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ABSTRACT With organizations seeking faster, cheaper, and smarter ways of delivering higher quality software, many are looking towards generative artificial intelligence (AI) to drive efficiencies and innovation throughout the software development lifecycle. However, generative AI can suffer from several fundamental issues, including a lack of traceability in concept generation and decision‐making, the potential for making incorrect inferences (hallucinations), shortcomings in response quality, and bias. Quality engineering (QE) has long been utilized to enable more efficient and effective delivery of higher quality software. A core aspect of QE is adopting quality models to support various lifecycle practices, including requirements definition, quality risk assessments, and testing. In this position paper, we introduce the application of QE to AI systems, consider shortcomings in existing AI quality models from the International Organization for Standardization (ISO), and propose extensions to ISO models based on the results of a survey. We also reflect on skills that IT graduates may need in the future, to support delivery of better‐quality AI. [ABSTRACT FROM AUTHOR]

Activity-dependent protein synthesis is crucial for long-lasting forms of synaptic plasticity. However, our understanding of translational mechanisms controlling GABAergic synapses is limited. One distinct form of inhibitory long-term potentiation (iLTP) enhances postsynaptic clusters of GABAARs and the primary inhibitory scaffold, gephyrin, to promote sustained synaptic strengthening. While we previously found that persistent iLTP requires mRNA translation, the mechanisms controlling plasticity-induced gephyrin translation remain unknown. We identify miR153 as a novel regulator of Gphn mRNA translation which controls gephyrin protein levels and synaptic clustering, ultimately impacting inhibitory synaptic structure and function. iLTP induction downregulates miR153, reversing its translational suppression of Gphn mRNA and promoting de novo gephyrin protein synthesis and synaptic clustering during iLTP. Finally, we find that reduced miR153 expression during iLTP is driven by an excitation-transcription coupling pathway involving calcineurin, NFAT and HDACs, which also controls the miRNA-dependent upregulation of GABAARs. Together, we delineate a miRNA-dependent post-transcriptional mechanism that controls the expression of the key synaptic scaffold, gephyrin, and may converge with parallel miRNA pathways to coordinate gene upregulation to maintain inhibitory synaptic plasticity. Synopsis: miR153 regulates inhibitory synapses by controlling translation of the major inhibitory synaptic scaffold, gephyrin. During plasticity, miR153 is transcriptionally repressed enabling gephyrin de novo synthesis, which supports long-term potentiation of inhibitory synapses. miR153 regulates inhibitory synapse strength by controlling translation of the scaffold protein, gephyrin. miR153-mediated reduced translation of gephyrin is required for persistent iLTP. During iLTP, miR153 transcriptional repression through calcineurin signaling enables increased gephyrin de novo synthesis and underlies synapse potentiation. miR153 regulates inhibitory synapses by controlling translation of the major inhibitory synaptic scaffold, gephyrin. During plasticity, miR153 is transcriptionally repressed enabling gephyrin de novo synthesis, which supports long-term potentiation of inhibitory synapses. [ABSTRACT FROM AUTHOR]

Predicting how nature's contributions to people (NCP) vary spatially remains a challenge. For NCP provided by mobile species, it is unclear how predictions need to account for the influence of multiple habitat types that act as sources, sinks and potential distractors of the NCP‐providing species. Existing approaches that do not account for these effects may inaccurately predict outcomes in real landscapes.To move beyond these limitations, we transfer quantitative inference approaches from movement ecology to explore how spatial habitat patterns determine the negative NCP of the invasive common brushtail possum Trichosurus vulpecula in New Zealand. We used a Bayesian model to investigate how the size of, and distance from, grassland and indigenous and exotic forest patches together contribute to relative possum density (measured by capture probability across a trapping network) in a heterogeneous 11,000‐ha landscape.We found that indigenous and exotic forest area were the most important factors in determining possum density. Although capture probability declined with increasing grassland area, the addition of grassland did not improve the relative model fit above one with indigenous forest as the only habitat.We expected differences in predicted possum density at habitat boundaries, for example, due to preferential foraging at edges. We found that indigenous and exotic forests contributed to capture probability interactively, such that capture probability at the between‐habitat edge was lower than expected, given the habitat area. We also found that models allowing for non‐linear habitat effects of exotic forests or grasslands, but not indigenous forests, were significantly better at predicting possum density than simpler models.Synthesis and applications. Our novel approach for spatial prediction can be applied to any of nature's contributions to people (NCP), and extended to identify trade‐offs and synergies among multiple NCP. For example, the negative NCP of possum density trades off with multiple known positive NCP from indigenous forests, including culturally significant non‐material NCP, and material NCP produced by exotic forests. We recommend that landscape management plans to maximise these positive NCP in future scenarios also consider how the risk of possum density may dampen net NCP provision. To minimise this negative NCP, our results support trap deployment in both indigenous and exotic forest. [ABSTRACT FROM AUTHOR]

The emergence of targeted therapies has transformed ovarian cancer treatment. However, biomarker profiling for precision medicine is limited by access to quality, tumour‐enriched tissue samples. The use of cell‐free DNA (cfDNA) in ascites presents a potential solution to this challenge. In this study, next‐generation sequencing was performed on ascites‐derived cfDNA samples (26 samples from 15 human participants with ovarian cancer), with matched DNA from ascites‐derived tumour cells (n = 5) and archived formalin‐fixed paraffin‐embedded (FFPE) tissue (n = 5). Similar tumour purity and variant detection were achieved with cfDNA compared to FFPE and ascites cell DNA. Analysis of large‐scale genomic alterations, loss of heterozygosity and tumour mutation burden identified six cases of high genomic instability (including four with pathogenic BRCA1 and BRCA2 mutations). Copy number profiles and subclone prevalence changed between sequential ascites samples, particularly in a case where deletions and chromothripsis in Chr17p13.1 and Chr8q resulted in changes in clinically relevant TP53 and MYC variants over time. Ascites cfDNA identified clinically actionable information, concordant to tissue biopsies, enabling opportunistic molecular profiling. This advocates for analysis of ascites cfDNA in lieu of accessing tumour tissue via biopsy. [ABSTRACT FROM AUTHOR]

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The coronavirus disease 2019 pandemic highlighted the need for more rapid and routine application of modeling approaches such as quantitative microbial risk assessment (QMRA) for protecting public health. QMRA is a transdisciplinary science dedicated to understanding, predicting, and mitigating infectious disease risks. To better equip QMRA researchers to inform policy and public health management, an Advances in Research for QMRA workshop was held to synthesize a path forward for QMRA research. We summarize insights from 41 QMRA researchers and experts to clarify the role of QMRA in risk analysis by (1) identifying key research needs, (2) highlighting emerging applications of QMRA; and (3) describing data needs and key scientific efforts to improve the science of QMRA. Key identified research priorities included using molecular tools in QMRA, advancing dose–response methodology, addressing needed exposure assessments, harmonizing environmental monitoring for QMRA, unifying a divide between disease transmission and QMRA models, calibrating and/or validating QMRA models, modeling co‐exposures and mixtures, and standardizing practices for incorporating variability and uncertainty throughout the source‐to‐outcome continuum. Cross‐cutting needs identified were to: develop a community of research and practice, integrate QMRA with other scientific approaches, increase QMRA translation and impacts, build communication strategies, and encourage sustainable funding mechanisms. Ultimately, a vision for advancing the science of QMRA is outlined for informing national to global health assessments, controls, and policies. [ABSTRACT FROM AUTHOR]

Abnormal alpha‐synuclein (αSyn) and iron accumulation in the brain play an important role in Parkinson's disease (PD). Herein, we aim to visualize αSyn inclusions and iron deposition in the brains of M83 (A53T) mouse models of PD in vivo. The fluorescent pyrimidoindole derivative THK‐565 probe was characterized by means of recombinant fibrils and brains from 10‐ to 11‐month‐old M83 mice. Concurrent wide‐field fluorescence and volumetric multispectral optoacoustic tomography (vMSOT) imaging were subsequently performed in vivo. Structural and susceptibility weighted imaging (SWI) magnetic resonance imaging (MRI) at 9.4 T as well as scanning transmission x‐ray microscopy (STXM) were performed to characterize the iron deposits in the perfused brains. Immunofluorescence and Prussian blue staining were further performed on brain slices to validate the detection of αSyn inclusions and iron deposition. THK‐565 showed increased fluorescence upon binding to recombinant αSyn fibrils and αSyn inclusions in post‐mortem brain slices from patients with PD and M83 mice. Administration of THK‐565 in M83 mice showed higher cerebral retention at 20 and 40 min post‐intravenous injection by wide‐field fluorescence compared to nontransgenic littermate mice, in congruence with the vMSOT findings. SWI/phase images and Prussian blue indicated the accumulation of iron deposits in the brains of M83 mice, presumably in the Fe3+ form, as evinced by the STXM results. In conclusion, we demonstrated in vivo mapping of αSyn by means of noninvasive epifluorescence and vMSOT imaging and validated the results by targeting the THK‐565 label and SWI/STXM identification of iron deposits in M83 mouse brains ex vivo. [ABSTRACT FROM AUTHOR]

The β and β′ subunits of the RNA polymerase (RNAP) are large proteins with complex multi‐domain architectures that include several insertional domains. Here, we analyze the domain organizations of RNAP‐β and RNAP‐β′ using sequence, experimentally determined structures and AlphaFold structure predictions. We observe that lineage‐specific insertional domains in bacterial RNAP‐β belong to a group that we call BEAN (broadly embedded annex). We observe that lineage‐specific insertional domains in bacterial RNAP‐β′ belong to a group that we call HABAS (hammerhead/barrel‐sandwich hybrid). The BEAN domain has a characteristic three‐dimensional structure composed of two square bracket‐like elements that are antiparallel relative to each other. The HABAS domain contains a four‐stranded open β‐sheet with a GD‐box‐like motif in one of the β‐strands and the adjoining loop. The BEAN domain is inserted not only in the bacterial RNAP‐β′, but also in the archaeal version of universal ribosomal protein L10. The HABAS domain is inserted in several metabolic proteins. The phylogenetic distributions of bacterial lineage‐specific insertional domains of β and β′ subunits of RNAP follow the Tree of Life. The presence of insertional domains can help establish a relative timeline of events in the evolution of a protein because insertion is inferred to post‐date the base domain. We discuss mechanisms that might account for the discovery of homologous insertional domains in non‐equivalent locations in bacteria and archaea. [ABSTRACT FROM AUTHOR]

Johnson's approximation is implemented in a finite element code to simulate the electric field dependence of a core–shell microstructure material. We show how the microstructure, based here on a 50:50 volume fraction, influences the measured effective permittivity as a function of applied voltage. Using a Johnson's parameter of β = 1.0 × 1010 Vm5/C3, verified from commercial BaTiO3‐based multilayer ceramic capacitors (MLCC), we show how the microstructure and the difference in core and shell conductivities alter the local fields generated and how this influences the voltage dependence of the effective permittivity. Systems that comprise a conductive core‐like material surrounded by a resistive shell experience little or modest voltage dependence due to the shell material providing shielding to large electric fields within the cores. Conversely, if the core material is more resistive than the shell material, substantial voltage dependence occurs with simulations showing over a 50% decrease in the effective permittivity. These simulations give improved understanding of voltage dependence and provide a method to help guide the design of future materials for MLCCs with improved performance. [ABSTRACT FROM AUTHOR]

Background: Radiolabeling is critical in complex chemical reactions involving positron emission tomography (PET) radiotracer production. The process is now automated within a synthesis module to enhance efficiency and reduce radiation exposure. The key to this automation is the use of radiation detectors to monitor radioactivity transfer and ensure the progression of reactions. However, the high cost of these detectors has motivated the need for a more affordable alternative. Purpose: This study aimed to develop a compact and cost‐efficient detector using scintillating fibers and silicon photomultipliers (SiPMs) to track radioactivity throughout PET radiotracer production. Methods: Monte Carlo simulations were performed with the Geant4‐based M‐TAG software for four detector geometries (single fiber, single fiber with bolus, 16‐fiber bundle, and spiral) to optimize the detector construction for better detection efficiency. The simulations scored the energy deposited into the scintillating fibers per simulated particle, which was used to estimate the expected voltage pulse height from the SiPM considering the total light collection efficiency. Based on the simulation results, two detector configurations (16‐fiber bundle and spiral fiber) were constructed using plastic scintillating fibers, optical fibers, a 6 mm ×$\times$ 6 mm SiPM, and commonly available electronic components. The detectors were calibrated using a Fluorine‐18 (18F$^{18}{\rm F}$) source with typical activity levels used in radiotracer production. Detector performances were subsequently evaluated through linearity tests and measurement uncertainty assessments. Errors up to ±5%$\pm 5\%$ were considered acceptable for troubleshooting purposes. Results: The calibration curves showed a linear response with changing activity for both detectors. The calibrated detectors offered real‐time activity measurements ranging from 0.10 to 49.41 GBq, with a 3‐s refresh rate. In the activity range above 0.145 GBq, the uncertainties were less than 5%$5\%$ for both the 16‐fiber and spiral configurations. The spiral detector recorded a signal with a half‐life of 105.88±0.40$105.88 \pm 0.40$ min, closely aligning with the reference half‐life of 18F$^{18}{\rm F}$. Conclusions: Cost‐efficient plastic scintillation fiber detectors were developed to facilitate the troubleshooting of automated synthesis of PET radiotracers. [ABSTRACT FROM AUTHOR]

Introduction: Interventions to support behaviour change in people living with chronic health conditions increasingly use patient groups as the mode of delivery, but these are often designed without consideration of the group processes that can shape intervention outcomes. This article outlines a new approach to designing group‐based behaviour change interventions that prioritizes recipients' shared social identity as group members in facilitating the adoption of established behaviour change techniques (BCTs). The approach is illustrated through an example drawn from research focused on people living with severe obesity. Methods: A prioritization process was undertaken in collaboration with stakeholders, including behaviour change experts, clinicians, and a former patient to develop an evidence‐based, group intervention informed by the social identity approach to health. Three phases of development are reported: (1) identification of the health problem; (2) delineation of intervention mechanisms and operationalization of BCTs for group delivery and (3) intervention manualization. The fourth phase, intervention testing and optimization, is reported elsewhere. Results: A group‐based behaviour change intervention was developed, consisting of 12 group sessions and 3 one‐to‐one consultations. The intervention aimed to support the development of shared social identity among recipients, alongside the delivery of evidence‐based BCTs, to improve the likelihood of successful intervention and health outcomes among people living with severe obesity. Conclusions: A manualized intervention, informed by the social identity approach to health, was systematically designed with input from stakeholders. The development approach employed can inform the design of behavioural interventions in other health contexts where group‐based delivery is planned. [ABSTRACT FROM AUTHOR]

ANK3 encodes ankyrin‐G, a protein involved in neuronal development and signaling. Alternative splicing gives rise to three ankyrin‐G isoforms comprising different domains with distinct expression patterns. Mono‐ or biallelic ANK3 variants are associated with non‐specific syndromic intellectual disability in 14 individuals (seven with monoallelic and seven with biallelic variants). In this study, we describe the clinical features of 13 additional individuals and review the data on a total of 27 individuals (16 individuals with monoallelic and 11 with biallelic ANK3 variants) and demonstrate that the phenotype for biallelic variants is more severe. The phenotypic features include language delay (92%), autism spectrum disorder (76%), intellectual disability (78%), hypotonia (65%), motor delay (68%), attention deficit disorder (ADD) or attention deficit hyperactivity disorder (ADHD) (57%), sleep disturbances (50%), aggressivity/self‐injury (37.5%), and epilepsy (35%). A notable phenotypic difference was presence of ataxia in three individuals with biallelic variants, but in none of the individuals with monoallelic variants. While the majority of the monoallelic variants are predicted to result in a truncated protein, biallelic variants are almost exclusively missense. Moreover, mono‐ and biallelic variants appear to be localized differently across the three different ankyrin‐G isoforms, suggesting isoform‐specific pathological mechanisms. [ABSTRACT FROM AUTHOR]

Background: Bolus materials have been used for decades in radiotherapy. Most frequently, these materials are utilized to bring dose closer to the skin surface to cover superficial targets optimally. While cavity filling, such as nasal cavities, is desirable, traditional commercial bolus is lacking, requiring other solutions. Recently, investigators have worked on utilizing 3D printing technology, including commercially available solutions, which can overcome some challenges with traditional bolus. Purpose: To utilize failure modes and effects analysis (FMEA) to successfully implement a comprehensive 3D printed bolus solution to replace commercial bolus in our clinic using a series of open‐source (or free) software products. Methods: 3D printed molds for bespoke bolus were created by exporting the DICOM structures of the bolus designed in the treatment planning system and manipulated to create a multipart mold for 3D printing. A silicone (Ecoflex 00–30) mixture is poured into the mold and cured to form the bolus. Molds for sheet bolus of five thicknesses were also created. A comprehensive FMEA was performed to guide workflow adjustments and QA steps. Results: The process map identified 39 and 30 distinct steps for the bespoke and flat sheet bolus workflows, respectively. The corresponding FMEA highlighted 119 and 86 failure modes, with 69 shared between the processes. Misunderstanding of plan intent was a potential cause for most of the highest‐scoring failure modes, indicating that physics and dosimetry involvement early in the process is paramount. Conclusion: FMEA informed the design and implementation of QA steps to guarantee a safe and high‐quality comprehensive implementation of silicone bolus from 3D printed molds. This approach allows for greater adaptability not afforded by traditional bolus, as well as potential dissemination to other clinics due to the open‐source nature of the workflow. [ABSTRACT FROM AUTHOR]

Background Aim Study design Results Conclusion Relevance to Clinical practice Parents of infants admitted to neonatal intensive care require support to minimize the impact on their mental health and to encourage engagement with their infants to support infant neurodevelopment. Many interventions aim to address this need, but there is a lack of research considering the accessibility of these for a multicultural population.To systematically identify sources of psychotherapeutic support available for parents with infants admitted to neonatal care (NNU, neonatal intensive care unit [NICU] and special care units), assess their accessibility and acceptability and identify challenges and facilitators.Six electronic databases with no restrictions on language or date were used to identify relevant studies following Preferred Items for Systematic Reviews and Meta‐analysis (PRISMA) guidelines. Publications were included in the review if they reviewed parent experience of an intervention actively in place to support parent experience during the neonatal unit stay. Any studies where the intervention's primary aim was infant focused, such as developmental care, were excluded. All publications were quality‐assessed using quality appraisal tools appropriate for their design type. Data were extracted line by line using Sekhon et al.'s theoretical acceptability framework and questionnaire.A total of 3309 studies were found, of which 36 studies met the inclusion criteria. Included studies were published worldwide between 2000 and 2023 and explored 15 different interventions. Challenges for parental engagement were due to preconceived ideas about intervention requirements and parents' ability to participate in them. Timely information and providers' experience in delivering the intervention were reported to support engagement and as being valuable for enhancing participant knowledge. The emotional content of interventions was found to be challenging by parents across most studies. This was prominent in interventions designed to be carried out in a group format and where keepsakes were created. However, the value of these interventions was in reducing parents' feelings of isolation through increased social support and providing a starting point for conversations with wider family and friends about the family's neonatal experience. Participant demographics were poorly reported, with only two studies taking into consideration the ethicality of the intervention.Poor reporting of participant demographics, and a focus on mothers as participants, means findings are not transferrable to the wider population of parents in neonatal units. Future studies should consider how to ensure that research and interventions are accessible to multicultural populations to improve the understanding of the acceptability of interventions. Better knowledge of neonates and the NNU setting amongst intervention providers could increase the accessibility of psychotherapeutic support for parents. Training for providers on how to manage sensitive conversations may also be beneficial to support parents during interventions.The impact of neonatal admission on parental mental health is increasingly recognized and reported. Interventions have been developed to reduce the negative impact on the mental health of parents. There continue to be significant health inequalities as a result of many services not taking into account the acceptability and accessibility of interventions in this setting for their multicultural populations. This review highlights the need for better reporting of participant demographics in research and the inclusion of those seldom heard to ensure interventions are culturally, religiously and linguistically appropriate for multicultural populations. [ABSTRACT FROM AUTHOR]

ABSTRACT Biological agents are widely used across medicine, including for immune‐mediated skin conditions such as psoriasis and atopic dermatitis. When used to treat a relevant pathological process, they demonstrate impressive efficacy and credible safety, helping to achieve remission and improved function and quality of life. However, with their expanded use, awareness and understanding of adverse reactions to biologicals have also increased. Herein, we discuss the pathomechanism of adverse reactions to biological agents used to treat skin conditions and apply these to Pichler's classification system. This classification differentiates five distinct types, namely overstimulation (type α), hypersensitivity or immunogenicity (β), immunodeviation (γ), cross‐reactivity (δ) and nonimmunologic adverse reactions (ε). This classification covers most types of adverse reactions associated with use of biological agents and could be used to better understand the reaction pathogenesis and manage the clinical features of biological adverse effects. [ABSTRACT FROM AUTHOR]

Interstitial lung diseases (ILDs) include a variety of inflammatory and fibrotic pulmonary conditions. This study employs high‐resolution metabolomics (HRM) to explore plasma metabolites and pathways across ILD phenotypes, including non‐fibrotic ILD, idiopathic pulmonary fibrosis (IPF), and non‐IPF fibrotic ILD. The study used 80 plasma samples for HRM, and involved linear trend and group‐wise analyses of metabolites altered in ILD phenotypes. We utilized limma one‐way ANOVA and mummichog algorithms to identify differences in metabolites and pathways across ILD groups. Then, we focused on metabolites within critical pathways, indicated by high pathway overlap sizes and low p‐values, for further analysis. Targeted HRM identified putrescine, hydroxyproline, prolyl‐hydroxyproline, aspartate, and glutamate with significant linear increases in more fibrotic ILD phenotypes, suggesting their role in ILD fibrogenesis. Untargeted HRM highlighted pathway alterations in lysine, vitamin D3, tyrosine, and urea cycle metabolism, all associated with pulmonary fibrosis. In addition, methylparaben level had a significantly increasing linear trend and was higher in the IPF than fibrotic and non‐ILD groups. This study highlights the importance of specific amino acids, metabolic pathways, and xenobiotics in the progression of pulmonary fibrosis. [ABSTRACT FROM AUTHOR]

Desmoplasia in breast cancer leads to heterogeneity in physical properties of the tissue, resulting in disparities in drug delivery and treatment efficacy among patients, thus contributing to high disease mortality. Personalized in vitro breast cancer models hold great promise for high‐throughput testing of therapeutic strategies to normalize the aberrant microenvironment in a patient‐specific manner. Here, tumoroids assembled from breast cancer cell lines (MCF7, SKBR3, and MDA‐MB‐468) and patient‐derived breast tumor cells (TCs) cultured in microphysiological systems including perfusable microvasculature reproduce key aspects of stromal and vascular dysfunction causing impaired drug delivery. Models containing SKBR3 and MDA‐MB‐468 tumoroids show higher stromal hyaluronic acid (HA) deposition, vascular permeability, interstitial fluid pressure (IFP), and degradation of vascular HA relative to models containing MCF7 tumoroids or models without tumoroids. Interleukin 8 (IL8) secretion is found responsible for vascular dysfunction and loss of vascular HA. Interventions targeting IL8 or stromal HA normalize vascular permeability, perfusion, and IFP, and ultimately enhance drug delivery and TC death in response to perfusion with trastuzumab and cetuximab. Similar responses are observed in patient‐derived models. These microphysiological systems can thus be personalized by using patient‐derived cells and can be applied to discover new molecular therapies for the normalization of the tumor microenvironment. [ABSTRACT FROM AUTHOR]

Aims: Histological grading of prostate cancer is a powerful prognostic tool, but current criteria for grade assignment are not fully optimised. Our goal was to develop and test a simplified histological grading model, based heavily on large cribriform/intraductal carcinoma, with optimised sensitivity for predicting metastatic potential. Methods and results: Two separate non‐overlapping cohorts were identified: a 419‐patient post‐radical prostatectomy cohort with long term clinical follow‐up and a 209‐patient post‐radical prostatectomy cohort in which all patients had pathologically confirmed metastatic disease. All prostatectomies were re‐reviewed for high‐risk histological patterns of carcinoma termed 'unfavourable histology'. Unfavourable histology is defined by any classic Gleason pattern 5 component, any large cribriform morphology (> 0.25 mm) or intraductal carcinoma, complex intraluminal papillary architecture, grade 3 stromogenic carcinoma and complex anastomosing cord‐like growth. For the outcome cohort, Kaplan–Meier analysis compared biochemical recurrence, metastasis and death between subjects with favourable and unfavourable histology, stratified by pathological stage and grade group. Multivariable Cox proportional hazards models evaluated adding unfavourable histology to the Memorial Sloan Kettering Cancer Center (MSKCC) post‐prostatectomy nomogram and stratification by percentage of unfavourable histology. At 15 years unfavourable histology predicted biochemical recurrence, with sensitivity of 93% and specificity of 88%, metastatic disease at 100 and 48% and death at 100 and 46%. Grade group 2 prostate cancers with unfavourable histology were associated with metastasis independent of pathological stage, while those without had no risk. Histological models for prediction of metastasis based on only large cribriform/intraductal carcinoma or increasing diameter of cribriform size improved specificity, but with lower sensitivity. Multivariable Cox proportional hazards models demonstrated that unfavourable histology significantly improved discriminatory power of the MSKCC post‐prostatectomy nomogram for biochemical failure (likelihood ratio test P < 0.001). In the retrospective review of a separate RP cohort in which all patients had confirmed metastatic disease, none had unequivocal favourable histology. Conclusions: Unfavourable histology at radical prostatectomy is associated with metastatic risk, predicted adverse outcomes better than current grading and staging systems and improved the MSKCC post‐prostatectomy nomogram. Most importantly, unfavourable histology stratified grade group 2 prostate cancers into those with and without metastatic potential, independent of stage. While unfavourable histology is driven predominantly by large cribriform/intraductal carcinoma, the recognition and inclusion of other specific architectural patterns add to the sensitivity for predicting metastatic disease. Moreover, a simplified dichotomous model improves communication and could increase implementation. [ABSTRACT FROM AUTHOR]

Background and Purpose: Inhibitors of voltage‐gated sodium channels (NaVs) are important anti‐epileptic drugs, but the contribution of specific channel isoforms is unknown since available inhibitors are non‐selective. We aimed to create novel, isoform selective inhibitors of Nav channels as a means of informing the development of improved antiseizure drugs. Experimental Approach: We created a series of compounds with diverse selectivity profiles enabling block of NaV1.6 alone or together with NaV1.2. These novel NaV inhibitors were evaluated for their ability to inhibit electrically evoked seizures in mice with a heterozygous gain‐of‐function mutation (N1768D/+) in Scn8a (encoding NaV1.6) and in wild‐type mice. Key Results: Pharmacologic inhibition of NaV1.6 in Scn8aN1768D/+ mice prevented seizures evoked by a 6‐Hz shock. Inhibitors were also effective in a direct current maximal electroshock seizure assay in wild‐type mice. NaV1.6 inhibition correlated with efficacy in both models, even without inhibition of other CNS NaV isoforms. Conclusions and Implications: Our data suggest NaV1.6 inhibition is a driver of efficacy for NaV inhibitor anti‐seizure medicines. Sparing the NaV1.1 channels of inhibitory interneurons did not compromise efficacy. Selective NaV1.6 inhibitors may provide targeted therapies for human Scn8a developmental and epileptic encephalopathies and improved treatments for idiopathic epilepsies. [ABSTRACT FROM AUTHOR]

ABSTRACT Eruptive melanocytic nevi (EMN) have been reported in the setting of immunosuppression, chemotherapy, and bullous skin disease, including less commonly, Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). This case report presents a 4‐year‐old girl who developed agminated EMN and nail changes after TEN. A systematic review of the literature supports clinically appropriate follow‐up of EMN, as there is no reports of malignancy in EMN following SJS/TEN, nor reports of pediatric melanoma arising within EMN of any etiology. Further study of the possible correlation of nail changes with the development of EMN and better characterization of the dermoscopic features of EMN could improve monitoring and care of these patients. [ABSTRACT FROM AUTHOR]

ABSTRACT Preventing malaria during pregnancy is of critical importance, yet there are no approved malaria vaccines for pregnant women due to lack of efficacy results within this population. Conducting a randomized trial in pregnant women throughout the entire duration of pregnancy is impractical. Instead, a randomized trial was conducted among women of childbearing potential (WOCBP), and some participants became pregnant during the 2‐year study. We explore a statistical method for estimating vaccine effect within the target subpopulation—women who can naturally become pregnant, namely, women who can become pregnant under a placebo condition—within the causal inference framework. Two vaccine effect estimators are employed to effectively utilize baseline characteristics and account for the fact that certain baseline characteristics were only available from pregnant participants. The first estimator considers all participants but can only utilize baseline variables collected from the entire participant pool. In contrast, the second estimator, which includes only pregnant participants, utilizes all available baseline information. Both estimators are evaluated numerically through simulation studies and applied to the WOCBP trial to assess vaccine effect against pregnancy malaria. [ABSTRACT FROM AUTHOR]

Introduction: Globally, medical schools are operationalising policies and programming to address Indigenous health inequities. Although progress has been made, challenges persist. In Canada, where this research is conducted, Indigenous representation within medical schools remains low, leaving a small number of Indigenous advocates leading unprecedented levels of equity‐related work, often with insufficient resources. The change needed within medical education cannot fall solely on the shoulders of Indigenous Peoples; non‐Indigenous Peoples must also be involved. This work aims to better understand the pathways of those engaged in this work, with careful consideration given to the facilitators and barriers to ongoing engagement. Methods: Data collection and analysis were informed by narrative inquiry, a methodology that relies on storytelling to uncover nuance and prompt reflection. In this paper, we focus on interview data collected from Canadian non‐Indigenous medical educators and leaders (n = 10). Participants represented different career stages, (early to late career) and occupied a mix of clinical, administrative and education roles. Results: Although each participant's entry into reconciliatory work was unique, we identified common drivers actuating their engagement. Oftentimes their participation was tied to administrative work or propelled by experiences within their roles that forced them to confront the systemic inequalities borne by Indigenous Peoples in both academic and healthcare settings. Some admitted to struggling with understanding their appropriate role in Indigenous reconciliation; their participation often proceeded without firm support. Conclusion: Medical schools have an obligation to ensure their faculty, including non‐Indigenous Peoples, are equipped to fulfil social accountability mandates regarding Indigenous health. Our findings generate a better understanding of the tensions inherent in this equity work. We urge others to reflect on their role in Indigenous reconciliation, or else medical schools risk generating a false sense of individual and institutional progress. This paper aims to better understand the pathways of non‐Indigenous medical educators and leaders engaged in Indigenous reconciliation. [ABSTRACT FROM AUTHOR]

This quantitative study explored the relationship between counselor burnout (Counselor Burnout Inventory, CBI), life balance (Life Balance Inventory, LBI), and self‐compassion (Self‐Compassion Scale, SCS) among 331 fully licensed and provisionally licensed counselors throughout the United States with at least 2 years of experience in various clinical settings and providing direct clinical services. Results of two canonical correlation analyses (CCAs) explored the relationship between (a) the subscales of the LBI and the CBI and (b) the subscales of the SCS and the CBI. Both CCAs indicated a statistically significant relationship demonstrating that: (a) increased life balance was associated with lower burnout and (b) increased self‐compassion was associated with lower burnout. Counselors experiencing burnout may turn to increasing their life balance or increasing self‐compassion practices to increase their quality of life. [ABSTRACT FROM AUTHOR]

This paper presents a detailed analysis of the endocast of one of the most complete Paranthropus robustus crania known, DNH 7, from the Drimolen site (South Africa), and compares it with the morphology of other australopithecine endocasts. We focus on endocranial volume, the impressions of cortical sulci, cranial sutures, and the pattern of cranial venous sinuses on the endocast. A noteworthy observation is the estimated endocranial capacity of 403 cm3, which is small for an adult Paranthropus. Fragmentary sulci identified in the frontal and temporal lobes of DNH 7 exhibit similarities with patterns observed in chimpanzees and gracile australopithecines. We observe the presence of a large remnant of an occipital‐marginal sinus on DNH 7 and provide an updated table of 13 Paranthropus endocasts that are scorable for this trait, which reinforces the hypothesis that an enlarged occipital‐marginal (O/M) sinus system was fixed across the three species of Paranthropus. In light of this, the possible functional significance of the occipital‐marginal sinus system is reevaluated considering the ontogenetic development of cranial venous blood flow in human children. This leads us to hypothesize that the ontogenetic development of cranial blood flow in Paranthropus and Australopithecus africanus infants were different and to suggest that Taung 1 was the only A. africanus specimen known to have exhibited an enlarged O/M sinus system because it was an immature individual. [ABSTRACT FROM AUTHOR]

Introduction: Research has found that a high percentage of people with diabetes experience stigma, with perceptions of stigma being significantly higher among people with Type 1 diabetes compared to those with Type 2 diabetes. These experiences of diabetes stigma can lead to psychological, behavioural and medical consequences. The aim of the current study was to explore the perceptions of diabetes stigma and propose strategies for addressing this from the perspective of key stakeholders. Methods: A mixed methods design was used, commencing with an online qualitative survey (n = 128) and followed by a World Café (n = 11), where attendees reflected on their own experiences with stigma and discussed the survey findings. Results: The survey indicated that 75% of those with Type 1 diabetes and 51% with Type 2 had experienced diabetes stigma. The World Café identified three main areas that participants felt impacted their experiences with stigma or had the potential to help improve stigma: healthcare interactions, public awareness and media representations. Conclusions: The findings supported previous research showing that diabetes stigma is prevalent among people with diabetes. The World Café was an excellent means of sharing knowledge and experiences among stakeholders, the findings of which will inform strategies to bring about change. Patient or Public Contribution: World Café is a collaborative method where stakeholders contribute to the production and analysis of data through rounds of discussion and feedback. [ABSTRACT FROM AUTHOR]

Introduction: Anxiety and depression in older adults (60+ years of age) are under‐diagnosed and under‐treated. Older adults are less likely to seek help for these problems due to a lack of awareness, difficulty accessing health care due to availability or disability and fear of loss of independence. Existing points of contact between older adults and non‐traditional services, for example, the Fire and Rescue Service (FRS), could provide opportunities to support help‐seeking for mental ill‐health. The FRS conduct Home Fire Safety Visits (HFSVs) with older adults and are well positioned to provide health‐related support. This study examines a range of perspectives on the potential role of the FRS in the identification of, and signposting for, anxiety and depression in older adults. Methods: This was a qualitative study carried out using mixed methods in West Midlands, UK. Semi‐structured interviews were conducted with older adults and health and social care providers (practitioners, managers, commissioners) to explore the acceptability of the FRS expanding its role to detect and signpost for anxiety and depression in older adults. Observations examined delivery of existing HFSVs to older adults. Data were combined and analysed using a reflexive thematic approach. Results: Eighteen health and social care providers and 8 older adults were interviewed; 10 HFSVs were observed. Two overarching themes were identified: (1) Potential role for the FRS and (2) Operationalising identification of mental health problems by FRS. Interviews and observations demonstrated how HFSVs offer a suitable opportunity to start conversations about mental health. All interview participants felt that although the FRS would be well placed to deliver an intervention, they would require training, support and a referral pathway co‐produced with and supported by health and social care partners. Conclusion: A whole‐system approach is needed if the FRS are to expand HFSVs to identify mental health problems in older adults and provide signposting to appropriate services. Patient or Public Contribution: J.S. is a public co‐investigator. A Patient Advisory Group contributed to the initial funding application, design and conduct of the study, including data analysis and advice on dissemination. [ABSTRACT FROM AUTHOR]

Endoplasmic reticulum stress triggers the unfolded protein response (UPR) to promote cell survival or apoptosis. Transient endoplasmic reticulum stress activation has been reported to trigger megakaryocyte production, and UPR activation has been reported as a feature of megakaryocytic cancers. However, the role of UPR signaling in megakaryocyte biology is not fully understood. We studied the involvement of UPR in human megakaryocytic differentiation using PMA (phorbol 12‐myristate 13‐acetate)‐induced maturation of megakaryoblastic cell lines and thrombopoietin‐induced differentiation of human peripheral blood‐derived progenitors. Our results demonstrate that an adaptive UPR is a feature of megakaryocytic differentiation and that this response is not associated with ER stress‐induced apoptosis. Differentiation did not alter the response to the canonical endoplasmic reticulum stressors DTT or thapsigargin. However, thapsigargin, but not DTT, inhibited differentiation, consistent with the involvement of Ca2+ signaling in megakaryocyte differentiation. [ABSTRACT FROM AUTHOR]

Computational quantification reduces observer‐related variability in histological assessment of metabolic dysfunction‐associated steatotic liver disease (MASLD). We undertook stain‐free imaging using the SteatoSITE resource to generate tools directly predictive of clinical outcomes. Unstained liver biopsy sections (n = 452) were imaged using second‐harmonic generation/two‐photon excitation fluorescence (TPEF) microscopy, and all‐cause mortality and hepatic decompensation indices constructed. The mortality index had greater predictive power for all‐cause mortality (index >.14 vs. .31 vs.

Background and Aims: Lifestyle intervention is the mainstay of therapy for metabolic dysfunction‐associated steatohepatitis (MASH), and liver fibrosis is a key consequence of MASH that predicts adverse clinical outcomes. The placebo response plays a pivotal role in the outcome of MASH clinical trials. Second harmonic generation/two‐photon excitation fluorescence (SHG/TPEF) microscopy with artificial intelligence analyses can provide an automated quantitative assessment of fibrosis features on a continuous scale called qFibrosis. In this exploratory study, we used this approach to gain insight into the effect of lifestyle intervention‐induced fibrosis changes in MASH. Methods: We examined unstained sections from paired liver biopsies (baseline and end‐of‐intervention) from MASH individuals who had received either routine lifestyle intervention (RLI) (n = 35) or strengthened lifestyle intervention (SLI) (n = 17). We quantified liver fibrosis with qFibrosis in the portal tract, periportal, transitional, pericentral, and central vein regions. Results: About 20% (7/35) and 65% (11/17) of patients had fibrosis regression in the RLI and SLI groups, respectively. Liver fibrosis tended towards no change or regression after each lifestyle intervention, and this phenomenon was more prominent in the SLI group. SLI‐induced liver fibrosis regression was concentrated in the periportal region. Conclusion: Using digital pathology, we could detect a more pronounced fibrosis regression with SLI, mainly in the periportal region. With changes in fibrosis area in the periportal region, we could differentiate RLI and SLI patients in the placebo group in the MASH clinical trial. Digital pathology provides new insight into lifestyle‐induced fibrosis regression and placebo responses, which is not captured by conventional histological staging. [ABSTRACT FROM AUTHOR]

A species' demographic history gives important context to contemporary population genetics and a possible insight into past responses to climate change; with an individual's genome providing a window into the evolutionary history of contemporary populations. Pairwise sequentially Markovian coalescent (PSMC) analysis uses information from a single genome to derive fluctuations in effective population size change over the last ~5 million years. Here, we apply PSMC analysis to two European nightjar (Caprimulgus europaeus) genomes, sampled in Northwest and Southern Europe, with the aim of revealing the demographic history of nightjar in Europe. We successfully reconstructed effective population size over the last 5 million years. Our analysis shows that in response to global climate change, the effective population size of nightjar broadly increased under stable warm periods and decreased during cooler spans and prolonged glacial periods. PSMC analysis on the pseudo‐diploid combination of the two genomes revealed fluctuations in gene flow between ancestral populations over time, with gene flow ceasing by the last‐glacial period. Our results are tentatively suggestive of divergence in the European nightjar population, with timings consistent with differentiation being driven by restriction to different refugia during periods of glaciation. Finally, our results suggest that migratory behaviour in nightjar likely evolved prior to the last‐glacial period, with long‐distance migration seemingly persisting throughout the Pleistocene. However, further genetic structure analysis of individuals from known breeding sites across the species' contemporary range is needed to understand the extent and origins of range‐wide differentiation in nightjar. [ABSTRACT FROM AUTHOR]

Metastasis‐directed therapy (MDT) for oligometastatic prostate cancer (PCa), including stereotactic body radiotherapy (SBRT), has shown promise but is still considered investigational. This is the 5‐year analysis of the TRANSFORM trial, the largest prospective cohort of men with oligometastatic PCa treated with SBRT‐based MDT. The primary endpoint was 5‐year treatment escalation‐free survival (TE‐FS), defined as freedom from any new cancer therapy other than further SBRT. In total, 199 men received SBRT; 76.4% were hormone‐naïve at baseline. The rate of 5‐year TE‐FS was 21.7% (95% confidence interval [CI]: 15.7%–28.7%) overall and 25.4% (95% CI: 18.1%–33.9%) in the hormone‐naïve subgroup. The subgroups with International Society of Urological Pathology Grade Groups 4–5 disease (hazard ratio [HR] = 1.48, 95% CI: 1.05–2.01, p =.026), a higher baseline prostate‐specific antigen (PSA) (HR = 1.06, 95% CI: 1.03–1.09, p <.001) and those who received prior androgen deprivation therapy (ADT) (HR = 2.13, 95% CI: 1.40–3.26, p <.001), were at greater risk of treatment escalation. Outcomes for participants with four or five initial lesions were comparable to those with one to three lesions. At last follow‐up, 18.9% (95% CI: 13.2%–25.7%) of participants were free from treatment escalation (median follow‐up of 67.9 months) and two participants had an undetectable PSA level. No treatment‐related grade three or higher adverse events were reported. The findings of this study demonstrate that SBRT‐based MDT is an effective option for delaying systemic treatment escalation in the context of oligometastatic PCa. Future randomised trials comparing SBRT‐based MDT to standard‐of‐care ADT‐based approaches are required to evaluate the impact of delaying ADT on survival. [ABSTRACT FROM AUTHOR]

Nature‐based tourism has a unique opportunity, and arguably responsibility, to promote widespread action on climate change. However, research suggests an aversion to providing information that might appear divisive or 'ruin' peoples day, particularly in places that are vulnerable to degradation.We explore how exposure to climate change information in vulnerable nature settings influences indicators of (i) the visitor experience and (ii) climate change engagement. Using a quasi‐experimental approach, we provided climate information on tourist boats operating on the Great Barrier Reef, Australia and compared visitor experiences with a control condition where climate information was not provided. Visitor surveys (n = 656) assessed perceptions and experiences.Overall, visitors on trips where climate information was provided were more likely to report that the reef experience exceeded their expectations and did not report any reduction in subjective trip satisfaction.However, we detected minimal effects of climate information on indicators of climate engagement (threat awareness, action awareness, or information seeking), suggesting room for improvement in interpretation approach and design. Indeed, visitors reported high levels of acceptability for incorporating more information about climate change, particularly about actions.Synthesis and applications: These results suggest that providing climate information does not undermine visitor experiences and while further research is required to determine the most effective approach for influencing climate change engagement, an appetite for more information exists. It is possible that what tourism operators are fearful of, may be an opportunity to improve outcomes aligned with both industry and environmental objectives. Read the free Plain Language Summary for this article on the Journal blog. Read the free Plain Language Summary for this article on the Journal blog. [ABSTRACT FROM AUTHOR]

Identifying and analysing isolated populations is critical for conservation. Isolation can make populations vulnerable to local extinction due to increased genetic drift and inbreeding, both of which should leave imprints of decreased genome‐wide heterozygosity. While decreases in heterozygosity among populations are frequently investigated, fewer studies have analysed how heterozygosity varies among individuals, including whether heterozygosity varies geographically along lines of discrete population structure or with continuous patterns analogous to isolation by distance. Here we explore geographical patterns of differentiation and individual heterozygosity in the threatened eastern barred bandicoot (Perameles gunnii) in Tasmania, Australia, using genomic data from 85 samples collected between 2008 and 2011. Our analyses identified two isolated demes undergoing significant genetic drift, and several areas of fine‐scale differentiation across Tasmania. We observed discrete genetic structures across geographical barriers and continuous patterns of isolation by distance, with little evidence of recent or historical migration. Using a recently developed analytical pipeline for estimating autosomal heterozygosity, we found individual heterozygosities varied within demes by up to a factor of two, and demes with low‐heterozygosity individuals also still contained those with high heterozygosity. Spatial interpolation of heterozygosity scores clarified these patterns and identified the isolated Tasman Peninsula as a location where low‐heterozygosity individuals were more common than elsewhere. Our results provide novel insights into the relationship between isolation‐driven genetic structure and local heterozygosity patterns. These may help improve translocation efforts, by identifying populations in need of assistance, and by providing an individualised metric for identifying source animals for translocation. [ABSTRACT FROM AUTHOR]

Objective: The Striped Bass Morone saxatilis is one of the most sought‐after recreational fish species along the US Atlantic coast. Regulations and a strong conservation ethic among anglers make Striped Bass among the most frequently released coastal marine fishes. A recent rule requires anglers to use circle hooks when targeting Striped Bass with natural baits, yet the conservation benefit of this action remains unclear. Methods: We used acoustic telemetry to monitor the fate of Striped Bass that were recreationally caught with baited hooks (n = 349) and to estimate the influence of various biological (fish size), fishery (fight time, handling time, hook location, bait type, and hook type), and environmental (water temperature and air temperature) variables on postrelease survival. Result: A semi‐quantitative score of fish release condition was the single best predictor of mortality. A broader dataset that included untagged fish (n = 716) was used to identify the best predictors of fish release condition, which included hook location and handling time. Conclusion: Contrary to expectations, the circle hooks used in this study did not result in lower release mortality than conventional J‐hooks. Impact statementStriped Bass are a popular recreational sport fish in the United States, with most fish being caught and released. To increase the survival of released fish, anglers are now required to use circle hooks when fishing with bait. This study found that using circle hooks does not increase the survival of released Striped Bass. [ABSTRACT FROM AUTHOR]

Background: Few studies have examined long‐term outcomes following oral immunotherapy (OIT); none have examined long‐term risks and benefits associated with distinct clinical outcomes (desensitization, remission). Methods: Participants completing the probiotic and peanut oral immunotherapy (PPOIT) ‐003 randomized trial were enrolled in a follow‐on study, PPOIT‐003LT. Peanut ingestion, reactions, and health‐related quality of life (HRQOL) were monitored prospectively. Outcomes at 1‐year and 2‐years post‐treatment were examined by treatment group and by post‐OIT clinical outcome (remission, desensitization without remission [DWR], allergic). Results: 86% (151/176) of eligible children enrolled. Post‐treatment peanut ingestion at 2‐years post‐treatment were similar for PPOIT (86.7%) and OIT (78.7%) groups, both higher than placebo (10.3%). Reactions reduced over time for all treatment and clinical outcome groups (PPOIT 31.7% to 23.3%, OIT 37.7% to 19.7%, placebo 13.8% to 6.9%; remission 27.5% to 15.9%; DWR 57.9% to 36.8%; allergic 11.6% to 7%). At 2‐years post‐treatment, similar proportions of remission and allergic participants reported reactions (RD 0.09 (95%CI −0.03, 0.20), p =.127), whereas more DWR participants reported reactions than remission (remission vs DWR: RD −0.21 (95%CI −0.39; −0.03), p =.02) and allergic (DWR vs allergic: RD 0.30 (95%CI 0.13, 0.47), p =.001) participants. At 2‐years post‐treatment, 0% remission versus 5.3% DWR versus 2.3% allergic participants reported adrenaline injector usage. Remission participants had significantly greater HRQOL improvement (adjusted for baseline) compared with both DWR (MD −0.54 (95%CI −0.99, −0.10), p =.017) and allergic (MD −0.82 (95%CI −1.25, −0.38), p <.001). Conclusion: By 2‐years post‐treatment, remission participants reported fewer reactions, less severe reactions and greater HRQOL improvement compared with DWR and allergic participants, indicating that remission is the patient‐preferred treatment outcome over desensitization or remaining allergic. [ABSTRACT FROM AUTHOR]

The barramundi (Lates calcarifer), a significant aquaculture species, typically displays silver to bronze coloration. However, attention is now drawn to rare variants like the "panda" phenotype, characterized by blotch‐like patterns of black (PB) and golden (PG) patches. This phenotype presents an opportunity to explore the molecular mechanisms underlying color variations in teleosts. Unlike stable color patterns in many fish, the "panda" variant demonstrates phenotypic plasticity, responding dynamically to unknown cues. We propose a complex interplay of genetic factors and epigenetic modifications, focusing on DNA methylation. Through a multiomics approach, we analyze transcriptomic and methylation patterns between PB and PG patches. Our study reveals differential gene expression related to melanosome trafficking and chromatophore differentiation. Although the specific gene responsible for the PB–PG difference remains elusive, candidate genes like asip1, asip2, mlph, and mreg have been identified. Methylation emerges as a potential contributor to the "panda" phenotype, with changes in gene promoters like hand2 and dynamin possibly influencing coloration. This research lays the groundwork for further exploration into rare barramundi color patterns, enhancing our understanding of color diversity in teleosts. Additionally, it underscores the "panda" phenotype's potential as a model for studying adult skin coloration. [ABSTRACT FROM AUTHOR]

The 2022 United States Food and Drug Administration (US FDA) draft guidance on diversity plan (DP), which will be implemented through the Diversity Action Plans by December 2025, under the 21st Century Cures Act, marks a pivotal effort by the FDA to ensure that registrational studies adequately reflect the target patient populations based on diversity in demographics and baseline characteristics. This white paper represents the culminated efforts of the International Consortium of Quality and Innovation (IQ) Diversity and Inclusion (D&I) Working Group (WG) to assess the implementation of the draft FDA guidance by members of the IQ consortium in the discipline of clinical pharmacology (CP). This article describes current practices in the industry and emphasizes the tools and techniques of quantitative pharmacology that can be applied to support the inclusion of a diverse population during global drug development, to support diversity and inclusion of underrepresented patient populations, in multiregional clinical trials (MRCTs). It outlines strategic and technical recommendations to integrate demographics, including age, sex/gender, race/ethnicity, and comorbidities, in multiregional phase III registrational studies, through the application of quantitative pharmacology. Finally, this article discusses the challenges faced during global drug development, which may otherwise limit the enrollment of a broader, potentially diverse population in registrational trials. Based on the outcomes of the IQ survey that provided the current awareness of diversity planning, it is envisioned that in the future, industry efforts in the inclusion of previously underrepresented populations during global drug development will culminate in drug labels that apply to the intended patient populations at the time of new drug application or biologics license application rather than through post‐marketing requirements. [ABSTRACT FROM AUTHOR]

Glyoxylic acid and glycine are widely considered to have been important prebiotic building blocks. Several mechanistic routes have been previously examined for conversion of glyoxylic acid to glycine. Here we provide evidence for a new mechanistic path. Glycine is spontaneously formed from glyoxylic acid in ammonium‐rich aqueous solutions at neutral pH; oxamic acid is generated as well. Hydride transfer from the glyoxylate‐derived hemiaminal to the corresponding iminium ion appears to underlie this transformation. This proposed mechanism parallels the well‐known Cannizzaro reaction mechanism, which leads us to suggest the designation “aza‐Cannizzaro reaction.” This discovery offers a new perspective on prebiotic nitrogen incorporation because glycine can be a source of nitrogen for more complex molecules, including other α‐amino acids. [ABSTRACT FROM AUTHOR]

Coastal regions are becoming increasingly vulnerable to flooding. Due to growing risk, there is a need for a variety of accessible flood inundation services and information to improve resilience and adaptation outcomes. To better understand these needs the National Oceanic and Atmospheric Administration's Office for Coastal Management and the Center for Operational Oceanographic Products and Services collaborated to host five virtual workshops during the COVID‐19 pandemic to understand inundation needs and deficits of five professional sectors: coastal planning, transportation and navigation, realty and insurance, health and human services, and natural resource and floodplain managers. This paper outlines the information collected from these workshops, shares recommendations for future research to improve equitable coastal resilience and highlights the value of remote engagement for knowledge coproduction. From the project results, we share cross‐cutting topics that emerged and propose a need for greater equity, inclusive engagement, interagency coordination and future research directions through scientist‐stakeholder coproduction workshops for improved coastal resilience. [ABSTRACT FROM AUTHOR]

Background Design Results Conclusions Squamous cell carcinoma (SCC) of presumed lung origin (PLO) is now the second most frequent histologic subtype of non‐small cell carcinoma after adenocarcinoma. The use of clinic‐genomic correlation provided by comprehensive genomic profiling (CGP) can revise clinicopathologic diagnoses of presumed primary lung SCC (PLO‐SCC) to diagnoses of metastatic SCC of cutaneous origin (C‐SCC).A total of 10 146 samples of clinically advanced PLO‐SCC (84% known Stage IV) passed QC metrics and were designated as PLO‐SCCs by review of test requisition forms, clinical notes, and pathology reports. One thousand seven hundred sixty‐one cases of known primary C‐SCC were also included in this study. All samples underwent hybrid capture‐based CGP (Foundation Medicine, Inc.) using a targeted gene panel to evaluate all classes of genomic alterations (GA), determine MSI, TMB, and genomic ancestry status. The mutational signature (MS) of each case was called by the decomposition method using reference signatures in the COSMIC database. PD‐L1 tumor cell expression was determined by IHC (22C3; Dako). All results were compared using the Fisher exact method with the false discovery rate corrected with a Benjamini–Hochberg adjustment.A total of 253 of 10 146 (2.5%) PLO‐SCC cases featured a UV+ MS; 812 of 1761 C‐SCC (46.1%) that also featured a UV radiation exposure MS (UV+) were also included in this study. PLO‐SCC UV+ cases used for sequencing included tissue samples from the lung (162), lymph node (34), soft tissue (33), liver (8), head and neck (7), brain (5), and skin thought to be metastatic sites from primary lung SCC (4). The PLO‐SCC UV+ patients were 78.7% male and had a median age of 72 years, which was younger and more frequently male gender than both the C‐SCC UV+ and C‐SCC UV− patients (p < 0.0001). Both the PLO‐SCC UV+ and C‐SCC UV+ featured greater GA per tumor than the PLO‐SCC UV− cases (p < 0.0001). In the PLO‐SCC UV− cases, tobacco exposure and APOBEC were the most frequent MSs. For the biomarkers associated with immune checkpoint inhibitor efficacy, when compared with the PLO‐SCC UV− cases, the PLO‐SCC UV+ cases featured more cases with TMB ≥10 mutations/Mb (88.5% vs. 36.5%; p < 0.0001) and ≥20 mutations/Mb (66.8% vs. 6.8%; p < 0.0001) and a trend for less frequent positive PD‐L1 (≥50% TPS) IHC staining (30.2% vs. 39.6%; p = 0.062). Compared to PLO‐SCC UV− cases, PLO‐SCC UV+ and C‐SCC UV+ cases were more likely to harbor clinically‐actionable GA in PTCH1 and NOTCH1/2 (p < 0.0001) and less likely to harbor clinically‐actionable GA in KRAS, PIK3CA, and PTEN (p < 0.0001). The frequency of PTCH1 GA in PLO‐SCC UV+ (32% vs. 0.9% in PLO‐SCC UV−) suggested that PLO‐SCC UV+ may include a mixture of C‐SCC and cutaneous basal cell carcinomas (C‐BCC) with squamous differentiation.When cases of PLO‐SCC undergo CGP, a small 2.5% subset of cases that featured a UV MS emerge that indicates that these tumors may actually represent metastatic cutaneous SCC or BCC with squamous differentiation. Given the significant treatment and clinical impact associated with the resolution of the true diagnosis of these cases, the use of genomic sequencing in PLO‐SCC may be clinically beneficial. [ABSTRACT FROM AUTHOR]

Communities have a strong role in protecting biodiversity. In addition to participation in restoration, a range of actions in the public or private sphere may support biodiversity. Despite this, there is a lack of clarity about what actions should be prioritized for behavior change campaigns. We developed and applied a method to prioritize community actions for biodiversity conservation that incorporates an expert‐based assessment of impact and a community‐informed measure of the likelihood of uptake. In stage 1, experts (n = 143) completed a survey that quantified the relative impact of actions based on best–worst scaling of perceived impact. In stage 2, surveyed community members (n = 3200) ranked the likelihood of adopting actions based on the ease or difficulty of performing each action, and the opportunity for change based on the proportion of respondents not yet engaging in each behavior. Experts gave the following actions the highest ranking for impact: voting for the environment (first), participating in restoration in ecological priority areas (second), and purchasing and protecting remnant bushland (third). When considering the disciplinary background and institutional background of experts, voting and participating in restoration activities remained in the upper ranked options. However, there was some divergence between these groups. For example, reducing beef consumption was ranked third by university‐based experts but ranked 28th by experts based in state government. Overall, community members ranked the following behaviors as most likely to be adopted: following quarantine laws (first), reducing plastic use (second), and managing pets (third). Top likelihood ranking of actions was minimally affected by community characteristics (nature relatedness, gender, location). Integrating these findings, the action ranked most favorably for impact, likelihood, and opportunity was participating in restoration. Choosing actions for behavior change campaigns requires consideration of the entire social–ecological system—from social factors that enable or constrain adoption to the ecological impact of actions across relevant social and ecological contexts. [ABSTRACT FROM AUTHOR]

Objective: Research regarding the therapeutic application of psychedelics and psychedelic‐assisted psychotherapy in the treatment of eating disorders (EDs) has begun to emerge. This systematic scoping review aimed to map and synthesise the existing evidence regarding the participant reported efficacy and perspectives concerning psychedelics in the treatment of EDs, and to identify significant research gaps. Method: A systematic search was undertaken across several databases in accordance with Preferred Reporting Items for Systematic reviews and Meta‐Analyses extension for Scoping Reviews guidelines. Results: 1290 publications were identified, 1135 after duplicates removed, with 17 meeting full‐eligibility criteria. Overall, findings suggested that most participants reported experiencing a meaningful reduction in their ED symptoms and having positive experiences or an openness to explore psychedelics as a treatment for ED symptoms, although some noted concerns of adverse effects and the importance of having psychological support to increase safety and efficacy. Conclusions: While preliminary research suggests psychedelics and psychedelic‐assisted psychotherapy may be a viable treatment option for ED symptoms, further research with more robust research designs is required to increase confidence in its efficacy, generalisability, and safety as a therapeutic medium. Highlights: While research regarding the efficacy of psychedelics in the treatment of eating disorders (EDs) is still in its infancy, preliminary findings have been promising.Participants across the included studies reported largely positive experiences and an openness to explore the use of psychedelics and psychedelic‐assisted psychotherapy as a treatment modality for EDs. However, some participants noted concerns about potential adverse effects (AEs) and the importance of ensuring psychological support was provided before, during, and/or after a psychedelic treatment experience.There is currently not enough evidence to determine which psychedelic substances are most efficacious for therapeutic intervention for EDs. Further research is therefore needed, with more robust research methodologies. [ABSTRACT FROM AUTHOR]

Eosinophilic dermatosis of hematologic malignancy (EDHM) is a cutaneous manifestation seen in patients with hematoproliferative and lymphoproliferative disorders, most commonly chronic lymphocytic leukemia. This systematic review aimed to summarize the therapeutic interventions of EDHM. A comprehensive search yielded 71 studies, predominantly case reports and series. The most frequently reported modalities were systemic and topical corticosteroids, as well as treatment of the underlying malignancy. Responses to these treatments varied. Targeted therapies, including dupilumab and omalizumab, showed promise, as did other modalities such as montelukast, dapsone, doxycycline, and phototherapy. Higher‐quality studies should be conducted to facilitate higher‐quality management recommendations for EDHM. [ABSTRACT FROM AUTHOR]