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Background: According to person-by-environment models, individual differences in traits may moderate the association between stressors and the development of psychopathology; however, findings in the literature have been inconsistent and little literature has examined adolescent brain structure as a moderator of the effects of stress on adolescent internalizing symptoms. The COVID-19 pandemic presented a unique opportunity to examine the associations between stress, brain structure, and psychopathology. Given links of cortical morphology with adolescent depression and anxiety, the current study investigated whether cortical morphology moderated the relationship between stress from the COVID-19 pandemic and the development of internalizing symptoms in familial high-risk adolescents., Methods: Prior to the COVID-19 pandemic, 72 adolescents (27 male) completed a measure of depressive and anxiety symptoms and underwent magnetic resonance imaging. T1-weighted images were acquired to assess cortical thickness and surface area. Approximately 6 to 8 months after COVID-19 was declared a global pandemic, adolescents reported their depressive and anxiety symptoms and pandemic-related stress., Results: Adjusting for pre-pandemic depressive and anxiety symptoms and stress, increased pandemic-related stress was associated with increased depressive but not anxiety symptoms. This relationship was moderated by cortical thickness and surface area in the anterior cingulate and cortical thickness in the medial orbitofrontal cortex such that increased stress was only associated with increased depressive and anxiety symptoms among adolescents with lower cortical surface area and higher cortical thickness in these regions., Conclusions: Results further our understanding of neural vulnerabilities to the associations between stress and internalizing symptoms in general and during the COVID-19 pandemic in particular., (Copyright © 2024 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

It is normally supposed that populations of the same species should evolve shared mechanisms of adaptation to common stressors due to evolutionary constraint. Here, we describe a system of within-species local adaptation to coastal habitats, Brassica fruticulosa, and detail surprising strategic variability in adaptive responses to high salinity. These different adaptive responses in neighboring populations are evidenced by transcriptomes, diverse physiological outputs, and distinct genomic selective landscapes. In response to high salinity Northern Catalonian populations restrict root-to-shoot Na + transport, favoring K + uptake. Contrastingly, Central Catalonian populations accumulate Na + in leaves and compensate for the osmotic imbalance with compatible solutes such as proline. Despite contrasting responses, both metapopulations were salinity tolerant relative to all inland accessions. To characterize the genomic basis of these divergent adaptive strategies in an otherwise non-saline-tolerant species, we generate a long-read-based genome and population sequencing of 18 populations (nine inland, nine coastal) across the B. fruticulosa species range. Results of genomic and transcriptomic approaches support the physiological observations of distinct underlying mechanisms of adaptation to high salinity and reveal potential genetic targets of these two very recently evolved salinity adaptations. We therefore provide a model of within-species salinity adaptation and reveal cryptic variation in neighboring plant populations in the mechanisms of adaptation to an important natural stressor highly relevant to agriculture., Competing Interests: Competing interests statement:The authors declare no competing interest.

Negative symptoms are often found in youth at clinical high risk (CHR) for psychosis. The present study explored the feasibility of using tDCS in conjunction with CBT in the treatment of negative symptoms in 5 youths at CHR. We sought to determine whether the protocol was feasible given the requirement for repeated visits over a three-week period, and to determine if measures of neurobiological change could be included, both acutely and following three weeks of stimulation. The results from this study suggest that the protocol is feasible for these youth, and the inclusion of MRI scanning sessions yielded good quality data., Competing Interests: Declaration of competing interest P.D.M., M.M.D., K.B., S.B., F.M., A.H., and J.A. have nothing to declare. A.M. is founder and shareholder of MCGRx Corp., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The terrestrial decomposition of remains and associated insect colonisation have been highly researched, and recently studies have expanded to investigate the aquatic decomposition of remains. However, there are instances where remains may experience both terrestrial and aquatic conditions simultaneously due to partial submersion in tidal areas, or influx or efflux of water caused by flood or drought. Decomposition and post-mortem interval (PMI) research to date has focused on remains wholly exposed to either terrestrial or aquatic environments, with limited consideration of dual simultaneous exposure. This study was conducted in artificial lentic environments to ascertain how simultaneous zones of terrestrial and aquatic environments on a single body may impact decomposition. Three trials were completed over a period of 12 months, with each trial consisting of 12 stillborn piglets; three partially submerged head exposed, three partially submerged abdomen exposed, three fully submerged aquatic controls and three terrestrial controls. Decomposition stage and rate were inferred from physical characteristics and insect activity. The decomposition rate of the exposed region of each piglet was significantly faster than the submerged region. The exposed zone of each was colonised by insects and reached skeletonization, whereas the submerged zone without orifice exposure had no insect activity and had a significantly slower decomposition rate. This indicated the ability to utilise terrestrial entomological approaches to estimate a minimum PMI for the exposed portion of the remains. However, without the ability to determine the amount of time the remains may have been submerged for, this estimation represents only a minimum PMSI, with the possibility the remains were submerged for a period of time without insect access and colonisation., (© 2024. The Author(s).)

This study investigated using a 160-slice multidetector computed tomography (CT) scanner for conscious image acquisition in dogs with upper airway disease, and describes findings in dogs that had previously undergone soft palate surgery. Seventeen client-owned dogs with upper airway disease were retrospectively reviewed, and classified into three groups: group I, "untreated brachycephalic obstructive airway syndrome (BOAS) patients"; group II, "previously treated BOAS patients"; and group III, "patients with respiratory disease other than BOAS". Data included signalment, clinical history, direct laryngoscopy and endoscopy findings, previous surgeries and CT findings. CT scans in group I revealed overlong and thickened soft palates in all dogs, and signs of laryngeal collapse in four dogs. Patients in group II exhibited normal soft palate lengths, while patients in group III displayed various findings such as nasopharyngeal narrowing and tracheal collapse. Upper airway examinations under general anaesthesia confirmed most CT findings. This study demonstrates the feasibility and value of conscious CT scanning for assessing upper airway diseases in dogs, providing valuable diagnostic information while eliminating the need for chemical immobilisation, thus reducing patient stress and cost. These findings offer new insight into upper airway anatomy in awake patients, especially in brachycephalic breeds, and lay a foundation for future research.

Background: The current literature supports the effectiveness of exercise, education, and self-management interventions for the long-term management of persistent low back pain. However, there is significant uncertainty about the implementation of interventions related to barriers, facilitators, and patient's preferences. This study will evaluate the Back to Living Well program implementation from a participant and organizational perspective. More specifically we address the following objectives: 1) identify program barriers and facilitators from participants' perspectives, 2) identify factors related to program, personal and contextual factors that contribute to negative and positive outcomes, and outcome trajectories, 3) identify factors influencing participants' selection of an in-person or e-health program, and 4) evaluate program specific barriers and facilitators from the organization and care delivery perspectives., Methods: This study will utilize a mixed-method convergent design including a longitudinal cohort strand and a longitudinal qualitative interview strand. The RE-AIM framework will be used to assess program implementation. Participants (n = 90, 1:1: in person or virtual) who choose to register in the program as well as staff (n = 10 to 15) involved in the delivery of the program will be invited to participate. Participants will participate in a 12-week physical activity, education, and self-management program. Implementation outcomes will be measured at 3-, 6-, 12-months, and six months after the end of the follow-ups. Interview scripts and directed content analysis will be constructed based on the Theoretical Domains Framework and the Neuromatrix Model of Pain, Theoretical Domains Framework. Staff interviews will be constructed and analyzed using the Consolidated Framework for Implementation Research. Participants will also complete pain, disability, quality of life and psychological questionnaires, wear an activity tracker at all time points, and complete weekly pain and activity limitation questions using a mobile application., Discussion: The study results will provide evidence to inform potential future implementation of the program. An effective, appropriately targeted, and well implemented exercise program for the long-term management (i.e., tertiary prevention) of LBP could minimize the burden of the condition on patients, the health care system and society., Trial Registration: ClinicalTrials.gov NCT05929846. This (Registration Date: July 3 2023) study has been approved by the Hamilton Integrated Research Ethics Board Project ID#15,354., (© 2024. The Author(s).)

Classified as marine debris, man made materials are polluting the world's oceans. Recently, glass reinforced plastic (GRP) has been shown to degrade and contaminate the coasts. In this pioneering study, fibreglass particles have been detected in the soft parts of oysters and mussels collected from natural populations, in front of an active boatyard. The presence of particulate glass, with concentrations up to 11,220 particles/kg ww in Ostrea edulis and 2740 particles/kg ww in Mytilus edulis, was confirmed by micro Raman spectroscopy. The results showed higher accumulation during the winter months, when boat maintenance activities are peaking and, through repair work, the release of glass fibres in the environment is more likely. Bivalves are considered high risk species due to their sessile nature and extensive filter feeding behaviour. The microparticle inclusion may contribute to adverse impacts on physiological processes and eventually to a decline in the overall health and subsequent death of the animal. The high costs involved in the proper GRP disposal and the lack of recycling facilities worldwide lead to boat abandonement and further contamination of the coasts. For the first time this study presents the extensive fibreglass contamination of natural bivalve populations, in a popular South England sailing harbour, designated a biological and geological site of specific scientific interest (SSRI)., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Objectives: Intensive interdisciplinary pain treatments (IIPTs) are programs that aim to improve functioning in youth with severe chronic pain. Little is known about how the brain changes after IIPT; however, decreased brain responses to emotional stimuli have been identified previously in pediatric chronic pain relative to healthy controls. We examined whether IIPT increased brain responses to emotional stimuli, and whether this change was associated with a reduction in pain interference., Patients and Methods: Twenty youths with chronic pain aged 14 to 18 years were scanned using functional magnetic resonance imaging, pre and post-IIPT. During the functional magnetic resonance imaging, patients were presented with emotional stimuli (ie, faces expressing happiness/fear), neutral expressions, and control (ie, scrambled) images. Patients completed a measure of pain interference pre and post-IIPT. Paired t tests were used to examine differences in brain activation in response to emotional versus neutral stimuli, pre to post-IIPT. Data from significant brain clusters were entered into linear mixed models to examine the relationships between brain activation and impairment pre and post-IIPT., Results: Patients demonstrated a decrease in middle frontal gyrus (MFG) activation in response to emotional stimuli (happy + fear) relative to scrambled images, between pre and post-IIPT ( P < 0.05). Lower MFG activation was associated with lower pain interference, pre and post-IIPT ( P < 0.05)., Conclusion: Contrary to our hypothesis, IIPT was associated with a reduction in MFG activation to emotional stimuli, and this change was associated with reduced pain interference. The MFG is a highly interconnected brain area involved in both pain chronification and antinociception. With further validation of these results, the MFG may represent an important biomarker for evaluating patient treatment response and target for future pain interventions., Competing Interests: Financial assistance was provided by generous community donations to the Vi Riddell Pain and Rehabilitation Centre through the Alberta Children’s Hospital Foundation (10016199). The authors declare no conflict of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: The aim was to determine the impact of consolidation of two rural level 1 trauma centers on adult trauma patients presenting to the remaining level 1 trauma center. To our knowledge, a study assessing the impact of trauma center consolidation on adult trauma patients had yet to be performed., Methods: A single institution, retrospective study was conducted at a rural level 1 trauma center. Adult trauma patients who presented to our center from January 2017 to January 2022 were included. The cohorts spanned 33 months pre- and post-consolidation. Multiple demographic and outcome measures were gathered. Data were analyzed using the student's t-test and Chi-squared testing., Results: There was a 33% increase in overall trauma activations and 9% increase in transfers from outside facilities post-consolidation. The post-consolidation group was significantly older, had higher mean injury severity score, and decreased hospital-free days. The post-consolidation group also saw an increase in ICU admission and surgical intervention. While there were no significant differences in ICU-free days or ventilator days, patients in the post-consolidation group with the highest level of activation who required both surgical intervention and ICU admission experienced decreased mortality., Conclusion: The consolidation of trauma services to a single level 1 trauma center in a rural Appalachian health system led to higher trauma volume and acuity, but most importantly decreased mortality for the most severely injured trauma patients., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Overarching theories such as the interactive specialization and maturational frameworks have been proposed to describe human functional brain development. However, these frameworks have not yet been systematically examined across the fMRI literature. Visual processing is one of the most well-studied fields in neuroimaging, and research in this area has recently expanded to include naturalistic paradigms that facilitate study in younger age ranges, allowing for an in-depth critical appraisal of these frameworks across childhood. To this end, we conducted a scoping review of 94 developmental visual fMRI studies, including both traditional experimental task and naturalistic studies, across multiple sub-domains (early visual processing, category-specific higher order processing, naturalistic visual processing). We found that across domains, many studies reported progressive development, but few studies describe regressive or emergent changes necessary to fit the maturational or interactive specialization frameworks. Our findings suggest a need for the expansion of developmental frameworks and clearer reporting of both progressive and regressive changes, along with well-powered, longitudinal studies., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose: ADP-ribosylation is a post-translational modification involving the transfer of one or more ADP-ribose units from NAD+ to target proteins. Dysregulation of ADP-ribosylation is implicated in neurodegenerative diseases. Here we report a novel homozygous variant in the ADPRS gene (c.545A>G, p.His182Arg) encoding the mono(ADP-ribosyl) hydrolase ARH3 found in 2 patients with childhood-onset neurodegeneration with stress-induced ataxia and seizures (CONDSIAS)., Methods: Genetic testing via exome sequencing was used to identify the underlying disease cause in two siblings with developmental delay, seizures, progressive muscle weakness, and respiratory failure following an episodic course. Studies in a cell culture model uncover biochemical and cellular consequences of the identified genetic change., Results: The ARH3 H182R variant affects a highly conserved residue in the active site of ARH3, leading to protein instability, degradation, and reduced expression. ARH3 H182R additionally fails to localize to the nucleus. The combination of reduced expression and mislocalization of ARH3 H182R resulted in accumulation of mono-ADP ribosylated species in cells., Conclusions: The children's clinical course combined with the biochemical characterization of their genetic variant develops our understanding of the pathogenic mechanisms driving CONDSIAS and highlights a critical role for ARH3-regulated ADP ribosylation in nervous system integrity.

Older adults who are frail are one of the most sedentary and the least physically active age groups. Prolonged sedentary time is associated with increased risk of negative health outcomes. To help design effective and sustainable content and optimize the uptake of sedentary behaviour interventions, an in-depth understanding of older adults' perceptions of sedentary behaviour is needed; however, most qualitative studies have been conducted in healthy older adults. The aim of this study was to explore perspectives of sedentary behaviour within the context of older adults who are pre-frail and frail after the winter and spring. We included participants if they: (1) spoke English or attended with a translator or caregiver, (2) were ≥ 60 years, and (3) were frail on the Morley Frail Scale. We utilized a qualitative description methodology including a semi-structured in-depth interview and thematic content analysis. Concepts from the COM-B (Capability Opportunity Motivation-Behaviour) model were used to guide the semi-structured interviews and analysis. To ensure credibility of the data, we used an audit trail and analyst triangulation. We recruited 21 older adults (72 ± 7.3 years, 13 females, 13 frail) from southwestern Ontario, Canada. Two individuals were lost to follow-up due to medical mistrust and worse health. We transcribed 39 audio recordings. We identified three salient themes: (1) older adults rationalize their sedentary behaviours through cognitive dissonance (reflective motivation), (2) urban cities in southwestern Ontario may not be "age-friendly" (physical opportunity), and (3) exercise is something people "have to do", but hobbies are for enjoyment despite medical conditions (psychological capability). Perspectives of sedentary behaviour were different in the winter versus spring, with participants perceiving themselves to be less active in winter. Incorporating dissonance-based interventions as part of an educational program could be used to target the reflective motivation and psychological capability components. Future research should consider interdisciplinary collaborations with environmental gerontology to develop age-friendly communities that promote meaningful mobility to target physical opportunity., (© 2024. The Author(s).)

Clinical studies of major depression (MD) generally focus on group effects, yet interindividual differences in brain function are increasingly recognized as important and may even impact effect sizes related to group effects. Here, we examine the magnitude of individual differences in relation to group differences that are commonly investigated (e.g., related to MD diagnosis and treatment response). Functional MRI data from 107 participants (63 female, 44 male) were collected at baseline, 2, and 8 weeks during which patients received pharmacotherapy (escitalopram, N  = 68) and controls ( N  = 39) received no intervention. The unique contributions of different sources of variation were examined by calculating how much variance in functional connectivity was shared across all participants and sessions, within/across groups (patients vs controls, responders vs nonresponders, female vs male participants), recording sessions, and individuals. Individual differences and common connectivity across groups, sessions, and participants contributed most to the explained variance (>95% across analyses). Group differences related to MD diagnosis, treatment response, and biological sex made significant but small contributions (0.3-1.2%). High individual variation was present in cognitive control and attention areas, while low individual variation characterized primary sensorimotor regions. Group differences were much smaller than individual differences in the context of MD and its treatment. These results could be linked to the variable findings and difficulty translating research on MD to clinical practice. Future research should examine brain features with low and high individual variation in relation to psychiatric symptoms and treatment trajectories to explore the clinical relevance of the individual differences identified here., Competing Interests: B.N.F. has received grant/research support from Alternative Funding Plan Innovations Award, Brain and Behavior Research Foundation, Canadian Institutes of Health Research, Hamilton Health Sciences Foundation, J. P. Bickell Foundation, Ontario Brain Institute, Ontario Mental Health Foundation, Society for Women's Health Research, Teresa Cascioli Charitable Foundation, Eli Lilly, and Pfizer and has received consultant and/or speaker fees from AstraZeneca, Bristol-Myers Squibb, Canadian Psychiatric Association, CANMAT, Daiichi Sankyo, Lundbeck, Pfizer, Servier, and Sunovion. R.M. has received consulting and speaking honoraria from AbbVie, Allergan, Janssen, KYE, Lundbeck, Otsuka, and Sunovion and research grants from CAN-BIND, CIHR, Janssen, Lallemand, Lundbeck, Nubiyota, OBI, and OMHF. S.P. has been a consultant to Takeda, Bristol Myers Squibb, Lundbeck; has had a research contract with Assurex; and has equity in Mensante. R.W.L. has received speaker and consultant honoraria or research funds from AstraZeneca, Brain Canada, Bristol-Myers Squibb, the Canadian Institutes of Health Research (CIHR), the Canadian Network for Mood and Anxiety Treatments, the Canadian Psychiatric Association, Eli Lilly, Janssen, Lundbeck, Lundbeck Institute, Medscape, Otsuka, Pfizer, Servier, St. Jude Medical, Takeda, the University Health Network Foundation, Vancouver Coastal Health Research Institute, Allergan, Asia-Pacific Economic Cooperation, BC Leading Edge Foundation, Healthy Minds Canada, Michael Smith Foundation for Health Research, MITACS, Myriad Neuroscience, Ontario Brain Institute, Otsuka, Unity Health, Viatris, and VGH-UBCH Foundation. S.H.K. has received honoraria or research funds from Abbott, Alkermes, Allergan, Boehringer Ingelheim, Brain Canada, CIHR, Janssen, Lundbeck, Lundbeck Institute, Ontario Brain Institute, Ontario Research Fund, Otsuka, Pfizer, Servier, Sunovion, and Sun Pharmaceutical and holds stock in Field Trip Health. D.J.M. has received consulting and speaking honoraria from Lundbeck and Genomind. C.S. has received consulting and speaking honoraria from Pfizer, Otsuka, Bayer, Eisai, and research grants from CAN-BIND, CIHR, OBI, and SEAMO. S.C.S. is a senior Scientific Advisor and shareholder in ADMdx, which receives NIH funding, and during the period of this research, he had research grants from Brain Canada, Canada Foundation for Innovation (CFI), Canadian Institutes of Health Research (CIHR), and the Ontario Brain Institute in Canada. Other authors declare no competing financial interests., (Copyright © 2024 van der Wijk et al.)

Older adults who are frail are likely to be sedentary. Prior interventions to reduce sedentary time in older adults have not been effective as there is little research about the context of sedentary behaviour (posture, location, purpose, social environment). Moreover, there is limited evidence on feasible measures to assess context of sedentary behaviour in older adults. The aim of our study was to determine the feasibility of measuring context of sedentary behaviour in older adults with pre-frailty or frailty using a combination of objective and self-report measures. We defined "feasibility process" using recruitment (20 participants within two-months), retention (85%), and refusal (20%) rates and "feasibility resource" if the measures capture context and can be linked (e.g., sitting-kitchen-eating-alone) and are all participants willing to use the measures. Context was assessed using a wearable sensor to assess posture, a smart home monitoring system for location, and an electronic or hard-copy diary for purpose and social context over three days in winter and spring. We approached 80 potential individuals, and 58 expressed interest; of the 58 individuals, 37 did not enroll due to lack of interest or medical mistrust (64% refusal). We recruited 21 older adults (72±7.3 years, 13 females, 13 frail) within two months and experienced two dropouts due to medical mistrust or worsening health (90% retention). The wearable sensor, indoor positioning system, and electronic diary accurately captured one domain of context, but the hard copy was often not completed with enough detail, so it was challenging to link it to the other devices. Although not all participants were willing to use the wearable sensor, indoor positioning system, or electronic diary, we were able to triage the measures of those who did. The use of wearable sensors and electronic diaries may be a feasible method to assess context of sedentary behaviour, but more research is needed with device-based measures in diverse groups., Competing Interests: NO authors have competing interests., (Copyright: © 2024 Rodrigues et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Developmental programming involves the accurate conversion of signalling levels and dynamics to transcriptional outputs. The transcriptional relay in the Notch pathway relies on nuclear complexes containing the co-activator Mastermind (Mam). By tracking these complexes in real time, we reveal that they promote the formation of a dynamic transcription hub in Notch ON nuclei which concentrates key factors including the Mediator CDK module. The composition of the hub is labile and persists after Notch withdrawal conferring a memory that enables rapid reformation. Surprisingly, only a third of Notch ON hubs progress to a state with nascent transcription, which correlates with polymerase II and core Mediator recruitment. This probability is increased by a second signal. The discovery that target-gene transcription is probabilistic has far-reaching implications because it implies that stochastic differences in Notch pathway output can arise downstream of receptor activation., Competing Interests: FD, CR, SB, JT, MG, SB No competing interests declared, (© 2023, DeHaro-Arbona et al.)

The adoption and maintenance of physical activity (PA) is an important health behavior. This paper presents the first comprehensive empirical test of the Physical Activity Adoption and Maintenance (PAAM) model, which proposes that a combination of explicit (e.g., intention) and implicit (e.g., habit,, affect) self-regulatory processes is involved in PA adoption and maintenance. Data were collected via online questionnaires in English, German, and Italian at two measurement points four weeks apart. The study included 422 participants (M age = 25.3, SD age = 10.1; 74.2% women) from Germany, Switzerland, Italy, Canada, and the U.S. The study results largely supported the assumptions of the PAAM model, indicating that intentions and habits significantly mediate the effects of past PA on future PA. In addition, the effect of past PA on future PA was shown to be significant through a mediation chain involving affect and habit. Although the hypothesis that trait self-regulation moderates the intention-behavior relationship was not supported, a significant moderating effect of affect on the same relationship was observed. The results suggest that interventions targeting both explicit and implicit processes may be effective in promoting PA adoption and maintenance., (© 2024. The Author(s).)

Objective: To evaluate the signalment and clinical, laboratory, treatment, and outcome features of dogs diagnosed with anticoagulant rodenticide (AR) intoxication in Saskatchewan., Animals: We studied 349 dogs., Procedure: Medical records from the Veterinary Medical Centre (Saskatoon, Saskatchewan) between 1999 and 2022 were reviewed. Cases were included if they met at least 1 of the following criteria: owner witnessed the dog ingesting an AR; AR was seen in the vomitus when emesis was induced; the dog had clinical signs of coagulopathy, with elevation of PT ± aPTT that normalized after vitamin K1 therapy, in the presence of appropriate clinical and paraclinical data and the absence of other causes of hypocoagulable state determined by the primary clinician., Results: Fifty-three percent of cases were seen between July and October. Most dogs (61%) came from an urban setting. Ninety-two percent of dogs ingested a 2nd-generation AR and the most frequent toxin was bromadiolone. Clinical signs were reported in 30% of AR intoxications and included lethargy (86%), dyspnea (55%), and evidence of external hemorrhage (44%). The most common site of hemorrhage was the pleural space, accounting for 43% of hemorrhage sites. Consumptive thrombocytopenia was reported in 24% of dogs with evidence of AR-induced hemorrhage, with moderate (platelet count < 60 K/μL) and marked (< 30 K/μL) thrombocytopenia in 7/12 and 2/12 dogs, respectively. Blood products were administered to 84% of dogs with AR-induced hemorrhage; the most common product administered was fresh frozen plasma (56% of cases). Among dogs with AR-induced hemorrhage, those that received blood products were more likely to survive to discharge (81%) compared to those that did not (19%) ( P = 0.017). Eighty-six percent of dogs with AR-induced hemorrhage survived to discharge., Conclusion and Clinical Relevance: The pleural space was the most common site of hemorrhage. Moderate thrombocytopenia was a common finding. Eighty-six percent of dogs with AR-induced hemorrhage survived to discharge., (Copyright and/or publishing rights held by the Canadian Veterinary Medical Association.)

Background: An improved understanding of which gastroesophageal adenocarcinoma (GOA) patients respond to both chemotherapy and immune checkpoint inhibitors (ICI) is needed. We investigated the predictive role and underlying biology of a 44-gene DNA damage immune response (DDIR) signature in patients with advanced GOA., Materials and Methods: Transcriptional profiling was carried out on pretreatment tissue from 252 GOA patients treated with platinum-based chemotherapy (three dose levels) within the randomized phase III GO2 trial. Cross-validation was carried out in two independent GOA cohorts with transcriptional profiling, immune cell immunohistochemistry and epidermal growth factor receptor (EGFR) fluorescent in situ hybridization (FISH) (n = 430)., Results: In the GO2 trial, DDIR-positive tumours had a greater radiological response (51.7% versus 28.5%, P = 0.022) and improved overall survival in a dose-dependent manner (P = 0.028). DDIR positivity was associated with a pretreatment inflamed tumour microenvironment (TME) and increased expression of biomarkers associated with ICI response such as CD274 (programmed death-ligand 1, PD-L1) and a microsatellite instability RNA signature. Consensus pathway analysis identified EGFR as a potential key determinant of the DDIR signature. EGFR amplification was associated with DDIR negativity and an immune cold TME., Conclusions: Our results indicate the importance of the GOA TME in chemotherapy response, its relationship to DNA damage repair and EGFR as a targetable driver of an immune cold TME. Chemotherapy-sensitive inflamed GOAs could benefit from ICI delivered in combination with standard chemotherapy. Combining EGFR inhibitors and ICIs warrants further investigation in patients with EGFR-amplified tumours., Competing Interests: Disclosure MAB reported personal fees from Ipsen, BMS and Servier. RDP reported personal fees from Eli Lilly, Bristol Myers Squib, and Servier and grants from AstraZeneca, Roche, Sanofi, Merck Sharp & Dohme, Five Prime Therapeutics and Jansen outside the submitted work. MJS reported grants from Cancer Research UK during the conduct of the GO2 study. PSH reported grants from Cancer Research UK during the conduct of the study and institutional research funding from Novartis, Pfizer, Eli Lilly, Daiichi-Sankyo and Eisai outside the submitted work. GL and RDK are employees of Almac Diagnostic Services. RT reported personal fees from Eli Lilly, Astellas and Almac Diagnostic Services outside the submitted work. All other authors have declared no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

We examine structural brain characteristics across three diagnostic categories: at risk for serious mental illness; first-presenting episode and recurrent major depressive disorder (MDD). We investigate whether the three diagnostic groups display a stepwise pattern of brain changes in the cortico-limbic regions. Integrated clinical and neuroimaging data from three large Canadian studies were pooled (total n = 622 participants, aged 12-66 years). Four clinical profiles were used in the classification of a clinical staging model: healthy comparison individuals with no history of depression (HC, n = 240), individuals at high risk for serious mental illness due to the presence of subclinical symptoms (SC, n = 80), first-episode depression (FD, n = 82), and participants with recurrent MDD in a current major depressive episode (RD, n = 220). Whole-brain volumetric measurements were extracted with FreeSurfer 7.1 and examined using three different types of analyses. Hippocampal volume decrease and cortico-limbic thinning were the most informative features for the RD vs HC comparisons. FD vs HC revealed that FD participants were characterized by a focal decrease in cortical thickness and global enlargement in amygdala volumes. Greater total amygdala volumes were significantly associated with earlier onset of illness in the FD but not the RD group. We did not confirm the construct validity of a tested clinical staging model, as a differential pattern of brain alterations was identified across the three diagnostic groups that did not parallel a stepwise clinical staging approach. The pathological processes during early stages of the illness may fundamentally differ from those that occur at later stages with clinical progression., Competing Interests: Declaration of competing interest Dr. Sidney Kennedy has received funding for Consulting or Speaking engagements from Abbvie, Boehringer-Ingelheim, Janssen, Lundbeck, Lundbeck Institute, Merck, Otsuka Pfizer, Sunovion and Servier. Dr. Kennedy has received Research Support from Abbott, Brain Canada, CIHR (Canadian Institutes of Health Research), Janssen, Lundbeck, Ontario Brain Institute, Otsuka, Pfizer, SPOR (Canada's Strategy for Patient-Oriented Research); and has stock/stock options in Field Trip Health. No other disclosures or conflict of interests stated by authors of this work. SJR has received consulting or research funding from Allergan, Janssen, Neurocrine, and Pfizer Canada., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Attention and executive function (EF) dysregulation are common in a number of disorders including autism and attention-deficit/hyperactivity disorder (ADHD). Better understanding of the relationship between indirect and direct measures of attention and EF and common neurodevelopmental diagnoses may contribute to more efficient and effective diagnostic assessment in childhood. We obtained cognitive (NIH Toolbox, Little Man Task, Matrix Reasoning Task, and Rey Delayed Recall) and symptom (CBCL, and BPMT) assessment data from the Adolescent Brain and Cognitive Development (ABCD) database for three groups, autistic (N = 110), ADHD (N = 878), and control without autism or ADHD diagnoses (N = 9130) and used ridge regression to determine which attention and EF assessments were most strongly associated with autism or ADHD. More variance was accounted for in the model for the ADHD group (31%) compared to the autism group (2.7%). Finally, we ran odds ratios (using clinical cutoffs where available and 2 standard deviations below the mean when not) for each assessment measure, which generally demonstrated a greater significance within the indirect measures when compared to the direct measures. These results add to the growing literature of symptom variably across diagnostic groups allowing for better understanding of presentations in autism and ADHD and how best to assess diagnosis. It also highlights the increased difficulty in differentiating autism and controls when compared to ADHD and controls and the importance of indirect measures of attention and EF in this differentiation., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Advanced magnetic resonance imaging (MRI) techniques indicate that concussion (i.e., mild traumatic brain injury) disrupts brain structure and function in children. However, the functional connectivity of brain regions within global and local networks (i.e., functional connectome) is poorly understood in pediatric concussion. This prospective, longitudinal study addressed this gap using data from the largest neuroimaging study of pediatric concussion to date to study the functional connectome longitudinally after concussion as compared with mild orthopedic injury (OI). Children and adolescents ( n  = 967) 8-16.99 years with concussion or mild OI were recruited from pediatric emergency departments within 48 h post-injury. Pre-injury and 1-month post-injury symptom ratings were used to classify concussion with or without persistent symptoms based on reliable change. Subjects completed a post-acute (2-33 days) and chronic (3 or 6 months via random assignment) MRI scan. Graph theory metrics were derived from 918 resting-state functional MRI scans in 585 children (386 concussion/199 OI). Linear mixed-effects modeling was performed to assess group differences over time, correcting for multiple comparisons. Relative to OI, the global clustering coefficient was reduced at 3 months post-injury in older children with concussion and in females with concussion and persistent symptoms. Time post-injury and sex moderated group differences in local (regional) network metrics of several brain regions, including degree centrality, efficiency, and clustering coefficient of the angular gyrus, calcarine fissure, cuneus, and inferior occipital, lingual, middle occipital, post-central, and superior occipital gyrus. Relative to OI, degree centrality and nodal efficiency were reduced post-acutely, and nodal efficiency and clustering coefficient were reduced chronically after concussion (i.e., at 3 and 6 months post-injury in females; at 6 months post-injury in males). Functional network alterations were more robust and widespread chronically as opposed to post-acutely after concussion, and varied by sex, age, and symptom recovery at 1-month post-injury. Local network segregation reductions emerged globally (across the whole brain network) in older children and in females with poor recovery chronically after concussion. Reduced functioning between neighboring regions could negatively disrupt specialized information processing. Local network metric alterations were demonstrated in several posterior regions that are involved in vision and attention after concussion relative to OI. This indicates that functioning of superior parietal and occipital regions could be particularly susceptibile to the effects of concussion. Moreover, those regional alterations were especially apparent at later time periods post-injury, emerging after post-concussive symptoms resolved in most and persisted up to 6 months post-injury, and differed by biological sex. This indicates that neurobiological changes continue to occur up to 6 months after pediatric concussion, although changes emerge earlier in females than in males. Changes could reflect neural compensation mechanisms.

Background: Stimulant medication is the primary pharmacological treatment for attention dysregulation and is commonly prescribed for children with Attention-Deficit/Hyperactivity Disorder (ADHD) and Autism. Neuroimaging studies of these groups commonly use a 24-48-hour washout period to mediate the effects of stimulant medication on functional connectivity (FC) metrics. However, the impact of washout on functional connectivity has received limited study., Methods: We used fMRI data from participants with diagnosis of Autism and ADHD (and an off stimulant control) from the Adolescent Brain and Cognitive Development (ABCD) and Autism Brain Imaging Data Exchange (ABIDE) databases to explore the effect of simulant washout on FC. Connectivity within and between the default mode (DMN) and fronto-parietal networks (FPN) was examined, as these networks have previously been implicated in attention dysregulation and associated with stimulant medication usage. For each diagnostic group, we assessed effects in interconnectivity between DMN and FPN, intraconnectivity within DMN, and intraconnectivity within FPN., Results: We found no significant effect of medication status in intra- and inter-connectivity of the DMN and the FPN in either diagnostic group., Implications: Our findings suggest that more information is needed about the effect of stimulant medication, and washout, on the FC of attention networks in clinical populations., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

While there is growing interest in the use of functional magnetic resonance imaging-functional connectivity (fMRI-FC) for biomarker research, low measurement reliability of conventional acquisitions may limit applications. Factors known to impact FC reliability include scan length, head motion, signal properties, such as temporal signal-to-noise ratio (tSNR), and the acquisition state or task. As tasks impact signal in a region-wise fashion, they likely impact FC reliability differently across the brain, making task an important decision in study design. Here, we use the densely sampled Midnight Scan Club (MSC) dataset, comprising 5 h of rest and 6 h of task fMRI data in 10 healthy adults, to investigate regional effects of tasks on FC reliability. We further considered how BOLD signal properties contributing to tSNR, that is, temporal mean signal (tMean) and temporal standard deviation (tSD), vary across the brain, associate with FC reliability, and are modulated by tasks. We found that, relative to rest, tasks enhanced FC reliability and increased tSD for specific task-engaged regions. However, FC signal variability and reliability is broadly dampened during tasks outside task-engaged regions. From our analyses, we observed signal variability was the strongest driver of FC reliability. Overall, our findings suggest that the choice of task can have an important impact on reliability and should be considered in relation to maximizing reliability in networks of interest as part of study design., (© 2023 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Background: As Parkinson's disease (PD) advances, management is challenged by an increasingly variable and inconsistent response to oral dopaminergic therapy, requiring special considerations by the provider. Continuous 24 h/day subcutaneous infusion of foslevodopa/foscarbidopa (LDp/CDp) provides steady dopaminergic stimulation that can reduce symptom fluctuation., Objective: Our aim is to review the initiation, optimization, and maintenance of LDp/CDp therapy, identify possible challenges, and share potential mitigations., Methods: Review available LDp/CDp clinical trial data for practical considerations regarding the management of patients during LDp/CDp therapy initiation, optimization, and maintenance based on investigator clinical trial experience., Results: LDp/CDp initiation, optimization, and maintenance can be done without hospitalization in the clinic setting. Continuous 24 h/day LDp/CDp infusion can offer more precise symptom control than oral medications, showing improvements in motor fluctuations during both daytime and nighttime hours. Challenges include infusion-site adverse events for which early detection and prompt management may be required, as well as systemic adverse events (eg, hallucinations) that may require adjustment of the infusion rate or other interventions. A learning curve should be anticipated with initiation of therapy, and expectation setting with patients and care partners is key to successful initiation and maintenance of therapy., Conclusion: Continuous subcutaneous infusion of LDp/CDp represents a promising therapeutic option for individuals with PD. Individualized dose optimization during both daytime and nighttime hours, coupled with patient education, and early recognition of certain adverse events (plus their appropriate management) are required for the success of this minimally invasive and highly efficacious therapy., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Anna Jeong is an employee of AbbVie Inc., and may hold AbbVie Inc. stock and/or stock options. Agnita J. W. Boon is a study investigator and has served as an advisory board member for AbbVie Inc., Stada, and Ever Pharma. She has received a research grant from Stichting ParkinsonFonds and the Erasmus Trust Fund. Amy M. Spiegel is an employee of AbbVie Inc., and may hold AbbVie Inc. stock and/or stock options. Arjun Tarakad declarations of interest: none. Eric Freire-Alvarez has received advisory, consulting, and lectures fees from AbbVie Inc., Teva, Bial, Zambon, Esteve, UCB, and Neuraxpharm; and is an investigator on studies funded by AbbVie Inc., Neuroderm, Cerevel, Roche, Anavex, Bial, Zambon, Impax, and Irlab. Enrique Urrea-Mendoza has received advisory/consulting fees from: AbbVie Inc., Defeat MSA USA, and Medtronic. Filip Bergquist has received advisory and lecture fees from AbbVie Inc., GKC, and Britannia; and research support in kind from GKC. He is a board member of Arvid Carlsson Research AB and receives salary from the University of Gothenburg and Sahlgrenska University Hospital. Jason Aldred is a member of the faculty of the University of Washington and Washington State University. He is a study investigator and has received honorarium from AbbVie Inc., Allergan (now AbbVie Inc.), Teva, US WorldMeds, Medtronic, and Abbott. He is an investigator in studies sponsored by AbbVie Inc., Biogen, Acadia, Northwestern University, Neuroderm, Massachusetts General Hospital, and AstraZeneca. He is also a scientific advisor for AbbVie Inc. He has a clinical practice through Selkirk Neurology. Jia Jia is an employee of AbbVie Inc., and may hold AbbVie Inc. stock and/or stock options. Jorge Zamudio is an employee of AbbVie Inc., and may hold AbbVie Inc. stock and/or stock options. Manon Bouchard has received honoraria for consultancy, lectures, and advisory boards from AbbVie Inc., Allergan (now AbbVie Inc.), Merz, Ipsen, Lilly, Novartis, Paladin, Sunovion, and UCB. She is an investigator for AbbVie Inc., ES-therapeutics, Biohaven, and Pfizer. Maurizio F. Facheris is an employee of AbbVie Inc., and may hold AbbVie Inc. stock and/or stock options. Michael J. Soileau has received advisory/consulting fees from: AbbVie Inc., Abbott, Mertz Therapeutics, Medtronic, and Supernus. He has received research support from: AbbVie Inc., Cerevel Therapeutics, CND Lifesciences, Praxis Precision Medicine, and Teva. He has served on the speaking bureau for: AbbVie Inc., Amneal Pharmaceuticals, Kyowa Kirin, and Neurocrine Pharmaceuticals. Martha P. Arroyo is a study investigator with Leo Pharma and Allakos, and has received honoraria and consultant fees from AbbVie Inc. and BMS. She has a clinical practice through Lakeside Dermatology. Nahome Fisseha is an employee of AbbVie Inc., and may hold AbbVie Inc. stock and/or stock options. Pavnit Kukreja is an employee of AbbVie Inc., and may hold AbbVie Inc. stock and/or stock options. Robert A. Hauser serves on a scientific advisory board for Inhibikase and Stoparkinson. He has received consulting fees from AbbVie Inc., Amneal Pharmaceuticals, Avanex, Biogen, BlueRock Therapeutics, Forsee Pharmaceuticals, Global Kinetics, Inhibikase, Jazz Pharmaceuticals, Kyowa Kirin, MDCE Suzhou, MedRhythms, Merck, Merz, Neurocrine, Neuroderm, Ovid Therapeutics, PD Neurotechnology, Pharma Two B, Regenxbio, Revance, Sage Therapeutics, Scion NeuroStim, Stoparkinson, Sunovion, Supernus Pharmaceuticals, Tolmar, Tremor Research Group, Tris Pharma, UCB, and Vivifi Biotech. He has received speaking fees from Acorda, Amneal Pharmaceuticals, Cerevel, Inhibikase, Kyowa Kirin, Neurocrine Biosciences, Sunovion, and Supernus. His University has received research support from AbbVie Inc., Aeon Biopharma, Annovis Bio Inc., Artizan Biosciences, Biogen MA, Bukwang Pharmaceutical Co. Ltd., Cavion Inc., Cerevance Inc., Cerevel Therapeutics, Cynapsus Therapeutics, Enterin Inc., Genetech, Global Kinetics Corporation, Hoffman-La Roche Inc., Impax Laboratories, Inhibikase Therapeutics, Integrative Research Laboratories Sweden, Lundbeck Inc., Michael J. Fox Foundation for Parkinson’s Research, National Parkinson’s Foundation, Neuraly Inc., Neurocrine Biosciences, Neuroderm, Parkinson’s & Movement Disorder Alliance, Pharma Two B Ltd., Revance Therapeutics, Sage Therapeutics, Sanofi Pharmaceuticals, Scion NeuroStim, SunPharma, and UCB BioPharma. He holds stock options in Axial Therapeutics, Enterin, and Inhibikase as well as holds stock in Revance Therapeutics. He has received intellectual property interests from a Parkinson’s Disease Diary through his University. He acknowledges a Center of Excellence grant from the Parkinson Foundation. Rajesh Pahwa serves as a consultant for Abbott, AbbVie Inc., ACADIA, Acorda, Adamas, Amneal, CalaHealth, Global Kinetics, Impel, Neuropharma, Kyowa, Lundbeck, Mitsubishi, Neurocrine, Orbis Bioscience, PhotoPharmics, Prilenia, Sunovion, Teva Neuroscience, and US WorldMeds. He receives research support from Abbott, AbbVie Inc., Addex, Biogen, Biohaven, Boston Scientific, EIP, Global Kinetics, Impax, Intec, Lilly, Neuroderm, Neuraly, Parkinson’s Foundation, Pharma 2B, Prelinia, Roche, SIS, Sun Pharma, Sunovion, Theranexus, Theravance, US WorldMeds, and Voyager. He is also an investigator for AbbVie Inc. Sarah Bray has received advisory fees from AbbVie Inc., receives a salary from NSW Health, and is a Nurse Coordinator on studies funded by AbbVie Inc. Sara Dhanani received advisory honoraria from Amneal and AbbVie Inc., and is an investigator on studies funded by AbbVie Inc. Saritha Talapala is an employee of AbbVie Inc., and may hold AbbVie Inc. stock and/or stock options. Victor S. C. Fung receives a salary from NSW Health; has received unrestricted research grants from the Michael J. Fox Foundation, AbbVie Inc., and Merz; and receives royalties from Health Press Ltd. and Taylor and Francis Group LLC., (© 2024 AbbVie Inc.)

Objective: There is increasing interest in early intervention and detection strategies for youth at-risk of developing a serious mental illness (SMI). Little is known about early factors that may be related to the later development of a SMI; thus, the aim of this study was to determine what clinical factors might relate to the development of in this study psychosis, bipolar disorder and severe or recurrent major depression in at-risk youth., Method: The sample consisted of 162 youth aged 12-26 years at different stages of risk. Thirty-one participants developed a SMI during the study. Those who made a transition were compared on a range of baseline clinical and functional measures with those who did not make the transition. A Cox regression model was used to assess the association between measures and later development of a SMI., Results: Female sex, attenuated psychotic symptoms as assessed with the Scale of Psychosis-Risk Symptoms (SOPS) and ratings on the K-10 Distress Scale, were found to be significantly associated with the later transition to mental illness. Females were 2.77 times more likely to transition compared to males. For the SOPS and K-10 scales, there is a 14% increase in the transition rate relative to a one-scale increase in SOPS and a 7% increase in the transition rate relative to a one-point increase in the K-10., Conclusions: Results from these longitudinal data provide further insight into the specific clinical measures that may be pertinent in early detection of mental illnesses., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Cardiovascular disease (CVD) is one of the leading causes of death in Belgium. Current strategies for the prevention and management of CVD focus on reducing low-density lipoprotein cholesterol (LDL-C) levels. This analysis assessed whether LDL-C goals, recommended by the European Society of Cardiology (ESC)/European Atherosclerosis Society (EAS) guidelines, were being achieved in a Belgian study population., Methods: The cross-sectional, observational, DA VINCI study enrolled patients prescribed lipid-lowering therapy (LLT) between 21 June 2017 and 20 November 2018. Data for patients from Belgium were extracted for this country-specific analysis. Primary endpoint was the proportion of patients who achieved 2016 ESC/EAS risk-based LDL-C goals; attainment of 2019 risk-based LDL-C goals was evaluated post hoc ., Results: Of 497 enrolled patients, 41% were female and mean age was 68 years. Among subjects with an LDL-C measurement on stabilised LLT, moderate-intensity statin monotherapy was the most prescribed LLT regimen (59%). Overall, 63% of patients achieved their risk-based LDL-C goals according to the 2016 ESC/EAS guidelines. Among patients with established ASCVD, risk-based LDL-C goal attainment was higher in patients with peripheral arterial disease (53%) than patients with coronary (37%) and cerebrovascular disease (42%). According to the updated 2019 ESC/EAS guidelines, less than half (41%) of patients achieved their risk-based LDL-C goal. The proportion of primary and secondary prevention patients who achieved 2019 risk-based LDL-C goals was 59% and 18%, respectively., Conclusion: These findings reveal a large gap between the LDL-C goals advocated by the ESC/EAS and the levels achieved in routine clinical practice in Belgium.

Background: Cardiovascular disease affects over 7 million people in the UK and statins are often prescribed to mitigate cardiovascular risks. The effect of statins on a number of cancers is debated and their effect on Bacillus Calmette-Guérin (BCG) responsiveness in non-muscle invasive urinary bladder cancer (NMIBC) is not fully understood., Aims: This study aims to explore the difference in HMG Co-A reductase (HMGCR) expression in NMIBC on immunochemistry in BCG responders and non-responders while on statins., Method: Three hundred and thirty-two cases of intravesical BCG treatment for high-risk NMIBC between November 2003 and December 2017 were identified. Patients taking statins for at least 12 months before the diagnosis of NIMBC and with a follow-up of at least 5 years were included. They were divided into BCG responders and non-responders. Tumour tissue from these patients was immunohistochemically stained and quantitative image analysis carried out to assess and compare HMGCR expression in the groups., Results & Conclusion: This study showed a differential expression of HMGCR in responders vs. non-responders to BCG for high-risk NMIBC on statins. This data should form the basis of a further research and multi-centre study in a larger cohort, using HMGCR as a biomarker of response in patients on statins., Competing Interests: Declaration of conflicting interestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

The presence of shoreline microplastics (1-5 mm) and mesoplastics (5-25 mm) in estuarine ecosystems is ubiquitous, but there remains little data on their composition, contamination status and ecological impacts. Chessel Bay Nature Reserve, situated in the internationally protected Itchen Estuary in Southampton, UK, has serious issues with shoreline plastic accumulation. In evaluating potentially adverse ecological impacts, the influence of quantities of shoreline microplastic (mp) and mesoplastic (MeP) material and adsorbed contaminants (PAHs and trace metals) on the biometrics and population dynamics of the burrowing supralittoral amphipod, Orchestia gammarellus, was assessed in this study. mp/MeP concentrations were variable in surface (0-42%: 0-422,640 mg/kg dry sediment) and subsurface horizons (0.001-10%: 11-97,797 mg/kg dry sediment). Secondary microplastics accounted for 77% of the total microplastic load (dominated by fragments and foams), but also comprised 23% nurdles/pellets (primary microplastics). Sorption mechanisms between contaminants and natural sediments were proposed to be the main contributor to the retention of PAHs and trace metal contaminants and less so, by mp/MeP. O. gammarellus populations showed a positive correlation with microplastic concentrations (Spearman correlation, R = 0.665, p = 0.036). Some reported toxicological thresholds were exceeded in sediments, but no impacts related to chemical contaminant concentrations were demonstrated. This study highlights a protected site with the severe plastic contamination, and the difficulty in demonstrating in situ ecotoxicological impacts., (© 2023. The Author(s).)

During development cells receive a variety of signals, which are of crucial importance to their fate determination. One such source of signal is the Notch signalling pathway, where Notch activity regulates expression of target genes through the core transcription factor CSL. To understand changes in transcription factor behaviour that lead to transcriptional changes in Notch active cells, we have probed CSL behaviours in real time, using in vivo Single Molecule Localisation Microscopy. Trajectory analysis reveals that Notch-On conditions increase the fraction of bound CSL molecules, but also the proportion of molecules with exploratory behaviours. These properties are shared by the co-activator Mastermind. Furthermore, both CSL and Mastermind, exhibit characteristics of local exploration near a Notch target locus. A similar behaviour is observed for CSL molecules diffusing in the vicinity of other bound CSL clusters. We suggest therefore that CSL acquires an exploratory behaviour when part of the activation complex, favouring local searching and retention close to its target enhancers. This change explains how CSL can efficiently increase its occupancy at target sites in Notch-On conditions., (© 2023 Baloul et al.)

Depression and anxiety are associated with grey matter changes in subcortical regions in adults and adolescents. Parent psychopathology is associated with offspring brain structure, but it's unclear whether altered brain structure in children is associated with severity of parental depression and anxiety symptoms. We examined 123 youth (Mean age = 13.64; 62% female) with no clinically significant history of depression or anxiety and one parent diagnosed with current or past depressive or anxiety disorders. Parents completed the Mini International Neuropsychiatric Interview to assess diagnostic status and the Beck Depression Inventory-II, and the Generalized Anxiety Disorder-7 to assess current symptom severity. Youth underwent T1 weighted structural Magnetic Resonance Imaging scans. Bivariate analyses revealed higher parental depressive severity was not significantly associated with offspring grey matter. Parental anxiety severity was significantly associated with less left global surface area. When controlling for offspring age, sex and intracranial volume (ICV), offspring right surface area was negatively associated with parental depressive severity at a trend level. In previously depressed parents, greater parental depressive severity was significantly associated with offspring decreased left and right surface area. There were no significant associations between parental anxiety severity in previously depressed parents and offspring subcortical or cortical brain regions. These results highlight associations between parental depressive symptom severity and offspring brain structure and suggest that even within an already high-risk group of adolescents, there may be altered cortical surface area depending on parent symptom severity. This may help identify youth most at risk for developing a mood disorder and could help further early intervention and identification efforts., Competing Interests: Declaration of competing interest All authors have no financial disclosures or conflicts of interest to declare., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Purpose: Low-density lipoprotein cholesterol (LDL-C) recommendations differ between the 2018 American College of Cardiology/American Heart Association (ACC/AHA) and 2019 European Society of Cardiology/European Atherosclerosis Society (ESC/EAS) guidelines for patients with atherosclerotic cardiovascular disease (ASCVD) (< 70 vs. < 55 mg/dl, respectively). In the DA VINCI study, residual cardiovascular risk was predicted in ASCVD patients. The extent to which relative and absolute risk might be lowered by achieving ACC/AHA versus ESC/EAS LDL-C recommended approaches was simulated., Methods: DA VINCI was a cross-sectional observational study of patients prescribed lipid-lowering therapy (LLT) across 18 European countries. Ten-year cardiovascular risk (CVR) was predicted among ASCVD patients receiving stabilized LLT. For patients with LDL-C ≥ 70 mg/dl, the absolute LDL-C reduction required to achieve an LDL-C of < 70 or < 55 mg/dl (LDL-C of 69 or 54 mg/dl, respectively) was calculated. Relative and absolute risk reductions (RRRs and ARRs) were simulated., Results: Of the 2039 patients, 61% did not achieve LDL-C < 70 mg/dl. For patients with LDL-C ≥ 70 mg/dl, median (interquartile range) baseline LDL-C and 10-year CVR were 93 (81-115) mg/dl and 32% (25-43%), respectively. Median LDL-C reductions of 24 (12-46) and 39 (27-91) mg/dl were needed to achieve an LDL-C of 69 and 54 mg/dl, respectively. Attaining ACC/AHA or ESC/EAS goals resulted in simulated RRRs of 14% (7-25%) and 22% (15-32%), respectively, and ARRs of 4% (2-7%) and 6% (4-9%), respectively., Conclusion: In ASCVD patients, achieving ESC/EAS LDL-C goals could result in a 2% additional ARR over 10 years versus the ACC/AHA approach., (© 2022. The Author(s).)

Speech deepfakes are artificial voices generated by machine learning models. Previous literature has highlighted deepfakes as one of the biggest security threats arising from progress in artificial intelligence due to their potential for misuse. However, studies investigating human detection capabilities are limited. We presented genuine and deepfake audio to n = 529 individuals and asked them to identify the deepfakes. We ran our experiments in English and Mandarin to understand if language affects detection performance and decision-making rationale. We found that detection capability is unreliable. Listeners only correctly spotted the deepfakes 73% of the time, and there was no difference in detectability between the two languages. Increasing listener awareness by providing examples of speech deepfakes only improves results slightly. As speech synthesis algorithms improve and become more realistic, we can expect the detection task to become harder. The difficulty of detecting speech deepfakes confirms their potential for misuse and signals that defenses against this threat are needed., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Mai et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

While findings show that throughout development, there are child- and age-specific patterns of brain functioning, there is also evidence for significantly greater inter-individual response variability in young children relative to adults. It is currently unclear whether this increase in functional "typicality" (i.e., inter-individual similarity) is a developmental process that occurs across early childhood, and what changes in BOLD response may be driving changes in typicality. We collected fMRI data from 81 typically developing 4-8-year-old children during passive viewing of age-appropriate television clips and asked whether there is increasing typicality of brain response across this age range. We found that the "increasing typicality" hypothesis was supported across many regions engaged by passive viewing. Post hoc analyses showed that in a priori ROIs related to language and face processing, the strength of the group-average shared component of activity increased with age, with no concomitant decline in residual signal or change in spatial extent or variability. Together, this suggests that increasing inter-individual similarity of functional responses to audiovisual stimuli is an important feature of early childhood functional brain development., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: The Coronavirus (COVID-19) pandemic has exacerbated the risk for poor physical and mental health outcomes among vulnerable older adults. Multicomponent interventions could potentially prevent or reduce the risk of becoming frail; however, there is limited evidence about utilizing alternative modes of delivery where access to in-person care may be challenging. This randomized feasibility trial aimed to understand how a multicomponent rehabilitation program can be delivered remotely to vulnerable older adults with frailty during the pandemic., Methods: Participants were randomized to either a multimodal or socialization arm. Over a 12-week intervention period, the multimodal group received virtual care at home, which included twice-weekly exercise in small group physiotherapy-led live-streamed sessions, nutrition counselling and protein supplementation, medication consultation via a videoconference app, and once-weekly phone calls from student volunteers, while the socialization group received only once-weekly phone calls from the volunteers. The RE-AIM (Reach, Effectiveness, Adoption, Implementation and Maintenance) framework was used to evaluate the feasibility of the program. The main clinical outcomes were change in the 5-times sit-to-stand test (5 × STS) and Depression, Anxiety and Stress Scale (DASS-21) scores. The feasibility outcomes were analyzed using descriptive statistics and expressed as frequencies and mean percent with corresponding confidence intervals (CI). Analysis of covariance (ANCOVA) was used for the effectiveness component., Results: The program enrolled 33% (n = 72) of referrals to the study (n = 220), of whom 70 were randomized. Adoption rates from different referral sources were community self-referrals (60%), community organizations (33%), and healthcare providers (25%). At the provider level, implementation rates varied from 75 to 100% for different aspects of program delivery. Participant's adherence levels included virtual exercise sessions 81% (95% CI: 75-88%), home-based exercise 50% (95% CI: 38-62%), protein supplements consumption 68% (95% CI: 55-80%), and medication optimization 38% (95% CI: 21-59%). Most participants (85%) were satisfied with the program. There were no significant changes in clinical outcomes between the two arms., Conclusion: The GERAS virtual frailty rehabilitation study for community-dwelling older adults living with frailty was feasible in terms of reach of participants, adoption across referral settings, adherence to implementation, and participant's intention to maintain the program. This program could be feasibly delivered to improve access to socially isolated older adults where barriers to in-person participation exist. However, trials with larger samples and longer follow-up are required to demonstrate effectiveness and sustained behavior change., Trial Registration: ClinicalTrials.gov NCT04500366. Registered August 5, 2020, https://clinicaltrials.gov/ct2/show/NCT04500366., (© 2023. The Author(s).)

We assessed different aspects of tactile perception in young children (3-6 years) with autism. Autistic and neurotypical children completed vibrotactile tasks assessing reaction time, amplitude discrimination (sequential and simultaneous) and temporal discrimination (temporal order judgment and duration discrimination). Autistic children had elevated and more variable reaction times, suggesting slower perceptual-motor processing speed and/or greater distractibility. Children with autism also showed higher amplitude discrimination and temporal order judgement thresholds compared to neurotypical children. Tactile perceptual metrics did not associate with social or tactile sensitivities measured by parent-reports. Altered tactile behavioral responses appear in early childhood, can be quantified but appear dissociated from sensitivity. This implies these measures are complementary, but not necessarily related, phenomena of atypical tactile perception in autism., (© 2022. The Author(s).)

Approximately 10% of births are preterm [PTB; <37 weeks gestational age (GA)], which confers risk for cognitive, behavioral, and mental health challenges. Using the large and relatively diverse (i.e., designed to reflect sociodemographic variation in the United States population) Adolescent Brain Cognitive Development Study (ABCD Study), we characterized the impact of PTB on brain structure in middle-late childhood (9-10 years). The ABCD sample covers the GA spectrum, and the large sample size (∼11,500) permits consideration of how associations between PTB and brain structure are impacted by GA, sex, birthweight, and analytic choices such as controlling for total brain size. We found a pattern of relative cortical thinning in temporoparietal and dorsal prefrontal regions and thickening of medial prefrontal and occipital regions in PTB compared with children born full term (≥37 weeks GA). This pattern was apparent when controlling for mean thickness and when considering moderate (>32 and <37 weeks GA) and very PTB (≤32 weeks GA) separately, relative to full term birth. Surface area (SA) and subcortical volumes showed reductions in PTB children that were largely attenuated when controlling for brain size. Effects on cortical thickness (CT) and surface area were partially mediated by birthweight. Although boys are at increased risk for adverse outcomes following PTB, there was limited evidence of sex differences of PTB effects. Finally, cortical thickness effects estimated in a "discovery" sample ( N  = 7528) predicted GA in a holdout "replication" sample ( N  = 2139). Our findings help to clarify the effects of PTB on brain structure into late childhood across the GA spectrum., Competing Interests: The authors declare no competing financial interests., (Copyright © 2023 Nath et al.)

Background: The impact of the stepwise implementation of the 2019 European Society of Cardiology (ESC)/European Atherosclerosis Society (EAS) treatment algorithm on low-density lipoprotein cholesterol (LDL-C) goal attainment was simulated in patients from the DA VINCI study., Methods: Monte Carlo simulation was used to evaluate treatment optimisation scenarios, based on a patient's risk category: statin intensification (step 1), addition of ezetimibe (step 2), and addition of a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor (step 3). Residual cardiovascular risk and predicted relative and absolute risk reduction (RRR and ARR) in cardiovascular events were assessed., Findings: In DA VINCI, 2482 patients did not achieve their 2019 ESC/EAS LDL-C goals and were included in the simulation. In patients without atherosclerotic cardiovascular disease (ASCVD) ( n  = 962), 27.0% ( n  = 259) and 57.0% ( n  = 548 ) are likely to achieve their LDL-C goals at step 1 and step 2, respectively. Of those at very high risk without ASCVD ( n  = 74), 88.1% ( n  = 65) are likely to achieve their LDL-C goals at step 3. In patients with ASCVD ( n  = 1520), 12.0% ( n  = 183), 42.1% ( n  = 641) and 93.2% ( n  = 1416) are likely to achieve their LDL-C goals at steps 1, 2 and 3, respectively. In patients with and without ASCVD, treatment optimisation may result in mean simulated RRR of 24.0% and 17.7%, respectively, and ARR of 8.1% and 2.6%, respectively., Interpretation: Most patients at high cardiovascular risk are unlikely to achieve LDL-C goals through statin optimisation and ezetimibe, and will require a PCSK9 inhibitor, leading to greater reduction in cardiovascular risk., Funding: Amgen., Competing Interests: JB has received speaker fees from Amgen and research grant support from AstraZeneca. SB is an employee of Amgen Ltd and holds stock in Amgen. GV is an employee of Amgen (Europe) GmbH and holds stock in Amgen. ALC has received research grant(s)/support from Amgen, Eli Lilly, Menarini, Mylan, Sanofi, and Sanofi-Regeneron; and has served as a consultant for or received fees from Aegerion, Akcea, Amgen, Amryt, AstraZeneca, Daiichi Sankyo, Esperion, Genzyme, Ionis Pharmaceuticals, Kowa, Medco, Menarini, MSD, Mylan, Novartis, Recordati, Regeneron, and Sanofi. NP has received consultancy fees and financial support for research projects from Amgen and Pfizer, and financial support for arranging and speaking at educational meetings from Amgen, MSD and Pfizer. He holds no stocks and shares in any such companies. NP is supported by the National Institute for Health Research Senior Investigator Awards, Biomedical Research Centre funding, and the British Heart Foundation Research Centre Excellence Award. He has received financial support from several pharmaceutical companies which manufacture lipid lowering agents, for consultancy fees (Pfizer and Amgen), research projects and staff (Pfizer and Amgen) and for arranging and speaking at educational meetings (MSD, Amgen and Pfizer). He holds no stocks and shares in any such companies. AJV-V has participated, or is currently participating, in research grants to Imperial College London from Amgen, Daiichi Sankyo, MSD, Pfizer, Regeneron, and Sanofi-Aventis; has received personal fees for consulting from Bayer and Regeneron; and has received fees for lectures from Akcea, Amgen, Mylan and Ferrer; all outside the submitted work. KKR reports grants from Amgen, Daiichi Sankyo, MSD, Pfizer, Regeneron and Sanofi; and has received personal fees from Abbott, Amarin, Amgen, AstraZeneca, Bayer, Beren Therapeutics, Biologix Pharma, Boehringer Ingelheim, Cargene, CSL Behring, CRISPR, Eli Lilly Esperion, Kowa, New Amsterdam, Novartis, Novo Nordisk, Pfizer, Regeneron, Resverlogix, Sanofi, Silence Therapeutics, SCRIBE Therapeutics, Vaxxinity and Viatris., (© 2023 The Author(s).)

Gastroesophageal adenocarcinoma is a disease of older adults that is associated with a very poor prognosis. It is less common and has better outcomes in females. The reason for this is unknown but may relate to signalling via the main oestrogen receptors (ER) α and β. In this study, we sought to investigate this using the GO2 clinical trial patient cohort. GO2 recruited older and/or frail patients with advanced gastroesophageal cancer. Immunohistochemistry was performed on tumour samples from 194 patients. The median age of the population was 76 years (range 52-90), and 25.3% were female. Only one (0.5%) tumour sample was positive for ERα, compared to 70.6% for ERβ expression. There was no survival impact according to ERβ expression level. Female sex and younger age were associated with lower ERβ expression. Female sex was also associated with improved overall survival. To our knowledge, this is the largest study worldwide of ER expression in a cohort of patients with advanced gastroesophageal adenocarcinoma. It is also unique, given the age of the population. We have demonstrated that female sex is associated with better survival outcomes with palliative chemotherapy but that this does not appear to be related to ER IHC expression. The differing ER expression according to age supports the concept of a different disease biology with age.

Background: Higher levels of PTSD symptoms are present among trauma-exposed females v. males in adulthood; however, much less is known about the emergence of this sex difference during development., Methods: In a multi-study sample of 7-18-year-olds ( n = 3397), we examined the effect of sex and age on the severity of PTSD symptoms after a single incident trauma at 1 month (T1), and on symptom change after a natural recovery period of 3 (T2) and 6 months (T3). PTSD scores were harmonised across measurement types, and linear regressions were used to determine sex and age effects, adjusting for study level variance and trauma type., Results: A sex × age interaction was observed at T1 ( p < 0.001) demonstrating that older age was associated with greater PTSD symptom severity in females ( β = 0.008, p = 0.047), but less severe symptoms in males ( β = -0.011, p = 0.014). The same pattern was observed at T2 and T3, with sex differences beginning to emerge by age 12 years. PTSD symptoms decreased naturally by ~25% at T2 with little further improvement by T3. Further, females showed a greater reduction in symptoms at T3 than males, although the same effect was not observed at T2., Conclusions: Sex differences in PTSD symptoms become apparent during adolescence, due to opposing changes in susceptibility occurring in females and males with age. Understanding the factors contributing to these findings is likely to provide wider insight into sex-specific psychological vulnerability to trauma-related psychopathology.

Social interactions like group inclusion, receiving praise, or treating others kindly can be motivating and enjoyable. Social reward sensitivity, including motivation and enjoyment, varies between individuals. In early childhood, this variation may relate to differences in social experience and development. Social reward questionnaires have been developed to measure individual differences in social enjoyment for adolescents and adults, but no early childhood measure currently exists. Here, we describe the development and validation of the parent/caregiver report Social Reward Questionnaire-Early Childhood (SRQ-EC) for children aged 3-7 years. The SRQ-EC was developed to quantify both wanting (motivation) and liking (enjoyment) of social rewards, which were considered in separate factor models. For wanting and liking models, exploratory ( N = 126) and confirmatory ( N = 344) factor analyses identified that three subscales best represented early childhood social reward sensitivity, which were: Sociability (large groups), Admiration (praise and positive attention), and Prosocial Interactions and Compliance (kindness and rule following). SRQ-EC subscales were internally consistent (ω = 0.76-0.91, α = 0.75-0.88, mean interitem correlations = 0.38-0.60) with high test-retest reliability over 2-weeks ( r = 0.66-0.85, all p < .001). Subscales differentially associated with other social behavior and personality measures, suggesting construct validity. SRQ-EC subscale scores further showed differential and significant associations with autistic-like traits in nonautistic children. These results suggest that SRQ-EC subscale scores are reliable for assessing social reward sensitivity during early childhood, which could offer key developmental insight regarding interindividual variation in early social behavior. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Developmental lateralization of brain function is imperative for behavioral specialization, yet few studies have investigated differences between hemispheres in structural connectivity patterns, especially over the course of development. The present study compares the lateralization of structural connectivity patterns, or topology, across children, adolescents, and young adults. We applied a graph theory approach to quantify key topological metrics in each hemisphere including efficiency of information transfer between regions (global efficiency), clustering of connections between regions (clustering coefficient [CC]), presence of hub-nodes (betweenness centrality [BC]), and connectivity between nodes of high and low complexity (hierarchical complexity [HC]) and investigated changes in these metrics during development. Further, we investigated BC and CC in seven functionally defined networks. Our cross-sectional study consisted of 211 participants between the ages of 6 and 21 years with 93% being right-handed and 51% female. Global efficiency, HC, and CC demonstrated a leftward lateralization, compared to a rightward lateralization of BC. The sensorimotor, default mode, salience, and language networks showed a leftward asymmetry of CC. BC was only lateralized in the salience (right lateralized) and dorsal attention (left lateralized) networks. Only a small number of metrics were associated with age, suggesting that topological organization may stay relatively constant throughout school-age development, despite known underlying changes in white matter properties. Unlike many other imaging biomarkers of brain development, our study suggests topological lateralization is consistent across age, highlighting potential nonlinear mechanisms underlying developmental specialization., (© 2022 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Background and Aims: Urinary bladder recurrences (UBRs) after radical nephroureterectomy (RNUx) are a known challenge in patients with upper-tract urothelial cancers (UTUCs). We aim to assess factors associated with UBR and clonal-relatedness with resected UTUC., Methods: Patients who underwent RNUx for UTUC between 1998 and 2015 in five institutions were identified. Clonal relatedness between primary UTUC and subsequent UBR in a sub-cohort was assessed using next-generation sequencing. A Kaplan-Meier curve was used to assess differences in UBR between two groups (with or without ureteroscopic biopsy)., Results: Of 267 patients with complete records, 73 (27.3%) had UBR during follow-up. The five-year UBR-free survival in all patients was 64.7%. The five-year UBR-free-survival was inferior in patients who underwent URS biopsy compared with patients who did not undergo ureteroscopic biopsy (49.9% vs 76.4%, p  < 0.001). History of bladder tumour (HR, 95% CI; 2.94, 1.73-5.00, p  < 0.001), ureteroscopic biopsy (HR, 95% CI; 2.21, 1.38-3.53, p  = 0.001) and preoperative urine cytology ≥C3 (HR, 95% CI; 2.06, 1.24-3.40, p  = 0.005) were independently associated with UBR. Patients with ureteroscopic biopsy (n = 3/5) showed identical mutational changes for common genes ( TP53 and FGFR3 ) between primary UTUC and subsequent UBR., Conclusions: Ureteroscopic biopsy of UTUC is a significant risk factor for UBR. Qualitative clonality assessment showed identical mutational signatures between primary UTUC and UBR.

There are thousands of well-maintained high-quality open-source software utilities for all aspects of scientific data analysis. For more than a decade, the Galaxy Project has been providing computational infrastructure and a unified user interface for these tools to make them accessible to a wide range of researchers. To streamline the process of integrating tools and constructing workflows as much as possible, we have developed Planemo, a software development kit for tool and workflow developers and Galaxy power users. Here we outline Planemo's implementation and describe its broad range of functionality for designing, testing, and executing Galaxy tools, workflows, and training material. In addition, we discuss the philosophy underlying Galaxy tool and workflow development, and how Planemo encourages the use of development best practices, such as test-driven development, by its users, including those who are not professional software developers., (© 2023 Bray et al.; Published by Cold Spring Harbor Laboratory Press.)

While research has linked alterations in functional connectivity of the default mode (DMN), cognitive control (CCN), and salience networks (SN) to depression and anxiety, little research has examined whether these alterations may be premorbid vulnerabilities. This study examined resting state functional connectivity (RSFC) of the CCN, DMN, and SN as markers of risk for developing an onset of a depressive or anxiety disorder in adolescents at high familial risk for these disorders. At baseline, 135 participants aged 11-17 completed resting-state functional magnetic resonance imaging, measures of internalizing symptoms, and diagnostic interviews to assess history of depressive and anxiety disorders. Diagnostic assessments were completed again at 9- or 18-month follow-up for 112 participants. At baseline, increased CCN connectivity to areas of the visual network, and decreased connectivity between the left SN and the precentral gyrus, predicted an increased likelihood of a new onset at follow-up. Increased connectivity between the right SN and postcentral gyrus at baseline predicted first episode onsets at follow-up. Altered connectivity between these regions may represent a risk factor for developing a clinically significant onset of an internalizing disorder. Results may have implications for understanding the neural bases of internalizing disorders for early identification and prevention efforts., (© 2022. The Author(s).)

Small gene effects involved in complex/omnigenic traits remain costly to analyse using current genome-wide association studies (GWAS) because of the number of individuals required to return meaningful association(s), a.k.a. study power. Inspired by field theory in physics, we provide a different method called genomic informational field theory (GIFT). In contrast to GWAS, GIFT assumes that the phenotype is measured precisely enough and/or the number of individuals in the population is too small to permit the creation of categories. To extract information, GIFT uses the information contained in the cumulative sums difference of gene microstates between two configurations: (i) when the individuals are taken at random without information on phenotype values, and (ii) when individuals are ranked as a function of their phenotypic value. The difference in the cumulative sum is then attributed to the emergence of phenotypic fields. We demonstrate that GIFT recovers GWAS, that is, Fisher's theory, when the phenotypic fields are linear (first order). However, unlike GWAS, GIFT demonstrates how the variance of microstate distribution density functions can also be involved in genotype-phenotype associations when the phenotypic fields are quadratic (second order). Using genotype-phenotype simulations based on Fisher's theory as a toy model, we illustrate the application of the method with a small sample size of 1000 individuals., (Creative Commons Attribution license.)

We present two methods to reveal protein-ligand unbinding mechanisms in biased unbinding simulations by clustering trajectories into ensembles representing unbinding paths. The first approach is based on a contact principal component analysis for reducing the dimensionality of the input data, followed by identification of unbinding paths and training a machine learning model for trajectory clustering. The second approach clusters trajectories according to their pairwise mean Euclidean distance employing the neighbor-net algorithm, which takes into account input data bias in the distances set and is superior to dendrogram construction. Finally, we describe a more complex case where the reaction coordinate relevant for path identification is a single intraligand hydrogen bond, highlighting the challenges involved in unbinding path reaction coordinate detection.

Lay Abstract: Personal interests in autism are a source of joy, pride, and assist with the formation of social relationships. However, highly intense engagement can also interfere with other activities including activities of daily living. Theories have suggested that intense interests relate to executive functioning, reward sensitivity, and anxiety symptoms; but none of these theories have been tested in early childhood. Understanding which behavioral traits relate to intense interests in early childhood could help understand how intense interests may emerge, while also providing clues for how to manage interest intensity and best promote the many benefits of personal interests. We recruited families with autistic and non-autistic children aged 3-6 years. Parents completed questionnaires to assess children's interest diversity and intensity, executive functioning, reward sensitivity, and anxiety symptoms. We found that for autistic and non-autistic children, greater difficulty shifting attention between activities related to more intense interests. In autistic children only, difficulty with inhibitory control of attention also related to more intense interests. However, reward sensitivity and anxiety symptoms did not relate to interest intensity. Based on these observations, assisting young children with developing executive functioning skills could help with mediating the interference of interests in daily life to ultimately promote the many benefits of personal interests.

Background Lowering low-density lipoprotein cholesterol (LDL-C) levels decreases major cardiovascular events and is recommended for patients at elevated cardiovascular risk. However, appropriate doses of statin therapy are often insufficient to reduce LDL-C in accordance with current guidelines. In such cases, treatment could be supplemented with nonstatin lipid-lowering therapy. Methods and Results A systematic literature review and network meta-analysis were conducted on randomized controlled trials of nonstatin lipid-lowering therapy added to maximally tolerated statins, including statin-intolerant patients. The primary objective was to assess relative efficacy of nonstatin lipid-lowering therapy in reducing LDL-C levels at week 12. Secondary objectives included the following: LDL-C level reduction at week 24 and change in non-high-density lipoprotein cholesterol and apolipoprotein B at week 12. There were 48 randomized controlled trials included in the primary network meta-analysis. All nonstatin agents significantly reduced LDL-C from baseline versus placebo, regardless of background therapy. At week 12, evolocumab, 140 mg every 2 weeks (Q2W)/420 mg once a month, and alirocumab, 150 mg Q2W, were the most efficacious regimens, followed by alirocumab, 75 mg Q2W, alirocumab, 300 mg once a month, inclisiran, bempedoic acid/ezetimibe fixed-dose combination, and ezetimibe and bempedoic acid used as monotherapies. Primary end point results were generally consistent at week 24, and for other lipid end points at week 12. Conclusions Evolocumab, 140 mg Q2W/420 mg once a month, and alirocumab, 150 mg Q2W, were consistently the most efficacious nonstatin regimens when added to maximally tolerated statins to lower LDL-C, non-high-density lipoprotein cholesterol, and apolipoprotein B levels and facilitate attainment of guideline-recommended risk-stratified lipoprotein levels.

Background: Identifying early biomarkers of serious mental illness (SMI)-such as changes in brain structure and function-can aid in early diagnosis and treatment. Whole brain structural and functional connectomes were investigated in youth at risk for SMI., Methods: Participants were classified as healthy controls (HC; n = 33), familial risk for serious mental illness (stage 0; n = 31), mild symptoms (stage 1a; n = 37), attenuated syndromes (stage 1b; n = 61), or discrete disorder (transition; n = 9) based on clinical assessments. Imaging data was collected from two sites. Graph-theory based analysis was performed on the connectivity matrix constructed from whole-brain white matter fibers derived from constrained spherical deconvolution of the diffusion tensor imaging (DTI) scans, and from the correlations between brain regions measured with resting state functional magnetic resonance imaging (fMRI) data., Results: Linear mixed effects analysis and analysis of covariance revealed no significant differences between groups in global or nodal metrics after correction for multiple comparisons. A follow up machine learning analysis broadly supported the findings. Several non-overlapping frontal and temporal network differences were identified in the structural and functional connectomes before corrections., Conclusions: Results suggest significant brain connectome changes in youth at transdiagnostic risk may not be evident before illness onset., (© 2022. The Author(s).)