tbuckley/cabot-search huggingface dataset:
Preserving professional credibility: grounded theory study of medical trainees' requests for clinical support
Authors: T. J T Kennedy, G. Regehr, G R. Baker, L. Lingard
Journal: BMJ (2009)

<b>Objective</b> To develop a conceptual framework of the influences on medical trainees' decisions regarding requests for clinical support from a supervisor. <b>Design</b> Phase 1: members of teaching teams in internal and emergency medicine were observed during regular clinical activities (216 hours) and subsequently completed brief interviews. Phase 2: 36 in depth interviews were conducted using videotaped vignettes to probe tacit influences on decisions to request support. Data collection and analysis used grounded theory methods. <b>Setting</b> Three teaching hospitals in an urban setting in Canada. <b>Participants</b> 124 members of teaching teams on general internal medicine wards and in the emergency department, comprising 31 attending physicians, 57 junior and senior residents, 28 medical students, and eight nurses. Purposeful sampling to saturation was conducted. <b>Results</b> Trainees' decisions about whether or not to seek clinical support were influenced by three issues: the clinical question (clinical importance, scope of practice), supervisor factors (availability, approachability), and trainee factors (skill, desire for independence, evaluation). Trainees perceived that requesting frequent/inappropriate support threatened their credibility and used rhetorical strategies to preserve credibility. These strategies included building a case for the importance of requests, saving requests for opportune moments, making a plan before requesting support, and targeting requests to specific team members. <b>Conclusions</b> Trainees consider not only clinical implications but also professional credibility when requesting support from clinical supervisors. Exposing the complexity of this process provides the opportunity to make changes to training programmes to promote timely supervision and provides a framework for further exploration of the impact of clinical training on quality of care of patients.
Microbial Variome Database: Point Mutations, Adaptive or Not, in Bacterial Core Genomes
Authors: Sujay Chattopadhyay, Fred Taub, Sandip Paul, Scott J. Weissman, Evgeni V. Sokurenko
Journal: Molecular Biology and Evolution (2013)

Analysis of genetic differences (gene presence/absence and nucleotide polymorphisms) among strains of a bacterial species is crucial to understanding molecular mechanisms of bacterial pathogenesis and selecting targets for novel antibacterial therapeutics. However, lack of genome-wide association studies on large and epidemiologically well-defined strain collections from the same species makes it difficult to identify the genes under positive selection and define adaptive polymorphisms in those genes. To address this need and to overcome existing limitations, we propose to create a "microbial variome"—a species-specific resource database of genomic variations based on molecular evolutionary analysis. Here, we present prototype variome databases of Escherichia coli and Salmonella enterica subspecies enterica (http://depts.washington.edu/sokurel/variome, last accessed March 26, 2013). The prototypes currently include the point mutations data of core protein-coding genes from completely sequenced genomes of 22 E. coli and 17 S. enterica strains. These publicly available databases allow for single- and multiple-field sorting, filtering, and searching of the gene variability data and the potential adaptive significance. Such resource databases would immensely help experimental research, clinical diagnostics, epidemiology, and environmental control of human pathogens.
Surgical treatment of chronic thromboembolic pulmonary hypertension
Authors: David P. Jenkins, Michael Madani, Eckhard Mayer, Kim Kerr, Nic Kim, Walter Klepetko, Marco Morsolini, Philippe Dartevelle
Journal: European Respiratory Journal (2012)

It is likely that chronic thromboembolic pulmonary hypertension (CTEPH) is more prevalent than currently recognised. Imaging studies are fundamental to decision making with respect to operability. All patients with suspected CTEPH should be referred to an experienced surgical centre. Currently, there is no risk scoring stratification system to guide operability assessment and it is predominantly based on surgical experience. The aim of pulmonary endarterectomy (PEA) is the removal of obstructive material to immediately reduce pulmonary vascular resistance. PEA affords the best chance of cure, but is difficult to perfect. Recognition and clearance of distal segmental and subsegmental disease is the main problem. The basic surgical techniques include: median sternotomy incision, cardiopulmonary bypass, arteriotomy incisions within pericardium, and a true endarterectomy with meticulous full distal dissection. Deep hypothermic circulatory arrest is recommended as the best means of reducing blood flow in the pulmonary artery to allow a clear field for dissection. In the recent PEACOG (PEA and COGnition) trial there was no evidence of cognitive impairment post-PEA. Reperfusion pulmonary oedema and residual pulmonary hypertension are unique post-operative complications post-PEA and are associated with increased mortality. However, in-hospital mortality is now <5% in experienced centres.
CUTANEOUS HYPERSENSITIVITY REACTIONS TO CELLULAR ISOANTIGENS IN RATS
Authors: J. W. Streilein, R. E. Billingham
Journal: The Journal of Experimental Medicine (1967)

Rats have been shown to be capable of displaying the various kinds of delayed cutaneous hypersensitivity reactions attributable to transplantation immunity previously described in guinea pigs, hamsters, rabbits, dogs, and man. The rat is unlike most other species in that much larger numbers of lymphoid cells are needed to incite these cutaneous reactions. With direct, transfer, or normal lymphocyte transfer reactions, the cutaneous responses were greater when donor and recipient differed at the Ag-B histocompatibility locus than when donor and recipient shared the same Ag-B alleles. An experiment was performed in which adult rats of a genetically defined backcross population, resulting from matings between DA and (DA x Lewis) F(1) hybrid rats, were inoculated intradermally with lymph node cells from DA rats sensitized against tissues from Lewis-strain donors. Some of the R(2) animals gave a biphasic transfer reaction with peak reactivities occurring first at 48 hr and recurring at 96-120 hr, while the others lacked this second component. Hemagglutination tests revealed that the R(2) rats giving the biphasic response possessed the Ag-B,1 antigen, which is also present in Lewis rats, whereas rats which gave monophasic reactions were homozygous for the Ag-B,4 antigenic determinant which is present in the DA strain. This suggested that the recall flare at 96-120 hr reflects proliferative activity on the part of the inoculated cells confronted by the disparate Ag-B isoantigen in the host's dermis. Skin homografts from R(1) animals bearing the Ag-B,1 antigen were uniformly rejected by DA hosts in 11 days or less, while grafts from backcross animals homozygous for the Ag-B,4 antigen usually lived longer, being rejected in 9 to 27 days. Evidence is also presented which suggests that specific isoantibodies may act synergistically with immune lymphocytes to bring about cutaneous inflammatory reactions in the rat.
Coordinated increase of γ-secretase reaction products in the plasma of some female Japanese sporadic Alzheimer's disease patients: quantitative analysis of p3-Alcα with a new ELISA system
Authors: Tomoko Konno, Saori Hata, Yukiko Hamada, Yuko Horikoshi-Sakuraba, Tadashi Nakaya, Yuhki Saito, Tohru Yamamoto, Takayuki Yamamoto, Masahiro Maeda, Takeshi Ikeuchi, Sam Gandy, Hiroyasu Akatsu, Toshiharu Suzuki
Journal: Molecular Neurodegeneration (2011)

Aggregatable amyloid β-peptide (Aβ) and non-aggregatable p3-Alcα are metabolic products of the γ-secretase cleavage of amyloid β-protein precursor (APP) and Alcadeinα (Alcα), respectively. Familial AD (FAD) -linked mutations in the presenilin 1 or 2 (PS1 or PS2) component of γ-secretase can cause alternative intramembranous processing of APP and Alcα, leading to a coordinated generation of variants of both Aβ and p3-Alcα. Variant Alcα peptides have been observed in the cerebrospinal fluid (CSF) of patients with mild cognitive impairment and sporadic Alzheimer's disease (AD). Since, like APP, Alcα is largely expressed in brain, one might predict that alternative processing of Alcα would be reflected in body fluids of some AD patients. These patients with misprocessing of multiple γ-secretase substrates might define an endophenotype of p3-Alcα, in whom AD is due either to dysfunction of γ-secretase or to a disorder of the clearance of hydrophobic peptides such as those derived from transmembrane domains.We developed a simple procedure for extraction of p3-Alcα from plasma and for analyzing this extract in a sensitive, p3-Alcα-specific sandwich enzyme-linked immunosorbent assay (ELISA) system. Plasma p3-Alcα levels and Aβ40 levels were examined in sporadic AD subjects from two independent Japanese cohorts. In some of these patients, levels of plasma p3-Alcα were significantly higher, and were accompanied by parallel changes in Aβ40 levels. This AD-related difference was more marked in female subjects, but this phenomenon was not observed in subjects with frontotemporal lobar degeneration (FTLD).Reagents and procedures have been established that enable extraction of p3-Alcα from plasma and for quantification of plasma p3-Alcα levels by ELISA. Some populations of AD subjects apparently show increased levels of both p3-Alcα and Aβ40. Quantification of p3-Alcα level may be useful as a readily accessible biomarker for a population of sporadic AD patients in which disease pathogenesis is associated with either dysfunction of γ-secretase or with a disorder of the clearance of transmembrane domain-derived peptides.
Differences in persistence of measles, mumps, rubella, diphtheria and tetanus antibodies between children with rheumatic disease and healthy controls: a retrospective cross-sectional study
Authors: Marloes W Heijstek, Pieter GM van Gageldonk, Guy AM Berbers, Nico M Wulffraat
Journal: Annals of the Rheumatic Diseases (2011)

<h3>Objectives</h3> To compare the persistence of measles, mumps, rubella, diphtheria and tetanus antibodies between patients with juvenile idiopathic arthritis (JIA) and healthy controls. <h3>Methods</h3> Measles, mumps, rubella (MMR) and diphtheria–tetanus toxoid (DT)-specific immunoglobulin G antibody concentrations were compared between 400 patients with JIA and 2176 healthy controls aged 1–19 years. Stored patient samples from the period 1997–2006 were obtained from one Dutch centre for paediatric rheumatology. Healthy control samples had been evaluated previously in a nationwide cohort. Participants had been vaccinated according to the Dutch immunisation programme. Antibody concentrations were measured by ELISA (MMR) or multiplex immunoassay (DT). <h3>Results</h3> Corrected for age and the number of vaccinations, lower vaccine-specific geometric mean antibody concentrations (GMC) were found in patients with JIA against mumps, rubella, diphtheria and tetanus (p≤0.001). Measles-specific GMC were higher (p&lt;0.001) compared with healthy controls. The prevalence of protective antibody concentrations was significantly lower in patients for mumps (OR 0.4; 95% CI 0.3 to 0.6), rubella (OR 0.4; 0.3 to 0.7), diphtheria (OR 0.1; 0.06 to 0.2) and tetanus (OR 0.1; 0.05 to 0.3). Seroprotection rates against measles did not differ between patients and healthy controls (OR 1.4; 0.8 to 2.5). Methotrexate and glucocorticosteroid use did not affect pathogen-specific GMC or seroprotection rates. <h3>Conclusions</h3> Patients with JIA had lower antibody concentrations and seroprotection rates than healthy controls against mumps, rubella, diphtheria and tetanus, but not measles. In these patients, regular assessment of antibody concentrations and further research on responses to other (booster) vaccines are warranted.
Inhaled salbutamol does not affect athletic performance in asthmatic and non-asthmatic cyclists
Authors: Sarah Koch, Martin J MacInnis, Benjamin C Sporer, James L Rupert, Michael S Koehle
Journal: British Journal of Sports Medicine (2013)

Rationale Salbutamol may affect lung function and exercise performance differently in individuals with and without asthma. Objectives To compare the effects of inhaled salbutamol on lung function, exercise performance and respiratory parameters during cycling exercise in athletes with a positive response to a eucapnic voluntary hyperpnoea (EVH+) and negative (EVH−) challenge, indicative of exercise-induced bronchoconstriction. Methods In a randomised controlled trial with a crossover design, a total of 49 well-trained male athletes (14 EVH+ and 35 EVH−) performed two simulated 10 km time-trials on a cycle ergometer 60 min after the inhalation of either 400 μg of salbutamol or a placebo. Lung function, assessed by forced expiratory volume in 1 s, was measured immediately before and 30 min after inhalation. Performance was measured by mean power output. Measurements &amp; main results Despite a significant increase in lung function after the inhalation of salbutamol compared to the placebo (p&lt;0.001), salbutamol did not affect athletes’ perceptions of dyspnoea (p&gt;0.05) or leg exertion (p&gt;0.05) during exercise. Salbutamol did not affect mean power output: EVH+ and EVH− athletes averaged 4.0 (0.5) and 4.1 (0.5) W/kg after salbutamol and 4.0 (0.5) W/kg and 4.0 (0.4) W/kg after placebo, respectively (p&gt;0.05 for each comparison). Conclusions The inhalation of salbutamol induced a significant increase in resting lung function in EVH+ and EVH− athletes but this improvement in lung function did not translate to improved exercise performance. Salbutamol had no discernible effect on key ventilatory and exercise parameters regardless of EVH challenge outcome.
Evidence for a B-cell -like helper function in mixed lymphocyte culture between immunocompetent thymus cells.
Authors: J W Kyminski, R T Smith
Journal: The Journal of Experimental Medicine (1975)

The immunocompetent subpopulation by mouse thymus cell (TH-2) was isolated by buoyant density centrifugation and by hydrocortisone pretreatment. TH-2 cells undergo a proliferative one-way or two-way mixed lymphocyte culture (MLC) response only when cultured with allogeneic or congenic peripheral lymphoid cells. However, mixtures of allogeneic TH-2 cells alone do not proliferate in either one-way or two-way MLC reactions. Such MLC mixtures are proliferative only if mitomycin-blocked peripheral lymphoid cells are also present in the mixture. The peripheral helper cell has been found to be of low net density, non-adherent, insensitive to anti-thy-1 serum cytotoxicity, but sensitive to the cytotoxic effets of anti-immunoglobulin serume plus complement. The helper effect does not depend on proliferation nor does it appear to involve demonstrable soluble mediators. The nature of failure of MLC between TH-2 subpopulations appears to be dependent on the exppression of some product of the K, I regions of the H-2 locus. Possible mechanisms by which a B-cell-like helper cell triggers TH-2 proliferation are discussed terms of the present knowledge of specific alloantigen receptor on T and B cells, and the immunoglobulin Fc region receptors on T cells.
Immunology of Respiratory Viral Infections
Authors: R C Welliver, P L Ogra
Journal: Annual Review of Medicine (1988)

Viral infections of the respiratory tract represent a major cause of morbidity and inconvenience in all age groups. In addition, several thousand deaths can be attributed annually to these infections, especially those occurring at the extremes of age. Knowledge of the nature of the immune response in the respiratory tract is essential to vaccine development and to understanding disease pathogenesis. This chapter describes advances in our understanding of how the immune system contributes to eradication of infection, prevention of subsequent infection, and pathogenesis of disease itself.
Laser-assisted uvulopalatoplasty for snoring: does it meet the expectations?
Authors: F. Larrosa, L. Hernandez, A. Morello, E. Ballester, L. Quinto, J.M. Montserrat
Journal: European Respiratory Journal (2004)

The high prevalence of habitual snoring (35% of the general population) and the increasing demand for an effective treatment have led, in the last decade, to the generalisation of laser-assisted uvulopalatoplasty (LAUP). However, acceptable studies on its effectiveness are lacking. The present randomised, placebo-controlled study included 25 nonapnoeic and mild obstructive sleep apnoea snorers to evaluate LAUP effectiveness for snoring. Group I received a one-stage LAUP treatment and group II a placebo (simulated snore surgery followed by an oral placebo). Before each treatment and 3 months after, the variables and procedures assessed were: body weight; sleepiness (Epworth sleepiness scale); quality of life (SF‐36); subjective snoring intensity (0–10 analogue scale); objective snoring intensity (average decibel intensity); snoring index (number of snores per hour); and apnoea/hypopnea index. No differences were observed in body weight, sleepiness, quality of life, subjective and objective intensity, and frequency of snoring, and apnoea/hypopnea index between the groups before and 3 months after treatment. In conclusion, this study provides evidence of the lack of effectiveness of one-stage laser-assisted uvulopalatoplasty for snoring in nonapnoeic and mild obstructive sleep apnoea patients, with the result that it does not meet the expectations generated by the procedure.
CD4+CD25+ Regulatory T Cells Do Not Significantly Contribute to Direct Pathway Hyporesponsiveness in Stable Renal Transplant Patients
Authors: David S. Game, Maria P. Hernandez-Fuentes, Afzal N. Chaudhry, Robert I. Lechler
Journal: Journal of the American Society of Nephrology (2003)

CD4(+)CD25(+) regulatory T cells have been shown to regulate a variety of autoimmune and allogeneic responses in mice and humans. The role of CD4(+)CD25(+) cells in regulating alloresponses in human transplant recipients remains uncertain. Previous research has demonstrated a reduced frequency of direct pathway donor-specific T cells in renal transplant recipients when compared with the frequency of T cells reactive to an HLA-matched third party. A number of mechanisms have been proposed to account for this finding; the purpose of this study was to determine whether CD4(+)CD25(+) cells play a significant role. Twelve stable renal transplant patients were investigated using limiting dilution assay (LDA) and ELISPOT for interferon-gamma to determine the effect of depleting CD4(+)CD25(+) cells on the direct pathway alloresponse. The percentage of CD4(+)CD25(+) cells in the peripheral blood of the study patients was equivalent to that of healthy controls. Furthermore, in no case did depletion of CD4(+)CD25(+) cells significantly increase the frequency of donor-specific T cells detected by LDA. This was also found with ELISPOT in all except one patient, in whom depletion revealed an increased frequency of alloreactive T cell to both donor and third party. Finally, kinetic analysis of the LDA data did not indicate regulation against donor when compared with third party. It is concluded that the action of CD4(+)CD25(+) regulatory cells is not the main mechanism of donor-specific hyporesponsiveness in the direct pathway of allorecognition.
Tumor-Infiltrating Lymphocytes and Response to Neoadjuvant Chemotherapy With or Without Carboplatin in Human Epidermal Growth Factor Receptor 2–Positive and Triple-Negative Primary Breast Cancers
Authors: Carsten Denkert, Gunter von Minckwitz, Jan C. Brase, Bruno V. Sinn, Stephan Gade, Ralf Kronenwett, Berit M. Pfitzner, Christoph Salat, Sherene Loi, Wolfgang D. Schmitt, Christian Schem, Karin Fisch, Silvia Darb-Esfahani, Keyur Mehta, Christos Sotiriou, Stephan Wienert, Peter Klare, Fabrice André, Frederick Klauschen, Jens-Uwe Blohmer, Kristin Krappmann, Marcus Schmidt, Hans Tesch, Sherko Kümmel, Peter Sinn, Christian Jackisch, Manfred Dietel, Toralf Reimer, Michael Untch, Sibylle Loibl
Journal: Journal of Clinical Oncology (2014)

Purpose Modulation of immunologic interactions in cancer tissue is a promising therapeutic strategy. To investigate the immunogenicity of human epidermal growth factor receptor 2 (HER2) –positive and triple-negative (TN) breast cancers (BCs), we evaluated tumor-infiltrating lymphocytes (TILs) and immunologically relevant genes in the neoadjuvant GeparSixto trial. Patients and Methods GeparSixto investigated the effect of adding carboplatin (Cb) to an anthracycline-plus-taxane combination (PM) on pathologic complete response (pCR). A total of 580 tumors were evaluated before random assignment for stromal TILs and lymphocyte-predominant BC (LPBC). mRNA expression of immune-activating (CXCL9, CCL5, CD8A, CD80, CXCL13, IGKC, CD21) as well as immunosuppressive factors (IDO1, PD-1, PD-L1, CTLA4, FOXP3) was measured in 481 tumors. Results Increased levels of stromal TILs predicted pCR in univariable (P &lt; .001) and multivariable analyses (P &lt; .001). pCR rate was 59.9% in LPBC and 33.8% for non-LPBC (P &lt; .001). pCR rates ≥ 75% were observed in patients with LPBC tumors treated with PMCb, with a significant test for interaction with therapy in the complete (P = .002) and HER2-positive (P = .006), but not the TNBC, cohorts. Hierarchic clustering of mRNA markers revealed three immune subtypes with different pCR rates (P &lt; .001). All 12 immune mRNA markers were predictive for increased pCR. The highest odds ratios (ORs) were observed for PD-L1 (OR, 1.57; 95% CI, 1.34 to 1.86; P &lt; .001) and CCL5 (OR, 1.41; 95% CI, 1.23 to 1.62; P &lt; .001). Conclusion Immunologic factors were highly significant predictors of therapy response in the GeparSixto trial, particularly in patients treated with Cb. After further standardization, they could be included in histopathologic assessment of BC.