PurposeMultiple sclerosis (MS) is an immune-mediated, neuroinflammatory disease of the central nervous system and in industrialised countries is the most common cause of progressive neurological ...disability in working age persons. While treatable, there is substantial interindividual heterogeneity in disease activity and response to treatment. Currently, the ability to predict at diagnosis who will have a benign, intermediate or aggressive disease course is very limited. There is, therefore, a need for integrated predictive tools to inform individualised treatment decision making.ParticipantsEstablished with the aim of addressing this need for individualised predictive tools, FutureMS is a nationally representative, prospective observational cohort study of 440 adults with a new diagnosis of relapsing-remitting MS living in Scotland at the time of diagnosis between May 2016 and March 2019.Findings to dateThe study aims to explore the pathobiology and determinants of disease heterogeneity in MS and combines detailed clinical phenotyping with imaging, genetic and biomarker metrics of disease activity and progression. Recruitment, baseline assessment and follow-up at year 1 is complete. Here, we describe the cohort design and present a profile of the participants at baseline and 1 year of follow-up.Future plansA third follow-up wave for the cohort has recently begun at 5 years after first visit and a further wave of follow-up is funded for year 10. Longer-term follow-up is anticipated thereafter.
Background:
Understanding breastfeeding knowledge, attitudes, and exposures among nonpregnant youth who are likely to be future parents may provide significant pathways to successfully increasing ...breastfeeding as the normal, accepted way of feeding infants. However, based on a recent review of the literature, only 3 studies have assessed these factors in nonpregnant, young adults in the United States in the past 10 years.
Objective:
The objective of this study was to gather more recent data regarding breastfeeding knowledge, attitudes, and prior exposure among undergraduate university students.
Methods:
This was a cross-sectional survey, conducted in November 2010. A convenience sample, consisting of undergraduates in attendance in 2 sections of an introductory nutrition class at a large research university, was used for this project (N = 248).
Results:
Breastfeeding knowledge was relatively good. However, overall breastfeeding attitudes were more neutral, which appeared to be explained by the belief that breastfeeding is painful, restrictive, and inconvenient, both in general and specifically for the working mother. Though support for breastfeeding in public was low, men were significantly less likely than women to believe it to be embarrassing or unacceptable. In addition, breastfeeding attitudes were more positive among older students and those who were breastfed as infants. Those who were breastfed as infants were also significantly more likely to intend to breastfeed future children.
Conclusions:
Though this sample indicates good breastfeeding knowledge, attitudes were more neutral, and support for breastfeeding in public appears low. This finding is contradictory and warrants further exploration.
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NUK, OILJ, SAZU, UKNU, UL, UM, UPUK, VSZLJ
We describe two pediatric patients with Duchenne muscular dystrophy that presented with acute neurologic deterioration and hypoxic respiratory failure requiring mechanical ventilation. These cases ...fulfill the clinical criteria for Fat Embolism Syndrome. Early recognition and aggressive supportive therapy with mechanical ventilation, right ventricular afterload reduction, and blood transfusion led to survival without any residual effects from the event. Fat Embolism Syndrome needs to be considered early in the course of patients with Duchenne muscular dystrophy who present with respiratory and neurological symptoms.
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DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
Cognitive decline is among the most feared aspects of ageing. We have generated induced pluripotent stem cells (iPSCs) from 24 people from the Lothian Birth Cohort 1936, whose cognitive ability was ...tested in childhood and in older age. Peripheral blood mononuclear cells (PBMCs) were reprogrammed using non-integrating oriP/EBNA1 backbone plasmids expressing six iPSC reprogramming factors (OCT3/4 (POU5F1), SOX2, KLF4, L-Myc, shp53, Lin28, SV40LT). All lines demonstrated STR matched karyotype and pluripotency was validated by multiple methods. These iPSC lines are a valuable resource to study molecular mechanisms underlying individual differences in cognitive ageing and resilience to age-related neurodegenerative diseases.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Carbonyl reductase 1 (Cbr1), a recently discovered contributor to tissue glucocorticoid metabolism converting corticosterone to 20β-dihydrocorticosterone (20β-DHB), is upregulated in adipose tissue ...of obese humans and mice and may contribute to cardiometabolic complications of obesity. This study tested the hypothesis that Cbr1-mediated glucocorticoid metabolism influences glucocorticoid and mineralocorticoid receptor activation in adipose tissue and impacts glucose homeostasis in lean and obese states.
The actions of 20β-DHB on corticosteroid receptors in adipose tissue were investigated first using a combination of in silico, in vitro, and transcriptomic techniques and then in vivo administration in combination with receptor antagonists. Mice lacking one Cbr1 allele and mice overexpressing Cbr1 in their adipose tissue underwent metabolic phenotyping before and after induction of obesity with high-fat feeding.
20β-DHB activated both the glucocorticoid and mineralocorticoid receptor in adipose tissue and systemic administration to wild-type mice induced glucose intolerance, an effect that was ameliorated by both glucocorticoid and mineralocorticoid receptor antagonism. Cbr1 haploinsufficient lean male mice had lower fasting glucose and improved glucose tolerance compared with littermate controls, a difference that was abolished by administration of 20β-DHB and absent in female mice with higher baseline adipose 20β-DHB concentrations than male mice. Conversely, overexpression of Cbr1 in adipose tissue resulted in worsened glucose tolerance and higher fasting glucose in lean male and female mice. However, neither Cbr1 haploinsfficiency nor adipose overexpression affected glucose dyshomeostasis induced by high-fat feeding.
Carbonyl reductase 1 is a novel regulator of glucocorticoid and mineralocorticoid receptor activation in adipose tissue that influences glucose homeostasis in lean mice.
•Carbonyl reductase 1 (Cbr1) is a novel regulator of adipose glucocorticoid metabolism and glucose homeostasis.•Cbr1 metabolises corticosterone to 20β-dihydrocorticosterone, which is both a glucocorticoid and mineralocorticoid receptor agonist.•Global knockdown of Cbr1 improves glucose tolerance in lean male mice.•Overexpression of Cbr1 in adipose tissue worsens glucose tolerance in lean male and female mice.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
BACKGROUNDDiabetic ketoacidosis (DKA) is a common presentation to an emergency department (ED), with the majority presenting to community EDs. Adherence to clinical guidelines in these EDs can reduce ...morbidity and mortality. Few methods to describe practice gaps for DKA management have been reported.
OBJECTIVESWe hypothesized that high-fidelity in situ simulation can be used to measure and compare the quality of the care provided to pediatric patients with DKA presenting to community EDs in the state of Indiana.
METHODSThis observational study examined multiprofessional teams caring for a simulated pediatric patient who presented with DKA to community EDs. The primary outcome was overall adherence to pediatric DKA guidelines as measured by a validated performance checklist. A composite adherence score (CAS) was calculated using the sum of 9 checklist performance parameters. Multivariable logistic regression was used to examine the impact of ED volume and characteristics on the scores.
RESULTSA 49 multiprofessional teams from 13 sites were enrolled. Of the 252 participants, 26 (10.3%) were physicians, 143 (56.7%) registered nurses, 25 (9.9%) respiratory therapists, and 58 (23.0%) were other. The overall CAS for all sites was 55.6% (25th, 75th interquartile range, 44.4%, 66.7%). Excessive intravenous fluid boluses were given by 53.1%, whereas 30.6% and 26.5% incorrectly administered insulin and sodium bicarbonate boluses, respectively. Only 10.2% used an appropriate intravenous fluid rate, and 57.1% performed an hourly glucose. No significant difference in the CAS was found due to pediatric ED volume or presence of an inpatient pediatric service.
CONCLUSIONSUsing validated in situ simulation; we revealed high variability in adherence to the pediatric DKA management guidelines at a wide range of community EDs. A statewide education initiative focused on decreasing variation and improving adherence to pediatric DKA guidelines is necessary for patient safety.
Whipple's disease is a rare multisystem chronic infection, involving the intestinal tract as well as various other organs. The causative agent, Tropheryma whipplei, is a Gram-positive bacterium about ...which little is known. Our aim was to investigate the biology of this organism by generating and analysing the complete DNA sequence of its genome.
We isolated and propagated T whipplei strain TW08/27 from the cerebrospinal fluid of a patient diagnosed with Whipple's disease. We generated the complete sequence of the genome by the whole genome shotgun method, and analysed it with a combination of automatic and manual bioinformatic techniques.
Sequencing revealed a condensed 925 938 bp genome with a lack of key biosynthetic pathways and a reduced capacity for energy metabolism. A family of large surface proteins was identified, some associated with large amounts of non-coding repetitive DNA, and an unexpected degree of sequence variation.
The genome reduction and lack of metabolic capabilities point to a host-restricted lifestyle for the organism. The sequence variation indicates both known and novel mechanisms for the elaboration and variation of surface structures, and suggests that immune evasion and host interaction play an important part in the lifestyle of this persistent bacterial pathogen.
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DOBA, GEOZS, IJS, IMTLJ, IZUM, KILJ, KISLJ, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SIK, UILJ, UKNU, UL, UM, UPCLJ, UPUK, VSZLJ
Newborn heel prick blood spots are routinely used to screen for inborn errors of metabolism and life-limiting inherited disorders. The potential value of secondary data from newborn blood spot ...archives merits ethical consideration and assessment of feasibility for public benefit. Early life exposures and behaviours set health trajectories in childhood and later life. The newborn blood spot is potentially well placed to create an unbiased and cost-effective population-level retrospective birth cohort study. Scotland has retained newborn blood spots for all children born since 1965, around 3 million in total. However, a moratorium on research access is currently in place, pending public consultation.
We conducted a Citizens' Jury as a first step to explore whether research use of newborn blood spots was in the public interest. We also assessed the feasibility and value of extracting research data from dried blood spots for predictive medicine.
Jurors delivered an agreed verdict that conditional research access to the newborn blood spots was in the public interest. The Chief Medical Officer for Scotland authorised restricted lifting of the current research moratorium to allow a feasibility study. Newborn blood spots from consented Generation Scotland volunteers were retrieved and their potential for both epidemiological and biological research demonstrated.
Through the Citizens' Jury, we have begun to identify under what conditions, if any, should researchers in Scotland be granted access to the archive. Through the feasibility study, we have demonstrated the potential value of research access for health data science and predictive medicine.
Genetic resistance is a cornerstone for managing clubroot (
). However, when used repeatedly, a clubroot resistance (CR) gene can be broken rapidly. In this study, canola inbred/hybrid lines carrying ...one or two CR genes (
and
) were assessed against
pathotype X by repeated exposure to the same inoculum source under a controlled environment. Lines carrying two CR genes, either
+
or
+
, showed partial resistance. Selected lines were inoculated with a field pathotype X population (L-G3) at 5 × 10
resting spores/g soil, and all clubs were returned to the soil they came from six weeks after inoculation. The planting was repeated for five cycles, with diseased roots being returned to the soil after each cycle. The soil inoculum was quantified using qPCR before each planting cycle. All lines with a single CR gene were consistently susceptible, maintaining high soil inoculum levels over time. The lines carrying two CR genes showed much lower clubroot severity, resulting in a 10-fold decline in soil inoculum. These results showed that the CR-gene stacking provided moderate resistance against
.
pathotype X, which may also help reduce the pathogen inoculum buildup in soil.
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