Publications by authors named "Peter Wilson"

784 Publications

Chocolate consumption and risk of coronary artery disease: the Million Veteran Program.

Am J Clin Nutr 2021 May 1;113(5):1137-1144. Epub 2021 Mar 1.

VA Boston Healthcare System, Boston, MA, USA.

Background: Although previous studies have suggested cocoa products may promote cardiovascular health in the general population, no public data are available from patients receiving care in a national integrated health care system.

Objectives: We tested the hypothesis that regular chocolate consumption is associated with a lower risk of coronary artery disease (CAD) events among participants of the Million Veteran Program (MVP). Secondary analysis examined if the main hypothesis was observed among participants with type 2 diabetes.

Methods: We analyzed data from MVP participants who completed the food frequency section of the MVP Lifestyle Survey and were free of CAD at the time of survey completion. CAD events during follow-up (International Statistical Classification of Diseases Ninth Revision codes 410-411 and 413-414, and Tenth Revision codes I20-I25 except I25.2) were assessed using electronic health records. We fitted a Cox proportional hazard model to estimate the RR of CAD.

Results: Of 188,447 MVP enrollees with survey data, mean ± SD age was 64 ± 12.0 y and 90% were men. For regular chocolate (28.3 g/serving) consumption of <1 serving/mo, 1-3 servings/mo, 1 serving/wk, 2-4 servings/wk, and ≥5 servings/wk, crude incidence rates (per 1000 person-years) for fatal and nonfatal CAD events or coronary procedures were 20.2, 17.5, 16.7, 17.1, and 16.9, respectively, during a mean follow-up of 3.2 y. After adjusting for age, sex, race, and lifestyle factors, the corresponding HRs (95% CIs) were 1.00 (ref), 0.92 (0.87, 0.96), 0.88 (0.83, 0.93), 0.89 (0.84, 0.95), and 0.89 (0.84, 0.96), respectively ( for linear trend < 0.0001). In a secondary analysis of 47,265 diabetics, we did not observe a decreasing trend in CAD mortality among those who consumed ≥1 serving of chocolate a month compared with those who consumed <1 serving/mo.

Conclusions: Regular chocolate consumption was associated with a lower risk of CAD among veterans, but was not associated with cardiovascular disease risk in veterans with type 2 diabetes.
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http://dx.doi.org/10.1093/ajcn/nqaa427DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8412179PMC
May 2021

Generalizability of the REDUCE-IT trial and cardiovascular outcomes associated with hypertriglyceridemia among patients potentially eligible for icosapent ethyl therapy: An analysis of the REduction of Atherothrombosis for Continued Health (REACH) registry.

Int J Cardiol 2021 Aug 25. Epub 2021 Aug 25.

FACT (French Alliance for Cardiovascular Trials), Paris, France; Assistance Publique-Hôpitaux de Paris, Hôpital Bichat, and INSERM U1148, Paris, France; Université de Paris, Paris, France; NHLI Imperial College, ICMS, Royal Brompton Hospital, London, United Kingdom. Electronic address:

Background: The REDUCE-IT (Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial) trial demonstrated that high-dose icosapent-ethyl reduced the risk of ischemic events in statin-treated patients with elevated triglycerides (TG) and either atherosclerotic cardiovascular disease (ASCVD) or diabetes plus at least one risk factor.

Methods And Results: Using data from REACH (Reduction of Atherothrombosis for Continued Health), a large international registry of outpatients with or at risk of ASCVD, we evaluated the proportion of patients potentially eligible for enrolment in REDUCE-IT and compared their outcomes to those excluded because of low TG. Among 62,464 patients with either ASCVD or diabetes enrolled in the REACH Registry, 1036/8418 (12.3%) patients in primary prevention and 6049/54046 (11.2%) patients in secondary prevention (11.3% overall) would have been eligible for inclusion in REDUCE-IT. Compared with patients excluded for low TG level, adjusted risk of the primary composite outcome of cardiovascular death, non-fatal myocardial infarction (MI), non-fatal stroke, unstable angina, or coronary revascularization was higher in the REDUCE-IT eligible group (HR:1.06, 95%CI:1.00-1.13, p = 0.04). In addition, unstable angina, non-fatal MI, percutaneous coronary intervention and coronary artery bypass grafting were also more frequent in the REDUCE-IT eligible group (HR:1.17, 95%CI:1.07-1.27, p < 0.001; HR:1.25, 95%CI:1.07-1.45, p < 0.001; HR:1.42, 95%CI:1.27-1.57, p < 0.001; HR:1.43, 95%CI:1.19-1.71, p < 0.001, respectively), whereas the adjusted risk of non-fatal stroke was lower (HR:0.64, 95%CI:0.54-0.75, p < 0.001).

Conclusion: In this large international registry of patients with or at high-risk of ASCVD, 11.3% met the REDUCE-IT trial selection criteria. REDUCE-IT eligible patients were found to be at higher risk of cardiac atherothrombotic events, but at lower risk of stroke than trial-ineligible patients with lower TG.
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http://dx.doi.org/10.1016/j.ijcard.2021.08.031DOI Listing
August 2021

Thermal disinfection at sub-optimal temperature of Pseudomonas aeruginosa biofilm on copper pipe and shower hose materials.

J Hosp Infect 2021 Aug 21. Epub 2021 Aug 21.

Environmental Research Laboratory, University College London Hospital, 235 Euston Road, London NW1 2BU.

Background: Hospital acquired infections caused by Pseudomonas aeruginosa have been linked to contaminated shower systems in healthcare. Thermal disinfection whereby colonised outlets are flushed with existing hot water supplies is a commonly used method to disinfect contaminated systems. Temperatures of 60°C are recommended for inactivation of P. aeruginosa; however, this is often not achievable at outlets.

Aim: The aim of this study was to investigate whether thermal disinfection at a sub-optimal temperature (58°C) can effectively eradicate planktonic P. aeruginosa and biofilm adherent on copper piping and shower hoses. Exposure times of up to 60 minutes and efficacy of repeated cycles were evaluated.

Methods: A type culture and an environmental strain of P. aeruginosa isolated from a hospital shower were tested. Planktonic bacteria and biofilm adhered to sections of copper pipe and shower hoses were exposed to water at 58°C for up to 60 minutes. Biofilms were tested with static water, flushing water and repeated cycles of disinfection. Remaining viable bacteria after disinfection were enumerated.

Findings: Planktonic P. aeruginosa remained viable after up to 60 minutes thermal disinfection. With static water, biofilm was removed from copper piping after 15 minutes but remained viable in shower hoses up to 60 minutes. With thermal flushing, biofilm was fully eradicated from copper piping after 2 minutes but remained viable on shower hoses. Repeated cycles did not shorten thermal disinfection exposure times.

Conclusion: Thermal disinfection at 58°C was effective at eliminating biofilm on copper; however, biofilm on shower hoses remained viable after 60 minutes exposure.
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http://dx.doi.org/10.1016/j.jhin.2021.08.016DOI Listing
August 2021

Effect of antibiotic stewardship interventions in primary care on antimicrobial resistance of Escherichia coli bacteraemia in England (2013-18): a quasi-experimental, ecological, data linkage study.

Lancet Infect Dis 2021 Aug 4. Epub 2021 Aug 4.

Global Digital Health Unit, Faculty of Medicine, Imperial College London, London, UK. Electronic address:

Background: Antimicrobial resistance is a major global health concern, driven by overuse of antibiotics. We aimed to assess the effectiveness of a national antimicrobial stewardship intervention, the National Health Service (NHS) England Quality Premium implemented in 2015-16, on broad-spectrum antibiotic prescribing and Escherichia coli bacteraemia resistance to broad-spectrum antibiotics in England.

Methods: In this quasi-experimental, ecological, data linkage study, we used longitudinal data on bacteraemia for patients registered with a general practitioner in the English National Health Service and patients with E coli bacteraemia notified to the national mandatory surveillance programme between Jan 1, 2013, and Dec 31, 2018. We linked these data to data on antimicrobial susceptibility testing of E coli from Public Health England's Second-Generation Surveillance System. We did an ecological analysis using interrupted time-series analyses and generalised estimating equations to estimate the change in broad-spectrum antibiotics prescribing over time and the change in the proportion of E coli bacteraemia cases for which the causative bacteria were resistant to each antibiotic individually or to at least one of five broad-spectrum antibiotics (co-amoxiclav, ciprofloxacin, levofloxacin, moxifloxacin, ofloxacin), after implementation of the NHS England Quality Premium intervention in April, 2015.

Findings: Before implementation of the Quality Premium, the rate of antibiotic prescribing for all five broad-spectrum antibiotics was increasing at rate of 0·2% per month (incidence rate ratio [IRR] 1·002 [95% CI 1·000-1·004], p=0·046). After implementation of the Quality Premium, an immediate reduction in total broad-spectrum antibiotic prescribing rate was observed (IRR 0·867 [95% CI 0·837-0·898], p<0·0001). This effect was sustained until the end of the study period; a 57% reduction in rate of antibiotic prescribing was observed compared with the counterfactual situation (ie, had the Quality Premium not been implemented). In the same period, the rate of resistance to at least one broad-spectrum antibiotic increased at rate of 0·1% per month (IRR 1·001 [95% CI 0·999-1·003], p=0·346). On implementation of the Quality Premium, an immediate reduction in resistance rate to at least one broad-spectrum antibiotic was observed (IRR 0·947 [95% CI 0·918-0·977], p=0·0007). Although this effect was also sustained until the end of the study period, with a 12·03% reduction in resistance rate compared with the counterfactual situation, the overall trend remained on an upward trajectory. On examination of the long-term effect following implementation of the Quality Premium, there was an increase in the number of isolates resistant to at least one of the five broad-spectrum antibiotics tested (IRR 1·002 [1·000-1·003]; p=0·047).

Interpretation: Although interventions targeting antibiotic use can result in changes in resistance over a short period, they might be insufficient alone to curtail antimicrobial resistance.

Funding: National Institute for Health Research, Economic and Social Research Council, Rosetrees Trust, and The Stoneygate Trust.
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http://dx.doi.org/10.1016/S1473-3099(21)00069-4DOI Listing
August 2021

Evaluation of cross-grazing deer with sheep or cattle, as means to reduces anthelmintic usage to control gastrointestinal and pulmonary nematodes in farmed red deer (Cervus elaphus) in New Zealand.

Vet Parasitol 2021 Oct 24;298:109534. Epub 2021 Jul 24.

School of Veterinary Science, Massey University, PB 11222, Palmerston North, 4442, New Zealand.

Recent reports indicate that gastrointestinal nematodes (GIN) are contributing to significant losses in deer productivity and that anthelmintic resistance has become an issue of concern for deer farmers in New Zealand. The aim of this study was to evaluate cross-grazing of deer with sheep or cattle as an aid for control of gastrointestinal and pulmonary nematode parasites of farmed red deer (Cervus elaphus) in New Zealand. This was a field study replicated over two years (2012 and 2013) for 16 weeks each year at two locations (Massey University, Palmerston North and Invermay AgResearch Centre, Mosgiel). Each farm replicate included four groups (19-20 deer) at each location: red deer cross-grazing with cattle (Deer/Cattle); red deer cross-grazing with sheep (Deer/Sheep); red deer grazing on their own (DeerOwn); and red deer grazing on their own and treated with anthelmintics every two weeks to suppress worm burdens, as a positive control (DeerSup). The key outcome was the number of anthelmintic treatments (AT) given to deer. The decision to treat individual resident deer in Deer/Cattle, Deer/Sheep and DeerOwn groups was based on "trigger" criteria including faecal egg count (FEC)≥250 eggs/g or Dictyocaulus faecal larval count (FLC)≥100 larvae/g or when growth rate was less than 80 % of the mean of the DeerSup group in the previous two weeks. In addition, to quantify the species of parasites cycling in each group, sets of three "tracer" deer were introduced to graze with each group at the mid-point and again at the end of each 16 week period in both years at both locations. Least squares means (LSM) of the number of AT given per animal for Deer/Sheep (3.4) and DeerOwn (3.3) groups were significantly higher than for the Deer/Cattle (2.7) group (p < 0.001). In tracer animals, the LSM of abomasal Trichostrongylus spp. were significantly fewer in the DeerOwn (17), Deer/Cattle (37) and DeerSup (54) groups than in the Deer/Sheep (952; p < 0.001) group. The LSM of the nematodes in the subfamily Ostertagiinae (=Ostertagia-type) were significantly more in the DeerOwn (1950) than in Deer/Sheep (370; p = 0.003) and DeerSup (238; p < 0.001) groups, but the number in the Deer/Cattle group (689) was not different to DeerOwn (p> 0.05). The LSM of lungworm were fewer in Deer/Sheep (3), Deer/Cattle (4) and DeerSup (3; p < 0.001) groups than in DeerOwn (40) group. The Deer/Cattle and DeerSup groups had significantly higher LSM of liveweight gain over the 16 weeks (p < 0.001) than the other two groups. This study demonstrated that cross-grazing with either sheep or cattle aided control of lungworm and gastrointestinal nematodes in young deer during autumn. However, the advantages varied between the use of sheep or cattle and in the ability to control different species of parasites.
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http://dx.doi.org/10.1016/j.vetpar.2021.109534DOI Listing
October 2021

A nuclear phylogenomic study of the angiosperm order Myrtales, exploring the potential and limitations of the universal Angiosperms353 probe set.

Am J Bot 2021 07 23;108(7):1087-1111. Epub 2021 Jul 23.

Department of Biological Sciences, University of Arkansas, Fayetteville, AR, 72701, USA.

Premise: To further advance the understanding of the species-rich, economically and ecologically important angiosperm order Myrtales in the rosid clade, comprising nine families, approximately 400 genera and almost 14,000 species occurring on all continents (except Antarctica), we tested the Angiosperms353 probe kit.

Methods: We combined high-throughput sequencing and target enrichment with the Angiosperms353 probe kit to evaluate a sample of 485 species across 305 genera (76% of all genera in the order).

Results: Results provide the most comprehensive phylogenetic hypothesis for the order to date. Relationships at all ranks, such as the relationship of the early-diverging families, often reflect previous studies, but gene conflict is evident, and relationships previously found to be uncertain often remain so. Technical considerations for processing HTS data are also discussed.

Conclusions: High-throughput sequencing and the Angiosperms353 probe kit are powerful tools for phylogenomic analysis, but better understanding of the genetic data available is required to identify genes and gene trees that account for likely incomplete lineage sorting and/or hybridization events.
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http://dx.doi.org/10.1002/ajb2.1699DOI Listing
July 2021

Jamides wananga, a new species from Papua New Guinea and Australia (Lepidoptera: Lycaenidae).

Zootaxa 2021 Jun 3;4981(1):107122. Epub 2021 Jun 3.

Biology Department, City College of New York, City University of New York, 160 Convent Ave., New York, NY 10031, USA; Ph.D. Program in Biology, Graduate Center, City University of New York, 365 Fifth Ave., New York, NY 10016, USA; Entomology Section, National Museum of Natural History, Manila 1000, Philippines.

Jamides wananga sp. n. is described and illustrated from Madang Province of Papua New Guinea and Dauan Island in the Torres Strait (Queensland, Australia). The new species is similar in appearance to several other Jamides Hübner species in the bochus-group. DNA sequence data and morphology were used to distinguish the nominotypical subspecies found on the New Guinea mainland from J. w. roxina subsp. n. on Dauan Island. Notes on the habitat and behaviour are also provided.
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http://dx.doi.org/10.11646/zootaxa.4981.1.5DOI Listing
June 2021

Individual differences in attentional lapses are associated with fiber-specific white matter microstructure in healthy adults.

Psychophysiology 2021 Sep 6;58(9):e13871. Epub 2021 Jun 6.

Cognitive Neuroscience Unit, School of Psychology, Deakin University, Geelong, VIC, Australia.

Attentional lapses interfere with goal-directed behaviors, which may result in harmless (e.g., not hearing instructions) or severe (e.g., fatal car accident) consequences. Task-related functional MRI (fMRI) studies have shown a link between attentional lapses and activity in the frontoparietal network. Activity in this network is likely to be mediated by the organization of the white matter fiber pathways that connect the regions implicated in the network, such as the superior longitudinal fasciculus I (SLF-I). In the present study, we investigate the relationship between susceptibility to attentional lapses and relevant white matter pathways in 36 healthy adults (23 females, M  = 31.56 years). Participants underwent a diffusion MRI (dMRI) scan and completed the global-local task to measure attentional lapses, similar to previous fMRI studies. Applying the fixel-based analysis framework for fiber-specific analysis of dMRI data, we investigated the association between attentional lapses and variability in microstructural fiber density (FD) and macrostructural (morphological) fiber-bundle cross section (FC) in the SLF-I. Our results revealed a significant negative association between higher total number of attentional lapses and lower FD in the left SLF-I. This finding indicates that the variation in the microstructure of a key frontoparietal white matter tract is associated with attentional lapses and may provide a trait-like biomarker in the general population. However, SLF-I microstructure alone does not explain propensity for attentional lapses, as other factors such as sleep deprivation or underlying psychological conditions (e.g., sleep disorders) may also lead to higher susceptibility in both healthy people and those with neurological disorders.
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http://dx.doi.org/10.1111/psyp.13871DOI Listing
September 2021

Dietary yogurt is distinct from other dairy foods in its association with circulating lipid profile: Findings from the Million Veteran Program.

Clin Nutr ESPEN 2021 06 20;43:456-463. Epub 2021 Mar 20.

Massachusetts Veterans Epidemiology and Research Information Center (MAVERIC), Boston Veterans Affairs Healthcare System, Boston, MA, USA; Division of Aging, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA; Department of Medicine, Harvard Medical School, Boston, MA, USA.

Background & Aims: Dyslipidemia is a major cardiovascular disease risk factor. Research has proposed mechanisms whereby yogurt may improve circulating lipid concentrations. However, at the population level, the association of yogurt, as distinct from other dairy foods, with these important risk factors is poorly understood. This study aimed to determine whether the circulating lipid profile associated with yogurt is different to the circulating lipid profile that is associated with non-yogurt dairy products, specifically milk and cheese.

Methods: The current study included the 192,564 US Veterans enrolled in the Million Veteran Program who reported frequency of yogurt consumption (assessed via food frequency questionnaire) and had lipid concentrations assessed. Trends were evaluated with linear regression. Mean age was 65 (SD = 11) years [20, 100 years].

Results: A one serve/day higher yogurt consumption was positively associated (coefficient ± SE) with the concentration of high-density lipoprotein cholesterol (HDLC) in individuals who were not (0.26 ± 0.12 mg/dL, P value = 0.025), and who were (0.25 ± 0.09, P value = 0.004), using antilipemic agents. Furthermore, higher yogurt consumption was inversely associated with the concentration of triglycerides, but only in individuals who were not using antilipemic agents (-1.46 ± 0.58, P value = 0.012).

Conclusion: These apparent beneficial associations of yogurt with HDLC and triglycerides were independent of consumption of non-yogurt dairy foods and were not observed for consumption of either milk or cheese. In this prospective cohort study of U.S. Veterans, we found a beneficial relationship between higher frequency of yogurt consumption with circulating HDLC and triglyceride concentrations that was distinct from non-yogurt dairy foods.
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http://dx.doi.org/10.1016/j.clnesp.2021.02.022DOI Listing
June 2021

Demonstration of neutron radiation-induced nucleation of supercooled water.

Phys Chem Chem Phys 2021 Jun;23(24):13440-13446

School of Biological, Earth, and Environmental Sciences, University of New South Wales, NSW 2052, Australia and The King's Institute, The King's School, Parramatta, NSW 2151, Australia.

We present here direct evidence for neutrons causing nucleation of supercooled water. Highly purified water (20 nm filtration) is cooled to well below freezing (as low as -20 °C) with a radioactive calibration source of neutrons/gamma-rays either present or removed during each of many control cooling runs for the same volume of water. When it is primarily neutrons irradiating the sample bulk, the non-equilibrium freezing point (also known as the "supercooling point") is, on average, +0.7 °C warmer than the control equivalent, with a statistical significance of greater than 5 Sigma, with systematic uncertainty included. This effect is not observed with water in the presence of gamma-rays instead of neutrons. While these neutrons should have theoretically had sufficient energy to mount the energy barrier, corroborating our results, their raising of supercooling temperature has never been reported experimentally to the best of our knowledge. The potential to use deeply supercooled solutions, not only water, as metastable detectors for radiation and perhaps dark matter or neutrino physics presents now a new avenue for exploration.
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http://dx.doi.org/10.1039/d1cp01083bDOI Listing
June 2021

The Structure of Relationships between the Human Exposome and Cardiometabolic Health: The Million Veteran Program.

Nutrients 2021 Apr 19;13(4). Epub 2021 Apr 19.

Massachusetts Veterans Epidemiology and Research Information Center (MAVERIC), Boston Veterans Affairs Healthcare System, Boston, MA 02130, USA.

The represents the array of dietary, lifestyle, and demographic factors to which an individual is exposed. Individual components of the exposome, or groups of components, are recognized as influencing many aspects of human physiology, including cardiometabolic health. However, the influence of the whole exposome on health outcomes is poorly understood and may differ substantially from the sum of its individual components. As such, studies of the complete exposome are more biologically representative than fragmented models based on subsets of factors. This study aimed to model the system of relationships underlying the way in which the diet, lifestyle, and demographic components of the overall exposome shapes the cardiometabolic risk profile. The current study included 36,496 US Veterans enrolled in the VA Million Veteran Program (MVP) who had complete assessments of their diet, lifestyle, demography, and markers of cardiometabolic health, including serum lipids, blood pressure, and glycemic control. The cohort was randomly divided into training and validation datasets. In the training dataset, we conducted two separate exploratory factor analyses (EFA) to identify common factors among exposures (diet, demographics, and physical activity) and laboratory measures (lipids, blood pressure, and glycemic control), respectively. In the validation dataset, we used multiple normal regression to examine the combined effects of exposure factors on the clinical factors representing cardiometabolic health. The mean ± SD age of participants was 62.4 ± 13.4 years for both the training and validation datasets. The EFA revealed 19 Exposure Common Factors and 5 Physiology Common Factors that explained the observed (measured) data. Multivariate regression in the validation dataset revealed the structure of associations between the Exposure Common Factors and the Physiology Common Factors. For example, we found that the factor for fruit consumption was inversely associated with the factor summarizing total cholesterol and low-density lipoprotein cholesterol (LDLC, = 0.008), and the latent construct describing light levels of physical activity was inversely associated with the blood pressure latent construct ( < 0.0001). We also found that a factor summarizing that participants who frequently consume whole milk are less likely to frequently consume skim milk, was positively associated with the latent constructs representing total cholesterol and LDLC as well as systolic and diastolic blood pressure ( = 0.0006 and <0.0001, respectively). Multiple multivariable-adjusted regression analyses of exposome factors allowed us to model the influence of the exposome as a whole. In this metadata-rich, prospective cohort of US Veterans, there was evidence of structural relationships between diet, lifestyle, and demographic exposures and subsequent markers of cardiometabolic health. This methodology could be applied to answer a variety of research questions about human health exposures that utilize electronic health record data and can accommodate continuous, ordinal, and binary data derived from questionnaires. Further work to explore the potential utility of including genetic risk scores and time-varying covariates is warranted.
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http://dx.doi.org/10.3390/nu13041364DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8073795PMC
April 2021

Levator ani muscle avulsion: Digital palpation versus tomographic ultrasound imaging.

Int J Gynaecol Obstet 2021 Apr 26. Epub 2021 Apr 26.

Department of Women's and Children's Health, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand.

Objective: To determine the diagnostic performance of digital palpation of levator ani muscle (LAM) avulsion compared with translabial tomographic ultrasound imaging (TUI).

Methods: A cross-sectional study, incorporating 195 women involved in a longitudinal cohort study. Palpation for levator integrity was performed, followed by a four-dimensional translabial ultrasound. LAM avulsion defects were diagnosed in the presence of puborectalis muscle detachment from its insertion. Post-processing analysis of ultrasound volumes for LAM integrity on TUI was performed blinded against palpation findings. Agreement between methods was assessed using Cohen's κ.

Results: In all, 388 paired assessments of LAM bilaterally, were available. Sixteen (8.2%) unilateral avulsion defects were detected on palpation. Sonographically, 31 (16%) were diagnosed with avulsions: 4.6% bilateral and 11.3% unilateral. An overall agreement of 91% was observed between digital palpation and TUI, yielding a Cohen's κ of 0.32 (95% confidence interval 0.15-0.48) demonstrating "fair agreement": and implying 25% sensitivity, 98% specificity, 63% positive predictive value, and 92% negative predictive value. Analysis of the first and last 20 palpations showed no change in performance during the 13-day study period.

Conclusion: Assessment of LAM avulsion defects by digital palpation is feasible but may require substantial training. Confirmation by imaging is crucial, especially if the diagnosis of avulsion may influence clinical management.
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http://dx.doi.org/10.1002/ijgo.13721DOI Listing
April 2021

Co-infection in critically ill patients with COVID-19: an observational cohort study from England.

J Med Microbiol 2021 Apr;70(4)

Department of Critical Care, Nottingham University Hospital NHS Trust, Nottingham NG5 1PB, UK.

During previous viral pandemics, reported co-infection rates and implicated pathogens have varied. In the 1918 influenza pandemic, a large proportion of severe illness and death was complicated by bacterial co-infection, predominantly and . A better understanding of the incidence of co-infection in patients with COVID-19 infection and the pathogens involved is necessary for effective antimicrobial stewardship. To describe the incidence and nature of co-infection in critically ill adults with COVID-19 infection in England. A retrospective cohort study of adults with COVID-19 admitted to seven intensive care units (ICUs) in England up to 18 May 2020, was performed. Patients with completed ICU stays were included. The proportion and type of organisms were determined at <48 and >48 h following hospital admission, corresponding to community and hospital-acquired co-infections. Of 254 patients studied (median age 59 years (IQR 49-69); 64.6 % male), 139 clinically significant organisms were identified from 83 (32.7 %) patients. Bacterial co-infections/ co-colonisation were identified within 48 h of admission in 14 (5.5 %) patients; the commonest pathogens were (four patients) and (two patients). The proportion of pathogens detected increased with duration of ICU stay, consisting largely of Gram-negative bacteria, particularly and . The co-infection/ co-colonisation rate >48 h after admission was 27/1000 person-days (95 % CI 21.3-34.1). Patients with co-infections/ co-colonisation were more likely to die in ICU (crude OR 1.78,95 % CI 1.03-3.08, =0.04) compared to those without co-infections/ co-colonisation. We found limited evidence for community-acquired bacterial co-infection in hospitalised adults with COVID-19, but a high rate of Gram-negative infection acquired during ICU stay.
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http://dx.doi.org/10.1099/jmm.0.001350DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8289210PMC
April 2021

Targeting nucleotide metabolism enhances the efficacy of anthracyclines and anti-metabolites in triple-negative breast cancer.

NPJ Breast Cancer 2021 Apr 6;7(1):38. Epub 2021 Apr 6.

Medicine, Dentistry and Biomedical Sciences: Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, Belfast, UK.

Triple-negative breast cancer (TNBC) remains the most lethal breast cancer subtype with poor response rates to the current chemotherapies and a lack of additional effective treatment options. We have identified deoxyuridine 5'-triphosphate nucleotidohydrolase (dUTPase) as a critical gatekeeper that protects tumour DNA from the genotoxic misincorporation of uracil during treatment with standard chemotherapeutic agents commonly used in the FEC regimen. dUTPase catalyses the hydrolytic dephosphorylation of deoxyuridine triphosphate (dUTP) to deoxyuridine monophosphate (dUMP), providing dUMP for thymidylate synthase as part of the thymidylate biosynthesis pathway and maintaining low intracellular dUTP concentrations. This is crucial as DNA polymerase cannot distinguish between dUTP and deoxythymidylate triphosphate (dTTP), leading to dUTP misincorporation into DNA. Targeting dUTPase and inducing uracil misincorporation during the repair of DNA damage induced by fluoropyrimidines or anthracyclines represents an effective strategy to induce cell lethality. dUTPase inhibition significantly sensitised TNBC cell lines to fluoropyrimidines and anthracyclines through imbalanced nucleotide pools and increased DNA damage leading to decreased proliferation and increased cell death. These results suggest that repair of treatment-mediated DNA damage requires dUTPase to prevent uracil misincorporation and that inhibition of dUTPase is a promising strategy to enhance the efficacy of TNBC chemotherapy.
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http://dx.doi.org/10.1038/s41523-021-00245-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8024381PMC
April 2021

Expression of tyrosine pathway enzymes in mice demonstrates that homogentisate 1,2-dioxygenase deficiency in the liver is responsible for homogentisic acid-derived ochronotic pigmentation.

JIMD Rep 2021 Mar 12;58(1):52-60. Epub 2020 Nov 12.

Department of Musculoskeletal & Ageing Science, Institute of Life Course and Medical Science University of Liverpool Liverpool United Kingdom.

Alkaptonuria (AKU) is caused by homogentisate 1,2-dioxygenase (HGD) deficiency. This study aimed to determine if HGD and other enzymes related to tyrosine metabolism are associated with the location of ochronotic pigment. Liver, kidney, skin, bone, brain, eyes, spleen, intestine, lung, heart, cartilage, and muscle were harvested from 6 AKU BALB/c (3 females, 3 males) and 4 male C57BL/6 wild type (WT) mice. , 4-hydroxyphenylpyruvate dioxygenase (-), tyrosine hydroxylase (), and tyrosinase () mRNA expression was investigated using qPCR. Adrenal gland and gonads from AKU mice were stained, followed by qPCR analysis of mRNA. The liver had the highest expression of , followed by the kidney, with none detected in cartilage or brain. Low-level expression was observed within developing male germ cells within the testis and epididymis in . 4- was most abundant in liver, with smaller amounts in kidney and low-level expression in other tissues. was expressed mainly in brain and was found primarily in the eyes. The tissue distribution of both and 4- suggest that ochronotic pigment in AKU mice is a consequence of enzymes within the liver, and not from enzymatic activity within ochronotic tissues. Excessive accumulation of HGA as ochronotic pigment in joints and other connective tissues originates from the circulation and therefore the extracellular fluid. The tissue distribution of both and suggests that these enzymes are not involved in the formation of HGA-derived ochronotic pigment.
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http://dx.doi.org/10.1002/jmd2.12184DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7932868PMC
March 2021

Navigating the link between processing speed and network communication in the human brain.

Brain Struct Funct 2021 May 11;226(4):1281-1302. Epub 2021 Mar 11.

Cognitive Neuroscience Unit, School of Psychology, Faculty of Health, Deakin University, 221 Burwood Highway, Burwood, VIC, 3125, Australia.

Processing speed on cognitive tasks relies upon efficient communication between widespread regions of the brain. Recently, novel methods of quantifying network communication like 'navigation efficiency' have emerged, which aim to be more biologically plausible compared to traditional shortest path length-based measures. However, it is still unclear whether there is a direct link between these communication measures and processing speed. We tested this relationship in forty-five healthy adults (27 females), where processing speed was defined as decision-making time and measured using drift rate from the hierarchical drift diffusion model. Communication measures were calculated from a graph theoretical analysis of the whole-brain structural connectome and of a task-relevant fronto-parietal structural subnetwork, using the large-scale Desikan-Killiany atlas. We found that faster processing speed on trials that require greater cognitive control are correlated with higher navigation efficiency (of both the whole-brain and the task-relevant subnetwork). In contrast, faster processing speed on trials that require more automatic processing are correlated with shorter path length within the task-relevant subnetwork. Our findings reveal that differences in the way communication is modelled between shortest path length and navigation may be sensitive to processing of automatic and controlled responses, respectively. Further, our findings suggest that there is a relationship between the speed of cognitive processing and the structural constraints of the human brain network.
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http://dx.doi.org/10.1007/s00429-021-02241-8DOI Listing
May 2021

Cataract risk stratification and prioritisation protocol in the COVID-19 era.

BMC Health Serv Res 2021 Feb 17;21(1):153. Epub 2021 Feb 17.

Ophthalmology Department, NHS Fife, Queen Margaret Hospital, Fife, Dunfermline, UK.

Background: The COVID-19 pandemic halted non-emergency surgery across Scotland. Measures to mitigate the risks of transmitting COVID-19 are creating significant challenges to restarting all surgical services safely. We describe the development of a risk stratification tool to prioritise patients for cataract surgery taking account both specific risk factors for poor outcome from COVID-19 infection as well as surgical 'need'. In addition we report the demographics and comorbidities of patients on our waiting list.

Methods: A prospective case review of electronic records was performed. A risk stratification tool was developed based on review of available literature on systemic risk factors for poor outcome from COVID-19 infection as well as a surgical 'need' score. Scores derived from the tool were used to generate 6 risk profile groups to allow prioritised allocation of surgery.

Results: There were 744 patients awaiting cataract surgery of which 66 (8.9 %) patients were 'shielding'. One hundred and thirty-two (19.5 %) patients had no systemic comorbidities, 218 (32.1 %) patients had 1 relevant systemic comorbidity and 316 (46.5 %) patients had 2 or more comorbidities. Five hundred and ninety patients (88.7 %) did not have significant ocular comorbidities. Using the risk stratification tool, 171 (23 %) patients were allocated in the highest 3 priority stages. Given an aging cohort with associated increase in number of systemic comorbidities, the majority of patients were in the lower priority stages 4 to 6.

Conclusions: COVID-19 has created an urgent challenge to deal safely with cataract surgery waiting lists. This has driven the need for a prompt and pragmatic change to the way we assess risks and benefits of a previously regarded as low-risk intervention. This is further complicated by the majority of patients awaiting cataract surgery being elderly with comorbidities and at higher risk of mortality related to COVID-19. We present a pragmatic method of risk stratifying patients on waiting lists, blending an evidence-based objective assessment of risk and patient need combined with an element of shared decision-making. This has facilitated safe and successful restarting of our cataract service.
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http://dx.doi.org/10.1186/s12913-021-06165-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7887562PMC
February 2021

No evidence that selection for egg production persistency causes loss of bone quality in laying hens.

Genet Sel Evol 2021 Feb 4;53(1):11. Epub 2021 Feb 4.

Departamento de Mineralogía Y Petrologia, Universidad de Granada, 18002, Granada, Spain.

Background: The physiological adaptations that have evolved for egg laying make hens susceptible to bone fractures and keel bone damage. In modern laying hen breeds, longer periods of egg laying could result in a greater risk of poor bone quality, and selection for increased egg production has frequently been stated to be a cause. However, the existing literature does not support this hypothesis. To test the hypothesis that egg production is associated with quality, breaking strength and density of bone, genetic correlations between these traits were estimated in White Leghorn and Rhode Island Red breeds. Genetic correlations of cortical and medullary bone material chemical properties with bone quality were also estimated, in order to identify methods to improve bone quality with appropriately targeted measurement of key traits.

Results: Estimates of heritability for bone quality traits were moderate (0.19-0.59) for both White Leghorn and Rhode Island Red breeds, except for the keel bone trait, which had a heritability estimate equal to zero. There was no evidence for genetic or phenotypic relationships between post-peak egg production and bone quality. In the White Leghorn breed, the estimate of the genetic correlation between pre-peak production/age at first egg and bone quality was significant and negative (- 0.7 to - 0.4). Estimates of heritability of thermogravimetric measurements of tibial medullary bone mineralisation were significant (0.18-0.41), as were estimates of their genetic correlations with tibia breaking strength and density (0.6-0.9).

Conclusions: The low genetic correlation of post-peak egg production with bone quality suggests that selection for increased persistency of egg production may not adversely affect bone quality. Onset of puberty and mineralisation of the medullary bone, which is a specialised adaptation for egg laying, were identified as important factors associated with the quality of the skeleton later during egg production. These are traits for which genetic, as well as environmental and management factors can positively impact the overall quality of the skeleton of laying hens.
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http://dx.doi.org/10.1186/s12711-021-00603-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7860618PMC
February 2021

Associations of biogeographic ancestry with hypertension traits.

J Hypertens 2021 04;39(4):633-642

Vanderbilt Genetics Institute, Vanderbilt University.

Objectives: Ethnic disparities in hypertension prevalence are well documented, though the influence of genetic ancestry is unclear. The aim of this study was to evaluate associations of geographic genetic ancestry with hypertension and underlying blood pressure traits.

Methods: We tested genetically inferred ancestry proportions from five 1000 Genomes reference populations (GBR, PEL, YRI, CHB, and LWK) for association with four continuous blood pressure (BP) traits (SBP, DBP, PP, MAP) and the dichotomous outcomes hypertension and apparent treatment-resistant hypertension in 220 495 European American, 59 927 African American, and 21 273 Hispanic American individuals from the Million Veteran Program. Ethnicity stratified results were meta-analyzed to report effect estimates per 10% difference for a given ancestry proportion in all samples.

Results: Percentage GBR was negatively associated with BP (P = 2.13 × 10-19, 7.92 × 10-8, 4.41 × 10-11, and 3.57 × 10-13 for SBP, DBP, PP, and MAP, respectively; coefficient range -0.10 to -0.21 mmHg per 10% increase in ancestry proportion) and was protective against hypertension [P = 2.59 × 10-5, odds ratio (OR) = 0.98] relative to other ancestries. YRI percentage was positively associated with BP (P = 1.63 × 10-23, 1.94 × 10-26, 0.012, and 3.26 × 10-29 for SBP, DBP, PP, and MAP, respectively; coefficient range 0.06-0.32 mmHg per 10% increase in ancestry proportion) and was positively associated with hypertension risk (P = 3.10 × 10-11, OR = 1.04) and apparent treatment-resistant hypertension risk (P = 1.86 × 10-4, OR = 1.04) compared with other ancestries. Percentage PEL was inversely associated with DBP (P = 2.84 × 10-5, beta = -0.11 mmHg per 10% increase in ancestry proportion).

Conclusion: These results demonstrate that risk for BP traits varies significantly by genetic ancestry. Our findings provide insight into the geographic origin of genetic factors underlying hypertension risk and establish that a portion of BP trait ethnic disparities are because of genetic differences between ancestries.
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http://dx.doi.org/10.1097/HJH.0000000000002701DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8362794PMC
April 2021

Cataract Surgery Redesign: Meeting Increasing Demand, Training, Audit and Patient-Centered Care.

Clin Ophthalmol 2021 25;15:289-297. Epub 2021 Jan 25.

Department of Ophthalmology, Queen Margaret Hospital, Dunfermline, Fife, UK.

Objective: The demand for cataract surgery in Fife (a well-defined region in southeast Scotland) was steadily increasing over 15 years. Cataract surgery was therefore being outsourced to meet demand with consequences on list mix, training needs, patient experience and staff morale. We aimed to redesign our services to meet local demand, retain a patient-centered service and continue to fulfil training needs.

Methods: We quantified cataract surgery delivery over an 18-month period: before, during and after redesign of services. We studied numbers of operations, trainee cases and number of outsourced cases. We also considered the economic implications of the redesign.

Results: We studied three periods (each of six months duration): before redesign (BR), redesign period (RP) and post-redesign (PR). Data were collected on total operation numbers, number of cases performed by trainees, and numbers performed out with normal working hours (weekend lists) and external providers. An economic analysis examined the cost of outsourcing cataracts during BR and RP and the costs of the redesign, including building, equipment and additional nursing staff.

Conclusion: Regional fulfilment of cataract surgery provision remains a continuous challenge within the NHS. We show that with minimal investment, smart redesign process and collaborative working, increased local provision is possible while fulfilling trainee needs and achieving the necessary clinical audits and national standards.
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http://dx.doi.org/10.2147/OPTH.S268190DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7846846PMC
January 2021

Overall survival of black and white men with metastatic castration-resistant prostate cancer (mCRPC): a 20-year retrospective analysis in the largest healthcare trust in England.

Prostate Cancer Prostatic Dis 2021 Sep 21;24(3):718-724. Epub 2021 Jan 21.

Department of Medical Oncology, Barts Health NHS Trust, London, UK.

Background: Prostate cancer in black men is associated with poorer outcomes than their white counterparts. However, most studies reporting this disparity were conducted in localized prostate cancer and primarily in the United States.

Methods: Data regarding prostate cancer incidence and mortality for East London between 2008 and 2010 were obtained from the UK National Disease Registration Service. We further evaluated survival outcomes of 425 cases of mCRPC in St Bartholomew's Hospital, East London, between 1997 and 2016, and analyzed whether ethnicity impacted on responses to different treatment types.

Results: The incidence of prostate cancer in black men was higher than white men in East London. Prostate cancer-specific mortality was proportional to incidence based on ethnic groups. In the detailed analysis of 425 patients, 103 patients (24%) were black (B), and the remainder white (W). Baseline characteristics were comparable in both groups, although black patients had a lower baseline hemoglobin (p < 0.001). Median overall survival for the total cohort was 25.5 months (B) vs 21.8 months (W) (hazard ratio (HR) = 0.81, p = 0.08). There was prolonged survival in the black population in those who only received hormone-based treatment throughout their treatment course; 39.7 months (B) vs 17.1 months (W) (HR = 0.54, p = 0.019).

Conclusion: Black men may do better than white men with mCRPC, in the context of equal access to healthcare. The study also suggests a greater margin of benefit of hormone-based therapy in the black subpopulation.
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http://dx.doi.org/10.1038/s41391-020-00316-xDOI Listing
September 2021

Age-related reproductive performance of the Adélie penguin, a long-lived seabird exhibiting similar outcomes regardless of individual life-history strategy.

J Anim Ecol 2021 04 1;90(4):931-942. Epub 2021 Feb 1.

Manaaki Whenua Landcare Research, Lincoln, New Zealand.

Age-related variation in reproductive performance in long-lived iteroparous vertebrate species is common, with performance being influenced by within-individual processes, such as improvement and senescence, in combination with among-individual processes, such as selective appearance and disappearance. Few studies of age-related reproductive performance have compared the role of these drivers within a metapopulation, subject to varying degrees of resource competition. We accounted for within- and among-individual changes among known-aged Adélie penguins Pygoscelis adeliae during 17 years (1997-2013), at three clustered colonies of disparate size, to understand patterns in age-related reproductive success during early and late adulthood. Age at first reproduction (AFR) was lowest, and number of breeding attempts highest, at the largest colony. Regardless of AFR, success improved with early post-recruitment experience. For both oldest and youngest recruitment groups, peak performance occurred at the end of their reproductive life span indicating a possible cost of reproduction. Intermediate recruitment groups reached peak performance in their mid-reproductive life span and with intermediate breeding experience, before decreasing. Breeding success was lowest for the initial breeding attempt regardless of AFR, but we observed subsequent variation relative to recruitment age. Gaining experience by delaying recruitment positively influenced reproductive performance early in the reproductive life span and was most evident for the youngest breeders. Oldest recruits had the highest initial and peak breeding success. Differences in AFR resulted in trade-offs in reproductive life span or timing of senescence but not in the overall number of breeding attempts. Patterns differed as a function of colony size, and thus competition for resources. Early life improvement in performance at the larger colonies was primarily due to within-individual factors and at the largest colony, AFR. Regardless of colony size late-life performance was positively related to the age at last reproduction, indicating selective disappearance of lower performing individuals. These results highlight that different life-history strategies were equally successful, indicating that individuals can overcome potential trade-offs associated with early- and late-life performance. These results have important implications for understanding the evolution of life-history strategies responsible for driving population change.
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http://dx.doi.org/10.1111/1365-2656.13422DOI Listing
April 2021

Discovery of rare variants associated with blood pressure regulation through meta-analysis of 1.3 million individuals.

Nat Genet 2020 12 23;52(12):1314-1332. Epub 2020 Nov 23.

Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.

Genetic studies of blood pressure (BP) to date have mainly analyzed common variants (minor allele frequency > 0.05). In a meta-analysis of up to ~1.3 million participants, we discovered 106 new BP-associated genomic regions and 87 rare (minor allele frequency ≤ 0.01) variant BP associations (P < 5 × 10), of which 32 were in new BP-associated loci and 55 were independent BP-associated single-nucleotide variants within known BP-associated regions. Average effects of rare variants (44% coding) were ~8 times larger than common variant effects and indicate potential candidate causal genes at new and known loci (for example, GATA5 and PLCB3). BP-associated variants (including rare and common) were enriched in regions of active chromatin in fetal tissues, potentially linking fetal development with BP regulation in later life. Multivariable Mendelian randomization suggested possible inverse effects of elevated systolic and diastolic BP on large artery stroke. Our study demonstrates the utility of rare-variant analyses for identifying candidate genes and the results highlight potential therapeutic targets.
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http://dx.doi.org/10.1038/s41588-020-00713-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7610439PMC
December 2020

PCSK9 loss of function is protective against extra-coronary atherosclerotic cardiovascular disease in a large multi-ethnic cohort.

PLoS One 2020 9;15(11):e0239752. Epub 2020 Nov 9.

Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA, United States of America.

Background: Therapeutic inhibition of PCSK9 protects against coronary artery disease (CAD) and ischemic stroke (IS). The impact on other diseases remains less well characterized.

Methods: We created a genetic risk score (GRS) for PCSK9 using four single nucleotide polymorphisms (SNPs) at or near the PCSK9 locus known to impact lower LDL-Cholesterol (LDL-C): rs11583680, rs11591147, rs2479409, and rs11206510. We then used our GRS to calculate weighted odds ratios reflecting the impact of a genetically determined 10 mg/dL decrease in LDL-C on several pre-specified phenotypes including CAD, IS, peripheral artery disease (PAD), abdominal aortic aneurysm (AAA), type 2 diabetes, dementia, chronic obstructive pulmonary disease, and cancer. Finally, we used our weighted GRS to perform a phenome-wide association study.

Results: Genetic and electronic health record data that passed quality control was available in 312,097 individuals, (227,490 White participants, 58,907 Black participants, and 25,700 Hispanic participants). PCSK9 mediated reduction in LDL-C was associated with a reduced risk of CAD and AAA in trans-ethnic meta-analysis (CAD OR 0.83 [95% CI 0.80-0.87], p = 6.0 x 10-21; AAA OR 0.76 [95% CI 0.68-0.86], p = 2.9 x 10-06). Significant protective effects were noted for PAD in White individuals (OR 0.83 [95% CI 0.71-0.97], p = 2.3 x 10-04) but not in other genetic ancestries. Genetically reduced PCSK9 function associated with a reduced risk of dementia in trans-ethnic meta-analysis (OR 0.86 [95% CI 0.78-0.93], p = 5.0 x 10-04).

Conclusions: Genetically reduced PCSK9 function results in a reduction in risk of several important extra-coronary atherosclerotic phenotypes in addition to known effects on CAD and IS, including PAD and AAA. We also highlight a novel reduction in risk of dementia, supporting a well-recognized vascular component to cognitive impairment and an opportunity for therapeutic repositioning.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0239752PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7652310PMC
January 2021

Interlayer Hybridization of Virgin Carbon, Recycled Carbon and Natural Fiber Laminates.

Materials (Basel) 2020 Nov 4;13(21). Epub 2020 Nov 4.

WMG, University of Warwick, Gibbet Hill Road, Coventry CV4 7AL, UK.

To meet sustainability objectives in the transport sector, natural fiber (NF) and recycled carbon fiber (RCF) have been developed, although they have been typically limited to low to medium performance components. This work has considered the effect of interlayer hybridization of woven NF and non-woven RCF with woven virgin carbon fibers (VCF) on the mechanical and damping performance of hybrid laminates, produced using double bag vacuum infusion (DBVI). The mean damping ratio of the pure laminates showed a trend of NF>RCF>VCF, which was inversely proportional to their modulus. The tensile, flexural and damping properties of hybrid laminates were dominated by the outermost ply. The VCF-RCF and VCF-NF hybrid laminates showed a comparatively greater mean damping ratio. The results of this work demonstrate a method for the uptake of alternative materials with a minimal impact on the mechanical properties and improved damping performance.
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http://dx.doi.org/10.3390/ma13214955DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7663664PMC
November 2020

Anatomical Distribution of Ochronotic Pigment in Alkaptonuric Mice is Associated with Calcified Cartilage Chondrocytes at Osteochondral Interfaces.

Calcif Tissue Int 2021 02 14;108(2):207-218. Epub 2020 Oct 14.

Department of Musculoskeletal & Ageing Science, Institute of Life Course and Medical Science, University of Liverpool, William Henry Duncan Building, 6 West Derby Street, Liverpool, L7 8TX, UK.

Alkaptonuria (AKU) is characterised by increased circulating homogentisic acid and deposition of ochronotic pigment in collagen-rich connective tissues (ochronosis), stiffening the tissue. This process over many years leads to a painful and severe osteoarthropathy, particularly affecting the cartilage of the spine and large weight bearing joints. Evidence in human AKU tissue suggests that pigment binds to collagen. The exposed collagen hypothesis suggests that collagen is initially protected from ochronosis, and that ageing and mechanical loading causes loss of protective molecules, allowing pigment binding. Schmorl's staining has previously demonstrated knee joint ochronosis in AKU mice. This study documents more comprehensively the anatomical distribution of ochronosis in two AKU mouse models (BALB/c Hgd, Hgd tm1a), using Schmorl's staining. Progression of knee joint pigmentation with age in the two AKU mouse models was comparable. Within the knee, hip, shoulder, elbow and wrist joints, pigmentation was associated with chondrons of calcified cartilage. Pigmented chondrons were identified in calcified endplates of intervertebral discs and the calcified knee joint meniscus, suggesting that calcified tissues are more susceptible to pigmentation. There were significantly more pigmented chondrons in lumbar versus tail intervertebral disc endplates (p = 0.002) and clusters of pigmented chondrons were observed at the insertions of ligaments and tendons. These observations suggest that loading/strain may be associated with increased pigmentation but needs further experimental investigation. The calcified cartilage may be the first joint tissue to acquire matrix damage, most likely to collagen, through normal ageing and physiological loading, as it is the first to become susceptible to pigmentation.
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http://dx.doi.org/10.1007/s00223-020-00764-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7820185PMC
February 2021

Inherited myeloproliferative neoplasm risk affects haematopoietic stem cells.

Nature 2020 10 14;586(7831):769-775. Epub 2020 Oct 14.

Broad Institute of MIT and Harvard, Cambridge, MA, USA.

Myeloproliferative neoplasms (MPNs) are blood cancers that are characterized by the excessive production of mature myeloid cells and arise from the acquisition of somatic driver mutations in haematopoietic stem cells (HSCs). Epidemiological studies indicate a substantial heritable component of MPNs that is among the highest known for cancers. However, only a limited number of genetic risk loci have been identified, and the underlying biological mechanisms that lead to the acquisition of MPNs remain unclear. Here, by conducting a large-scale genome-wide association study (3,797 cases and 1,152,977 controls), we identify 17 MPN risk loci (P < 5.0 × 10), 7 of which have not been previously reported. We find that there is a shared genetic architecture between MPN risk and several haematopoietic traits from distinct lineages; that there is an enrichment for MPN risk variants within accessible chromatin of HSCs; and that increased MPN risk is associated with longer telomere length in leukocytes and other clonal haematopoietic states-collectively suggesting that MPN risk is associated with the function and self-renewal of HSCs. We use gene mapping to identify modulators of HSC biology linked to MPN risk, and show through targeted variant-to-function assays that CHEK2 and GFI1B have roles in altering the function of HSCs to confer disease risk. Overall, our results reveal a previously unappreciated mechanism for inherited MPN risk through the modulation of HSC function.
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http://dx.doi.org/10.1038/s41586-020-2786-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7606745PMC
October 2020

Single-agent carboplatin AUC10 in metastatic seminoma: A multi-centre UK study of 216 patients.

Eur J Cancer 2020 Oct 8. Epub 2020 Oct 8.

Department of Medical Oncology, St Bartholomew's Hospital, London, EC1A 7BE, UK. Electronic address:

Background: Radiotherapy and cisplatin-based combination chemotherapy are accepted standard-of-care treatments for metastatic seminoma with excellent survival outcomes but with established short- and long-term morbidity. Carboplatin monotherapy may be a less toxic alternative; however early historic studies at AUC7 showed inferior outcomes.

Objectives: To evaluate multi-institutional data on and toxicity and longer-term survival for metastatic seminoma patients treated with the single-agent carboplatin AUC10.

Methods: We undertook a multi-institutional analysis incorporating all men with the International Germ Cell Cancer Collaborative Group good-prognosis metastatic seminoma treated until 2018. Carboplatin AUC10 was given every 21 days. Toxicity, progression-free survival (PFS), disease-specific survival (DSS) and overall survival were noted. Variables predictive of progression were identified.

Results And Limitations: 216 patients were treated. The three-year PFS rate was 96.5%, and five-year DSS was 98.3%. There were seven relapses, of which 5 were successfully salvaged with further chemotherapy ± surgery, and three non-seminoma-related deaths. There were no treatment-related deaths. Of 148/216 evaluable patients for toxicity, 37% and 27% suffered >/ = grade III neutropenia and thrombocytopenia, respectively. Twelve percent of patients needed a platelet or blood transfusion (or both). The incidence of febrile neutropenia was 5%.

Conclusion: For metastatic seminoma, carboplatin AUC10 harbours a similar oncological efficacy to established therapies, with a low failure risk. The major acute toxicity was myelosuppression. Our study establishes carboplatin AUC10 as another standard-of-care treatment option for good-prognosis metastatic seminoma, with a potentially lower toxicity profile than other therapies.
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http://dx.doi.org/10.1016/j.ejca.2020.08.031DOI Listing
October 2020
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