Anthracyclines induce cardiotoxicity through a shared gene expression response signature.

TOP2 inhibitors (TOP2i) are effective drugs for breast cancer treatment. However, they can cause cardiotoxicity in some women. The most widely used TOP2i include anthracyclines (AC) Doxorubicin (DOX), Daunorubicin (DNR), Epirubicin (EPI), and the anthraquinone Mitoxantrone (MTX). It is unclear whether women would experience the same adverse effects from all drugs in this class, or if specific drugs would be preferable for certain individuals based on their cardiotoxicity risk profile. To investigate this, we studied the effects of treatment of DOX, DNR, EPI, MTX, and an unrelated monoclonal antibody Trastuzumab (TRZ) on iPSC-derived cardiomyocytes (iPSC-CMs) from six healthy females. All TOP2i induce cell death at concentrations observed in cancer patient serum, while TRZ does not. A sub-lethal dose of all TOP2i induces limited cellular stress but affects calcium handling, a function critical for cardiomyocyte contraction. TOP2i induce thousands of gene expression changes over time, giving rise to four distinct gene expression response signatures, denoted as TOP2i early-acute, early-sustained, and late response genes, and non-response genes. There is no drug- or AC-specific signature. TOP2i early response genes are enriched in chromatin regulators, which mediate AC sensitivity across breast cancer patients. However, there is increased transcriptional variability between individuals following AC treatments. To investigate potential genetic effects on response variability, we first identified a reported set of expression quantitative trait loci (eQTLs) uncovered following DOX treatment in iPSC-CMs. Indeed, DOX response eQTLs are enriched in genes that respond to all TOP2i. Next, we identified 38 genes in loci associated with AC toxicity by GWAS or TWAS. Two thirds of the genes that respond to at least one TOP2i, respond to all ACs with the same direction of effect. Our data demonstrate that TOP2i induce thousands of shared gene expression changes in cardiomyocytes, including genes near SNPs associated with inter-individual variation in response to DOX treatment and AC-induced cardiotoxicity.

Evolutionarily Young African Rhinoceros Gammaretroviruses.

High-throughput sequences were generated from DNA and cDNA from four Southern white rhinoceros (Ceratotherium simum simum) located in the Taronga Western Plain Zoo in Australia. Virome analysis identified reads that were similar to Mus caroli endogenous gammaretrovirus (McERV). Previous analysis of perissodactyl genomes did not recover gammaretroviruses. Our analysis, including the screening of the updated white rhinoceros (Ceratotherium simum) and black rhinoceros (Diceros bicornis) draft genomes identified high-copy orthologous gammaretroviral ERVs. Screening of Asian rhinoceros, extinct rhinoceros, domestic horse, and tapir genomes did not identify related gammaretroviral sequences in these species. The newly identified proviral sequences were designated SimumERV and DicerosERV for the white and black rhinoceros retroviruses, respectively. Two long terminal repeat (LTR) variants (LTR-A and LTR-B) were identified in the black rhinoceros, with different copy numbers associated with each (n = 101 and 373, respectively). Only the LTR-A lineage (n = 467) was found in the white rhinoceros. The African and Asian rhinoceros lineages diverged approximately 16 million years ago. Divergence age estimation of the identified proviruses suggests that the exogenous retroviral ancestor of the African rhinoceros ERVs colonized their genomes within the last 8 million years, a result consistent with the absence of these gammaretroviruses from Asian rhinoceros and other perissodactyls. The black rhinoceros germ line was colonized by two lineages of closely related retroviruses and white rhinoceros by one. Phylogenetic analysis indicates a close evolutionary relationship with ERVs of rodents including sympatric African rats, suggesting a possible African origin of the identified rhinoceros gammaretroviruses. IMPORTANCE Rhinoceros genomes were thought to be devoid of gammaretroviruses, as has been determined for other perissodactyls (horses, tapirs, and rhinoceros). While this may be true of most rhinoceros, the African white and black rhinoceros genomes have been colonized by evolutionarily young gammaretroviruses (SimumERV and DicerosERV for the white and black rhinoceros, respectively). These high-copy endogenous retroviruses (ERVs) may have expanded in multiple waves. The closest relative of SimumERV and DicerosERV is found in rodents, including African endemic species. Restriction of the ERVs to African rhinoceros suggests an African origin for the rhinoceros gammaretroviruses.

Functional and clinical studies reveal pathophysiological complexity of CLCN4-related neurodevelopmental condition.

Missense and truncating variants in the X-chromosome-linked CLCN4 gene, resulting in reduced or complete loss-of-function (LOF) of the encoded chloride/proton exchanger ClC-4, were recently demonstrated to cause a neurocognitive phenotype in both males and females. Through international clinical matchmaking and interrogation of public variant databases we assembled a database of 90 rare CLCN4 missense variants in 90 families: 41 unique and 18 recurrent variants in 49 families. For 43 families, including 22 males and 33 females, we collated detailed clinical and segregation data. To confirm causality of variants and to obtain insight into disease mechanisms, we investigated the effect on electrophysiological properties of 59 of the variants in Xenopus oocytes using extended voltage and pH ranges. Detailed analyses revealed new pathophysiological mechanisms: 25% (15/59) of variants demonstrated LOF, characterized by a "shift" of the voltage-dependent activation to more positive voltages, and nine variants resulted in a toxic gain-of-function, associated with a disrupted gate allowing inward transport at negative voltages. Functional results were not always in line with in silico pathogenicity scores, highlighting the complexity of pathogenicity assessment for accurate genetic counselling. The complex neurocognitive and psychiatric manifestations of this condition, and hitherto under-recognized impacts on growth, gastrointestinal function, and motor control are discussed. Including published cases, we summarize features in 122 individuals from 67 families with CLCN4-related neurodevelopmental condition and suggest future research directions with the aim of improving the integrated care for individuals with this diagnosis.

Poor compliance and exemptions facilitate ongoing deforestation.

Many nations are struggling to reduce deforestation, despite having extensive environmental protection laws in place and commitments to international agreements that address the biodiversity and climate crises. We developed a novel framework to quantify the extent to which contemporary deforestation is being captured under national and subnational laws. We then applied this framework to northern Australia as a case study, a development and deforestation hotspot with ecosystems of global significance. First, deforestation may be compliant under all relevant legislation, either through assessment and approval or because of exemptions in the legislation. Second, deforestation may be compliant under at least one relevant law, but not all. Third, there may be no evidence of deforestation assessment or exemption from assessment, despite their apparent requirement, which could mean the deforestation is potentially noncompliant. Finally, deforestation may occur in an area or under circumstances that are beyond the intended scope of any relevant legislation. All deforestation that we analyzed was hypothetically covered by one or more laws. However, 65% of deforestation was potentially noncompliant with at least one law. Because multiple laws could be relevant to a given clearing event, the majority of clearing was still compliant with at least one law, but of these events, only a small proportion was explicitly approved (19%). The remaining were permitted under various exemptions. Of all the legislation we analyzed, most of the exempt clearing occurred under one subnational law and most potentially noncompliant clearing occurred under one national law. Our results showed that even a nation with a suite of mature environmental protection laws is falling well short of achieving international commitments regarding deforestation. Our framework can be used to pinpoint the pathways of policy change required for nations to align local laws with these international accords.

Cumplimiento deficiente y exenciones que facilitan la deforestación Resumen Muchos países luchan por reducir la deforestación, a pesar de contar con amplias leyes de protección del medio ambiente y de sus compromisos con los acuerdos internacionales que abordan la crisis de la biodiversidad y el clima. Por ello desarrollamos un novedoso marco para cuantificar hasta qué punto la deforestación actual se recopila en las leyes nacionales y subnacionales. Después aplicamos este marco al norte de Australia como estudio de caso, un punto caliente de desarrollo y deforestación con ecosistemas de importancia mundial. En primer lugar, la deforestación puede ser compatible con toda la legislación pertinente, ya sea mediante evaluación y aprobación o debido a exenciones en la legislación. En segundo lugar, la deforestación puede ser compatible con al menos una ley pertinente, pero no con todas. En tercer lugar, puede que no haya pruebas de evaluación de la deforestación o de exención de la evaluación, a pesar de su aparente requisito, lo que podría significar que la deforestación es potencialmente no conforme. Por último, la deforestación puede producirse en una zona o en circunstancias que quedan fuera del ámbito de aplicación de la legislación pertinente. Toda la deforestación analizada era hipotéticamente legal según una o más leyes. Sin embargo, el 65% de la deforestación no cumplía potencialmente al menos una ley. Dado que varias leyes podían ser pertinentes para un determinado caso de deforestación, la mayoría de las deforestaciones seguían cumpliendo al menos una ley, pero de estos casos, sólo una pequeña proporción estaba explícitamente aprobada (19%). El resto estaba permitido en virtud de diversas exenciones. De toda la legislación que analizamos, la mayor parte de la compensación exenta se produjo en virtud de una ley subnacional y la mayor parte de la compensación potencialmente no conforme se produjo en virtud de una ley nacional. Nuestros resultados muestran que incluso un país con un conjunto de leyes maduras de protección del medio ambiente está muy lejos de cumplir los compromisos internacionales en materia de deforestación. Nuestro marco puede utilizarse para determinar las vías de cambio político necesarias para que los países adapten su legislación local a los acuerdos internacionales.

Niche-based approach to explore the impacts of environmental disturbances on biodiversity.

Globally, species are increasingly at risk from compounding threatening processes, an increasingly prominent driver of which is environmental disturbances. To facilitate effective conservation efforts following such events, methods that evaluate potential impacts across multiple species and provide landscape-scale information are needed to guide targeted responses. Often, the geographic overlap between a disturbance and species' distribution is calculated and then used as a proxy for potential impact. However, such methods do not account for the important influence of environmental heterogeneity throughout species' ranges. To address this shortcoming, we quantified the effects of environmental disturbances on species' environmental niche space. Using the Australian 2019 and 2020 Black Summer fires as a case study, we applied a niche-centric approach to examine the potential impacts of these fires on 387 vertebrate species. We examined the utility of established and novel niche metrics to assess the potential impacts of large-scale disturbance events on species by comparing the potential effects of the fires as determined by our various niche measures to those derived from geographic-based measures of impact. We examined the quality of environmental space affected by the disturbance by quantifying the position in niche space where the disturbance occurred (center or margin), the uniqueness of the environmental space that was burned, and the degree to which the remaining, unburned portion of the niche differed from a species' original prefire niche. There was limited congruence between the proportion of geographic and niche space affected, which showed that geographic-based approaches in isolation may have underestimated the impact of the fires for 56% of modeled species. For each species, when combined, these metrics provided a greater indication of postdisturbance recovery potential than geographic-based measures alone. Accordingly, the integration of niche-based analyses into conservation assessments following large-scale disturbance events will lead to a more nuanced understanding of potential impacts and guide more informed and effective conservation actions.

Estrategia basada en los nichos para explorar el impacto de la perturbación ambiental sobre la biodiversidad Resumen En todo el mundo, las especies corren un riesgo cada vez mayor de verse amenazadas por procesos combinados, entre los que destacan las perturbaciones ambientales. Para facilitar una labor de conservación eficaz después de estos fenómenos, se necesitan métodos que evalúen el impacto potencial en varias especies y proporcionen información a escala de paisaje para orientar las respuestas específicas. A menudo, se calcula el traslape geográfico entre una perturbación y la distribución de las especies y se utiliza como indicador del impacto potencial. Sin embargo, estos métodos no tienen en cuenta la influencia importante de la heterogeneidad ambiental en toda el área de distribución de las especies. Para abordar esta deficiencia, cuantificamos los efectos de las perturbaciones ambientales en el espacio del nicho ambiental de las especies. Usamos los incendios australianos de Black Summer de 2019 y 2020 como caso de estudio y aplicamos un enfoque centrado en el nicho para examinar los impactos potenciales de estos incendios en 387 especies de vertebrados. Analizamos la utilidad de las métricas nuevas y establecidas de nicho para evaluar los impactos potenciales de los eventos de perturbación a gran escala para las especies con la comparación de los efectos potenciales de los incendios determinados por nuestras diversas medidas de nicho con los derivados de las medidas de impacto basadas en la geografía. Examinamos la calidad del espacio ambiental afectado por la perturbación al cuantificar la posición en el espacio del nicho donde se produjo la perturbación (centro o margen), la singularidad del espacio ambiental que se quemó y el grado en que la parte restante no quemada del nicho difería del nicho original de una especie antes del incendio. Hubo una congruencia limitada entre la proporción del espacio geográfico y del nicho afectado, lo que demostró que los enfoques geográficos aislados pueden subestimar el impacto de los incendios para el 56% de las especies modeladas. Para cada especie, estas métricas combinadas proporcionaron una mayor indicación del potencial de recuperación tras las perturbaciones que las medidas geográficas por sí solas. Por lo tanto, la integración de los análisis basados en nichos en las evaluaciones de conservación tras perturbaciones a gran escala permitirá comprender mejor los impactos potenciales y orientar las acciones de conservación de manera más informada y eficaz.

Acceptability and feasibility of screening with a pediatric care provider-led social determinants of health identification tool.

BACKGROUND: Complex social determinants of health may not be easily recognized by health care providers and pose a unique challenge in the vulnerable pediatric population where patients may not be able to advocate for themselves. The goal of this study was to examine the acceptability and feasibility of health care providers using an integrated brief pediatric screening tool in primary care and hospital settings. METHODS: The framework of the Child and Adolescent Needs and Strengths (CANS) and Pediatric Intermed tools was used to inform the selection of items for the 9-item Child and Adolescent Needs and Strengths-Pediatric Complexity Indicator (CANS-PCI). The tool consisted of three domains: biological, psychological, and social. Semi-structured interviews were conducted with health care providers in pediatric medical facilities in Ottawa, Canada. A low inference and iterative thematic synthesis approach was used to analyze the qualitative interview data specific to acceptability and feasibility. RESULTS: Thirteen health care providers participated in interviews. Six overarching themes were identified: acceptability, logistics, feasibility, pros/cons, risk, and privacy. Overall, participants agreed that a routine, trained provider-led pediatric tool for the screening of social determinants of health is important (n = 10, 76.9%), acceptable (n = 11; 84.6%), and feasible (n = 7, 53.8%). INTERPRETATION: Though the importance of social determinants of health are widely recognized, there are limited systematic methods of assessing, describing, and communicating amongst health care providers about the biomedical and psychosocial complexities of pediatric patients. Based on this study's findings, implementation of a brief provider-led screening tool into pediatric care practices may contribute to this gap.

Youth, caregiver and healthcare professional perspectives on planning the implementation of a trauma-informed care programme: A qualitative study.

AIMS: To explore youth, caregiver and staff perspectives on their vision of trauma-informed care, and to identify and understand potential considerations for the implementation of a trauma-informed care programme in an inpatient mental health unit within a paediatric hospital. DESIGN AND METHODS: We applied the Interpretive Description approach, guided by complexity theory and the Implementation Roadmap, and used Applied Thematic Analysis methods. FINDINGS: Twenty-five individuals participated in individual or group interviews between March and June 2022, including 21 healthcare professionals, 3 youth and 1 caregiver. We identified two overarching themes. The first theme, 'Understanding and addressing the underlying reasons for distress', related to participants' understanding and vision of TIC in the current setting comprising: (a) 'Participants' understanding of TIC'; (b) 'Trauma screening and trauma processing within TIC'; (c) 'Taking "a more individualized approach"'; (d) 'Unit programming'; and (e) "Connecting to the community". The second theme, 'Factors that support or limit successful TIC implementation' comprises: (a) 'The need for a broad "cultural shift"'; (b) 'The physical environment on the unit'; and (c) 'Factors that may limit successful implementation'. CONCLUSION: We identified five key domains to consider within trauma-informed care implementation: (a) the centrality of engagement with youth, caregivers and staff in trauma-informed care delivery and implementation, (b) trauma-informed care core programme components, (c) factors that may support or limit success in implementing trauma-informed care within the mental health unit and (d) hospital-wide and (e) the importance of intersectoral collaboration (partnering with external organizations and sectors). IMPACT: When implementing TIC, there is an ongoing need to increase clarity regarding TIC interventions and implementation initiatives. Youth, caregiver and healthcare professional participants shared considerations important for planning the delivery and implementation of trauma-informed care in their setting. We identified five key domains to consider within trauma-informed care implementation: (a) the centrality of relational engagement, (b) trauma-informed care programme components, (c) factors that may support or limit successful implementation of trauma-informed care within the mental health unit and (d) hospital-wide and (e) the importance of intersectoral collaboration. Organizations wishing to implement trauma-informed care should consider ongoing engagement with all relevant knowledge user groups throughout the process. REPORTING METHOD: Standards for Reporting Qualitative Research (SRQR). PATIENT OR PUBLIC CONTRIBUTION: The local hospital research institute's Patient and Family Advisory Committee reviewed the draft study methods and provided feedback.

PHARMACOKINETIC PROFILES OF ORAL PHENYLBUTAZONE, MELOXICAM, AND FIROCOXIB IN SOUTHERN BLACK RHINOCEROS (DICEROS BICORNIS MINOR).

The pharmacokinetic profile of selected NSAIDs in southern black rhinoceros (Diceros bicornis minor) were studied. Phenylbutazone (PBZ), meloxicam (MEL), and firocoxib (FIR) were administered orally to five captive, black rhinoceros, and blood was collected at predetermined time points for NSAID quantification and noncompartmental pharmacokinetic (PK) analysis. Phenylbutazone 4.0 mg/kg PO q12h for three doses, MEL 0.3 mg/kg PO q24h administered twice, and a single oral dose of FIR 0.1 mg/kg, were tested with a minimum washout time of 2 wk. PBZ reached a median (range) peak concentration (Cmax) of 9.42 (2.74-11.5) g/ml at a mean (range) time (Tmax) of 6.00 (4.00 to >12.00) h, and the median (range) elimination half-life (T1/2) was 6.07 (3.95-6.49) h. Phenylbutazone pharmacokinetic parameters for black rhinoceros in this study were similar to domestic horses. Meloxicam reached a median (range) Cmax of 0.576 (0.357-0.655) µg/ml at a median (range) time (Tmax) of 6.00 (4.00-12.00) h; the median (range) T1/2 of MEL was 14.0 (12.4-17.9) h. These results demonstrate that once-daily administration of MEL at 0.3 mg/kg resulted in a serum concentration of greater than 0.200 µg/ml from 2 to 24 h in four animals, which is within the analgesic range (0.200-0.400 µg/ml) for this drug in other species postulated by other studies. A single dose of firocoxib (0.1 mg/kg) reached a median (range) peak concentration (Cmax) of 15.7 (9.65-17.3) ng/ml at a median (range) Tmax of 4.00 (4.00-6.00) h. The median (range) elimination T1/2 of FIR was 4.96 (4.47-6.51) h, which is faster than in the horse. The data suggest that extrapolation from equine FIR dosage recommendations is inappropriate for black rhinoceros.

Savoir détecter l'exposition des enfants à la violence entre partenaires intimes, qu'elle soit présumée ou divulguée, et savoir intervenir.

L'exposition des enfants à la violence entre partenaires intimes (EEVPI), qu'il s'agisse des parents ou d'autres proches, représente près de la moitié de tous les cas qui font l'objet d'une enquête et sont corroborés par les services de protection de l'enfance du Canada. Les atteintes affectives, physiques et comportementales associées à l'EEVPI sont semblables aux effets d'autres formes de maltraitance envers les enfants. Il peut être difficile d'établir quels enfants et adolescents sont exposés à la violence entre partenaires intimes (VPI) en raison des comportements non spécifiques parfois associés à une telle exposition, de même que de la stigmatisation et du secret entourant souvent ce type de violence. Par ailleurs, une intervention en toute sécurité auprès des enfants et des adolescents chez qui on présume une exposition à la VPI peut être compliquée par la nécessité d'également tenir compte de la sécurité et du bien-être d'un proche non contrevenant. Le présent document de principes propose une approche fondée sur des données probantes mise au point par le projet VEGA (Violence, Evidence, Guidance, Action ou violence, données probantes, conseils, action) pour détecter l'exposition des enfants et des adolescents à la VPI et intervenir en toute sécurité auprès d'eux.

Recognizing and responding to children with suspected exposure to intimate partner violence between caregivers.

Children's exposure to intimate partner violence (CEIPV) between parents and other caregivers accounts for nearly half of all cases investigated and substantiated by child welfare authorities in Canada. The emotional, physical, and behavioural impairments associated with CEIPV are similar to effects of other forms of child maltreatment. The identification of children and youth who have been exposed to intimate partner violence (IPV) can be challenging due to the non-specific behaviours sometimes associated with such exposure, and the stigma and secrecy that often characterize IPV. Also, responding safely to children and youth with suspected CEIPV can be complicated by the need to consider the safety and well-being of a non-offending caregiver. This position statement presents an evidence-informed approach developed by the Violence, Evidence, Guidance, Action (VEGA) Project for the safe recognition and response to children and youth who are suspected of being exposed to IPV.

Identifying child maltreatment during virtual medical appointments through the COVID-19 pandemic: A physician-based survey.

Background: Throughout the COVID-19 pandemic there has been a documented decline in reports to child protective services, despite an increased incidence of child maltreatment. This is concerning for increasing missed cases. This study aims to examine if and how Canadian paediatricians are identifying maltreatment in virtual medical appointments. Methods: A survey was sent through the Canadian Paediatric Surveillance Program (CPSP) to 2770 practicing general and subspecialty paediatricians. Data was collected November 2021 to January 2022. Results: With a 34% (928/2770) response rate, 704 surveys were eligible for analysis. At least one case of child maltreatment was reported by 11% (78/700) of respondents following a virtual appointment. The number of cases reported was associated with years in medical practice (P = 0.026) but not with the volume (P = 0.735) or prior experience (P = 0.127) with virtual care, or perceived difficulty in identifying cases virtually (Cramer's V = 0.096). The most common factors triggering concern were the presence of social stressors, or a clear disclosure. The virtual physical exam was not contributory. Nearly one quarter (24%, 34/143) required a subsequent in-person appointment prior to reporting the case and 32% (207/648) reported concerns that a case had been identified late, or missed, following a virtual appointment. Some commented that clear harm resulted. Conclusions: Many barriers to detecting child maltreatment were identified by paediatricians who used virtual care. This survey reveals that virtual care may be an important factor in missed cases of child maltreatment and may present challenges to timely identification.

RLIM Is a Candidate Dosage-Sensitive Gene for Individuals with Varying Duplications of Xq13, Intellectual Disability, and Distinct Facial Features.

Interpretation of the significance of maternally inherited X chromosome variants in males with neurocognitive phenotypes continues to present a challenge to clinical geneticists and diagnostic laboratories. Here we report 14 males from 9 families with duplications at the Xq13.2-q13.3 locus with a common facial phenotype, intellectual disability (ID), distinctive behavioral features, and a seizure disorder in two cases. All tested carrier mothers had normal intelligence. The duplication arose de novo in three mothers where grandparental testing was possible. In one family the duplication segregated with ID across three generations. RLIM is the only gene common to our duplications. However, flanking genes duplicated in some but not all the affected individuals included the brain-expressed genes NEXMIF, SLC16A2, and the long non-coding RNA gene FTX. The contribution of the RLIM-flanking genes to the phenotypes of individuals with different size duplications has not been fully resolved. Missense variants in RLIM have recently been identified to cause X-linked ID in males, with heterozygous females typically having normal intelligence and highly skewed X chromosome inactivation. We detected consistent and significant increase of RLIM mRNA and protein levels in cells derived from seven affected males from five families with the duplication. Subsequent analysis of MDM2, one of the targets of the RLIM E3 ligase activity, showed consistent downregulation in cells from the affected males. All the carrier mothers displayed normal RLIM mRNA levels and had highly skewed X chromosome inactivation. We propose that duplications at Xq13.2-13.3 including RLIM cause a recognizable but mild neurocognitive phenotype in hemizygous males.

Evaluating the impact of biodiversity offsetting on native vegetation.

Biodiversity offsetting is a globally influential policy mechanism for reconciling trade-offs between development and biodiversity loss. However, there is little robust evidence of its effectiveness. We evaluated the outcomes of a jurisdictional offsetting policy (Victoria, Australia). Offsets under Victoria's Native Vegetation Framework (2002-2013) aimed to prevent loss and degradation of remnant vegetation, and generate gains in vegetation extent and quality. We categorised offsets into those with near-complete baseline woody vegetation cover ("avoided loss", 2702 ha) and with incomplete cover ("regeneration", 501 ha), and evaluated impacts on woody vegetation extent from 2008 to 2018. We used two approaches to estimate the counterfactual. First, we used statistical matching on biophysical covariates: a common approach in conservation impact evaluation, but which risks ignoring potentially important psychosocial confounders. Second, we compared changes in offsets with changes in sites that were not offsets for the study duration but were later enrolled as offsets, to partially account for self-selection bias (where landholders enrolling land may have shared characteristics affecting how they manage land). Matching on biophysical covariates, we estimated that regeneration offsets increased woody vegetation extent by 1.9%-3.6%/year more than non-offset sites (138-180 ha from 2008 to 2018) but this effect weakened with the second approach (0.3%-1.9%/year more than non-offset sites; 19-97 ha from 2008 to 2018) and disappeared when a single outlier land parcel was removed. Neither approach detected any impact of avoided loss offsets. We cannot conclusively demonstrate whether the policy goal of 'net gain' (NG) was achieved because of data limitations. However, given our evidence that the majority of increases in woody vegetation extent were not additional (would have happened without the scheme), a NG outcome seems unlikely. The results highlight the importance of considering self-selection bias in the design and evaluation of regulatory biodiversity offsetting policy, and the challenges of conducting robust impact evaluations of jurisdictional biodiversity offsetting policies.

Accelerated shifts in terrestrial life zones under rapid climate change.

Rapid climate change is impacting biodiversity, ecosystem function, and human well-being. Though the magnitude and trajectory of climate change are becoming clearer, our understanding of how these changes reshape terrestrial life zones-distinct biogeographic units characterized by biotemperature, precipitation, and aridity representing broad-scale ecosystem types-is limited. To address this gap, we used high-resolution historical climatologies and climate projections to determine the global distribution of historical (1901-1920), contemporary (1979-2013), and future (2061-2080) life zones. Comparing the historical and contemporary distributions shows that changes from one life zone to another during the 20th century impacted 27 million km2 (18.3% of land), with consequences for social and ecological systems. Such changes took place in all biomes, most notably in Boreal Forests, Temperate Coniferous Forests, and Tropical Coniferous Forests. Comparing the contemporary and future life zone distributions shows the pace of life zone changes accelerating rapidly in the 21st century. By 2070, such changes would impact an additional 62 million km2 (42.6% of land) under "business-as-usual" (RCP8.5) emissions scenarios. Accelerated rates of change are observed in hundreds of ecoregions across all biomes except Tropical Coniferous Forests. While only 30 ecoregions (3.5%) had over half of their areas change to a different life zone during the 20th century, by 2070 this number is projected to climb to 111 ecoregions (13.1%) under RCP4.5 and 281 ecoregions (33.2%) under RCP8.5. We identified weak correlations between life zone change and threatened vertebrate richness, levels of vertebrate endemism, cropland extent, and human population densities within ecoregions, illustrating the ubiquitous risks of life zone changes to diverse social-ecological systems. The accelerated pace of life zone changes will increasingly challenge adaptive conservation and sustainable development strategies that incorrectly assume current ecological patterns and livelihood provisioning systems will persist.

How to prioritize species recovery after a megafire.

Due to climate change, megafires are increasingly common and have sudden, extensive impacts on many species over vast areas, leaving decision makers uncertain about how best to prioritize recovery. We devised a decision-support framework to prioritize conservation actions to improve species outcomes immediately after a megafire. Complementary locations are selected to extend recovery actions across all fire-affected species' habitats. We applied our method to areas burned in the 2019-2020 Australian megafires and assessed its conservation advantages by comparing our results with outcomes of a site-richness approach (i.e., identifying areas that cost-effectively recover the most species in any one location). We found that 290 threatened species were likely severely affected and will require immediate conservation action to prevent population declines and possible extirpation. We identified 179 subregions, mostly in southeastern Australia, that are key locations to extend actions that benefit multiple species. Cost savings were over AU$300 million to reduce 95% of threats across all species. Our complementarity-based prioritization also spread postfire management actions across a wider proportion of the study area compared with the site-richness method (43% vs. 37% of the landscape managed, respectively) and put more of each species' range under management (average 90% vs. 79% of every species' habitat managed). In addition to wildfire response, our framework can be used to prioritize conservation actions that will best mitigate threats affecting species following other extreme environmental events (e.g., floods and drought).

Debido al cambio climático, los mega incendios son cada vez más comunes y tienen un impacto repentino y extenso sobre muchas especies en inmensas superficies, lo que deja a los tomadores de decisiones con incertidumbre sobre cuál es la mejor manera de priorizar la recuperación. Diseñamos un marco de apoyo a las decisiones para priorizar las acciones de conservación para mejorar los resultados para las especies inmediatamente después de un mega incendio. Para esto, se seleccionan localidades complementarias para extender las acciones de recuperación por todos los hábitats de las especies afectadas por el incendio. Aplicamos nuestro método a las áreas afectadas por los mega incendios de 2019-2020 en Australia y analizamos las ventajas de conservación del método mediante la comparación entre nuestros resultados y aquellos de un enfoque en la riqueza de especies (es decir, la identificación de las áreas que recuperan de manera rentable la mayor cantidad de especies en cualquier localidad única). Encontramos que 290 especies amenazadas estuvieron probablemente afectadas de manera severa y requerirán acciones inmediatas de conservación para prevenir la declinación poblacional y la posible eliminación. Identificamos 179 subregiones, la mayoría en el sureste de Australia, que son localidades clave para extender las acciones que benefician a muchas especies. El ahorro en los gastos fue de más de AU$300 millones para reducir el 95% de las amenazas para todas las especies. Nuestra priorización basada en la complementariedad también extendió las acciones de manejo posterior al incendio a una mayor proporción del área de estudio en comparación con el método de riqueza de especies (43% versus 37% del paisaje gestionado, respectivamente) y colocó más de la distribución de cada especie bajo manejo (en promedio 90% versus 79% del hábitat manejado de cada especie). Además de la respuesta a los incendios, nuestro marco puede usarse para priorizar las acciones de conservación que mitiguen de mejor manera las amenazas que afectan a las especies después de otros eventos ambientales extremos (p. ej., inundaciones y sequía).

Family Quality of Life Perceived by Mothers of Children with ASD and ADHD.

Existing research has compared Family Quality of Life (FQOL) in autism spectrum disorder (ASD) populations and typically developing populations but has not yet explored differences in FQOL across ASD, attention-deficit/hyperactivity disorder (ADHD), and comorbid ASD and ADHD populations (ASD + ADHD). In the present study, 117 North American mothers of 92 sons and 25 daughters (ages 6-11) with ASD, ADHD, or ASD + ADHD completed an online survey exploring FQOL. An ANOVA failed to show group differences in overall FQOL, however, mothers of children with ASD + ADHD reported significantly lower family Emotional Well-being than mothers of children with ASD only. The results of this study provide insight into FQOL in families of children with ASD and/or ADHD. Greater research is needed in this area to understand how mothers of children with ASD, ADHD, or ASD + ADHD experience FQOL. The COVID-19 pandemic, which ran concurrent with this study, potentially influenced results.

La négligence en matière de soins médicaux : travailler auprès des enfants, des adolescents et des familles.

Les soins de santé sont un droit fondamental pour tous les enfants. Lorsque les besoins de santé de l'enfant ne sont pas respectés, quelle qu'en soit la raison, les professionnels de la santé doivent réfléchir aux obstacles en cause et aux processus nécessaires pour trouver des solutions. Des obstacles sociaux, économiques ou autres peuvent empêcher les parents d'accéder aux soins pour leur enfant. Il arrive que les avis, les priorités ou les valeurs des professionnels de la santé de l'enfant divergent de ceux des parents, ce qui compromet les soins à l'enfant. Dans certains cas, l'abstention des personnes qui s'occupent de l'enfant à assurer les soins nécessaires peut être considérée comme de la négligence en matière de soins médicaux. Des habiletés et des connaissances particulières peuvent aider les professionnels de la santé à éviter de telles situations et à collaborer avec efficacité avec la famille lorsque ces situations se produisent. Le présent document de principes offre une approche que peuvent utiliser les professionnels de la santé pour promouvoir l'intérêt supérieur, le bien-être et la sécurité des enfants ou des adolescents vulnérables à la négligence en matière de soins médicaux.

Medical neglect: Working with children, youth, and families.

All children have a basic right to health care. When a child's health care needs are not met, for any reason, health care providers (HCPs) must consider the barriers involved and the processes required to resolve the situation. Social, economic, or other barriers can prevent parents from accessing care for their child. Sometimes differing opinions, priorities, or values, between a child's HCPs and parents come to impede the child receiving needed medical care. In some cases, caregiver failure to ensure needed care may be considered medical neglect. Specific skills and knowledge can help HCPs to prevent such situations from arising, and to work effectively with the family if they do. This statement offers an approach that HCPs can use to promote the best interests, well-being, and safety of children or youth at risk for medical neglect.

Development of Pediatric Hospital Position Statements on Medical and Non-Prescribed Cannabis.

The pediatric demand for medical cannabis has been increasing. This has necessitated the need to develop hospital statements and policies at the Children's Hospital of Eastern Ontario (CHEO) to provide clinicians and administrators with recommendations for working with patients and caregivers seeking the use of prescribed or non-prescribed cannabis. Through a structured working group, two hospital position statements and policies on the pediatric use of medical and non-prescribed cannabis were developed for patients served at CHEO. In highlighting the procedural framework and position statements, these policies provide valuable recommendations and resources to other hospitals seeking to develop similar administrative action. In a changing medical landscape, best practices and policies are needed for hospital administrators on the patient use of medical and non-prescribed cannabis. The authors highlight recent policy work and position statements from CHEO, providing a valuable reference to all pediatric and adult hospitals.

Impact of regulatory variation across human iPSCs and differentiated cells.

Induced pluripotent stem cells (iPSCs) are an essential tool for studying cellular differentiation and cell types that are otherwise difficult to access. We investigated the use of iPSCs and iPSC-derived cells to study the impact of genetic variation on gene regulation across different cell types and as models for studies of complex disease. To do so, we established a panel of iPSCs from 58 well-studied Yoruba lymphoblastoid cell lines (LCLs); 14 of these lines were further differentiated into cardiomyocytes. We characterized regulatory variation across individuals and cell types by measuring gene expression levels, chromatin accessibility, and DNA methylation. Our analysis focused on a comparison of inter-individual regulatory variation across cell types. While most cell-type-specific regulatory quantitative trait loci (QTLs) lie in chromatin that is open only in the affected cell types, we found that 20% of cell-type-specific regulatory QTLs are in shared open chromatin. This observation motivated us to develop a deep neural network to predict open chromatin regions from DNA sequence alone. Using this approach, we were able to use the sequences of segregating haplotypes to predict the effects of common SNPs on cell-type-specific chromatin accessibility.