tbuckley/cabot-search huggingface dataset:
TUC urges BMA to join forces on day of action to highlight crisis in NHS
Authors: Gareth Iacobucci
Journal: BMJ (2016)

The BMA has been urged to join forces with the Trades Union Congress for a national day of demonstration and strike action to support the junior doctors and the NHS.

The proposal was made at the BMA’s special representatives meeting in London on Tuesday 3 May and was backed by a series of speakers at the event.

At that meeting the BMA’s chair of council, Mark Porter, accused the government of being in “denial” over the financial crisis facing the NHS. Funding cuts, diminishing morale among doctors, and ever growing demand from patients were placing intolerable pressure on the medical workforce, he said, and he called on ministers to take immediate action.1

Junior doctors held the first all-out …
Phase I/IIa trial targeting p16<sup>INK4a</sup> by peptide vaccination in patients with human papillomavirus-associated cancer.
Authors: Miriam Reuschenbach, Mohammed Rafiyan, Claudia Pauligk, Julia Karbach, Matthias Kloor, Elena-Sophie Prigge, Madeleine Sauer, Elke Jäger, Salah-Eddin Al-Batran, Magnus von Knebel Doeberitz
Journal: Journal of Clinical Oncology (2015)

e14030 Background: Therapeutic vaccines for patients with HPV-associated neoplasia are considered interesting strategies to improve treatment outcomes. Classically the HPV oncogene products E6/E7 have been used as antigens in clinical studies; however so far the induction of successful treatment responses in cancer patients appears difficult. It is a hallmark of HPV-associated cancers that as a direct consequence of HPV oncogene activity the cellular protein p16INK4a is strongly overexpressed. With at the same time absent or very low expression in normal tissues this expression pattern renders p16INK4a an interesting novel vaccine target. We performed a phase I/IIa first-in-man trial to evaluate the safety and immunogenicity of vaccination with p16INK4a. Methods: 26 patients with advanced p16INK4a-overexpressing, HPV DNA-positive cancer (anogenital region, head and neck) were included after completion of standard treatment. The protocolcomprised a total of 12 subcutaneous applications of a p16INK4peptide (P16_37-63) mixed with Montanide ISA-51 VG over a six months period. After an initial interim safety assessment after the first 10 patients the primary endpoint was the induction of a cellular and/or humoral immune response against peptide P16_37-63. Secondary endpoints were safety of immunization with P16_37-63 and tumor response according to RECIST. Results: 20 patients received at least 4 applications and were evaluable for induction of an immune response. CD4 T cells were induced in 11/20 patients, CD8 T cells in 4/20 and antibodies in 14/20 patients. No SUSAR or SAR was documented. All reported SAEs were expectable and not related to study therapy. No patients discontinued trial participation due to unacceptable toxicities and no dose limiting toxicities occurred. The best tumor response was classified as stable disease in 10 patients during the treatment and 3 remained stable until end of follow-up. Conclusions: Vaccination with P16_37-63 induces cellular and humoral immune responses and does not cause toxicities. Further trials will be designed to assess whether this approach may be an adjuvant therapeutic strategy for patients with HPV-associated cancers. Clinical trial information: NCT01462838.
Adoptive immunotherapy of acute myeloid leukemia (AML) with allogenic CAR t-cells targeting CD123.
Authors: Roman Galetto, Celine Lebuhotel, Patricia Francon, Agnes Gouble, Julianne Smith
Journal: Journal of Clinical Oncology (2015)

3041 Background: Chimeric antigen receptor (CAR)-redirected T-cells have given rise to long-term durable remissions and remarkable objective response rates in patients with refractory leukemia, raising hopes that a wider application of CAR technology may lead to a new paradigm in cancer treatment. A limitation of the current autologous approach is that CAR T-cells must be manufactured on a
Plasma Surfactant Protein-D, Matrix Metalloproteinase-7, and Osteopontin Index Distinguishes Idiopathic Pulmonary Fibrosis from Other Idiopathic Interstitial Pneumonias
Authors: Eric S. White, Meng Xia, Susan Murray, Rachel Dyal, Candace M. Flaherty, Kevin R. Flaherty, Bethany B. Moore, Ling Cheng, Tracy J. Doyle, Julian Villalba, Paul F. Dellaripa, Ivan O. Rosas, Jonathan D. Kurtis, Fernando J. Martinez
Journal: American Journal of Respiratory and Critical Care Medicine (2016)

Rationale: Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal interstitial lung disease (ILD) characterized by abnormal extracellular matrix (ECM) remodeling. We hypothesized that ECM remodeling might result in a plasma profile of proteins specific for IPF that could distinguish patients with IPF from other idiopathic ILDs.Objectives: To identify biomarkers that might assist in distinguishing IPF from non-IPF ILD.Methods: We developed a panel of 35 ECM, ECM-related, and lung-specific analytes measured in plasma from 86 patients with IPF (derivation cohort) and in 63 patients with IPF (validation cohort). Comparison groups included patients with rheumatoid arthritis–associated ILD (RA-ILD; n = 33), patients with alternative idiopathic ILDs (a-ILD; n = 41), and healthy control subjects (n = 127). Univariable and multivariable logistic regression models identified biomarkers that differentiated patients with IPF from those with a-ILD. Both continuous and diagnostic threshold versions of biomarkers were considered; thresholds were chosen to maximize summed diagnostic sensitivity and specificity in univariate receiver-operating characteristic curve analysis. A diagnostic score was created from the most promising analytes.Measurements and Main Results: Plasma surfactant protein (SP)-D > 31 ng/ml, matrix metalloproteinase (MMP)-7 > 1.75 ng/ml, and osteopontin > 6 ng/ml each significantly distinguished patients with IPF from patients with a-ILD, both individually and in a combined index. The odds ratio for IPF when at least one analyte in the index exceeded the threshold was 4.4 (95% confidence interval, 2.0–9.7; P = 0.0003). When at least two analytes were elevated, the odds ratio for IPF increased to 5.0 (95% confidence interval, 2.2–11.5; P = 0.0002).Conclusions: A biomarker index of SP-D, MMP-7, and osteopontin enhanced diagnostic accuracy in patients with IPF compared with those with non-IPF ILD. Our data suggest that this biomarker index may improve diagnostic confidence in IPF.
Is modern-day schizophrenic outcome still negative?
Authors: M Harrow, R R Grinker, M L Silverstein, P Holzman
Journal: American Journal of Psychiatry (1978)

To evaluate formulations about more positive outcome in modern-day schizophrenic patients, the authors assessed 132 young patients 2.7 years after hospital discharge. Despite modern treatment techniques, only 14%-17% of the 79 schizophrenic patients in the study group were functioning effectively without relapses; 50% had adjusted very poorly. The schizophrenic patients were functioning significantly more poorly than the nonschizophrenic patients in all areas (p less than .01), showing poor adjustment, high symptom levels, and high rehospitalization rates. The two major acute subgroups (schizo-affective and acute schizophrenic patients) were functioning better than those with paranoid and chronic schizophrenia. Overall, the authors conclude, diagnosis carries prognostic implications. Schizophrenic outcome is more favorable today than it was in Bleuler and Kraepelin's era, but it is still relatively negative.
A phase II study of two dosing regimens of GSK 1363089 (GSK089), a dual MET/VEGFR2 inhibitor, in patients (pts) with papillary renal carcinoma (PRC)
Authors: R. Srinivasan, W. M. Linehan, U. Vaishampayan, T. Logan, S. M. Shankar, L. J. Sherman, Y. Liu, T. K. Choueiri
Journal: Journal of Clinical Oncology (2009)

5103 Background: GSK089 is a potent, orally available small molecule inhibitor of MET and VEGFR2. Activating mutations and/or amplifications in MET have been described in pts with PRC. Two of 4 PRC pts treated with intermittent dosing of GSK089 on a Phase I study sustained partial responses (PR) for 1 and &gt; 3 years respectively. The aim of the current study is to evaluate the efficacy, safety and tolerability of 2 dosing regimens of GSK089 as a single agent in pts with advanced sporadic PRC (SPRC) or hereditary PRC (HPRC). Methods: Adults with advanced PRC are enrolled in 2 cohorts with different dosing schedules of GSK089: cohort 1) 240 mg/day on days 1–5 of every 14 days (5-on/9-off); cohort 2) 80 mg daily. Pts are stratified based on status of MET-pathway activation (activating MET mutation, MET [7q31] amplification, or trisomy 7). The primary endpoint is RECIST response rate, assessed every 8 weeks. Plasma markers reflecting potential effects of MET inhibition and anti-VEGF therapy are analyzed. Results: As of December 15, 2008, 37 pts were enrolled in the 5-on/9-off cohort (19 with MET activation including 5 HPRC, 18 SPRC without MET activation or unknown MET status), and 16 pts in the daily dosing cohort (2 with HPRC, 14 SPRC with unknown MET status). Enrollment is ongoing in cohort 2. In cohort 1, of the 35 evaluable pts, 4 pts (2 HPRC and 2 SPRC) had confirmed PRs and 27 had stable disease (SD) as best response with 6 ≥12mo, 3 ≥ 9mo and 3 ≥ 6mo. Four of 5 HPRC pts (1 not evaluated) had shrinkage (15–53%) in all measurable tumors. Twenty-three SPRC pts had shrinkage (2–58%) in the sum of measurable tumors. In cohort 2, of the 9 evaluable pts, 2 (both SPRC) had confirmed PRs, and 7 had SD. The most frequent adverse events (AEs) associated with GSK089 were fatigue, hypertension, nausea, vomiting, diarrhea, and increased ALT/AST, primarily grades 1 and 2. Preliminary results from cohort 1 indicated that plasma shed Met (sMET) and VEGF increased and sVEGFR2 decreased after 2 cycles with changes maintained after 4 cycles. Conclusions: GSK089 is well tolerated and demonstrates anti-tumor activity in pts with PRC with both 5-on/9-off and daily dosing. VEGF, sVEGFR2, and sMET are promising pharmacodynamic markers for biological activity of GSK089. [Table: see text]
Impact of Demographic Characteristics, Staging Methods and Treatment in a European Locally Advanced Cervical Cancer (Lacc) Population
Authors: E. Sanz-Garcia, M. Gil-Martin, C. Linossi, X. Perez-Martin, L. Fariñas-Madrid, S. Marin I Borras, R. Verges, A. Gil, J. Ponce Sebastia, V. Rodriguez-Freixinos, J.M. Del Campo, X. Garcia Del Muro, B. Pardo Burdalo, A. Oaknin
Journal: Annals of Oncology (2014)
Unnatural practices, unspeakable actions: a study of delayed auditory feedback in schizophrenia
Authors: T E Goldberg, J M Gold, R Coppola, D R Weinberger
Journal: American Journal of Psychiatry (1997)

It has been suggested that auditory hallucinations and delusions of control in persons with schizophrenia could involve a disconnection between an "intention center" and a "monitoring center."To test this model directly, the authors used a delayed auditory feedback paradigm in which the subject hears his or her own speech delayed electronically by a fraction of a second. In normal, subjects this produces dysfluency, which is thought to occur because an expectancy about the perceptual arrival of speech, formed in a monitoring center on the basis of corollary discharge from an intention center, is violated. If, however, a disconnection were present in schizophrenia, such an expectancy would not be formed; hence, less dysfluency should occur. Fifteen patients with chronic schizophrenia (10 of whom experienced auditory hallucinations and/or delusions of control) and 19 normal subjects were studied.Rather than exhibiting less dysfluency than the normal subjects, patients with delusions and/or hallucinations exhibited significantly more dysfluency.These results do not support a cognitive model of disconnection.
A randomized prospective open labeled study of oral amoxicillin-clavulanate with intravenous ceftriaxone and amikacin in low risk febrile neutropenia
Authors: J. F. Dominic, L. Kumar, V. Kochupillai, V. Raina, A. Sharma, S. Bakshi, T. Seth, A. Kapil
Journal: Journal of Clinical Oncology (2006)

18551 Background: Empiric oral antibiotic administration is a treatment option in low risk febrile neutropenia. Methods: Low risk febrile neutropenia patients (expected neutropenic duration &lt;7 days with no comorbid features) between 15 and 75 years of age were randomized to receive either oral amoxicillin-clavulanate 625 mg twice daily and levofloxacin 500 mg once daily or intravenous (i.v.) ceftriaxone 2 g and amikacin 15 mg/kg once daily. Most patients were treated on out patient basis. The primary end point was response to therapy- defervescence of fever within 72 hours with improvement in any clinical manifestation of infection and no recurrence of fever for 48 hours without use of antipyretics. Use of growth factors was not permitted except in treatment failure. The study was cleared by the institute ethics committee. Results: Sixty four episodes in 53 patients were evaluable, 33 in the i.v. group and 31 in the oral antibiotics group. The underlying diagnosis was bone and soft tissue sarcomas in 32 episodes, hematological cancers in 22 and other solid cancers in 10. The groups were equally matched for age (median 25 years in the i.v. arm and 19 years in the oral arm), gender, type of cancer, baseline absolute neutrophil count (median 200/μL in both arms) and duration of neutropenia (5 days and 4 days in the i.v. and oral groups respectively). A focus of infection was identified clinically in 15% of episodes and microbiologically in 11% of episodes; 57% of which were gram positive organisms and the rest gram negative. Seventy two percent (95% confidence interval 58% to 88%) in the i.v. arm and 77% (95% confidence interval 63% to 92%) in the oral arm responded to therapy. The only serious toxicity was one episode of convulsions in the i.v. group. All treatment failures received second line i.v. antibiotics. There was no mortality in either group. Comparing the two groups for equivalence (assuming a 25% difference between the two arms as unequal) the two groups were found to be equivalent with a power of 59% (p = 0.03). Conclusion: Oral antibiotics have comparable efficacy as intravenous antibiotics in the management of low risk febrile neutropenia. No significant financial relationships to disclose.
A Sense of Closure
Authors: Jürgen L. Holleck
Journal: Annals of Internal Medicine (2016)

On Being a Patient3 May 2016A Sense of ClosureJürgen L. Holleck, MDJürgen L. Holleck, MDFrom Yale University School of Medicine and VA Connecticut Healthcare System, West Haven, Connecticut.Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/M15-2225 Audio Reading - “A Sense of Closure” Audio. Michael A. LaCombe, MD, Annals Associate Editor, reads "A Sense of Closure," by J.L. Holleck. Your browser does not support the audio element. Audio player progress bar Step backward in current audio track Play current audio trackPause current audio track Step forward in current audio track Mute current audio trackUnmute current audio track 00:00/ SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail We were the last skiers inside the small, rustic hut at the top of the mountain. A group of three ski patrol members were the only others, and they hunkered around a table in what seemed to be a recertification prep session. One of the men who seemed to be more senior presented scenarios: “A middle-aged skier is lying unresponsive at the edge of the trail. … ” His tone was confident; his build was stocky with broad shoulders, probably an accomplished athlete in his day. I studied his face for clues as to age and listened in, wanting to ... Author, Article, and Disclosure InformationAffiliations: From Yale University School of Medicine and VA Connecticut Healthcare System, West Haven, Connecticut.Corresponding Author: Jürgen L. Holleck, MD, Department of Internal Medicine, VA Connecticut Healthcare System, 950 Campbell Avenue, Mailstop 111, West Haven, CT 06516; e-mail, Jurgen.[email protected]gov. PreviousarticleNextarticle Advertisement Audio Reading - “A Sense of Closure” Audio. Michael A. LaCombe, MD, Annals Associate Editor, reads "A Sense of Closure," by J.L. Holleck. Your browser does not support the audio element. Audio player progress bar Step backward in current audio track Play current audio trackPause current audio track Step forward in current audio track Mute current audio trackUnmute current audio track 00:00/ FiguresReferencesRelatedDetails Metrics 3 May 2016Volume 164, Issue 9Page: 628KeywordsDeceptionFearFemurGratitudeHealth careMemoryPreexposure prophylaxisScarsShouldersWheelchairs ePublished: 3 May 2016 Issue Published: 3 May 2016 Copyright & PermissionsCopyright © 2016 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
Doctors are urged to measure blood pressure in both arms
Authors: Susan Mayor
Journal: BMJ (2016)

A different systolic blood pressure in each arm is associated with increased risk of cardiovascular events including death, shows a large cohort study of people with no pre-existing vascular disease.1

Previous studies have shown reduced survival linked to a difference in blood pressure between arms in people with established vascular disease or high cardiovascular risk, but the potential association in the general population is unknown.

Researchers analysed blood pressure measurements taken …
Myeloid-derived suppressor cells promote B-cell production of IgA in a TNFR2-dependent manner
Authors: Xia Xu, Qinghong Meng, Ulrike Erben, Peigang Wang, Rainer Glauben, Anja A Kühl, Hao Wu, Chung Wah Ma, Minghua Hu, Yuanyuan Wang, Wei Sun, Junying Jia, Xinyi Wu, Wei Chen, Britta Siegmund, Zhihai Qin
Journal: Cellular and Molecular Immunology (2016)
Antisocial personality disorder in patients with substance abuse disorders: a problematic diagnosis?
Authors: L J Gerstley, A I Alterman, A T McLellan, G E Woody
Journal: American Journal of Psychiatry (1990)

The authors' literature review suggests that the relationship between antisocial personality disorder and substance abuse is complex and not yet fully understood. The confusion regarding the relationship between the disorders may be magnified by the emphasis in DSM-III and DSM-III-R on behavioral criteria and their failure to require that antisocial behaviors exist independently of substance abuse. The DSM-III and DSM-III-R formulations of antisocial personality disorder may encompass two subgroups of substance abusers--"true" psychopathic individuals and symptomatic psychopaths with little psychopathy. Psychoneurotic symptoms and favorable treatment responses might be found more often in the latter group.
The Acquirement Of Rituximab Resistance Is Associated With De-Regulation Of The PI3K/Akt/mTOR Signaling Pathway Leading To Chemotherapy Resistance In Burkitt Lymphoma Pre-Clinical Models
Authors: Sarah Frys, Andrew Skomra, Natalie M Czuczman, Cory Mavis, Delphine C.M. Rolland, Megan Lim, Aradhana Awasthi, Mitchell S. Cairo, Myron S. Czuczman, Francisco J. Hernandez-Ilizaliturri, Matthew J. Barth
Journal: Blood (2013)
Herniated Lumbar Intervertebral Disk
Authors: Richard A. Deyo, Sohail K. Mirza
Journal: New England Journal of Medicine (2016)

Pain from disk herniation, the leading cause of sciatica, usually resolves within several weeks with conservative therapy. In patients with sciatica for 6 weeks, pain relief is faster with surgery than with conservative therapy; however, outcomes are similar at 1 year.
Transcatheter Aortic Valve Replacement: State of the Art and Future Directions
Authors: Mackram F. Eleid, David R. Holmes
Journal: Annual Review of Medicine (2016)

Transcatheter aortic valve replacement (TAVR) is a transformational and rapidly evolving treatment for patients with aortic stenosis who require valve replacement. Novel technological advancements have made this percutaneous minimally invasive therapy a first-line treatment for many patients at extreme risk for conventional cardiac surgery. New devices and improvements in existing devices have reduced procedural complications, and scientific trials are investigating the role of TAVR in lower-risk aortic stenosis populations, in patients with aortic regurgitation, and in patients with bicuspid aortic valve disease. Finally, there is intense interest in identifying patients in whom the risk-benefit ratio of TAVR is not favorable and should not be performed.
Clinical features of cases of influenza A (H1N1)v in Osaka prefecture, Japan, May 2009
Authors: N Komiya, Y Gu, H Kamiya, Y Yahata, T Matsui, Y Yasui, N Okabe
Journal: Eurosurveillance (2009)

This report describes the clinical characteristics of influenza A(H1N1)v virus infection in Osaka. By the end of May, 171 cases had been reported in Osaka. Most patients were from one school. No patient had a serious underlying medical condition.Clinical symptoms were mild and resembled those of seasonal influenza. The sensitivity of the rapid antigen test was 77%. Antivirals were given to the majority of the cases. Early antiviral treatment may have shortened the duration of fever.
Suppressors of cytokine signaling proteins 1 and 3 regulate the immune response to interferon-alpha.
Authors: Jason M. Zimmerer, Gregory B. Lesinski, Sri Vidya Kondadasula, Brian Becknell, William E. Carson
Journal: Cancer Research (2006)

Proc Amer Assoc Cancer Res, Volume 47, 2006

5560 

Suppressor of cytokine signaling (SOCS) proteins are important regulators of cytokine signal transduction and we hypothesized that SOCS proteins modulate IFN-α signal transduction and gene regulation in immune effector cells Increased levels of transcripts for SOCS1, SOCS2, SOCS3, and CIS (> 4.0 fold compared with baseline; p < 0.001) were identified in human peripheral blood mononuclear cells (PBMCs), natural killer (NK) cells, and T cells within 1–2 hours of stimulation with IFN-α (102–105 U/ml). Immunoblot analysis confirmed the expression of these factors at the protein level. Consistent with these findings, cells treated with IFN-α exhibited rapid phosphorylation of STAT1 (P-STAT1) at tyrosine 701 followed by a prompt return to baseline levels at 4 hours. Transcripts for SOCS proteins were also rapidly induced in patients with metastatic melanoma following the intravenous administration of high dose IFN-α-2b (20 MU/m2) and exhibited significant interpatient variation (e.g. 8.0 to 160 fold induction for SOCS1). Over-expression of SOCS1 and SOCS3, but not SOCS2 in the Jurkat T cell line significantly inhibited the formation of P-STAT1 (p < 0.001) and the transcription of interferon-stimulated genes (ISGs; p < 0.045 for IFIT2, ISG20, and OAS1) post-exposure to IFN-α. Transfection of normal T cells with SOCS1 or SOCS3 small interference RNAs led to significantly enhanced generation of P-STAT1 and increased transcription of multiple ISGs in response to IFN-α (all p values < 0.05). The induction of P-STAT1 and subsequent transcription of ISGs in IFN-α-treated splenocytes was significantly greater in SOCS1- and SOCS3-deficient mice than in splenocytes derived from their respective background counterparts (all p values < 0.05). Consistent with this, tumor-bearing SOCS1-deficient mice exhibited prolonged survival in response to treatment with IFN-α as compared to SOCS1-competent mice of the same background (p < 0.01). Of note, 60% of SOCS-deficient mice were routinely cured of their tumors with IFN-α treatment as opposed to 0% of the control group. These results indicate that SOCS proteins are critical negative regulators of IFN-α signal transduction in immune effector cells and that inhibition of SOCS activity significantly enhances the immune response to exogenous IFN-α.