E Buring, Peter T Campbell, Tess V Clendenen, Neal D Freedman, Susan M Gapstur, Edward L Giovannucci, Gary G Goodman, Christopher A Haiman, Gloria Y F Ho, Ronald L Horst, Tao Hou, Wen-Yi Huang, Mazda Jenab, Michael E Jones, Corinne E Joshu, Vittorio Krogh, I-Min Lee, Jung Eun Lee, Satu Männistö, Loic Le Marchand, Alison M Mondul, Marian L Neuhouser, Elizabeth A Platz, Mark P Purdue, Elio Riboli, Trude Eid Robsahm, Thomas E Rohan, Shizuka Sasazuki, Minouk J Schoemaker, Sabina Sieri, Meir J Stampfer, Anthony J Swerdlow, Cynthia A Thomson, Steinar Tretli, Schoichiro Tsugane, Giske Ursin, Kala Visvanathan, Kami K White, Kana Wu, Shiaw-Shyuan Yaun, Xuehong Zhang, Walter C Willett, Mitchel H Gail, Regina G Ziegler, Stephanie A Smith-Warner
Journal: JNCI Journal of the National Cancer Institute (2018)

Experimental and epidemiological studies suggest a protective role for vitamin D in colorectal carcinogenesis, but evidence is inconclusive. Circulating 25-hydroxyvitamin D (25(OH)D) concentrations that minimize risk are unknown. Current Institute of Medicine (IOM) vitamin D guidance is based solely on bone health.
Cognitive-Behavioral and Psychodynamic Therapy in Adolescents with Social Anxiety Disorder: A Multicenter Randomized Controlled Trial
Authors: Simone Salzer, Annette Stefini, Klaus-Thomas Kronmüller, Eric Leibing, Falk Leichsenring, Peter Henningsen, Hamid Peseschkian, Günter Reich, Rita Rosner, Uwe Ruhl, Yvonne Schopf, Christiane Steinert, Eva Vonderlin, Regina Steil
Journal: Psychotherapy and Psychosomatics (2018)

Although social anxiety disorder (SAD) has an early onset and is frequently found in adolescence, evidence for psychotherapeutic treatments of SAD in adolescents is rather scarce. Within the Social Phobia Psychotherapy Research Network (SOPHO-NET), we examined the efficacy of cognitive-behavioral (CBT) and psychodynamic therapy (PDT) compared to a waiting list (WL) in these patients.In a multicenter randomized controlled superiority trial, 107 patients, aged 14-20 years, were randomized to CBT (n = 34), PDT (n = 34), or WL (n = 39). Assessments were made at baseline, at the end of treatment, and 6 and 12 months after termination. The Liebowitz Social Anxiety Scale for Children and Adolescents (LSAS-CA) applied by raters masked to the treatment condition was used as the primary outcome. As secondary outcomes, rates of response and remission and the Social Phobia Anxiety Inventory (SPAI) were used.Both treatments were superior to WL in the LSAS-CA (CBT: p = 0.0112, d = 0.61, 95% CI 0.14-1.08; PDT: p = 0.0261, d = 0.53, 95% CI 0.06-1.00). At the end of treatment, response rates were 66, 54, and 20% for CBT, PDT, and WL. The corresponding remission rates were 47, 34, and 6%, respectively. CBT and PDT were significantly superior to WL regarding remission (CBT: p = 0.0009, h = 1.0; PDT: p = 0.0135, h = 0.74), response (CBT: p = 0.0004, h = 0.97; PDT: p = 0.0056, h = 0.72), and the SPAI (CBT: p = 0.0021, d = 0.75, 95% CI 0.27-1.22; PDT: p = 0.0060, d = 0.66, 95% CI 0.19-1.13). Treatment effects were stable at 6- and 12-month follow-ups.These results are comparable to the large SOPHO-NET trial in adults (n = 495). Early treatments for social anxiety are needed in order to prevent chronic manifestation of SAD.
AB0034 Looking for a sle signature on peripheral b cell subsets: does a preponderant cd38+plasmablast-subpopulation lack cd73 as a sign of a disturbed adenosine axis?
Authors: M. Siekierka-Harreis, M. Schroedter, G. Chehab, J. Richter, M. Schneider, G. Pongratz
Journal: Annals of the Rheumatic Diseases (2018)

Background  Systemic Lupus Erythematosus (SLE) is an autoimmune disorder characterised by polyclonal Bcell activation, production of dsDNA-autoantibodies and cytokines. Subsets of Bcells play a central role in SLE-pathogenesis. The inflammatory milieu is characterised by the accumulation of adenosine, which confers immunosuppressive effects.  Objectives  In SLE, the role of CD73, an enzyme involved in the extracellular generation of adenosine from ATP, is not well characterised. This study aimed to characterise expression of CD73 Bcell subsets of SLE-patients as compared to healthy controls (HC).  Methods  Bcell subsets were characterised from peripheral blood of 23 SLE patients attending the outpatient clinic at the Rheumatology Unit of University Hospital Dusseldorf and of 15 HC by FACS. All patients fulfilled the revised SLE-criteria of ACR and were randomly collected in clinical remission state (SLEDAI 1.1±1.9).  Results  By comparison of Bcell subsets between SLE and HC, CD38 was dominantly expressed by SLE-patients (SLE 74.2%±12.9% vs. HC 64.2%±12.2%; p(MWU)=0.018). Furthermore, SLE-patients showed an increase in CD19 +IgD CD27+CD38 high plasmablasts (SLE 2.1%±3.4% vs HC 0,4%±0.4%, p(MWU)  Conclusions  Our study confirms CD38 +plasmablasts as being increased in peripheral blood from SLE patients as compared to HC. Furthermore, the data reveal a deficiency for CD73 on SLE plasmablasts, which suggests a decreased anti-inflammatory capacity of SLE plasmablasts as compared to HC, supporting the notion of a disturbed adenosine axis in SLE. On the other hand, the enlarged CD73 +exhausted memory pool in SLE could point to an accelerated flow of CD73 +B cells into an exhausted B cell fraction. These findings support the hypothesis of dysregulation of the adenosine axis in SLE even in inactive SLE patients.  References  [1] Szabo K, Papp G, Szanto A, Tarr T, Zeher M. A comprehensive investigation on the distribution of circulating follicular T helper cells and B cell subsets in primary Sjogren’s syndrome and systemic lupus erythematosus. Clinical and experimental immunology2016;183(1):76–89.  [2] Jacobi AM, Reiter K, Mackay M, Aranow C, Hiepe F, Radbruch A, et al. Activated memory B cell subsets correlate with disease activity in systemic lupus erythematosus: delineation by expression of CD27, IgD, and CD95. Arthritis and Rheumatism2008;58(6):1762–73.  [3] Deaglio S, Dwyer KM, Gao W, Friedman D, Usheva A, Erat A, et al. Adenosine generation catalyzed by CD39 and CD73 expressed on regulatory T cells mediates immune suppression. The Journal of Experimental Medicine2007;204(6):1257–65.  [4] Hasko G, Linden J, Cronstein B, Pacher P. Adenosine receptors: therapeutic aspects for inflammatory and immune diseases. Nature Reviews Drug Discovery2008;7(9):759–70.  Disclosure of Interest  None declared
THU0298 Peritenon extensor tendon inflammation, synovitis and enthesopathy in psoriatic arthritis: what is the connexion?
Authors: C. Macía Villa, S. Falcao, H.B. Hammer, M. Gutierrez, E. De Miguel
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> Metacarpophalangeal joint (MCPj) swelling in Psoriatic Arthritis (PsA) can be produced both by intra-articular synovitis (IAS) and peritenon extensor tendon inflammation (PTI). This last lesion has been reported as an enthesitis-like lesion. <h3>Objectives</h3> To evaluate if PTI is a synovitis or enthesitis related lesion using MASEI (Madrid Sonographic Enthesis Index) to analyse the existence of association with IAS and PTI. <h3>Methods</h3> 27 consecutive non selected PsA patients were included. An expert rheumatologist obtained the US images from the dorsal aspect of 2nd to 5th MCPj of both hands evaluating IAS and PTI, and also performed the MASEI examination. In addition to the PD item of MASEI (defined as signal in bone profile or intratendon or bursa at the enthesis), PD OMERACT was evaluated as present or absent (defined as signal in the enthesis ≤2 mm to the bone profile). We used a MyLab 70 XVG machine, Esaote, Genova, Italy, with a greyscale (GS) 13 MHz probe and 7.1 MHz power Doppler (PD) frequency, PRF 750 Hz and 60 Gain. 3–5 s videos of each MCPj and enthesis were obtained in transverse and longitudinal views for further reliability analysis. Reliability of IAS and PTI was performed by 5 readers (true US result was the consensus of at least three) and MASEI's reliability was performed by 3 readers (true US result was the consensus of at least two). For reliability analysis, mean Cohen kappa was used for IAS and PTI, and intraclass correlation coefficient (ICC) for MASEI based on a mean-rating three readers, absolute-agreement, two-way mixed effect model. Statistical association between IAS, PTI and MASEI was analysed with T student test. SPSS statistical package version 20 (SPSS Inc, Chicago, IL) was used. <h3>Results</h3> Eighteen patients had PTI PD (66,7%), same for SIA PD. Inter-reader reliability for PTI and SIA was 0.685 and 0.680 kappa values respectively. Inter-reader reliability for MASEI was excellent ICC 0,922 (IC 95% 0,852–0,962), similar to PD MASEI ICC 0,921 (IC 95% 0,851–0,962) and PD OMERACT ICC 0.895 (IC 95% 0,802–0,949). Association data are shown in table 1. <h3>Conclusions</h3> In PsA, IAS at MCPj didn't show any association with enthesitis. However, PTI showed a significant statistically association with active enthesitis (PD MASEI and PD OMERACT). This finding reinforces the idea that PTI at MCPj level is related with the swelling of the functional enthesis related to the retinaculum pulley structure. <h3>References</h3> [1] Mc Gonagle D, et al. The concept of a synovio-enthesal complex and its implications for understanding joint inflammation and damage in psoriatic arthritis and beyond. A&amp;R2001;56(8):2482–91. [2] De Miguel E, et al. Validity of enthesis ultrasound assessment in spondyloarthropathy. ARD2009;68:169–74. <h3>Disclosure of Interest</h3> None declared
AB1405-HPR The comparison of posterior shoulder tightness in patients having chronic neck pain and in healthy subjects
Authors: H.E TURKSAN, G. YALÇINKAYA, S. OZALEVLI, O. KALEMCI
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> Chronic neck pain (CNP) causes the disruption of the thoracic region and the shoulder girdle biomechanics besides the cervical region.The shoulder capsule is often thickened in shoulder problems, which causes shoulder tightness. In the literature, the effect of CNP on shoulder tightness was not investigated. <h3>Objectives</h3> The purpose of this study is to investigate the posterior shoulder tightness (PST) in patients having CNP and to interpret the effect of patients functional level and posture. <h3>Methods</h3> Non-specific CNP patients (n=16, female) and healthy subjects (n=16, female) were included and no shoulder problem was identified. The severity of the pain with Visual Analogue Scale (VAS); PST with bubble inclinometer; functional disability level with Neck Disability Index (NDI); influence of posture with New York Postural Rating Scale (NYPRS), upper limb muscle strength evaluated with handgrip. The Mann-Whitney U test Pearson correlation analysis was used to determine the relationship between PST and functional disability levels. <h3>Results</h3> Age and BMI values of healthy subjects and patients with CNP were similar (p&gt;0.05). The mean duration of disease in patients with CNP was 60.63±35.37 months. Patients with CNP had lower PST values than healthy subjects, namely shoulder tightness is more than healthy subjects (p&lt;0.001). The functional disability level score was higher in patients with CNP than in healthy subjects (p&lt;0.001). NYPRS scores were lower in patients with CNP than in healthy subjects, namely the posture was more adversely affected in these patients (p&lt;0.001). Handgrip values were lower and he pain severity at rest and activity was significantly higher in patients with CNP than in healthy subjects (p&lt;0.001, Table 1). PST correlated well with the NYPS value (r=−0.56, p=0.03) and functional disability level (r=−0.63, p&lt;0.001) in patients with CNP. <h3>Conclusions</h3> Pain and upper limb muscle strength loss due to problem in patients with CNP, adversely affect patients' posture and reduce their functional levels. For these reasons, it is suggested that the shoulder girdle should be evaluated besides the neck area in the treatment of patients having CNP and treatment should be included with appropriate physiotherapy and exercise program from the early period. <h3>Reference</h3> [1] Kolber MJ, et al. The reliability, minimal detectable change and construct validity of a clinical measurement for identifying posterior shoulder tightness. N Am J Sports Phys Ther, 2010;5: 208–19. <h3>Disclosure of Interest</h3> None declared
SAT0526 Is relapse rate of giant cell arteritis in real-life experience lower than in the controlled trials? results of a retrospective, multi-centre cohort study
Authors: F. Alibaz-Oner, M.A. Balci, O.N. Pamuk, O. Zengin, M. Tasci, A. Dogru, O. Bayindir, S. Yavuz, A. Cefle, M.E. Tezcan, M.F. Oksuz, O. Kucuksahin, A. Omma, S. Yasar Bilge, T. Kasifoglu, Z. Erturk, C. Bes, A.U. Unal, B. Armagan, E. Gonullu, A. Yazici, O. Karadag, E. Dalkilic, K. Aksu, G. Keser, H. Direskeneli
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Objectives</h3> Corticosteroids (CS) are accepted as the standard first-line treatment for giant cell arteritis (GCA). However, controlled trials of tocilizumab and abatacept demonstrated relapse rates of up to 70%–80% in patients on CS-only protocols in 12–24 months. Though level of evidence is low and not suggested by guidelines (except for methotrexate), conventional immunosuppressives (ISs) are also commonly used. We aimed to assess the relapse rates in patients with GCA in routine practice, retrospectively. <h3>Methods</h3> We assembled a retrospective cohort of patients with GCA from Turkey. All data was abstracted from records. Relapse was defined as any new manifestation or increased acute-phase response leading to the change of the CS dose or use of a new therapeutic agent by the treating physician. <h3>Results</h3> The study included 156 (F/M: 95/61) patients with GCA (table 1). The mean age at disease onset was 67.8±9.1 years. Polimyalgia Rheumatica was also present in 48 (30,8%) patients. Diagnosis was proven histopathologically in 99 patients.All patients received 1 mg/kg/day CS for remission induction, additional CS pulses were given to 36 (23.1%) patients. Conventional ISs including methotrexate and azathioprine were used in 89 (56.1%) and 26 (16.6%) patients respectively, while 10 (6.4%) patients received biologic treatments (8 tocilizumab,2 etanercept). Fourty-four (28.2%) patients used only CS during follow-up. Follow-up of at least 6 months was available for 132 patients, and median follow-up duration was 35 (6–268) months. Relapses occurred in 27 (20.5%) patients during follow-up. Mortality rate was 7.5% (n=10) during follow-up. VDI score was 2.4±1.7. Main causes of damage were related to CS treatments such as cataract, osteoporosis and diabetes mellitus. <h3>Conclusions</h3> In this first multi-centre series of GCA from Turkey, we observed that only one fifth of patients had relapses during a mean follow-up of 35 months. This lower relapse frequency suggests a different clinical spectrum in routine practice compared to patients included in controlled trials. Our results also suggest that there is a clear need for a steroid sparing agent in patients with GCA, that is a older aged population prone to CS side effects. <h3>Disclosure of Interest</h3> None declared