Project description:Infections caused by Mycobacterium abscessus and Mycobacterium massiliense are on the rise among humans. Although macrolides, including clarithromycin (CLR) and azithromycin (AZM), are key antibiotics for the treatment of M. abscessus and M. massiliense infections, treatment regimens for these infections are still largely undefined. In this study, we evaluated the in vitro, ex vivo, and in vivo activities of moxifloxacin (MXF) in combination with macrolides against clinically isolated M. abscessus and M. massiliense strains. Overall, CLR, AZM, and MXF alone showed activity against both species in vitro, ex vivo, and in vivo. When MXF was combined with a macrolide against M. abscessus isolates, antagonism was observed in 65.4% (17/26) of the strains with CLR and 46.2% (12/26) of the strains with AZM in vitro as well as in 66.7% (10/15) of the strains with CLR and 40.0% (6/15) of the strains with AZM in macrophages as determined by the fractional inhibitory concentration index. In contrast, either indifferent or synergistic effects of the MXF-macrolide combinations were observed against only M. massiliense strains. Moreover, a murine infection model showed similar results. Antagonism between the MXF and macrolide combinations was observed in five out of seven M. abscessus strains, while indifferent and synergistic effects for these combinations were observed for three of the six M. massiliense strains tested, respectively. In conclusion, the activity of MXF in combination with a macrolide differed for M. abscessus and M. massiliense infections and the addition of MXF to macrolide therapy had no benefit for the treatment of M. abscessus infections.
Project description:We explore the ways in which residents of Neolithic Çatalhöyük in Anatolia differentiated themselves as well as the ways in which they did not. We integrate numerous data sets in order to assess patterns of inequality (A) across buildings with contemporaneous occupations, (B) between buildings that did or did not burn at abandonment, and (C) through time. We use Gini coefficients so as to maximize comparability with other studies of inequality in the ancient and modern worlds, discussing the underlying data and our results to clarify and enhance the value of the quantitative analyses. We evaluate whether or not trajectories of inequality align across data sets in order to determine how far success in one realm correlated with success in another. Our results indicate no unified trajectory of inequality through time. We perceive broadly similar access to staple foods, but not to goods less directly related to survival; relatively elevated income inequality during the middle portion of the site's occupation, plausibly deliberately tamped down; and no evidence for institutionalized or lasting economic or social inequality. These findings shed light on Neolithic social dynamics and also contribute to broader discussions of inequality and the social ramifications of early agropastoralism.
Project description:A pervasive opposition to genetically modified (GM) foods has developed from the notion that they pose a risk to human and environmental health. Other techniques for the genetic modification of plants, such as sexual crossing and mutagenesis breeding, have mostly remained unchallenged. This research aims to investigate public perception of plant breeding technologies. Specifically, sexual crossing, mutagenesis, transgenics (GM) and gene editing. It was expected that attitudes and intentions would be most positive and the perception of risk lowest for plant genetic modification through sexual crosses. Scores on these variables were expected to be similar between mutagenesis, GM and gene editing. It was also expected that attitudes, intentions and risk perception would change (becoming more positive) once participants learned about foods developed through these technologies. Participants reported their attitudes, intentions and risk perception at two points in time. At Time 2, they were presented with pictures of food items developed through sexual crossing, GM and mutagenesis. The results showed that mutagenesis stood out as the most negatively perceived technology, whereas genetic development via sexual crosses was generally perceived as positive. The results highlight the importance of messaging, framing in consumer attitudes.
Project description:Glycosaminoglycan (GAG) mimetics are synthetic or semi-synthetic analogues of heparin or heparan sulfate, which are designed to interact with GAG binding sites on proteins. The preclinical stages of drug development rely on efficacy and toxicity assessment in animals and aim to apply these findings to clinical studies. However, such data may not always reflect the human situation possibly because the GAG binding site on the protein ligand in animals and humans could differ. Possible inter-species differences in the GAG-binding sites on antithrombin III, heparanase, and chemokines of the CCL and CXCL families were examined by sequence alignments, molecular modelling and assessment of surface electrostatic potentials to determine if one species of laboratory animal is likely to result in more clinically relevant data than another. For each protein, current understanding of GAG binding is reviewed from a protein structure and function perspective. This combinatorial analysis shows chemokine dimers and oligomers can present different GAG binding surfaces for the same target protein, whereas a cleft-like GAG binding site will differently influence the types of GAG structures that bind and the species preferable for preclinical work. Such analyses will allow an informed choice of animal(s) for preclinical studies of GAG mimetic drugs.
Project description:Survival outcomes for kidney transplant candidates based on expanded criteria donor (ECD) kidney type is unknown. A retrospective cohort study was undertaken of prospectively collected registry data of all waitlisted kidney failure patients receiving dialysis in the United Kingdom. All patients listed for their first kidney-alone transplant between 2000-2019 were included. Treatment types included; living donor; standard criteria donor (SCD); ECD60 (deceased donor aged ≥60 years); ECD50-59 (deceased donor aged 50-59 years with two from the following three; hypertension; raised creatinine and/or death from stroke) or remains on dialysis. The primary outcome was all-cause mortality, with time-to-death from listing analyzed using time-dependent non-proportional Cox regression models. The study cohort comprised 47,917 waitlisted kidney failure patients, of whom 34,558 (72.1%) received kidney transplantation. ECD kidneys (n = 7,356) were stratified as ECD60 (n = 7,009) or ECD50-59 (n = 347). Compared to SCD, both ECD60 (Hazard Ratio 1.126, 95% CI 1.093-1.161) and ECD50-59 (Hazard Ratio 1.228, 95% CI 1.113-1.356) kidney recipients have higher all-cause mortality. However, compared to dialysis, both ECD60 (Hazard Ratio 0.194, 95% CI 0.187-0.201) and ECD50-59 (Hazard Ratio 0.218, 95% CI 0.197-0.241) kidney recipients have lower all-cause mortality. ECD kidneys, regardless of definition, provide equivalent and superior survival benefits in comparison to remaining waitlisted.
Project description:OBJECTIVE:To examine the use of the term 'metric' in health and social sciences' literature, focusing on the interval scale implication of the term in Modern Test Theory (MTT). MATERIALS AND METHODS:A systematic search and review on MTT studies including 'metric' or 'interval scale' was performed in the health and social sciences literature. The search was restricted to 2001-2005 and 2011-2015. A Text Mining algorithm was employed to operationalize the eligibility criteria and to explore the uses of 'metric'. The paradigm of each included article (Rasch Measurement Theory (RMT), Item Response Theory (IRT) or both), as well as its type (Theoretical, Methodological, Teaching, Application, Miscellaneous) were determined. An inductive thematic analysis on the first three types was performed. RESULTS:70.6% of the 1337 included articles were allocated to RMT, and 68.4% were application papers. Among the number of uses of 'metric', it was predominantly a synonym of 'scale'; as adjective, it referred to measurement or quantification. Three incompatible themes 'only RMT/all MTT/no MTT models can provide interval measures' were identified, but 'interval scale' was considerably more mentioned in RMT than in IRT. CONCLUSION:'Metric' is used in many different ways, and there is no consensus on which MTT metric has interval scale properties. Nevertheless, when using the term 'metric', the authors should specify the level of the metric being used (ordinal, ordered, interval, ratio), and justify why according to them the metric is at that level.
Project description:Bone marrow samples from discarded femoral heads are often used as healthy controls in studies investigating the in vitro characteristics of cells from patients with hematologic malignancies. Since patient samples are usually derived from iliac crest aspirates, this carries the risk that the properties of the cells from both sources might be different due to the site and method of harvesting. Comparing BM cells from iliac crest aspirates and femoral heads from age-matched healthy donors, we show that, while mesenchymal stromal cells have indistinguishable properties between both sources, hematopoietic stem and progenitor cells (HSPC) from femoral heads show a considerable proliferative advantage in vitro. These data therefore suggest that experiments comparing leukemic cells from the iliac crest to healthy HSPC obtained from femoral heads should be interpreted with caution.
Project description:Previous reports identifying discordance between multiparameter tests at the individual patient level have been largely attributed to methodological shortcomings of multiple in silico studies. Comparisons between tests, when performed using actual diagnostic assays, have been predicted to demonstrate high degrees of concordance. OPTIMA prelim compared predicted risk stratification and subtype classification of different multiparameter tests performed directly on the same population. Three hundred thirteen women with early breast cancer were randomized to standard (chemotherapy and endocrine therapy) or test-directed (chemotherapy if Oncotype DX recurrence score >25) treatment. Risk stratification was also determined with Prosigna (PAM50), MammaPrint, MammaTyper, NexCourse Breast (IHC4-AQUA), and conventional IHC4 (IHC4). Subtype classification was provided by Blueprint, MammaTyper, and Prosigna. Oncotype DX predicted a higher proportion of tumors as low risk (82.1%, 95% confidence interval [CI] = 77.8% to 86.4%) than were predicted low/intermediate risk using Prosigna (65.5%, 95% CI = 60.1% to 70.9%), IHC4 (72.0%, 95% CI = 66.5% to 77.5%), MammaPrint (61.4%, 95% CI = 55.9% to 66.9%), or NexCourse Breast (61.6%, 95% CI = 55.8% to 67.4%). Strikingly, the five tests showed only modest agreement when dichotomizing results between high vs low/intermediate risk. Only 119 (39.4%) tumors were classified uniformly as either low/intermediate risk or high risk, and 183 (60.6%) were assigned to different risk categories by different tests, although 94 (31.1%) showed agreement between four of five tests. All three subtype tests assigned 59.5% to 62.4% of tumors to luminal A subtype, but only 121 (40.1%) were classified as luminal A by all three tests and only 58 (19.2%) were uniformly assigned as nonluminal A. Discordant subtyping was observed in 123 (40.7%) tumors. Existing evidence on the comparative prognostic information provided by different tests suggests that current multiparameter tests provide broadly equivalent risk information for the population of women with estrogen receptor (ER)-positive breast cancers. However, for the individual patient, tests may provide differing risk categorization and subtype information.
Project description:Isolation of Mycobacterium abscessus subspecies abscessus (MAA) is common during Mycobacterium avium complex (MAC) lung disease therapy, but there is limited information about the clinical significance of the MAA isolates.We identified 53 of 180 patients (29%) treated for MAC lung disease who had isolation of MAA during MAC lung disease therapy. Patients were divided into those without (group 1) and those with (group 2) MAA lung disease.There were no significant demographic differences between patients with and without MAA isolation or between groups 1 and 2. Group 1 and 2 patients had similar total sputum cultures obtained (P = .7; 95% CI, -13.4 to 8.6) and length of follow-up (P = .8; 95% CI, -21.5 to 16.1). Group 2 patients had significantly more total positive cultures for MAA (mean±SD, 15.0 ± 11.1 vs 1.2 ± 0.4; P < .0001; 95% CI, -17.7 to -9.9), were significantly more likely to develop new or enlarging cavitary lesions while on MAC therapy (P > .0001), and were significantly more likely to meet all three American Thoracic Society diagnostic criteria for nontuberculous mycobacterial disease (21 of 21 [100%] vs 0 of 32 [0%]; P < .0001) compared with group 1 patients. Group 1 patients were significantly more likely to have single, positive MAA cultures than group 2 patients (25 of 31 vs 0 of 21; P < .0001).Microbiologic and clinical follow-up after completion of MAC lung disease therapy is required to determine the significance of MAA isolated during MAC lung disease therapy. Single MAA isolates are not likely to be clinically significant.
Project description:ObjectivesAs coronavirus disease 2019 is a novel disease, treatment strategies continue to be debated. This provides the intensive care community with a unique opportunity as the population of coronavirus disease 2019 patients requiring invasive mechanical ventilation is relatively homogeneous compared with other ICU populations. We hypothesize that the novelty of coronavirus disease 2019 and the uncertainty over its similarity with noncoronavirus disease 2019 acute respiratory distress syndrome resulted in substantial practice variation between hospitals during the first and second waves of coronavirus disease 2019 patients.DesignMulticenter retrospective cohort study.SettingTwenty-five hospitals in the Netherlands from February 2020 to July 2020, and 14 hospitals from August 2020 to December 2020.PatientsOne thousand two hundred ninety-four critically ill intubated adult ICU patients with coronavirus disease 2019 were selected from the Dutch Data Warehouse. Patients intubated for less than 24 hours, transferred patients, and patients still admitted at the time of data extraction were excluded.Measurements and main resultsWe aimed to estimate between-ICU practice variation in selected ventilation parameters (positive end-expiratory pressure, Fio2, set respiratory rate, tidal volume, minute volume, and percentage of time spent in a prone position) on days 1, 2, 3, and 7 of intubation, adjusted for patient characteristics as well as severity of illness based on Pao2/Fio2 ratio, pH, ventilatory ratio, and dynamic respiratory system compliance during controlled ventilation. Using multilevel linear mixed-effects modeling, we found significant (p ≤ 0.001) variation between ICUs in all ventilation parameters on days 1, 2, 3, and 7 of intubation for both waves.ConclusionsThis is the first study to clearly demonstrate significant practice variation between ICUs related to mechanical ventilation parameters that are under direct control by intensivists. Their effect on clinical outcomes for both coronavirus disease 2019 and other critically ill mechanically ventilated patients could have widespread implications for the practice of intensive care medicine and should be investigated further by causal inference models and clinical trials.