tbuckley/cabot-search huggingface dataset:
Implementation of rapid drug-susceptibility testing for patients at high risk of multidrug-resistant tuberculosis in Cambodia
Authors: Natalie Lorent, Chanda Kong, Reaksmey Pe, Tharin Kim, Sopheak Sok, Sopheak Thai, Rigouts Leen, Lynen Lut
Journal: European Respiratory Journal (2013)

Introduction: WHO recommends rapid DST for all patients at increased risk of MDR TB, which has substantial logistical, financial and operational implications for low-income, high TB burden countries.  Aim: To evaluate yield and feasibility of implementing rapid DST in a referral TB clinic in Phnom Penh, Cambodia.  Methods: Prospective cohort study. All consecutive patients seen between 1/2/’12-1/2/’13 fulfilling any criterion for DST (i.e. prior TB treatment, exposure to MDR TB, new TB with smear-positivity at end of intensive phase, HIV-infection) underwent Xpert® MTB/RIF, conventional culture/DST, and MTBDR Plus®  line probe assay (LPA) if Xpert RIF-resistant.  Results: 132/343 patients with active TB disease were eligible for rapid DST (median age 42 years (IQR 32-52), 71 male (54%)): 61 (46%) HIV-infected patients, 44 (42%) patients with previous TB (34 completed treatment, 9 interrupted, 2 relapsed), 25 (20%) non-converters at end of intensive phase; 1 MDR TB contact. Xpert RIF-resistance was detected in 12/132 cases (number needed to test: 11). LPA confirmed 5 as MDR TB, conventional culture/DST 9 (1 rifampicin mono-resistance, 2 pending). 11 patients were referred for second line treatment within 8 days (1-19) of providing sputum (one refused), with 10 effectively started within 17 days (14-30) (one died). Treatment delays were due to pending confirmatory DST and limited treatment capacity.  Conclusion: Xpert rapidly and adequately identified TB patients eligible for second line drugs. Our data support the recent recommendation that confirmatory LPA-testing is not required in patients at high risk for MDR TB identified by Xpert as RIF-resistant.
A pharmacokinetic study of high-dose continuous infusion cisplatin in children with solid tumors.
Authors: C Dominici, F Petrucci, S Caroli, A Alimonti, A Clerico, M A Castello
Journal: Journal of Clinical Oncology (1989)

The pharmacokinetics of cisplatin were investigated in 14 patients, aged 10 months through 13 years who were affected by solid malignant tumors. High-dose cisplatin (40 mg/m2/d) was administered with repeated courses for five days as a continuous intravenous (IV) infusion. Total platinum (Pt) levels in plasma and urine and free (protein-unbound) Pt levels in plasma ultrafiltrate were determined by inductively coupled plasma atomic emission spectrometry (ICP-AES). Areas under the concentration v time curve (AUCs) for mean total and free Pt levels were calculated for the 120-hour period of infusion and for the 384 and 120 hours following its completion, respectively. Half-lives of total and free Pt in plasma were calculated for the 216 hours following completion of infusion in five patients at their first course. The fraction of the administered Pt dose excreted in urine as Pt was determined for the five-day period of infusion and seven-day period after its completion. A total of 36 courses were studied. Maximum average Pt levels were reached after 120 hours of infusion: at the first course, 3.22 and 0.17 micrograms/mL for total and free Pt, respectively. Platinum levels declined according to a biexponential model, with initial half-lives of 18.3 and 16.9 minutes, and terminal half-lives of 81.9 and 59.0 hours as determined for total and free Pt, respectively. In the second and third courses studied there was a progressive increase in mean Pt plasma levels. Consequently, the free drug exposure as measured by AUC increased in all patients with repeated courses: 47.7% for the second and 124.4% for the third course, when compared with the first. At the same time, the mean fraction of the dose excreted in the urine for the 12-day period considered, was 44.1% for the first course, 36.2% for the second, and 28.4% for the third. The progressive enhancement of tissue exposure to the free cytotoxic drug, resulting from a reduced renal clearance of Pt with sequential courses of cisplatin, produced mainly increased toxicity while therapeutic effect progressively diminished.
Abstract P324: Impact of Energy Drinks on Electrocardiographic and Blood Pressure Parameters: A Meta-Analysis of Clinical Studies
Authors: Sachin A Shah, Carolyn S Lacey, Ian C Riddock, Michael Lee, Anthony E Dargush
Journal: Circulation (2013)

Introduction: Energy drinks capture 47% of the beverage market share internationally. Several studies have tried to evaluate the health risks of energy drink consumption but a general consensus does not exist. We performed a meta-analysis to assess the cardiovascular effects of energy drinks on notable electrocardiographic and blood pressure parameters. Methods: A literature search in PubMed, CINAHL, Cochrane database and by hand searching of relevant references was performed. Human clinical studies published in the English language were included if evaluating the impact of an energy drink on the QT/QTc interval or systolic blood pressure (SBP). Diastolic blood pressure (DBP) and heart rate (HR) were also assessed. A weighted mean change from baseline was calculated using the DerSimonian and Laird random-effects model for all endpoints. Subgroup and sensitivity analyses were performed to assess heterogeneity. Results: Our initial search identified 351 studies of which 7 were ultimately included. A total of 93 and 132 individual subjects were incorporated for the QT/QTc interval and SBP analyses respectively. Compared to baseline, QT/QTc interval prolonged significantly by 10.0msec [95%CI 0.41 to 19.67; Cochrane Q p=0.505] and SBP increased significantly by 3.5mmHg [95%CI 0.92 to 6.11; Cochrane Q p=0.635]. DBP and HR increased non-significantly. These effects were maintained in most subgroup and sensitivity analyses. Conclusions: Energy drinks significantly prolong the QT/QTc interval and raise SBP. DBP and HR are increased non-significantly. Further safety evaluation of energy drink consumption is warranted to guide public health policy.
Production and Characterization of Human Cell-Adapted Murine Rauscher Virus Pseudotype of Murine Sarcoma Virus 2
Authors: D. V. Ablashi, G. R. Armstrong, W. Turner
Journal: JNCI Journal of the National Cancer Institute (1973)

Journal Article Production and Characterization of Human Cell-Adapted Murine Rauscher Virus Pseudotype of Murine Sarcoma Virus Get access D. V. Ablashi, D. V. Ablashi Search for other works by this author on: Oxford Academic PubMed Google Scholar G. R. Armstrong, G. R. Armstrong Search for other works by this author on: Oxford Academic PubMed Google Scholar W. Turner W. Turner Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 50, Issue 2, February 1973, Pages 381–386, https://doi.org/10.1093/jnci/50.2.381 Published: 01 February 1973 Article history Received: 03 August 1972 Accepted: 11 October 1972 Published: 01 February 1973
Ethical debate: Informed consent in medical research Informed consent---a response to recent correspondence Changing the BMJ's position on informed consent would be counterproductive Informed consent---a publisher's duty Trial subjects must be fully involved in design and approval of trials Studies that do not have informed consent from participants should not be published
Authors: L. Doyal, J S Tobias, M. Warnock, L. Power, H. Goodare
Journal: BMJ (1998)

# Informed consent in medical research {#article-title-2}

In the issue of 12 April 1997 the BMJ invited comment on the acceptable limits of informed consent in medical studies. In view of the large correspondence this generated, we invited the two original commentators, Len Doyal and Jeffrey Tobias, to revisit the subject. We also invited comments from three people who are not doctors, researchers, or medical ethicists: two of them represent the views of patients and potential patients

# Informed consent—a response to recent correspondence {#article-title-3}

Editorial by Smith and Personal views pp 1026-7 

The publication of the debate between myself and Jeffrey Tobias about the acceptable limits of informed consent in medical research has generated an immense and varied number of letters to the BMJ .1–4 This in itself is gratifying, whether or not correspondents agree with my arguments. It provides ample evidence of widespread and serious deliberation about the moral boundaries of the rights of participants in research.



Previous articles and comment on informed consent are available on our website (see Collections)



Many correspondents either explicitly or implicitly endorse the hard line that I take in my paper on the right of competent people to an acceptable level of information before agreeing to participate in medical research. Other contributions confirm my emphasis on the moral importance of the principle of informed consent but, in light of the highly specific circumstances where I argue that the principle must be qualified, question the degree or clarity of my own commitment to it. What is important here is our shared belief in the moral imperative of respecting human autonomy in almost all circumstances.

I still disagree with those authors who argue that it is not necessary to obtain informed consent if this will lead to the methodological compromise, or possible cancellation, of potentially beneficial studies involving clinical interventions that carry minimal risks. What these …
Diabetes Care for Emerging Adults: Recommendations for Transition From Pediatric to Adult Diabetes Care Systems
Authors: Anne Peters, Lori Laffel
Journal: Diabetes Care (2011)

During childhood and adolescence, there is a gradual shift from diabetes care supervised by parents and other adults to self-care management. The actual change from pediatric to adult health care providers signals a more abrupt change that requires preparation by patients, their families, and their health care providers. A number of publications from the U.S. and other countries have highlighted substantial gaps in care during this transition period between pediatric and adult care that often arise in later adolescence and the subsequent developmental stage of life termed “emerging adulthood.” This is a critical time when patients not only assume responsibility for their diabetes self-care and interactions with the health care system but when they become more independent, potentially moving out of their parents’ home to attend college or to join the workforce (1). In the context of these transitions and the developmental issues of this age-group, gaps in diabetes care can result in suboptimal health care utilization, deteriorating glycemic control, increased occurrence of acute complications, emergence of chronic complications of diabetes that may go undetected or untreated, and psychosocial, behavioral, and emotional challenges. With the increasing incidence of both type 1 and type 2 diabetes in childhood, adolescence, and young adulthood, there is an increase in the absolute numbers of youth with diabetes in this transition period, highlighting the need for a framework of care and education for this population and a call for additional research in this area.

Substantial challenges relating to the transitional period include the following:
Individual decline of FEV1 show diversity in COPD
Authors: Jukka Koskela, Aleksi Kallio, Henna Kupiainen, Ari Lindqvist, Maritta Kilpeläinen, Janne Pitkäniemi, Vuokko Kinnula, Tarja Laitinen
Journal: European Respiratory Journal (2012)

Our objective is to develop methods to gain better understanding of individual development of lung functions in COPD sub-phenotypes.  The patients (N=600) have been recruited from two Finnish University Hospitals. Their medical records have been carefully evaluated including spirometry results. A mixed effects-model was used to obtain predictors for the individual development of FEV1. To manage the within-patient variation of consecutive measures, simulation methods were used to determine which patients were presenting significantly declining development. Logistic regression analysis was conducted to determine the characteristics of decliners.  The COPD patients represent all stages of the disease. Mean follow-up time was 5.9 years (range 2-12) and with mean 9.4 spirometries (range 3-36) per patient. Twelve percent of patients were identified as constant decliners. The decliners had a mean rate of decline of -101 (95% CI, -58 to -171) ml/year, whereas residual patients had mean rate of -35 (95% CI, 25 to -88) ml/year. When numerous co-morbidities and clinical characteristics were tested, only mental disorders (OR=1.75) were shown to associate with poor development of FEV1. Patients who had been able to stop smoking and patients whose diagnosis had been done at early stages (better FEV1 baseline level) of the disease, showed protective effect (OR=0.52 and OR=0.98/% of FEV1 predicted, respectively).  Our preliminary results suggest that COPD patients show diversity in their risk of future FEV1 decline. Development of robust screening protocols at early stages of COPD might be of value in revealing the rapid decliners.
Lung Pathology in U.S. Coal Workers with Rapidly Progressive Pneumoconiosis Implicates Silica and Silicates
Authors: Robert A. Cohen, Edward L. Petsonk, Cecile Rose, Byron Young, Michael Regier, Asif Najmuddin, Jerrold L. Abraham, Andrew Churg, Francis H. Y. Green
Journal: American Journal of Respiratory and Critical Care Medicine (2015)

Rationale: Recent reports of progressive massive fibrosis and rapidly progressive pneumoconiosis in U.S. coal miners have raised concerns about excessive exposures to coal mine dust, despite reports of declining dust levels.Objectives: To evaluate the histologic abnormalities and retained dust particles in available coal miner lung pathology specimens, and to compare these findings with those derived from corresponding chest radiographs.Methods: Miners with severe disease and available lung tissue were identified through investigator outreach. Demographic as well as smoking and work history information was obtained. Chest radiographs were interpreted according to the International Labor Organization classification scheme to determine if criteria for rapidly progressive pneumoconiosis were confirmed. Pathology slides were scored by three expert pulmonary pathologists using a standardized nomenclature and scoring system.Measurements and Main Results: Thirteen cases were reviewed, many of which had features of accelerated silicosis and mixed dust lesions. Twelve had progressive massive fibrosis, and 11 had silicosis. Only four had classic lesions of simple coal workers’ pneumoconiosis. Four had diffuse interstitial fibrosis with chronic inflammation, and two had focal alveolar proteinosis. Polarized light microscopy revealed large amounts of birefringent mineral dust particles consistent with silica and silicates; carbonaceous coal dust was less prominent. On the basis of chest imaging studies, specimens with features of silicosis were significantly associated (P = 0.047) with rounded (type p, q, or r) opacities, whereas grade 3 interstitial fibrosis was associated (P = 0.02) with the presence of irregular (type s, t, or u) opacities.Conclusions: Our findings suggest that rapidly progressive pneumoconiosis in these miners was associated with exposure to coal mine dust containing high concentrations of respirable silica and silicates.
Effect of granulocyte macrophage-colony stimulating factor on Langerhans cells in normal and healthy atopic subjects
Authors: None Smith, None Allen, None Groves, None Barker
Journal: British Journal of Dermatology (1998)

Granulocyte macrophage‐colony stimulating factor (GM‐CSF) is a multipotent cytokine produced by many cutaneous cell types including keratinocytes. Langerhans cells (LC) represent the major antigen‐presenting cells in skin, and in vitro studies demonstrate that GM‐CSF is of pivotal importance in LC. Healthy volunteers (n = 3 non‐atopic, n = 3 with atopy) received recombinant human GM‐CSF (0.05 μg/mL) by intradermal injection for 3 days to the same site. Diluent was injected in a similar manner as control. Biopsies were taken 24 h after the final injection and examined immunohistochemically for LC and inflammatory cell markers. Compared with control sites, intradermal GM‐CSF resulted in shortening of dendritic cell processes and redistribution of LC in the epidermis; numbers of CD1a + cells in the epidermis were significantly decreased (P< 0.005), while those in the dermis were significantly increased (P< 0.05) following intradermal GM‐CSF when compared with controls. Double labelling studies on epidermal CD1a + cells indicated de novo expression of intercellular adhesion molecule (ICAM)‐1 and increased expression of HLA‐DR following GM‐CSF (P< 0.005, P< 0.005, respectively). Additional findings included a marked mixed inflammatory cell infiltrate in the dermis and increased expression of the endothelial cell adhesion molecules E‐selectin and ICAM‐1. These data indicate that in normal human skin, GM‐CSF induces changes in the phenotype and distribution of CD1a + cells consistent with LC functional maturation and exit from the epidermis to the dermis. As these events are central to the initiation of cutaneous inflammation, GM‐CSF may potentially play a critical role in the pathogenesis of inflammatory dermatoses.
Acute leukemia during pregnancy: the Toronto Leukemia Study Group experience with long-term follow-up of children exposed in utero to chemotherapeutic agents.
Authors: E E Reynoso, F A Shepherd, H A Messner, H A Farquharson, M B Garvey, M A Baker
Journal: Journal of Clinical Oncology (1987)

The incidence of acute leukemia in pregnancy is low and even referral centers have limited experience. Although the short-term risks for children exposed in utero to cytotoxic agents are predictable, there is no information on long-term complications. We report here our experience in the treatment of seven cases of acute leukemia diagnosed during pregnancy, and a literature review of 51 cases published since 1975. Fifty-three patients received chemotherapy during their pregnancies. Forty-nine of the 58 cases resulted in the birth of 50 live infants. Twenty-eight infants were born prematurely, and four had low birth-weights for their gestational age. Thirty-three percent of the newborns exposed to chemotherapy in the last month of pregnancy were cytopenic at birth, but other perinatal complications were not increased. Only one child (present series) had obvious congenital malformations, and this same infant later developed a neuroblastoma arising in the adrenal gland and a papillary carcinoma of the thyroid. Follow-up data are not provided in most previously reported cases, but long-term follow-up of our cases from 1 to 17 years has shown normal growth and development and no further malignancies. A central registry is strongly advised in order to document the long-term complications arising in children exposed to chemotherapy in utero.
The topology of pen-2, a γ-secretase subunit, revisited: evidence for a reentrant loop and a single pass transmembrane domain
Authors: Xulun Zhang, Chunjiang J. Yu, Sangram S. Sisodia
Journal: Molecular Neurodegeneration (2015)

The γ-secretase complex, composed of transmembrane proteins termed presenilin (PS), anterior pharynx defective (APH), nicastrin (NCT), and presenilin enhancer-2 (Pen-2) catalyzes intramembranous hydrolysis of a variety of Type I membrane protein substrates. In order to understand aspects of subunit assembly, interactions, dynamics and catalysis, it is essential to clarify the membrane topology of each polypeptide. Hydophathicity plots predict that the 101 amino acid Pen-2 molecule has two hydrophobic domains (HP1 and HP2) that may serve as transmembrane spanning domains. Earlier reports indicated that transiently overexpressed Pen-2 uses these two hydrophobic domains as transmembrane helices that generates a “U-shaped” hairpin topology with both amino- (N-) and carboxyl-(C-) termini facing the lumen. In this report, we have reexamined the topology of endogenous Pen-2 and Pen-2 chimeras that are stably expressed in mammalian cells, and have assessed the function of these molecules in rescuing γ-secretase activity in Pen-2-deficient fibroblasts. We confirm that the Pen-2 C-terminus is lumenal, but the N-terminus of Pen-2 is exposed to the cytoplasm, thus indicating that HP1 does not traverse the lipid bilayer as a transmembrane domain. Domain swapping studies reveal the importance of specific regions within the first hydrophobic domain of Pen-2 that are critical for generating the topology that is a prerequisite for mediating PS1 endoproteolysis and γ-secretase activity. Finally, we report that the first fourteen amino acids of the Pen-2 HP1 are required for γ-secretase activity. We propose that the first hydrophobic domain of Pen-2 forms a structure similar to a reentrant loop while the second hydrophobic domain spans the lipid bilayer.
Elevated levels of prostacyclin and VEGF in the rejection process after lung transplantation
Authors: Annika Andersson Sjöland, Lena Thiman, Ingrid Skog, Lennart Hansson, Leif Eriksson, Leif Bjermer, Gunilla Westergren-Thorsson, Anna-Karin Larsson Callerfelt
Journal: European Respiratory Journal (2013)

Background: Many lung-transplanted (LTx) patients develop bronchiolitis obliterans syndrome (BOS) with characteristic extracellular matrix in the bronchioles. The increased production of matrix molecules is accompanied with increased alveolar tissue and lumen area of vessels in patients with histologically characterized rejection, obliterative bronchiolitis (OB). In this study we hypothesize that vascular endothelial growth factor (VEGF) and prostacyclin (PGI2) are involved in the rejection processes with accompanied vessel remodelling after LTx. We investigated fibroblast phenotypes regarding production of VEGF/PGI2 and expression of VEGFR2/PGI receptor (R).  Methods: Isolated lung fibroblasts from distal biopsies were incubated with TGF-β. PGI2, measured as 6-keto prostaglandinF1α and VEGF were analyzed in medium. Fibroblast phenotypes were identified by immunohistochemical methods by combining antibodies against prolyl 4-hydroxylase (p4OH) with VEGFR2 or PGIR in patients with OB. Vessels were identified with antibody against vWillebrand factor.  Results: PGI2 expression was significantly higher in LTx compared to control subjects (p=0.02). VEGF production in patients that had developed BOS was increased 7 fold after TGF-β stimulation compared to a 2.7 fold increase in patients without BOS. Both the number of fibroblasts expressing p4OH/VEGFR2 and p4OH/PGIR were increased in patients with OB compared to healthy controls (p=0.048,p=0.024). The number of p4OH/VEGFR2 fibroblasts correlated with lumen area of vessels (R 0.80 p  Conclusions: Our results suggest that PGI2/PGIR and VEGF/VEGFR2 may contribute to the changes of vessels and fibroblast phenotype found after LTx.