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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).)

Background: Prader-Willi syndrome (PWS) is a rare and complex neurodevelopmental disorder resulting from absent paternal expression of maternally imprinted genes at chromosomal locus 15q11-13. This absence of expression occurs as a consequence of a deletion on the chromosome 15 of paternal origin (ca. 70%), a chromosome 15 maternal uniparental disomy (mUPD; ca. 25%), or an imprinting centre defect (IC; ca. 1-3%). At birth, individuals with PWS are severely hypotonic and fail to thrive. Hyperphagia and characteristic physical and neuropsychiatric phenotypes become apparent during childhood. The risk for the development of a co-morbid psychotic illness increases during the teenage years, specifically in those with PWS due to the presence of an mUPD. The primary aim of this literature review is to inform clinical practice. To achieve this, we have undertaken a systematic analysis of the clinical research literature on prevalence, presentation, course, characteristics, diagnosis and treatment of psychotic illness in people with PWS. The secondary aim is to identify clinical aspects of psychotic illness in PWS in need of further investigation., Methods and Findings: A systematic literature review on psychosis in PWS was conducted on the databases Web of Knowledge, PubMed and Scopus, using the terms "((Prader-Willi syndrome) OR (Prader Willi Syndrome)) AND ((psychosis) OR (psychotic illness))". All articles written in English and reporting original human research were reviewed. In all but three of the 16 cohort studies in which the genetic types were known, the authors reported higher rates of psychosis in people with PWS resulting from an mUPD, compared to those with the deletion subtype of PWS. When psychosis was present the presentation was psychosis similar regardless of genetic type and was usually characterised by an acute onset of hallucinations and delusions accompanied by confusion, anxiety and motor symptoms., Conclusions: The onset of confusion, an affective cyclical pattern with the presence of abnormal mental beliefs and experiences, usually of rapid onset is suggestive of the development of psychotic illness. Phenomenologically, this psychosis in people with PWS is atypical in comparison to schizophrenia and bipolar disorder in the general population. The relationship to psychosis in the general population and the optimum treatments remain uncertain., (© 2024. The Author(s).)

53BP1 acts at the crossroads between DNA repair and p53-mediated stress response. With its interactors p53 and USP28, it is part of the mitotic surveillance (or mitotic stopwatch) pathway (MSP), a sensor that monitors the duration of cell division, promoting p53-dependent cell cycle arrest when a critical time threshold is surpassed. Here, we show that Polo-like kinase 1 (PLK1) activity is essential for the time-dependent release of 53BP1 from kinetochores. PLK1 inhibition, which leads to 53BP1 persistence at kinetochores, prevents cytosolic 53BP1 association with p53 and results in a blunted MSP. Strikingly, the identification of CENP-F as the kinetochore docking partner of 53BP1 enabled us to show that measurement of mitotic timing by the MSP does not take place at kinetochores, as perturbing CENP-F-53BP1 binding had no measurable impact on the MSP. Taken together, we propose that PLK1 supports the MSP by generating a cytosolic pool of 53BP1 and that an unknown cytosolic mechanism enables the measurement of mitotic duration., (© 2023 The Authors. Published under the terms of the CC BY 4.0 license.)

Polo-like kinase 4 (PLK4) is a key regulator of centriole biogenesis, but how PLK4 selects a single site for procentriole assembly remains unclear. Using ultrastructure expansion microscopy, we show that PLK4 localizes to discrete sites along the wall of parent centrioles. While there is variation in the number of sites PLK4 occupies on the parent centriole, most PLK4 localize at a dominant site that directs procentriole assembly. Inhibition of PLK4 activity leads to stable binding of PLK4 to the centriole and increases occupancy to a maximum of nine sites. We show that self-phosphorylation of an unstructured linker promotes the release of active PLK4 from the centriole to drive the selection of a single site for procentriole assembly. Preventing linker phosphorylation blocks PLK4 turnover, leading to supernumerary sites of PLK4 localization and centriole amplification. Therefore, self-phosphorylation is a major driver of the spatial patterning of PLK4 at the centriole and plays a critical role in selecting a single centriole duplication site., (© 2023 Scott et al.)

The study of sex differences in Alzheimer's disease is increasingly recognized as a key priority in research and clinical development. People with Down syndrome represent the largest population with a genetic link to Alzheimer's disease (>90% in the 7th decade). Yet, sex differences in Alzheimer's disease manifestations have not been fully investigated in these individuals, who are key candidates for preventive clinical trials. In this double-centre, cross-sectional study of 628 adults with Down syndrome [46% female, 44.4 (34.6; 50.7) years], we compared Alzheimer's disease prevalence, as well as cognitive outcomes and AT(N) biomarkers across age and sex. Participants were recruited from a population-based health plan in Barcelona, Spain, and from a convenience sample recruited via services for people with intellectual disabilities in England and Scotland. They underwent assessment with the Cambridge Cognitive Examination for Older Adults with Down Syndrome, modified cued recall test and determinations of brain amyloidosis (CSF amyloid-β 42 / 40 and amyloid-PET), tau pathology (CSF and plasma phosphorylated-tau181) and neurodegeneration biomarkers (CSF and plasma neurofilament light, total-tau, fluorodeoxyglucose-PET and MRI). We used within-group locally estimated scatterplot smoothing models to compare the trajectory of biomarker changes with age in females versus males, as well as by apolipoprotein ɛ4 carriership. Our work revealed similar prevalence, age at diagnosis and Cambridge Cognitive Examination for Older Adults with Down Syndrome scores by sex, but males showed lower modified cued recall test scores from age 45 compared with females. AT(N) biomarkers were comparable in males and females. When considering apolipoprotein ɛ4, female ɛ4 carriers showed a 3-year earlier age at diagnosis compared with female non-carriers (50.5 versus 53.2 years, P = 0.01). This difference was not seen in males (52.2 versus 52.5 years, P = 0.76). Our exploratory analyses considering sex, apolipoprotein ɛ4 and biomarkers showed that female ɛ4 carriers tended to exhibit lower CSF amyloid-β 42/amyloid-β 40 ratios and lower hippocampal volume compared with females without this allele, in line with the clinical difference. This work showed that biological sex did not influence clinical and biomarker profiles of Alzheimer's disease in adults with Down syndrome. Consideration of apolipoprotein ɛ4 haplotype, particularly in females, may be important for clinical research and clinical trials that consider this population. Accounting for, reporting and publishing sex-stratified data, even when no sex differences are found, is central to helping advance precision medicine., Competing Interests: O.B. reported receiving personal fees from ADx NeuroSciences outside the submitted work. H.Z. declares that he has served on scientific advisory boards and/or as a consultant for Abbvie, Alector, Annexon, Artery Therapeutics, AZTherapies, CogRx, Denali, Eisai, Nervgen, Pinteon Therapeutics, Red Abbey Labs, Passage Bio, Roche, Samumed, Siemens Healthineers, Triplet Therapeutics and Wave, has given lectures in symposia sponsored by Cellectricon, Fujirebio, Alzecure, Biogen and Roche and is a co-founder of Brain Biomarker Solutions in Gothenburg AB, which is a part of the GU Ventures Incubator Program, outside the submitted work. K.B. declares that he has served as a consultant, on advisory boards, or data monitoring committees for Abcam, Axon, BioArctic, Biogen, JOMDD/Shimadzu, Julius Clinical, Lilly, MagQu, Novartis, Pharmatrophix, Prothena, Roche Diagnostics and Siemens Healthineers and is a co-founder of Brain Biomarker Solutions in Gothenburg AB, which is a part of the GU Ventures Incubator Program, outside the submitted work. D.A. reported receiving personal fees for advisory board services and/or speaker honoraria from Fujirebio-Europe, Roche, Nutricia, Krka Farmacéutica and Esteve, outside the submitted work. A.L. has served as a consultant or on advisory boards for Fujirebio-Europe, Roche, Biogen and Nutricia, outside the submitted work. J.F. reported receiving personal fees for service on the advisory boards, adjudication committees or speaker honoraria from AC Immune, Novartis, Lundbeck, Roche, Fujirebio and Biogen, outside the submitted work. 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Down's syndrome is associated with pathological ageing and a propensity for early-onset Alzheimer's disease. The early symptoms of dementia in people with Down's syndrome may reflect frontal lobe vulnerability to amyloid deposition. Auditory predictive processes rely on the bilateral auditory cortices with the recruitment of frontal cortices and appear to be impaired in pathologies characterized by compromised frontal lobe. Hence, auditory predictive processes were investigated to assess Down's syndrome pathology and its relationship with pathological ageing. An auditory electroencephalography (EEG) global-local paradigm was presented to the participants, in which oddball stimuli could either violate local or higher level global rules. We characterised predictive processes in individuals with Down's syndrome and their relationship with pathological ageing, with a focus on the EEG event-related potential called Mismatch Negativity (MMN) and the P300. In Down's syndrome, we also evaluated the EEG components as predictor of cognitive decline 1 year later. We found that predictive processes of detection of auditory violations are overall preserved in Down's syndrome but also that the amplitude of the MMN to local deviancies decreases with age. However, the 1-year follow-up of Down's syndrome found that none of the ERPs measures predicted subsequent cognitive decline. The present study provides a novel characterization of electrophysiological markers of local and global predictive processes in Down's syndrome., (© 2022 The Authors. European Journal of Neuroscience published by Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

This study investigates whether tau has (i) an independent effect from amyloid-β on changes in cognitive and functional performance and (ii) a synergistic relationship with amyloid-β in the exacerbation of decline in aging Down syndrome (DS). 105 participants with DS underwent baseline PET [ 18 F]-AV1451 and PET [ 11 C]PiB scans to quantify tau deposition in Braak regions II-VI and the Striatum and amyloid-β status respectively. Linear Mixed Effects models were implemented to assess how tau and amyloid-β deposition are related to change over three time points. Tau was a significant independent predictor of cognitive and functional change. The three-way interaction between time, [ 11 C]PiB status and tau was significant in the models of episodic memory and visuospatial cognition. Baseline tau is a significant predictor of cognitive and functional decline, over and above the effect of amyloid-β status. Results suggest a synergistic relationship between amyloid-β status and tau as predictors of change in memory and visuospatial cognition., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Hepatocyte polyploidization is a tightly controlled process that is initiated at weaning and increases with age. The proliferation of polyploid hepatocytes in vivo is restricted by the PIDDosome-P53 axis, but how this pathway is triggered remains unclear. Given that increased hepatocyte ploidy protects against malignant transformation, the evolutionary driver that sets the upper limit for hepatocyte ploidy remains unknown. Here we show that hepatocytes accumulate centrioles during cycles of polyploidization in vivo. The presence of excess mature centrioles containing ANKRD26 was required to activate the PIDDosome in polyploid cells. As a result, mice lacking centrioles in the liver or ANKRD26 exhibited increased hepatocyte ploidy. Under normal homeostatic conditions, this increase in liver ploidy did not impact organ function. However, in response to chronic liver injury, blocking centriole-mediated ploidy control leads to a massive increase in hepatocyte polyploidization, severe liver damage, and impaired liver function. These results show that hyperpolyploidization sensitizes the liver to injury, posing a trade-off for the cancer-protective effect of increased hepatocyte ploidy. Our results may have important implications for unscheduled polyploidization that frequently occurs in human patients with chronic liver disease., (© 2022 Sladky et al.; Published by Cold Spring Harbor Laboratory Press.)

Multiciliated cells (MCCs) are terminally differentiated epithelia that assemble multiple motile cilia used to promote fluid flow. To template these cilia, MCCs dramatically expand their centriole content during a process known as centriole amplification. In cycling cells, the master regulator of centriole assembly Polo-like kinase 4 (PLK4) is essential for centriole duplication; however recent work has questioned the role of PLK4 in centriole assembly in MCCs. To address this discrepancy, we created genetically engineered mouse models and demonstrated that both PLK4 protein and kinase activity are critical for centriole amplification in MCCs. Tracheal epithelial cells that fail centriole amplification accumulate large assemblies of centriole proteins and do not undergo apical surface area expansion. These results show that the initial stages of centriole assembly are conserved between cycling cells and MCCs and suggest that centriole amplification and surface area expansion are coordinated events., Competing Interests: GL, CD, AM, CJ, MS, AH No competing interests declared, (© 2022, LoMastro et al.)

Down's syndrome results from trisomy of chromosome 21, a genetic change which also confers a probable 100% risk for the development of Alzheimer's disease neuropathology (amyloid plaque and neurofibrillary tangle formation) in later life. We aimed to assess the effectiveness of diffusion-weighted imaging and connectomic modelling for predicting brain amyloid plaque burden, baseline cognition and longitudinal cognitive change using support vector regression. Ninety-five participants with Down's syndrome successfully completed a full Pittsburgh Compound B (PiB) PET-MR protocol and memory assessment at two timepoints. Our findings indicate that graph theory metrics of node degree and strength based on the structural connectome are effective predictors of global amyloid deposition. We also show that connection density of the structural network at baseline is a promising predictor of current cognitive performance. Directionality of effects were mainly significant reductions in the white matter connectivity in relation to both PiB + status and greater rate of cognitive decline. Taken together, these results demonstrate the integral role of the white matter during neuropathological progression and the utility of machine learning methodology for non-invasively evaluating Alzheimer's disease prognosis., (Copyright © 2022. Published by Elsevier Inc.)

Centrosomes are microtubule-organizing centers comprised of a pair of centrioles and the surrounding pericentriolar material. Abnormalities in centriole number are associated with cell division errors and can contribute to diseases such as cancer. Centriole duplication is limited to once per cell cycle and is controlled by the dosage-sensitive Polo-like kinase 4 (PLK4). Here, we show that PLK4 abundance is translationally controlled through conserved upstream open reading frames (uORFs) in the 5' UTR of the mRNA. Plk4 uORFs suppress Plk4 translation and prevent excess protein synthesis. Mice with homozygous knockout of Plk4 uORFs ( Plk4 Δ u/ Δ u ) are viable but display dramatically reduced fertility because of a significant depletion of primordial germ cells (PGCs). The remaining PGCs in Plk4 Δ u/ Δ u mice contain extra centrioles and display evidence of increased mitotic errors. PGCs undergo hypertranscription and have substantially more Plk4 mRNA than somatic cells. Reducing Plk4 mRNA levels in mice lacking Plk4 uORFs restored PGC numbers and fully rescued fertility. Together, our data uncover a specific requirement for uORF-dependent control of PLK4 translation in counterbalancing the increased Plk4 transcription in PGCs. Thus, uORF-mediated translational suppression of PLK4 has a critical role in preventing centriole amplification and preserving the genomic integrity of future gametes., (© 2022 Phan et al.; Published by Cold Spring Harbor Laboratory Press.)

Background: The majority of paediatric injury outcomes studies focus on mortality rather than the impact on long-term quality of life, health care use and other health-related outcomes. This study sought to determine predictors of 12-month functional and psychosocial outcomes for children sustaining major injury in NSW., Methods: The study included all children < 16 years requiring intensive care or an injury severity score (ISS) ≥ 9 treated in NSW at a paediatric trauma centre (PTC). Children were identified through the three PTCs and NSW Trauma Registry. The paediatric Quality of Life Inventory (PedsQL) and EuroQol five-dimensional EQ-5D-Y were used to measure HRQoL post-injury, completed via parent/carer proxy recruited through NSW PTCs., Results: There were 510 children treated at the three NSW PTCs during the 15-month study period. The mean (SD) age was 6.7 (6.0) years, with a median NISS (New Injury Severity Score) of 11 (IQR: 9-18). Regression analysis showed worse psychosocial health at twelve months was associated with hospital length of stay (LoS) and number of body regions injured (F 2 , 65  = 5.85, p = 0.005). Physical outcome was associated with LoS and intensive care unit (ICU) admission (F 2,66  = 13.48, p < 0.001). Hospital LoS was significantly associated with NISS and head injury (F 2,398  = 51.5, p < 0.001)., Conclusion: Hospital length of stay and polytrauma are independent factors that negatively influence psychological and physical outcomes of children with major injuries. Early intervention to enable emotional well-being, discharge home and long-term follow up such as dedicated family support and rehabilitation at home could reduce preventable poor outcomes., Competing Interests: Declaration of Competing Interest BB is employed by NSW Ambulance, however he had no role in data collection or analysis for this project. All other authors declare no conflicts of interest., (Copyright © 2022. Published by Elsevier Ltd.)

Introduction: The duration of endotracheal intubation is thought to be the most important factor in the development of acquired laryngotracheal stenosis (LTS); however, there is a paucity of studies examining the incidence of LTS in the paediatric burn population. The aim of this study was to determine the incidence of LTS in paediatric burns patients requiring mechanical ventilation to develop guidelines for consideration of a tracheostomy., Methods: A retrospective review of all children treated at The Children's Hospital at Westmead (CHW) Burns Unit (BU) from December 2009 to December 2019 who required intubation for their burn injury., Results: During the 10-year study period 115 patients required endotracheal intubation after having sustained a burn injury. Of these 11 were excluded. The mean age was 6.2 years (0-16), with the majority of patients being male (65%). The average TBSA was 18.5% with a range of 0.1-70%. Flame was the most common mechanism of burn (n = 59). Burns to the head and/or neck were the most common indication for intubation with the mean duration of intubation 6.1 days (range 0-40). Tracheostomies were performed on two patients (1.9%). LTS was found in two patients (1.9%)., Conclusion: LTS in the paediatric burn population post mechanical ventilation appears to be a rare event. Endotracheal intubation can safely be used as the route of airway access in paediatric burns patients. Based on our experience, a definitive recommendation on the timing of tracheostomy in the paediatric burn patient cannot be made., Competing Interests: None., (IJBT Copyright © 2022.)

Introduction : The Down syndrome population has a high prevalence for dementia, often showing their first clinical symptoms in their 40s. Methods : In a longitudinal cohort, we investigate whether amyloid deposition at time point 1 (TP1) could predict cortical thickness change at time point 2 (TP2). The association between tau burden and cortical thickness was also examined at time point 3 (TP3). Results : Between TP1 and TP2 there was pronounced cortical thinning in temporo-parietal cortices and cortical thickening in the frontal cortex. Baseline amyloid burden was strongly associated to cortical thinning progression, especially in the temporo-parietal regions. At TP3, tau deposition negatively correlated with cortical atrophy in regions where tau usually accumulates at later Braak stages. Discussion : A higher amount of amyloid accumulation triggers a cascade of changes of disease-causing processes that eventually lead to dementia. As expected, we found that regions where tau usually accumulates were those also displaying high levels of cortical atrophy., Competing Interests: All authors declare no competing interests. This research was funded by different grants from the Medical Research Council (grant ID number: 98480), the Alzheimer's Research UK (grant ID number: ARUK‐PG2015‐23), and the National Institutes of Health (NIH) (grant ID number: U01AG051406‐01 Neurodegeneration in Aging Down Syndrome [NiAD]). Additional support came from the National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre, the NIHR Collaborations in Leadership for Applied Health Research and Care (CLAHRC) for the East of England, the NIHR Cambridge Dementia Biomedical Research Unit, the Down Syndrome Association, and the Health Foundation. Dr Concepcion Padilla is currently funded by a Sara Borrell Postdoctoral Fellowship (CD20/00133, Carlos III Health Institute) and she was previously paid from a grant awarded to the Cambridge Intellectual and Developmental Disabilities Research Group by the Alzheimer Research UK (grant ID number: ARUK‐PG2015‐23). She has been paid as a lecturer at the Open University of Catalonia and at the Rioja International University, Spain. She received travel grants for attending conferences from the Guarantors of Brain and Alzheimer Research UK. She has nothing else to disclose. Mr Victor Montal is currently receiving a salary from the Memory Unit and the Biomedical Research Institute Sant Pau (IIB Sant Pau), Neurology Department, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain. He received consulting fees from personal consultancy related to a R21 grant of Dr Vannini at the Mass General Hospital. He has nothing else to disclose. Madeleine J. Walpert is currently paid as a policy advisor at Alzheimer's Research UK and previously received a postdoctoral fellowship as a research associate by Alzheimer's Research UK. She has nothing else to disclose. Young T. Hong receives his salary from the University of Cambridge. He is also supported by the United States (US) National Institutes of Health as part of the NiAD—Cambridge team. He has nothing else to disclose. Tim D. Fryer receives his salary from the University of Cambridge. He has nothing else to disclose. Dr Jonathan P. Coles is supported by the NIHR Cambridge Biomedical Research Centre. He has nothing else to disclose. Dr Franklin I. Aigbirhio receives his salary from the University of Cambridge. He was awarded with an Engineering and Physical Sciences Research Council (EPSRC) Project grant as a co‐applicant, although only the principal applicant was funded. He has led the Dementia Platform UK Imaging Network, receiving no payments. He has nothing else to disclose. Dr Sigan L. Hartley received a grant from the US National Institutes of Health, although it is not related to this study. She has nothing else to disclose. Dr Ann D. Cohen was awarded with the grants R01 AG052446, P01 AG025204, R01 AG063525, U01 AG051197, U01 AG051406, P30 AG066468, U19 AG068054, RF1 AG052525, R01 AG056351, and UL1 TR001857‐04S1; however, all of them were made to the University of Pittsburgh. She has been involved in the International Society to Advance Alzheimer's Research and Treatment (ISTAART) advisory board. She has nothing else to disclose. Dr Dana L. Tudorascu is paid by the University of California Irvine. She has participated on a Data Safety Monitoring Board (DSMB), receiving no payments. She has nothing else to disclose. Dr Bradley T. Christian: The NIH provided support to his institution for this research. He is involved and receives funding from the following projects: NIH/National Institute on Aging (NIA) PET Imaging agents for a4b2 Nicotinic Receptors, P30 AG062715 NIH/NIA Wisconsin Alzheimer's Disease Research Center, U54 HD090256 NIH/NICHD The Wisconsin Intellectual and Developmental Disabilities Research Center, R01 AG021155 NIH/NIA The longitudinal course of neural function and amyloid in people at risk for Alzheimer's Disease (AD), R01 AG027161‐11 NIH/NIA Wisconsin Registry for Alzheimer Prevention, R01 AG059312 Algebraic Formulations for Characterizing Structural Brain Connectivity Changes and Pathology Transmission Networks in Preclinical Alzheimer's Disease, R01 AG062167 NIH/NIA Longitudinal Investigation of Cardiorespiratory Fitness and AD Biomarkers in an At‐Risk Cohort, R01 AG063752‐01 NIH/NIA Statistical methods to improve reproducibility and reduce technical variability in heterogeneous multimodal neuroimaging studies of Alzheimer's Disease, R61 HD100973‐01 NIH/NIA Clinical trials to prevent Alzheimer's Disease in Down Syndrome, R01 AG060737‐03S1 NIH/NIA Wisconsin Longitudinal Study–Initial Lifetime's Impact on Alzheimer's Disease and Related Dementias (WLSILIAD Study), R01 AG70028 NIH INCLUDE Lifestyle Risk and Resiliency Factors and Alzheimer's Disease in Down syndrome, and R01 AG058533‐01A1 Health and Aging Brain among Latino Elders (HABLE‐AT[N]). He has also participated on a DSMB for the UO1 AG15001 NCE NIH/NICHD/NIA Neurodegeneration in Aging Down Syndrome (NiAD) project, receiving no payments for his involvement. He has received Cerveau and AVID, that was made to the institution. He has nothing else to disclose. Dr Benjamin L. Handen receives funding from the National Institute on Aging and the National Institute of Child Development, Autism Speaks, and Roche. He receives book royalties from Oxford University Press. He is also chair of a DSMB for a Department. of Defense funded study in autism. He has nothing else to disclose. Dr William E. Klunk is supported by the NIH/NIA. He is involved on a DSMB for Biogen. He has nothing else to disclose. Prof Anthony J. Holland was awarded with a grant from the Alzheimer's Research UK. He has been the President of the International Prader Willi Syndrome Organization. This was a volunteer post, and no payments were made. He has nothing else to disclose. Dr Shahid H. Zaman is paid by the UK National Health Service (NHS) and has received funding to attend meetings or conferences by the NIH and the Collaborations in Leadership for Applied Health Research and Care (CLAHRC) for the East of England. He has attended a DSMB meeting as part of a NIH‐funded on‐going research project. He has nothing else to disclose., (© 2022 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, LLC on behalf of Alzheimer's Association.)

Background: Prader-Willi syndrome (PWS), is a genetically determined neurodevelopmental disorder, associated with intellectual disabilities and a high incidence of obesity, diabetes mellitus, and respiratory disorders. We hypothesised that COVID-19, a viral infection which more severely affects people with these conditions, would, in people with PWS, present atypically and result in severe outcomes., Method: A structured on-line questionnaire was piloted with parents and professionals at the International Prader-Willi Syndrome Organization (IPWSO) and promoted internationally through their global network. Family members/other carers were asked to complete if someone they cared for with PWS was strongly suspected or confirmed as having COVID-19., Results: Over 1 year of the pandemic 72 responses were received, 47 adults, 25 children. The following underlying conditions were present: 16 people with PWS were overweight and 18 obese, five had diabetes mellitus and 18 sleep apnoea. Main presenting symptoms were raised temperature, fatigue/daytime sleepiness, dry cough, headache/pain, and feeling unwell, with illnesses generally lasting less than a week. Length of illness was not significantly related to age, BMI, sex, or genetic subtype. No one was ventilated or in an intensive care unit or died, one person was in hospital for four days needing oxygen., Conclusions: Contrary to our hypothesis, the PWS cohort had asymptomatic infection or mild illness. A possible explanation, supported by anecdotal evidence from parents and professional carers, is that people with PWS have a degree of innate immunity to viral infections. However, likely selection effects and a relatively low number of responses means that further evidence is needed to test this hypothesis., (© 2022. The Author(s).)

Background: Individuals with Down syndrome (DS) are at significant risk for early onset Alzheimer's disease (AD), likely due to the triplication of genes on chromosome 21 that facilitate AD neuropathology. To aid the effective early diagnosis of dementia in DS, we demonstrate the strategy of using single point assessment of cognitive performance with scoring normed for degree of intellectual disability to generate age related prevalence data for acquired mild cognitive impairment (AMCI)., Methods: Four hundred and twelve adults with DS were assessed using the Neuropsychological Assessment of dementia in adults with Intellectual Disability. Normative data, banded by degree of intellectual disability, allowed identification of AMCI by atypical deviation from expected performance., Results: AMCI was evident in approximately 20% of adults with DS aged 40 and under, 40% aged 41-50 and 45% aged 51 and over. Relative risk increased significantly in those aged 46 and over. Analysis of prevalence by 5-year age bands revealed two peaks for higher prevalence of AMCI., Conclusions: Psychometric data indicate single point assessment of AMCI is possible for the majority of adults with DS. Two peaks for age-related prevalence of AMCI suggest the risk for onset of AD conferred by trisomy of chromosome 21 is moderated by another factor, possibly ApoE status., (© 2021 The Authors. International Journal of Geriatric Psychiatry published by John Wiley & Sons Ltd.)

Background: Timely definitive paediatric trauma care influences patient and parental physical and emotional outcomes. New South Wales (NSW) covers a large geographical area with all three NSW paediatric trauma centres (PTC) located in two approximated major cities, meaning it is inevitable that some injured children receive initial treatment locally and then require transfer. Little is known about the factors that then impact timely arrival of injured children to definitive care., Methods: This included children admitted between July 2015 and September 2016, <16 years with an injury severity (ISS) ≥9; or requiring intensive care admission; or deceased following injury. Children were identified through the three PTCs, NSW Trauma Registry and NSW Medical Retrieval Registry., Results: There were 593 children admitted following injury and 46% required transfer to a PTC. There was no significant difference in age, ISS, ICU admission or head injury (AIS >2) between transferred and directly transported cohorts. There were significant differences in mechanism of injury between the two groups (χ 2 (9) = 45.9, p < 0.001). The median (IQR) time to book a transfer from arrival at the referring facility, was 146.5 (86-238) minutes. Time from injury to arrival at the PTC more than doubled for children transferred, with significant and unwarranted variability between transporting agencies resulting in unwarranted delays to surgical intervention. For example, time spent at the referring facility by Aeromedical Retrieval Service was less than half that of the Newborn & paediatric Emergency Transport Service [53 (IQR:47-61) vs 115 (84-155) minutes (p <0.001)]., Conclusion: Clinicians caring for paediatric trauma patients in facilities outside trauma centres require the capability and opportunity to identify and notify early those requiring transfer for ongoing management. The provision of a streamlined referral and transfer process for all paediatric trauma patients requiring treatment in NSW PTCs would reduce the burden on the referring facility, reduce variation amongst transport providers and improve time to definitive care., Competing Interests: Declaration of Competing Interest BB is employed by NSW Ambulance, however he had no role in data collection or analysis for this project. All other authors declare no conflicts of interest., (Copyright © 2021. Published by Elsevier Ltd.)

Objective: Presentations to EDs for major paediatric injury are considerably lower than for adults. International studies report lower levels of critical intervention, including intubation, required in injured children. A New South Wales study demonstrated an adverse event rate of 7.6% in children with major injury. Little is known about the care and interventions received by children presenting to Australian EDs with major injury., Methods: The ED care of injured children <16 years who ultimately received definitive care at a New South Wales Paediatric Trauma Centre between July 2015 and September 2016, and had an Injury Severity Score ≥9, required intensive care admission or died were included., Results: There were 491 injured children who received treatment at 64 EDs, half (49.4%, n = 243) were treated initially in a Paediatric Trauma Centre. One third (32.8%) sustained an Injury Severity Score >12, more than half (n = 251, 51.1%) of children were classified as a triage category 1 or 2, and 38.3% received trauma team activation. Critical intervention was infrequent. Intubation was documented in 9.2% (n = 45), needle thoracostomy and activation of massive transfusion protocol in two (0.4%) and eight (1.6%) had intraosseous access established. Only a small proportion (14.7%, n = 63) had two or more observations outside the normal range., Conclusion: A small proportion of children arriving in the ED post-major trauma have deranged clinical observations and receive critical interventions. The limited exposure in the management of trauma in paediatric patients requires measures to ensure clinicians have adequate training, skills and confidence to manage these clinical presentations in all EDs., (© 2021 Australasian College for Emergency Medicine.)

Primary microcephaly is a brain growth disorder characterized by a severe reduction of brain size and thinning of the cerebral cortex. Many primary microcephaly mutations occur in genes that encode centrosome proteins, highlighting an important role for centrosomes in cortical development. Centrosomes are microtubule organizing centers that participate in several processes, including controlling polarity, catalyzing spindle assembly in mitosis, and building primary cilia. Understanding which of these processes are altered and how these disruptions contribute to microcephaly pathogenesis is a central unresolved question. In this review, we revisit the different models that have been proposed to explain how centrosome dysfunction impairs cortical development. We review the evidence supporting a unified model in which centrosome defects reduce cell proliferation in the developing cortex by prolonging mitosis and activating a mitotic surveillance pathway. Finally, we also extend our discussion to centrosome-independent microcephaly mutations, such as those involved in DNA replication and repair., (© 2021 Phan and Holland; Published by Cold Spring Harbor Laboratory Press.)

Loss of function mutations in the E3 ubiquitin ligase TRIM37 result in MULIBREY nanism, a disease characterized by impaired organ growth and a high propensity to develop different tumor types. Additionally, increased copy number of TRIM37 is a feature of some breast cancers and neuroblastomas. The molecular role played by TRIM37 in such loss and gain of function conditions has been a focus of research in the last decade, which led notably to the identification of critical roles of TRIM37 in centrosome biology. Specifically, deletion of TRIM37 results in the formation of aberrant centrosomal proteins assemblies, including Centrobin-PLK4 assemblies, which can act as extra MTOCs, thus resulting in defective chromosome segregation. Additionally, TRIM37 overexpression targets the centrosomal protein CEP192 for degradation, thereby preventing centrosome maturation and increasing the frequency of mitotic errors. Interestingly, increased TRIM37 protein levels sensitize cells to the PLK4 inhibitor centrinone. In this review, we cover the emerging roles of TRIM37 in centrosome biology and discuss how this knowledge may lead to new therapeutic strategies to target specific cancer cells.