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Introduction: Children exposed to trauma are vulnerable to developing post-traumatic stress disorder (PTSD) and other adverse mental health outcomes. In low-and middle-income countries (LMICs), children are at increased risk of exposure to severe trauma and co-occurring adversities. However, relative to high-income countries, there is limited evidence of the factors that predict good versus poor psychological recovery following trauma exposure in LMIC children, and the role of caregiver support in these high-adversity communities., Methods and Analysis: We will conduct a longitudinal, observational study of 250 children aged 8-16 years and their caregivers in South Africa, following child exposure to acute trauma. Dyads will be recruited from community hospitals following a potentially traumatic event, such as a motor vehicle accident or assault. Potential participants will be identified during their hospital visit, and if they agree, will subsequently be contacted by study researchers. Assessments will take place within 4 weeks of the traumatic event, with 3-month and 6-month follow-up assessments. Participants will provide a narrative description of the traumatic event and complete questionnaires designed to give information about social and psychological risk factors. Child PTSD symptoms will be the primary outcome, and wider trauma-related mental health (depression, anxiety, behavioural problems) will be secondary outcomes. Regression-based methods will be used to examine the association of psychosocial factors in the acute phase following trauma, including caregiver support and responding, with child PTSD and wider mental health outcomes., Ethics and Dissemination: Ethical approvals have been granted by Stellenbosch University and the University of Bath, with additional approvals to recruit via hospitals and healthcare clinics being granted by the University of Cape Town, the Department of Health and the City of Cape Town. Study findings will be disseminated via publication in journals, workshops for practitioners and policy-makers, and public engagement events., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: It has been proposed that children and young people living in low- and middle-income countries (LMICs) are not only exposed more frequently to trauma but also have a higher likelihood of encountering traumas of greater severity than those living in high-income countries (HICs). This may lead to higher rates of post-traumatic stress symptoms (PTSS). However, developmental pathways to risk or resilience after trauma exposure in LMICs are underresearched., Methods: We examined early parenting and attachment as potentially important formative factors for later stress reactivity in a longitudinal cohort of South African children (N = 449). Parenting and attachment were assessed at child age 18 months, and interpersonal trauma exposure, PTSS and parenting stress were measured at 13 years (N = 333; core sample with data on all measures: N = 213). Following a vulnerability-stress approach, separate regression models were run to investigate whether parent-child attachment at 18 months, parental sensitivity and intrusiveness during play at 12 months, and current parenting stress at 13 years, interacted with adolescents' extent of interpersonal trauma exposure to predict their PTSS levels at 13 years., Results: We found no predictive effects of either early attachment or current parenting stress in relation to child PTSS. There was some evidence for predictive influences of parental early intrusiveness and sensitivity on adolescent outcomes, though associations were unexpectedly positive for the latter. No interaction effects supporting a vulnerability-stress model were found., Conclusions: Overall, we found limited evidence that elements of the early parent-child environment predict child risk/resilience to trauma in LMIC children. Future studies should include more frequent assessments of relevant constructs to capture changes over time and consider further what comprises adaptive parenting in high-risk contexts., (© 2023 The Authors. Journal of Child Psychology and Psychiatry published by John Wiley & Sons Ltd on behalf of Association for Child and Adolescent Mental Health.)

Consecutive interactions of 3Na + or 1Ca 2+ with the Na + /Ca 2+ exchanger (NCX) result in an alternative exposure (access) of the cytosolic and extracellular vestibules to opposite sides of the membrane, where ion-induced transitions between the outward-facing (OF) and inward-facing (IF) conformational states drive a transport cycle. Here, we investigate sub-state populations of apo and ion-bound species in the OF and IF states by analyzing detergent-solubilized and nanodisc-reconstituted preparations of NCX_Mj with 19 F-NMR. The 19 F probe was covalently attached to the cysteine residues at entry locations of the cytosolic and extracellular vestibules. Multiple sub-states of apo and ion-bound species were observed in nanodisc-reconstituted (but not in detergent-solubilized) NCX_Mj, meaning that the lipid-membrane environment preconditions multiple sub-state populations toward the OF/IF swapping. Most importantly, ion-induced sub-state redistributions occur within each major (OF or IF) state, where sub-state interconversions may precondition the OF/IF swapping. In contrast with large changes in population redistributions, the sum of sub-state populations within each inherent state (OF or IF) remains nearly unchanged upon ion addition. The present findings allow the further elucidation of structure-dynamic modules underlying ion-induced conformational changes that determine a functional asymmetry of ion access/translocation at opposite sides of the membrane and ion transport rates concurring physiological demands.

Cytosolic Ca 2+ and Na + allosterically regulate Na + /Ca 2+ exchanger (NCX) proteins to vary the NCX-mediated Ca 2+ entry/exit rates in diverse cell types. To resolve the structure-based dynamic mechanisms underlying the ion-dependent allosteric regulation in mammalian NCXs, we analyze the apo, Ca 2+ , and Na + -bound species of the brain NCX1.4 variant using hydrogen-deuterium exchange mass spectrometry (HDX-MS) and molecular dynamics (MD) simulations. Ca 2+ binding to the cytosolic regulatory domains (CBD1 and CBD2) rigidifies the intracellular regulatory loop (5L6) and promotes its interaction with the membrane domains. Either Na + or Ca 2+ stabilizes the intracellular portions of transmembrane helices TM3, TM4, TM9, TM10, and their connecting loops (3L4 and 9L10), thereby exposing previously unappreciated regulatory sites. Ca 2+ or Na + also rigidifies the palmitoylation domain (TMH2), and neighboring TM1/TM6 bundle, thereby uncovering a structural entity for modulating the ion transport rates. The present analysis provides new structure-dynamic clues underlying the regulatory diversity among tissue-specific NCX variants., (© 2024. The Author(s).)

Young people who are currently or were previously in state care have consistently been found to have much higher rates of mental health and neurodevelopmental difficulties than the general youth population. While a number of high-quality reviews highlight what research has been undertaken in relation to the mental health of young people with care experience and the gaps in our knowledge and understanding, there is, until now, no consensus, so far as we aware, as to where our collective research efforts should be directed with this important group. Through a series of UK wide workshops, we undertook a consultative process to identify an agreed research agenda between those with lived experience of being in care ( n  = 15), practitioners, policy makers and researchers ( n  = 59), for future research regarding the mental health of young people with care experience, including those who are neurodiverse/have a neurodevelopmental difficulty. This consensus statement identified 21 foci within four broad categories: how we conceptualize mental health; under-studied populations; under-studied topics; and underused methodologies. We hope that those who commission, fund and undertake research will engage in this discussion about the future agenda for research regarding the mental health of young people with care experience., (© 2023 The Authors. Child & Family Social Work published by John Wiley & Sons Ltd.)

Purpose: Mesonephric-like adenocarcinomas (MLA) of the female genital tract represent a rare and relatively recently described neoplasm exhibiting characteristic morphologic and immunohistochemical findings commonly associated with a KRAS-mutation. Most cases display an aggressive clinical behavior, but knowledge about treatment approaches is limited, especially for targeting KRAS., Methods: We report a series of eight cases with a detailed molecular analysis for KRAS. These cases as well as the data of previously published cases with detailed information regarding KRAS-mutational events were reviewed for a potential targeted approach and its prognostic impact., Results: Both the uterine and ovarian MLA harbor a somatic KRAS-mutation in about 85% of the reported cases, affecting the hotspot codons 12 and 13. 15.7% of the endometrial and 15.6% of ovarian MLA are wild type for KRAS. A p.G12A-alteration was seen in 5.6% (5/89) of the endometrial and in 6.2% (2/32) of the ovarian tumors, for p.G12C in 7.9% and 6.2%, for p.G12D in 32.6% and 34.5% and for p.G12V in 36% and 37.5%, respectively. Very limited data are available regarding the prognostic impact of different mutational sites within the KRAS-gene without significant prognostic impact., Conclusion: Because of a specific p.G12C-KRAS somatic mutation, only the minority of MLA (7.9% with uterine and 6.2% with ovarian primary) are potentially targetable by sotarasib in that rare but aggressive subtype of adenocarcinoma of the female genital tract. Until now, the different location of a somatic KRAS-mutation is of no prognostic impact., (© 2023. The Author(s).)

Background: Subpopulations of myocardial c-kit pos cells have the ability to stimulate regeneration in ischemic heart disease by paracrine effects. The left atrial appendage (LAA), which is easy accessible during cardiac surgery, may represent a perfect source for c-kit pos cell extraction for autologous cell therapies in the living human. So far, frequency and distribution of c-kit pos cells in LAA are unknown., Methods: LAAs of patients who underwent cardiac surgery due to coronary artery disease (coronary artery bypass graft, CABG), valvular heart disease or both and of two body donors were examined. Tissue was fixed in 4 % paraformaldehyde, embedded in paraffin, dissected in consecutive sections and stained for c-kit pos cells. In parallel, grade of fibrosis, amount of fat per section and cells positive for mast cell tryptase were examined., Results: We collected 27 LAAs (37.0 % female, mean left ventricular ejection fraction 50.4 %, 63.0 % persistent atrial fibrillation (AF)). Most of the patients underwent combined CABG and valve surgery (51.9 %). C-kit pos cells were detected in 3 different regions: A) Attached to the epicardial fat layer, B) close to vascular structures and C) between cardiomyocytes. C-kit pos cells ranged from 0.05 c-kit pos cells per mm 2 to 67.5 c-kit pos cells per mm 2 . We found no association between number of c-kit pos cells and type of AF, amount of fibrosis or amount of fat. Up to 72 % of c-kit pos cells also showed a positive staining for mast cell tryptase., Conclusion: C-kit pos cells are frequent in LAAs of cardiovascular patients with a rather homogenous distribution throughout the LAA. The LAA can therefore be considered as a source for extraction of a reasonable quantity of autologous cardiac progenitor cells in the living human patient., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Gerhard Hindricks has received grants through the Leipzig Heart Institute from Boston Scientific (Boston Scientific Corporation, Marlborough, Massachusetts, USA), and Abbott/St. Jude Medical (Abbott Laboratories, Chicago, Illinois, USA), no personal payments are to declare. All other authors state that there is nothing to declare., (© 2023 Published by Elsevier Ltd.)

Objectives: Life Story Work (LSW) is used to promote the mental health and well-being of children and adolescents living in out-of-home care. LSW should be offered to all but is conventionally delivered in high-intensity ways. Low-intensity approaches are more accessible but there is significant variation and little guidance for supporting adolescents. We aimed to create guidance for Adolescent-Focused Low-Intensity LSW., Design: Realist review., Data Sources: MEDLINE, Embase, PsycINFO, Sociology Collection (ProQuest), CINAHL, CDAS, Web of Science (SCIE, SSCI), Social Care Online and grey literature sources. Searches were performed between December 2021 and March 2022., Eligibility Criteria: Documents on children and adolescents in care, LSW and/or low-intensity interventions to improve mental health were included. Documents focusing on parenting style and contact with birth family were excluded., Analysis: Documents were analysed using a realist logic of analysis. In consultation with Content Expert Groups (comprising professionals and care leavers), we developed an initial programme theory. Data relating to and challenging the initial programme theory were extracted and context-mechanism-outcome-configurations developed, critiqued and refined in an iterative fashion. Interpretations were drawn from context-mechanism-outcome-configurations to enhance the programme theory., Results: 75 documents contributed to the analysis. Generally, studies were small-scale and lacked in-depth methods and evaluation descriptions. Findings indicated important factors contribute to the development of high-quality Adolescent-Focused Low-Intensity LSW. Adolescent-Focused Low-Intensity LSW should be person-centred, begin in the now, involve co-construction, record everyday positive life events and be supported by trained carer(s). Context-mechanism-outcome-configurations relating to these themes are reported., Conclusions: Using this knowledge we developed initial practice guidance to support social care to deliver better quality Adolescent-Focused Low-Intensity LSW more consistently. To address gaps in our knowledge about the impact of Adolescent-Focused Low-Intensity LSW, further primary research is needed to strengthen understandings of how this intervention works (or not) in different contexts., Prospero Registration Number: CRD42021279816., Competing Interests: Competing interests: SH offers consultancy services in social media and Digital Life Story Work via www.digitallifestorywork.co.uk. KW is the CEO of The Fostering Network. The remaining authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ.)

Parent-child agreement on measures of child posttraumatic stress disorder (PTSD) is moderate at best, and understanding of this discrepancy is limited. To address this, we conducted an item-level investigation of parent-child symptom agreement to examine the potential influence of parental posttraumatic stress symptoms (PTSS) on parents' reports of their child's PTSS. We also examined heart rate (HR) indices as possible independent indicators of child PTSD, examining patterns of association with parent versus child report. Parent-child dyads (N = 132, child age: 6-13 years, 91.7% White) were recruited after the child's hospital admission following an acute, single-incident traumatic event. At 1-month posttrauma, questionnaires assessing children's PTSS (self- and parental reports) and parental PTSS were administered. For a subset of participants (n = 70), children's HR recordings were obtained during a trauma narrative task and analyzed. Parent and child reports of child PTSS were weakly positively correlated, r = .25. Parental PTSS were found to be stronger positive predictors of parental reports of child PTSS than the children's own symptom reports, β = 0.60 vs. β = 0.14, and were associated with higher parent-reported child PTSS relative to child reports. Finally, children's self-reported PTSS were associated with HR indices, whereas parent reports were not, βs = -.33-.30 vs. βs = -.15-.01. Taken together, children's self-reported PTSS could be a more accurate reflection of their posttrauma physiological distress than parent reports. The potential influence of parental PTSS on their perceptions of their child's symptoms warrants further consideration., (© 2023 The Authors. Journal of Traumatic Stress published by Wiley Periodicals LLC on behalf of International Society for Traumatic Stress Studies.)

Social support has been linked to posttrauma adjustment in children and adolescents, but the components of good support remain poorly defined. We conducted qualitative interviews with 30 youths aged 7-16 years after being admitted to a hospital following a single-incident trauma, predominantly injury or illness. The aim was to identify youths' support needs and examine the support they received across different recovery stages. Thematic analysis revealed that although participants appreciated increased attention and warm support during their hospital stay, most wanted their lives to return to normal soon afterward and were frustrated by barriers to achieving this. Participants received support from different sources, but parents and peers were the most important providers of emotional support and the people with whom these individuals most frequently engaged in trauma-related conversations. Furthermore, although it was important that schools were sensitive to the youths' potential limitations regarding their ability to engage with lessons, emotional support from teachers was less valued. Overall, this study implies that ecological models incorporating multiple interacting layers capture the structure of youths' posttrauma support systems well. These findings may be used to tailor posttrauma interventions more closely to child and adolescent needs at different recovery stages and highlight the importance of having parents and, where possible, peers involved in posttrauma interventions or prevention programs., (© 2023 The Authors. Journal of Traumatic Stress published by Wiley Periodicals LLC on behalf of International Society for Traumatic Stress Studies.)

Resource-oriented narrative trauma therapy (ResonaT; Hiller u. Hensel, 2019) is an innovative and creative approach within existing narrative trauma procedures. It is based on the three core elements of modern trauma therapy (actualisation, resource activation, dual attention) and invokes the neurobiological self-healing mechanism of memory reconsolidation. Due to its low demands on the children, its resourceful and gentle actualisation of the traumatic material, the distance-creating use of animal protagonists and a supportive therapeutic relationship, it is particularly suitable for children and adolescents with complex trauma sequelae. Through specific structuring (orientation to the leading symptoms, elaboration of central basic emotions, allocation of current triggers to earlier traumatic events), the narratives can be formulated precisely for each child.The workload for the therapists is made considerably easier by the availability of around 100 elaborated, topic-specific narratives.

The plasma membrane (NCX) and mitochondrial (NCLX) Na + /Ca 2+ exchangers are structurally related proteins, although they operate under strictly different ionic conditions and membrane potentials. In contrast with NCX, NCLX can transport either Li + or Na + in exchange for Ca 2+ . Whereas the crystal structure of the archaeal NCX (NCX_Mj) describes the binding sites for alternative binding of 3Na + or 1Ca 2+ , these features remain elusive for NCLX due to the lack of structural information. To elucidate the ion-binding features of mitochondrial NCLX, we analyzed here the Li + -transporting NCLX_Mj mutant, produced by replacing the ion-coordinating residues in the archaeal NCX (NCX_Mj) to match the ion-coordinating residues of human NCLX. The NCLX_Mj-mediated Na + /Ca 2+ or Li + /Ca 2+ exchange rates are insensitive to varying voltage, consistent with an electroneutral ion exchange. Molecular dynamics (MD) simulations revealed that NCLX_Mj contains two novel Li + binding sites with four ion-coordinating residues, derived from the three Na + binding sites of NCX_Mj. The ion-coordination modes, observed in the MD simulations, were further supported by two-dimensional infrared (2D IR) spectroscopy and by testing the mutational effects on the ion fluxes. Collectively, our results revealed a structural basis for Li + binding and electroneutral transport (2Na + /Li + :1Ca 2+ ) by NCLX_Mj, meaning that the NCLX-mediated electroneutral transport may predefine mitochondrial Ca 2+ and Na + signaling to modulate cellular functions., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest, (Copyright © 2022. Published by Elsevier Ltd.)

Objective: To assess the feasibility of an ED presenting complaint (PC) tool that categorised all ED PCs into 10 categories., Methods: A retrospective analysis of 1445 consecutive patient encounters was conducted. The primary outcome was the frequency of use of the 10 PC categories., Results: Of the 1203 patient encounters meeting inclusion criteria, the PC tool was completed by clinicians in 574 (47.7%). When completed, the tool's 10 options were selected for most presentations (72.3%)., Conclusion: The PC tool captured the majority of presenting complaints in 10 categories. External validation is recommended., (© 2022 The Authors. Emergency Medicine Australasia published by John Wiley & Sons Australia, Ltd on behalf of Australasian College for Emergency Medicine.)

The dissociative subtype of post-traumatic stress disorder (PTSD-DS) was introduced in the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5), and is characterised by symptoms of either depersonalisation or derealisation, in addition to a diagnosis of post-traumatic stress disorder (PTSD). This systematic review and meta-analysis sought to estimate the point prevalence of current PTSD-DS, and the extent to which method of assessment, demographic and trauma variables moderate this estimate, across different methods of prevalence estimation. Studies included were identified by searching MEDLINE (EBSCO), PsycInfo, CINAHL, Academic Search Complete and PTSDpubs, yielding 49 studies that met the inclusion criteria ( N = 8214 participants). A random-effects meta-analysis estimated the prevalence of PTSD-DS as 38.1% (95% CI 31.5-45.0%) across all samples, 45.5% (95% CI 37.7-53.4%) across all diagnosis-based and clinical cut-off samples, 22.8% (95% CI 14.8-32.0%) across all latent class analysis (LCA) and latent profile analysis (LPA) samples and 48.1% (95% CI 35.0-61.3%) across samples which strictly used the DSM-5 PTSD criteria; all as a proportion of those already with a diagnosis of PTSD. All results were characterised by high levels of heterogeneity, limiting generalisability. Moderator analyses mostly failed to identify sources of heterogeneity. PTSD-DS was more prevalent in children compared to adults, and in diagnosis-based and clinical cut-off samples compared to LCA and LPA samples. Risk of bias was not significantly related to prevalence estimates. The implications of these results are discussed further.

We report on the direct search for cosmic relic neutrinos using data acquired during the first two science campaigns of the KATRIN experiment in 2019. Beta-decay electrons from a high-purity molecular tritium gas source are analyzed by a high-resolution MAC-E filter around the end point at 18.57 keV. The analysis is sensitive to a local relic neutrino overdensity ratio of η<9.7×10^{10}/α (1.1×10^{11}/α) at a 90% (95%) confidence level with α=1 (0.5) for Majorana (Dirac) neutrinos. A fit of the integrated electron spectrum over a narrow interval around the end point accounting for relic neutrino captures in the tritium source reveals no significant overdensity. This work improves the results obtained by the previous neutrino mass experiments at Los Alamos and Troitsk. We furthermore update the projected final sensitivity of the KATRIN experiment to η<1×10^{10}/α at 90% confidence level, by relying on updated operational conditions.

Background: Understanding the course of post-traumatic stress disorder (PTSD) and the factors that impact this is essential to inform decisions about when and for whom screening and intervention are likely to be beneficial., Objective: To provide meta-analytic evidence of the course of recovery from PTSD in the first year following trauma, and the factors that influence that recovery., Method: We conducted a meta-analysis of observational studies of adult PTSD prevalence which included at least two assessments within the first 12 months following trauma exposure, examining prevalence statistics through to 2 years post-trauma. We examined trauma intentionality (intentional or non-intentional), PTSD assessment method (clinician or self-report), sample sex distribution, and age as moderators of PTSD prevalence over time., Results: We identified 78 eligible studies including 16,484 participants. Pooled prevalence statistics indicated that over a quarter of individuals presented with PTSD at 1 month post-trauma, with this proportion reducing by a third between 1 and 3 months. Beyond 3 months, any prevalence changes were detected over longer intervals and were small in magnitude. Intentional trauma, younger age, and female sex were associated with higher PTSD prevalence at 1 month. In addition, higher proportions of females, intentional trauma exposure, and higher baseline PTSD prevalence were each associated with larger reductions in prevalence over time., Conclusions: Recovery from PTSD following acute trauma exposure primarily occurs in the first 3 months post-trauma. Screening measures and intervention approaches offered at 3 months may better target persistent symptoms than those conducted prior to this point., Highlights: PTSD rates in the immediate aftermath of trauma exposure decline from 27% at 1 month to 18% at 3 months post-trauma, showing significant spontaneous recovery.Problems appear to stabilize after 3 months.Screening/intervention for PTSD at 3 months post-trauma is indicated., Competing Interests: No potential conflict of interest was reported by the authors., (© 2022 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.)

Chlorophyll f is a new type of chlorophyll isolated from cyanobacteria. The absorption and fluorescence characteristics of chlorophyll f permit these oxygenic-photosynthetic organisms to thrive in environments where white light is scarce but far-red light is abundant. To explore the ligand properties of chlorophyll f and its energy transfer profiles we established two different in vitro reconstitution systems. The reconstituted peridinin-chlorophyll f protein complex (chlorophyll f-PCP) showed a stoichiometry ratio of 4:1 between peridinin and chlorophyll f, consistent with the peridinin:chlorophyll a ratio from native PCP complexes. Using emission wavelength at 712 nm, the excitation fluorescence featured a broad peak at 453 nm and a shoulder at 511 nm confirming energy transfer from peridinin to chlorophyll f. In addition, by using a synthetic peptide mimicking the first transmembrane helix of light-harvesting chlorophyll proteins of plants, we report that chlorophyll f, similarly to chlorophyll b, did not interact with the peptide contrarily to chlorophyll a, confirming the accessory role of chlorophyll f in photosystems. The binding of chlorophyll f, even in the presence of chlorophylls a and b, by PCP complexes shows the flexibility of chlorophyll-protein complexes and provides an opportunity for the introduction of new chlorophyll species to extend the photosynthetic spectral range., (© 2021. The Author(s), under exclusive licence to Springer Nature B.V.)

Introduction: Adolescents are the fastest growing group entering social care and are most at risk of mental ill-health. Life Story Work (LSW) is an existing transdiagnostic intervention thought to improve the well-being and mental health of children and adolescents under the care of a local authority by assisting the processing of trauma. Yet LSW is poorly evidenced, lacks standardisation and focuses on younger children. LSW is also high-intensity, relying on specialist input over several months. Adolescent-focused low-intensity-LSW is a promising alternative. However, there is poor evidence on how LSW, let alone low-intensity-LSW should be delivered to adolescents. We aim to identify why, how, in what contexts, for whom and to what extent low-intensity-LSW interventions can be delivered to adolescents with care-experience., Methods and Analysis: Undertaking a realist review, we will: (1) develop an initial programme theory (PrT) of adolescent-focused low-intensity-LSW by consulting with two key expert panels (care-experienced and professional stakeholders), and by searching the literature to identify existing relevant theories; (2) undertake a comprehensive literature search to identify secondary data to develop and refine our emerging PrT. Searches will be run between 12/2021-06/2022 in databases including MEDLINE, PsycINFO, ASSIA and relevant sources of grey literature; (3) select, extract and organise data; (4) synthesise evidence using a realist logic of analysis and undertake further iterative data searching and consultation with our expert panels; (5) write up and share the refined PrT with our expert panels for their final comments. From this process guidance will be developed to help improve the delivery of LSW to support the mental health needs of adolescents with care-experience., Ethics and Dissemination: Ethical approval is not required. Dissemination will include input from expert panels. We will develop academic, practice and youth focused outputs targeting adolescents, their carers, social, healthcare, and educational professionals, academics, and policymakers., Prospero Registration Number: CRD42021279816., Competing Interests: Competing interests: SPH offers consultancy services in social media and Digital Life Story Work via https://www.digitallifestorywork.co.uk/. LR is Director of Strategy of The Care Leaders, KW is the CEO of The Fostering Network. The remaining authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)

The Na +/ Ca 2+ exchangers (NCXs) modulate the Ca2+ signaling and homeostasis in health and disease. The transport cycle turnover rates (kcat) and the kcat/Km values of eukaryotic NCXs are ~10 4 -times higher than those of prokaryotic NCXs. Three ion-coordinating residues (out of twelve) differ between eukaryotic NCXs and NCX&#95;Mj. The replacement of three ion-coordinating residues in NCX&#95;Mj does not increase kcat, probably due to the structural rigidity of NCX&#95;Mj. Phospholipids and cholesterol increase (up to 10-fold) the transport rates in the cardiac NCX1.1, but not in NCX&#95;Mj. A lipid environment can partially contribute to the huge kinetic variances among NCXs., (Copyright © 2021. Published by Elsevier B.V.)

The GERmanium Detector Array (Gerda) collaboration searched for neutrinoless double- β decay in 76 Ge using isotopically enriched high purity germanium detectors at the Laboratori Nazionali del Gran Sasso of INFN. After Phase I (2011-2013), the experiment benefited from several upgrades, including an additional active veto based on LAr instrumentation and a significant increase of mass by point-contact germanium detectors that improved the half-life sensitivity of Phase II (2015-2019) by an order of magnitude. At the core of the background mitigation strategy, the analysis of the time profile of individual pulses provides a powerful topological discrimination of signal-like and background-like events. Data from regular 228 Th calibrations and physics data were both considered in the evaluation of the pulse shape discrimination performance. In this work, we describe the various methods applied to the data collected in Gerda Phase II corresponding to an exposure of 103.7 kg year. These methods suppress the background by a factor of about 5 in the region of interest around Q β β = 2039  keV, while preserving ( 81 ± 3 ) % of the signal. In addition, an exhaustive list of parameters is provided which were used in the final data analysis., (© The Author(s) 2022.)

The cytosolic pH decline from 7.2 to 6.9 results in 90% inactivation of mammalian Na + /Ca 2+ exchangers (NCXs) due to protons interactions with regulatory and transport domains ("proton block"). Remarkably, the pH titration curves of mammalian and prokaryotic NCXs significantly differ, even after excluding the allosteric effects through regulatory domains. This is fascinating since "only" three (out of twelve) ion-coordinating residues (T50S, E213D, and D240N) differ between the archaeal NCX&#95;Mj and mammalian NCXs although they contain either three or two carboxylates, respectively. To resolve the underlying mechanisms of pH-dependent regulation, the ion-coordinating residues of NCX&#95;Mj were mutated to imitate the ion ligation arrays of mammalian NCXs; the mutational effects were tested on the ion binding/transport by using ion-flux assays and two-dimensional infrared (2D IR) spectroscopy. Our analyses revealed that two deprotonated carboxylates ligate 3Na + or 1Ca 2+ in NCX prototypes with three or two carboxylates. The Na + /Ca 2+ exchange rates of NCX&#95;Mj reach saturation at pH 5.0, whereas the Na + /Ca 2+ exchange rates of the cardiac NCX1.1 gradually increase even at alkaline pHs. The T50S replacement in NCX&#95;Mj "recapitulates" the pH titration curves of mammalian NCX by instigating an alkaline shift. Proteolytic shaving of regulatory CBD domains activates NCX1.1, although the normalized pH-titration curves are comparable in trypsin treated and untreated NCX1.1. Thus, the T50S-dependent alkaline shift sets a dynamic range for "proton block" function at physiological pH, whereas the CBDs (and other regulatory modes) modulate incremental changes in the transport rates rather than affect the shape of pH dependent curves., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Evidence from high-income countries (HICs) has documented a higher rate of post-traumatic stress disorder (PTSD) in females than males. However, data are limited on sex differences in PTSD from low- and middle-income countries (LMICs), despite particularly high levels of trauma experienced by LMIC youth., Objectives: In a sample of adolescents from an impoverished South African community, we examined sex differences in PTSD, as well as co-occurring depression, adolescent age, and the type and extent of trauma exposure as potential contributors to female vulnerability., Methods: Participants were recruited from high schools in the Khayelitsha area of Cape Town. Self-reported trauma exposure, PTSD and depressive symptoms were measured in 797 adolescents (62% female) aged 13-17 years. Poisson regressions were used to examine Risk Ratios (RR) based on probable PTSD diagnoses, and linear regressions were applied to assess posttraumatic stress symptom (PTSS) severity., Results: 92% of adolescents reported trauma exposure, of whom 28% had probable PTSD. Prevalence of PTSD was higher for females than for males, even when controlling for total trauma exposure (RR = 1.71, p < .001) and co-occurring depressive symptoms (RR = 1.45, p = .005). By contrast, sex differences in depression were eliminated after controlling for co-occurring PTSS. There was little evidence of age effects on the emergence of sex differences. At lower thresholds of interpersonal trauma, females showed higher levels of PTSS compared to males, but no sex differences were found at high levels of exposure., Conclusion: Higher PTSD rates are observed in adolescent females in a high adversity-LMIC sample suggesting sex differences are robust across international contexts. Sex differences in PTSD are unlikely to be explained by co-occurring depression and in this context sex differences in depression may be secondary to trauma and PTSD. However, exposure to significant interpersonal trauma appears to overrule any specific female vulnerability., Competing Interests: No potential conflict of interest was reported by the author(s)., (© 2021 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.)

We report on the light sterile neutrino search from the first four-week science run of the KATRIN experiment in 2019. Beta-decay electrons from a high-purity gaseous molecular tritium source are analyzed by a high-resolution MAC-E filter down to 40 eV below the endpoint at 18.57 keV. We consider the framework with three active neutrinos and one sterile neutrino. The analysis is sensitive to the mass, m&#95;{4}, of the fourth mass state for m&#95;{4}^{2}≲1000  eV^{2} and to active-to-sterile neutrino mixing down to |U&#95;{e4}|^{2}≳2×10^{-2}. No significant spectral distortion is observed and exclusion bounds on the sterile mass and mixing are reported. These new limits supersede the Mainz results for m&#95;{4}^{2}≲1000  eV^{2} and improve the Troitsk bound for m&#95;{4}^{2}<30  eV^{2}. The reactor and gallium anomalies are constrained for 100<Δm&#95;{41}^{2}<1000  eV^{2}.

Objective: The aim of the present study was to describe the epidemiology and clinical features of patients presenting to the ED with suspected and confirmed COVID-19., Methods: The COVID-19 ED (COVED) Project is an ongoing prospective cohort study in Australian EDs. This analysis presents data from eight sites across Victoria and Tasmania for July 2020 (during Australia's 'second wave'). All adult patients who met criteria for 'suspected COVID-19' and underwent testing for SARS-CoV-2 in the ED were eligible for inclusion. Study outcomes included a positive SARS-CoV-2 test result and mechanical ventilation., Results: In the period 1 July to 31 July 2020, there were 30 378 presentations to the participating EDs and 2917 (9.6%; 95% confidence interval 9.3-9.9) underwent testing for SARS-CoV-2. Of these, 50 (2%) patients returned a positive result. Among positive cases, two (4%) received mechanical ventilation during their hospital admission compared to 45 (2%) of the SARS-CoV-2 negative patients (odds ratio 1.7, 95% confidence interval 0.4-7.3; P = 0.47). Two (4%) SARS-CoV-2 positive patients died in hospital compared to 46 (2%) of the SARS-CoV-2 negative patients (odds ratio 1.7, 95% confidence interval 0.4-7.1; P = 0.49). Strong clinical predictors of a positive SARS-CoV-2 result included self-reported fever, non-smoking status, bilateral infiltrates on chest X-ray and absence of a leucocytosis on first ED blood tests (P < 0.05)., Conclusion: In this prospective multi-site study from July 2020, a substantial proportion of ED patients required SARS-CoV-2 testing, isolation and enhanced infection prevention and control precautions. Presence of SARS-CoV-2 on nasopharyngeal swab was not associated with death or mechanical ventilation., (© 2020 Australasian College for Emergency Medicine.)

The GERmanium Detector Array (Gerda) collaboration searched for neutrinoless double- β decay in 76 Ge with an array of about 40 high-purity isotopically-enriched germanium detectors. The experimental signature of the decay is a monoenergetic signal at Q β β = 2039.061 ( 7 )  keV in the measured summed energy spectrum of the two emitted electrons. Both the energy reconstruction and resolution of the germanium detectors are crucial to separate a potential signal from various backgrounds, such as neutrino-accompanied double- β decays allowed by the Standard Model. The energy resolution and stability were determined and monitored as a function of time using data from regular 228 Th calibrations. In this work, we describe the calibration process and associated data analysis of the full Gerda dataset, tailored to preserve the excellent resolution of the individual germanium detectors when combining data over several years., (© The Author(s) 2021.)

The GERmanium Detector Array (GERDA) experiment searched for the lepton-number-violating neutrinoless double-β (0νββ) decay of ^{76}Ge, whose discovery would have far-reaching implications in cosmology and particle physics. By operating bare germanium diodes, enriched in ^{76}Ge, in an active liquid argon shield, GERDA achieved an unprecedently low background index of 5.2×10^{-4} counts/(keV kg yr) in the signal region and met the design goal to collect an exposure of 100 kg yr in a background-free regime. When combined with the result of Phase I, no signal is observed after 127.2 kg yr of total exposure. A limit on the half-life of 0νββ decay in ^{76}Ge is set at T&#95;{1/2}>1.8×10^{26}  yr at 90% C.L., which coincides with the sensitivity assuming no signal.

Objective: The number of patients with suspected COVID-19 presenting to Australian EDs continues to impose a burden on healthcare services. Isolation is an important aspect of infection prevention and control, but has been associated with undesirable consequences among hospital inpatients. The aim of the present study was to determine if isolation is associated with an increased length of stay (LOS) in the ED., Methods: The Registry for Emergency Care Project is a prospective cohort study with a series of nested sub-studies. The present study was a retrospective analysis of adult patients allocated an Australasian Triage Scale category of 1 or 2 who presented to a tertiary ED between 18 and 31 May 2020. The primary outcome was ED LOS. Regression methods were used to determine the independent association between ED isolation and LOS., Results: There were 447 patients who met inclusion criteria, of which 123 (28%) were managed in isolation. The median (interquartile range) ED LOS was 259 (210-377) min for the isolation group and 204 (126-297) min for the non-isolation group, a difference in median ED LOS of 55 min (P < 0.001). Isolation was independently associated with a 23% increase in ED LOS (P = 0.002) and doubled the odds of an ED stay of more than 4 h (adjusted odds ratio 2.2 [1.4-3.4], P = 0.001)., Conclusion: Consistent with the anecdotal experience of Australian ED clinicians, the present study demonstrated an increased ED LOS for patients managed in isolation. Enhanced infection prevention and control precautions will be required during and beyond the current pandemic, creating significant ongoing challenges for emergency care systems., (© 2020 Australasian College for Emergency Medicine.)

Clinical practice guidelines, such as those focusing on traumatic stress treatment, can play an important role in promoting inclusion and equity. Based on a review of 14 international trauma treatment guidance documents that explicitly mentioned children, we reflect on two areas in which these guidelines can become more inclusive and equitable; a) representation of children's cultural background and b) children's opportunity to have their voice heard. While a few guidelines mentioned that treatment should be tailored to children's cultural needs, there was little guidance on how this could be done. Moreover, there still appears to be a strong white Western lens across all stages of producing and evaluating the international evidence base. The available documentation also suggested that no young people under the age of 18 had been consulted in the guideline development processes. To contribute to inclusion and equity, we suggest five elements for future national guideline development endeavours. Promoting research and guideline development with, by, and for currently under-represented communities should be a high priority for our field. Our national, regional and global professional associations are in an excellent position to (continue to) stimulate conversation and action in this domain., Competing Interests: No potential conflict of interest was reported by the authors., (© 2020 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.)

Selective recognition and transport of Na + and Ca 2+ ions by sodium-calcium exchanger (NCX) proteins is a primary prerequisite for Ca 2+ signaling and homeostasis. Twelve ion-coordinating residues are highly conserved among NCXs, and distinct NCX orthologs contain two or three carboxylates, while sharing a common ion-exchange stoichiometry (3Na + :1Ca 2+ ). How these structural differences affect the ion-binding affinity, selectivity, and transport rates remains unclear. Here, the mutational effects of three carboxylates (E54, E213, and D240) were analyzed on the ion-exchange rates in the archaeal NCX from Methanococcus jannaschii and ion-induced structure-affinity changes were monitored by attenuated total reflection-Fourier-transform infrared spectroscopy (ATR-FTIR). The D240N mutation elevated the ion-transport rates by twofold to threefold, meaning that the deprotonation of D240 is not essential for transport catalysis. In contrast, mutating E54 or E213 to A, D, N, or Q dramatically decreased the ion-transport rates. ATR-FTIR revealed high- and low-affinity binding of Na + or Ca 2+ with E54 and E213, but not with D240. These findings reveal distinct structure-affinity states at specific ion-binding sites in the inward-facing (IF) and outward-facing orientation. Collectively, two multidentate carboxylate counterparts (E54 and E213) play a critical role in determining the ion coordination/transport in prokaryotic and eukaryotic NCXs, whereas the ortholog substitutions in prokaryotes (aspartate) and eukaryotes (asparagine) at the 240 position affect the ion-transport rates differently (k cat ), probably due to the structural differences in the transition state., (© 2020 Federation of European Biochemical Societies.)

Objective: The aim of the present study was to describe the epidemiological and clinical features of ED patients with suspected and confirmed COVID-19., Methods: The COVID-19 Emergency Department (COVED) Project is an ongoing prospective cohort study that includes all adult patients presenting to The Alfred Hospital ED who undergo testing for SARS-CoV-2. Current guidelines recommend testing for patients with fevers or chills, acute respiratory symptoms or a high-risk exposure history, as well as implementation of infection prevention and control precautions for all suspected and confirmed cases. Study outcomes include a positive SARS-CoV-2 test result and intensive respiratory support., Results: In the period 1-30 April 2020, 702 of 3453 ED patients (20%; 95% CI 19-22) were tested, with a significant increase during the study period (incident rate ratio 1.019; 95% confidence interval 1.017-1.021, P < 0.001). The primary outcome of a positive SARS-CoV-2 test was recorded in 14 patients (2%; 95% confidence interval 1-3). Shortness of breath (77%), fatigue (100%), myalgia (67%) and diarrhoea (67%) were common among positive cases, while close contact (9%), fever (0%) and healthcare occupation (0%) were not. No positive cases required intensive respiratory support in the ED., Conclusions: The volume of ED patients with suspected COVID-19 is increasing. Low numbers of positive cases precluded development of accurate predictive tools, but the COVED Project is fulfilling an important role in monitoring the burden of infection prevention and control requirements on the ED. The increasing number of patients meeting isolation criteria has the potential to impact on patient flow and may lead to ED overcrowding., (© 2020 Australasian College for Emergency Medicine.)

The Karlsruhe Tritium Neutrino (KATRIN) experiment aims at measuring the effective electron neutrino mass with a sensitivity of 0.2 eV/c 2 , i.e., improving on previous measurements by an order of magnitude. Neutrino mass data taking with KATRIN commenced in early 2019, and after only a few weeks of data recording, analysis of these data showed the success of KATRIN, improving on the known neutrino mass limit by a factor of about two. This success very much could be ascribed to the fact that most of the system components met, or even surpassed, the required specifications during long-term operation. Here, we report on the performance of the laser Raman (LARA) monitoring system which provides continuous high-precision information on the gas composition injected into the experiment's windowless gaseous tritium source (WGTS), specifically on its isotopic purity of tritium-one of the key parameters required in the derivation of the electron neutrino mass. The concentrations c x for all six hydrogen isotopologues were monitored simultaneously, with a measurement precision for individual components of the order 10 -3 or better throughout the complete KATRIN data taking campaigns to date. From these, the tritium purity, ε T , is derived with precision of <10 - 3 and trueness of <3 × 10 -3 , being within and surpassing the actual requirements for KATRIN, respectively., Competing Interests: The authors declare no conflict of interest.

Objective: The COVID-19 Emergency Department (COVED) Quality Improvement Project aims to provide regular and real-time clinical information to ED clinicians caring for patients with suspected and confirmed COVID-19. The present study summarises data from the first 2 weeks of the study., Methods: COVED is an ongoing prospective cohort study that commenced on 1 April 2020. It includes all adult patients presenting to a participating ED who undergo testing for SARS-CoV-2. Data are collected prospectively and entered into a bespoke registry. Outcomes include a positive SARS-CoV-2 polymerase chain reaction test result and requirement for intensive respiratory support., Results: In the period 1-14 April 2020, 240 (16%) of 1508 patients presenting to The Alfred Emergency and Trauma Centre met inclusion criteria. Of these, 11 (5%) tested positive for SARS-CoV-2. The mean age of patients was 60 years and the commonest symptoms were acute shortness of breath (n = 122 [67%]), cough (n = 108 [56%]) or fever (n = 98 [51%]). Overseas travel or known contact with a confirmed case was reported by 24 (14%) and 16 (10%) patients, respectively. Fever or hypoxia was recorded in 23 (10%) and 11 (5%) patients, respectively. Eleven (5%) patients received mechanical ventilation in the ED, of whom none tested positive for SARS-CoV-2., Conclusions: Among patients presenting to a tertiary ED with suspected COVID-19, only a small proportion tested positive for SARS-CoV-2. Although the low incidence of positive cases currently precludes the development of predictive tools, the COVED Project demonstrates that the rapid establishment of an agile clinical registry for emergency care is feasible., (© 2020 Australasian College for Emergency Medicine.)

Objective: In Australia, the current ED burden related to COVID-19 is from 'suspected' rather than 'confirmed' cases. The initial aim of the Registry for Emergency Care (REC) Project is to determine the impact of isolation processes on the emergency care of all patients., Methods: The REC Project builds on the COVID-19 Emergency Department Quality Improvement (COVED) Project. Outcomes measured include times to critical assessment and management., Results: Clinical tools will be generated to inform emergency care, both during and beyond the COVID-19 pandemic., Conclusions: The REC Project will support ED clinicians in the emergency care of all patients., (© 2020 Australasian College for Emergency Medicine.)

We present the first search for bosonic superweakly interacting massive particles (super-WIMPs) as keV-scale dark matter candidates performed with the GERDA experiment. GERDA is a neutrinoless double-β decay experiment which operates high-purity germanium detectors enriched in ^{76}Ge in an ultralow background environment at the Laboratori Nazionali del Gran Sasso (LNGS) of INFN in Italy. Searches were performed for pseudoscalar and vector particles in the mass region from 60  keV/c^{2} to 1  MeV/c^{2}. No evidence for a dark matter signal was observed, and the most stringent constraints on the couplings of super-WIMPs with masses above 120  keV/c^{2} have been set. As an example, at a mass of 150  keV/c^{2} the most stringent direct limits on the dimensionless couplings of axionlike particles and dark photons to electrons of g&#95;{ae}<3×10^{-12} and α^{'}/α<6.5×10^{-24} at 90% credible interval, respectively, were obtained.

Background: Cross-sectional evidence suggests females in late adolescence exhibit higher rates of post-traumatic stress symptoms (PTSS) than males and younger age groups. However, longitudinal evidence is limited, and underlying factors are not well understood. We investigated the emergence of sex differences in PTSS from childhood to adolescence in a large, longitudinal UK cohort, and tested whether these could be explained by overlap between PTSS and depressive symptoms, or onset of puberty., Methods: Trauma exposure and PTSS were assessed at ages 8, 10, 13 (parent-report) and 15 (self-report) years in a sub-sample of 9966 children and adolescents from the ALSPAC cohort-study. Analyses of PTSS focused on those who reported potential trauma-exposure at each time-point (ranged from n = 654 at 15 years to n = 1231 at 10 years). Age at peak-height velocity (APHV) was used as an indicator of pubertal timing., Results: There was no evidence of sex differences in PTSS at ages 8 and 10, but females were more likely to show PTSS at ages 13 (OR 1.54, p = 0.002) and 15 (OR 2.04, p = .001), even once symptoms related to depression were excluded. We found little evidence that the emergence of sex differences was related to pubertal timing (as indexed by APHV)., Conclusions: Results indicate that females show higher levels of PTSS in adolescence but not during childhood. The emergence of this sex difference does not seem to be explained by overlap with depressive symptoms, while the influence of pubertal status requires further investigation.

Objectives: There is an urgency to support Australian ED clinicians with real-time tools as the COVID-19 pandemic evolves. The COVID-19 Emergency Department (COVED) Quality Improvement Project has commenced and will provide flexible and responsive clinical tools to determine the predictors of key ED-relevant clinical outcomes., Methods: The COVED Project includes all adult patients presenting to a participating ED and meeting contemporary testing criteria for COVID-19. The dataset has been embedded in the electronic medical record and the COVED Registry has been developed., Results: Outcomes measured include being COVID-19 positive and requiring intensive respiratory support. Regression methodology will be used to generate clinical prediction tools., Conclusion: This project will support EDs during this pandemic., (© 2020 Australasian College for Emergency Medicine.)

Background: Both fatigue and sleep difficulties are common symptoms of mental health presentations such as depression and anxiety. Despite this, little is known about how psychologists in Child and Adolescent Mental Health Services (CAMHS) assess and treat these common symptoms., Method: Qualitative interviews with nine psychologists working in CAMHS analysed using thematic analysis., Results: Fatigue and sleep problems do not tend to be the focus of assessment because they are seen to be part of other presentations and not accorded priority. Psychologists struggled to differentiate fatigue from sleep problems, with greater clarity about sleep problems, which appear to be more routinely assessed. A number of barriers to addressing fatigue and sleep problems were identified, including lack of motivation from young people to make behavioural changes to address fatigue and/or sleep difficulties. Psychologists wished for more training, access to information for young people and families and more service integration with paediatric physical health settings., Conclusion: Sleep problems and fatigue may not be thoroughly assessed and addressed in CAMHS and are often conflated, with the focus on enquiring about sleep, not fatigue. Further research is required to elucidate whether the themes identified are more pervasive. Potential interventions include training and information provision.

Background: The latest version of the International Classification of Diseases (ICD-11) proposes a posttraumatic stress disorder (PTSD) diagnosis reduced to its core symptoms within the symptom clusters re-experiencing, avoidance and hyperarousal. Since children and adolescents often show a variety of internalizing and externalizing symptoms in the aftermath of traumatic events, the question arises whether such a conceptualization of the PTSD diagnosis is supported in children and adolescents. Furthermore, although dysfunctional posttraumatic cognitions (PTCs) appear to play an important role in the development and persistence of PTSD in children and adolescents, their function within diagnostic frameworks requires clarification., Methods: We compiled a large international data set of 2,313 children and adolescents aged 6 to 18 years exposed to trauma and calculated a network model including dysfunctional PTCs, PTSD core symptoms and depression symptoms. Central items and relations between constructs were investigated., Results: The PTSD re-experiencing symptoms strong or overwhelming emotions and strong physical sensations and the depression symptom difficulty concentrating emerged as most central. Items from the same construct were more strongly connected with each other than with items from the other constructs. Dysfunctional PTCs were not more strongly connected to core PTSD symptoms than to depression symptoms., Conclusions: Our findings provide support that a PTSD diagnosis reduced to its core symptoms could help to disentangle PTSD, depression and dysfunctional PTCs. Using longitudinal data and complementing between-subject with within-subject analyses might provide further insight into the relationship between dysfunctional PTCs, PTSD and depression., (© 2019 Association for Child and Adolescent Mental Health.)

Heart rate (HR) alterations in the immediate aftermath of trauma-exposure have been proposed to be potentially useful markers for child and adolescent posttraumatic stress disorder (PTSD). However, it is not yet clear if this holds true for measures taken more distal to the trauma, and no studies have investigated the predictive validity of more sensitive HR variability (HRV) indices. We recruited 76 parent-child pairs (child age 6 to 13 years) after the child experienced a traumatic event leading to presentation at a hospital emergency department. At 1-month post trauma (T1), HR recordings were obtained at rest, and while children verbally recounted their traumatic experience, both alone and together with a parent. Child post-traumatic stress symptoms (PTSS) were assessed concurrently (T1), and at 3 (T2) and 6-month (T3) follow-ups. We found that for T1, elevated mean HR during trauma narratives, but not at baseline, was positively associated with PTSS, with some evidence that HRV-indices were negatively cross-sectionally associated with PTSS. Furthermore, T1 HR indices predicted PTSS at T2 and partially at T3, although these effects did not hold when T1 PTSS were added to the model. Findings suggest that, consistent with the adult literature, HR indices in children may be a concurrent marker of higher PTSS and may be predictive of longer term distress. The findings encourage further investigations that track child HR and HRV in relation to PTSS over time after trauma, in order to examine how biological profiles evolve in those with persistent symptoms.

A discovery that neutrinos are Majorana fermions would have profound implications for particle physics and cosmology. The Majorana character of neutrinos would make possible the neutrinoless double-β (0νββ) decay, a matter-creating process without the balancing emission of antimatter. The GERDA Collaboration searches for the 0νββ decay of 76 Ge by operating bare germanium detectors in an active liquid argon shield. With a total exposure of 82.4 kg⋅year, we observe no signal and derive a lower half-life limit of T 1/2 > 0.9 × 10 26 years (90% C.L.). Our T 1/2 sensitivity, assuming no signal, is 1.1 × 10 26 years. Combining the latter with those from other 0νββ decay searches yields a sensitivity to the effective Majorana neutrino mass of 0.07 to 0.16 electron volts., (Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

The cell membrane (NCX) and mitochondrial (NCLX) Na + /Ca 2+ exchangers control Ca 2+ homeostasis. Eleven (out of twelve) ion-coordinating residues are highly conserved among eukaryotic and prokaryotic NCXs, whereas in NCLX, nine (out of twelve) ion-coordinating residues are different. Consequently, NCXs exhibit high selectivity for Na + and Ca 2+ , whereas NCLX can exchange Ca 2+ with either Na + or Li + . However, the underlying molecular mechanisms and physiological relevance remain unresolved. Here, we analyzed the NCX&#95;Mj-derived mutant NCLX&#95;Mj (with nine substituted residues) imitating the ion selectivity of NCLX. Site-directed fluorescent labeling and ion flux assays revealed the nearly symmetric accessibility of ions to the extracellular and cytosolic vestibules in NCLX&#95;Mj (K int  = 0.8-1.4), whereas the extracellular vestibule is predominantly accessible to ions (K int  = 0.1-0.2) in NCX&#95;Mj. HDX-MS (hydrogen-deuterium exchange mass-spectrometry) identified symmetrically rigidified core helix segments in NCLX&#95;Mj, whereas the matching structural elements are asymmetrically rigidified in NCX&#95;Mj. The HDX-MS analyses of ion-induced conformational changes and the mutational effects on ion fluxes revealed that the "Ca 2+ -site" (S Ca ) of NCLX&#95;Mj binds Na + , Li + , or Ca 2+ , whereas one or more additional Na + /Li + sites of NCLX&#95;Mj are incompatible with the Na + sites (S ext and S int ) of NCX&#95;Mj. Thus, the replacement of ion-coordinating residues in NCLX&#95;Mj alters not only the ion selectivity of NCLX&#95;Mj, but also the capacity and affinity for Na + /Li + (but not for Ca 2+ ) binding, bidirectional ion-accessibility, the response of the ion-exchange to membrane potential changes, and more. These structure-controlled functional features could be relevant for differential contributions of NCX and NCLX to Ca 2+ homeostasis in distinct sub-cellular compartments., (Copyright © 2018 Elsevier B.V. All rights reserved.)

The GERmanium Detector Array (Gerda) is a low background experiment located at the Laboratori Nazionali del Gran Sasso in Italy, which searches for neutrinoless double-beta decay of 76 Ge into 76 Se+2e - . Gerda has been conceived in two phases. Phase II, which started in December 2015, features several novelties including 30 new 76 Ge enriched detectors. These were manufactured according to the Broad Energy Germanium (BEGe) detector design that has a better background discrimination capability and energy resolution compared to formerly widely-used types. Prior to their installation, the new BEGe detectors were mounted in vacuum cryostats and characterized in detail in the Hades underground laboratory in Belgium. This paper describes the properties and the overall performance of these detectors during operation in vacuum. The characterization campaign provided not only direct input for Gerda Phase II data collection and analyses, but also allowed to study detector phenomena, detector correlations as well as to test the accuracy of pulse shape simulation codes., (© The Author(s) 2019.)

Prokaryotic and eukaryotic Na + /Ca 2+ exchangers (NCX) control Ca 2+ homeostasis. NCX orthologs exhibit up to 10 4 -fold differences in their turnover rates (k cat ), whereas the ratios between the cytosolic (cyt) and extracellular (ext) K m values (K int = K m Cyt /K m Ext ) are highly asymmetric and alike (K int ≤ 0.1) among NCXs. The structural determinants controlling a huge divergence in k cat at comparable K int remain unclear, although 11 (out of 12) ion-coordinating residues are highly conserved among NCXs. The crystal structure of the archaeal NCX (NCX&#95;Mj) was explored for testing the mutational effects of pore-allied and loop residues on k cat and K int . Among 55 tested residues, 26 mutations affect either k cat or K int , where two major groups can be distinguished. The first group of mutations (14 residues) affect k cat rather than K int . The majority of these residues (10 out of 14) are located within the extracellular vestibule near the pore center. The second group of mutations (12 residues) affect K int rather than k cat , whereas the majority of residues (9 out 12) are randomly dispersed within the extracellular vestibule. In conjunction with computational modeling-simulations and hydrogen-deuterium exchange mass-spectrometry (HDX-MS), the present mutational analysis highlights structural elements that differentially govern the intrinsic asymmetry and transport rates. The key residues, located at specific segments, can affect the characteristic features of local backbone dynamics and thus, the conformational flexibility of ion-transporting helices contributing to critical conformational transitions. The underlying mechanisms might have a physiological relevance for matching the response modes of NCX variants to cell-specific Ca 2+ and Na + signaling., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Purpose: Cancer of the prostate (CaP) is the leading cancer among men in sub-Saharan Africa (SSA). A substantial proportion of these men with CaP are diagnosed at late (usually incurable) stages, yet little is known about the etiology of CaP in SSA., Methods: We established the Men of African Descent and Carcinoma of the Prostate Network, which includes seven SSA centers partnering with five US centers to study the genetics and epidemiology of CaP in SSA. We developed common data elements and instruments, regulatory infrastructure, and biosample collection, processing, and shipping protocols. We tested this infrastructure by collecting epidemiologic, medical record, and genomic data from a total of 311 patients with CaP and 218 matched controls recruited at the seven SSA centers. We extracted genomic DNA from whole blood, buffy coat, or buccal swabs from 265 participants and shipped it to the Center for Inherited Disease Research (Baltimore, MD) and the Centre for Proteomics and Genomics Research (Cape Town, South Africa), where genotypes were generated using the UK Biobank Axiom Array., Results: We used common instruments for data collection and entered data into the shared database. Double-entered data from pilot participants showed a 95% to 98% concordance rate, suggesting that data can be collected, entered, and stored with a high degree of accuracy. Genotypes were obtained from 95% of tested DNA samples (100% from blood-derived DNA samples) with high concordance across laboratories., Conclusion: We provide approaches that can produce high-quality epidemiologic and genomic data in multicenter studies of cancer in SSA.

The developing world is seeing rapid growth in the availability of biological mass spectrometry (MS), particularly through core facilities. As proteomics and metabolomics becomes locally feasible for investigators in these nations, application areas associated with high burden in these nations, such as infectious disease, will see greatly increased research output. This article evaluates the rapid growth of MS in South Africa (currently approaching 20 laboratories) as a model for establishing MS core facilities in other nations of the developing world. Facilities should emphasize new services rather than new instruments. The reduction of the delays associated with reagent and other supply acquisition would benefit both facilities and the users who make use of their services. Instrument maintenance and repair, often mediated by an in-country business for an international vendor, is also likely to operate on a slower schedule than in the wealthiest nations. A key challenge to facilities in the developing world is educating potential facility users in how best to design experiments for proteomics and metabolomics, what reagents are most likely to introduce problematic artifacts, and how to interpret results from the facility. Here, we summarize the experience of 6 different institutions to raise the level of biological MS available to researchers in South Africa.

The GERDA experiment searches for the lepton-number-violating neutrinoless double-β decay of ^{76}Ge (^{76}Ge→^{76}Se+2e^{-}) operating bare Ge diodes with an enriched ^{76}Ge fraction in liquid argon. The exposure for broad-energy germanium type (BEGe) detectors is increased threefold with respect to our previous data release. The BEGe detectors feature an excellent background suppression from the analysis of the time profile of the detector signals. In the analysis window a background level of 1.0&#95;{-0.4}^{+0.6}×10^{-3}  counts/(keV kg yr) has been achieved; if normalized to the energy resolution this is the lowest ever achieved in any 0νββ experiment. No signal is observed and a new 90% C.L. lower limit for the half-life of 8.0×10^{25}  yr is placed when combining with our previous data. The expected median sensitivity assuming no signal is 5.8×10^{25}  yr.

Na + /Ca 2+ exchanger (NCX) proteins operate through the alternating access mechanism, where the ion-binding pocket is exposed in succession either to the extracellular or the intracellular face of the membrane. The archaeal NCX&#95;Mj ( Methanococcus jannaschii NCX) system was used to resolve the backbone dynamics in the inward-facing (IF) and outward-facing (OF) states by analyzing purified preparations of apo- and ion-bound forms of NCX&#95;Mj-WT and its mutant, NCX&#95;Mj-5L6-8. First, the exposure of extracellular and cytosolic vestibules to the bulk phase was evaluated as the reactivity of single cysteine mutants to a fluorescent probe, verifying that NCX&#95;Mj-WT and NCX&#95;Mj-5L6-8 preferentially adopt the OF and IF states, respectively. Next, hydrogen-deuterium exchange-mass spectrometry (HDX-MS) was employed to analyze the backbone dynamics profiles in proteins, preferentially adopting the OF (WT) and IF (5L6-8) states either in the presence or absence of ions. Characteristic differences in the backbone dynamics were identified between apo NCX&#95;Mj-WT and NCX&#95;Mj-5L6-8, thereby underscoring specific conformational patterns owned by the OF and IF states. Saturating concentrations of Na + or Ca 2+ specifically modify HDX patterns, revealing that the ion-bound/occluded states are much more stable (rigid) in the OF than in the IF state. Conformational differences observed in the ion-occluded OF and IF states can account for diversifying the ion-release dynamics and apparent affinity ( K m ) at opposite sides of the membrane, where specific structure-dynamic elements can effectively match the rates of bidirectional ion movements at physiological ion concentrations., (© 2017 by The American Society for Biochemistry and Molecular Biology, Inc.)

Members of the Ca(2+)/cation exchanger superfamily (Ca(2+)/CA) share structural similarities (including highly conserved ion-coordinating residues) while exhibiting differential selectivity for Ca(2+), Na(+), H(+), K(+), and Li(+). The archaeal Na(+)/Ca(2+) exchanger (NCX&#95;Mj) and its mammalian orthologs are highly selective for Na(+), whereas the mitochondrial ortholog (NCLX) can transport either Li(+) or Na(+) in exchange with Ca(2+). Here, structure-based replacement of ion-coordinating residues in NCX&#95;Mj resulted in a capacity for transporting either Na(+) or Li(+), similar to the case for NCLX. This engineered protein may serve as a model for elucidating the mechanisms underlying ion selectivity and ion-coupled alternating access in NCX and similar proteins.

Tissue-specific splice variants of Na(+)/Ca(2+) exchangers contain 2 Ca(2+)-binding regulatory domains (CBDs), CBD1 and CBD2. Ca(2+) interaction with CBD1 activates sodium-calcium exchangers (NCXs), and Ca(2+) binding to CBD2 alleviates Na(+)-dependent inactivation. A combination of mutually exclusive (A, B) and cassette (C-F) exons in CBD2 raises functionally diverse splice variants through unknown mechanisms. Here, the effect of exons on CBDs backbone dynamics were investigated in the 2-domain tandem (CBD12) of the brain, kidney, and cardiac splice variants by using hydrogen-deuterium exchange mass spectrometry and stopped-flow techniques. Mutually exclusive exons stabilize interdomain interactions in the apoprotein, which primarily predefines the extent of responses to Ca(2+) binding. Deuterium uptake levels were up to 20% lower in the cardiac vs. the brain CBD12, reveling that elongation of the CBD2 FG loop by cassette exons rigidifies the interdomain Ca(2+) salt bridge at the 2-domain interface, which secondarily modulates the Ca(2+)-bound states. In matching splice variants, the extent of Ca(2+)-induced rigidification correlates with decreased (up to 10-fold) Ca(2+) off rates, where the cardiac CBD12 exhibits the slowest Ca(2+) off rates. Collectively, structurally disordered/dynamic segments at mutually exclusive and cassette exons have local and distant effects on the folded structures nearby the Ca(2+) binding sites, which may serve as a structure-dynamic basis for splicing-dependent regulation of NCX., (© FASEB.)