tbuckley/cabot-search huggingface dataset:
Significance of the Isolation of <i>Candida</i> Species from Respiratory Samples in Critically Ill, Non-neutropenic Patients
Authors: MUSTAFA EL-EBIARY, ANTONI TORRES, NEUS FÁBREGAS, JORGE PUIG de la BELLACASA, JULIÁ GONZÁLEZ, JOSEP RAMIREZ, DOLORES del BAÑO, CARMEN HERNÁNDEZ, M. T. JIMÉNEZ de ANTA
Journal: American Journal of Respiratory and Critical Care Medicine (1997)

The diagnosis of pulmonary candidiasis is still controversial. We undertook a prospective study on 25 non-neutropenic, mechanically ventilated ( > 72 h) patients who died in our ICU with the aim of assessing the incidence and significance of the isolation of Candida species from quantitative cultures of immediate postmortem lung biopsies and different respiratory sampling techniques. Immediate postmortem respiratory samples (endotracheal aspirate, protected specimen brush [PSB], bronchoalveolar lavage [BAL], blind biopsies [average 14/patient], and bilateral bronchoscopically guided biopsies [two per patient]) were taken from all patients. Lung tissue specimens were histologically examined. Respiratory samples were classified as having Candida or otherwise. Ten (40%) patients had at least one pulmonary biopsy yielding Candida spp. Among these 10 patients with Candida isolates, only two had definite pulmonary candidiasis. A total of 470 microorganisms were isolated from 280 of 375 (77%) lung biopsy samples in all 25 patients. Candida species represented 9% (n = 40) of the isolates, corresponding to 10 patients (40%). In the 10 patients in whom Candida species was isolated from pulmonary biopsies, this was always associated with the isolation of the same microorganism from one of the sampling methods. Quantitative cultures of Candida species from different sampling methods correlated well among each other but could not discriminate the presence from absence of Candida pneumonia. A logistic regression model adjusted for the presence of antibiotics, days of antibiotic treatment, mechanical ventilation period, age, ARDS, parenteral nutrition, and gender did not show any independent risk factor for developing positive pulmonary samples for Candida species. The incidence of Candida isolation from pulmonary biopsies in critically ill mechanically ventilated, non-neutropenic patients who die is high (40%). However, the incidence of definite Candida pneumonia was 8%. We also found that Candida colonization is uniform throughout the different lung regions, and that the presence of Candida in respiratory samples, independently of quantitative cultures, is not a good marker of Candida pneumonia in critically ill, non-neutropenic, non-AIDS patients. El-Ebiary M, Torres A, Fàbregas N, de la Bellacasa JP, González J, Ramirez J, del Baño D, Hernández C, Jiménez de Anta MT. Significance of the isolation of Candida species from respiratory samples in critically ill, non-neutropenic patients: an immediate postmortem histologic study.
Abstract 17713: A Three year Retrospective Analysis of Adverse Cardiac Outcomes in Heart Failure Patients Using Cocaine on Beta-blockers
Authors: Bimaje Akpa, Victor Nwazue, Varija Bhoggireddy, Henry Okafor
Journal: Circulation (2014)

Background: It is an established fact that beta-blockers (BB) improve survival in patients with HFrEF. However cocaine abusers with HFrEF are currently excluded from this life-saving treatment due to concerns with a theoretical risk of unopposed alpha adrenergic receptor-mediated coronary vasospasms and possible myocardial infarctions (MI). Our study seeks to compare heart failure (HF) outcomes in patients on beta blockers with surreptitious cocaine abuse to those not receiving beta blockers. Methods: From our HF registry, we retrospectively identified 132 patients admitted to the hospital for CHF with related complaints like chest pain or shortness of breath between 2006 and 2008 and cocaine positive drug test. We reviewed the concomitant use of BB in relation to the primary composite end points: MI, total ER visits, HF related admissions 2006-2008, ejection fraction (EF), mean BNP and all- cause mortality. Characteristics of patients with and without BB use were compared using chi-square for categorical and t-test for continuous variables. Considering the variance in baseline characteristics between patients, we also adjusted for co-founding factors like age, sex, Body mass index (BMI) and race before evaluating the independent relationship between BB use and the composite primary endpoints listed above. Results: BB were used in 60 patients (45%), no distinction was made between selective BBs or nonselective BBs. The analysis of our cohort data showed no significant difference in the number of MI (p - 0.819), ER visits (p - 0.627), HF- related admissions (p-0.382), mean BNP (p-0.480), EF (p-0.273) in HF patients using cocaine on BB vs those not on BB. Findings were similar after adjusting for cofounding variables - race, sex, BMI and race (OR for having an MI with BB use was 1.185[95% CI 0.277-5.069]). Conclusions: BB treatment of HFrEF with concomitant cocaine abuse may be safer than previously suggested. Prospectively randomized trials will be needed to clarify the safety of beta blockers in cocaine abusing HFrEF patients. Limitations: Our study was limited by the absence of distinction between selective and nonselective BB as alpha-blocking BBs like carvedilol have been proposed as safe since they can moderate the theoretical alpha mediated effects of cocaine.
Variation in lung cancer diagnosis in England
Authors: Paul Cane, Karen Linklater, George Santis, Lars Holmberg, Henrik Moller
Journal: European Respiratory Journal (2013)

Objective  There are several key investigations used in lung cancer diagnosis such as EBUS and PET scanning that some units have better access to than others. Part of the LungPath study aimed to access the degree of this inequality and measure how it affects lung cancer patients.  Method  Twenty willing NHS Trusts were randomly selected to participate in the LungPath study. Each centre agreed to submit data on each new lung cancer patient seen during the study period of six months. Data collected included anonymised pathology reports from all investigations performed along with clinical data and the dates of all radiological investigations performed. Each individual patient’s diagnostic pathway was mapped using the data collected. In addition, we collected information about typical waiting times for key investigations and whether these investigations were available on-site or at another institution. We analysed the patient pathways from the 20 different centres to see if there were differences in availability and use of  Results  We found there were dramatic differences in the availability and use of some key investigations, particularly EBUS and PET-scanning. We also found that the stage of the diagnostic pathway that these investigations were used varied and in many cases differed from national guidelines.  Conclusion  There are marked differences in the availability and use of EBUS and PET-scanning within different centres diagnosing lung cancer in England. There are implications for commissioners for more equal service provision and opportunities for education of clinicians to make best use of these resources.
Infallibility of a normal platelet count/spleen diameter ratio in ruling out oesophageal varices?
Authors: D J Brotman, R G O’Brien
Journal: Gut (2004)

We read with interest that an abnormal platelet count/spleen diameter ratio predicts the presence of oesophageal varices ( Gut 2003; 52 :1200–5). This otherwise excellent article contained a statistical error that we would like to bring to your attention.

The authors reported 100% sensitivity for the diagnostic test (platelet count/spleen diameter ratio at a cut off value of 909) in ruling out the diagnosis of oesophageal varices: all patients with varices had an abnormal ratio. The reported 95% confidence interval (CI) for the sensitivity was 100–100%. This is simply incorrect, and is was probably calculated using …
Pyridoxine-Unresponsive Homocystinuria
Authors: Vivian E. Shih, Mary L. Efron
Journal: New England Journal of Medicine (1970)

HOMOCYSTINURIA due to cystathionine synthase deficiency was recognized as an entity in 1962.1 , 2 It is characterized by dislocation of the lenses, mental retardation, skeletal abnormalities and thromboembolic phenomena. Patients may have some or all of the symptoms and signs. Vascular accident is a frequent cause of death. Methionine, the precursor of homocystine, is also present in increased amounts in the blood and urine; it is formed by the remethylation of homocysteine. Attempts to lower the accumulation of methionine and homocysteine in the body by restriction of methionine intake and high doses of pyridoxine, a cofactor for cystathionine synthase, have been . . .
Immunity conferred by smallpox vaccine
Authors: A. Jacobs
Journal: BMJ (2002)

Editor—I am disappointed that Beeching et al do not provide a reference for their statement that immunity conferred by smallpox vaccination fades after 10-20 years, or earlier in some people.1 After watching a recent BBC programme about smallpox2 I was curious to know whether the smallpox vaccination I had had in childhood would still protect me.

It has been remarkably difficult to find out. Information on the website of the Centers for Disease Control and Prevention says, “Most estimates suggest immunity from the vaccination lasts 3 to 5 years.”3 On the other hand, the World Health Organization's website says, “Anyone who has been vaccinated against smallpox . . . will have some level of protection. The vaccination may not still be fully effective, but it is likely to protect you from the worst effects of the disease.”4

There is little published work on the subject: a Medline search using the search string “smallpox AND immunity AND duration” returned only nine papers, and most of these were not relevant to the question. One of the papers found that immunity can last up to 50 years,5 which is in stark contrast to the information on the Centers for Disease Control and Prevention's website.

Instead of saying that immunity fades after 10-20 years, perhaps a more honest statement would be that the duration of immunity is unknown.
Gene therapy for cardiovascular disease: advances in vector development, targeting, and delivery for clinical translation
Authors: Melvin Y. Rincon, Thierry VandenDriessche, Marinee K. Chuah
Journal: Cardiovascular Research (2015)

Gene therapy is a promising modality for the treatment of inherited and acquired cardiovascular diseases. The identification of the molecular pathways involved in the pathophysiology of heart failure and other associated cardiac diseases led to encouraging preclinical gene therapy studies in small and large animal models. However, the initial clinical results yielded only modest or no improvement in clinical endpoints. The presence of neutralizing antibodies and cellular immune responses directed against the viral vector and/or the gene-modified cells, the insufficient gene expression levels, and the limited gene transduction efficiencies accounted for the overall limited clinical improvements. Nevertheless, further improvements of the gene delivery technology and a better understanding of the underlying biology fostered renewed interest in gene therapy for heart failure. In particular, improved vectors based on emerging cardiotropic serotypes of the adeno-associated viral vector (AAV) are particularly well suited to coax expression of therapeutic genes in the heart. This led to new clinical trials based on the delivery of the sarcoplasmic reticulum Ca2+-ATPase protein (SERCA2a). Though the first clinical results were encouraging, a recent Phase IIb trial did not confirm the beneficial clinical outcomes that were initially reported. New approaches based on S100A1 and adenylate cyclase 6 are also being considered for clinical applications. Emerging paradigms based on the use of miRNA regulation or CRISPR/Cas9-based genome engineering open new therapeutic perspectives for treating cardiovascular diseases by gene therapy. Nevertheless, the continuous improvement of cardiac gene delivery is needed to allow the use of safer and more effective vector doses, ultimately bringing gene therapy for heart failure one step closer to reality.
BMS-911543, A Selective JAK2 Inhibitor: A Multicenter Phase 1/2a Study In Myelofibrosis
Authors: Animesh Pardanani, Andrew W. Roberts, John F. Seymour, Kate Burbury, Srdan Verstovsek, Hagop M. Kantarjian, Kebede Begna, Hiroyuki Yoshitsugu, Toni Ann Gestone, Penny Phillips, Guan Xing, Gerson Peltz, Matthew V Lorenzi, Leila Alland, Adrian Woolfson, Ayalew Tefferi
Journal: Blood (2013)
Foxp3<sup>+</sup> regulatory T cells are expanded in severe atopic dermatitis patients
Authors: L. M. Roesner, S. Floess, T. Witte, S. Olek, J. Huehn, T. Werfel
Journal: Allergy (2015)

Abstract Regulatory T cells (Tregs) are known to play critical roles in homeostasis and immune responses in the skin. Whether Treg frequencies are altered in atopic dermatitis (AD) patients has been addressed by several studies, leading to conflicting results. The detection of Tregs by FOXP3 expression may lead to false‐positive results as activated T cells without regulatory function may transiently upregulate this transcription factor. In contrast, measurement of the DNA methylation status of a region within the FOXP3 locus that is selectively demethylated only in bona fide Tregs (Treg‐specific demethylated region, TSDR) represents a reliable method to quantify Tregs. Here, we measured circulating Treg frequencies of adult patients and detected a positive correlation with disease severity. Subsequent surface marker analysis revealed higher frequencies of CD45RA + CCR7 ‐ tissue‐homing Tregs in the patient group with a tendency of reduced expression of CD39 compared with healthy donors, a marker for the highly suppressive T REM subtype.
Comparison of hemodynamic effects of inhaled nitric oxide (iNO) and inhaled epoprostenol (iEPO) in patients with pulmonary hypertension (PH)
Authors: Shilpa A. DeSouza, Kristen D. Sagliani, Ioana R. Preston, Kari E. Roberts, Archan Shah, Nicholas S. Hill
Journal: European Respiratory Journal (2011)

Rationale:  Acute vasodilator testing with iNO during right heart catheterization in pulmonary arterial hypertension predicts suvival and response to calcium channel blockers. iEPO is less expensive than iNO with fewer systemic effects than intravenous EPO. We hypothesized that iEPO has similar vasodilatory efficacy as iNO and their combination has additive effects.   Methods:  Prospective double-blinded study of PH treatment-naive consecutive patients. Patients >18 years, WHO Group1-5 with pulmonary capillary wedge pressures ≤ 20 were included. Patients received iNO, iEPO and their combination in random order, with a washout phase between treatments. Hemodynamics at baseline and treatments were reported as%change, means±SD. Correlation was assessed with regression analysis. p   Results:  Patients enrolled: Group 1 (11), Group 2 (9), Group 3 (1), Group 4 (1), Group 5 (1). 2 did not complete the study (hypoxemia and dyspnea respectively). Mean pulmonary artery pressures (mPAP) in Groups 1, 2 and other groups were 47±12, 35±7 and 35±9.2. Mean pulmonary vascular resistances (PVR) were 628±352, 416±323 and 397±80. Mean cardiac outputs (CO) were 5.0±1.3, 4.7±1.3 and 4.9±0.6. The 2 vasodilators correlated significantly and did not have additive effects.   Conclusions:  iNO and iEPO have similar effects on hemodynamics in PH patients. iEPO may be a less expensive alternative.
The Role of Multidrug Resistance Efflux Pumps in Cancer: Revisiting a JNCI Publication Exploring Expression of the MDR1 (P-glycoprotein) Gene
Authors: Michael M Gottesman, Ira H Pastan
Journal: JNCI Journal of the National Cancer Institute (2015)

The Journal of the National Cancer Institute published our paper entitled “Expression of a Multidrug Resistance Gene in Human Cancers” (1) 26 years ago. It was the first systematic determination of whether the energy-dependent multidrug efflux pump P-glycoprotein (P-gp), the product of the ABCB1 (MDR1) gene, was expressed in human cancers and has been cited over 1200 times. Four hundred cancers were studied, and the conclusion was that expression was widespread both in intrinsically drug-resistant cancers such as colon, pancreatic, liver, adrenocortical, and kidney cancers, and in some cancers that acquired resistance, such as leukemias, lymphomas, breast cancer, and neuroblastoma. Other cancers at the time of initial presentation, such as lung cancers (except for neuroendocrine tumors), ovarian cancer, esophageal cancer, and mesothelioma expressed little or no P-glycoprotein. The major conclusions of this paper, which have withstood the test of time (see below) were: 1) that P-gp was expressed at levels sufficient to confer drug resistance in many different difficult-to-treat cancers, 2) that its expression appeared during the acquisition of resistance for some cancers, indicating a possible role for P-gp in acquired resistance, 3) that many cancers did not appear to express P-gp mRNA at detectable levels and therefore efforts to inhibit P-gp and reverse resistance in these cancers were unlikely to succeed, and 4) that it remained to be proven whether P-gp expression, though perhaps sufficient for drug resistance in cancers, was the main cause of resistance in any cancer. Considerable effort has been devoted to answer this last question: Are P-gp or other multidrug transporters discovered since (see below) useful targets for drug development with the possible outcome of reversing multidrug resistance in cancer?
Risk factors for and clinical implications of mixed Candida/bacterial bloodstream infections
Authors: S.-H. Kim, Y.K. Yoon, M.J. Kim, J.W. Sohn
Journal: Clinical Microbiology and Infection (2012)

Mixed Candida/bacterial bloodstream infections (BSIs) have been reported to occur in more than 23% of all episodes of candidaemia. However, the clinical implications of mixed Candida/bacterial BSIs are not well known. We performed a retrospective case-control study of all consecutive patients with candidaemia over a 5-year period to determine the risk factors for and clinical outcomes of mixed Candida/bacterial BSIs (cases) compared with monomicrobial candidaemia (controls). Thirty-seven (29%) out of 126 patients with candidaemia met the criteria for cases. Coagulase-negative staphylococci were the predominant bacteria (23%) in cases. In multivariate analysis, duration of previous hospital stay ≥7 weeks (odds ratio (OR), 2.86; 95% confidence interval (CI), 1.09-7.53), prior antibiotic therapy ≥7 days (OR, 0.33; 95% CI, 0.14-0.82) and septic shock at the time of candidaemia (OR, 2.60; 95% CI, 1.14-5.93) were significantly associated with cases. Documented clearance of candidaemia within 3 days after initiation of antifungal therapy was less frequent in cases (63% vs. 84%; p = 0.035). The difference in the rate of treatment failure at 2 weeks was not significant between cases (68%) and controls (62%; p = 0.55). The crude mortality at 6 weeks and survival through 100 days did not differ between the two patient groups (p = 0.56 and p = 0.80, respectively). Mixed Candida/bacterial BSIs showed a lower clearance rate of candidaemia during the early period of antifungal therapy, although the treatment response and survival rate were similar regardless of concurrent bacteraemia. Further studies on the clinical relevance of species-specific Candida-bacterial interactions are needed.
Resource Implications of Head Injuries on an Acute Surgical Unit
Authors: R J Li Williams, R Hittinger, G Glazer
Journal: Journal of the Royal Society of Medicine (1994)

Head injuries are expensive and demanding in terms of resources. In the UK, most are cared for outside neurosurgical centres. In the absence of specialist rehabilitation services, patients with on-going disability add to those admitted for observation and treatment on acute surgical wards. We audited the workload pattern and financial implications related to head injuries on a general surgical unit in a central London teaching hospital. Data collected prospectively at the time of admission and derived from departmental computerized information systems included clinical outcome, hospital stay and its relationship to severity of injury and other factors. Ward, departmental (accident and emergency (A & E), intensive therapy unit (ITU), radiology, and theatre) and neurosurgical referral costs were derived. Long-term social and rehabilitation costs were not calculated. Over a 6 month period 899 patients with head injuries were treated in the A & E department, of whom 156 were admitted. Of the admitted patients 68% were classified as minor; 22% as moderate; and 10% as severe head injuries. Fifty-one per cent of adult admissions were intoxicated by alcohol. Prolonged hospital stay was related to age, severity of head injury, mechanism of injury, associated injuries and preexisting neuropsychiatric conditions (including alcoholism). Six patients died. The direct cost of these head injuries patients was estimated at 173,500 pounds, during which time they occupied 7.6% of our unit's adult inpatient capacity. Twenty-four hour observation of 76 patients with minor head injuries contributed 9700 pounds (5.6%) to this figure. Associated extracranial injuries cost a further 46,500 pounds.(ABSTRACT TRUNCATED AT 250 WORDS)
Publication bias: the case for an international registry of clinical trials.
Authors: R J Simes
Journal: Journal of Clinical Oncology (1986)

A problem in evaluating different therapies from a review of clinical trials is that the published clinical trial literature may be biased in favor of positive or promising results. In this report, a model is proposed for reviewing clinical trial results which is free from publication bias based on the selection of trials registered in advance in a registry. The value of a registry is illustrated by comparing a review of published clinical trials located by a literature search with a review of registered trials contained in a cancer trials registry. Two therapeutic questions are examined: the survival impact of initial alkylating agent (AA) v combination chemotherapy (CC) in advanced ovarian cancer, and the survival impact of AA/prednisone v CC in multiple myeloma. In advanced ovarian cancer, a pooled analysis of published clinical trials demonstrates a significant survival advantage for combination chemotherapy (median survival ratio of CC to AA, 1.16; P = .02). However, no significant difference in survival is demonstrated based on a pooled analysis of registered trials (median survival ratio, 1.05; P = .25). For multiple myeloma, a pooled analysis of published trials also demonstrates a significant survival advantage for CC (median survival ratio, 1.26; P = 04), especially for poor risk patients (ratio, 1.66; P = .002). A pooled analysis of registered trials also shows a survival benefit for patients receiving combination chemotherapy (all patients, P = .06; poor risk, P = .03), but the estimated magnitude of the benefit is reduced (all patients: ratio, 1.11; poor risk: ratio, 1.22). These examples illustrate an approach to reviewing the clinical trial literature, which is free from publication bias, and demonstrate the value and importance of an international registry of all clinical trials.