Takshan/R1 huggingface dataset:
Cerium oxide and barium sulfate nanoparticle inhalation affects gene expression in alveolar epithelial cells type II.

BACKGROUND: Understanding the molecular mechanisms of nanomaterial interacting with cellular systems is important for appropriate risk assessment. The identification of early biomarkers for potential (sub-)chronic effects of nanoparticles provides a promising approach towards cost-intensive and animal consuming long-term studies. As part of a 90-day inhalation toxicity study with CeO2 NM-212 and BaSO4 NM-220 the present investigations on gene expression and immunohistochemistry should reveal details on underlying mechanisms of pulmonary effects. The role of alveolar epithelial cells type II (AEII cells) is focused since its contribution to defense against inhaled particles and potentially resulting adverse effects is assumed. Low dose levels should help to specify particle-related events, including inflammation and oxidative stress. RESULTS: Rats were exposed to clean air, 0.1, 0.3, 1.0, and 3.0 mg/m3 CeO2 NM-212 or 50.0 mg/m3 BaSO4 NM-220 and the expression of 391 genes was analyzed in AEII cells after one, 28 and 90 days exposure. A total number of 34 genes was regulated, most of them related to inflammatory mediators. Marked changes in gene expression were measured for Ccl2, Ccl7, Ccl17, Ccl22, Ccl3, Ccl4, Il-1α, Il-1ß, and Il-1rn (inflammation), Lpo and Noxo1 (oxidative stress), and Mmp12 (inflammation/lung cancer). Genes related to genotoxicity and apoptosis did not display marked regulation. Although gene expression was less affected by BaSO4 compared to CeO2 the gene pattern showed great overlap. Gene expression was further analyzed in liver and kidney tissue showing inflammatory responses in both organs and marked downregulation of oxidative stress related genes in the kidney. Increases in the amount of Ce were measured in liver but not in kidney tissue. Investigation of selected genes on protein level revealed increased Ccl2 in bronchoalveolar lavage of exposed animals and increased Lpo and Mmp12 in the alveolar epithelia. CONCLUSION: AEII cells contribute to CeO2 nanoparticle caused inflammatory and oxidative stress reactions in the respiratory tract by the release of related mediators. Effects of BaSO4 exposure are low. However, overlap between both substances were detected and support identification of potential early biomarkers for nanoparticle effects on the respiratory system. Signs for long-term effects need to be further evaluated by comparison to a respective exposure setting.
RNA isolation from precision-cut lung slices (PCLS) from different species.

BACKGROUND: Functional 3D organ models such as precision-cut lung slices (PCLS) have recently captured the attention of biomedical research. To enable wider implementation in research and development, these new biologically relevant organ models are being constantly refined. A very important issue is to improve the preparation of high-quality RNA (ribonucleic acid) from PCLS for drug discovery and development of new therapies. Gene expression analysis at different levels is used as an important experimental readout. Genome-wide analysis using microarrays is mostly applied for biomarker selection in disease models or in comprehensive toxicological studies. Specific biomarker testing by reverse transcriptase quantitative polymerase chain reaction (RTqPCR) is often used in efficacy studies. Both applications require high-quality RNA as starting material for the generation of reliable data. Additionally, a small number of slices should be sufficient for satisfactory RNA isolation to allow as many experimental conditions as possible to be covered with a given tissue sample. Unfortunately, the vast amount of agarose in PCLS impedes RNA extraction according to the standard procedures. RESULTS: We established an optimized protocol for RNA isolation from PCLS from humans, rats, mice, marmosets, and rhesus macaques based on the separation of lysis and precipitation steps and a magnetic-bead cleanup procedure. The resulting RNA is of high purity and possesses a high degree of integrity. There are no contaminations affecting RTqPCR efficiency or any enzymatic step in sample preparation for microarray analysis. CONCLUSIONS: In summary, we isolated RNA from PCLS from different species that is well suited for RTqPCR and for microarray analysis as downstream applications.
Use of geographically weighted logistic regression to quantify spatial variation in the environmental and sociodemographic drivers of leptospirosis in Fiji: a modelling study.

BACKGROUND: Leptospirosis is a globally important zoonotic disease, with complex exposure pathways that depend on interactions between human beings, animals, and the environment. Major drivers of outbreaks include flooding, urbanisation, poverty, and agricultural intensification. The intensity of these drivers and their relative importance vary between geographical areas; however, non-spatial regression methods are incapable of capturing the spatial variations. This study aimed to explore the use of geographically weighted logistic regression (GWLR) to provide insights into the ecoepidemiology of human leptospirosis in Fiji. METHODS: We obtained field data from a cross-sectional community survey done in 2013 in the three main islands of Fiji. A blood sample obtained from each participant (aged 1-90 years) was tested for anti-Leptospira antibodies and household locations were recorded using GPS receivers. We used GWLR to quantify the spatial variation in the relative importance of five environmental and sociodemographic covariates (cattle density, distance to river, poverty rate, residential setting [urban or rural], and maximum rainfall in the wettest month) on leptospirosis transmission in Fiji. We developed two models, one using GWLR and one with standard logistic regression; for each model, the dependent variable was the presence or absence of anti-Leptospira antibodies. GWLR results were compared with results obtained with standard logistic regression, and used to produce a predictive risk map and maps showing the spatial variation in odds ratios (OR) for each covariate. FINDINGS: The dataset contained location information for 2046 participants from 1922 households representing 81 communities. The Aikaike information criterion value of the GWLR model was 1935·2 compared with 1254·2 for the standard logistic regression model, indicating that the GWLR model was more efficient. Both models produced similar OR for the covariates, but GWLR also detected spatial variation in the effect of each covariate. Maximum rainfall had the least variation across space (median OR 1·30, IQR 1·27-1·35), and distance to river varied the most (1·45, 1·35-2·05). The predictive risk map indicated that the highest risk was in the interior of Viti Levu, and the agricultural region and southern end of Vanua Levu. INTERPRETATION: GWLR provided a valuable method for modelling spatial heterogeneity of covariates for leptospirosis infection and their relative importance over space. Results of GWLR could be used to inform more place-specific interventions, particularly for diseases with strong environmental or sociodemographic drivers of transmission. FUNDING: WHO, Australian National Health & Medical Research Council, University of Queensland, UK Medical Research Council, Chadwick Trust.
Indicators for evaluating European population health: a Delphi selection process.

BACKGROUND: Indicators are essential instruments for monitoring and evaluating population health. The selection of a multidimensional set of indicators should not only reflect the scientific evidence on health outcomes and health determinants, but also the views of health experts and stakeholders. The aim of this study is to describe the Delphi selection process designed to promote agreement on indicators considered relevant to evaluate population health at the European regional level. METHODS: Indicators were selected in a Delphi survey conducted using a web-platform designed to implement and monitor participatory processes. It involved a panel of 51 experts and 30 stakeholders from different areas of knowledge and geographies. In three consecutive rounds the panel indicated their level of agreement or disagreement with indicator's relevance for evaluating population health in Europe. Inferential statistics were applied to draw conclusions on observed level of agreement (Scott's Pi interrater reliability coefficient) and opinion change (McNemar Chi-square test). Multivariate analysis of variance was conducted to check if the field of expertise influenced the panellist responses (Wilk's Lambda test). RESULTS: The panel participated extensively in the study (overall response rate: 80%). Eighty indicators reached group agreement for selection in the areas of: economic and social environment (12); demographic change (5); lifestyle and health behaviours (8); physical environment (6); built environment (12); healthcare services (11) and health outcomes (26). Higher convergence of group opinion towards agreement on the relevance of indicators was seen for lifestyle and health behaviours, healthcare services, and health outcomes. The panellists' field of expertise influenced responses: statistically significant differences were found for economic and social environment (p < 0.05 in round 1 and 2), physical environment (p < 0.01 in round 1) and health outcomes (p < 0.01 in round 3). CONCLUSIONS: The high levels of participation observed in this study, by involving experts and stakeholders and ascertaining their views, underpinned the added value of using a transparent Web-Delphi process to promote agreement on what indicators are relevant to appraise population health.
Systematic review of azacitidine regimens in myelodysplastic syndrome and acute myeloid leukemia.

Background: 5-Azacitidine administered as a 7-day dosing regimen (7-0-0) is approved in high risk IPSS myelodysplastic syndrome (MDS) patients. Alternative regimens such as a 5-day (5-0-0) or 7-day with a weekend break (5-2-2) are commonly used. No randomized controlled trial has been done directly comparing all three dosing regimens. The objective of this study was to compare the efficacies of the 5-0-0, 5-2-2, and 7-0-0 regimens in MDS and AML. Methods: A systematic review was conducted using MEDLINE, EMBASE and CENTRAL. Eligible studies were randomized controlled trials (RCTs), observational prospective and retrospective studies. The primary clinical outcomes were Objective Response Rate (ORR) defined as the sum of complete response (CR), partial response (PR), and hematological improvement (HI) as defined by the IWG 2006 criteria. A meta-analysis of simple proportions was conducted using a random effects model with weights defined according to Laird and Mosteller. Comparisons between groups were not attempted due to the heterogeneity of study designs. Results: The only RCT directly comparing alternative azacitidine regimens showed no difference in ORR between the 5-0-0 and 5-2-2 regimens. All other RCTs compared a dosing regimen to conventional care. The pooled proportion of ORR was 44.8% with 95% CI (42.8%, 45.5%) for 7-0-0, 41.2% with 95% CI (39.2%, 41.9%) for 5-0-0, and 45.8% with 95% CI (42.6%, 46.4%) for 5-2-2. Conclusions: Indirect comparison of alternative azacitidine dosing regimens in MDS and AML shows a benefit for the 7-day regimen in attaining ORR. Additional RCTs are required to definitively address this comparison.
Cadaveric surgery in core gynaecology training: a feasibility study.

Background: Fresh frozen cadaver training has been proposed as a better model than virtual reality simulators in laparoscopy training. We aimed to explore the relationship between cadaveric surgical training and increased surgical confidence. To determine feasibility, we devised two 1-day cadaveric surgical training days targeted at trainees in obstetrics and gynaecology. Seven defined surgical skills were covered during the course of the day. The relationship between surgical training and surgical confidence was explored using both quantitative (confidence scores) and qualitative tools (questionnaires). Results: Participants rated a consistent improvement in their level of confidence after the training. They universally found the experience positive and three overarching themes emerged from the qualitative analysis including self-concept, social persuasion and stability of task. Conclusions: It is pragmatically feasible to provide procedure-specific cadaveric surgical training alongside supervised clinical training. This small, non-generalisable study suggests that cadaveric training may contribute to an increase in surgical self-confidence and efficacy. This will form the basis of a larger study and needs to be explored in more depth with a larger population.
Mortality in American Veterans with the HLA-B27 gene.

OBJECTIVE: To compare survival in American veterans with and without the HLA-B27 (B27) gene. METHODS: Mortality was evaluated in a national cohort of veterans with clinically available B27 test results between October 1, 1999, and December 31, 2011. The primary outcome was the mortality difference between B27-positive and B27-negative veterans, adjusted for age, sex, race, and diagnoses codes for diseases that may have influenced both B27 testing and mortality, including psoriasis, inflammatory bowel disease, spondyloarthritis (SpA), and other types of inflammatory arthritis. The secondary outcomes were the adjusted mortality HR for B27+ and B27- veterans, in subgroups with and without SpA. RESULTS: Among veterans with available B27 test results, 27,652 (84.7%) were B27- and 4978 (15.3%) were B27+. The mean followup time was 4.6 years. Mortality was higher in the B27+ group than in the B27- group (HR 1.15, 95% CI 1.03-1.27). Mortality was also higher in the B27+ subgroups with SpA (HR 1.35, 95% CI 1.06-1.72) and without SpA (HR 1.11, 95% CI 0.99-1.24), but the difference was significant only in the subgroup with SpA. CONCLUSION: B27 positivity was associated with an increased mortality rate in a cohort of veterans clinically selected for B27 testing, after adjustment for SpA. In the subgroup with SpA, the mortality rate was associated with B27 positivity, and in the subgroup without SpA, there was a nonsignificant association between B27+ and mortality.
Emergence of Mycobacterium simiae: A retrospective study from a tertiary care center in Lebanon.

OBJECTIVE: The objective of this study is to describe the clinical significance of Mycobacterium simiae at a major tertiary care center in Lebanon. METHODS: This is a retrospective study of patients with positive cultures for M. simiae isolated between 2004 and 2016 at the American University of Beirut Medical Center. RESULTS: This study included 103 M. simiae isolates recovered from 51 patients. Their mean age was 62.7 years. The majority were males and smokers. Specimens were mostly from respiratory sources (97%). Common comorbidities included chronic lung disease (such as chronic obstructive pulmonary disease), solid tumor, systemic disease, and diabetes mellitus. Productive cough and dyspnea were the most common symptoms. Frequent radiographic findings were infiltrates and nodules on chest X-ray and nodules, infiltrates, and bronchiectasis on chest computed tomography scan. Among 18 tested isolates, 5.8% were resistant to clarithromycin, 11.7% to amikacin, and 70-100% to other antimicrobials. Out of 13 patients receiving early treatment, 5 noted improvement, one had recurrence of symptoms, two received alternative diagnosis, and five died. Two of those deaths were related to M. simiae. Common treatment regimens included clarithromycin in different combinations with trimethoprim-sulfamethoxazole, moxifloxacin, and amikacin. Moreover, clofazimine was used in only two patients whose isolates were resistant to all but one agent. Duration of treatment ranged from 6-24 months. CONCLUSION: In Lebanon, M. simiae is increasingly encountered with true infection rates of at least 47%. Furthermore, the prevalence of multidrug resistance among the Lebanese M. simiae isolates is very high limiting the treatment options.
A multicentre, randomised, non-inferiority clinical trial comparing a nifurtimox-eflornithine combination to standard eflornithine monotherapy for late stage Trypanosoma brucei gambiense human African trypanosomiasis in Uganda.

BACKGROUND: While the combination of nifurtimox and eflornithine (NECT) is currently recommended for the treatment of the late stage human African trypansomiasis (HAT), single-agent eflornithine was still the treatment of choice when this trial commenced. This study intended to provide supportive evidence to complement previous trials. METHODS: A multi-centre randomised, open-label, non-inferiority trial was carried out in the Trypanosoma brucei gambiense endemic districts of North-Western Uganda to compare the efficacy and safety of NECT (200 mg/kg eflornithine infusions every 12 h for 7 days and 8 hourly oral nifurtimox at 5 mg/kg for 10 days) to the standard eflornithine regimen (6 hourly at 100 mg/kg for 14 days). The primary endpoint was the cure rate, determined as the proportion of patients alive and without laboratory signs of infection at 18 months post-treatment, with no demonstrated trypanosomes in the cerebrospinal fluid (CSF), blood or lymph node aspirates, and CSF white blood cell count < 20 /μl. The non-inferiority margin was set at 10%. RESULTS: One hundred and nine patients were enrolled; all contributed to the intent-to-treat (ITT), modified intent-to-treat (mITT) and safety populations, while 105 constituted the per-protocol population (PP). The cure rate was 90.9% for NECT and 88.9% for eflornithine in the ITT and mITT populations; the same was 90.6 and 88.5%, respectively in the PP population. Non-inferiority was demonstrated for NECT in all populations: differences in cure rates were 0.02 (95% CI: -0.07-0.11) and 0.02 (95% CI: -0.08-0.12) respectively. Two patients died while on treatment (1 in each arm), and 3 more during follow-up in the NECT arm. No difference was found between the two arms for the secondary efficacy and safety parameters. A meta-analysis involving several studies demonstrated non-inferiority of NECT to eflornithine monotherapy. CONCLUSIONS: These results confirm findings of earlier trials and support implementation of NECT as first-line treatment for late stage T. b. gambiense HAT. The overall risk difference for cure between NECT and eflornithine between this and two previous randomised controlled trials is 0.03 (95% CI: -0.02-0.08). The NECT regimen is simpler, safer, shorter and less expensive than single-agent DFMO. TRIAL REGISTRATION: ISRCTN ISRCTN03148609 (registered 18 April 2008).
The value of PET/CT with FES or FDG tracers in metastatic breast cancer: a computer simulation study in ER-positive patients.

BACKGROUND: The aim of this study was to evaluate the effect on the number of performed biopsies and costs associated with implementing positron emission tomography (PET) and computed tomography (PET/CT) with 16α-[(18)F]fluoro-17β-oestradiol (FES) or 2-[(18)F]fluoro-2-deoxy-D-glucose (FDG) as an upfront imaging test for diagnosing metastatic breast cancer (MBC) in comparison with the standard work-up in oestrogen receptor-positive women with symptoms. METHODS: A published computer simulation model was adapted and validated. Three follow-up strategies were evaluated in a simulated cohort of women with primary breast cancer over a 5-year-time horizon: (1) the standard work-up, (2) upfront FES-PET/CT and (3) upfront FDG-PET/CT. The main outcome was the number of avoided biopsies to assess MBC. The costs for all three strategies were calculated based on the number of imaging tests and biopsies. The incremental cost-effectiveness ratio (ICER) to avoid a biopsy was calculated only based on the costs of initial imaging and staging tests. RESULTS: The FES-PET/CT strategy decreased the number of biopsies by 39 ± 9%, while upfront FDG-PET/CT increased the number of biopsies by 38 ± 15% when compared with the standard work-up. Both PET/CT strategies reduced the number of imaging tests and false positives when compared with the standard work-up. The number of false negatives decreased only in the FES-PET/CT strategy. The ICER in the FES-PET/CT strategy per avoided biopsy was 12.1 ± 3.4 thousand Euro. In the FDG-PET/CT strategy, the costs were higher and there were no avoided biopsies as compared with the standard work-up, hence this was an inferior strategy in terms of cost effectiveness. CONCLUSIONS: The number of performed biopsies was lower in the FES-PET/CT strategy at an ICER of 12.1 ± 3.4 thousand Euro per biopsy avoided, whereas the application of the FDG-PET/CT did not reduce the number of biopsies and was more expensive. Whether the FES-PET/CT strategy has additional benefits for patients in terms of therapy management has to be evaluated in clinical studies.
Bicarbonate does not improve hemodynamics in critically ill patients who have lactic acidosis. A prospective, controlled clinical study.

STUDY OBJECTIVE: To determine whether correction of acidemia using bicarbonate improves hemodynamics in patients who have lactic acidosis. DESIGN: Prospective, randomized, blinded, crossover study. Each patient sequentially received sodium bicarbonate and equimolar sodium chloride. The order of the infusions was randomized. SETTING: Intensive care unit of a tertiary care hospital. PATIENTS: Fourteen patients who had metabolic acidosis (bicarbonate less than 17 mmol/L and base excess less than -10) and increased arterial lactate (mean, 7.8 mmol/L). All had pulmonary artery catheters and 13 were receiving catecholamines. MEASUREMENTS AND MAIN RESULTS: Sodium bicarbonate (2 mmol/kg body weight over 15 minutes) increased arterial pH (7.22 to 7.36, P less than 0.001), serum bicarbonate (12 to 18 mmol/L, P less than 0.001), and partial pressure of CO2 in arterial blood (PaCO2) (35 to 40 mm Hg, P less than 0.001) and decreased plasma ionized calcium (0.95 to 0.87 mmol/L, P less than 0.001). Sodium bicarbonate and sodium chloride both transiently increased pulmonary capillary wedge pressure (15 to 17 mm Hg, and 14 to 17 mm Hg, P less than 0.001) and cardiac output (18% and 16%, P less than 0.01). The mean arterial pressure was unchanged. Hemodynamic responses to sodium bicarbonate and sodium chloride were the same. These data have more than 90% power of detecting a 0.5 L/min (7%) change in mean cardiac output after administration of sodium bicarbonate compared with that after sodium chloride. Even the 7 most acidemic patients (mean pH, 7.13; range, 6.90 to 7.20) had no significant hemodynamic changes after either infusion. CONCLUSIONS: Correction of acidemia using sodium bicarbonate does not improve hemodynamics in critically ill patients who have metabolic acidosis and increased blood lactate or the cardiovascular response to infused catecholamines in these patients. Sodium bicarbonate decreases plasma ionized calcium and increases PaCO2.