tbuckley/cabot-search huggingface dataset:
Antidepressants versus placebo in major depression: an overview
Authors: Arif Khan, Walter A. Brown
Journal: World Psychiatry (2015)

Although the early antidepressant trials which included severely ill and hospitalized patients showed substantial drug‐placebo differences, these robust differences have not held up in the trials of the past couple of decades, whether sponsored by pharmaceutical companies or non‐profit agencies. This narrowing of the drug‐placebo difference has been attributed to a number of changes in the conduct of clinical trials. First, the advent of DSM‐III and the broadening of the definition of major depression have led to the inclusion of mildly to moderately ill patients into antidepressant trials. These patients may experience a smaller magnitude of antidepressant‐placebo differences. Second, drug development regulators, such as the U.S. Food and Drug Administration and the European Medicines Agency, have had a significant, albeit underappreciated, role in determining how modern antidepressant clinical trials are designed and conducted. Their concerns about possible false positive results have led to trial designs that are poor, difficult to conduct, and complicated to analyze. Attempts at better design and patient selection for antidepressant trials have not yielded the expected results. As of now, antidepressant clinical trials have an effect size of 0.30, which, although similar to the effects of treatments for many other chronic illnesses, such as hypertension, asthma and diabetes, is less than impressive.
Salmonellosis cases caused by a rare Salmonella Enteritidis PT6c associated with travel to Bulgaria, June-July 2008
Authors: P Petrov, K Parmakova, A Siitonen, G Asseva, T Kauko, M Kojouharova, T Kantardjiev
Journal: Eurosurveillance (2009)

In June 2008 an outbreak of gastroenteritis was registered in Sunny Beach resort situated on the Black Sea coast in Bulgaria, affecting 14 employees of a hotel, five of whom tested positive for Salmonella Enteritidis. During June-July 2008 four sporadic S. Enteritidis cases were also reported and two of them were foreign tourists. In the same period S. Enteritidis cases connected with travel to Bulgaria were reported to the European Centre for Disease Prevention and Control (ECDC) from Finland, United Kingdom, Sweden, Germany and Norway. We describe a study performed to find out relatedness between Bulgarian and Finnish S. Enteritidis isolates using phage typing (PT) and pulse-field gel electrophoresis (PFGE). Fifteen S. Enteritidis isolates from Bulgaria and 195 from Finland (including 28 from travellers to Bulgaria) were phage typed. Within Bulgarian isolates four different PTs were found and PT6c with eight strains was predominant. Nineteen out of 28 strains isolated from the Finns visiting Bulgaria belonged also to PT6c. PFGE typing (with one enzyme) of all S. Enteritidis PT6c strains (8 Bulgarian and 19 Finnish isolates) showed indistinguishable PFGE profile. The typing results thus demonstrated a link between Bulgarian and Finnish S. Enteritidis isolates. We conclude that S. Enteritidis PT6c was the cause of salmonella outbreak in Sunny Beach and was exported to Finland, and likely to the United Kingdom, Norway, Sweden and Germany.
DNA methylation‐based prognosis and epidrivers in hepatocellular carcinoma
Authors: Augusto Villanueva, Anna Portela, Sergi Sayols, Carlo Battiston, Yujin Hoshida, Jesús Méndez‐González, Sandrine Imbeaud, Eric Letouzé, Virginia Hernandez‐Gea, Helena Cornella, Roser Pinyol, Manel Solé, Josep Fuster, Jessica Zucman‐Rossi, Vincenzo Mazzaferro, Manel Esteller, Josep M. Llovet
Journal: Hepatology (2015)

Epigenetic deregulation has emerged as a driver in human malignancies. There is no clear understanding of the epigenetic alterations in hepatocellular carcinoma (HCC) and of the potential role of DNA methylation markers as prognostic biomarkers. Analysis of tumor tissue from 304 patients with HCC treated with surgical resection allowed us to generate a methylation-based prognostic signature using a training-validation scheme. Methylome profiling was done with the Illumina HumanMethylation450 array (Illumina, Inc., San Diego, CA), which covers 96% of known cytosine-phosphate-guanine (CpG) islands and 485,000 CpG, and transcriptome profiling was performed with Affymetrix Human Genome U219 Plate (Affymetrix, Inc., Santa Clara, CA) and miRNA Chip 2.0. Random survival forests enabled us to generate a methylation signature based on 36 methylation probes. We computed a risk score of mortality for each individual that accurately discriminated patient survival both in the training (221 patients; 47% hepatitis C-related HCC) and validation sets (n = 83; 47% alcohol-related HCC). This signature correlated with known predictors of poor outcome and retained independent prognostic capacity of survival along with multinodularity and platelet count. The subset of patients identified by this signature was enriched in the molecular subclass of proliferation with progenitor cell features. The study confirmed a high prevalence of genes known to be deregulated by aberrant methylation in HCC (e.g., Ras association [RalGDS/AF-6] domain family member 1, insulin-like growth factor 2, and adenomatous polyposis coli) and other solid tumors (e.g., NOTCH3) and describes potential candidate epidrivers (e.g., septin 9 and ephrin B2).A validated signature of 36 DNA methylation markers accurately predicts poor survival in patients with HCC. Patients with this methylation profile harbor messenger RNA-based signatures indicating tumors with progenitor cell features.
Road Traffic Accidents before and after Seatbelt Legislation-Study in a District General Hospital
Authors: J Thomas
Journal: Journal of the Royal Society of Medicine (1990)

Injuries among samples of car accident cases attending the Accident & Emergency (A & E) department of a District General Hospital (DGH) in the year before and after the introduction of seat belt legislation were classified applying the Abbreviated Injury Scale using information recorded in the patient case notes. Those who died or did not attend an A & E department were not included in the sampling frame. The number of those who escaped injury increased by 40% and those with mild and moderate injuries decreased by 35% after seatbelt legislation. There was a significant reduction in soft tissue injuries to the head. Only whiplash injuries to the neck showed a significant increase.
Margaret McCartney: Daily drug shortages place avoidable pressure on primary care
Authors: M. McCartney
Journal: BMJ (2015)

Margaret McCartney: Daily drug shortages place avoidable pressure on primary care Margaret McCartney general practitioner, GlasgowThere's no clobetasone, ferrous fumarate, gentisone ear drops, metoprolol, valsartan, or mefenamic acid.These are not rare, esoteric drugs but workhorses of daily prescribing.Every day work is interrupted by news of what's not available.Pharmacists with no stock phone the practice receptionists to tell them that patients need alternative prescriptions.
The single nucleotide polymorphism MDM2-SNP309 predicts for sensitivity of B-CLL cells to the non-genotoxic activator of the p53 pathway Nutlin-3a
Authors: Inge Tinhofer, Irina Seyfried, Markus Stocher, Sebastian Hofbauer, Peter Daniel, Richard Greil
Journal: Clinical Cancer Research (2008)

AACR Centennial Conference: Translational Cancer Medicine-- July 20-23, 2008; Monterey, CA

B27 

Background:    The single nucleotide polymorphism (SNP) at position 309 in the promoter region of MDM2, a negative regulator of p53, has been linked to increased cancer risk in various solid tumor models. We have recently identified the SNP309 genotype as independent prognostic factor for overall survival in B-CLL (Gryshchenko et al, JCO 2008). Nutlin-3a, a small molecule inhibitor of the p53-MDM2 interaction reactivates p53 and induces p53-dependent apoptosis. We hypothesized that sensitivity of B-CLL cells to nutlin-3a-induced apoptosis might differ between cells from SNP309 T/T, T/G or G/G carriers.    Methods:    The SNP309 genotype of B-CLL cells was assessed by RT-PCR. In addition, the p53 status was assessed by single-stranded conformation polymorphism (SSCP) and fluorescence-in-situ-hybridization (FISH) analysis, respectively. Sensitivity of B-CLL cells to apoptosis induced by nutlin-3a was determined by flow cytometry using annexin V-FITC/7-AAD staining. Extent and kinetics of p53 stabilization following nutlin-3a treatment was determined by Western blot analysis.    Results:    We observed significant induction of apoptosis in B-CLL cells treated with nutlin-3a in a dose- and time-dependent manner. The percentages of apoptotic B-CLL cells were significantly higher in B-CLL samples from SNP309 T/G or G/G as compared to T/T carriers. In addition, higher sensitivity of SNP309 T/G or G/G variants to nutlin-3a treatment was not specific for B-CLL cells, but also observed in CD19+ B-cells from healthy controls. Addition of nutlin-3a significantly increased expression levels of p53 and downstream targets such as Bax and Puma in a time-dependent manner. Importantly, we could confirm previous reports of synergistic action of nutlin-3a when combined with fludarabine for induction of apoptosis in B-CLL cells.    Conclusions: Our analysis identified a cohort of patients which might particularly profit from therapeutic targeting of p53/MDM2 interactions in B-CLL. It has to be clarified in future studies whether nutlin-3a, besides its synergistic activity together with fludarabine, generally enhances the sensitivity of tumor cells to apoptosis induced by DNA-targeting drugs or radiotherapy and thus might be exploited therapeutically. These studies should not only include hematopoietic neoplasias but also models of solid tumors.
Updated overall survival (OS) and progression-free survival (PFS) by blinded independent central review (BICR) of sunitinib (SU) versus placebo (PBO) for patients (Pts) with advanced unresectable pancreatic neuroendocrine tumors (NET).
Authors: E. Raymond, P. Niccoli, J. Raoul, Y. Bang, I. Borbath, C. Lombard-Bohas, J. W. Valle, P. Metrakos, D. Smith, A. Vinik, J. Chen, D. Hoersch, D. E. Castellano, H. F. Kennecke, J. Picus, G. Van Hazel, D. Lu, R. C. Chao, S. Patyna, E. Van Cutsem
Journal: Journal of Clinical Oncology (2011)

4008 Background: In a double-blind phase 3 trial, SU improved PFS vs PBO (11.4 vs 5.5 months; HR 0.418, 95% CI 0.263, 0.662; p=0.0001) and was well tolerated in pts with advanced well-differentiated, unresectable NET that had progressed in ≤12 months (NEJM, Feb 2011). Initial OS showed a benefit for SU over PBO, but median OS was not reached (NR). Here we report updated results of median OS and also PFS assessed by BICR to correct for potential unblinding due to identifiable adverse events (AE). Methods: Pts were randomized 1:1 to SU 37.5 mg as a continuous daily dose or PBO, each with best supportive care. Primary endpoint was PFS; secondary endpoint was OS. Median OS and HR were estimated using Kaplan-Meier (K-M) methods and Cox proportional hazards models. Baseline and on-study CT/MRI scans were evaluated by a 2-reader, 2-time point lock, followed by a sequential locked-read, batch-mode paradigm by blinded, third-party radiologists. Results: 171 pts were randomized (SU, n=86; PBO, n=85) from 6/2007 to 4/2009. The trial ended early when an independent data monitoring committee noted efficacy favoring SU and more serious AEs and deaths with PBO. The study was unblinded at closure, and pts were offered open-label SU. At study end, there were 9 and 21 deaths in SU and PBO arms, respectively; HR of 0.409 (95% CI 0.187, 0.894; p=0.0204) favoring SU. By 6/2010, there were 34 and 39 deaths, respectively; median OS was 30.5 (95% CI 20.6, NR) and 24.4 (95% CI: 16.3, NR) months, respectively. The HR of 0.737 (95% CI 0.465, 1.168; p=0.1926) continued to favor SU; a K-M plot showed early/persistent separation of curves. For BICR analysis, scans were collected for 170 (99.4%) pts, with 160 (93.6%) having complete scan sets/time points. Median PFS by BICR was 12.6 vs 5.8 months for SU and PBO (HR 0.315 [95% CI 0.181, 0.546; p=0.000015]). Conclusions: SU led to a 6.1-month improvement in median OS vs PBO, and BICR analysis confirmed the investigator-assessed PFS benefit of SU. These updated results support the robustness of the initial findings and the clinical benefit of treatment with sunitinib.
Telomerase (h-TERT) and targeting EGFR in non small cell lung carcinoma: A combined immunohistochemistry and chromogenic in situ hybridization study based on tissue microarrays
Authors: Athanassios Stamatelopoulos, Evangellos Tsiambas, Petros Michos, Ioannis Gakidis, Andreas Karameris, Dimosthenes Bouros
Journal: European Respiratory Journal (2011)

Purpose:  Our aim was the evaluation of EGFR gene and protein alterations in NSCLC and the potential role of telomerase in the regulation of its expression.   Methods:  Using tissue microarray technology, forty (n=40) paraffin embedded histologically confirmed primary NSCLCs were cored twice at a diameter of 1mm and re-embedded into a recipient block. Immunohistochemistry was performed by the use of monoclonal antibodies anti-EGFR (31G7), and anti-telomerase/h-TERT (44F12). Also, a Chromogenic in situ hybridization protocol was applied based on the use of EGFR gene and chromosome 7 centromeric probes. Computerized Image Analysis was performed for the evaluation of immunohistochemistry results.   Results:  EGFR overexpression was observed in 23/40 (57.5%) cases correlating to stage (p=0.001) and histological type (p=0.04). Telomerase was overexpressed in all examined cases (high and moderate levels) correlating to stage (p=0.001). A significant value of concordance (kappa=0.686, 0.677-0.695) was assessed comparing telomerase and EGFR protein expression. EGFR gene amplification was identified in 2/40 (5%) cases associating to histological type (p=0.027) and chromosome 7 aneuploidy in 7/40 (17.5%) cases.   Conclusions:  NSCLC is characterized by rare cases of EGFR gene amplification and this genetic event maybe affect the efficacy of targeted therapeutic strategies based on monoclonal antibodies. Also, the strong concordance between EGFR and telomerase overexpression demonstrates that the enzyme is potentially involved in the growth-controlling gene expression.
What is suspected heart failure with preserved left ventricular systolic function?
Authors: D. Leibowitz
Journal: BMJ (2001)

Editor—Caruana et al's study focuses on the well established difficulties in the diagnosis of diastolic heart failure in the community.1 I question the authors' conclusions that most patients in the community with a diagnosis of diastolic heart failure have unrelated conditions.

Proposed criteria for the diagnosis of diastolic heart failure require definitive evidence of congestive heart failure by clinical criteria, physical examination, chest radiography, response to diuretics, etc as a starting point.2,3 The authors do not provide the indications that led the primary physicians to refer the patients for echocardiography; the clinical suspicion of diastolic heart failure should rely on more than symptoms of dyspnoea at rest or on exertion, for which the differential diagnosis is broad.

The authors consider a history of coronary artery disease or electrocardiographic changes consistent with coronary disease to be an alternative explanation for the patients' symptoms. In patients with normal systolic function and without acute ischaemia, physiological stress testing would be mandatory to support this claim; however, no such evaluation was performed.

Lastly, in an elderly population (mean age 71) an E:A ratio of <1.0 is a normal finding and should not be construed as indicating diastolic dysfunction.4 The use of mitral filling variables in the evaluation of diastolic heart failure is problematic, and it is to be hoped that newer echocardiographic techniques such as tissue Doppler and flow propagation will prove more accurate.5
Allergic rhinitis in asthmatic children
Authors: Violeta Stojanovska, Jane Buzarov
Journal: European Respiratory Journal (2011)

Objective:  Examine the prevalence and clinical expression off allergic rhinitis in children with bronchial asthma.   Material and methods:  120 children were evaluated in the period (2006-2009).69 (57,5%) male mean age 8,3 years. The following parameters were substancial for determining the diagnosis:history,clinic condition. Routine and specific examinations.   Results:  Allergic rhinhitis was displayed in 68,7% of the children. Intermittent asthma was presented in 30,9%; mild persistent asthma in 44,8%, while 5,2% of patient had severe persistent asthma. Intermittent rhinitis was demonstrated in 14 children and 12 from them have had moderate-severe degree. Persistent allergic rhinitis had 65 children and in 41,5% of them have had moderate-severe rhinitis.Nasal symptoms preceded asthma in 65,8% of patients. The others were both diseases appeared in the same time. Positive skin tests to Dermatophagoides pteronyssinus had 2/3 of children. Over 80% of them were with persistent allergic rhinitis and asthma. Pollen sensitivity was confirmed in 20,9% of the children, but almost all of them were with Dermatophagoides sensitivity. Sneezing and rhinorrea were presented in 22,8% of the children (almost in all of the children with pollen sensitivity.) Concomitant sinusitis was presented in 67% of the children with asthma and rhinitis, but in over 90% of the children with Dermatophagoides sensitivity. Associated conjunctivitis had 20,3% of the patients, but almost all of the children that were with pollen sensitivity.   Conclusion:  Epidemiological studies consistently shown that asthma and rhinhitis often coexist in the same patients, and our study confirmed also strong association between allergic rhinitis and asthma in childhood.
Association of depression with 10-year poststroke mortality
Authors: P. L. P. Morris, R. G. Robinson, P. Andrzejewski, J. Samuels, T. R. Price
Journal: American Journal of Psychiatry (1993)

Depression has been linked to higher than expected mortality from natural causes, particularly among elderly patients with physical illness. The authors examined the effect of depression on mortality among a group of stroke patients followed up for 10 years.A consecutive series of 103 patients was assessed for major or dysthymic (minor) depression approximately 2 weeks after stroke with the use of a structured mental status examination and DSM-III diagnostic criteria. Vital status was determined for 91 of these patients 10 years later.Forty-eight (53%) of the 91 patients had died. Patients with diagnoses of either major or minor depression were 3.4 times more likely to have died during the follow-up period than were nondepressed patients, and this relationship was independent of other measured risk factors such as age, sex, social class, type of stroke, lesion location, and level of social functioning. The mortality rate among depressed patients with few social contacts was especially high: over 90% had died.These results indicate that depressed mood following stroke is associated with an increased risk of subsequent mortality. Patients who are depressed and socially isolated seem to be particularly vulnerable.
Expression of a CD44 variant containing exons 8 to 10 is a useful independent factor for the prediction of prognosis in colorectal cancer patients.
Authors: A Yamaguchi, T Urano, T Goi, M Saito, K Takeuchi, K Hirose, G Nakagawara, H Shiku, K Furukawa
Journal: Journal of Clinical Oncology (1996)

To determine the expression of the CD44 variant containing a variant exon 8 to 10 product (CD44v8-10) in colorectal cancer and to evaluate its prognostic value.CD44v8-10 was studied in resected tumors and normal mucosae obtained from 215 colorectal cancer patients (118 colon cancer and 97 rectal cancer). The expression of CD44v8-10 was analyzed immunohistochemically using the anti-CD44v8-10 monoclonal antibody (mAb) 44-1V.One hundred of 215 cancer tissues expressed CD44v8-10. Positive staining was intense mainly on the cell membranes. There was no significant correlation between expression of CD44v8-10 and histologic type, primary tumor, lymphatic invasion, venous invasion, or peritoneal invasion. There were significant correlations between CD44v8-10 immunoreactivity and both lymph node and hematogenous metastasis. Patients with CD44v8-10-positive tumors had a greater relative risk of death compared with those whose tumors were CD44v8-10-negative. Among 169 patients who underwent curative resection, CD44v8-10 expression correlated with a high recurrence rate. The 5- and 10-year survival rates were 90.3% of patients with CD44v8-10-negative tumors, and 72.1% and 58.0% of those with CD44v8-10-positive tumors, respectively; these differences between the two groups of patients were significant (P < .01). In multivariate analysis using the Cox regression model, CD44v8-10 expression emerged as an independent prognostic indicator.The results suggest that CD44v8-10 plays a role in metastasis of colorectal cancer, and tha CD44v8-10 expression may be a biologic marker of prognostic significance.
Threats to polio eradication in high-conflict areas in Pakistan and Nigeria: a polling study of caregivers of children younger than 5 years
Authors: Gillian K SteelFisher, Robert J Blendon, Sherine Guirguis, Amanda Brulé, Narayani Lasala-Blanco, Michael Coleman, Vincent Petit, Mashrur Ahmed, Noah Mataruse, Melissa Corkum, Mazhar Nisar, Eran N Ben-Porath, Susan Gigli, Christoph Sahm
Journal: The Lancet Infectious Diseases (2015)
Headaches and the Treatment of Blood Pressure
Authors: Malcolm Law, Joan K. Morris, Rachel Jordan, Nicholas Wald
Journal: Circulation (2005)

Uncertainty exists over whether blood pressure-lowering drugs prevent headache.A meta-analysis was carried out of the 94 randomized placebo-controlled trials of 4 different classes of blood pressure-lowering drugs (thiazides, beta-blockers, ACE inhibitors, and angiotensin II receptor antagonists) in fixed doses in which data on headache were reported. There were 17,641 participants who were allocated blood pressure-lowering drugs and 6603 who were allocated placebo. Treatment lowered systolic and diastolic blood pressures by 9.4 and 5.5 mm Hg, respectively, on average. One third fewer people on average reported headache in the treated groups (8.0%) than the placebo groups (12.4%) (odds ratio, 0.67; 95% CI, 0.61 to 0.74; P<0.001). About 1 in 30 treated persons benefited by having headache prevented. The prevalence of headache was reduced (P<0.001) in trials of each of the 4 classes of drugs.Our results show that blood pressure-lowering drugs prevent a significant proportion of headaches. That this effect is seen with pharmacologically unrelated classes of drugs indicates that it is likely to be due to the reduction in blood pressure per se, the only recognized action that the drugs have in common. This in turn indicates that high blood pressure is a cause of headache, but this conclusion is not supported by observational studies of blood pressure and headache. The uncertainty over whether high blood pressure causes headache does not, however, detract from the practical benefits of the use of blood pressure-lowering drugs in preventing headaches and cardiovascular disease.