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Class Ib Ribonucleotide Reductases: Activation of a Peroxido-MnIIMnIII to Generate a Reactive Oxo-MnIIIMnIV Oxidant.
Doyle, L, Magherusan, A, Xu, S, Murphy, K, Farquhar, ER, Molton, F, Duboc, C, Que, L, McDonald, AR
Inorganic chemistry. 2024;(4):2194-2203
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Abstract
In the postulated catalytic cycle of class Ib Mn2 ribonucleotide reductases (RNRs), a MnII2 core is suggested to react with superoxide (O2·-) to generate peroxido-MnIIMnIII and oxo-MnIIIMnIV entities prior to proton-coupled electron transfer (PCET) oxidation of tyrosine. There is limited experimental support for this mechanism. We demonstrate that [MnII2(BPMP)(OAc)2](ClO4) (1, HBPMP = 2,6-bis[(bis(2 pyridylmethyl)amino)methyl]-4-methylphenol) was converted to peroxido-MnIIMnIII (2) in the presence of superoxide anion that converted to (μ-O)(μ-OH)MnIIIMnIV (3) via the addition of an H+-donor (p-TsOH) or (μ-O)2MnIIIMnIV (4) upon warming to room temperature. The physical properties of 3 and 4 were probed using UV-vis, EPR, X-ray absorption, and IR spectroscopies and mass spectrometry. Compounds 3 and 4 were capable of phenol oxidation to yield a phenoxyl radical via a concerted PCET oxidation, supporting the proposed mechanism of tyrosyl radical cofactor generation in RNRs. The synthetic models demonstrate that the postulated O2/Mn2/tyrosine activation mechanism in class Ib Mn2 RNRs is plausible and provides spectral insights into intermediates currently elusive in the native enzyme.
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Cost-effectiveness and willing-to-pay thresholds for vertebral augmentation of osteoporotic vertebral fractures, what are they based on: a systematic review.
Pron, G, Hwang, M, Nasralla, M, Smith, R, Cheung, A, Murphy, K
BMJ open. 2023;(7):e062832
Abstract
OBJECTIVE Although there is substantial clinical evidence on the safety and effectiveness of vertebral augmentation for osteoporotic vertebral fractures, cost-effectiveness is less well known. The objective of this study is to provide a systematic review of cost-effectiveness studies and policy-based willingness-to-pay (WTP) thresholds for different vertebral augmentation (VA) procedures, vertebroplasty (VP) and balloon kyphoplasty (BK), for osteoporotic vertebral fractures (OVFs). DESIGN A systematic review targeting cost-effectiveness studies of VA procedures for OVFs. DATA SOURCES Six bibliographic databases were searched from inception up to May 2021. ELIGIBILITY CRITERIA FOR STUDY SELECTION Studies were eligible if meeting all predefined criteria: (1) VP or BK intervention, (2) OVFs and (3) cost-effectiveness study. Articles not written in English, abstracts, editorials, reviews and those reporting only cost data were excluded. DATA EXTRACTION AND SYNTHESIS Information was extracted on study characteristics, cost-effective estimates, summary decisions and payer WTP thresholds. Incremental cost-effective ratio (ICER) was the main outcome measure. Studies were summarised by a structured narrative synthesis organised by comparisons with conservative management (CM). Two independent reviewers assessed the quality (risk of bias) of the systematic review and cost-effectiveness studies by peer-reviewed checklists. RESULTS We identified 520 references through database searching and 501 were excluded as ineligible by titles and abstract. Ten reports were identified as eligible from 19 full-text reviews. ICER for VP versus CM evaluated as cost per quality-adjusted life-year (QALY) ranged from €22 685 (*US$33 395) in Netherlands to £-2240 (*US$-3273), a cost-saving in the UK. ICERs for BK versus CM ranged from £2706 (*US$3954) in UK to kr600 000 (*US$90 910) in Sweden. ICERs were within payer WTP thresholds for a QALY based on historical benchmarks. CONCLUSIONS Both VP and BK were judged cost-effective alternatives to CM for OVFs in economic studies and were within WTP thresholds in multiple healthcare settings.
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Correlates of physical activity and sedentary behavior in adults living with overweight and obesity: A systematic review.
Curran, F, Davis, ME, Murphy, K, Tersigni, N, King, A, Ngo, N, O'Donoghue, G
Obesity reviews : an official journal of the International Association for the Study of Obesity. 2023;(11):e13615
Abstract
Overweight and obesity are consistently associated with lower physical activity (PA) levels and greater sedentary behavior (SB) in population studies. To date, no review has evaluated the factors associated with these behaviors in the specific population who have developed obesity/overweight. The aim of this systematic review was to identify the correlates/determinants of SB and PA in adults with overweight and obesity. Five databases were searched for studies, which reported factors or outcomes relating to PA or SB in adults living with overweight/obesity, published from 1980 to 2021. The factors were categorized using a socioecological model, strength, and direction of association. Of 34,058 articles retrieved, 45 studies were included, and 155 factors were identified. Self-efficacy, intrinsic motivation, exercise enjoyment, self-perceived good health, and social support were consistently associated with higher levels of PA. Consistent negative correlations were married females, increased BMI, obesity severity, pain, number of comorbidities, lack of time, energy, and willpower, and hilly terrain. Few studies (n = 12) examined SB, and no evidence for consistent associations were found. This review identified several correlates specific to PA in this population. Further studies are required to identify directionality and distal correlates for PA and all correlate levels of SB.
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2021 American College of Rheumatology Guideline for the Treatment of Juvenile Idiopathic Arthritis: Recommendations for Nonpharmacologic Therapies, Medication Monitoring, Immunizations, and Imaging.
Onel, KB, Horton, DB, Lovell, DJ, Shenoi, S, Cuello, CA, Angeles-Han, ST, Becker, ML, Cron, RQ, Feldman, BM, Ferguson, PJ, et al
Arthritis care & research. 2022;(4):505-520
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OBJECTIVE To provide recommendations for the management of juvenile idiopathic arthritis (JIA) with a focus on nonpharmacologic therapies, medication monitoring, immunizations, and imaging, irrespective of JIA phenotype. METHODS We developed clinically relevant Patient/Population, Intervention, Comparison, and Outcomes questions. After conducting a systematic literature review, the Grading of Recommendations Assessment, Development and Evaluation approach was used to rate the quality of evidence (high, moderate, low, or very low). A Voting Panel including clinicians and patients/caregivers achieved consensus on the direction (for or against) and strength (strong or conditional) of recommendations. RESULTS Recommendations in this guideline include the use of physical therapy and occupational therapy interventions; a healthy, well-balanced, age-appropriate diet; specific laboratory monitoring for medications; widespread use of immunizations; and shared decision-making with patients/caregivers. Disease management for all patients with JIA is addressed with respect to nonpharmacologic therapies, medication monitoring, immunizations, and imaging. Evidence for all recommendations was graded as low or very low in quality. For that reason, more than half of the recommendations are conditional. CONCLUSION This clinical practice guideline complements the 2019 American College of Rheumatology JIA and uveitis guidelines, which addressed polyarthritis, sacroiliitis, enthesitis, and uveitis, and a concurrent 2021 guideline on oligoarthritis, temporomandibular arthritis, and systemic JIA. It serves as a tool to support clinicians, patients, and caregivers in decision-making. The recommendations take into consideration the severity of both articular and nonarticular manifestations as well as patient quality of life. Although evidence is generally low quality and many recommendations are conditional, the inclusion of caregivers and patients in the decision-making process strengthens the relevance and applicability of the guideline. It is important to remember that these are recommendations. Clinical decisions, as always, should be made by the treating clinician and patient/caregiver.
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2021 American College of Rheumatology Guideline for the Treatment of Juvenile Idiopathic Arthritis: Recommendations for Nonpharmacologic Therapies, Medication Monitoring, Immunizations, and Imaging.
Onel, KB, Horton, DB, Lovell, DJ, Shenoi, S, Cuello, CA, Angeles-Han, ST, Becker, ML, Cron, RQ, Feldman, BM, Ferguson, PJ, et al
Arthritis & rheumatology (Hoboken, N.J.). 2022;(4):570-585
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Abstract
OBJECTIVE To provide recommendations for the management of juvenile idiopathic arthritis (JIA) with a focus on nonpharmacologic therapies, medication monitoring, immunizations, and imaging, irrespective of JIA phenotype. METHODS We developed clinically relevant Patient/Population, Intervention, Comparison, and Outcomes questions. After conducting a systematic literature review, the Grading of Recommendations Assessment, Development and Evaluation approach was used to rate the quality of evidence (high, moderate, low, or very low). A Voting Panel including clinicians and patients/caregivers achieved consensus on the direction (for or against) and strength (strong or conditional) of recommendations. RESULTS Recommendations in this guideline include the use of physical therapy and occupational therapy interventions; a healthy, well-balanced, age-appropriate diet; specific laboratory monitoring for medications; widespread use of immunizations; and shared decision-making with patients/caregivers. Disease management for all patients with JIA is addressed with respect to nonpharmacologic therapies, medication monitoring, immunizations, and imaging. Evidence for all recommendations was graded as low or very low in quality. For that reason, more than half of the recommendations are conditional. CONCLUSION This clinical practice guideline complements the 2019 American College of Rheumatology JIA and uveitis guidelines, which addressed polyarthritis, sacroiliitis, enthesitis, and uveitis, and a concurrent 2021 guideline on oligoarthritis, temporomandibular arthritis, and systemic JIA. It serves as a tool to support clinicians, patients, and caregivers in decision-making. The recommendations take into consideration the severity of both articular and nonarticular manifestations as well as patient quality of life. Although evidence is generally low quality and many recommendations are conditional, the inclusion of caregivers and patients in the decision-making process strengthens the relevance and applicability of the guideline. It is important to remember that these are recommendations. Clinical decisions, as always, should be made by the treating clinician and patient/caregiver.
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Acute effects of MDMA on trust, cooperative behaviour and empathy: A double-blind, placebo-controlled experiment.
Borissova, A, Ferguson, B, Wall, MB, Morgan, CJ, Carhart-Harris, RL, Bolstridge, M, Bloomfield, MA, Williams, TM, Feilding, A, Murphy, K, et al
Journal of psychopharmacology (Oxford, England). 2021;(5):547-555
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Abstract
BACKGROUND 3,4-Methylenedioxymethamphetamine (MDMA) is being actively researched as an adjunct to psychotherapy. It may be beneficial to trust, empathy and cooperative behaviour due to its acute prosocial effects. AIM: To test (a) the acute effects of MDMA on measures of empathy, trust and cooperative behaviour, and (b) subacute changes in mood three days after MDMA administration. METHODS Twenty-five participants (n=7 female), participated in this double-blind, repeated-measures, placebo-controlled experiment. Participants attended two acute sessions, one week apart. Each acute session was followed by a subacute session three days later. Participants received placebo (100 mg ascorbic acid) during one acute session, and MDMA (100 mg MDMA-HCl) at the other, with order counterbalanced. Participants completed the following tasks assessing prosocial behaviour: a trust investment task, a trustworthy face rating task, an empathic stories task, a public project game, a dictator game and an ultimatum game. Participants reported subjective effects. Blood was taken pre-drug, 2 and 4 hours post-drug, and tested for plasma MDMA levels. RESULTS MDMA acutely increased self-reported 'closeness to others' and 'euphoria' and increased plasma concentrations of MDMA. MDMA did not significantly change task-based empathy, trust or cooperative behaviour. Using Bayesian analyses, we found evidence that MDMA and placebo did not differ in their effects on empathy and cooperative behaviour. MDMA did not significantly change subacute mood and this was supported by our Bayesian analyses. CONCLUSION Despite augmentation in plasma MDMA levels and subjective drug effects, we found no increase in prosocial behaviour in a laboratory setting.
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Quinoa in Ecuador: Recent Advances under Global Expansion.
Hinojosa, L, Leguizamo, A, Carpio, C, Muñoz, D, Mestanza, C, Ochoa, J, Castillo, C, Murillo, A, Villacréz, E, Monar, C, et al
Plants (Basel, Switzerland). 2021;(2)
Abstract
Quinoa is a highly diverse crop domesticated in the Andean region of South America with broad adaptation to a wide range of marginal environments. Quinoa has garnered interest worldwide due to its nutritional and health benefits. Over the last decade, quinoa production has expanded outside of the Andean region, prompting multiple studies investigating the potential for quinoa cultivation in novel environments. Currently, quinoa is grown in countries spanning five continents, including North America, Europe, Asia, Africa, and Oceania. Here, we update the advances of quinoa research in Ecuador across different topics, including (a) current quinoa production situation with a focus on breeding progress, (b) traditional seed production, and (c) the impact of the work of the nongovernment organization "European Committee for Training and Agriculture" with quinoa farmers in Chimborazo province. Additionally, we discuss genetic diversity, primary pests and diseases, actions for adapting quinoa to tropical areas, and recent innovations in quinoa processing in Ecuador. Finally, we report a case study describing a participatory breeding project between Washington State University and the Association of Andean Seed and Nutritional Food Producers Mushuk Yuyay in the province of Cañar.
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Randomised, cOntrolled Multicentre trial of 26 weeks subcutaneous liraglutide (a glucagon-like peptide-1 receptor Agonist), with or without contiNuous positive airway pressure (CPAP), in patients with type 2 diabetes mellitus (T2DM) and obstructive sleep apnoEa (OSA) (ROMANCE): study protocol assessing the effects of weight loss on the apnea-hypnoea index (AHI).
Sprung, VS, Kemp, GJ, Wilding, JP, Adams, V, Murphy, K, Burgess, M, Emegbo, S, Thomas, M, Needham, AJ, Weimken, A, et al
BMJ open. 2020;(7):e038856
Abstract
INTRODUCTION Obstructive sleep apnoea (OSA) and type 2 diabetes mellitus (T2DM) often occur concurrently, and untreated OSA may potentially amplify the high risk of cardiovascular disease in T2DM. Compliance with continuous positive airway pressure (CPAP), the conventional treatment for OSA, can be poor and considering weight loss is the most effective treatment for OSA. This trial examines whether the glucagon-like peptide-1 receptor agonist liraglutide, a glucose-lowering therapy associated with significant weight loss used in T2DM, can improve the severity and symptoms of OSA. METHODS AND ANALYSIS This is an outpatient, single-centred, open-labelled, prospective, phase IV randomised controlled trial in a two-by-two factorial design. One hundred and thirty-two patients with newly diagnosed OSA (apnoea-hypopnoea index (AHI) ≥15 events/hour), and existing obesity and T2DM (glycated haemoglobin (HbA1c) ≥47 mmol/mol), will be recruited from diabetes and sleep medicine outpatient clinics in primary and secondary care settings across Liverpool. Patients will be allocated equally, using computer-generated random, permuted blocks of unequal sizes, to each of the four treatment arms for 26 weeks: (i) liraglutide (1.8 mg once per day) alone, (ii) liraglutide 1.8 mg once per day with CPAP, (iii) CPAP alone (conventional care) or (iv) no treatment (control). The primary outcome measure is change in OSA severity, determined by AHI. Secondary outcome measures include effects on glycaemic control (glycated haemoglobin (HbA1c)), body weight and quality of life measures. Exploratory measures include measures of physical activity, MRI-derived measures of regional body composition including fat mass (abdominal subcutaneous, visceral, neck and liver fat) and skeletal muscle mass (cross-sectional analysis of thigh), indices of cardiac function (using transthoracic echocardiography) and endothelial function. ETHICAL APPROVAL The study has been approved by the North West Liverpool Central Research Ethics Committee (14/NW/1019) and it is being conducted in accordance with the Declaration of Helsinki and Good Clinical Practice. TRIAL REGISTRATION NUMBERS ISRCTN16250774. EUDRACT No. 2014-000988-41. UTN U1111-1139-0677.
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Repeat JAK2 V617F testing in patients with suspected essential thrombocythaemia.
Kearney, L, Lee Tokar, L, Flynn, C, Mykytiv, V, Murphy, K, Langabeer, SE
Journal of clinical pathology. 2020;(11):772
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A study protocol for a randomised crossover study evaluating the effect of diets differing in carbohydrate quality on ileal content and appetite regulation in healthy humans.
Byrne, CS, Blunt, D, Burn, J, Chambers, E, Dagbasi, A, Franco Becker, G, Gibson, G, Mendoza, L, Murphy, K, Poveda, C, et al
F1000Research. 2019;:258
Abstract
Introduction: A major component of the digesta reaching the colon from the distal ileum is carbohydrate. This carbohydrate is subject to microbial fermentation and can radically change bacterial populations in the colon and the metabolites they produce, particularly short-chain fatty acids (SCFA). However, very little is currently known about the forms and levels of carbohydrate in the ileum and the composition of the ileal microbiota in humans. Most of our current understanding of carbohydrate that is not absorbed by the small intestine comes from ileostomy models, which may not reflect the physiology of an intact gastrointestinal tract. Methods: We will investigate how ileal content changes depending on diet using a randomised crossover study in healthy humans. Participants will be inpatients at the research facility for three separate 4-day visits. During each visit, participants will consume one of three diets, which differ in carbohydrate quality: 1) low-fibre refined diet; 2) high-fibre diet with intact cellular structures; 3) high-fibre diet where the cellular structures have been disrupted (e.g. milling, blending). On day 1, a nasoenteric tube will be placed into the distal ileum and its position confirmed under fluoroscopy. Ileal samples will be collected via the nasoenteric tube and metabolically profiled, which will determine the amount and type of carbohydrate present, and the composition of the ileal microbiota will be measured. Blood samples will be collected to assess circulating hormones and metabolites. Stool samples will be collected to assess faecal microbiota composition. Subjective appetite measures will be collected using visual analogue scales. Breath hydrogen will be measured in real-time as a marker of intestinal fermentation. Finally, an in vitro continuous fermentation model will be inoculated with ileal fluid in order to understand the shift in microbial composition and SCFA produced in the colon following the different diets. Registration: ISRCTN11327221.