Initial catalyst dormancy has been mitigated for the enantioselective polymerization of propylene oxide using a tethered bimetallic chromium(III) salen complex. A detailed mechanistic study provided ...insight into the species responsible for this induction period and guided efforts to remove them. High-resolution electrospray ionization–mass spectrometry and density functional theory computations revealed that a μ-hydroxide and a bridged 1,2-hydroxypropanolate complex are present during the induction period. Kinetic studies and additional computation indicated that the μ-hydroxide complex is a short-lived catalyst arrest state, where hydroxide dissociation from one metal allows for epoxide enchainment to form the 1,2-hydroxypropanolate arrest state. While investigating anion dependence on the induction period, it became apparent that catalyst activation was the main contributor for dormancy. Using a 1,2-diol or water as chain transfer agents (CTAs) led to longer induction periods as a result of increased 1,2-hydroxyalkanolate complex formation. With a minor catalyst modification, rigorous drying conditions, and avoiding 1,2-diols as CTAs, the induction period was essentially removed.
Schistosomiasis is a major neglected tropical disease (NTD) affecting both humans and animals. The morbidity and mortality inflicted upon livestock in the Afrotropical region has been largely ...overlooked, in part due to a lack of validated sensitive and specific tests, which do not require specialist training or equipment to deliver and interpret. As stressed within the recent WHO NTD 2021-2030 Roadmap and Revised Guideline for schistosomiasis, inexpensive, non-invasive, and sensitive diagnostic tests for livestock-use would also facilitate both prevalence mapping and appropriate intervention programmes. The aim of this study was to assess the sensitivity and specificity of the currently available point-of-care circulating cathodic antigen test (POC-CCA), designed for Schistosoma mansoni detection in humans, for the detection of intestinal livestock schistosomiasis caused by Schistosoma bovis and Schistosoma curassoni. POC-CCA, together with the circulating anodic antigen (CAA) test, miracidial hatching technique (MHT), Kato-Katz (KK) and organ and mesentery inspection (for animals from abattoirs only), were applied to samples collected from 195 animals (56 cattle and 139 small ruminants (goats and sheep) from abattoirs and living populations) from Senegal. POC-CCA sensitivity was greater in the S. curassoni-dominated Barkedji livestock, both for cattle (median 81%; 95% credible interval (CrI): 55%-98%) and small ruminants (49%; CrI: 29%-87%), than in the S. bovis-dominated Richard Toll ruminants (cattle: 62%; CrI: 41%-84%; small ruminants: 12%, CrI: 1%-37%). Overall, sensitivity was greater in cattle than in small ruminants. Small ruminants POC-CCA specificity was similar in both locations (91%; CrI: 77%-99%), whilst cattle POC-CCA specificity could not be assessed owing to the low number of uninfected cattle surveyed. Our results indicate that, whilst the current POC-CCA does represent a potential diagnostic tool for cattle and possibly for predominantly S. curassoni-infected livestock, future work is needed to develop parasite- and/or livestock-specific affordable and field-applicable diagnostic tests to enable determination of the true extent of livestock schistosomiasis.
Due to the extensive use of botanical dietary supplements by consumers in the United States, there is a need for appropriate research and data to support safety assessments. Complexity and ...variability, both natural and introduced, of botanical dietary supplements make research on these products difficult. Botanical dietary supplements are regulated by the Food and Drug Administration (FDA) under the Federal Food, Drug, and Cosmetic Act (FD&C Act), as amended by the 1994 Dietary Supplement Health and Education Act (DSHEA). They are regulated as a category of food, which differs from the regulation of pharmaceutical products. Both manufacturers and the FDA are faced with the challenge of determining the best approaches for evaluating and monitoring the safety of botanical products. High quality botanicals research requires accurate identification and characterization of the material being studied. Inconsistent results in efficacy studies of botanical dietary supplements have led to efforts to improve the rigor and reproducibility of research in the field. Addressing the challenges associated with botanical dietary supplement safety is a global effort requiring coordination between numerous stakeholders, including researchers, suppliers, manufacturers, and regulators, all of whom play a role in ensuring that high quality products are available on the market.
•The use of botanical dietary supplements is widespread in the United States.•High quality botanicals research requires accurate characterization of products.•The complexity and variability of these supplements present many challenges.•Both manufacturers and regulators are responsible for the safety of these products.•Addressing the challenges in botanical safety is an important public health goal.
Protein aggregation is an established pathogenic mechanism in Alzheimer's disease, but little is known about the initiation of this process in vivo. Intracerebral injection of dilute, amyloid-β ...(Aβ)-containing brain extracts from humans with Alzheimer's disease or β-amyloid precursor protein (APP) transgenic mice induced cerebral β-amyloidosis and associated pathology in APP transgenic mice in a time- and concentration-dependent manner. The seeding activity of brain extracts was reduced or abolished by Aβ immunodepletion, protein denaturation, or by Aβ immunization of the host. The phenotype of the exogenously induced amyloidosis depended on both the host and the source of the agent, suggesting the existence of polymorphic Aβ strains with varying biological activities reminiscent of prion strains.
Health anxiety (HA), or hypochondriasis, is a psychological problem characterized by a preoccupation with the belief that one is physically unwell. A 2007 Cochrane review (Thomson and Page, 2007) ...found cognitive behavioural therapy (CBT) to be an effective intervention for individuals with HA. Similar findings were reported in a recent meta-analysis (Olatunji et al., 2014), which did not employ a systematic search strategy. The current review aimed to investigate the efficacy of CBT for HA, and to update the existing reviews.
A systematic search was conducted following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidance, including randomized controlled trials that compared CBT with a control condition for people with HA. Five hundred and sixty-seven studies were found in the original search, of which 14 were included in the meta-analysis.
Meta-analysis was conducted on 21 comparisons and a large effect size for CBT compared with a control condition was found at post therapy d = 1.01 (95% confidence interval 0.77-1.25), as well as at 6- and 12-month follow-up.
This systematic review and meta-analysis provides support for the hypothesis that CBT is an effective intervention for HA when compared with a variety of control conditions, e.g. treatment-as-usual, waiting list, medication, and other psychological therapies.
Biodiversity hotspots, which harbor more endemic species than elsewhere on Earth, are increasingly threatened. There is a need to accelerate collection efforts in these regions before threatened or ...endangered species become extinct. The diverse geographical, ecological, genetic, morphological, and behavioral data generated from the on-site collection of an individual specimen are useful for many scientific purposes. However, traditional methods for specimen preparation in the field do not permit researchers to retrieve neuroanatomical data, disregarding potentially useful data for increasing our understanding of brain diversity. These data have helped clarify brain evolution, deciphered relationships between structure and function, and revealed constraints and selective pressures that provide context about the evolution of complex behavior. Here, we report our field-testing of two commonly used laboratory-based techniques for brain preservation while on a collecting expedition in the Congo Basin and Albertine Rift, two poorly known regions associated with the Eastern Afromontane biodiversity hotspot. First, we found that transcardial perfusion fixation and long-term brain storage, conducted in remote field conditions with no access to cold storage laboratory equipment, had no observable impact on cytoarchitectural features of lizard brain tissue when compared to lizard brain tissue processed under laboratory conditions. Second, field-perfused brain tissue subjected to prolonged post-fixation remained readily compatible with subsequent immunohistochemical detection of neural antigens, with immunostaining that was comparable to that of laboratory-perfused brain tissue. Third, immersion-fixation of lizard brains, prepared under identical environmental conditions, was readily compatible with subsequent iodine-enhanced X-ray microcomputed tomography, which facilitated the non-destructive imaging of the intact brain within its skull. In summary, we have validated multiple approaches to preserving intact lizard brains in remote field conditions with limited access to supplies and a high degree of environmental exposure. This protocol should serve as a malleable framework for researchers attempting to rescue perishable and irreplaceable morphological and molecular data from regions of disappearing biodiversity. Our approach can be harnessed to extend the numbers of species being actively studied by the neuroscience community, by reducing some of the difficulty associated with acquiring brains of animal species that are not readily available in captivity.
There is increasing interest in applying systems Human Factors and Ergonomics (HFE) methods in sport. Risk assessment (RA) methods can be used identify risks which may impact the performance of ...individual athletes, teams, and overall sports systems; however, they have not yet been tested in sport. This study sets out to apply and compare three systems thinking-based RA methods in the context of elite sports performance and report on the frequency and types of the risks identified. The Systems-Theoretic Process Analysis (STPA) method, the Event Analysis of Systemic Teamwork Broken Links (EAST-BL) method, and the Networked Hazard Analysis and Risk Management System (Net-HARMS) method were applied to elite women's road cycling to identify all the credible risks that could degrade optimal team performance. The findings demonstrate that all three methods appear to provide useful results in a context other than safety, and that multiple risks threatening the performance of the cycling team were identified. Whilst the frequency and types of risks differed across the methods applied, there are additional theoretical, methodological, and practical implications to be considered prior to the selection and use of systems thinking-based RA approaches. Recommendations and directions for future HFE and sports science research are discussed.
•There is a growing interest around applying systems Human Factors and Ergonomics methods in sport.•This study applied and compared three risk assessment methods to sports performance: STPA, EAST-BL, and Net-HARMS.•All three risk assessment methods identified credible risks that could degrade the optimal performance of an elite cycling team.•There is a need for further, systems thinking-based risk assessment and Human Factors and Ergonomics methods in sport.
Septic shock is common and has unacceptably high morbidity, mortality, and associated cost with numerous failed attempts at developing effective therapies. Endotoxin, one of the most potent mediators ...of sepsis, is found in high levels in approximately 50% of patients with septic shock. Polymyxin B (PMX) hemoperfusion has been shown in numerous studies to successfully remove endotoxin and potentially improve outcomes. EUPHRATES (Evaluating the Use of Polymyxin B Hemoperfusion in a Randomized controlled trial of Adults Treated for Endotoxemia and Septic shock) is a theragnostic trial (matching blood measurement to treatment capability) of PMX hemoperfusion in patients with septic shock and confirmed endotoxemia as measured by the endotoxin activity assay (EAA).
EUPHRATES is a pivotal regulatory trial that is multi-centered, placebo-controlled and blinded. The trial is being conducted in fifty ICUs in the United States and Canada and is powered to enroll 360 patients. Patients with persistent septic shock despite adequate fluid resuscitation on vasopressors for more than 2 and less than 30 hours are eligible for measurement of the EAA. Those with EAA ≥0.60 are eligible to be randomized to treatment with two sessions of PMX hemoperfusion 24 hours apart. The primary endpoint for the trial is 28-day all-cause mortality.
Unique features of the trial include absence of systemic inflammatory response (SIRS) criteria as a requirement for inclusion, use of the EAA to confirm endotoxemia as a requisite for treatment, and use of a detailed "façade" hemoperfusion event as a blinding mechanism. The outcomes of the second interim analysis included a resizing of the trial to 650 patients and the addition of an exclusion criterion of subjects with multiple organ dysfunction score (MODS) ≤ 9. Results are anticipated in 2016.
Clinicaltrials.gov identifier: NCT01046669. Registered: January 8, 2010.
The systems thinking tenets were developed based on a synthesis of contemporary accident causation theory, models and approaches and encapsulate 15 features of complex systems that interact to create ...both safety and adverse events. Whilst initial testing provided supportive evidence, the tenets have not yet been subject to formal validation. This article presents the findings from a three-round Delphi study undertaken to refine and validate the tenets and assess their suitability for inclusion in a unified model of accident causation. Participants with expertise in accident causation and systems thinking provided feedback on the tenets and associated definitions until an acceptable level of consensus was achieved. The results reduced the original 15 tenets to 14 and 10 were identified as important to include in unified model of accident causation. The refined systems thinking tenets are presented along with future research directions designed to facilitate their use in safety practice.
Practitioner summary: This article presents a refined and validated set of systems thinking tenets which describe features of complex systems that interact to create adverse events. The tenets can be used by practitioners to proactively identify safety leading indicators and contributory factors during adverse event analysis.
Congenital adrenal hyperplasia with apparent combined P450C17 and P450C21 deficiency is associated with accumulation of steroid metabolites, indicating impaired activity of 17α-hydroxylase and ...21-hydroxylase. However, no mutations have been reported in the CYP17 and CYP21 genes, which encode these P450 enzymes. Affected girls are born with ambiguous genitalia, but their circulating androgens are low, and virilisation does not progress. We aimed to investigate the underlying molecular basis of congenital adrenal hyperplasia with apparent combined P450C17 and P450C21 deficiency in affected children.
We did sequence analysis of the human gene encoding P450 oxidoreductase, an enzyme that is important in electron transfer from NADPH to P450C17 and P450C21. We studied two unrelated families with a total of three affected children and 100 healthy controls. Wild-type and mutant P450 oxidoreductase proteins were bacterially expressed, purified, and assayed for cytochrome c reductase activity.
We identified four mutations encoding single aminoacid changes in P450 oxidoreductase. All patients were compound heterozygotes, whereas their parents and an unaffected sibling harboured a mutation in only one allele. By contrast, no mutations were noted in the controls. Bacterial expression of recombinant mutant proteins revealed deficient or reduced enzyme activity.
Molecular pathogenesis of this form of congenital adrenal hyperplasia is caused by mutations in the gene encoding P450 oxidoreductase. Deficiency of this enzyme could suggest an alternative pathway in human androgen synthesis, present only in fetal life, which explains the combination of antenatal androgen excess and postnatal androgen deficiency.
Published online June 14,2004 http://image.thelancet.com/extras/04art4419web.pdf
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