tbuckley/cabot-search huggingface dataset:
Therapeutic Efficacy of Interleukin 12/Interleukin 23 Blockade in Generalized Pustular Psoriasis Regardless of<i>IL36RN</i>Mutation Status
Authors: Akiko Arakawa, Thomas Ruzicka, Jörg C. Prinz
Journal: JAMA Dermatology (2016)

Generalized pustular psoriasis von Zumbusch type (GPP) is the most severe manifestation of psoriasis. The etiology of GPP is only partially understood, and GPP lacks approved treatments. Loss-of-function mutations in the interleukin 36 (IL-36) receptor antagonist (IL36RN), an inhibitor of innate immune activation in the skin, and therapeutic efficacy of IL-1 blockade in a subset of patients with GPP are viewed as evidence for an autoinflammatory pathogenesis. A pathogenic role of T cells has not been considered.To test whether ustekinumab, a monoclonal antibody blocking IL-12 and IL-23, is an effective treatment modality for patients in whom GPP treatment with conventional psoriasis drugs or antagonists of tumor necrosis factor (TNF) has not been sufficiently effective, is contraindicated, or has lost efficacy.We treated a series of 4 patients with GPP with ustekinumab, which was applied on an outpatient basis according to the dosing regimen approved for psoriasis vulgaris. In 3 patients it was combined with low doses of the retinoid acitretin. IL36RN mutations were determined in all 4 patients by means of targeted sequencing of genomic DNA.The response to therapy was assessed by clinical examination.The 4 patients were female. Sequencing of IL36RN identified a homozygous mutation in case 1 (Pro76Leu). The other 3 patients carried no rare IL36RN variants. Overall GPP duration ranged from 50 to 146 months. Ustekinumab treatment is currently ongoing in all 4 patients without loss of efficacy, currently reaching treatment durations of 17 (case 1) to 44 months (case 3). Ustekinumab treatment induced sustained remissions in all 4 GPP patients. This response was independent of IL36RN mutations and consolidated by combination with low doses of the retinoid acitretin.Ustekinumab-induced remissions suggest that T cells play a crucial role in GPP pathogenesis based on the documented role that IL-12 and IL-23 play in autoimmune diseases through differentiating helper T cell 1 (TH1) and maintaining TH17 responses. Acitretin treatment may support ustekinumab efficacy, possibly by suppressing TH17 responses through the retinoid-related orphan receptors, RORγt and RORα. Combining IL-12/IL-23 blockade and acitretin may constitute an efficient treatment modality interfering with GPP pathomechanisms.
Daily Home Spirometry: An Effective Tool for Detecting Progression in Idiopathic Pulmonary Fibrosis
Authors: Anne-Marie Russell, Huzaifa Adamali, Philip L. Molyneaux, Pauline T. Lukey, Richard P. Marshall, Elisabetta A. Renzoni, Athol U. Wells, Toby M. Maher
Journal: American Journal of Respiratory and Critical Care Medicine (2016)

Rationale: Recent clinical trial successes have created an urgent need for earlier and more sensitive endpoints of disease progression in idiopathic pulmonary fibrosis (IPF). Domiciliary spirometry permits more frequent measurement of FVC than does hospital-based assessment, which therefore affords the opportunity for a more granular insight into changes in IPF progression.Objectives: To determine the feasibility and reliability of measuring daily FVC in individuals with IPF.Methods: Subjects with IPF were given handheld spirometers and instruction on how to self-administer spirometry. Subjects recorded daily FEV1 and FVC for up to 490 days. Clinical assessment and hospital-based spirometry was undertaken at 6 and 12 months, and outcome data were collected for 3 years.Measurements and Main Results: Daily spirometry was recorded by 50 subjects for a median period of 279 days (range, 13–490 d). There were 18 deaths during the active study period. Home spirometry showed excellent correlation with hospital-obtained readings. The rate of decline in FVC was highly predictive of outcome and subsequent mortality when measured at 3 months (hazard ratio [HR], 1.040; 95% confidence interval [CI], 1.021–1.062; P ≤ 0.001), 6 months (HR, 1.024; 95% CI, 1.014–1.033; P < 0.001), and 12 months (HR, 1.012; 95% CI, 1.007–1.016; P = 0.001).Conclusions: Measurement of daily home spirometry in patients with IPF is highly clinically informative and is feasible to perform for most of these patients. The relationship between mortality and rate of change of FVC at 3 months suggests that daily FVC may be of value as a primary endpoint in short proof-of-concept IPF studies.
Ar-V7 Splice Variant and Resistance to Enzalutamide and Abiraterone in Men with Metastatic Castration-Resistant Prostate Cancer (Mcrpc): Overall Survival Results
Authors: E.S. Antonarakis, C. Lu, H. Wang, B. Luber, M. Nakazawa, J. Roeser, Y. Chen, H.L. Fedor, T.L. Lotan, Q. Zheng, A.M. De Marzo, J.T. Isaacs, W.B. Isaacs, R. Nadal, C.J. Paller, S.R. Denmeade, M.A. Carducci, M.A. Eisenberger, J. Luo
Journal: Annals of Oncology (2014)
Spinal-Fluid Acidosis and the Diagnosis of Pulmonary Encephalopathy
Authors: Roger J. Bulger, Robert W. Schrier, William P. Arend, August G. Swanson
Journal: New England Journal of Medicine (1966)

THERE has been an increasing interest in the study of cerebrospinal-fluid acid–base values because alterations in brain function during systemic acid–base disorders correlate poorly with blood or serum pH. This lack of correlation is related to the slow movement of charged ions between the cerebrospinal fluid and the blood. Although most acid–base disorders drive the cerebrospinal-fluid pH in the same direction as the arterial pH, the cerebrospinal fluid is generally affected to a lesser degree. One exception is respiratory acidosis, in which the cerebrospinal-fluid pH is depressed as drastically as the blood pH because carbon dioxide diffuses so readily into . . .
Fusion adds little value to decompression for lumbar spinal stenosis, studies show
Authors: Susan Mayor
Journal: BMJ (2016)

Fusion of affected vertebrae in treating lumbar spinal stenosis achieves no improvement in clinical outcomes, including disability due to low back pain, when compared with decompression surgery, the results of two randomised trials have shown.1 2

Lumbar spinal stenosis is caused by gradual narrowing of the spinal canal and typically causes low back and leg pain, particularly when walking. It is now the commonest indication for spinal surgery, which involves decompression of neural structures by laminectomy. The additional use of lumbar fusion to fuse two or more vertebrae with the aim of minimising spinal instability is growing, …
An intersubject dose-escalation study of tesetaxel administered orally once every 3 weeks and once weekly for 3 consecutive weeks in patients with advanced or metastatic solid tumors.
Authors: M. Beeram, S. C. Novick, A. Qureshi, A. Patnaik, K. Papadopoulos, A. W. Tolcher
Journal: Journal of Clinical Oncology (2010)

TPS159 Background: Tesetaxel is an orally active tubulin-binding inhibitor that has completed multiple phase II trials. In multiple cancer cell lines and human tumor xenografts that overexpress P-glycoprotein, this activity substantially exceeds that of paclitaxel and docetaxel. In phase IIa studies, tesetaxel administered once every 3 weeks (27-35 mg/m2) has shown clinical activity in patients (pts) with advanced breast cancer and advanced gastric cancer (overall response rates of 38% and 20%, respectively) when administered as 2nd-line therapy. Myelosuppression (primarily neutropenia) was the most common adverse event. Pooled data from phase IIa studies showed that neutropenia was directly related to Cmax. Since taxanes as a class exhibit activity that can be schedule-related, we speculated that weekly dosing might show different results for safety, activity, and pharmacokinetics (PK). To test that assumption, we conducted an intersubject dose-escalation study to evaluate these parameters giving the drug once weekly for 3 consecutive weeks, and we compared those results to the every 3 week schedule. Methods: Pts with an advanced or metastatic solid tumor malignancy, ECOG PS ≤ 2, and adequate organ function are eligible to participate. Tesetaxel was initially given once every 3 weeks at doses ranging from 18 mg/m2 to 27 mg/m2, escalated in increments of 3 mg/m2. In the 2nd part of this ongoing study, tesetaxel is administered in 28-day cycles once weekly for 3 consecutive weeks beginning at a flat dose of 25 mg per cycle (administered as 10, 10, and 5 mg) and escalated in increments of 5 mg per total cycle dose to the MTD. A minimum of 2 treatment cycles are prescribed; absent progressive disease, pts may receive additional cycles. A total of 26 pts have been treated to date, with continuing accrual. Serial plasma samples have been collected for batch analysis of drug and metabolite concentrations. Comparative safety, efficacy, and PK from the 2 schedules will be presented to evaluate schedule-related effects of this novel agent. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Genta Genta Chemotherapy Foundation Genta
Cluster of atypical adult Guillain-Barré syndrome temporally associated with neurological illness due to EV-D68 in children, South Wales, United Kingdom, October 2015 to January 2016
Authors: Christopher J Williams, Rhys H Thomas, Trevor P Pickersgill, Marion Lyons, Gwen Lowe, Rhianwen E Stiff, Catherine Moore, Rachel Jones, Robin Howe, Huw Brunt, Anna Ashman, Brendan W Mason
Journal: Eurosurveillance (2016)

We report a cluster of atypical Guillain-Barré syndrome in 10 adults temporally related to a cluster of four children with acute flaccid paralysis, over a 3-month period in South Wales, United Kingdom. All adult cases were male, aged between 24 and 77 years. Seven had prominent facial diplegia at onset. Available electrophysiological studies showed axonal involvement in five adults. Seven reported various forms of respiratory disease before onset of neurological symptoms. The ages of children ranged from one to 13 years, three of the four were two years old or younger. Enterovirus testing is available for three children; two had evidence of enterovirus D68 infection in stool or respiratory samples. We describe the clinical features, epidemiology and state of current investigations for these unusual clusters of illness.
The Relationship of Parathyroidectomy and Bisphosphonates With Fracture Risk in Primary Hyperparathyroidism
Authors: Michael W. Yeh, Hui Zhou, Annette L. Adams, Philip H.G. Ituarte, Ning Li, In-Lu Amy Liu, Philip I. Haigh
Journal: Annals of Internal Medicine (2016)

The comparative effectiveness of surgical and medical treatments on fracture risk in primary hyperparathyroidism (PHPT) is unknown.To measure the relationship of parathyroidectomy and bisphosphonates with skeletal outcomes in patients with PHPT.Retrospective cohort study.An integrated health care delivery system.All enrollees with biochemically confirmed PHPT from 1995 to 2010.Bone mineral density (BMD) changes and fracture rate.In 2013 patients with serial bone density examinations, total hip BMD increased transiently in women with parathyroidectomy (4.2% at <2 years) and bisphosphonates (3.6% at <2 years) and declined progressively in both women and men without these treatments (-6.6% and -7.6%, respectively, at >8 years). In 6272 patients followed for fracture, the absolute risk for hip fracture at 10 years was 20.4 events per 1000 patients who had parathyroidectomy and 85.5 events per 1000 patients treated with bisphosphonates compared with 55.9 events per 1000 patients without these treatments. The risk for any fracture at 10 years was 156.8 events per 1000 patients who had parathyroidectomy and 302.5 events per 1000 patients treated with bisphosphonates compared with 206.1 events per 1000 patients without these treatments. In analyses stratified by baseline BMD status, parathyroidectomy was associated with reduced fracture risk in both osteopenic and osteoporotic patients, whereas bisphosphonates were associated with increased fracture risk in these patients. Parathyroidectomy was associated with fracture risk reduction in patients regardless of whether they satisfied criteria from consensus guidelines for surgery.Retrospective study design and nonrandom treatment assignment.Parathyroidectomy was associated with reduced fracture risk, and bisphosphonate treatment was not superior to observation.National Institute on Aging.
Correlation of Somatic Mutations and Clinical Characteristics at Presentation in Patients with Essential Thrombocytemia
Authors: Aleksandar Eftimov, Irina Panovska-Stavridis, Marija Popova-Simjanovska, Martin Ivanovski, Aleksandar Stojanovic, Lidija Cevreska, Nadica Geshkovska Matevska, Aleksandar J Dimovski
Journal: Blood (2014)
Neuropsychological testing of patients with borderline personality disorder
Authors: K M O'Leary, P Brouwers, D L Gardner, R W Cowdry
Journal: American Journal of Psychiatry (1991)

This study examined whether a battery of neuropsychological tests could detect cognitive deficits--particularly in the areas of perception, learning, and memory--in patients with borderline personality disorder. The test battery was completed by 16 research outpatients with borderline personality disorder, typified by behavioral dyscontrol and diagnosed according to DSM-III-R criteria and the Diagnostic Interview for Borderline Patients. A comparison group of 16 normal volunteers also completed the test battery.The performance of the borderline patients was significantly impaired in comparison with that of the normal group on memory tests requiring uncued recall of complex, recently learned material. Cues given on an auditory memory task partially corrected that deficit. The patients' performance was also significantly impaired on several visual perceptual tests. These deficits do not appear to have been attributable to attentional problems, psychomotor impairment, current major depression, or history of alcohol abuse.The observed difficulties in separating essential from extraneous visual information and in recalling complex material may be relevant in understanding some of the clinical features of borderline personality disorder. The observed memory improvement resulting from cueing suggests specific strategies that may be used to aid patients' recall of complex material.
PWE-423 Human factors training (hft) through simulation based scenarios in endoscopic haemostasis improves teamworking
Authors: A Goel, J Geraghty, M Pimblett, M Dickinson, PL Shields
Journal: Gut (2015)

<h3>Introduction</h3> In the early 1970s, number of air crashes were attributed to human error. HFT is well recognised for improving safety in aviation. Medical errors rank high amongst the leading causes of death and HFT is increasingly been recognised to reduce errors in CPR and anaesthetics. The value of HFT in endoscopy has not been evaluated. <h3>Method</h3> We delivered haemostasis and HFT to Gastroenterology Specialty trainee Registrars (StRs) at Lancashire simulation centre. A computer-based life-sized manikin with human physiology emulation capability was used. Its vital signs were controlled remotely. The manikin could talk and was connected to ECG, Pulse rate, SpO2 and BP monitor. Endoscopy equipment and porcine stomach models were used. Haemostatic methods including adrenaline injection, haemoclip placement, Haemospray, Sengstaken tube and Danis stent insertion were practiced. Introductory presentations on Human factors were delivered. 4 scenarios were written to provide ‘high-stress/high-stakes’ events that are encountered infrequently, but where rapid and professional responses are crucial i.e. patients with an upper GI bleed developing periarrest whilst in endoscopy unit. Each scenario involving 5 to 6 StRs was facilitated by Gastroenterologists and Simulation skills educators. Feedback was provided by peer observation. Microteaching was delivered using video assisted debrief. Pre and post course feedback was obtained. <h3>Results</h3> 23 StRs attended. Prior to this course 55% StRs have had no HFT, 14% had self directed learning, 9% received lectures and 22% had formal workshop based HFT. Data analysis showed improvement in all areas of Human Factor: decision making, situational awareness, team working and leadership skills. On the Likert scale (1 strongly disagree, 5 strongly agree) StRs felt scenarios were useful (Median 5, IQR 1), amount of information was appropriate (Median 5, IQR 1) and hands on training was useful (Median 5, IQR 1). StRs reported increased awareness of managing acutely ill patients in relation to sedation issues (Median 4, IQR 2), principles of resuscitation and fluid management (Median 4, IQR 2), improved leadership, teamwork and communication (Median 5, IQR 1). Qualitative feedback was positive. StRs however recommended smaller groups in future courses. 90% StRs felt that training on Human Factors and their influence on patient safety should be compulsory. <h3>Conclusion</h3> Human patient simulation provides ‘real life’ environment to observe Human Factors and allows chance to debrief, something that is difficult in the busy workplace. StRs benefit from HFT and report improvement in their skills. We recommend that HFT in endoscopy should be incorporated in competency based training curriculum and rolled out nationally. <h3>Disclosure of interest</h3> None Declared.
Hemochromatosis with Megaloblastic Anemia Responding to Folic Acid
Authors: Norma Granville, William Dameshek
Journal: New England Journal of Medicine (1958)

THE pattern of iron metabolism in hemochromatosis has been well established. Thus, it has been shown that the absorption of iron from the gastrointestinal tract is greatly increased in addition to the increased affinity for iron by the body tissues.1 2 3 Congenital and acquired hemochromatosis have the same fundamental defect of increased iron absorption. In the former, there appears to be an inherited defect in the so-called mucosal "block," thus allowing the absorption of undue amounts of iron from the intestinal tract. Most commonly, patients with the congenital type of hemochromatosis have normal hemoglobin levels, and thus they can afford frequent . . .
Colonic microbiota can promote rapid local improvement of murine colitis by thioguanine independently of T lymphocytes and host metabolism
Authors: I Oancea, R Movva, I Das, D Aguirre de Cárcer, V Schreiber, Y Yang, A Purdon, B Harrington, M Proctor, R Wang, Y Sheng, M Lobb, R Lourie, P Ó Cuív, J A Duley, J Begun, T H J Florin
Journal: Gut (2016)

Mercaptopurine (MP) and pro-drug azathioprine are 'first-line' oral therapies for maintaining remission in IBD. It is believed that their pharmacodynamic action is due to a slow cumulative decrease in activated lymphocytes homing to inflamed gut. We examined the role of host metabolism, lymphocytes and microbiome for the amelioration of colitis by the related thioguanine (TG).C57Bl/6 mice with or without specific genes altered to elucidate mechanisms responsible for TG's actions were treated daily with oral or intrarectal TG, MP or water. Disease activity was scored daily. At sacrifice, colonic histology, cytokine message, caecal luminal and mucosal microbiomes were analysed.Oral and intrarectal TG but not MP rapidly ameliorated spontaneous chronic colitis in Winnie mice (point mutation in Muc2 secretory mucin). TG ameliorated dextran sodium sulfate-induced chronic colitis in wild-type (WT) mice and in mice lacking T and B lymphocytes. Remarkably, colitis improved without immunosuppressive effects in the absence of host hypoxanthine (guanine) phosphoribosyltransferase (Hprt)-mediated conversion of TG to active drug, the thioguanine nucleotides (TGN). Colonic bacteria converted TG and less so MP to TGN, consistent with intestinal bacterial conversion of TG to so reduce inflammation in the mice lacking host Hprt. TG rapidly induced autophagic flux in epithelial, macrophage and WT but not Hprt-/- fibroblast cell lines and augmented epithelial intracellular bacterial killing.Treatment by TG is not necessarily dependent on the adaptive immune system. TG is a more efficacious treatment than MP in Winnie spontaneous colitis. Rapid local bacterial conversion of TG correlated with decreased intestinal inflammation and immune activation.
P281 The effectiveness of acupuncture in managing symptoms in CF adults
Authors: EF Nash, H Bradley, E Chapman, R Rashid, JL Whitehouse
Journal: Thorax (2015)

<h3>Introduction and objectives</h3> People with cystic fibrosis (CF) experience a wide spectrum of symptoms, both physical and psychological, which are often troublesome and can result in significantly impaired quality of life. Acupuncture has a strong evidence base in the treatment of a wide variety of symptoms, however there is currently very limited evidence for its role in the management of symptoms in people with CF. The objective of this pilot study was to provide preliminary evidence of the effectiveness and patient acceptance of this treatment in our large regional adult CF centre. <h3>Methods</h3> In this observational prospective study, we offered acupuncture to CF inpatients attending our large regional adult CF centre if they were suffering from range of symptoms. Patients were asked to specify the symptoms being treated and its severity before and after treatment, as well as whether treatment achieved the desired outcome, whether they suffered any ill effects, whether it is a valuable service and whether they feel we should continue to offer acupuncture to patients. They were also offered the option of making free-text comments on their experience of the service. <h3>Results</h3> 106 patients were included over a 12-month period. 50 patients were treated for pain (back/neck/shoulder pain, n = 28; unspecified location, n = 12; headache, n = 5, chest pain, n = 4, toe pain, n = 1) with pain significantly reducing after treatment (median severity 7 (IQR 6–8) vs. 4 (IQR 3–5), p &lt; 0.001). 25 patients were treated for stress/anxiety with symptoms significantly reducing after treatment (median severity 8 (IQR 7–9) vs. 5 (IQR 3.6–6), p &lt; 0.001). 10 patients were treated for breathlessness/tight chest with symptoms significantly reducing after treatment (median severity 7 (IQR 6–8) vs. 5 (IQR 4–6), p = 0.001). 21 patients were treated for a range of other symptoms including low energy levels, reduced appetite and constipation. 95 patients reported that treatment had achieved the desired result and 10 patients reported that it was too early to tell. 1 patient felt ‘a bit sick’ after treatment, but no other adverse effects were reported. All patients felt that acupuncture was a valuable service and should continue to be offered. 30 patients commented that the service should be available more frequently. <h3>Conclusions</h3> Acupuncture was greatly appreciated by CF adults, with significant improvements in a wide variety of symptoms. A randomised controlled study is required to confirm these benefits.