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Small populations with limited range are often threatened by inbreeding and reduced genetic diversity, which can reduce fitness and exacerbate population decline. One of the most extreme natural examples is the Devils Hole pupfish ( Cyprinodon diabolis ), an iconic and critically endangered species with the smallest known range of any vertebrate. This species has experienced severe declines in population size over the last 30 years and suffered major bottlenecks in 2007 and 2013, when the population shrunk to 38 and 35 individuals, respectively. Here, we analysed 30 resequenced genomes of desert pupfishes from Death Valley, Ash Meadows and surrounding areas to examine the genomic consequences of small population size. We found extremely high levels of inbreeding ( F ROH = 0.34-0.81) and an increased amount of potentially deleterious genetic variation in the Devils Hole pupfish as compared to other species, including unique, fixed loss-of-function alleles and deletions in genes associated with sperm motility and hypoxia. Additionally, we successfully resequenced a formalin-fixed museum specimen from 1980 and found that the population was already highly inbred prior to recent known bottlenecks. We thus document severe inbreeding and increased mutation load in the Devils Hole pupfish and identify candidate deleterious variants to inform management of this conservation icon.

Objectives: Emotional and interpersonal dysfunction appears central to nonsuicidal self-injury (NSSI), yet research examining the interplay of these factors among individuals with NSSI is limited. This study aimed to specify such associations before and after daily stressful events among individuals with (vs. without) NSSI., Methods: Young adult participants (M age  = 20.4) with past-year (n = 56) or no history (n = 47) of NSSI completed daily diary assessments over a 2-week period., Results: No differences in rates of positive or negative interpersonal experiences before or after stressful events were identified. NSSI participants, however, reported greater negative emotion following stressful events compared with non-NSSI participants. The presence (vs. absence) of a positive interpersonal experience following a stressful event was related to lower negative emotional responses only in the NSSI group., Conclusion: Positive interpersonal experiences may downregulate negative emotions following stressful events among individuals with NSSI, highlighting the potential relevance of interpersonal emotion regulation to this population., (© 2022 Wiley Periodicals LLC.)

Background: Low-income minority populations often confront barriers to professional nonpharmacologic management of chronic pain and, without this care, may have poorer daily function., Objective: To examine the association of professional nonpharmacologic chronic pain management in the past year categorized as physical interventions or mind-body interventions with current functional status., Design: Online, population-based survey., Setting: Community-dwelling Latinos from five southwestern states (California, Texas, Arizona, Nevada, and New Mexico)., Participants: The survey was offered to all Latino online panel members aged 35 to 75 years in 5 states (N = 1007). With weights, this sample represented 11,016,135 persons. Of 516 respondents (51%), 486 (94%) had valid surveys and, of these, 102 members (21%) had chronic noncancer pain. With weights, they represented 1,140,170 persons with chronic pain., Interventions: Not applicable., Main Outcome Measures: Daily impairment in mobility and in activities of daily living (ADLs)., Results: Of the weighted sample, 37.2% reported daily impairment in mobility and 29.4% in ADLs. Professional physical interventions for chronic pain were received by 41.2% and mind-body interventions received by 33.4% but usually with physical interventions. Adjusted odds ratios (AOR) of daily mobility impairment for respondents who used physical interventions with mind-body interventions or alone were both less than 0.10 (p < .01) versus none. Only professional physical intervention was associated with decreased odds for daily impairment in ADLs (AOR = 0.07; 95% confidence interval = 0.01 to 0.94; p = .045)., Conclusions: In a weighted sample of Latinos with chronic pain, professional physical interventions reduced the likelihood of daily impairment in mobility and ADLs., (© 2021 American Academy of Physical Medicine and Rehabilitation.)

Integrating across motivational models suggests that different self-damaging behaviors (SDBs) are enacted for similar reasons. However, it remains unclear whether some motives are more relevant to certain SDBs than others. To answer this question, the present study compared the salience of 8 potentially shared motives across 3 exemplar SDBs, selected to represent different points along the internalizing and externalizing spectra: binge drinking, disordered eating (binge eating, purging, fasting), and nonsuicidal self-injury (NSSI). Seven hundred and four first-year university students (73% female, M age  = 17.97) completed monthly surveys assessing their engagement in and motives for SDBs. Motives were conceptualized as either interpersonal (bonding with others, conforming with others, communicating strength, communicating distress, reducing demands) or intrapersonal (reducing negative emotions, enhancing positive emotions, punishing oneself). Multilevel models compared endorsement of each motive across SDBs. Results revealed that SDBs were motivated by similar goals, albeit to different degrees. Although some exceptions emerged, interpersonal motives were most salient to binge drinking, followed by disordered eating, and then NSSI. In contrast, intrapersonal motives were most salient to NSSI, followed by disordered eating, and then binge drinking. Motivational differences were also found within disordered eating. For example, punishing oneself was more relevant to purging and fasting than binge eating, whereas relieving negative emotions was more relevant to binge eating and purging than fasting. Similar to dimensional models that position SDBs on internalizing or externalizing spectra, the salience of motives for binge drinking and NSSI may fall on distinct spectra (i.e., interpersonal and intrapersonal, respectively), with motives for disordered eating exhibiting elements consistent with both spectra. This study supports a common motivational framework for investigating and potentially treating a variety of topographically distinct SDBs., (Copyright © 2022. Published by Elsevier Ltd.)

Objective: Behavioral models of nonsuicidal self-injury (NSSI) propose that experiencing desirable consequences following NSSI reinforces the behavior. However, these models do not specify whether experiencing more desirable consequences relative to other people (between-person), an individual's own average (within-person), or both, predicts NSSI severity. To address this gap, this study investigated the prospective, within- and between-person associations of desirable NSSI consequences with NSSI frequency (number of episodes) and versatility (number of methods)., Methods: Two hundred and ten individuals (93.81% female, M age  = 22.95) with a history of NSSI completed online surveys assessing NSSI consequences, frequency, and versatility every three months for one year., Results: Within-person increases in desirable emotional consequences were unrelated to NSSI frequency three months later but predicted increases in NSSI versatility. Within-person increases in desirable social consequences predicted decreases in NSSI frequency three months later but were unrelated to NSSI versatility. Between-person variability in desirable consequences was unrelated to NSSI severity., Conclusions: Findings were partially consistent with behavioral models of NSSI. Going forward, we recommend that: (1) behavioral models articulate the salience of within-person fluctuations in consequences; (2) research clarifies the role of social consequences; and (3) clinicians use repeated assessments of emotional consequences to identify periods of elevated NSSI risk., (© 2022 The American Association of Suicidology.)

Elimination of hepatitis C virus (HCV), a leading cause of liver disease in the USA and globally, has been made possible with the advent of highly efficacious direct acting antivirals (DAAs). DAA regimens offer cure of HCV with 8-12 weeks of a well-tolerated once daily therapy. With increasingly straightforward diagnostic and treatment algorithms, HCV infection can be managed not only by specialists, but also by primary care providers. Engaging primary care providers greatly increases capacity to diagnose and treat chronic HCV and ultimately make HCV elimination a reality. However, barriers remain at each step in the HCV cascade of care from screening to evaluation and treatment. Since primary care is at the forefront of patient contact, it represents the ideal place to concentrate efforts to identify barriers and implement solutions to achieve universal HCV screening and increase curative treatment., (© 2022. The Author(s), under exclusive licence to Society of General Internal Medicine.)

Introduction: People report multiple motives for nonsuicidal self-injury (NSSI), but few studies have examined how these motives relate to one another. This study identified person-centered classes of NSSI motives, their NSSI and psychopathological correlates, and their utility in predicting future NSSI across two samples., Methods: Participants were adolescents and young adults (aged 15-35) with recent NSSI recruited from online forums (n = 155, Sample 1) or the community (n = 127, Sample 2). Participants completed measures of NSSI, emotion regulation difficulties, borderline personality disorder (BPD), depression, and reported on their NSSI over 12 months., Results: Latent profile analyses yielded five classes in each sample: low interpersonal, self-punishment/interpersonal, moderate intra/interpersonal, high intra/interpersonal, and mainly interpersonal motives. Classes were not associated with lifetime NSSI characteristics, but highly motivated participants reported more severe depression and BPD symptoms, and greater emotion dysregulation than low-motivated participants. Those in the mainly interpersonal (Sample 1) and self-punishment/interpersonal (Sample 2) motives classes reported greater NSSI frequency during follow-up., Conclusions: This study identified five classes of NSSI motives. Participants who report multiple motives for NSSI may be more clinically severe, whereas those who report strong desires to communicate with others or punish themselves may be at the highest risk for more frequent NSSI over time., (© 2022 The American Association of Suicidology.)

Skeletal muscle growth is largely dependent on the proliferation and differentiation of muscle-specific stem cells known as satellite cells (SC). Previous work has shown that dietary inclusion of the vitamin D3 metabolite, 25-hydroxycholecalciferol (25OHD3), also called calcidiol, can promote skeletal muscle growth in post-hatch broiler chickens. Improving vitamin D status of broiler breeder hens by feeding 25OHD3 in addition to vitamin D3 has also been shown to positively impact progeny. Yet, whether combined pre- and post-hatch supplementation with 25OHD3 produces an additive or synergistic SC-mediated, skeletal muscle growth response remains unanswered. To evaluate the effect of combined maternal and post-hatch dietary 25OHD3 supplementation on the growth and SC mitotic activity of the Pectoralis major (PM) muscles in broiler chickens, a randomized complete block design experiment with the main effects of maternal diet (MDIET) and post-hatch diet (PDIET) arranged in a 2 × 2 factorial treatment structure was conducted. From 25 to 36 wk of age, broiler breeder hens were fed 1 of 2 MDIET formulated to provide 5,000 IU D3 (MCTL) or 2,240 IU of D3 + 2,760 IU of 25OHD3 per kg of feed (M25OHD3). Their male broiler chick offspring (n = 400) hatched from eggs collected from 35 to 36 wk of age were reared in raised floor pens. Broilers were fed 1 of 2 PDIET formulated to provide 5,000 IU of D3 per kg of feed (PCTL) or 2,240 IU of D3 + 2,760 IU of 25OHD3 per kg of feed (P25OHD3). Muscle was collected at days 4, 8, 15, 22, and 29 and stored until immunofluorescence analysis. Data were analyzed as a 2-way ANOVA with SAS GLIMMIX. Dietary 25OHD3 was effectively transferred from hen plasma to egg yolks (P = 0.002) and to broiler progeny plasma (days 4 to 22; P ≤ 0.044). Including 25OHD3 in either MDIET or PDIET altered PM hypertrophic growth prior to day 29 (P ≥ 0.001) and tended to reduce Wooden Breast severity (P ≤ 0.089). Mitotic SC populations were increased in PM of MCTL:P25OHD3 and M25OHD:PCTL-fed broilers at d 4 (P = 0.037). At d 8, the PM mitotic SC populations were increased 33% by P25OHD3 (P = 0.054). The results of this study reveal that combined maternal and post-hatch 25OHD3 supplementation does not produce additive or synergistic effects on SC-mediated broiler muscle growth. However, vitamin D status improvement through dietary 25OHD3 inclusion in either the maternal or post-hatch diet stimulated broiler breast muscle growth by increasing proliferating SC populations., (© The Author(s) 2022. Published by Oxford University Press on behalf of the American Society of Animal Science. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Transactional developmental theories propose that poor parenting behaviors contribute to youth substance use, and youth substance use contributes to poor parenting behaviors. However, research aimed at testing these theories has not distinguished: (1) between- and within-person sources of variance; (2) maternal and paternal parenting behaviors; and (3) alcohol, marijuana, and other illicit drug use. This study addressed these limitations by investigating the reciprocal associations between maternal and paternal warmth and hostility with alcohol, marijuana, and other illicit drug use among justice-involved adolescents, an at-risk population for substance use. 1354 justice-involved adolescents (86.4% male; M age  = 16.04 [SD = 0.14], range = 14-17; 41.4% Black, 33.5% Hispanic, 20.2% White, 4.8% other race/ethnicity) completed self-reports assessing parental warmth, parental hostility, and substance use every six months for 36 months. Random-intercept structural equation models disaggregated between- and within-person associations. At the between-person level, maternal and paternal warmth were negatively associated with alcohol, marijuana, and other illicit drug use, whereas maternal and paternal hostility were positively associated with alcohol, marijuana, and other illicit drug use. At the within-person level, maternal and paternal warmth predicted decreases in marijuana and other illicit drug use, and paternal warmth predicted decreases in alcohol use six months later. Maternal hostility predicted increases in subsequent marijuana and other illicit drug use. Marijuana and other illicit drug use predicted decreases in subsequent paternal hostility. The results are partially consistent with transactional developmental models proposing recursive influences between parenting behaviors and youth substance use. Evocative effects were in the opposite direction than expected and specific to fathers, such that youth drug use was related to improvements in the father-youth relationship. The results support the potential utility of family-based interventions for substance use among justice-involved adolescents., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Amyotrophic lateral sclerosis (ALS) patients show a myriad of energetic abnormalities, such as weight loss, hypermetabolism, and dyslipidaemia. Evidence suggests that these indices correlate with and ultimately affect the duration of survival. This review aims to discuss ALS metabolic abnormalities in the context of autophagy, the primordial system acting at the cellular level for energy production during nutrient deficiency. As the primary pathway of protein degradation in eukaryotic cells, the fundamental role of cellular autophagy is the adaptation to metabolic demands. Therefore, autophagy is tightly coupled to cellular metabolism. We review evidence that the delicate balance between autophagy and metabolism is aberrant in ALS, giving rise to intracellular and systemic pathophysiology observations. Understanding the metabolism autophagy crosstalk can lead to the identification of novel therapeutic targets for ALS.

Lipid metabolism is profoundly dysregulated in amyotrophic lateral sclerosis (ALS), yet the lipid composition of the white matter, where the myelinated axons of motor neurons are located, remains uncharacterised. We aimed to comprehensively characterise how myelin is altered in ALS by assessing its lipid and protein composition. We isolated white matter from the motor cortex from post-mortem tissue of ALS patients (n = 8 sporadic ALS cases and n = 6 familial ALS cases) and age- and sex-matched controls (n = 8) and conducted targeted lipidomic analyses, qPCR for gene expression of relevant lipid metabolising enzymes and Western blotting for myelin proteins. We also quantified myelin density by using spectral confocal reflectance microscopy (SCoRe). Whilst myelin protein composition was similar in ALS and control tissue, both the lipid levels and the expression of their corresponding enzymes were dysregulated, highlighting altered lipid metabolism in the white matter as well as a likely change in myelin composition. Altered myelin composition could contribute to motor neuron dysfunction, and this highlights how oligodendrocytes may play a critical role in ALS pathogenesis.

Amyotrophic lateral sclerosis (ALS) is caused by selective degeneration of motor neurons in the brain and spinal cord; however, the primary cell death pathway(s) mediating motor neuron demise remain elusive. We recently established that necroptosis, an inflammatory form of regulated cell death, was dispensable for motor neuron death in a mouse model of ALS, implicating other forms of cell death. Here, we confirm these findings in ALS patients, showing a lack of expression of key necroptotic effector proteins in spinal cords. Rather, we uncover evidence for ferroptosis, a recently discovered iron-dependent form of regulated cell death, in ALS. Depletion of glutathione peroxidase 4 (GPX4), an anti-oxidant enzyme and central repressor of ferroptosis, occurred in post-mortem spinal cords of both sporadic and familial ALS patients. GPX4 depletion was also an early and universal feature of spinal cords and brains of transgenic mutant superoxide dismutase 1 (SOD1 G93A ), TDP-43 and C9orf72 mouse models of ALS. GPX4 depletion and ferroptosis were linked to impaired NRF2 signalling and dysregulation of glutathione synthesis and iron-binding proteins. Novel BAC transgenic mice overexpressing human GPX4 exhibited high GPX4 expression localised to spinal motor neurons. Human GPX4 overexpression in SOD1 G93A mice significantly delayed disease onset, improved locomotor function and prolonged lifespan, which was attributed to attenuated lipid peroxidation and motor neuron preservation. Our study discovers a new role for ferroptosis in mediating motor neuron death in ALS, supporting the use of anti-ferroptotic therapeutic strategies, such as GPX4 pathway induction and upregulation, for ALS treatment., (© 2021. The Author(s), under exclusive licence to ADMC Associazione Differenziamento e Morte Cellulare.)

Mutations in profilin 1 (PFN1) have been identified in rare familial cases of Amyotrophic Lateral Sclerosis (ALS). PFN1 is involved in multiple pathways that could intervene in ALS pathology. However, the specific pathogenic role of PFN1 mutations in ALS is still not fully understood. We hypothesized that PFN1 could play a role in regulating autophagy pathways and that PFN1 mutations could disrupt this function. We used patient cells (lymphoblasts) or tissue (post-mortem) carrying PFN1 mutations (M114T and E117G), and designed experimental models expressing wild-type or mutant PFN1 (cell lines and novel PFN1 mice established by lentiviral transgenesis) to study the effects of PFN1 mutations on autophagic pathway markers. We observed no accumulation of PFN1 in the spinal cord of one E117G mutation carrier. Moreover, in patient lymphoblasts and transfected cell lines, the M114T mutant PFN1 protein was unstable and deregulated the RAB9-mediated alternative autophagy pathway involved in the clearance of damaged mitochondria. In vivo, motor neurons expressing M114T mutant PFN1 showed mitochondrial abnormalities. Our results demonstrate that the M114T PFN1 mutation is more deleterious than the E117G variant in patient cells and experimental models and suggest a role for the RAB9-dependent autophagic pathway in ALS.

Introduction: Improved treatment regimens have led to increased survival rates among childhood cancer survivors (CCS), and more than 84% of all children diagnosed with cancer will experience long-term survival or cure. Survivors are susceptible to late effects of cancer treatment often requiring lifelong follow-up care, as many of these conditions can be prevented or mitigated with surveillance. Integrating primary care (PC) and childhood cancer survivorship care can improve follow-up for survivors, however, little integrative research exists. This scoping review aims to: identify and describe existing models of care that integrate PC and childhood cancer survivorship care, examine the effectiveness of these models of care, and characterise the barriers and facilitators for the integration of PC for CCS., Methods and Analysis: A comprehensive empirical literature search of three electronic databases (PubMed, CINAHL, and Embase) was employed to identify potentially relevant citations on 1 October 2020. The population, independent variables/intervention, comparator, outcomes, timing, setting and study design/other limiters (PICOTSS) framework was used to inform protocol development. The Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) checklist and explanation will be used to report study findings. The search strategy will be completed again prior to publication to ensure recent empirical research is accounted for., Ethics and Dissemination: This research is exempt from Institutional Review Board (IRB) review. Approval from a research ethics board for this study was not required as it does not involve human participants or unpublished secondary data. The findings from this scoping review will be disseminated through peer-reviewed scientific manuscripts, clinical conference presentations, professional networks and digital communications using social media platforms such as Twitter. This study has been registered with Open Science Framework: https://osf.io/92xbg., Competing Interests: Competing interests: Author LK received an honorarium by the Southern California Association for Pediatric Hematology Oncology Nurses (SCAPHON)., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: In light of recent evidence that the coronavirus disease 2019 (COVID-19) pandemic has resulted in marked increases in depression, anxiety, substance use, and other mental health concerns among Canadian adolescents, we investigated the rates of self-harm thoughts and behaviours in this population. Specifically, this study explored: (1) the demographic and geographic distributions of suicidal ideation (SI) and deliberate self-harm (DSH), and (2) the associations of mental health and substance use with SI and DSH., Method: A total of 809 Canadian adolescents, aged 12-18 years, completed an online survey between June 17, 2020 and July 31, 2020., Results: 44% of adolescents reported experiencing SI since the pandemic began, while 32% reported engaging in DSH. SI and DSH were more common among youth who: identified as transgender, non-binary or gender fluid; who did not reside with both parents; and who reported psychiatric concerns or frequent cannabis use., Conclusion: Canadian adolescents appear to be experiencing higher rates of self-harm thoughts and behaviours relative to before the COVID-19 pandemic. It is important for adults who are likely to interact with distressed youth to be aware of potential warning signs that a youth is struggling with self-harm, and to refer youth to specialty mental health services where appropriate.

Amyotrophic lateral sclerosis is a late-onset adult neurodegenerative disease, although there is mounting electrophysiological and pathological evidence from patients and animal models for a protracted preclinical period of motor neuron susceptibility and dysfunction, long before clinical diagnosis. The key molecular mechanisms linked to motor neuron vulnerability in amyotrophic lateral sclerosis have been extensively studied using transcriptional profiling in motor neurons isolated from adult mutant superoxide dismutase 1 mice. However, neonatal and embryonic motor neurons from mutant superoxide dismutase 1 mice show abnormal morphology and hyperexcitability, suggesting preceding transcriptional dysregulation. Here, we used RNA sequencing on motor neurons isolated from embryonic superoxide dismutase 1 G93A mice to determine the earliest molecular mechanisms conferring neuronal susceptibility and dysfunction known in a mouse model of amyotrophic lateral sclerosis. Transgenic superoxide dismutase 1 G93A mice expressing the spinal motor neuron homeobox HB9:green fluorescent protein reporter allowed unambiguous identification and isolation of motor neurons using fluorescence-activated cell sorting. Gene expression profiling of isolated motor neurons revealed transcriptional dysregulation in superoxide dismutase 1 G93A mice as early as embryonic Day 12.5 with the majority of differentially expressed genes involved in RNA processing and α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate-mediated glutamate receptor signalling. We confirmed dysregulation of the α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate receptor Subunit 2, at transcript and protein levels, in embryonic superoxide dismutase 1 G93A mouse motor neurons and human motor neurons derived from amyotrophic lateral sclerosis patient induced pluripotent stem cells harbouring pathogenic superoxide dismutase 1 mutations. Mutant superoxide dismutase 1 induced pluripotent stem cell-derived motor neurons showed greater vulnerability to α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate-mediated excitotoxicity, consistent with α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate receptor Subunit 2 downregulation. Thus, α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate receptor Subunit 2 deficiency leading to enhanced α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate receptor signalling, calcium influx, hyperexcitability, and chronic excitotoxicity is a very early and intrinsic property of spinal motor neurons that may trigger amyotrophic lateral sclerosis pathogenesis later in life. This study reinforces the concept of therapeutic targeting of hyperexcitability and excitotoxicity as potential disease-modifying approaches for amyotrophic lateral sclerosis., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Sex steroid hormones have been implicated as disease modifiers in the neurodegenerative disorder amyotrophic lateral sclerosis (ALS). Androgens, signalling via the androgen receptor (AR), predominate in males, and have widespread actions in the periphery and the central nervous system (CNS). AR translocates to the cell nucleus when activated upon binding androgens, whereby it regulates transcription of target genes via the classical genomic signalling pathway. We previously reported that AR protein is decreased in the lumbar spinal cord tissue of symptomatic male SOD1 G93A mice. Here, we further explored the changes in AR within motor neurons (MN) of the CNS, assessing their nuclear AR content and propensity to degenerate by endstage disease in male SOD1 G93A mice. We observed that almost all motor neuron populations had undergone significant loss in nuclear AR in SOD1 G93A mice. Interestingly, loss of nuclear AR was evident in lumbar spinal MNs as early as the pre-symptomatic age of 60 days. Several MN populations with high AR content were identified which did not degenerate in SOD1 G93A mice. These included the brainstem ambiguus and vagus nuclei, and the sexually dimorphic spinal MNs: cremaster, dorsolateral nucleus (DLN) and spinal nucleus of bulbocavernosus (SNB). In conclusion, we demonstrate that AR loss directly associates with MN vulnerability and disease progression in the SOD1 G93A mouse model of ALS., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 McLeod, Chiam, Perera, Lau, Boon and Turner.)

Chronic hepatitis C virus (HCV) increases the risk for hepatocellular carcinoma. Despite higher prevalence of HCV in persons born 1945-1965 (baby boomer), screening has not been widely adopted. Both primary care providers (PCPs) and associate care providers (ACPs) need to be educated about the rationale and methods to screen for HCV. In five Federally Qualified Health Centers serving low-income Hispanic communities, PCPs and ACPs attended a 50-min training lecture about HCV epidemiology, screening methods, and evaluation. Using a 12-item questionnaire, knowledge and attitudes were compared for PCPs and ACPs at baseline (pre-test) and following training (post-test). A higher proportion of PCPs correctly answered 3 of 6 knowledge questions on both pre-test and post-test but ACPs' showed more improvement in knowledge (all P < 0.05). ACPs had more favorable attitudes about linking patients to care on pre- and post-tests than PCPs, and ACPs' attitudes improved on all 6 items versus 4 for PCPs. Both PCPs and ACPs improved knowledge and attitudes after training about HCV screening but ACPs had more favorable attitudes than PCPs. Engaging the entire primary care practice team in learning about HCV screening promotes knowledge and attitudes necessary for successful implementation., (© 2020. American Association for Cancer Education.)

Background: Amyotrophic lateral sclerosis (ALS) is a complex, late-onset, neurodegenerative disease with a genetic contribution to disease liability. Genome-wide association studies (GWAS) have identified ten risk loci to date, including the TNIP1/GPX3 locus on chromosome five. Given association analysis data alone cannot determine the most plausible risk gene for this locus, we undertook a comprehensive suite of in silico, in vivo and in vitro studies to address this., Methods: The Functional Mapping and Annotation (FUMA) pipeline and five tools (conditional and joint analysis (GCTA-COJO), Stratified Linkage Disequilibrium Score Regression (S-LDSC), Polygenic Priority Scoring (PoPS), Summary-based Mendelian Randomisation (SMR-HEIDI) and transcriptome-wide association study (TWAS) analyses) were used to perform bioinformatic integration of GWAS data (N cases = 20,806, N controls = 59,804) with 'omics reference datasets including the blood (eQTLgen consortium N = 31,684) and brain (N = 2581). This was followed up by specific expression studies in ALS case-control cohorts (microarray N total = 942, protein N total = 300) and gene knockdown (KD) studies of human neuronal iPSC cells and zebrafish-morpholinos (MO)., Results: SMR analyses implicated both TNIP1 and GPX3 (p < 1.15 × 10 -6 ), but there was no simple SNP/expression relationship. Integrating multiple datasets using PoPS supported GPX3 but not TNIP1. In vivo expression analyses from blood in ALS cases identified that lower GPX3 expression correlated with a more progressed disease (ALS functional rating score, p = 5.5 × 10 -3 , adjusted R 2 = 0.042, B effect = 27.4 ± 13.3 ng/ml/ALSFRS unit) with microarray and protein data suggesting lower expression with risk allele (recessive model p = 0.06, p = 0.02 respectively). Validation in vivo indicated gpx3 KD caused significant motor deficits in zebrafish-MO (mean difference vs. control ± 95% CI, vs. control, swim distance = 112 ± 28 mm, time = 1.29 ± 0.59 s, speed = 32.0 ± 2.53 mm/s, respectively, p for all < 0.0001), which were rescued with gpx3 expression, with no phenotype identified with tnip1 KD or gpx3 overexpression., Conclusions: These results support GPX3 as a lead ALS risk gene in this locus, with more data needed to confirm/reject a role for TNIP1. This has implications for understanding disease mechanisms (GPX3 acts in the same pathway as SOD1, a well-established ALS-associated gene) and identifying new therapeutic approaches. Few previous examples of in-depth investigations of risk loci in ALS exist and a similar approach could be applied to investigate future expected GWAS findings., (© 2021. The Author(s).)

Nonsuicidal self-injury (NSSI) typically begins in adolescence and remits by early adulthood, but few prospective studies have investigated the long-term impact of NSSI initiation and cessation on young people's wellbeing. We examined changes in psychosocial risk associated with NSSI onset and offset in an accelerated longitudinal study of 662 adolescents (12-18 years old) who were followed biennially for 10 years. Of the 133 participants who reported NSSI, 100 had stopped engaging in NSSI by the study's end. NSSI initiation was associated with concurrent increases in depression, anxiety, externalizing symptoms, peer victimization, alcohol, tobacco and illicit substance use, and concurrent declines in physical self-concept, parent, and peer support. As NSSI persisted, youth experienced further increases in anxiety and cannabis use, and declines in physical self-concept. NSSI cessation was associated with concurrent increases in alcohol, cannabis, and tobacco use. With sustained cessation, however, youth experienced gradual improvements in depression, anxiety, externalizing symptoms, peer victimization, as well as gradual reductions in alcohol and tobacco use. By early adulthood, participants who reported ongoing NSSI worked fewer hours and were more likely to delay medical treatment for financial reasons versus those without NSSI histories, and reported less environmental mastery versus those who had discontinued NSSI. Youth who had discontinued NSSI, in turn, reported less environmental mastery and self-acceptance versus youth who never engaged in NSSI. These results contextualize NSSI cessation alongside indicators of psychological, social, and behavioral wellbeing, and underscore the persistence of psychosocial vulnerability after NSSI has resolved. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

This study examines the indirect effects of affect dysregulation and suppression on the associations between family stress from confinement, maltreatment, and adolescent mental health during COVID-19. We examined both adolescent and caregiver perspectives to yield a more well-rounded understanding of these associations than afforded in previous research. Using both adolescent ( N  = 809, M age  = 15.66) and caregiver ( N  = 578) samples, family stress from confinement, exposure to physical and psychological maltreatment, affect dysregulation and suppression, and youth internalizing and externalizing symptoms were measured in the summer of 2020, following three months of stay-at-home orders due to COVID-19. Affect dysregulation partially accounted for the associations between family stress from confinement and psychological maltreatment on both internalizing and externalizing symptoms for youth and caregiver report. Suppression partially accounted for the associations between family stress and maltreatment on internalizing and externalizing symptoms in the youth sample, but only for internalizing symptoms in the caregiver sample. Understanding family predictors of adolescents' mental health concerns and their underlying mechanisms, affect dysregulation and suppression, can inform mental health interventions during and following the COVID-19 pandemic., (© The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2021.)

The objective of this study was to conduct an ecologically valid test of etiological models of deliberate self-harm (DSH) during the COVID-19 pandemic. Using a sample of Canadian adolescents, we investigated: (1) the association between COVID-19-related stress and DSH; (2) whether emotion regulation (ER) difficulties mediated/moderated this association, including whether these effects differed by age; and (3) whether the mediating/moderating effects of ER difficulties were stronger among socially distanced youth. Canadian adolescents (N = 809) aged 12-18 were recruited on social media and completed an online survey. COVID-19-related stress was associated with recent DSH. Nonacceptance of emotional responses and limited access to ER strategies fully mediated this association. The indirect effect through nonacceptance of emotional responses was stronger among more socially distanced youth, whereas the indirect effect through limited access to ER strategies was stronger among older and more socially distanced youth. COVID-19-related stress and ER difficulties did not interact to predict DSH, nor did age or social distancing moderate these interactions. These results align with etiological models proposing central roles for stress and ER difficulties in DSH. Furthermore, this study underscores a need to support adolescents, particularly older teens with reduced in-person interactions, in adaptively coping with pandemic-related stress., (Copyright © 2021 Elsevier B.V. All rights reserved.)

The selective degeneration of both upper motor neurons (UMNs) and lower motor neurons (LMNs) is the pathological hallmark of amyotrophic lateral sclerosis (ALS). Unlike the simple organisation of LMNs in the brainstem and spinal cord, UMNs are embedded in the complex cytoarchitecture of the primary motor cortex, which complicates their identification. UMNs therefore remain a challenging neuronal population to study in ALS research, particularly in the early pre-symptomatic stages of animal models. A better understanding of the mechanisms that lead to selective UMN degeneration requires unequivocal visualization and cellular identification of vulnerable UMNs within the heterogeneous cortical neuronal population and circuitry. Here, we review recent novel gene delivery methods developed to cellularly identify vulnerable UMNs and modulate their activity in various mouse models. A critical overview of retrograde tracers, viral vectors encoding reporter genes and transgenic reporter mice used to visualize UMNs in mouse models of ALS is provided. Functional targeting of UMNs in vivo with the advent of optogenetic and chemogenetic technology is also discussed. These exciting gene delivery techniques will facilitate improved anatomical mapping, cell-specific gene expression profiling and targeted manipulation of UMN activity in mice. These advancements in the field pave the way for future work to uncover the precise role of UMNs in ALS and improve future therapeutic targeting of UMNs.

Cortical hyperexcitability is an early and intrinsic feature of both sporadic and familial forms of amyotrophic lateral sclerosis (ALS).. Importantly, cortical hyperexcitability appears to be associated with motor neuron degeneration, possibly via an anterograde glutamate-mediated excitotoxic process, thereby forming a pathogenic basis for ALS. The presence of cortical hyperexcitability in ALS patients may be readily determined by transcranial magnetic stimulation (TMS), a neurophysiological tool that provides a non-invasive and painless method for assessing cortical function. Utilising the threshold tracking TMS technique, cortical hyperexcitability has been established as a robust diagnostic biomarker that distinguished ALS from mimicking disorders at early stages of the disease process. The present review discusses the pathophysiological and diagnostic utility of cortical hyperexcitability in ALS., (Copyright © 2021. Published by Elsevier B.V.)

Most patients with advanced solid cancers exhibit features of cachexia, a debilitating syndrome characterized by progressive loss of skeletal muscle mass and strength. Because the underlying mechanisms of this multifactorial syndrome are incompletely defined, effective therapeutics have yet to be developed. Here, we show that diminished bone morphogenetic protein (BMP) signaling is observed early in the onset of skeletal muscle wasting associated with cancer cachexia in mouse models and in patients with cancer. Cancer-mediated factors including Activin A and IL-6 trigger the expression of the BMP inhibitor Noggin in muscle, which blocks the actions of BMPs on muscle fibers and motor nerves, subsequently causing disruption of the neuromuscular junction (NMJ), denervation, and muscle wasting. Increasing BMP signaling in the muscles of tumor-bearing mice by gene delivery or pharmacological means can prevent muscle wasting and preserve measures of NMJ function. The data identify perturbed BMP signaling and denervation of muscle fibers as important pathogenic mechanisms of muscle wasting associated with tumor growth. Collectively, these findings present interventions that promote BMP-mediated signaling as an attractive strategy to counteract the loss of functional musculature in patients with cancer., (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Autophagy, which mediates the delivery of cytoplasmic substrates to the lysosome for degradation, is essential for maintaining proper cell homeostasis in physiology, ageing, and disease. There is increasing evidence that autophagy is defective in neurodegenerative disorders, including motor neurons affected in amyotrophic lateral sclerosis (ALS). Restoring impaired autophagy in motor neurons may therefore represent a rational approach for ALS. Here, we demonstrate autophagy impairment in spinal cords of mice expressing mutant TDP-43 Q331K or co-expressing TDP-43 WTxQ331K transgenes. The clinically approved anti-hypertensive drug rilmenidine was used to stimulate mTOR-independent autophagy in double transgenic TDP-43 WTxQ331K mice to alleviate impaired autophagy. Although rilmenidine treatment induced robust autophagy in spinal cords, this exacerbated the phenotype of TDP-43 WTxQ331K mice, shown by truncated lifespan, accelerated motor neuron loss, and pronounced nuclear TDP-43 clearance. Importantly, rilmenidine significantly promoted mitophagy in spinal cords TDP-43 WTxQ331K mice, evidenced by reduced mitochondrial markers and load in spinal motor neurons. These results suggest that autophagy induction accelerates the phenotype of this TDP-43 mouse model of ALS, most likely through excessive mitochondrial clearance in motor neurons. These findings also emphasise the importance of balancing autophagy stimulation with the potential negative consequences of hyperactive mitophagy in ALS and other neurodegenerative diseases., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

To investigate the origins and stages of vertebrate adaptive radiation, we reconstructed the spatial and temporal histories of adaptive alleles underlying major phenotypic axes of diversification from the genomes of 202 Caribbean pupfishes. On a single Bahamian island, ancient standing variation from disjunct geographic sources was reassembled into new combinations under strong directional selection for adaptation to the novel trophic niches of scale-eating and molluscivory. We found evidence for two longstanding hypotheses of adaptive radiation: hybrid swarm origins and temporal stages of adaptation. Using a combination of population genomics, transcriptomics, and genome-wide association mapping, we demonstrate that this microendemic adaptive radiation of novel trophic specialists on San Salvador Island, Bahamas experienced twice as much adaptive introgression as generalist populations on neighboring islands and that adaptive divergence occurred in stages. First, standing regulatory variation in genes associated with feeding behavior ( prlh , cfap20 , and rmi1 ) were swept to fixation by selection, then standing regulatory variation in genes associated with craniofacial and muscular development ( itga5 , ext1 , cyp26b1 , and galr2 ) and finally the only de novo nonsynonymous substitution in an osteogenic transcription factor and oncogene ( twist1 ) swept to fixation most recently. Our results demonstrate how ancient alleles maintained in distinct environmental refugia can be assembled into new adaptive combinations and provide a framework for reconstructing the spatiotemporal landscape of adaptation and speciation., Competing Interests: The authors declare no competing interest.

Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disorder caused by loss of motor neurons. ALS incidence is skewed towards males with typically earlier age of onset and limb site of onset. The androgen receptor (AR) is the major mediator of androgen effects in the body and is present extensively throughout the central nervous system, including motor neurons. Mutations in the AR gene lead to selective lower motor neuron degeneration in male spinal bulbar muscular atrophy (SBMA) patients, emphasising the importance of AR in maintaining motor neuron health and survival. To evaluate a potential role of AR in onset and progression of ALS, we generated SOD1 G93A mice with either neural AR deletion or global human AR overexpression. Using a Cre-LoxP conditional gene knockout strategy, we report that neural deletion of AR has minimal impact on the disease course in SOD1 G93A male mice. This outcome was potentially confounded by the metabolically disrupted Nestin-Cre phenotype, which likely conferred the profound lifespan extension observed in the SOD1 G93A double transgenic male mice. In addition, overexpression of human AR produced no benefit to disease onset and progression in SOD1 G93A mice. In conclusion, the disease course of SOD1 G93A mice is independent of AR expression levels, implicating other mechanisms involved in mediating the sex differences in ALS. Our findings using Nestin-Cre mice, which show an inherent metabolic phenotype, led us to hypothesise that targeting hypermetabolism associated with ALS may be a more potent modulator of disease, than AR in this mouse model.

Antisense oligonucleotides (ASOs) are an emerging class of gene-specific therapeutics for diseases associated with the central nervous system (CNS). However, ASO delivery across the blood-brain barrier (BBB) to their CNS target cells remains a major challenge. Since ASOs are mainly taken up into the brain capillary endothelial cells interface through endosomal routes, entrapment in the endosomal compartment is a major obstacle for efficient CNS delivery of ASOs. Therefore, we evaluated the effectiveness of a panel of cell-penetrating peptides (CPPs) bearing several endosomal escape domains for the intracellular delivery, endosomal release and antisense activity of FDA-approved Spinraza (Nusinersen), an ASO used to treat spinal muscular atrophy (SMA). We identified a CPP, HA2-ApoE(131-150), which, when conjugated to Nusinersen, showed efficient endosomal escape capability and significantly increased the level of full-length functional mRNA of the survival motor neuron 2 (SMN2) gene in SMA patient-derived fibroblasts. Treatment of SMN2 transgenic adult mice with this CPP-PMO conjugate resulted in a significant increase in the level of full-length SMN2 in the brain and spinal cord. This work provides proof-of-principle that integration of endosomal escape domains with CPPs enables higher cytosolic delivery of ASOs, and more importantly enhances the efficiency of BBB-permeability and CNS activity of systemically administered ASOs., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Sphingolipids are complex lipids. They play a structural role in neurons, but are also involved in regulating cellular communication, and neuronal differentiation and maturation. There is increasing evidence to suggest that dysregulated metabolism of sphingolipids is linked to neurodegenerative processes in amyotrophic lateral sclerosis (ALS), Parkinson's disease and Gaucher's disease. In this review, we provide an overview of the role of sphingolipids in the development and maintenance of the nervous system. We describe the implications of altered metabolism of sphingolipids in the pathophysiology of certain neurodegenerative diseases, with a primary focus on ALS. Finally, we provide an update of potential treatments that could be used to target the metabolism of sphingolipids in neurodegenerative diseases., (Copyright © 2020. Published by Elsevier Ltd.)

Cell penetrating peptides (CPPs) are being increasingly used as efficient vectors for intracellular delivery of biologically active agents, such as therapeutic antisense oligonucleotides (ASOs). Unfortunately, ASOs have poor cell membrane permeability. The conjugation of ASOs to CPPs have been shown to significantly improve their cellular permeability and therapeutic efficacy. CPPs are often covalently conjugated to ASOs through a variety of chemical linkages. Most of the reported approaches for ligation of CPPs to ASOs relies on methodologies that forms non-native bond due to incompatibility with in-solution phase conjugation. These approaches have low efficiency and poor yields. Therefore, in this study, we have exploited native chemical ligation (NCL) as an efficient strategy for synthesizing CPP-ASO conjugates. A previously characterized CPP [ApoE(133-150)] was used to conjugate to a peptide nucleic acid (PNA) sequence targeting human survival motor neuron-2 (SMN2) mRNA which has been approved by the FDA for the treatment of spinal muscular atrophy. The synthesis of ApoE(133-150)-PNA conjugate using chemo-selective NCL was highly efficient and the conjugate was obtained in high yield. Toward synthesizing trifunctional CPP-ASO conjugates, we subsequently conjugated different functional moieties including a phosphorodiamidate morpholino oligonucleotide (PMO), an additional functional peptide or a fluorescent dye (Cy5) to the thiol that was generated after NCL. The in vitro analysis of the bifunctional CPP-PNA and trifunctional CPP-(PMO)-PNA, CPP-(peptide)-PNA and CPP-(Cy5)-PNA showed that all conjugates are cell-permeable and biologically active. Here we demonstrated chemo-selective NCL as a highly efficient and superior conjugation strategy to previously published methods for facile solution-phase synthesis of bi-/trifunctional CPP-ASO conjugates., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Dastpeyman, Karas, Amin, Turner and Shabanpoor.)

Objective: We examined how personality traits are associated with eating pathology (EP) across a range of severities and symptom subtypes., Method: The National Comorbidity Survey Adolescent Supplement (N = 10,148) was used to compare personality across severities (i.e., clinical Eating Disorders [EDs], subclinical disordered eating, preclinical weight concerns, or no weight/EP [no W/EP]), subclinical subtypes (i.e., Binge Eating Only, Binge-Purge, Binge-Restrict, Restrict-Purge, or no W/EP), and clinical subtypes (i.e., Anorexia Nervosa [AN]), Bulimia Nervosa [BN], Binge Eating Disorder [BED], internalizing disorders, or no ED or internalizing disorder) of EP., Results: More severe EP was associated with more extreme personality trait endorsements. Impulsivity-related traits did not consistently distinguish binge eating/purging from restricting subtypes, although behavioral disinhibition differentiated adolescents with BN or BED from AN., Conclusion: Personality traits related to affectivity and impulsivity were more consistently associated with severity rather than subtype of EP., (© 2020 Wiley Periodicals LLC.)

Community health workers (CHWs) can reduce health disparities for low income patients but type of contact and outcomes has had limited study. Low-income Hispanic primary care patients with hemoglobin A1c [HbA1c] ≥ 9% received care managment (CM) over 6 months classified as: (CM1) telephone only; (CM2) clinic visit but no calls; (CM3) clinic visit with calls; and (CM4) ≥ 2 visits ± calls. Type of CM delivery and time to DM control (HbA1c < 9%) examined in Cox proportional hazards model and more rapid control within 6 months using logistic regression. Models adjusted for demographics, clinical, and health care variables. At baseline, 523 patients had mean HbA1c 10.9% (SD = 1.7%), mean age 57.9 years (SD = 10), 58.5% women, 87.6% Hispanic, and 55.5% uninsured. CM types for patients: 51 (9.8%) CM1; 192 (36.7%) CM2; 44 (8.4%) CM3; and 236 (45.4%) CM4. Median time to HbA1c control was 197 days (95% CI [71, 548]) and 41.5% achieved control within 6 months. Compared with CM1, control was more rapid for CM2 (Hazard ratio [HR] 1.45, 95% CI [1.01, 2.09], p = 0.043) and CM4 but not significant (HR [95% CI] 1.29 [0.91, 1.83], p = 0.15). Adjusted odds of more rapid control within 6 months were twofold higher for CM2 (p = 0.04) and CM4 (p = 0.055), respectively, versus CM1. CM2 did not differ from CM1. DM control was less likely for CM by telephone only than face-to-face in clinic. To benefit vulnerable patients with uncontrolled DM, in-person engagement may be required.

Over the past 20 years, there has been a drastically increased understanding of the genetic basis of Amyotrophic Lateral Sclerosis. Despite the identification of more than 40 different ALS-causing mutations, the accumulation of neurotoxic misfolded proteins, inclusions, and aggregates within motor neurons is the main pathological hallmark in all cases of ALS. These protein aggregates are proposed to disrupt cellular processes and ultimately result in neurodegeneration. One of the main reasons implicated in the accumulation of protein aggregates may be defective autophagy, a highly conserved intracellular "clearance" system delivering misfolded proteins, aggregates, and damaged organelles to lysosomes for degradation. Autophagy is one of the primary stress response mechanisms activated in highly sensitive and specialised neurons following insult to ensure their survival. The upregulation of autophagy through pharmacological autophagy-inducing agents has largely been shown to reduce intracellular protein aggregate levels and disease phenotypes in different in vitro and in vivo models of neurodegenerative diseases. In this review, we explore the intriguing interface between ALS and autophagy, provide a most comprehensive summary of autophagy-targeted drugs that have been examined or are being developed as potential treatments for ALS to date, and discuss potential therapeutic strategies for targeting autophagy in ALS.

Cytoplasmic accumulation of TDP-43 is a disease hallmark for many cases of amyotrophic lateral sclerosis (ALS), associated with a neuroinflammatory cytokine profile related to upregulation of nuclear factor κB (NF-κB) and type I interferon (IFN) pathways. Here we show that this inflammation is driven by the cytoplasmic DNA sensor cyclic guanosine monophosphate (GMP)-AMP synthase (cGAS) when TDP-43 invades mitochondria and releases DNA via the permeability transition pore. Pharmacologic inhibition or genetic deletion of cGAS and its downstream signaling partner STING prevents upregulation of NF-κB and type I IFN induced by TDP-43 in induced pluripotent stem cell (iPSC)-derived motor neurons and in TDP-43 mutant mice. Finally, we document elevated levels of the specific cGAS signaling metabolite cGAMP in spinal cord samples from patients, which may be a biomarker of mtDNA release and cGAS/STING activation in ALS. Our results identify mtDNA release and cGAS/STING activation as critical determinants of TDP-43-associated pathology and demonstrate the potential for targeting this pathway in ALS., Competing Interests: Declaration of Interests S.L.M. declares consultancy with IFM Therapeutics and Quench Bio and received funding from GlaxoSmithKline. S.L.M. and C.-H.Y. are named inventors on International Patent Application No. PCT/AU2019051201. All other authors declare no competing interests., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease targeting motor neurons which shows sexual dimorphism in its incidence, age of onset, and progression rate. All steroid hormones, including androgens, estrogens, and progestogens, have been implicated in modulating ALS. Increasing evidence suggests that steroid hormones provide neuroprotective and neurotrophic support to motor neurons, either directly or via surrounding glial cell interactions, by activating their respective nuclear hormone receptors and initiating transcriptional regulatory responses. The SOD1G93A transgenic mouse also shows sex-specific differences in age of onset and progression, and remains the most widely used model in ALS research. To provide a more comprehensive understanding of the influences of steroid hormone signaling in ALS, we systemically characterized sex hormone receptor expression at transcript and protein levels, cellular localization, and the impact of disease course in lumbar spinal cords of male and female SOD1G93A mice. We found that spinal motor neurons highly express nuclear androgen receptor (AR), estrogen receptor (ER)α, ERβ, and progesterone receptor with variations in glial cell expression. AR showed the most robust sex-specific difference in expression and was downregulated in male SOD1G93A mouse spinal cord, in association with depletion in 5α-reductase type 2 isoform, which primarily metabolizes testosterone to 5α-dihydrotestosterone. ERα was highly enriched in reactive astrocytes of SOD1G93A mice and ERβ was strongly upregulated. The 5α-reductase type 1 isoform was upregulated with disease progression and may influence local spinal cord hormone levels. In conclusion, steroid hormone receptor expression is dynamic and cell-type specific in SOD1G93A mice which may provide targets to modulate progression in ALS., (© Endocrine Society 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Achieving practice change can be challenging when guidelines shift from a selective risk-based strategy to a broader population health strategy, as occurred for hepatitis C (HCV) screening (2012-2013). We aimed to evaluate patient and provider barriers that contributed to suboptimal HCV screening and linkage-to-care rates after implementation of an intervention to improve HCV screening and linkage-to-care processes in a large, public integrated healthcare system following the guidelines change. As part of a mixed-methods study, we collected data through patient surveys (n = 159), focus groups (n = 9) and structured observation of providers and staff (n = 9). We used these findings to then inform domains for the second phase, which consisted of semi-structured interviews with patients across the screening-treatment continuum (n = 24) and providers and staff at primary care and hepatology clinics (n = 21). We transcribed and thematically analysed interviews using an integrated inductive and deductive framework. We identified lack of clarity about treatment cost, treatment complications and likelihood of cure as ongoing patient-level barriers to screening and linkage to care. Provider-level barriers included scepticism about establishing HCV screening as a quality metric given competing clinical priorities, particularly for patients with multiple comorbidities. However, most felt positively about adding HCV as a quality metric to enhance HCV screening and linkage to care. Provider engagement yielded suggestions for process improvements that resulted in increased stakeholder buy-in and real-time enhancements to the HCV screening process intervention. Systematic data collection at baseline and during practice change implementation may facilitate adoption and adaptation to improve HCV screening guideline implementation. Findings identified several key opportunities and lessons to enhance the impact of practice change interventions to improve HCV screening and treatment delivery., (© 2020 John Wiley & Sons Ltd.)

Motor neuron degeneration in amyotrophic lateral sclerosis (ALS) caused by mutations in superoxide dismutase 1 (SOD1) is partly non-cell autonomous, involving cellular dysfunction of astrocytes. Whether non-cell autonomous effects occur in other forms of ALS, such as TAR DNA binding protein 43 (TDP-43)-related disease, remains unclear. Here, we characterised the impact of mutant TDP-43 expression on primary astrocytes derived from transgenic TDP-43 A315T mice. Mutant TDP-43 astrocytes revealed evidence for TDP-43 pathology, shown by cytoplasmic TDP-43 inclusions and accumulation in insoluble cell fractions which was exacerbated by proteasomal inhibition. L-glutamate uptake, measured using an [ 3 H]D-aspartate assay, was impaired in mutant TDP-43 astrocytes, while ATP accumulation was abnormal, suggesting mutant TDP-43 induced astrocytic dysfunction. Astrocyte activation coupled with spinal and cortical motor neuron loss in transgenic TDP-43 A315T mice could imply non-cell autonomous effects of astrocytes in vivo. These data demonstrate mutant TDP-43-mediated cell autonomous effects on astrocytes that may contribute to motor neuron pathology in ALS.

Motor neuron degeneration in amyotrophic lateral sclerosis (ALS) is proposed to occur by necroptosis, an inflammatory form of regulated cell death. Prior studies implicated necroptosis in ALS based on accumulation of necroptotic markers in affected tissues of patients and mouse models, and amelioration of disease in mutant superoxide dismutase 1 (SOD1 G93A ) mice with inhibition of the upstream necroptotic mediators, receptor interacting protein kinase 1 (RIPK1), and RIPK3. To definitively address the pathogenic role of necroptosis in ALS, we genetically ablated the critical terminal executioner of necroptosis, mixed lineage kinase domain-like protein (MLKL), in SOD1 G93A mice. Disease onset, progression, and survival were not affected in SOD1 G93A mice lacking MLKL. Motor neuron degeneration and activation of neuroinflammatory cells, astrocytes, and microglia, were independent of MLKL expression in SOD1 G93A mice. While RIPK1 accumulation occurred in spinal cords of SOD1 G93A mice in late stage disease, RIPK3 and MLKL expression levels were not detected in central nervous system tissues from normal or SOD1 G93A mice at any disease stage. These findings demonstrate that necroptosis does not play an important role in motor neuron death in ALS, which may limit the potential of therapeutic targeting of necroptosis in the treatment of neurological disorders.

Comparison of cardiovascular disease (CVD) risk calculators in Latinx majority populations living with HIV can assist clinicians in selecting a calculator and interpreting results. 10-year CVD risks were estimated for 652 patients seen ≥ 2 times over 12 months in a public clinic using three risk calculators: Atherosclerotic CVD risk Calculator (ASCVD), Framingham Risk Calculator (FRC), and Data Collection on Adverse Effects of Anti-HIV Drugs Study (D:A:D) Calculator. Median estimated 10-year CVD risk in this population was highest using FRC (11%), followed by D:A:D (10%), and lowest with ASCVD (5%; p < 0.001). However, D:A:D classified 44.3% in a high/very high risk category compared to FRC (20.7%) and ASCVD (33.4%) (all p < 0.001). ASCVD risk estimates differed significantly by race/ethnicity (p < 0.001). Risk varied widely across three risk calculators and by race/ethnicity, and providers should be aware of these differences when choosing a calculator for use in majority minority populations.

The ATP-gated P2X7 ion channel has emerging roles in amyotrophic lateral sclerosis (ALS) progression. Pharmacological blockade of P2X7 with Brilliant Blue G can ameliorate disease in SOD1 G93A mice, but recent data suggests that this antagonist displays poor penetration of the central nervous system (CNS). Therefore, the current study aimed to determine whether the CNS-penetrant P2X7 antagonist, JNJ-47965567, could ameliorate ALS progression in SOD1 G93A mice. A flow cytometric assay revealed that JNJ-47965567 impaired ATP-induced cation dye uptake in a concentration-dependent manner in murine J774 macrophages. Female and male SOD1 G93A mice were injected intraperitoneally with JNJ-47965567 (30 mg/kg) or 2-(hydroxypropyl)-beta-cyclodextrin (vehicle control) three times a week from disease onset until end stage, when tissues were collected and studied. JNJ-47965567 did not impact weight loss, clinical score, motor (rotarod) coordination or survival compared to control mice. NanoString analysis revealed altered spinal cord gene expression in JNJ-47965567 mice compared to control mice, but such differences were not confirmed by quantitative PCR. Flow cytometric analyses revealed no differences between treatments in the frequencies or activation status of T cell or dendritic cell subsets in lymphoid tissues or in the concentrations of serum cytokines. Notably, serum IL-27, IFNβ and IL-10 were present in relatively high concentrations compared to other cytokines in both groups. In conclusion, JNJ-47965567 administered thrice weekly from disease onset did not alter disease progression or molecular and cellular parameters in SOD1 G93A mice.

Purpose: Chronic medical conditions are a risk factor for the onset of suicidal thoughts and behaviors in adults. However, few studies have examined this association in adolescents. The present study explored the association between chronic medical conditions and the emergence of suicidal thoughts and behaviors in an adolescent sample representative of the U.S.A., Method: Using data from the National Comorbidity Survey-Adolescent Supplement (10,148 Americans between ages 13-17), discrete-time survival analyses were performed to examine the odds of developing suicidal ideation, planning, and attempts, given prior presence of a chronic medical condition. Multivariate models controlled for sociodemographic factors and the presence of comorbid mental health conditions. Post-hoc sensitivity analyses examined associations between timing of chronic medical condition onset and later suicidal thoughts and behaviors., Results: Multivariate analyses showed that dermatological conditions, asthma, allergies, headache, and back/neck pain were associated with elevated odds of suicidal ideation, while cardiovascular conditions were associated with increased odds of suicide attempts. Additionally, cardiovascular conditions were associated with increased risk of suicide planning and attempts among adolescents with suicidal ideation. Chronic medical conditions that began in adolescence were associated with the greatest risk of later suicidal thoughts and behaviors, compared to chronic medical conditions that began in early or middle childhood., Conclusion: Consistent with research in middle and older adults, physical health conditions are associated with increased risk for the onset of suicidal thoughts and behaviors in adolescents. Mental health screening for adolescents with chronic medical conditions may help parents and physicians identify suicidality early.

Objective: To examine factors influencing initial engagement, ongoing participation, learned behaviors, and subjective functional outcomes after a trial of the Living Better Beyond Pain (LBBP) chronic pain self-management program., Design: Qualitative study using the Grounded Theory approach., Setting: Two 60-minute focus groups and phone interviews in May 2017., Subjects: Focus groups with 18 participants who completed LBBP and six-month measures; telephone interviews with 17 participants who stopped attending., Methods: Study coordinators randomly selected program completers for focus groups and conducted phone interviews with noncompleters. Inductive thematic analysis was used to identify patterns in semantic content with a recursive process applied to focus group transcripts and interview transcriptions to codify into themes. Themes were categorized according to the Theory of Planned Behavior., Results: Focus group and telephone interview participants were primarily Hispanic and unemployed. Attitudes fostering participation in LBBP included dissatisfaction with the status quo, need to reduce pain medication, and lack of training and knowledge about chronic pain. Positive social norms from meeting others with chronic pain and support from the LBBP team encouraged attendance and adoption of behaviors. Transportation, pain, and competing activities were barriers, whereas adapting activities for the disabled was a facilitator. Maintaining behaviors and activities at home was challenging but ultimately rewarding due to improvement in daily function with less pain medication., Conclusions: This qualitative study complements quantitative results showing clinically significant improvements in function after the LBBP program by adding practical insights into ways to increase participation and outcomes. Participants strongly endorsed the need for chronic pain self-management training., (© 2018 American Academy of Pain Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Hepatitis C virus (HCV) disproportionately affects disadvantaged communities., Objective: To examine processes and outcomes of Screen, Treat, Or Prevent Hepatocellular Carcinoma (STOP HCC), a multicomponent intervention for HCV screening and care in safety-net primary care practices., Design: Mixed-methods retrospective analysis., Setting: 5 federally qualified health centers (FQHCs) and 1 family medicine residency program serving low-income communities in diverse locations with largely Hispanic populations., Patients: Persons born in 1945 through 1965 (baby boomers) who had never been tested for HCV and were followed through May 2018., Intervention: The Reach, Effectiveness, Adoption, Implementation, and Maintenance (RE-AIM) model guided implementation and evaluation. Test costs were covered for uninsured patients., Measurements: All practices tested patients for anti-HCV antibody (anti-HCV) and HCV RNA. For uninsured patients with chronic HCV in 4 practices, quantitative data also enabled assessment of HCV staging, specialist teleconsultation, direct-acting antiviral (DAA) treatment, and sustained virologic response (SVR). Implementation fidelity and adaptation were assessed qualitatively., Results: Anti-HCV screening was done in 13 334 of 27 700 baby boomers (48.1%, varying by practice from 19.8% to 71.3%). Of 695 anti-HCV-positive patients, HCV RNA was tested in 520 (74.8%; 48.9% to 92.9% by practice), and 349 persons (2.6% of those screened) were diagnosed with chronic HCV. In 4 FQHCs, 174 (84.9%) of 205 uninsured patients with chronic HCV had disease staging, 145 (70.7%) had teleconsultation review, 119 (58.0%) were recommended to start DAA therapy, 82 (40.0%) initiated free DAA therapy, 74 (36.1%) completed therapy (27.8% to 60.0% by practice), and 70 (94.6% of DAA completers) achieved SVR. Implementation was promoted by multilevel practice engagement, patient navigation, and anti-HCV screening with reflex HCV RNA testing., Limitation: No control practices were included, and data were missing for some variables., Conclusion: Despite a similar framework for STOP HCC implementation, performance varied widely across safety-net practices, which may reflect practice engagement as well as infrastructure or cost challenges beyond practice control., Primary Funding Source: Cancer Prevention & Research Institute of Texas and Centers for Medicare & Medicaid Services.

Neuromuscular and neurodegenerative diseases are mostly modeled using genetically modified animals such as mice. However, animal models do not recapitulate all the phenotypes that are specific to human disease. This is mainly due to the genetic, anatomical and physiological difference in the neuromuscular systems of animals and humans. The emergence of direct and indirect human somatic cell reprogramming technologies may overcome this limitation because they enable the use of disease and patient-specific cellular models as enhanced platforms for drug discovery and autologous cell-based therapy. Induced pluripotent stem cells (iPSCs) and urine-derived stem cells (USCs) are increasingly employed to recapitulate the pathophysiology of various human diseases. Recent cell-based modeling approaches utilize highly complex differentiation systems that faithfully mimic human tissue- and organ-level dysfunctions. In this review, we discuss promising cellular models, such as USC- and iPSC-based approaches, that are currently being used to model human neuromuscular and neurodegenerative diseases., (Copyright © 2019 Sato, Takizawa, Nakamura, Turner, Shabanpoor and Aoki.)

Background: Nonsuicidal self-injury (NSSI) is highly prevalent among adolescent and emerging adult females. Most studies examining the relationship between stress and NSSI largely have relied on aggregate self-report measures of stress and between-person models. Using data from two prospective samples, this manuscript tests the hypothesis that within-person models of NSSI provide better clinical markers of risk for NSSI than between-person models of NSSI., Methods: Two samples (Sample 1: 220 high-risk girls, M age = 14.68, SD = 1.36, baseline assessment and 3-month follow-ups for 18 months; Sample 2: 40 emerging adult females with a history of NSSI, M age = 21.55, SD = 2.14, 14 days with daily retrospective reports) were followed prospectively and completed validated measures of stress and NSSI. Models were adjusted for age and depression., Results: In Sample 1, a within-person model demonstrated that higher-than-usual (but not average) stress levels predicted NSSI within the same 3-month wave. In Sample 2, results from a within-person model with daily diary assessment data showed that higher-than-usual stress (but not average daily stress) predicted same-day NSSI., Conclusions: Together, our results suggest that higher-than-usual stress, relative to one's typical stress level, but not average stress levels, signals times of enhanced risk for NSSI. These results highlight the clinical utility of repeated assessments of stress., (© 2019 Association for Child and Adolescent Mental Health.)

Objective: We used a daily diary to examine (1) the frequency of three types of NSSI thoughts and urges (fleeting thoughts, persistent thoughts, and intense urges), (2) the correlates of NSSI thought and urges within and across days, (3) strategies that aid in resisting NSSI thoughts and urges, and (4) the prospective association of daily NSSI thoughts and urges with NSSI behavior over 12 months., Method: Sixty adults (aged 18-35) completed a two-week daily diary and follow-ups every 3 months for one year., Results: Fleeting NSSI thoughts were reported on 48% of days, whereas persistent thoughts (11%) and intense urges (17%) were less common. Within days, earlier stress predicted more persistent NSSI thoughts, whereas earlier perceived support predicted less intense NSSI urges. Furthermore, NSSI thoughts and urges were positively associated with same-day stress and avoidant coping. Problem-focused coping was associated with greater success resisting same-day fleeting thoughts and intense urges, as well as success resisting next-day persistent thoughts. Perceived support was associated with less intense same-day urges, but also less success resisting these urges. Over the follow-up, persistent thoughts predicted less frequent NSSI, whereas intense urges predicted more frequent NSSI., Conclusions: NSSI thoughts and urges are commonly experienced and deserve further attention., (© 2018 The American Association of Suicidology.)