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The vascular glycocalyx is a gel layer between endothelium and the blood, 0.5 µm thick. Evidence is presented from published studies to indicate that hyperglycaemia causes damage to the vascular glycocalyx. This damage results in microalbuminuria, excess fluid transfer to the interstitium, reduction in nitric oxide (NO) production by arterial endothelium, and leukocyte and platelet adhesion to endothelium leading to atherothrombosis. The lack of NO production proceeds from the fact that glycocalyx is the mechanotransducer transmitting the signal for increased shear stress between blood and arterial wall, and this function is inhibited by hyperglycaemia. When hyperinsulinaemia is also present, the problem is compounded by general arterial dilatation leading to low shear rates throughout the arterial tree. These findings explain the predisposition to atherothrombosis in the pre-diabetic condition of insulin resistance/metabolic syndrome/obesity and diabetes mellitus. It is proposed that greater efforts than ever are required to detect occult insulin resistance, to treat such patients and diabetics with ever more strict blood glucose control while minimising insulin levels, and to carry out further research into how glycocalyx structure and function can be preserved. [ABSTRACT FROM AUTHOR]

Background In England and Wales, the Mental Capacity Act 2005 ( MCA) provides a new legal framework to regulate substitute decision-making relating to the welfare of adults who lack the capacity to make one or more autonomous decisions about their care and support. Any substitute decision made on behalf of an adult lacking capacity must be in his/her 'best interests'. However, the value of adopting established principles and procedures for substitute decision-making in practice is uncertain, and little is known about the legal or ethical dynamics of social care support, including the day-to-day residential support provided to adults with intellectual disabilities (ID). Methods This paper reports a qualitative, grounded theory analysis of 21 interviews with support workers working in residential care homes for adults with ID, and observations of care practices. Results In contrast to the narrow legal responsibilities placed upon them, it is argued that support workers interpret substitute decision-making within a broad moral account of their care role, orientating their support towards helping residents to live 'a life like ours'. In so doing, support workers describe how they draw on their own values and life experiences to shape the substitute decisions that they make on behalf of residents. Conclusions Support workers' accounts reveal clear discrepancies between the legal regulation of substitute decision-making and the ways that these support workers make sense of their work. Such discrepancies have implications both for the implementation of the MCA, and for the role of support workers' values in the conceptualisation and delivery of 'good' care. [ABSTRACT FROM AUTHOR]

BACKGROUND: Psychotic illness is strongly associated with the maternal uniparental disomy (mUPD) genetic subtype of Prader-Willi syndrome (PWS), but not the deletion subtype (delPWS). This study investigates the clinical features of psychiatric illness associated with PWS. We consider possible genetic and other mechanisms that may be responsible for the development of psychotic illness, predominantly in those with mUPD. METHOD: The study sample comprised 119 individuals with genetically confirmed PWS, of whom 46 had a history of psychiatric illness. A detailed clinical and family psychiatric history was obtained from these 46 using the PAS-ADD, OPCRIT, Family History and Life Events Questionnaires. RESULTS: Individuals with mUPD had a higher rate of psychiatric illness than those with delPWS (22/34 v. 24/85, p<0.001). The profile of psychiatric illness in both genetic subtypes resembled an atypical affective disorder with or without psychotic symptoms. Those with delPWS were more likely to have developed a non-psychotic depressive illness (p=0.005) and those with mUPD a bipolar disorder with psychotic symptoms (p=0.00005). Individuals with delPWS and psychotic illness had an increased family history of affective disorder. This was confined exclusively to their mothers. CONCLUSIONS: Psychiatric illness in PWS is predominately affective with atypical features. The prevalence and possibly the severity of illness are greater in those with mUPD. We present a 'two-hit' hypothesis, involving imprinted genes on chromosome 15, for the development of affective psychosis in people with PWS, regardless of genetic subtype. [ABSTRACT FROM AUTHOR]

BACKGROUND: Recent research suggests that preclinical Alzheimer's disease (AD) in people with Down syndrome (DS) is characterized by changes in personality/behaviour and executive dysfunction that are more prominent than deterioration in episodic memory. This study examines the relationship between executive dysfunction and the clinical and preclinical features of AD in DS. To determine the specificity of this relationship, performance on executive function (EF) measures is contrasted with performance on memory measures. METHODS: One hundred and three people with DS (mean age 49 years, range 36-72) with mild to moderate learning disabilities (LD) took part. Dementia diagnosis was based on the CAMDEX informant interview conducted with each participant's main carer. Reported changes in personality/behaviour and memory were recorded. Participants completed six EF and six memory measures (two of which also had a strong executive component) and the BPVS (as a measure of general intellectual ability). First, performance was compared between those with and without established dementia of Alzheimer's type (DAT), controlling for age and LD severity using ANCOVA. Next, the degree to which informant-reported changes predicted cognitive test performance was examined within the non-DAT group using multiple regression analyses. RESULTS: The DAT group (N=25) showed a consistent pattern of impaired performance relative to the non-DAT group (N=78), across all measures. Within the non-DAT group, number of informant-reported personality/behaviour changes was a significant predictor of performance on two EF and two 'executive memory' tests (but not on episodic memory tests). Informant-reported memory changes, however, were associated with impaired performance on a delayed recall task only. CONCLUSIONS: These findings provide further evidence for a specific impairment in frontal-lobe functioning in the preclinical stages of AD in DS. Implications for the assessment, diagnosis, and management of dementia in DS are discussed. [ABSTRACT FROM AUTHOR]

Background This study is part of a larger UK-wide study investigating psychiatric illness in people with Prader-Willi syndrome (PWS), and describes the longitudinal aspect of psychiatric illness, in particular psychotic illness, and examines the use and role of psychotropic medication. Method A total of 119 individuals with genetically confirmed PWS were included in the study. An informant-based questionnaire was administered for each participant to screen for a history of psychopathology. Those who screened positive were visited at their homes to obtain further information. This assessment included a full psychiatric history and mental state examination using the Psychiatric Assessment Schedule for Adults with Developmental Disability and the Operational Criteria Checklist for psychotic and affective illness to collect information regarding phenomenology and course of illness, and a modified life events questionnaire. At the end of the study period, informant-based telephone interviews were again carried out, up to 2.5 years after the initial screening. Information regarding medication usage was collected. Results The results confirm previous findings that psychiatric illness in people with PWS resembles an affective disorder. Individuals with the maternal uniparental disomy genetic subtype had a more severe course of illness than those with the deletion genetic subtype in terms of a greater risk of recurrence, more episodes, higher incidence and a possibly poorer response to medication with more side-effects. Individuals with a recurrent episode during the follow-up period had a poorer course of illness. Selective serotonin reuptake inhibitor medication is frequently used, and beneficial effects may reflect fundamental pathological processes in PWS. Mood-stabilizing medication was found to be of little benefit and reasons for this are examined. Conclusion The longitudinal course of psychiatric illness and response to medication in people with PWS is fully described. Further research is needed regarding the effect of psychotropic medications, particularly mood-stabilizing medication. These data will enable informed decisions to be made regarding management options and provide information on the possible long-term outcome of illness. [ABSTRACT FROM AUTHOR]

Background Research into the excessive eating behaviour associated with Prader-Willi syndrome (PWS) to date has focused on homeostatic and behavioural investigations. The aim of this study was to examine the role of the reward system in such eating behaviour, in terms of both the pattern of food preferences and the neural substrates of incentive in the amygdala and orbitofrontal cortex (OFC). Method Participants with PWS ( n = 18) were given a food preference interview to examine food preferences and to inform the food-related incentive task to be conducted during the neuroimaging. Thirteen individuals with PWS took part in the positron emission tomography (PET) study, the design of which was based on a previous study of non-obese, non-PWS controls. For the task, participants were asked to consider photographs of food and to choose the food they would most like to eat in two conditions, one of high and one of low incentive foods, tailored to each participant's preferences. For comparison of the food preference data, 12 non-PWS individuals were given one part of the interview. Results Individuals with PWS expressed relative liking of different foods and showed preferences that were consistent over time, particularly for sweet foods. The participants with PWS did give the foods in the high incentive condition a significantly higher incentive value than the foods in the low incentive condition. However, activation of the amygdala and medial OFC was not associated with the prospect of highly valued foods as predicted in those with PWS. Conclusions It would appear that incentive motivation alone plays a less powerful role in individuals with PWS than in those without the syndrome. This is likely to be due to the overriding intrinsic drive to eat because of a lack of satiety in those with PWS, and the impact of this on activity in the incentive processing regions of the brain. Activity in such reward areas may not then function to guide behaviour selectively towards the consumption of high preference foods. [ABSTRACT FROM AUTHOR]

OBJECTIVE: In the context of recent legal and social policy developments, which encourage clinicians to support vulnerable adults in making their own financial decisions, we explored understanding of basic financial concepts among adults with mild learning disabilities. METHOD: Using the literature about typically developing children, five measures entailing identification and ordering tasks were devised and were used to examine understanding of quantity, numbers and money among 30 men and women using specialist clinical services (mean FSIQ = 61.80; SD=10.59). RESULTS: The concept of quantity was easier to understand than those of numbers and money, and task difficulties increased with the magnitudes involved. The different types of conceptual understanding were closely related. CONCLUSIONS: These measures may be useful for analysing difficulties in, and informing interventions to maximize, independent financial decision making. [ABSTRACT FROM AUTHOR]

Background: Despite numerous reports of changes in satiety, food preference, and eating habits in patients with frontotemporal dementia, there have been few systematic studies.Objectives: To investigate the frequency of changes in eating behaviours and the sequence of development of eating behaviours in frontotemporal dementia and Alzheimer's disease, using a caregiver questionnaire.Methods: Three groups of patients were studied: frontal variant frontotemporal dementia (fv-FTD) (n = 23), semantic dementia (n = 25), and Alzheimer's disease (n = 43). Level of education and dementia severity was similar in the three groups. The questionnaire consisted of 36 questions investigating five domains: swallowing problems, appetite change, food preference, eating habits, and other oral behaviours.Results: The frequencies of symptoms in all five domains, except swallowing problems, were higher in fv-FTD than in Alzheimer's disease, and changes in food preference and eating habits were greater in semantic dementia than in Alzheimer's disease. In semantic dementia, the developmental pattern was very clear: a change in food preference developed initially, followed by appetite increase and altered eating habits, other oral behaviours, and finally swallowing problems. In fv-FTD, the first symptom was altered eating habits or appetite increase. In Alzheimer's disease, the pattern was not clear although swallowing problems developed in relatively early stages.Conclusions: Change in eating behaviour was significantly more common in both of the frontotemporal dementia groups than in Alzheimer's disease. It is likely that the changing in eating behaviours reflects the involvement of a common network in both variants of frontotemporal dementia-namely, the ventral (orbitobasal) frontal lobe, temporal pole, and amygdala. [ABSTRACT FROM AUTHOR]

Background: Few studies describe in detail the pregnancy and early development of infants with Prader-Willi syndrome (PWS). However, variations at these early stages may partially account for differences in the later phenotype. A recent paper described an abnormally high number of problems in pregnancy and early infancy in a large sample of people with PWS but this sample was not homogeneous with respect to age and potentially liable to cohort effects. Aims: To describe the early development of infants with PWS, younger and more homogeneous for age, and to investigate whether such high rates of perinatal problems are still present despite medical advances and whether there are differences according to the genetic subtypes. Study Design: Using a structured interview, data were collected from mothers and from relevant GP and hospital records. Subjects: Forty-six babies with PWS, born in a six-year period 2000-2006, and their mothers. Outcome Measures: Problems arising during pregnancy, the birth process and the neonatal period and the birth characteristics of the babies. Results: An abnormally high number of problems associated with the early developmental period similar to those previously reported were observed. The only significant difference between the genetic subtypes was that mother's age was positively correlated with birth weight for UPD (and negatively correlated for deletion subtypes). Conclusions: High rates of, and variability in, the nature and severity of problems arising during early development have been confirmed. To establish whether variability in the later phenotype is influenced by such differences requires a longitudinal study. [ABSTRACT FROM AUTHOR]

Inguinal hernia repair is one of the most performed procedures in children, but aspects of care remain controversial. The aim of this review was to provide a critical appraisal of recently published guidelines on the management of inguinal hernias in children, by the American Academy of Pediatrics (2023) and the European Pediatric Surgeons' Association Evidence and Guideline Committee (2022). This was achieved by delineating areas of controversy and reviewing the most relevant recent literature on these topics. Currently available moderate-to-low quality evidence recommends postponing hernia repair in premature infants until after discharge, to reduce the risk of respiratory difficulties and recurrence. Laparoscopic repair provides similar outcomes to open but may shorten operative time in bilateral cases. No clear recommendation can be made for contralateral exploration, therefore should be evaluated case by case. In preterm infants, consideration of regional anaesthesia may reduce post-operative apnoea and pain, with no difference in neurodevelopment outcomes., (© 2024 Paediatrics and Child Health Division (The Royal Australasian College of Physicians).)

Centrioles define centrosome structure and function. Deregulation of centriole numbers can cause developmental defects and cancer. The p53 tumor suppressor limits the growth of cells lacking or harboring additional centrosomes and can be engaged by the "mitotic surveillance" or the "PIDDosome pathway", respectively. Here, we show that early B cell progenitors frequently present extra centrioles, ensuing their high proliferative activity and related DNA damage. Extra centrioles are efficiently cleared during B cell maturation. In contrast, centriole loss upon Polo-like kinase 4 (Plk4) deletion causes apoptosis and arrests B cell development. This defect can be rescued by co-deletion of Usp28, a critical component of the mitotic surveillance pathway, that restores cell survival and maturation. Centriole-deficient mature B cells are proliferation competent and mount a humoral immune response. Our findings imply that progenitor B cells are intolerant to centriole loss but permissive to centriole amplification, a feature potentially facilitating their malignant transformation., (© 2024. The Author(s).)

Centrosomes ensure accurate chromosome segregation during cell division. Although the regulation of centrosome number is well-established, less is known about the suppression of non-centrosomal MTOCs (ncMTOCs). The E3 ligase TRIM37, implicated in Mulibrey nanism and 17q23-amplified cancers, has emerged as a key regulator of both centrosomes and ncMTOCs. Yet, the mechanism by which TRIM37 achieves enzymatic activation to target these mesoscale structures had remained unknown. Here, we elucidate TRIM37's activation process, beginning with TRAF domain-directed substrate recognition, progressing through B-box domain-mediated oligomerization, and culminating in RING domain dimerization. Using optogenetics, we demonstrate that TRIM37's E3 activity is directly coupled to the assembly state of its substrates, activating only when centrosomal proteins cluster into higher-order assemblies resembling MTOCs. This regulatory framework provides a mechanistic basis for understanding TRIM37-driven pathologies and, by echoing TRIM5's restriction of the HIV capsid, unveils a conserved activation blueprint among TRIM proteins for controlling mesoscale assembly turnover., Competing Interests: Declaration of interests The authors declare no competing interests.

Centrosomes are the canonical microtubule organizing centers (MTOCs) of most mammalian cells, including spermatocytes. Centrosomes comprise a centriole pair within a structurally ordered and dynamic pericentriolar matrix (PCM). Unlike in mitosis, where centrioles duplicate once per cycle, centrioles undergo two rounds of duplication during spermatogenesis. The first duplication is during early meiotic prophase I, and the second is during interkinesis. Using mouse mutants and chemical inhibition, we have blocked centriole duplication during spermatogenesis and determined that non-centrosomal MTOCs (ncMTOCs) can mediate chromosome segregation. This mechanism is different from the acentriolar MTOCs that form bipolar spindles in oocytes, which require PCM components, including gamma-tubulin and CEP192. From an in-depth analysis, we identified six microtubule-associated proteins, TPX2, KIF11, NuMA, and CAMSAP1-3, that localized to the non-centrosomal MTOC. These factors contribute to a mechanism that ensures bipolar MTOC formation and chromosome segregation during spermatogenesis when centriole duplication fails. However, despite the successful completion of meiosis and round spermatid formation, centriole inheritance and PLK4 function are required for normal spermiogenesis and flagella assembly, which are critical to ensure fertility., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Objective: This paper investigates Burn First Aid Treatment (BFAT) provided to Aboriginal and Torres Strait Islander children in Australia at the scene of injury using data from a population-based cohort study., Study Design: The participants were 208 Aboriginal and Torres Strait Islander children aged < 16 years who sustained a burns injury between 2015-2018, and their carers. The primary outcome measure was gold standard BFAT, (defined as at least 20 min of cool, running water within 3 h of the injury); additional measures included type of first aid, length of first aid provided, and carer's knowledge of first aid., Results: Of the 208 caregivers, 168 provided open-ended responses that indicated first aid was applied to their child; however, only 34 received gold standard BFAT at the scene of the injury, 110 did not receive correct BFAT, and 24 were unsure what first aid was applied., Conclusion: This study highlights an important need for communities to have access to appropriate evidence-based and co-designed BFAT education and training., (Copyright © 2024. Published by Elsevier Ltd.)

Studying essential genes required for dynamic processes in live mice is challenging as genetic perturbations are irreversible and limited by slow protein depletion kinetics. The first-generation auxin-inducible-degron (AID) system is a powerful tool for analyzing inducible protein loss in cultured cells. However, auxin administration is toxic to mice, preventing its long-term use in animals. Here, we use an optimized second-generation AID system to achieve the conditional and reversible loss of the essential centrosomal protein CEP192 in live mice. We show that the auxin derivative 5-Ph-IAA is well tolerated over two weeks and drives near-complete CEP192-mAID degradation in less than one hour in vivo . Prolonged CEP192 loss led to cell division failure and cell death in proliferative tissues. Thus, the second-generation AID system is well suited for rapid and/or sustained protein depletion in live mice, offering a valuable new tool for interrogating protein function in vivo .

Background: Hospital-acquired urinary tract infections (UTIs) have a detrimental effect on patients, families, and hospital resources. The Sydney Children's Hospital Network (SCHN) participates in the NSQIP-Pediatric (NSQIP-P) to monitor postoperative complications. NSQIP-P data revealed that the median UTI rate at SCHN was 1.75% in 2019, 3.5 times higher than the NSQIP-P target rate of 0.5%. Over three quarters of the NSQIP-P identified patients with UTI also had a urinary catheterization performed intraoperatively. A quality improvement project was conducted between mid-2018 and 2021 to minimize catheter-associated UTIs (CAUTIs) at SCHN., Study Design: NSQIP-P samples include pediatric (younger than 18 years) surgical patients from an 8-day cycle operative log. NSQIP-P data are statistically analyzed by the American College of Surgeons and provide biannual internationally benchmarked reports. The project used clinical redesign methodology with a 6-phase process for quality improvement projects., Results: The objectives of the project were to reduce urinary catheter duration of use, educate parents or carers, and improve catheter care and insertion technique by health staff. The duration of a urinary catheter in situ reduced from a median of 4.5 to 3 days from 2017 to 2021. The median NSQIP-P UTI rate at SCHN was reduced by 47.4% from 1.75% in 2019 to 0.9% in 2022., Conclusions: A multifactorial approach in quality improvement has been shown to be an effective strategy to reduce UTI rates at SCHN, and patient outcomes were improved within a 3-year timeframe. Although this project has reduced UTI rates at SCHN, there remain opportunities for further improvement., (Copyright © 2024 by the American College of Surgeons. Published by Wolters Kluwer Health, Inc. All rights reserved.)

The objective of the Australian Traumatic Brain Injury (AUS-TBI) Initiative is to develop a data dictionary to inform data collection and facilitate prediction of outcomes of people who experience moderate-severe TBI in Australia. The aim of this systematic review was to summarize the evidence of the association between demographic, injury event, and social characteristics with outcomes, in people with moderate-severe TBI, to identify potentially predictive indicators. Standardized searches were implemented across bibliographic databases to March 31, 2022. English-language reports, excluding case series, which evaluated the association between demographic, injury event, and social characteristics, and any clinical outcome in at least 10 patients with moderate-severe TBI were included. Abstracts and full text records were independently screened by at least two reviewers in Covidence. A pre-defined algorithm was used to assign a judgement of predictive value to each observed association. The review findings were discussed with an expert panel to determine the feasibility of incorporation of routine measurement into standard care. The search strategy retrieved 16,685 records; 867 full-length records were screened, and 111 studies included. Twenty-two predictors of 32 different outcomes were identified; 7 were classified as high-level (age, sex, ethnicity, employment, insurance, education, and living situation at the time of injury). After discussion with an expert consensus group, 15 were recommended for inclusion in the data dictionary. This review identified numerous predictors capable of enabling early identification of those at risk for poor outcomes and improved personalization of care through inclusion in routine data collection.

Objectives: The aim of this study was to characterise the dynamic immune profile of paediatric burn patients for up to 18 months post-burn., Methods: Flow cytometry was used to measure 25 cell markers, chemokines and cytokines which reflected both pro-inflammatory and anti-inflammatory immune profiles. Peripheral blood mononuclear cells from 6 paediatric burn patients who had returned for repeated burn and scar treatments for > 4 timepoints within 12 months post-burn were compared to four age-matched healthy controls., Results: While overall proportions of T cells, NK cells and macrophages remained relatively constant, over time percentages of these immune cells differentiated into effector and proinflammatory cell phenotypes including Th17 and activated γδ T cells. Circulating proportions of γδ T cells increased their expression of pro-inflammatory mediators throughout the burn recovery, with a 3-6 fold increase of IL-17 at 1-3 weeks, and NFκβ 9-18 months post-burn. T-regulatory cell plasticity was also observed, and Treg phenotype proportions changed from systemically reduced skin-homing T-regs (CCR4 + ) and increased inflammatory (CCR6 + ) at 1-month post-burn, to double-positive cell types (CCR4 + CCR6 + ) elevated in circulation for 18 months post-burn. Furthermore, Tregs were observed to proportionally express less IL-10 but increased TNF-α over 18 months., Conclusion: Overall, these results indicate the circulating percentages of immune cells do not increase or decrease over time post-burn, instead they become highly specialised, inflammatory and skin-homing. In this patient population, these changes persisted for at least 18 months post-burn, this 'immune distraction' may limit the ability of immune cells to prioritise other threats post-burn, such as respiratory infections., Competing Interests: The authors have no conflicts of interest to declare., (© 2024 The Authors. Clinical & Translational Immunology published by John Wiley & Sons Australia, Ltd on behalf of Australian and New Zealand Society for Immunology, Inc.)

The efficacy of current antimitotic cancer drugs is limited by toxicity in highly proliferative healthy tissues. A cancer-specific dependency on the microtubule motor protein KIF18A therefore makes it an attractive therapeutic target. Not all cancers require KIF18A, however, and the determinants underlying this distinction remain unclear. Here, we show that KIF18A inhibition drives a modest and widespread increase in spindle assembly checkpoint (SAC) signaling from kinetochores which can result in lethal mitotic delays. Whether cells arrest in mitosis depends on the robustness of the metaphase-to-anaphase transition, and cells predisposed with weak basal anaphase-promoting complex/cyclosome (APC/C) activity and/or persistent SAC signaling through metaphase are uniquely sensitive to KIF18A inhibition. KIF18A-dependent cancer cells exhibit hallmarks of this SAC:APC/C imbalance, including a long metaphase-to-anaphase transition, and slow mitosis overall. Together, our data reveal vulnerabilities in the cell division apparatus of cancer cells that can be exploited for therapeutic benefit., (© 2024. The Author(s).)