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1.
A pragmatic, open-label, randomized controlled trial of Plasma-Lyte-148 versus standard intravenous fluids in children receiving kidney transplants (PLUTO).
Hayes, WN, Laing, E, Brown, R, Silsby, L, Smith, L, Thomas, H, Kaloyirou, F, Sharma, R, Griffiths, J, Hume-Smith, H, et al
Kidney international. 2024;(2):364-375
Abstract
Acute electrolyte and acid-base imbalance is experienced by many children following kidney transplant. This is partly because doctors give very large volumes of artificial fluids to keep the new kidney working. When severe, fluid imbalance can lead to seizures, cerebral edema and death. In this pragmatic, open-label, randomized controlled trial, we randomly assigned (1:1) pediatric kidney transplant recipients to Plasma-Lyte-148 or standard of care perioperative intravenous fluids (predominantly 0.45% sodium chloride and 0.9% sodium chloride solutions). We then compared clinically significant electrolyte and acid-base abnormalities in the first 72 hours post-transplant. The primary outcome, acute hyponatremia, was experienced by 53% of 68 participants in the Plasma-Lyte-148 group and 58% of 69 participants in the standard fluids group (odds ratio 0·77 (0·34 - 1·75)). Five of 16 secondary outcomes differed with Plasma-Lyte-148: hypernatremia was significantly more frequent (odds ratio 3·5 (1·1 - 10·8)), significantly fewer changes to fluid prescriptions were made (rate ratio 0·52 (0·40-0·67)), and significantly fewer participants experienced hyperchloremia (odds ratio 0·17 (0·07 - 0·40)), acidosis (odds ratio 0·09 (0·04 - 0·22)) and hypomagnesemia (odds ratio 0·21 (0·08 - 0·50)). No other secondary outcomes differed between groups. Serious adverse events were reported in 9% of participants randomized to Plasma-Lyte-148 and 7% of participants randomized to standard fluids. Thus, perioperative Plasma-Lyte-148 did not change the proportion of children who experienced acute hyponatremia compared to standard fluids. However fewer fluid prescription changes were made with Plasma-Lyte-148, while hyperchloremia and acidosis were less common.
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Study protocol for the sheMATTERS study (iMproving cArdiovascular healTh in new moThERS): a randomized behavioral trial assessing the effect of a self-efficacy enhancing breastfeeding intervention on postpartum blood pressure and breastfeeding continuation in women with hypertensive disorders of pregnancy.
Dayan, N, Smith, G, Nedelchev, A, Abenhaim, H, Brown, R, Da Costa, D, Ali, S, Perlman, J, Nguyen, TV, Dennis, CL, et al
BMC pregnancy and childbirth. 2023;(1):68
Abstract
BACKGROUND Individuals with hypertensive disorders of pregnancy (HDP) have an elevated lifetime risk of chronic hypertension, metabolic syndrome, and premature cardiovascular disease. Because breastfeeding duration and exclusivity have been associated in observational studies with improved cardiovascular health, optimizing breastfeeding in those with HDP might be an unrealized cardio-prevention approach, in particular because individuals with HDP have more breastfeeding challenges. Breastfeeding supportive interventions targeting one's breastfeeding self-efficacy have been shown to improve breastfeeding rates. METHODS We designed an open-label, multi-center 1:1 randomized behavioral trial to test whether a previously validated self-efficacy enhancing breastfeeding intervention can improve breastfeeding duration and/or exclusivity, and lower postpartum blood pressure at 12 months. Randomization is computer-generated and stratified by site (four hospitals in Montreal, Quebec and one hospital in Kingston, Ontario; all in Canada). Included are breastfeeding participants with HDP (chronic/gestational hypertension or preeclampsia) who delivered a live singleton infant at > 34 weeks, speak English or French, and have no contraindications to breastfeeding. Informed and written consent is obtained at hospitalization for delivery or a re-admission with hypertension within 1 week of discharge. Participants assigned to the intervention group receive a breastfeeding self-efficacy-based intervention delivered by a trained lactation consultant in hospital, with continued reactive/proactive support by phone or text message for up to 6 months postpartum. Regardless of group assignment, participants are followed for self-reported outcomes, automated office blood pressure, and home blood pressure at several time points with end of follow-up at 12 months. DISCUSSION This study will assess whether an intensive nurse-led behavioral intervention can improve breastfeeding rates and, in turn, postpartum blood pressure - an early marker for atherosclerotic cardiovascular disease. If effective, this form of enhanced breastfeeding support, along with closer BP and metabolic surveillance, can be implemented broadly in individuals lactating after HDP. TRIAL REGISTRATION ClinicalTrials.gov, # NCT04580927 , registered on Oct 9, 2020.
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Bioetics Issues of Artificial Placenta and Artificial Womb Technology.
Medori, MC, Bonetti, G, Donato, K, Dhuli, K, Henehan, G, Brown, R, Sieving, P, Sykora, P, Marks, R, Falsini, B, et al
La Clinica terapeutica. 2023;(Suppl 2(6)):243-248
Abstract
The worldwide infertility crisis and the increase in mortality and morbidity among infants, due to preterm births and associated complications, have stimulated research into artificial placenta (AP) and artificial womb (AW) technology as novel solutions. These technologies mimic the natural environment provided in the mother's womb, using chambers that ensure the supply of nutrients to the fetus and disposal of waste substances through an appropriate mechanism. This review aims to highlight the background of AP and AW technologies, revisit their historical development and proposed applications, and discuss challenges and bioethical and moral issues. Further research is required to investigate any negative effects of these new technologies, and ethical concerns pertaining to the structure and operation of this newly developed technology must be addressed and resolved prior to its introduction to the public sphere.
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An ACAT inhibitor suppresses SARS-CoV-2 replication and boosts antiviral T cell activity.
Wing, PAC, Schmidt, NM, Peters, R, Erdmann, M, Brown, R, Wang, H, Swadling, L, , , Newman, J, Thakur, N, et al
PLoS pathogens. 2023;(5):e1011323
Abstract
The severity of disease following infection with SARS-CoV-2 is determined by viral replication kinetics and host immunity, with early T cell responses and/or suppression of viraemia driving a favourable outcome. Recent studies uncovered a role for cholesterol metabolism in the SARS-CoV-2 life cycle and in T cell function. Here we show that blockade of the enzyme Acyl-CoA:cholesterol acyltransferase (ACAT) with Avasimibe inhibits SARS-CoV-2 pseudoparticle infection and disrupts the association of ACE2 and GM1 lipid rafts on the cell membrane, perturbing viral attachment. Imaging SARS-CoV-2 RNAs at the single cell level using a viral replicon model identifies the capacity of Avasimibe to limit the establishment of replication complexes required for RNA replication. Genetic studies to transiently silence or overexpress ACAT isoforms confirmed a role for ACAT in SARS-CoV-2 infection. Furthermore, Avasimibe boosts the expansion of functional SARS-CoV-2-specific T cells from the blood of patients sampled during the acute phase of infection. Thus, re-purposing of ACAT inhibitors provides a compelling therapeutic strategy for the treatment of COVID-19 to achieve both antiviral and immunomodulatory effects. Trial registration: NCT04318314.
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Role of lipoprotein(a) in atherosclerotic cardiovascular disease: A review of current and emerging therapies.
Alhomoud, IS, Talasaz, A, Mehta, A, Kelly, MS, Sisson, EM, Bucheit, JD, Brown, R, Dixon, DL
Pharmacotherapy. 2023;(10):1051-1063
Abstract
Lipoprotein(a), or Lp(a), is structurally like low-density lipoprotein (LDL) but differs in that it contains glycoprotein apolipoprotein(a) [apo(a)]. Due to its prothrombotic and proinflammatory properties, Lp(a) is an independent risk factor for atherosclerotic cardiovascular disease (ASCVD) and aortic valve stenosis. Lp(a) levels are genetically determined, and it is estimated that 20%-25% of the global population has an Lp(a) level ≥50 mg/dL (or ≥125 nmol/L). Diet and lifestyle interventions have little to no effect on Lp(a) levels. Lipoprotein apheresis is the only approved treatment for elevated Lp(a) but is time-intensive for the patient and only modestly effective. Pharmacological approaches to reduce Lp(a) levels and its associated risks are of significant interest; however, currently available lipid-lowering therapies have limited effectiveness in reducing Lp(a) levels. Although statins are first-line agents to reduce LDL cholesterol levels, they modestly increase Lp(a) levels and have not been shown to change Lp(a)-mediated ASCVD risk. Alirocumab, evolocumab, and inclisiran reduce Lp(a) levels by 20-25%, yet the clinical implications of this reduction for Lp(a)-mediated ASCVD risk are uncertain. Niacin also lowers Lp(a) levels; however, its effectiveness in mitigating Lp(a)-mediated ASCVD risk remains unclear, and its side effects have limited its utilization. Recommendations for when to screen and how to manage individuals with elevated Lp(a) vary widely between national and international guidelines and scientific statements. Three investigational compounds targeting Lp(a), including small interfering RNA (siRNA) agents (olpasiran, SLN360) and an antisense oligonucleotide (pelacarsen), are in various stages of development. These compounds block the translation of messenger RNA (mRNA) into apo(a), a key structural component of Lp(a), thereby substantially reducing Lp(a) synthesis in the liver. The purpose of this review is to describe current recommendations for screening and managing elevated Lp(a), describe the effects of currently available lipid-lowering therapies on Lp(a) levels, and provide insight into emerging therapies targeting Lp(a).
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Nutrition of School-Aged Children and Adolescents in Europe and Central Asia Region: A Literature and Survey Review.
Mates, E, Lelijveld, N, Ali, Z, Sadler, K, Yarparvar, A, Walters, T, Brown, R, Rodriques, B
Food and nutrition bulletin. 2023;(1):51-61
Abstract
BACKGROUND Middle childhood and adolescence are critical times for the growth, development, and establishment of healthy eating habits. The Europe and Central Asia (ECA) region has been through economic and nutrition transitions over the past 20 years, which are likely to have affected the nutritional status of this group. OBJECTIVE This review aimed to collate data on the nutritional status and dietary patterns of school-aged children (SAC) and adolescents (5-19 years) across the ECA region in order to inform policy and programming decisions. METHODS A systematic search of the literature in Pubmed, Cochrane, and ScienceDirect databases was conducted (April 2019), complemented by a systematic review of nationally representative surveys. Inclusion criteria were any data on micronutrient deficiencies, overweight, stunting, wasting, thinness, or dietary patterns in SAC and adolescents in the 21 UNICEF-defined countries of ECA, published since the year 2000. RESULTS Results included 134 published papers and 6 sources of survey data. The majority of studies were conducted in Turkey (56%), with all other countries having fewer than 10 studies each; 8 countries in the region having no studies on this age group at all. The most significant nutrition issue was overweight and obesity. Micronutrient deficiencies, particularly anemia, emerge as a further challenge. Dietary patterns were worse in urban areas and boys. CONCLUSIONS The findings of this review suggest that there are 3 critical areas that need immediate attention: the promotion of healthy diets and physical activity to address high levels of overweight/obesity, anemia prevention efforts, and addressing the considerable data gaps for SAC and adolescent nutrition.
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Do bone elasticity and postmortem interval affect forensic fractographic analyses?
Skinner, J, Langley, N, Joseph, M, Herrick, J, Brown, R, Waletzki, B, Goguen, P, Shyamsunder, L, Rajan, S
Journal of forensic sciences. 2023;(3):757-767
Abstract
Forensic fractographic features of bone reliably establish crack propagation in perimortem injuries. We investigated if similar fracture surface features characterize postmortem fractures. Experimentally induced peri- and postmortem fractures were used to assess if fractographic features vary as bone elasticity decreases during the postmortem interval (PMI). Thirty-seven unembalmed, defleshed human femoral shafts from males and females aged 33-81 years were fractured at varying PMIs with a drop test frame using a three-point bending setup and recorded with a high-speed camera. Vital statistics, cause of death, PMI length, temperature, humidity, collagen percentage, water loss, fracture energy, and fractography scores were recorded for each sample. Results showed that fractographic features associated with perimortem fractures were expressed in PMIs up to 40,600 accumulated degree hours (ADH), or 60 warm weather days. Hackle was the most consistently expressed feature, occurring in all fractures regardless of ADH. The most variable characteristics were wake features (78.4%) and arrest ridges (70.3%). Collagen percentage did not correlate strongly with ADH (r = -0.04, p = 0.81); however, there was a strong significant correlation between ADH and water loss (r = 0.74, p < 0.001). Multinomial logistic regression showed no association between fractographic feature expression and ADH or collagen percentage. In conclusion, forensic fractographic features reliably determine initiation and directionality of crack propagation in experimentally induced PMIs up to 40,600 ADH, demonstrating the utility of this method into the recent postmortem interval. This expression of reliable fractographic features throughout the early PMI intimates these characteristics may not be useful standalone features for discerning peri- versus postmortem fractures.
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Clinical, histological and molecular profiling of different stages of alcohol-related liver disease.
Ventura-Cots, M, Argemi, J, Jones, PD, Lackner, C, El Hag, M, Abraldes, JG, Alvarado, E, Clemente, A, Ravi, S, Alves, A, et al
Gut. 2022;(9):1856-1866
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Abstract
OBJECTIVE Alcohol-related liver disease (ALD) ranges from never-decompensated ALD (ndALD) to the life-threatening decompensated phenotype, known as alcohol-related hepatitis (AH). A multidimensional study of the clinical, histological and molecular features of these subtypes is lacking. DESIGN Two large cohorts of patients were recruited in an international, observational multicentre study: a retrospective cohort of patients with ndALD (n=110) and a prospective cohort of patients with AH (n=225). Clinical, analytical, immunohistochemistry and hepatic RNA microarray analysis of both disease phenotypes were performed. RESULTS Age and mean alcohol intake were similar in both groups. AH patients had greater aspartate amino transferase/alanine amino transferase ratio and lower gamma-glutamyl transferase levels than in ndALD patients. Patients with AH demonstrated profound liver failure and increased mortality. One-year mortality was 10% in ndALD and 50% in AH. Histologically, steatosis grade, ballooning and pericellular fibrosis were similar in both groups, while advanced fibrosis, Mallory-Denk bodies, bilirubinostasis, severe neutrophil infiltration and ductular reaction were more frequent among AH patients. Transcriptome analysis revealed a profound gene dysregulation within both phenotypes when compare to controls. While ndALD was characterised by deregulated expression of genes involved in matrisome and immune response, the development of AH resulted in a marked deregulation of genes involved in hepatocyte reprogramming and bile acid metabolism. CONCLUSIONS Despite comparable alcohol intake, AH patients presented with worse liver function compared with ndALD patients. Bilirubinostasis, severe fibrosis and ductular reaction were prominent features of AH. AH patients exhibited a more profound deregulation of gene expression compared with ndALD patients.
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Applied phenomics and genomics for improving barley yellow dwarf resistance in winter wheat.
Silva, P, Evers, B, Kieffaber, A, Wang, X, Brown, R, Gao, L, Fritz, A, Crain, J, Poland, J
G3 (Bethesda, Md.). 2022;(7)
Abstract
Barley yellow dwarf is one of the major viral diseases of cereals. Phenotyping barley yellow dwarf in wheat is extremely challenging due to similarities to other biotic and abiotic stresses. Breeding for resistance is additionally challenging as the wheat primary germplasm pool lacks genetic resistance, with most of the few resistance genes named to date originating from a wild relative species. The objectives of this study were to (1) evaluate the use of high-throughput phenotyping to improve barley yellow dwarf assessment; (2) identify genomic regions associated with barley yellow dwarf resistance; and (3) evaluate the ability of genomic selection models to predict barley yellow dwarf resistance. Up to 107 wheat lines were phenotyped during each of 5 field seasons under both insecticide treated and untreated plots. Across all seasons, barley yellow dwarf severity was lower within the insecticide treatment along with increased plant height and grain yield compared with untreated entries. Only 9.2% of the lines were positive for the presence of the translocated segment carrying the resistance gene Bdv2. Despite the low frequency, this region was identified through association mapping. Furthermore, we mapped a potentially novel genomic region for barley yellow dwarf resistance on chromosome 5AS. Given the variable heritability of the trait (0.211-0.806), we obtained a predictive ability for barley yellow dwarf severity ranging between 0.06 and 0.26. Including the presence or absence of Bdv2 as a covariate in the genomic selection models had a large effect for predicting barley yellow dwarf but almost no effect for other observed traits. This study was the first attempt to characterize barley yellow dwarf using field-high-throughput phenotyping and apply genomic selection to predict disease severity. These methods have the potential to improve barley yellow dwarf characterization, additionally identifying new sources of resistance will be crucial for delivering barley yellow dwarf resistant germplasm.
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Effects of Hazelnut Consumption on Cardiometabolic Risk Factors and Acceptance: A Systematic Review.
Brown, R, Ware, L, Tey, SL
International journal of environmental research and public health. 2022;(5)
Abstract
Despite being rich sources of monounsaturated fat and a number of vitamins, minerals, and phytonutrients, hazelnuts have received less attention than some other nut types. A qualitative systematic review was carried out to determine the effects of hazelnut consumption on acceptance and markers of cardiometabolic health, including blood lipids and lipoproteins, apolipoproteins A1 and B100, body weight and composition, blood pressure, glycemia, antioxidant status, oxidative stress, inflammation, and endothelial function. In total, 22 intervention studies (25 publications) met our inclusion criteria. The findings indicate some improvements in cardiometabolic risk factors; however, limitations in study design mean interpretation is problematic. The inclusion of hazelnuts in the diet did not adversely affect body weight and composition. Acceptance of hazelnuts remained stable over time confirming nut consumption guidelines are feasible and sustainable. Future studies using more robust study designs in a variety of populations are required to draw more definitive conclusions on the health benefits of hazelnut consumption.