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Introduction The logic behind the neuropsychological rehabilitation of the impulsive criminal is to treat the behavioral manifestations of these individuals as the product of a real pre-frontal syndrome, capable of causing deficits in the planning of behavior, in self-regulation, in the inhibition of impulsiveness and more generally in social and interpersonal skills. With the term prefrontal workout, literally “prefrontal workout” Eagleman (2011) refers to a real form of rehabilitation intended for subjects characterized by strong impulsive tendencies. Neurofeedback is used in prefrontal training. This technique mainly uses electroencephalography (EEG) and functional magnetic resonance imaging (fMRI) as indicators of brain function. Objectives The premise of prefrontal training is that through rehabilitation, and therefore repeated practice, the frontal areas of our brain can be trained in order to improve the “control” of subcortical circuits and limbic areas responsible for impulsive and potentially destructive behavioral forces. Although this rehabilitation proposal does not specifically concern deviant individuals, it is intended for subjects with impulsive tendencies and difficulty in repressing a stimulus-seeking behavior, skills that fall within the category of frontal functions. Methods It is possible that similar strategies can also be used effectively against deviant individuals, working to improve their ability to inhibit a behavioral tendency and reinforcing everything with real-time feedback. There is a very high incidence of attention deficit, hyperactivity disorder and related symptoms among people convicted of crimes, and a great many criminal acts involve impulsive behavior or loss of emotional control such as anger. Better control of behavior and emotions are among the most commonly reported outcomes of neurotherapeutic treatment. Results Research and clinical experience also demonstrate the positive effects of neurofeedback with alcohol and drug abuse and depression, both common accompaniments of criminal behavior ( Fielenbach S. 2019; Margarita R. 2016; Konicar L. 2015). Conclusions Certainly, research in this field is at a preliminary stage, and the limitations of these techniques are numerous. There are, for example, several doubts about which is the best strategy for the patient to use to control mental activity and inhibit, for example, the search for the substance to which one is addicted. Although promising, the literature highlights sometimes conflicting results: in this regard, see the meta-analysis by Cortese and colleagues (2016) and the document published by Youcha and colleagues (2008). Disclosure of Interest None Declared

Introduction Background: At the end of 2019, a novel coronavirus (COVID-19) was identified in China. The high potential of human-to-human transmission led to subsequent COVID-19 global pandemic. Public health strategies, including reduced social contact and lockdown have been adopted in many countries. Nonetheless, social distancing and isolation could also represent risk factors for mental disorders, resulting in loneliness, reduced social support and under-detection of mental health needs. Along with this, social distancing determines a relevant obstacle for direct access to psychiatric care services. The pandemic generates the urgent need for integrating technology into innovative models of mental healthcare. Objectives In this paper, we discuss the potential role of Telepsichologyy (TP) and other cutting-edge technologies in the management of mental health assistance. Methods We narratively review the literature to examine the advantages and risks related to the extensive application of these new therapeutic settings, along with the possible limitations and ethical concerns. Results Telemental health services may be particularly flexible and appropriate for the support of patients, family members and healthcare providers during this COVID-19 pandemic. The integration of TP with other technological innovations (eg, mobile apps, virtual reality, big data and artificial intelligence (AI)) opens up interesting future perspectives for the improvement of mental health assistance. Conclusions Telepsichologyy is a promising and growing way to deliver mental health services; but it is still underused. The COVID-19 pandemic may serve as an opportunity to introduce and promote, among numerous mental health professionals, the knowledge of the possibilities offered by the digital era. Disclosure of Interest None Declared

Introduction The process of integrating technology into mental health pathways represents a social transformation that we are gradually getting used to. But does it represent a valid alternative to face-to-face care processes? In this paper we will consider telesychology as a tool for treating anxiety and depression and its validity. Anxiety and depression are harmful to individuals, suffering from these disorders, their caregivers, and the economy. Remote delivery of psychotherapy has been established as a viable alternative to traditional in-person psychotherapy for treating anxiety and depression. However, literature comparing and evaluating the variety of remote delivery modalities of psychotherapy has not yet been integrated. Objectives This review examines the efficiency – to - practice and the limits of e-therapy and its mediums: telephone, video, and online-administered psychotherapy, for treatment of anxiety and depression. Methods A comprehensive literature search, conducted using PubMed and PsycINFO included systematic reviews, randomized controlled trials, and cost-analysis studies focused on a remote delivery method of e-psychotherapy for anxiety and depression Results Overall, interventions delivered through telephone, video, and online modalities, have generally demonstrated good efficiency in treating anxiety and depression; also comorbid with other disorders. The literature also suggested that telehealth psychotherapy is accessible, convenient, and cost-effective. In evaluating the reviews on the databases, it also emerged that among the many psychological therapies for anxiety disorders, delivered digitally (CBT, Attention bias modification, Exposure therapy, Applied relaxation, Bibliotherapy, Psychodynamic therapy, Mindfulness, Behavioral stress management, Counseling), the best digital therapy is internet-based cognitive behavioral therapy (iCBT), in particular for Social Anxiety Disorder (SAD). Despite this, overall, the efficiency and practical benefits of remote psychotherapy interventions in treating anxiety and depression across a diverse range of patient groups suggested that it is an appropriate alternative for those who cannot access in-person psychotherapy. Conclusions Further research evaluating the efficiency and practical benefits of e-psychotherapy for anxiety and depression is much needed for patients with limited access to in-person psychological care. Moreover, it remains to evaluate the maintenance of therapeutic gains after the end of the treatments. Disclosure of Interest None Declared

Introduction The types of Electronic-Based Therapy & Intervention are spreading rapidly, especially after the onset of COVID, and several authors are dealing specifically with digital psychology and psychiatry, implementing new techniques and methodologies (Festa, Martinotti, 2022).The latest technological innovations related to metaverse and holography are emerging as new digital mediums and a reflection on their potential in the psychological field is urgent. Telepsychology, which currently uses text, audio and video-based communication as a medium, will see the way to relate to the patient with the “new digital presence” amplified at 360 degrees. This will of course revolutionize some aspects of classic psychological intervention: “physical proximity” will have a completely different meaning. New technologies through the digital medium have the power to cancel space, thus allowing the intervention to be separated from the sharing of the same physical environment. The first great epochal upheaval produced by new technologies in the field of the psychological profession is precisely this: psychological intervention no longer necessarily coincides with the sharing of the same physical space, space and intervention becoming independent. Objectives We will soon and increasingly refer to associations, national and international professional associations and institutions that deal with the subject, such as the American Psychological Association, the International Society for Mental Health Online, the Online Therapy Institute, to have guidelines on best practice with respect to psychological performance online. This will be accompanied by specific training courses for clinicians who decide to work using technological tools and courses related to telepsychology and the development of a professional online identity. Methods Holographic technology will revolutionize our “internal and external world”, and it is the task of psychological science to cultivate questions and provide answers both on the impact that this technology will have on the life of the average man and on the possibilities of use for our profession. The distance of the real world from the digital one is getting smaller with each passing day. Results Our habits, our way of working, having fun have changed in different ways and in a very short time. Our physical, cognitive and sensory boundaries have expanded and our way of life has “evolved”. Conclusions We find ourselves passing through and going through a phase, which began in the 1980s, which is not without shadows and settles into mass cultural aspects. The contradictions, abnormal uses and abuses of technology, but which accompany every innovative transformation and which we should gradually manage wisely, are also typical of this phase. We will see what the future holds! Disclosure of Interest None Declared

Reproduction can reduce energy allocation to other life-history traits such as survival and growth. Resource constraints give rise to (co)variation in life-history traits and to heterogeneity in energy acquisition and allocation. At each reproductive opportunity, females face a choice between allocation to current reproduction or to maintenance. Many studies compare reproductive trade-offs between two consecutive years, but few account for the cumulative effects of reproduction over multiple years, a crucial factor in understanding life-history evolution in long-lived iteroparous species. We compared short- (interannual) and long-term (cumulative) reproductive trade-offs with a 14-year capture-mark-recapture study of eastern grey kangaroos, where females can have substantial skeletal growth for several years after maturation. We used a multivariate approach to compare how interannual and multi-annual cumulative reproduction affected growth (n = 378 measurements), mass change (n = 376 measurements) and subsequent reproduction (n = 388 measurements), and to quantify (co)variation between these traits among individuals (n = 107) and years (n = 14). Interannually, young females that reproduced experienced decreased skeletal growth compared to young females that did not reproduce. Reproductive females of all ages experienced reduced mass gain and weaning probability in the following year. The cumulative effects of multiple reproductions included decreased skeletal growth, mass gain and weaning probability in the following year. These effects increased with age and reproductive rate. We found positive trait correlations between mass change, leg growth and subsequent reproduction among individuals and years, though weaker at the cumulative than interannual level. Females experience dynamic interannual and cumulative trade-offs. Our analyses of cumulative costs of reproduction revealed long-term trade-offs as well as cumulative costs that were not apparent when estimating interannual costs. Trait correlations suggested heterogeneity in growth and reproduction among females. Years of increased growth were followed by years of increased reproduction, and years of poor growth were followed by years of poor reproduction. Our exploration of both interannual and cumulative costs of reproduction underscores the need to account for long-term reproductive histories to better understand reproductive trade-offs in long-lived iteroparous species., (© 2024 The Author(s). Journal of Animal Ecology published by John Wiley & Sons Ltd on behalf of British Ecological Society.)

Kv1.3 is a multifunctional potassium channel implicated in multiple pathologies, including cancer. However, how it is involved in disease progression is not fully clear. We interrogated the interactome of Kv1.3 in intact cells using BioID proximity labeling, revealing that Kv1.3 interacts with STAT3- and p53-linked pathways. To prove the relevance of Kv1.3 and of its interactome in the context of tumorigenesis, we generated stable melanoma clones, in which ablation of Kv1.3 remodeled gene expression, reduced proliferation and colony formation, yielded fourfold smaller tumors, and decreased metastasis in vivo in comparison to WT cells. Kv1.3 deletion or pharmacological inhibition of mitochondrial Kv1.3 increased mitochondrial Reactive Oxygen Species release, decreased STAT3 phosphorylation, stabilized the p53 tumor suppressor, promoted metabolic switch, and altered the expression of several BioID-identified Kv1.3-networking proteins in tumor tissues. Collectively, our work revealed the tumor-promoting Kv1.3-interactome landscape, thus opening the way to target Kv1.3 not only as an ion-conducting entity but also as a signaling hub.

Race-conscious research identifies health disparities with 1) rigorous and responsible data collection, 2) intentionality and considered analyses, and 3) interpretation of results that advance health equity. Individual registries must overcome specific challenges to promote race-conscious research, and this paper describes ways to achieve this with a focus on the international Extracorporeal Life Support Organization (ELSO) registry. This article reviews ELSO registry publications that studied race with outcomes to consider whether research outputs align with race-conscious concepts and describe the direction of associations reported. Studies were identified via secondary analysis of a comprehensive scoping review on ECMO disparities. Of 32 multicenter publications, two (6%) studied race as the primary objective. Statistical analyses, confounder adjustment, and inclusive, antibiased language were inconsistently used. Only two (6%) papers explicitly discussed mechanistic drivers of inequity such as structural racism, and five (16%) discussed race variable limitations or acknowledged unmeasured confounders. Extracorporeal Life Support Organization registry publications demonstrated more adverse ECMO outcomes for underrepresented/minoritized populations than non-ELSO studies. With the objective to promote race-conscious ELSO registry research outputs, we provide a comprehensive understanding of race variable limitations, suggest reasoned retrospective analytic approaches, offer ways to interpret results that advance health equity, and recommend practice modifications for data collection., Competing Interests: Disclosure: The authors have no conflicts of interest to report., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the ASAIO.)

Predation has direct effects on prey population dynamics through mortality, and it can induce indirect effects through fear. The indirect effects of predation have been documented experimentally, but few studies have quantified them in nature so that their role in prey population dynamics remains controversial. Given the expanding or reintroduced populations of large predators in many areas, the quantification of indirect effects of predation is crucial. We sought to evaluate the direct and indirect fitness effects of intense cougar (Puma concolor) predation using 48 years of data on marked bighorn sheep (Ovis canadensis) on Ram Mountain, Alberta, Canada. We compared years of intense cougar predation with years with no or occasional cougar predation. We first quantified the effects of predation on neonatal, weaning, and overwinter lamb survival, three metrics potentially affected by direct and indirect effects. We then investigated the possible indirect effects of intense cougar predation on lamb production, female summer mass gain, and lamb mass at weaning. We found strong effects of cougar predation on lamb survival, lamb production, and seasonal mass gain of lambs and adult females. In years with high predation, neonatal, weaning, and overwinter lamb survival declined by 18.4%, 19.7% and 20.8%, respectively. Indirect effects included a 14.2% decline in lamb production. Female summer mass gain decreased by 15.6% and lamb mass at weaning declined by 8.0% in years of intense cougar predation. Our findings bring key insights on the impacts of predation on prey fitness by reporting moderate to large effects on recruitment and illustrate the importance of indirect effects of predation on population dynamics., (© 2024 The Author(s). Ecology published by Wiley Periodicals LLC on behalf of The Ecological Society of America.)

Background: There are about 7,000 rare diseases that affect 10% of the world population. Primary biliary cholangitis, an autoimmune chronic liver disease of the interlobular bile ducts, is one of the most common causes of chronic cholestasis. However, it is a rare, often underdiagnosed and undertreated, disease which can lead to cirrhosis and liver failure. We aimed to assess the proportion of undetected primary biliary cholangitis patients in primary care through a clinical management process., Methods: We made two extractions of the clinical data concerning liver diseases, risk factors and laboratory tests from the databases of a sample of general practitioners, with a check and correction of mistakes. The clinical data of the patients without liver disease and major risk factors, and with serum Alkaline Phosphatase above the laboratory reference values, were re-evaluated by each general practitioner with an expert gastroenterologist. The patients with elevated Alkaline Phosphatase values and without evidence of intrahepatic or extrahepatic causes of cholestasis were considered suspected for primary biliary cholangitis and assessed for antimitochondrial antibodies test and specialist' s evaluation, according to present guidelines., Results: A total of 20,480 adults attending 14 general practitioners in the province of Brescia, Northern Italy, were included in the study. Nine patients had a prior primary biliary cholangitis diagnosis, with a prevalence of 43.9/100000. After excluding 2094 (10.2%) patient with liver diseases or other causes of cholestasis, 121 subjects with Alkaline Phosphatase above the reference values were re-evaluated by the general practitioners and gastroenterologist, and 27 patients without symptoms or signs of cholestasis were considered suspected for primary biliary cholangitis: 9 of them were tested for antimitochondrial antibodies, and three new primary biliary cholangitis cases were detected (+33%)., Discussion and Conclusions: This study shows that there is a not negligible burden of undetected cases of adult rare diseases that can be diagnosed in primary care, through a disease management procedure, without modifying the routine clinical practice.

Background: The evaluation of midpalatal suture maturation is essential to undertake the most predictable maxillary expansion approach. Several factors, such as age, gender, and facial growth patterns, seem to be involved in midpalatal suture staging and, consequently, in its opening; however, the link between these variables and the stages of midpalatal suture development remains poorly understood. Our study aimed to analyse the midpalatal suture maturation in relation to age, sex, and skeletal growth patterns by CBCT., Methods: We enrolled 263 patients (119 males and 144 females) aged from 8 to 20 years. The midpalatal suture maturation was defined according to Angelieri et al.'s classification using a low-dose CBCT. The chi-square test and linear regression were applied to investigate the suture stages by age, sex, and vertical and sagittal growth patterns., Results: Stage A was present in 8- and 9-year-olds with a larger prevalence in boys, while the prevalence of stage E increased progressively with age. Stage D was the most prevalent in our sample. The statistical analysis described that stage A was more likely in the youngest subjects, and stage E in the oldest participants. The males tended to have lower maturation stages. Moreover, the hypodivergent and normodivergent subjects tended to have higher maturation stages, while Class III was more likely in subjects in stages D or E., Conclusions: A total of 127 patients were in stages A, B, and C, showing an unfused suture. In young individuals, the opening of the midpalatal suture leads to a proper facial growth development by correcting the transverse superior hypoplasia. The midpalatal sutural maturation classification was related to age, sex, and divergence.

The nine-member CLC gene family of Cl - chloride-transporting membrane proteins is divided into plasma membrane-localized Cl - channels and endo-/lysosomal Cl - /H + antiporters. Accessory proteins have been identified for ClC-K and ClC-2 channels and for the lysosomal ClC-7, but not the other CLCs. Here, we identified TMEM9 Domain Family Member B (TMEM9B), a single-span type I transmembrane protein of unknown function, to strongly interact with the neuronal endosomal ClC-3 and ClC-4 transporters. Co-expression of TMEM9B with ClC-3 or ClC-4 dramatically reduced transporter activity in Xenopus oocytes and transfected HEK cells. For ClC-3, TMEM9B also induced a slow component in the kinetics of the activation time course, suggesting direct interaction. Currents mediated by ClC-7 were hardly affected by TMEM9B, and ClC-1 currents were only slightly reduced, demonstrating specific interaction with ClC-3 and ClC-4. We obtained strong evidence for direct interaction by detecting significant Förster Resonance Energy Transfer (FRET), exploiting fluorescence lifetime microscopy-based (FLIM-FRET) techniques between TMEM9B and ClC-3 and ClC-4, but hardly any FRET with ClC-1 or ClC-7. The discovery of TMEM9B as a novel interaction partner of ClC-3 and ClC-4 might have important implications for the physiological role of these transporters in neuronal endosomal homeostasis and for a better understanding of the pathological mechanisms in CLCN3- and CLCN4 -related pathological conditions.

Pediatric intensive care is a rapidly developing medical specialty and with evolving understanding of pediatric pathophysiology and advances in technology, most children in the developed world are now surviving to intensive care and hospital discharge. As mortality rates for children with critical illness continue to improve, increasing PICU survivorship is resulting in significant long-term consequences of intensive care in these vulnerable patients. Although impairments in physical, psychosocial and cognitive function are well documented in the literature and the importance of establishing follow-up programs is acknowledged, no standardized or evidence-based approach to long-term follow-up in the PICU exists. This narrative review explores pediatric post-intensive care syndrome and summarizes the multifactorial deficits and morbidity that can occur in these patients following recovery from critical illness and subsequent discharge from hospital. Current practices around long-term follow-up are explored with discussion focusing on gaps in research and understanding with suggested ways forward and future directions., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 Quadir, Festa, Gilchrist, Thompson, Pride and Basu.)

Ion channels are critical in enabling ion movement into and within cells and are important targets for pharmacological interventions in different human diseases. In addition to their ion transport abilities, ion channels interact with signalling and scaffolding proteins, which affects their function, cellular positioning, and links to intracellular signalling pathways. The study of "channelosomes" within cells has the potential to uncover their involvement in human diseases, although this field of research is still emerging. LRRC8A is the gene that encodes a crucial protein involved in the formation of volume-regulated anion channels (VRACs). Some studies suggest that LRRC8A could be a valuable prognostic tool in different types of cancer, serving as a biomarker for predicting patients' outcomes. LRRC8A expression levels might be linked to tumour progression, metastasis, and treatment response, although its implications in different cancer types can be varied. Here, publicly accessible databases of cancer patients were systematically analysed to determine if a correlation between VRAC channel expression and survival rate exists across distinct cancer types. Moreover, we re-evaluated the impact of LRRC8A on cellular proliferation and migration in colon cancer via HCT116 LRRC8A-KO cells, which is a current topic of debate in the literature. In addition, to investigate the role of LRRC8A in cellular signalling, we conducted biotin proximity-dependent identification (BioID) analysis, revealing a correlation between VRAC channels and cell-cell junctions, mechanisms that govern cellular calcium homeostasis, kinases, and GTPase signalling. Overall, this dataset improves our understanding of LRRC8A/VRAC and explores new research avenues while identifying promising therapeutic targets and promoting inventive methods for disease treatment., (© 2024. The Author(s).)

Objectives: Adjunctive therapy with vitamin C, hydrocortisone, and thiamin has been evaluated in adults, but randomized controlled trial (RCT) data in children are lacking. We aimed to test the feasibility of vitamin C, hydrocortisone, and thiamin in PICU patients with septic shock; and to explore whether the intervention is associated with increased survival free of organ dysfunction., Design: Open-label parallel, pilot RCT multicenter study. The primary endpoint was feasibility. Clinical endpoints included survival free of organ dysfunction censored at 28 days and nine secondary outcomes, shock reversal, and two proxy measures of intervention efficacy., Setting: Six PICUs in Australia and New Zealand., Patients: Children of age between 28 days and 18 years requiring vasoactive drugs for septic shock between August 2019 and March 2021., Interventions: Patients were assigned 1:1 to receive 1 mg/kg hydrocortisone every 6 hours (q6h), 30 mg/kg ascorbic acid q6h, and 4 mg/kg thiamin every 12 hours (n = 27), or standard septic shock management (n = 33)., Measurements and Main Results: Sixty of 77 (78%) eligible patients consented with 91% of approached parents providing consent. The median time from randomization to intervention was 44 (interquartile range [IQR] 29-120) min. Seventy of seventy-seven (28%) patients had received IV steroids before randomization. Median survival alive and free of organ dysfunction was 20.0 (0.0-26.0) days in the intervention and 21.0 (0.0-25.0) days in the standard care group. Median PICU length of stay was 5.3 (2.5-11.3) days in the intervention group versus 6.9 (3.0-11.5) days in the control group. Shock reversal occurred at a median of 35.2 (14.6-101.2) hours in the intervention group versus 47.3 (22.4-106.8) hours in the standard care group (median difference -12 hr; 95% CI, -56.8 to 32.7 hr)., Conclusions: In children requiring vasopressors for septic shock, a protocol comparing adjunctive treatment with high-dose vitamin C, hydrocortisone, and thiamin versus standard care was feasible. These findings assist in making modifications to the trial protocol to enable a better-designed larger RCT., Competing Interests: Drs. Schlapbach and Long received funding from the National Health and Medical Research Council Practitioner Fellowship, the Children`s Hospital Foundation, the Emergency Medicine Foundation Queensland, Financial Markets for Children Australia, the Gold Coast Hospital Foundation, and Children’s Health Queensland Study, Education and Research Trust Account grant. Dr. George’s institution received funding from Gold Coast Hospital Foundation and Emergency Medicine Foundation. Drs. Singh and Festa’s institution received funding from the University of Queensland. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies.)

DGGE (denaturing gradient gel electrophoresis) is a nucleic acid separation technique applied to the evaluation of microbial biodiversity. This technique is quite rapid and cheap compared to other types of analysis. Here we describe the comparison of nematode communities inhabiting different ecosystems. After an ecologically representative sampling collection and the nematode extraction from soil, nematodes are centrifuged in Eppendorf tubes to facilitate DNA extraction. DNA from the whole community of each type of soil is extracted, amplified with primers for 18 S rDNA and used in DGGE analysis. The profiles of DGGE can be analyzed with appropriate software, and biodiversity indices can be estimated., (© 2024. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: The NITric oxide during cardiopulmonary bypass (CPB) to improve Recovery in Infants with Congenital heart defects (NITRIC) trial, a 1320-patient, multicentre, randomised controlled trial, is aiming to improve survival free of ventilation after CPB by using nitric oxide delivered into the oxygenator of the CPB. Objective: To provide a statistical analysis plan before completion of patient recruitment and data monitoring. Final analyses for this study will adhere to this statistical analysis plan, which details all key pre-planned analyses. Stata scripts for analyses have been prepared alongside this statistical analysis plan. Methods: The statistical analysis plan was designed collaboratively by the chief investigators and trial statistician and builds on the previously published study protocol. All authors remain blinded to treatment allocation. Detail is provided on statistical analyses including cohort description, analysis of primary and secondary outcomes and adverse events. Statistical methods to compare outcomes are planned in detail to ensure methods are verifiable and reproducible. Results: The statistical analysis plan developed provides the trial outline, list of mock tables, and analysis scripts. The plan describes statistical analyses on cohort and baseline description, primary and secondary outcome analyses, process of care measures, physiological descriptors, and safety and adverse event reporting. We define the pre-specified subgroup analyses and the respective statistical tests used to compare subgroups. Conclusion: The statistical analysis plan for the NITRIC trial establishes detailed pre-planned analyses alongside Stata scripts to analyse the largest trial in the field of neonatal and paediatric heart surgery. The plan ensures standards for trial analysis validity aiming to minimise bias of analyses. Trial registration: ACTRN12617000821392., Competing Interests: Yves d’Udekem receives consultancy fees from Actelion (Janssen) and travel fees from Berlin Heart., (© 2021 College of Intensive Care Medicine of Australia and New Zealand.)

Objective: Most interventions in paediatric critical care lack high grade evidence. We aimed to identify the key research priorities and key clinical outcome measures pertinent to research in paediatric intensive care patients. Design: Modified three-stage Delphi study combining staged online surveys, followed by a face-to-face discussion and final voting. Setting: Paediatric intensive care units in Australia and New Zealand. Participants: Medical and nursing staff working in intensive care. Main outcome measurements: Self-reported priorities for research. Results: 193 respondents provided a total of 267 research questions and 234 outcomes. In Stage 3, the top 56 research questions and 50 outcomes were discussed face to face, which allowed the identification of the top 20 research questions with the Hanlon prioritisation score and the top 20 outcomes. Topics centred on the use of intravenous fluids (restrictive v liberal fluids, use of fluid resuscitation bolus, early inotrope use, type of intravenous fluid, and assessment of fluid responsiveness), and patient- and family-centred outcomes (health-related quality of life, liberation) emerged as priorities. While mortality, length of stay, and organ support/organ dysfunction were considered important and the most feasible outcomes, long term quality of life and neurodevelopmental measures were rated highly in terms of their importance. Conclusions: Using a modified Delphi method, this study provides guidance towards prioritisation of research topics in paediatric critical care in Australia and New Zealand, and identifies study outcomes of key relevance to clinicians and experts in the field., Competing Interests: No relevant disclosures., (© 2021 College of Intensive Care Medicine of Australia and New Zealand.)

Individual behavior varies for many reasons, but how early in life are such differences apparent, and are they under selection? We investigated variation in early-life behavior in a wild eastern gray kangaroo ( Macropus giganteus ) population, and quantified associations of behavior with early survival. Behavior of young was measured while still in the pouch and as subadults, and survival to weaning was monitored. We found consistent variation between offspring of different mothers in levels of activity at the pouch stage, in flight initiation distance (FID) as subadults, and in subadult survival, indicating similarity between siblings. There was no evidence of covariance between the measures of behavior at the pouch young versus subadult stages, nor of covariance of the early-life behavioral traits with subadult survival. However, there was a strong covariance between FIDs of mothers and those of their offspring tested at different times. Further, of the total repeatability of subadult FID (51.5%), more than half could be attributed to differences between offspring of different mothers. Our results indicate that 1) behavioral variation is apparent at a very early stage of development (still in the pouch in the case of this marsupial); 2) between-mother differences can explain much of the repeatability (or "personality") of juvenile behavior; and 3) mothers and offspring exhibit similar behavioral responses to stimuli. However, 4) we found no evidence of selection via covariance between early-life or maternal behavioral traits and juvenile survival in this wild marsupial., Competing Interests: The authors affirm that they possess no identifiable financial conflicts of interest or personal affiliations that could be perceived as exerting influence over the research presented in this paper., (© The Author(s) 2023. Published by Oxford University Press on behalf of the International Society for Behavioral Ecology.)

Objectives: This systematic review investigates the use of adaptive designs in randomized controlled trials (RCTs) in pediatric critical care., Data Sources: PICU RCTs, published between 1986 and 2020, stored in the www.PICUtrials.net database and MEDLINE, EMBASE, CENTRAL, and LILACS databases were searched (March 9, 2022) to identify RCTs published in 2021. PICU RCTs using adaptive designs were identified through an automated full-text screening algorithm., Study Selection: All RCTs involving children (< 18 yr old) cared for in a PICU were included. There were no restrictions to disease cohort, intervention, or outcome. Interim monitoring by a Data and Safety Monitoring Board that was not prespecified to change the trial design or implementation of the study was not considered adaptive., Data Extraction: We extracted the type of adaptive design, the justification for the design, and the stopping rule used. Characteristics of the trial were also extracted, and the results summarized through narrative synthesis. Risk of bias was assessed using the Cochrane Risk of Bias Tool 2., Data Synthesis: Sixteen of 528 PICU RCTs (3%) used adaptive designs with two types of adaptations used; group sequential design and sample size reestimation. Of the 11 trials that used a group sequential adaptive design, seven stopped early due to futility and one stopped early due to efficacy. Of the seven trials that performed a sample size reestimation, the estimated sample size decreased in three trials and increased in one trial., Conclusions: Little evidence of the use of adaptive designs was found, with only 3% of PICU RCTs incorporating an adaptive design and only two types of adaptations used. Identifying the barriers to adoption of more complex adaptive trial designs is needed., Competing Interests: The authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2023 by the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies.)

Introduction: Despite growing awareness of neurodevelopmental impairments in children with congenital heart disease (CHD), there is a lack of large, longitudinal, population-based cohorts. Little is known about the contemporary neurodevelopmental profile and the emergence of specific impairments in children with CHD entering school. The performance of standardised screening tools to predict neurodevelopmental outcomes at school age in this high-risk population remains poorly understood. The NITric oxide during cardiopulmonary bypass to improve Recovery in Infants with Congenital heart defects (NITRIC) trial randomised 1371 children <2 years of age, investigating the effect of gaseous nitric oxide applied into the cardiopulmonary bypass oxygenator during heart surgery. The NITRIC follow-up study will follow this cohort annually until 5 years of age to assess outcomes related to cognition and socioemotional behaviour at school entry, identify risk factors for adverse outcomes and evaluate the performance of screening tools., Methods and Analysis: Approximately 1150 children from the NITRIC trial across five sites in Australia and New Zealand will be eligible. Follow-up assessments will occur in two stages: (1) annual online screening of global neurodevelopment, socioemotional and executive functioning, health-related quality of life and parenting stress at ages 2-5 years; and (2) face-to-face assessment at age 5 years assessing intellectual ability, attention, memory and processing speed; fine motor skills; language and communication; and socioemotional outcomes. Cognitive and socioemotional outcomes and trajectories of neurodevelopment will be described and demographic, clinical, genetic and environmental predictors of these outcomes will be explored., Ethics and Dissemination: Ethical approval has been obtained from the Children's Health Queensland (HREC/20/QCHQ/70626) and New Zealand Health and Disability (21/NTA/83) Research Ethics Committees. The findings will inform the development of clinical decision tools and improve preventative and intervention strategies in children with CHD. Dissemination of the outcomes of the study is expected via publications in peer-reviewed journals, presentation at conferences, via social media, podcast presentations and medical education resources, and through CHD family partners., Trial Registration Number: The trial was prospectively registered with the Australian New Zealand Clinical Trials Registry as 'Gene Expression to Predict Long-Term Neurodevelopmental Outcome in Infants from the NITric oxide during cardiopulmonary bypass to improve Recovery in Infants with Congenital heart defects (NITRIC) Study - A Multicentre Prospective Trial'., Trial Registration: ACTRN12621000904875., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Chloroplast calcium homeostasis plays an important role in modulating the response of plants to abiotic and biotic stresses. One of the greatest challenges is to understand how chloroplast calcium-permeable pathways and sensors are regulated in a concerted manner to translate specific information into a calcium signature and to elucidate the downstream effects of specific chloroplast calcium dynamics. One of the six homologs of the mitochondrial calcium uniporter (MCU) was found to be located in chloroplasts in the leaves and to crucially contribute to drought- and oxidative stress-triggered uptake of calcium into this organelle., Methods: In the present study we integrated comparative proteomic analysis with biochemical, genetic, cellular, ionomic and hormone analysis in order to gain an insight into how chloroplast calcium channels are integrated into signaling circuits under watered condition and under drought stress., Results: Altogether, our results indicate for the first time a link between chloroplast calcium channels and hormone levels, showing an enhanced ABA level in the cmcu mutant already in well-watered condition. Furthermore, we show that the lack of cMCU results in an upregulation of the calcium sensor CAS and of enzymes of chlorophyll synthesis, which are also involved in retrograde signaling upon drought stress, in two independent KO lines generated in Col-0 and Col-4 ecotypes., Conclusions: These observations point to chloroplasts as important signaling hubs linked to their calcium dynamics. Our results obtained in the model plant Arabidopsis thaliana are discussed also in light of our limited knowledge regarding organellar calcium signaling in crops and raise the possibility of an involvement of such signaling in response to drought stress also in crops., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Corti, Festa, Stein, Stevanato, Siroka, Navazio, Vothknecht, Alboresi, Novák, Formentin and Szabò.)

Aim: We describe the experience of a new paediatric heart transplant (HT) centre in Australia. New South Wales offers quaternary paediatric cardiac services including comprehensive care pre- and post-HT; however, perioperative HT care has previously occurred at the national paediatric centre or in adult centres. Internationally, perioperative HT care is highly protocol-driven and a majority of HT occurs in low volume centres. Establishing a low volume paediatric HT centre in New South Wales offers potential for quality HT care close to home., Methods: Retrospective review of programme data for the first 12 months was undertaken. Patient selection was audited against the programme's intended initiation criteria. Longitudinal patient data on outcomes and complications were obtained from patient medical records., Results: The programme's initial phase offered HT to children with non-congenital heart disease and no requirement for durable mechanical circulatory support. Eight patients met criteria for HT referral. Three underwent interstate transfer to the national paediatric centre. Five children (13-15 years, weight 36-85 kg) underwent HT in the new programme. Individual predicted 90-day mortality was 1.3-11.6%, with increased risk for recipients transplanted from veno-arterial extracorporeal membrane oxygenation (VA-ECMO) and with restrictive/hypertrophic cardiomyopathies. Survival at 90 days and for duration of follow-up is 100%. Observed programme benefits include mitigation of family dislocation and improved continuity of care within a family-centred programme., Conclusion: Audit of the first 12 months' activity of a second paediatric HT centre in Australia demonstrates adherence to proposed patient selection criteria and excellent 90-day patient outcomes. The programme demonstrates feasibility of care close to home, providing continuity for all patients including those requiring increased rehabilitation and psychosocial support post-transplantation., (© 2023 Paediatrics and Child Health Division (The Royal Australasian College of Physicians).)

The decline of most caribou (Rangifer tarandus) populations underlines the need to understand the determinants of key demographic parameters. In migratory caribou, we have limited information on rates and drivers of pre-weaning mortality. We fitted 60 pregnant females of the Rivière-aux-Feuilles caribou herd with GPS camera collars to track the survival of calves from birth to weaning in 2016-2018. Over the three years, calf survival rate before weaning, i.e. to 01-Sep, approximately three months of age, was 0.63 (CI 0.50-0.77). Summer mortality risk was mainly influenced by calf birth date, with calves born earlier in the calving season having a lower mortality risk than those born later. Mortality also increased when calves experienced low or high temperature during calving. This study provides the first estimates of pre-weaning survival of migratory caribou calves in this herd, illustrating the value of new technologies to collect data otherwise difficult to obtain in widely distributed migratory populations. This approach can easily be extended to other large herbivores and predators. Our study brings new insights on how climate change may affect summer juvenile survival given the increased temperatures and faster changes in plant phenology expected in the future., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Reflux asthma is an entity characterized by typical symptoms and, in some cases, is "silent"; it is more dangerous when associated with obesity and sleep apnea syndrome. Numerous studies demonstrate its high prevalence in the general population, particularly in the pediatric population, where, despite medical specialists' treatment, asthma symptoms remain poorly controlled with a high risk of acute exacerbations. This clinical study aims to show how the addition of a particular type of alginate (Deflux Plus sachets) containing hyaluronic acid and melatonin at low doses administered over a prolonged period of 6 months causes a reduction in vagal reflex stimulation of the esophagus and pulmonary microaspiration reflexes by regulating lower esophageal sphincter motility in asthmatic patients, improving the asthma control test (ATC) score. In the reported statistical analysis, receiver operating characteristic curves were performed for sensitivity and specificity for the analyzed parameters, including the ACT score, with statistically significant data p<0.0001. We conclude that combining conventional therapy for reflux asthma with alginates may improve the risk of acute asthma exacerbations and dynamic lung volumes.

In terrestrial and marine ecosystems, migrants from protected areas may buffer the risk of harvest-induced evolutionary changes in exploited populations that face strong selective harvest pressures. Understanding the mechanisms favoring genetic rescue through migration could help ensure evolutionarily sustainable harvest outside protected areas and conserve genetic diversity inside those areas. We developed a stochastic individual-based metapopulation model to evaluate the potential for migration from protected areas to mitigate the evolutionary consequences of selective harvest. We parameterized the model with detailed data from individual monitoring of two populations of bighorn sheep subjected to trophy hunting. We tracked horn length through time in a large protected and a trophy-hunted populations connected through male breeding migrations. We quantified and compared declines in horn length and rescue potential under various combinations of migration rate, hunting rate in hunted areas and temporal overlap in timing of harvest and migrations, which affects the migrants' survival and chances to breed within exploited areas. Our simulations suggest that the effects of size-selective harvest on male horn length in hunted populations can be dampened or avoided if harvest pressure is low, migration rate is substantial, and migrants leaving protected areas have a low risk of being shot. Intense size-selective harvest impacts the phenotypic and genetic diversity in horn length, and population structure through changes in proportions of large-horned males, sex ratio and age structure. When hunting pressure is high and overlaps with male migrations, effects of selective removal also emerge in the protected population, so that instead of a genetic rescue of hunted populations, our model predicts undesirable effects inside protected areas. Our results stress the importance of a landscape approach to management, to promote genetic rescue from protected areas and limit ecological and evolutionary impacts of harvest on both harvested and protected populations., Competing Interests: None declared., (© 2023 The Authors. Evolutionary Applications published by John Wiley & Sons Ltd.)

Background: COVID-19 pandemic research efforts have focused on disease phenotypes in adults. A distinct spectrum of illness has been documented in paediatric populations. We aimed to review paediatric intensive care unit (ICU) admissions in Australia, across differing variant predominant phases of the pandemic., Methods: Data reported to the Short PeRiod IncideNce sTudy of Severe Acute Respiratory Infection (SPRINT-SARI) Australia, across 49 ICUs from February 2020 to June 2022 were extracted. We defined 'child' as patients aged <12 years, 'adolescent' as patients aged 12-17 years, and 'young adult' as patients aged 18-25 years., Findings: We identified 226 paediatric ICU admissions with COVID-19, representing 3.9% of ICU admissions across the study period. Comorbidity was present in 34.6% of children, 51.4% of adolescents, and 48.7% of young adults. The need for respiratory support was highest in young adults. While 28.3% of patients <18 years required invasive ventilation, in-hospital mortality in paediatric patients was 3.6%. During the Omicron period, there was an increase in the annualised incidence of age-specific COVID-19 ICU admissions per 100,000 population, albeit a decrease in the incidence per 1000 SARS-CoV-2 notifications., Interpretation: This study demonstrated an appreciable burden of COVID-19 in paediatric patients. Adolescent patients presented phenotypically similar to young adults, however, illness severity was lower in younger cohorts. The Omicron phase of the pandemic demonstrated an increased age-specific population incidence of COVID-19 ICU admissions, albeit a reduced incidence when based on SARS-CoV-2 notifications., Funding: SPRINT-SARI Australia is supported by the Department of Health, Commonwealth of Australia [Standing Deed SON60002733]., Competing Interests: Professor Andrew A Udy has the following disclosures: funding for SPRINT-SARI (Department of Health, Commonwealth of Australia [Standing Deed SON60002733]) is provided to 10.13039/501100001779Monash University as the administering institution; recipient of Grant funding (paid to 10.13039/501100001779Monash University) from the 10.13039/501100000925National Health and Medical Research Council (NHMRC) Australia, for research projects outside of the current work; recipient of Grant funding (paid to 10.13039/501100001779Monash University) from the Medical Research Future Fund (MRFF) Australia, for research projects outside of the current work; recipient of financial support from Integra Lifesciences for the delivery of a presentation at the Neurosurgical Society of Australasia Conference 2022; recipient of in-kind support (trial consumables) from Integra Lifesciences, for research projects outside of the current work. Associate Professor Philip N Britton has the following disclosures: recipient of the NHMRC Early Career Fellowship – APP1145817; recipient of the Royal Australian College of Physicians Foundation Cottrell Research Establishment Fellowship 2022. Associate Professor Nigel W Crawford has the following disclosure: member and current Chair of the National Vaccine Advisory Committee (ATAGI). There are no further conflicts of interest to declare., (© 2023 The Author(s).)

The exploration of natural preventive molecules for nutraceutical and pharmaceutical use has recently increased. In this scenario, marine microorganisms represent an underestimated source of bioactive products endowed with beneficial effects on health that include anti-oxidant, anti-inflammatory, differentiating, anti-tumor, and anti-angiogenic activities. Here, we tested the potential chemopreventive and anti-angiogenic activities of an extract from the marine coastal diatom Skeletonema marinoi Sarno and Zingone ( Sm ) on prostate cancer (PCa) and endothelial cells. We also tested one of the main carotenoids of the diatom, the xanthophyll pigment fucoxanthin (Fuco). Fuco from the literature is a potential candidate compound involved in chemopreventive activities. Sm extract and Fuco were able to inhibit PCa cell growth and hinder vascular network formation of endothelial cells. The reduced number of cells was partially due to growth inhibition and apoptosis. We studied the molecular targets by qPCR and membrane antibody arrays. Angiogenesis and inflammation molecules were modulated. In particular, Fuco downregulated the expression of Angiopoietin 2, CXCL5, TGFβ, IL6, STAT3, MMP1, TIMP1 and TIMP2 in both prostate and endothelial cells. Our study confirmed microalgae-derived drugs as potentially relevant sources of novel nutraceuticals, providing candidates for potential dietary or dietary supplement intervention in cancer prevention approaches.

Mobile pastoralism was a key lifeway in the Late Bronze and Iron Age of Northwest China and played a crucial role in the regional socio-cultural development, as well as the formation of transregional networks. In this paper we analyse the complete faunal assemblage from House F2 in Shirenzigou, on the Eastern Tianshan Mountains, in combination with radiocarbon dating and spatial analysis, to explore local animal resources exploitation strategies and related socio-economic implications. Our results show an intensive multipurpose caprine management, while the exploitation of other domestic taxa, cattle, horses and dogs, was limited. This pastoral economy was supplemented with some hunting. The differentiated use of space in F2 indicates that basic domestic tasks were carried out in the structure, however its position within the landscape and the predominance of bone tools related to warfare and socialization activities, suggests that it was not an ordinary dwelling, it may also have served as a watch post for the summer encampment within the gully. Our findings constitute an important contribution on the discussion on animal resources exploitation strategies and their relationship with evolving socio-economic complexity in the Eastern Tianshan region in the late first millennium BCE., (© 2023. The Author(s).)