Dual comb spectroscopy (DCS) of near-infrared H
O absorption has been demonstrated in the past for low-uncertainty flow measurements in ground test ramjets. However, H
O is scarce at actual ramjet ...flight altitudes, so oxygen is a preferable absorption target. Here, we demonstrate DCS of the O
A-band (13000-13200 cm
) and fit temperature and velocity across different flow conditions in a ground-test ramjet, demonstrating precisions of 3-5% and 7-11% respectively in five minutes and total uncertainty estimates of 7-9% and 8-12% respectively. The DCS measurements and uncertainty estimates are compared to predicted values for the test facility.
Lyme disease, caused by Borrelia burgdorferi, B. afzelii and B. garinii, is a chronic, multi-systemic infection and the spectrum of tissues affected can vary with the Lyme disease strain. For ...example, whereas B. garinii infection is associated with neurologic manifestations, B. burgdorferi infection is associated with arthritis. The basis for tissue tropism is poorly understood, but has been long hypothesized to involve strain-specific interactions with host components in the target tissue. OspC (outer surface protein C) is a highly variable outer surface protein required for infectivity, and sequence differences in OspC are associated with variation in tissue invasiveness, but whether OspC directly influences tropism is unknown. We found that OspC binds to the extracellular matrix (ECM) components fibronectin and/or dermatan sulfate in an OspC variant-dependent manner. Murine infection by isogenic B. burgdorferi strains differing only in their ospC coding region revealed that two OspC variants capable of binding dermatan sulfate promoted colonization of all tissues tested, including joints. However, an isogenic strain producing OspC from B. garinii strain PBr, which binds fibronectin but not dermatan sulfate, colonized the skin, heart and bladder, but not joints. Moreover, a strain producing an OspC altered to recognize neither fibronectin nor dermatan sulfate displayed dramatically reduced levels of tissue colonization that were indistinguishable from a strain entirely deficient in OspC. Finally, intravital microscopy revealed that this OspC mutant, in contrast to a strain producing wild type OspC, was defective in promoting joint invasion by B. burgdorferi in living mice. We conclude that OspC functions as an ECM-binding adhesin that is required for joint invasion, and that variation in OspC sequence contributes to strain-specific differences in tissue tropism displayed among Lyme disease spirochetes.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The calcimimetic AMG 073 reduces parathyroid hormone and calcium x phosphorus in secondary hyperparathyroidism.
A need exists for a therapy that lowers parathyroid hormone (PTH) without increasing ...calcium x phosphorus in patients with secondary hyperparathyroidism. The calcimimetic AMG 073 increases the sensitivity of the parathyroid calcium-sensing receptor to extracellular calcium, thereby reducing PTH secretion. Consequently, AMG 073 may provide a novel therapy for secondary hyperparathyroidism.
Seventy-eight hemodialysis patients with secondary hyperparathyroidism were enrolled into this 18-week, double-blind, randomized, placebo-controlled, dose titration study. Daily oral AMG 073 doses were administered to determine the effect on PTH, serum calcium, phosphorus, and calcium x phosphorus.
The mean baseline PTH was similar in patients administered AMG 073 or placebo (632 ± 280.1 pg/mL vs. 637 ± 455.9 pg/mL, respectively). PTH decreased by 26.0% in the AMG 073-treated group, compared with an increase of 22.0% in the placebo group (P < 0.001). A greater proportion in the AMG 073 group (38%) had a decrease in PTH ≥30%, compared with the placebo group (8%) (P = 0.001). Decreases in PTH were independent of baseline vitamin D usage. Patients receiving AMG 073 had an 11.9% decrease in calcium x phosphorus compared with a 10.9% increase in the placebo group (P < 0.001). Use of vitamin D sterols, as well as both calcium and noncalcium-containing phosphate binders. were similar between treatment groups. Administration of AMG 073 was safe and well tolerated in this 18-week study.
The calcimimetic AMG 073 decreases both PTH and calcium x phosphorus levels in hemodialysis patients with secondary hyperparathyroidism.
The NS5A protein plays a critical role in the replication of HCV and has been the focus of numerous research efforts over the past few years. NS5A inhibitors have shown impressive in vitro potency ...profiles in HCV replicon assays, making them attractive components for inclusion in all oral combination regimens. Early work in the NS5A arena led to the discovery of our first clinical candidate, MK‐4882 2‐((S)‐pyrrolidin‐2‐yl)‐5‐(2‐(4‐(5‐((S)‐pyrrolidin‐2‐yl)‐1H‐imidazol‐2‐yl)phenyl)benzofuran‐5‐yl)‐1H‐imidazole. While preclinical proof‐of‐concept studies in HCV‐infected chimpanzees harboring chronic genotype 1 infections resulted in significant decreases in viral load after both single‐ and multiple‐dose treatments, viral breakthrough proved to be a concern, thus necessitating the development of compounds with increased potency against a number of genotypes and NS5A resistance mutations. Modification of the MK‐4882 core scaffold by introduction of a cyclic constraint afforded a series of tetracyclic inhibitors, which showed improved virologic profiles. Herein we describe the research efforts that led to the discovery of MK‐8742, a tetracyclic indole‐based NS5A inhibitor, which is currently in phase 2b clinical trials as part of an all‐oral, interferon‐free regimen for the treatment of HCV infection.
Effective treatment of chronic hepatitis C with direct‐acting antivirals will require combination therapy with multiple agents that target different steps in the viral replication cycle and impose a high barrier to resistance. MK‐8742 is a potent inhibitor of hepatitis C virus non‐structural protein 5A (HCV NS5A) that is being developed as a component of an once‐daily, all‐oral, interferon‐free regimen for the treatment of chronic HCV infection.
Early empiric antibiotic therapy in patients can improve clinical outcomes in Gram-negative bacteraemia. However, the widespread prevalence of antibiotic-resistant pathogens compromises our ability ...to provide adequate therapy while minimizing use of broad antibiotics. We sought to determine whether readily available electronic medical record data could be used to develop predictive models for decision support in Gram-negative bacteraemia.
We performed a multi-centre cohort study, in Canada and the USA, of hospitalized patients with Gram-negative bloodstream infection from April 2010 to March 2015. We analysed multivariable models for prediction of antibiotic susceptibility at two empiric windows: Gram-stain-guided and pathogen-guided treatment. Decision-support models for empiric antibiotic selection were developed based on three clinical decision thresholds of acceptable adequate coverage (80%, 90% and 95%).
A total of 1832 patients with Gram-negative bacteraemia were evaluated. Multivariable models showed good discrimination across countries and at both Gram-stain-guided (12 models, areas under the curve (AUCs) 0.68–0.89, optimism-corrected AUCs 0.63–0.85) and pathogen-guided (12 models, AUCs 0.75–0.98, optimism-corrected AUCs 0.64–0.95) windows. Compared to antibiogram-guided therapy, decision-support models of antibiotic selection incorporating individual patient characteristics and prior culture results have the potential to increase use of narrower-spectrum antibiotics (in up to 78% of patients) while reducing inadequate therapy.
Multivariable models using readily available epidemiologic factors can be used to predict antimicrobial susceptibility in infecting pathogens with reasonable discriminatory ability. Implementation of sequential predictive models for real-time individualized empiric antibiotic decision-making has the potential to both optimize adequate coverage for patients while minimizing overuse of broad-spectrum antibiotics, and therefore requires further prospective evaluation.
Readily available epidemiologic risk factors can be used to predict susceptibility of Gram-negative organisms among patients with bacteraemia, using automated decision-making models.
No effective pharmacological or non-pharmacological interventions exist for patients with long COVID. We aimed to describe recovery 1 year after hospital discharge for COVID-19, identify factors ...associated with patient-perceived recovery, and identify potential therapeutic targets by describing the underlying inflammatory profiles of the previously described recovery clusters at 5 months after hospital discharge.
The Post-hospitalisation COVID-19 study (PHOSP-COVID) is a prospective, longitudinal cohort study recruiting adults (aged ≥18 years) discharged from hospital with COVID-19 across the UK. Recovery was assessed using patient-reported outcome measures, physical performance, and organ function at 5 months and 1 year after hospital discharge, and stratified by both patient-perceived recovery and recovery cluster. Hierarchical logistic regression modelling was performed for patient-perceived recovery at 1 year. Cluster analysis was done using the clustering large applications k-medoids approach using clinical outcomes at 5 months. Inflammatory protein profiling was analysed from plasma at the 5-month visit. This study is registered on the ISRCTN Registry, ISRCTN10980107, and recruitment is ongoing.
2320 participants discharged from hospital between March 7, 2020, and April 18, 2021, were assessed at 5 months after discharge and 807 (32·7%) participants completed both the 5-month and 1-year visits. 279 (35·6%) of these 807 patients were women and 505 (64·4%) were men, with a mean age of 58·7 (SD 12·5) years, and 224 (27·8%) had received invasive mechanical ventilation (WHO class 7–9). The proportion of patients reporting full recovery was unchanged between 5 months (501 25·5% of 1965) and 1 year (232 28·9% of 804). Factors associated with being less likely to report full recovery at 1 year were female sex (odds ratio 0·68 95% CI 0·46–0·99), obesity (0·50 0·34–0·74) and invasive mechanical ventilation (0·42 0·23–0·76). Cluster analysis (n=1636) corroborated the previously reported four clusters: very severe, severe, moderate with cognitive impairment, and mild, relating to the severity of physical health, mental health, and cognitive impairment at 5 months. We found increased inflammatory mediators of tissue damage and repair in both the very severe and the moderate with cognitive impairment clusters compared with the mild cluster, including IL-6 concentration, which was increased in both comparisons (n=626 participants). We found a substantial deficit in median EQ-5D-5L utility index from before COVID-19 (retrospective assessment; 0·88 IQR 0·74–1·00), at 5 months (0·74 0·64–0·88) to 1 year (0·75 0·62–0·88), with minimal improvements across all outcome measures at 1 year after discharge in the whole cohort and within each of the four clusters.
The sequelae of a hospital admission with COVID-19 were substantial 1 year after discharge across a range of health domains, with the minority in our cohort feeling fully recovered. Patient-perceived health-related quality of life was reduced at 1 year compared with before hospital admission. Systematic inflammation and obesity are potential treatable traits that warrant further investigation in clinical trials.
UK Research and Innovation and National Institute for Health Research.
The aim of this systematic review is to describe QoL in individuals with PFP, and determine the impact of PFP interventions on QoL.
Five databases were searched for studies reporting QoL in ...individuals with PFP, with mean age under 50 years. Data were pooled based on QoL tool (e.g. Knee Injury and Osteoarthritis Outcome Score KOOS QoL subscale, Short-Form 36 item health survey SF-36) using random-effects models, or through narrative synthesis where inadequate data were available.
Individuals with PFP, had worse KOOS-QOL scores (pooled mean: 4795% CI: 34 to 61 and health-related QoL (pooled SF-36 PCS and MCS: 4795% CI: 41 to 53 and 5495% CI: 47 to 62, respectively) compared with pain-free controls and population norms. Physical interventions were associated with improvements in knee- and health-related QoL in individuals with PFP in repeated measures studies. However, the effect of physical interventions compared to a control treatment was conflicting.
Individuals with PFP aged under 50 years, have markedly reduced knee- and health-related QoL compared to pain-free controls and population norms. Knee- and health-related QoL may improve following intervention, but it is unclear if these improvements are greater than that which occur in a control group.
•People with patellofemoral pain have impaired quality of life.•Quality of life is worse than the general population.•Quality of life is worse than pain-free people.•Physical therapy may improve quality of life.
The intestinal microbiome has been associated with response to immune checkpoint inhibitors (ICIs) in humans and causally implicated in ICI responsiveness in animal models. Two recent human trials ...demonstrated that fecal microbiota transplant (FMT) from ICI responders can rescue ICI responses in refractory melanoma, but FMT has specific limitations to scaled use.
We conducted an early-phase clinical trial of a cultivated, orally delivered 30-species microbial consortium (Microbial Ecosystem Therapeutic 4, MET4) designed for co-administration with ICIs as an alternative to FMT and assessed safety, tolerability and ecological responses in patients with advanced solid tumors.
The trial achieved its primary safety and tolerability outcomes. There were no statistically significant differences in the primary ecological outcomes; however, differences in MET4 species relative abundance were evident after randomization that varied by patient and species. Increases in the relative abundance of several MET4 taxa, including Enterococcus and Bifidobacterium, taxa previously associated with ICI responsiveness, were observed and MET4 engraftment was associated with decreases in plasma and stool primary bile acids.
This trial is the first report of the use of a microbial consortium as an alternative to FMT in advanced cancer patients receiving ICI and the results justify the further development of microbial consortia as a therapeutic co-intervention for ICI treatment in cancer.
•MET4-IO is a first-in-class oral multi-strain microbiome therapeutic in advanced cancer patients receiving immunotherapy.•The trial achieved its primary safety and tolerability outcomes.•No differences in the primary ecological outcomes were observed.•Differences in MET4 species relative abundance were evident after randomization that varied by patient and species.•The efficacy of MET4 with anti-PD1 will be explored in a phase II study in advanced head and neck cancer patients.
This study was undertaken to investigate the population structure of U.S. rice (Oryza sativa L.). A total of 115 U.S. rice cultivars and 30 ancestral accessions introduced from Asia were genotyped by ...means of 169 simple sequence repeat (SSR) markers that are well distributed throughout the rice genome. SSR-based clustering analysis identified three groups of U.S. rice cultivars that were recognizable as temperate japonica with short to medium grains, tropical japonica with medium grains, and tropical japonica with long grains. Indica cultivars were represented among ancestral accessions, but always clustered independently. Indica germplasm has been used for cultivar improvement, but never directly in U.S. rice production. Cluster analysis of cultivars based on four time periods representing their first release date or introduction (1900-1929, 1930-1959, 1960-1979, and 1980-2000) resulted in the identification of the same three groups. This suggests that the population structure in U.S. rice was established before 1930 and remains essentially intact today, despite a large amount of controlled crossing and artificial selection as a part of the breeding process. Fifty-seven percent of U.S. rice cultivars were developed from intragroup crosses, indicating the availability of substantial genetic variability within each group. Similar results were obtained using genetic distance-based and model-based clustering methods. Information about population structure and associated phenotypic characteristics recognized by geneticists and breeders paves the way for coordinated association mapping studies in the future.
IntroductionThis double-blind, randomised controlled trial (RCT) aims to estimate the effect of a physiotherapist-led intervention with targeted strengthening compared with a physiotherapist-led ...intervention with standardised stretching, on hip-related quality of life (QOL) or perceived improvement at 6 months in people with femoroacetabular impingement (FAI) syndrome. We hypothesise that at 6 months, targeted strengthening physiotherapist-led treatment will be associated with greater improvements in hip-related QOL or greater patient-perceived global improvement when compared with standardised stretching physiotherapist-led treatment.Methods and analysisWe will recruit 164 participants with FAI syndrome who will be randomised into one of the two intervention groups, both receiving one-on-one treatment with the physiotherapist over 6 months. The targeted strengthening physiotherapist-led treatment group will receive a personalised exercise therapy and education programme. The standardised stretching physiotherapist-led treatment group will receive standardised stretching and personalised education programme. Primary outcomes are change in hip-related QOL using International Hip Outcome Tool-33 and patient-perceived global improvement. Secondary outcomes include cost-effectiveness, muscle strength, range of motion, functional task performance, biomechanics, hip cartilage structure and physical activity levels. Statistical analyses will make comparisons between both treatment groups by intention to treat, with all randomised participants included in analyses, regardless of protocol adherence. Linear mixed models (with baseline value as a covariate and treatment condition as a fixed factor) will be used to evaluate the treatment effect and 95% CI at primary end-point (6 months).Ethics and disseminationThe study protocol was approved (La Trobe University Human Ethics Committee (HEC17-080)) and prospectively registered with the Australian New Zealand Clinical Trials Registry. The findings of this RCT will be disseminated through peer reviewed scientific journals and conferences. Patients were involved in study development and will receive a short summary following the completion of the RCT.Trial registration numberACTRN12617001350314
PDF
