tbuckley/cabot-search huggingface dataset:
Antibiotic treatment failure in four common infections in UK primary care 1991-2012: longitudinal analysis
Authors: C. J. Currie, E. Berni, S. Jenkins-Jones, C. D. Poole, M. Ouwens, S. Driessen, H. de Voogd, C. C. Butler, C. L. Morgan
Journal: BMJ (2014)

<b>Objective</b> To characterise failure of antibiotic treatment in primary care in the United Kingdom in four common infection classes from 1991 to 2012. <b>Design</b> Longitudinal analysis of failure rates for first line antibiotic monotherapies associated with diagnoses for upper and lower respiratory tract infections, skin and soft tissue infections, and acute otitis media. <b>Setting</b> Routine primary care data from the UK Clinical Practice Research Datalink (CPRD). <b>Main outcome measures</b> Adjusted rates of treatment failure defined by standardised criteria and indexed to year 1 (1991=100). <b>Results</b> From 58 million antibiotic prescriptions in CPRD, we analysed 10 967 607 monotherapy episodes for the four indications: 4 236 574 (38.6%) for upper respiratory tract infections; 3 148 947 (28.7%) for lower respiratory tract infections; 2 568 230 (23.4%) for skin and soft tissue infections; and 1 013 856 (9.2%) for acute otitis media. In 1991, the overall failure rate was 13.9% (12.0% for upper respiratory tract infections; 16.9% for lower respiratory tract infections; 12.8% for skin and soft tissue infections; and 13.9% for acute otitis media). By 2012, the overall failure rate was 15.4%, representing an increase of 12% compared with 1991 (adjusted value indexed to first year (1991) 112, 95% confidence interval 112 to 113). The highest rate was seen in lower respiratory tract infections (135, 134 to 136). While failure rates were below 20% for most commonly prescribed antibiotics (amoxicillin, phenoxymethylpenicillin (penicillin-V), and flucloxacillin), notable increases were seen for trimethoprim in the treatment of upper respiratory tract infections (from 29.2% in 1991-95 to 70.1% in 2008-12) and for ciprofloxacin (from 22.3% in 1991-95 to 30.8% in 2008-12) and cefalexin (from 22.0% in 1991-95 to 30.8% in 2008-12) in the treatment of lower respiratory tract infections. Failure rates for broad spectrum penicillins, macrolides, and flucloxacillin remained largely stable. <b>Conclusions</b> From 1991 to 2012, more than one in 10 first line antibiotic monotherapies for the selected infections were associated with treatment failure. Overall failure rates increased by 12% over this period, with most of the increase occurring in more recent years, when antibiotic prescribing in primary care plateaued and then increased.
Quantitative Analysis of HER2 Receptors Expression <i>In Vivo</i> by Near-Infrared Optical Imaging.
Authors: J. Capala, V. Chernomordik, M. Hassan, R. Zielinski, A. Gandjbakhche
Journal: Cancer Research (2009)

Abstract Purpose: HER2 overexpression has been associated with a poor prognosis and resistance to therapy in breast cancer patients. However, up to now, quantitative estimates of this important characteristic have been limited to ex vivo ELISA essays of tissue biopsies and/or PET-based analysis. We aim at developing a novel approach in optical imaging, involving specific probes that do not interfere with the binding of the therapeutic agents, thus, excluding competition between therapy and imaging. Affibody-based molecular probes seem to be ideal for in vivo analysis of HER2 receptors using near-infrared optical imaging. To achieve quantification of HER2 receptors and overcome experimental uncertainties, we analyze post-injection temporal variations of the fluorescence intensity in the tumor area.Experimental design: Quantitative in vivo near-infrared imaging uses HER2-specific albumin-binding domain-fused-(ZHER2:342)2 Affibody molecules, labeled with AlexaFluor750 dye, as targeting agents. Subcutaneous tumor xenografts, expressing different levels of HER2 (BT474, MDA-MB361, MCF7, U251), are imaged at different times post-injection. Mathematical modeling allowed assessment of correlation between measured characteristics and HER2 expression levels from ex-vivo assays of the same tumors.Results: Affibody-Alexa Fluor conjugates may be used as a specific near-infrared probe for the non-invasive imaging of HER2-positive tumors, while analysis of the imaging parameters, directly estimated from the sequence of optical images, provides quantitative insight on the HER2 overexpression, as suggested by observed correlation between tumor cell amplification/overexpression of HER2, and these parameters.Conclusions: Method might potentially be employed in clinic for noninvasive monitoring of the HER2 expression variation in response to therapeutic intervention. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5002.
Metabolic and immunologic features of Chinese patients with atypical diabetes mellitus.
Authors: K C Tan, I R Mackay, P Z Zimmet, B R Hawkins, K S Lam
Journal: Diabetes Care (2000)

OBJECTIVE: To determine whether atypical diabetes mellitus (ADM) is present in the Chinese population in Hong Kong. RESEARCH DESIGN AND METHODS: The records of Chinese patients who attended the Diabetes Clinic at Queen Mary Hospital were reviewed. We identified 11 patients who initially presented with acute diabetic ketoacidosis but subsequently displayed clinical features more typical of type 2 diabetes. Metabolic studies and HLA typing were performed to characterize this group of Chinese patients with ADM. RESULTS: C-peptide response of the patients with ADM 1 h after a standard meal was intermediate between that of type 1 diabetic patients (matched for age and duration of diabetes) and that of nondiabetic control subjects (matched for age and BMI) (analysis of variance, P = 0.02). Insulin sensitivity measured by a short insulin tolerance test was not significantly different between patients with ADM and their matched nondiabetic control subjects. HLA typing showed that none of the patients with ADM had the DR3 allele and that the frequency of DR9 was not increased. Only one patient had significantly increased levels of antibodies to GAD and islet cell antigen 512. CONCLUSIONS: ADM, which was first described in African-Americans, is seen also in Chinese subjects. These patients have significant residual C-peptide secretory capacity and should not be misdiagnosed and treated as patients with type 1 diabetes with life-long insulin therapy.
A Single-Nucleotide Polymorphism in the Aromatase Gene Is Associated with the Efficacy of the Aromatase Inhibitor Letrozole in Advanced Breast Carcinoma
Authors: Ramon Colomer, Mariano Monzo, Ignasi Tusquets, Juli Rifa, José M. Baena, Agusti Barnadas, Lourdes Calvo, Francisco Carabantes, Carmen Crespo, Montserrat Muñoz, Antonio Llombart, Arrate Plazaola, Rosa Artells, Monstsrrat Gilabert, Belen Lloveras, Emilio Alba
Journal: Clinical Cancer Research (2008)

Abstract Purpose: To evaluate the efficacy of treatment with the aromatase inhibitor letrozole in breast cancer patients segregated with respect to DNA polymorphisms of the aromatase gene CYP19. Patients and Methods: Postmenopausal patients (n = 67) with hormone receptor–positive metastatic breast cancer were treated with the aromatase inhibitor letrozole. PCR allelic discrimination was used to examine three single-nucleotide polymorphisms (SNP) in DNA obtained from breast carcinoma tissue. Two SNPs analyzed (rs10046 and rs4646) were located in the 3′ untranslated region and one (rs727479) was in the intron of the aromatase CYP19 gene. The primary end point of treatment efficacy was time to progression (TTP). Results: Median age was 62 years and median number of metastatic sites was 2. Observed allelic SNP frequencies were rs10046, 71%; rs4646, 46%; and rs727479, 63%. Of the 67 patients, 65 were evaluable for efficacy. Median TTP was 12.1 months. We observed no relationship between TTP and the rs10046 or rs727479 variants. In contrast, we found that TTP was significantly improved in patients with the rs4646 variant, compared with the wild-type gene (17.2 versus 6.4 months; P = 0.02). Conclusion: In patients with hormone receptor–positive metastatic breast cancer treated with the aromatase inhibitor letrozole, the presence of a SNP in the 3′ untranslated region of the CYP19 aromatase gene is associated with improved treatment efficacy. Testing for the CYP19 rs4646 SNP as a predictive tool for breast cancer patients on antiaromatase therapy deserves prospective evaluation.
A two-dimensional video analysis of shoulder injuries in rugby tackles
Authors: J Usman, A S McIntosh
Journal: British Journal of Sports Medicine (2011)

Background Studies indicate that the risk of shoulder injury in rugby union football is high and that the tackle is a leading cause of shoulder injury. Qualitative video analysis of the game events in rugby, such as the tackle, can provide important insights into the causes of injury and injury prevention. Objective To describe shoulder injury mechanisms in rugby union football using a qualitative video analysis protocol. Design A case control study design was applied using shoulder injury and other/no-injury cases collected prospectively from Super 14 matches between 2006 and 2008. A qualitative video analysis method was applied to code skill performance and injury risk factors. Setting Professional provincial rugby competition (Super 14 competition) between 2006 and 2008. Participants Professional Australian male rugby players. Assessment of risk factors The analysis focused on the identification of shoulder loading patterns, either direct or indirect (eg, loading of the hand or arm). The characteristics were compared to an existing dataset in a case-control framework. Main outcome measurements OR for skill and specific injury risk factors were calculated. Results Two main shoulder injury mechanisms were (1) falling on an outstretched hand during a tackle and (2) direct impact to the tip of the shoulder during a tackle causing injuries to the glenohumeral joint and the acromioclavicular joint. Conclusion The results provided valuable information in understanding the mechanism of shoulder injuries in rugby union football. Improvements in shoulder padding and tackle skills, for both the ball carrier and tackler, are required to reduce the incidence of shoulder injury.
Characterization of a right atrial subsidiary pacemaker and acceleration of the pacing rate by HCN over-expression
Authors: Gwilym M. Morris, Alicia D'Souza, Halina Dobrzynski, Ming Lei, Moinuddin Choudhury, Rudi Billeter, Yelena Kryukova, Richard B. Robinson, Paul A. Kingston, Mark R. Boyett
Journal: Cardiovascular Research (2013)

Although the right atrium (RA contains subsidiary atrial pacemaker (SAP) tissue that can take over from the sinoatrial node (SAN) in sick sinus syndrome (SSS), SAP tissue is bradycardic. Little is known about SAP tissue and one aim of the study was to characterize ion channel expression to obtain insight into SAP pacemaker mechanisms. A second aim was to determine whether HCN over-expression (a 'biopacemaker'-like strategy) can accelerate the pacemaker rate producing a pacemaker that is similar in nature to the SAN. SAP tissue was isolated from the rat and the leading pacemaker site was characterized. Cell size at the leading pacemaker site in the SAP was smaller than in the RA and comparable to that in the SAN. mRNA levels showed the SAP to be similar to, but distinct from, the SAN. For example, in the SAN and SAP, expression of Tbx3 and HCN1 was higher and Nav1.5 and Cx43 lower than in the RA. Organ-cultured SAP tissue beat spontaneously, but at a slower rate than the SAN. Adenovirus-mediated gene transfer of HCN2 and the chimeric protein HCN212 significantly increased the pacemaker rate of the SAP close to that of the native SAN, but HCN4 was ineffective. SAP tissue near the inferior vena cava is bradycardic, but shares characteristics with the SAN. Pacing can be accelerated by the over-expression of HCN2 or HCN212. This provides proof of concept for the use of SAP tissue as a substrate for biopacemaking in the treatment of SSS.
Pathway-Based Serum microRNA Profiling and Survival in Patients with Advanced Stage Non–Small Cell Lung Cancer
Authors: Yan Wang, Jian Gu, Jack A. Roth, Michelle A.T. Hildebrandt, Scott M. Lippman, Yuanqing Ye, John D. Minna, Xifeng Wu
Journal: Cancer Research (2013)

Abstract This study was designed to identify TGF-β signaling pathway-related serum microRNAs (miRNA) as predictors of survival in advanced non–small cell lung cancer (NSCLC). Serum samples from 391 patients with advanced NSCLC were collected before treatment. Global miRNA microarray expression profiling based on sera from four patients with good survival (&amp;gt;24 months) and four patients with poor survival (&amp;lt;6 months) was used to identify 140 highly expressed serum miRNAs, among which 35 miRNAs had binding sites within the 3′-untranslated regions of a panel of 11 genes in the TGF-β signaling pathway and were assayed by quantitative RT-PCR for their associations with survival in a training (n = 192) and testing set (n = 191). Out of the 35 miRNAs, survival analysis using Cox regression model identified 17 miRNAs significantly associated with 2-year patient survival. MiR-16 exhibited the most statistically significant association: high expression of miR-16 was associated with a significantly better survival [adjusted hazard ratio (HR) = 0.4, 95% confidence interval (CI): 0.3–0.5]. A combined 17-miRNA risk score was created that was able to identify patients at the highest risk of death. Those with a high-risk score had a 2.5-fold increased risk of death compared with those with a low risk score (95% CI: 1.8–3.4; P = 1.1 × 10−7). This increase in risk of death was corresponding to a 7.8-month decrease in median survival time (P = 9.5 × 10−14). Our results suggest that serum miRNAs could serve as predictors of survival for advanced NSCLC. Cancer Res; 73(15); 4801–9. ©2013 AACR.
Enhanced Efficacy of Therapeutic Cancer Vaccines Produced by Co-Treatment with<i>Mycobacterium tuberculosis</i>Heparin-Binding Hemagglutinin, a Novel TLR4 Agonist
Authors: In Duk Jung, Soo Kyung Jeong, Chang-Min Lee, Kyung Tae Noh, Deok Rim Heo, Yong Kyoo Shin, Cheol-Heui Yun, Won-Jung Koh, Shizuo Akira, Jake Whang, Hwa-Jung Kim, Won Sun Park, Sung Jae Shin, Yeong-Min Park
Journal: Cancer Research (2011)

Effective activation of dendritic cells (DCs) toward T helper (Th)-1 cell polarization would improve DC-based antitumor immunotherapy, helping promote the development of immunotherapeutic vaccines based on T-cell immunity. To achieve this goal, it is essential to develop effective immune adjuvants that can induce powerful Th1 cell immune responses. The pathogenic organism Mycobacterium tuberculosis includes certain constitutes, such as heparin-binding hemagglutinin (HBHA), that possess a strong immunostimulatory potential. In this study, we report the first clarification of the functions and precise mechanism of HBHA in immune stimulation settings relevant to cancer. HBHA induced DC maturation in a TLR4-dependent manner, elevating expression of the surface molecules CD40, CD80, and CD86, MHC classes I and II and the proinflammatory cytokines IL-6, IL-12, IL-1β, TNF-α, and CCR7, as well as stimulating the migratory capacity of DCs in vitro and in vivo. Mechanistic investigations established that MyD88 and TRIF signaling pathways downstream of TLR4 mediated secretion of HBHA-induced proinflammatory cytokines. HBHA-treated DCs activated naïve T cells, polarized CD4(+) and CD8(+) T cells to secrete IFN-γ, and induced T-cell-mediated cytotoxicity. Notably, systemic administration of DCs that were HBHA-treated and OVA(251-264)-pulsed ex vivo greatly strengthened immune priming in vivo, inducing a dramatic regression of tumor growth associated with long-term survival in a murine E.G7 thymoma model. Together, our findings highlight HBHA as an immune adjuvant that favors Th1 polarization and DC function for potential applications in DC-based antitumor immunotherapy.
Patients with cystic fibrosis should not be intubated and ventilated
Authors: Mark Rosenthal
Journal: Journal of the Royal Society of Medicine (2010)

The use of pro–con debates is one of the most useful ways of learning about a difficult subject as debating a position one may or may not agree with allows one to look at the facts with a more critical eye and allows the audience to hear both sides of an issue rarely present in a guest lecture where only a single narrative argument is usually promulgated. There should be more of them.
Escape of mouse mastocytoma P815 after nearly complete rejection is due to antigen-loss variants rather than immunosuppression.
Authors: C Uyttenhove, J Maryanski, T Boon
Journal: The Journal of Experimental Medicine (1983)

Even though mastocytoma P815 often undergoes a nearly complete rejection in syngeneic mice, the tumor cells almost always escape to form progressive tumors. We found that this was not due to the establishment of an immunosuppressed state because genetically marked P815 cells, that were injected in mice where tumor escape was occurring, were readily rejected. An analysis of escaping tumor cell populations with anti-P815 cytolytic T lymphocyte (CTL) clones showed the presence of stable resistant variants. Using antigen-loss variants found in escaping populations or selected in vitro with CTL clones, we were able to define four different tumor-associated antigenic specificities, each recognized by a specific CTL clone. One of these specificities was absent from all escaping tumor cells and another had been lost by some of them.
Oesophageal pH monitoring is of limited value in the diagnosis of "reflux-cough"
Authors: R.N. Patterson
Journal: European Respiratory Journal (2004)

Reflux-cough is a diagnosis based on demonstrating both gastro-oesophageal reflux and a positive response to anti-reflux therapy. The authors sought to determine early and long-term response to therapy in patients with a "positive" 24 h oesophageal pH study, and identify any features which might predict response. Patients with chronic cough were recruited from July 1998 to July 2002. Those with a positive pH study were given dietary advice and an 8-week trial of omeprazole (20 mg <i>b.i.d.</i>). Response was judged after 8 weeks (clinical follow-up), and at long-term follow-up (telephone questionnaire). A total of 146 patients underwent pH monitoring with 82 (56.2%) "positive" studies. Follow-up data was available in 60 patients, with 49 receiving anti-reflux therapy, of which 20 (40.8%) reported a positive treatment response. At long-term follow-up (median 30 months), there was a significantly lower response (14 out of 49, 28.5%), with no significant difference in either acid exposure times (distal/proximal) or symptom correlation between responders and nonresponders at early or long-term follow-up. In conclusion, despite "positive" pH studies, over half of the patients (55.1%) failed torespond to therapy. No features on pH monitoring accurately predicted response. Short-term response did not predict long-term response. The precise role for pH monitoring in the assessment of chronic cough remains to be defined.
Effects of Blood Pressure Lowering on Cerebral White Matter Hyperintensities in Patients With Stroke
Authors: Carole Dufouil, John Chalmers, Oguzhan Coskun, Véronique Besançon, Marie-Germaine Bousser, Pierre Guillon, Stephen MacMahon, Bernard Mazoyer, Bruce Neal, Mark Woodward, Nathalie Tzourio-Mazoyer, Christophe Tzourio
Journal: Circulation (2005)

The prevalence of white matter hyperintensities (WMHs) detected on cerebral MRI is associated with hypertension, but it is not known whether blood pressure lowering can arrest their progression. We report here the results of an MRI substudy of PROGRESS (Perindopril Protection Against Recurrent Stroke Study), a randomized trial of blood pressure lowering in subjects with cerebrovascular disease.The substudy comprised 192 participants who had a cerebral MRI both at baseline and after a mean follow-up time of 36 months (SD=6.0 months). At the first MRI, WMHs were graded with a visual rating scale from A (no WMH) to D (severe WMH). Participants were assigned to a combination of perindopril plus indapamide (or their placebos; 58%) or to single therapy with perindopril (or placebo). At the time of the second MRI, the blood pressure reduction in the active arm compared with the placebo arm was 11.2 mm Hg for systolic blood pressure and 4.3 mm Hg for diastolic blood pressure. Twenty-four subjects (12.5%) developed new WMHs at follow-up. The risk of new WMH was reduced by 43% (95% CI -7% to 89%) in the active treatment group compared with the placebo group (P=0.17). The mean total volume of new WMHs was significantly reduced in the active treatment group (0.4 mm3 [SE=0.8]) compared with the placebo group (2.0 mm3 [SE=0.7]; P=0.012). This difference was greatest for patients with severe WMH at entry, 0.0 mm3 (SE=0) in the active treatment group versus 7.6 mm3 (SE=1.0) in the placebo group (P<0.0001).These results indicate that an active blood pressure-lowering regimen stopped or delayed the progression of WMHs in patients with cerebrovascular disease.
Diazepam Treatment of Early Signs of Exacerbation in Schizophrenia
Authors: William T. Carpenter, Robert W. Buchanan, Brian Kirkpatrick, Alan F. Breier
Journal: American Journal of Psychiatry (1999)

Therapeutic intervention at the earliest phase of symptom exacerbation in schizophrenia is an important clinical need, but specific pharmacotherapeutic interventions for this phase of illness have not been established. This study examined diazepam efficacy for this phase of treatment.A double-blind, randomized clinical trial with 53 schizophrenic patients compared diazepam with placebo (with fluphenazine treatment for a comparison group). Treatment was initiated at the earliest signs of exacerbation, and symptom progression was the dependent measure used to evaluate efficacy.Diazepam was statistically superior to placebo in preventing symptom progression and was comparable to fluphenazine.Efficacy data support the use of diazepam in treating prodromal and early warning signs of symptom exacerbation in schizophrenia. This therapeutic strategy may be especially important for patients who refuse antipsychotic drugs or as a supplemental approach in a treatment plan that emphasizes low-dose antipsychotic therapy.
Inflammatory mediators in human acute pancreatitis: clinical and pathophysiological implications
Authors: J Mayer
Journal: Gut (2000)

<h3>BACKGROUND</h3> The time course and relationship between circulating and local cytokine concentrations, pancreatic inflammation, and organ dysfunction in acute pancreatitis are largely unknown. <h3>PATIENTS AND METHODS</h3> In a prospective clinical study, we measured the proinflammatory cytokines interleukin (IL)-1β, IL-6 and IL-8, the anti-inflammatory cytokine IL-10, interleukin 1β receptor antagonist (IL-1RA), and the soluble IL-2 receptor (sIL-2R), and correlated our findings with organ and systemic complications in acute pancreatitis. In 51 patients with acute pancreatitis admitted within 72 hours after the onset of symptoms, these parameters were measured daily for seven days. In addition, 33 aspirates from ascites and the lesser sac were measured. <h3>RESULTS</h3> Sixteen patients had mild acute pancreatitis (AP) and 35 severe AP (Atlanta classification); 18 patients developed systemic complications requiring treatment. All mediators were increased in AP. sIL-2R, IL-10, and IL-6 were significantly elevated in patients with distant organ failure. An imbalance in IL-1β/IL-1RA was found in severe AP and pulmonary failure. Peak serum sIL-2R predicted lethal outcome and IL-1RA was an early marker of severity. IL-6 was the best prognostic parameter for pulmonary failure. <h3>CONCLUSION</h3> Our results suggest that local mediator release, with a probable IL-1β-IL-1RA imbalance in severe cases, is followed by the systemic appearance of pro- and anti-inflammatory mediators. The pattern of local and systemic mediators in complicated AP suggests a role for systemic lymphocyte activation (triggered by local release of mediators) in distant organ complications in severe AP.