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Psychological trait differences between ultrarunners (completing more than a standard 42.195 km marathon) and sub-ultrarunners (≤42.195 km) have been assumed, but not robustly examined. The current study investigated trait differences between competitive and recreational runners at sub-ultra and ultramarathon distances. Six hundred and eleven participants (334 recreational, 400 sub-ultrarunner) completed an online, anonymous survey assessing five traits: mental toughness (MT), grit, motivation, general self-efficacy (GSE), and personality. Bayesian ANOVAs indicated at least moderate evidence for differences within Distance for grit-perseverance of effort (PE) and intrinsic motivation (IM), such that ultrarunners scored higher than sub-ultrarunners. Similarly, we observed at least moderate evidence that competitive runners scored higher than recreational runners on overall grit, grit-PE, GSE, IM, and extrinsic motivation (EM). Interaction effects provided moderate evidence for greater MT and overall grit in competitive ultrarunners. Evidence for other differences were anecdotal or favoured the null hypothesis. This study represents a novel investigation into the psychological makeup of runners. We suggest that aspects of motivation, grit, and self-efficacy, but not personality, may differentiate competitive from recreational runners, and ultrarunners from sub-ultrarunners. The identification of these trait differences may benefit runners and coaches wanting to progress in distance or competition level, with broader application to workplace or academic contexts. Further research is needed to develop a clearer conceptualisation of mental toughness, and build upon the novel findings of this study, particularly given the paucity of literature that exists within this context., Competing Interests: Declaration of competing interest The authors declare that they have no known conflicts of interest that could have influenced the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Competing Interests: Conflict of interest statement. None declared.

Introduction: Peer workers operating within health care settings can offer unique perspectives based on their own lived experience. Within alcohol and other drug (AOD) rehabilitation services, the potential value of peer work is becoming increasingly recognised. This qualitative study aimed to evaluate a newly implemented peer worker program located across three rehabilitation services in Tasmania, Australia., Methods: Online interviews were conducted with eight clients, seven peer workers, and five non-peer worker employees with varied experience with peer worker programs. All interviews were audio-recorded and transcribed verbatim., Results: Guided by an overarching exploratory-descriptive methodological framework, thematic analysis generated three overarching themes: 1) Enhancing and supporting client experiences (what peer workers did in their role to improve client experiences, 2) Changing experiences with AOD rehabilitation (the unique benefits and changes that peer work brings to AOD rehabilitation services) and 3) Finding organizational value (how defining peer work and the feasibility of the peer worker role was challenged by different organizational factors). Overall, peer work was viewed as a positive addition to all rehabilitation services that was able to enhance client experiences through various mechanisms, such as by sharing their own stories, assisting with understanding, and creating safety. Peer work was also able to create change in AOD services, by instilling hope and reducing stigma. However, ongoing challenges with defining the peer worker role in a way that offers organizational recognition and financial security remain., Conclusion: Peer workers offer a unique and valuable perspective when working within rehabilitation services. Through their own lived experience peer workers were able to support clients and assist them in their recovery. These findings highlight the potential benefit of peer work programs within AOD rehabilitation services., Competing Interests: Declaration of competing interest This article presents a qualitative evaluation of a peer worker program implemented by the Drug Education Network (DEN). In the interest of full transparency, we disclose the following potential conflicts of interest: MD is a paid staff member of DEN, who was involved in the implementation of the program. Their firsthand experience with the program's implementation provided valuable insights and their involvement provided the additional logistical resources needed to conduct the research across the state, yet we acknowledge the potential for a conflict of interest. To mitigate these, this author was not involved in the screening or interviewing of any organizational non-peer worker employees or peer workers that they may have had previous contact with. In addition, MD followed a pre-defined interview schedule developed by HE, and all interviews were reviewed by the chief investigator. We affirm that their role did not compromise the objective evaluation of the program. AM is a senior academic at the University of Tasmania and a voluntary Board member of DEN. While their involvement with DEN may pose a perceived conflict, this author was not directly involved in the implementation of the program, or in the data collection and initial data analysis. HE was the lead investigator for this evaluation study and has no direct affiliation with DEN, ensuring an independent perspective in the research process and analysis. Despite these affiliations, all procedures and analyses were conducted with the utmost integrity and objectivity. The findings and conclusions presented in this article are the result of rigorous and unbiased research practices., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Training outcomes of mindfulness interventions for anxiety have been extensively researched. Less is known about the acute effects of mindfulness induction and associated mechanisms. This systematic review aimed to identify 1) the effect of mindfulness induction on pre-post measures of state anxiety and attention among adults experiencing high levels of anxiety; and 2) the impact of predictors, mediators and moderators on post-induction changes in anxiety and attention. State distress and mindfulness were included as secondary outcomes., Methods: A systematic search was conducted in November 2021 in electronic databases using relevant search terms. Five studies (four randomised controlled trials and one non-randomised controlled trial) were included, comprising a total of 277 participants with elevated trait/generalised anxiety. Each study used a brief audio-based mindfulness induction exercise., Results: The meta-analysis indicated mindfulness induction had medium and large effects on state anxiety (k = 3, n = 100, g = -0.60, 95%CI [-1.04, -0.16]; p = .008) and state mindfulness (k = 2, n = 110, g = 0.91, 95%CI [0.52, 1.30], p < .001), respectively, when compared with non-therapeutic control conditions. Furthermore, two studies showed small and moderate effects of mindfulness on state anxiety when compared to therapeutic active controls, but were not pooled in a meta-analysis. While results could not be pooled for attention, there was limited evidence of behavioural improvements on tasks measuring aspects of attention following mindfulness induction. However, one study found an increase in Low Beta to High Beta ratio and a reduction in Beta activity in the Anterior Cingulate Cortex following mindfulness induction. Moreover, another study found aspects of state mindfulness mediated reductions in state anxiety., Limitations: A small number of studies were included in the review, with high risk of bias and low certainty of evidence present., Conclusion: The findings support the use of mindfulness induction to reduce state anxiety in anxious individuals but suggest gains in state mindfulness may be a more realistic expected outcome. Further controlled trials are needed to delineate the relative effects of objectively assessed anxiety outcomes from mindfulness induction in clinically defined samples., Competing Interests: Declaration of competing interest The authors have no competing interests to declare., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Attentional bias towards food related stimuli has been proposed as a potential target for dieting intervention, however the evidence supporting a relationship between attentional bias and food intake is mixed. Theory holds that food related attentional bias should be positively associated with measures of stimulus-controlled eating, and that implicit processes such as impulsivity moderate this association. The aim of the present study was to examine whether the proposed relationship between food-related attentional bias and stimulus control exists, and whether it is moderated by impulsivity., Method: A community sample of 68 participants completed a food-related attentional bias task and impulsiveness scale during a laboratory visit, after which they recorded their real-world eating in real-time over 14 days using Ecological Momentary Assessment (EMA). During this time, participants also responded to 4-5 randomly timed assessments per day. Food outlet presence (e.g., fast food restaurants, cafes, corner stores etc.) was assessed during both eating and non-eating assessments. EMA data was then used to determine levels of stimulus controlled eating for each participant., Findings: Substantial variation was seen in both our measure of both food-related attentional bias (Range: 33.9 to 80.0) and in the degree to which the participant's eating could be categorised as being under stimulus control (Range: 0.50 to 0.93). However, food-related attentional bias scores were not a significant independent predictor of stimulus control and nor was this relationship moderated by impulsivity., Conclusion: Contrary to theoretical predictions, we found no evidence that of an association between attentional bias, impulsivity, and stimulus control. More work is needed to better understand the implicit processes underlying eating behaviour in the real-world., 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.)

Streptococcus pneumoniae is a commensal bacterium and invasive pathogen that causes millions of deaths worldwide. The pneumococcal vaccine offers limited protection, and the rise of antimicrobial resistance will make treatment increasingly challenging, emphasizing the need for new antipneumococcal strategies. One possibility is to target antioxidant defenses to render S. pneumoniae more susceptible to oxidants produced by the immune system. Human peroxidase enzymes will convert bacterial-derived hydrogen peroxide to hypothiocyanous acid (HOSCN) at sites of colonization and infection. Here, we used saturation transposon mutagenesis and deep sequencing to identify genes that enable S. pneumoniae to tolerate HOSCN. We identified 37 genes associated with S. pneumoniae HOSCN tolerance, including genes involved in metabolism, membrane transport, DNA repair, and oxidant detoxification. Single-gene deletion mutants of the identified antioxidant defense genes sodA , spxB , trxA, and ahpD were generated and their ability to survive HOSCN was assessed. With the exception of Δ ahpD , all deletion mutants showed significantly greater sensitivity to HOSCN, validating the result of the genome-wide screen. The activity of hypothiocyanous acid reductase or glutathione reductase, known to be important for S. pneumoniae tolerance of HOSCN, was increased in three of the mutants, highlighting the compensatory potential of antioxidant systems. Double deletion of the gene encoding glutathione reductase and sodA sensitized the bacteria significantly more than single deletion. The HOSCN defense systems identified in this study may be viable targets for novel therapeutics against this deadly pathogen. IMPORTANCE Streptococcus pneumoniae is a human pathogen that causes pneumonia, bacteremia, and meningitis. Vaccination provides protection only against a quarter of the known S. pneumoniae serotypes, and the bacterium is rapidly becoming resistant to antibiotics. As such, new treatments are required. One strategy is to sensitize the bacteria to killing by the immune system. In this study, we performed a genome-wide screen to identify genes that help this bacterium resist oxidative stress exerted by the host at sites of colonization and infection. By identifying a number of critical pneumococcal defense mechanisms, our work provides novel targets for antimicrobial therapy., Competing Interests: The authors declare no conflict of interest.

This systematic review aimed to identify 1) the effect of mindfulness training on pre-post measures of anxiety and attention among adults experiencing high levels of generalised anxiety; and 2) the impact of predictors, mediators and moderators on post-intervention changes in anxiety or attention. Trait mindfulness and distress measures were included as secondary outcomes. A systematic search was conducted in November 2021 in electronic databases using relevant search terms. Eight articles comprising four independent studies were included ( N  = 334). All studies included participants diagnosed with generalised anxiety disorder (GAD) who participated in an 8-week manualised program. The meta-analysis indicated that mindfulness training had a large effect on anxiety symptoms ( g  = -1.92, 95% CI [-3.44, -0.40]) when compared to inactive (i.e., care as usual, waitlist) or non-specified (i.e., condition not defined) controls. However, a significant effect was not found when compared to active controls. Effects for depression, worry and trait mindfulness did not reach statistical significance, despite small-large effect sizes favouring mindfulness compared to inactive/non-specified controls. Our narrative review found evidence that changes in aspects of trait mindfulness mediate anxiety reduction following mindfulness training. However, a small number of studies were available for inclusion in the review, with high risk of bias and low certainty of evidence present. Overall, the findings support the use of mindfulness training programs for GAD and indicate mechanisms that may differ from those involved in other cognitive therapy approaches. Further RCTs with evidence-based controls are needed to clarify techniques most beneficial for generalised anxiety to support individually tailored treatment., Supplementary Information: The online version contains supplementary material available at 10.1007/s12144-023-04695-x., Competing Interests: Competing InterestOn behalf of all authors, the corresponding author states that there is no conflict of interest., (© The Author(s) 2023.)

STAT6 (signal transducer and activator of transcription 6) is a transcription factor that plays a central role in the pathophysiology of allergic inflammation. We have identified 16 patients from 10 families spanning three continents with a profound phenotype of early-life onset allergic immune dysregulation, widespread treatment-resistant atopic dermatitis, hypereosinophilia with esosinophilic gastrointestinal disease, asthma, elevated serum IgE, IgE-mediated food allergies, and anaphylaxis. The cases were either sporadic (seven kindreds) or followed an autosomal dominant inheritance pattern (three kindreds). All patients carried monoallelic rare variants in STAT6 and functional studies established their gain-of-function (GOF) phenotype with sustained STAT6 phosphorylation, increased STAT6 target gene expression, and TH2 skewing. Precision treatment with the anti-IL-4Rα antibody, dupilumab, was highly effective improving both clinical manifestations and immunological biomarkers. This study identifies heterozygous GOF variants in STAT6 as a novel autosomal dominant allergic disorder. We anticipate that our discovery of multiple kindreds with germline STAT6 GOF variants will facilitate the recognition of more affected individuals and the full definition of this new primary atopic disorder., (© 2023 Sharma et al.)

Background: Many human disease phenotypes manifest differently by sex, making the development of methods for incorporating X and Y-chromosome data into analyses vital. Unfortunately, X and Y chromosome data are frequently excluded from large-scale analyses of the human genome and epigenome due to analytical complexity associated with sex chromosome dosage differences between XX and XY individuals, and the impact of X-chromosome inactivation (XCI) on the epigenome. As such, little attention has been given to considering the methods by which sex chromosome data may be included in analyses of DNA methylation (DNAme) array data., Results: With Illumina Infinium HumanMethylation450 DNAme array data from 634 placental samples, we investigated the effects of probe filtering, normalization, and batch correction on DNAme data from the X and Y chromosomes. Processing steps were evaluated in both mixed-sex and sex-stratified subsets of the analysis cohort to identify whether including both sexes impacted processing results. We found that identification of probes that have a high detection p-value, or that are non-variable, should be performed in sex-stratified data subsets to avoid over- and under-estimation of the quantity of probes eligible for removal, respectively. All normalization techniques investigated returned X and Y DNAme data that were highly correlated with the raw data from the same samples. We found no difference in batch correction results after application to mixed-sex or sex-stratified cohorts. Additionally, we identify two analytical methods suitable for XY chromosome data, the choice between which should be guided by the research question of interest, and we performed a proof-of-concept analysis studying differential DNAme on the X and Y chromosome in the context of placental acute chorioamnionitis. Finally, we provide an annotation of probe types that may be desirable to filter in X and Y chromosome analyses, including probes in repetitive elements, the X-transposed region, and cancer-testis gene promoters., Conclusion: While there may be no single "best" approach for analyzing DNAme array data from the X and Y chromosome, analysts must consider key factors during processing and analysis of sex chromosome data to accommodate the underlying biology of these chromosomes, and the technical limitations of DNA methylation arrays., (© 2023. The Author(s).)

Feed additives are critical components for poultry health and the economic viability of antibiotic-free poultry production. The aim of the present study is to evaluate the safety of a novel algal-derived feed additive, a dried biomass powder produced from Chlamydomonas reinhardtii strain crAL082, modified to express an N-acetylmuramoyl-L-alanine amidase (EC 3.5.1.28) and a lysozyme-type enzyme (EC 3.2.1.17). A 42-day oral toxicity study showed that the crAL082 dried biomass powder was fully tolerated by broiler chicken based on the lack of detrimental effects found in performance, mortality, hematology, blood clinical chemistry, and histopathologic results compared with those of a nontreated control group, resulting in a "No Observed Adverse Effect Level" of 5000 ppm, the highest dose tested. The study demonstrates the first-ever safety result of a C. reinhardtii microalgae dried biomass powder used as a feed additive in broiler chickens. Furthermore, safety is shown for the two additional enzymes expressed within the C. reinhardtii crAL082 strain and ingested by the birds.

Objectives: Although the literature provides guidance regarding patient-reported outcome (PRO) implementation barriers, patients' perspectives are underreported. This study aimed to improve the understanding of patient experiences with PRO tools through examining perceptions of and attitudes toward PROs and expectations of data use after collection., Methods: Ethnographic human-centered design approaches were used to conduct free-form interviews. Two case studies of existing PRO use in clinics also were examined. Unstructured thematic analyses were performed using notes taken during these interviews., Results: Patients generally reported a good understanding of the need for PRO collection, both for research and clinical use. Many expected that results would be acted upon by the clinicians promptly. Thematic analyses identified the following patient perception topics: transparency, individualization to patient needs, timely response, different "identities" while accessing care locally compared with at a destination center, and preference for brief PROs., Conclusions: Design and implementation of PRO assessments into patient care should include the patients as key end users. Transparency of the purpose for data collection is critical for broader patient adoption. Ensuring that only necessary and sufficient data are collected for clinical action, and associated research may help minimize burden and maximize patient participation.

Genome-wide sequencing (GWS) is a standard of care for diagnosis of suspected genetic disorders, but the proportion of patients found to have pathogenic or likely pathogenic variants ranges from less than 30% to more than 60% in reported studies. It has been suggested that the diagnostic rate can be improved by interpreting genomic variants in the context of each affected individual's full clinical picture and by regular follow-up and reinterpretation of GWS laboratory results. Trio exome sequencing was performed in 415 families and trio genome sequencing in 85 families in the CAUSES study. The variants observed were interpreted by a multidisciplinary team including laboratory geneticists, bioinformaticians, clinical geneticists, genetic counselors, pediatric subspecialists, and the referring physician, and independently by a clinical laboratory using standard American College of Medical Genetics and Genomics (ACMG) criteria. Individuals were followed for an average of 5.1 years after testing, with clinical reassessment and reinterpretation of the GWS results as necessary. The multidisciplinary team established a diagnosis of genetic disease in 43.0% of the families at the time of initial GWS interpretation, and longitudinal follow-up and reinterpretation of GWS results produced new diagnoses in 17.2% of families whose initial GWS interpretation was uninformative or uncertain. Reinterpretation also resulted in rescinding a diagnosis in four families (1.9%). Of the families studied, 33.6% had ACMG pathogenic or likely pathogenic variants related to the clinical indication. Close collaboration among clinical geneticists, genetic counselors, laboratory geneticists, bioinformaticians, and individuals' primary physicians, with ongoing follow-up, reanalysis, and reinterpretation over time, can improve the clinical value of GWS., Competing Interests: The authors declare no competing interests., (© 2022 The Authors.)

The endocannabinoid system is known to be involved in mechanisms relevant to PTSD aetiology and maintenance, though this understanding is mostly based on animal models of the disorder. Here we review how human paradigms can successfully translate animal findings to human subjects, with the view that substantially increased insight into the effect of endocannabinoid signalling on stress responding, emotional and intrusive memories, and fear extinction can be gained using modern paradigms and methods for assessing the state of the endocannabinoid system in PTSD., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Neurobiological models indicate that acute stress facilitates bottom-up stimulus processing while impairing top-down executive control. To test this hypothesis, the present study investigated the effects of acute stress on behavioural and electrophysiological measures of human attentional networks, and behavioural measures of working memory. Forty-five female participants (M ag e  = 22.1, SD = 2.4) performed the Attention Network Test (ANT) and the n-back task before and after the Maastricht Acute Stress Test (MAST; n = 23) or a non-stressful MAST-placebo (n = 22). Subjective distress ratings and salivary cortisol concentrations revealed a successful stress induction. Increased salivary cortisol at baseline was associated with slower reaction times across both tasks, suggesting a general detrimental effect of cortisol on cognitive functioning. Despite these findings, however, the hypothesised effects of the acute stress manipulation were not found for either task. Supplementary analyses indicated that these results were unrelated to the magnitude or duration of the stress response. Our results therefore suggest the standard version of the ANT may be insensitive to the effects of acute stress, and that higher cognitive loads may be necessary to observe stress effects on the n-back task., (Copyright © 2021. Published by Elsevier Inc.)

Background: The endocannabinoid system is gaining increasing attention as a favorable target for improving posttraumatic stress disorder (PTSD) treatments. Exposure therapy is the gold-standard treatment for PTSD, and fear extinction learning is a key concept underlying successful exposure., Methods: This study examined the role of genetic endocannabinoid polymorphisms in a fear extinction paradigm with PTSD compared to healthy participants (N = 220). Participants provided saliva for genotyping, completed a fear conditioning and extinction task, with blood samples taken before and after the task (n = 57). Skin conductance was the outcome and was analyzed using mixed models., Results: Results for cannabinoid receptor type 1 polymorphisms suggested that minor alleles of rs2180619 and rs1049353 were associated with poorer extinction learning in PTSD participants. The minor allele of the fatty acid amide hydrolase (FAAH) polymorphism rs324420 was associated with worse extinction in PTSD participants. Subanalysis of healthy participants (n = 57) showed the FAAH rs324420 genotype effect was dependent on plasma arachidonoyl ethanolamide (AEA) level, but not oleoylethanolamide or 2-arachidonoyl glycerol. Specifically, higher but not lower AEA levels in conjunction with the minor allele of FAAH rs324420 were associated with better extinction learning., Conclusions: These findings provide translational evidence that cannabinoid receptor 1 and AEA are involved in extinction learning in humans. FAAH rs324420's effect on fear extinction is moderated by AEA plasma level in healthy controls. These findings imply that FAAH inhibitors may be effective for targeting anxiety in PTSD, but this effect needs to be explored further in clinical populations., (© 2021 Wiley Periodicals LLC.)

Monoamine neurotransmitter disorders present predominantly with neurologic features, including dystonic or dyskinetic cerebral palsy and movement disorders. Genetic conditions that lead to secondary defects in the synthesis, catabolism, transport, and metabolism of biogenic amines can lead to neurotransmitter abnormalities, which can present with similar features. Eleven patients with secondary neurotransmitter abnormalities were enrolled between 2011 and 2015. All patients underwent research-based whole exome and/or whole genome sequencing (WES/WGS). A trial of treatment with levodopa/carbidopa and 5-hydroxytryptophan was initiated. In six families with abnormal neurotransmitter profiles and neurological phenotypes, variants in known disease-causing genes (KCNJ6, SCN2A, CSTB in 2 siblings, NRNX1, KIF1A and PAK3) were identified, while one patient had a variant of uncertain significance in a candidate gene (DLG4) that may explain her phenotype. In 3 patients, no compelling candidate genes were identified. A trial of neurotransmitter replacement therapy led to improvement in motor and behavioral symptoms in all but two patients. The patient with KCNJ6 variant did not respond to L-dopa therapy, but rather experienced increased dyskinetic movements even at low dose of medication. The patient's symptoms harboring the NRNX1 deletion remained unaltered. This study demonstrates the utility of genome-wide sequencing in further understanding the etiology and pathophysiology of neurometabolic conditions, and the potential of secondary neurotransmitter deficiencies to serve as novel therapeutic targets. As there was a largely favorable response to therapy in our case series, a careful trial of neurotransmitter replacement therapy should be considered in patients with cerebrospinal fluid (CSF) monoamines below reference range., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Brain-derived neurotropic factor (BDNF) is a potent regulator of memory processes and is believed to influence the consolidation of fear extinction memories. No previous human study has tested the effect of unstimulated BDNF on fear extinction recall, and no study has tested the association between plasma BDNF levels and psychophysiological responding during an extinction paradigm. We tested the association between fear responses during a 2-day differential conditioning, extinction and extinction recall paradigm and Val66Met genotype in a group of healthy participants (N = 191). There were no group differences during habituation or acquisition. Met allele carriers compared to Val homozygotes displayed higher responses to the CS + compared to the CS- during extinction learning and had higher responding to both the CS+ and CS- during extinction recall. Plasma levels of BDNF protein that were collected in a sub-sample of the group (n = 56) moderated the effect of Met allele presence, such that lower BDNF level was associated with higher skin conductance response in the Met but not Val group to the CS+ during extinction learning and to both the CS+ and CS- during extinction recall. The current results extend previous observations of a Val66Met effect during fear extinction learning to extinction recall and show for the first time that these effects are moderated by plasma BDNF level., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: The diagnosis of alpha-1-antitrypsin (A1AT) deficiency has been hindered by obscurity concerning the testing process and treatment implications. In this study, we aimed to identify regional differences in the diagnostic rates for A1AT deficiency in the western Canadian provinces of British Columbia (BC) and Alberta (AB)., Methods: The number of A1AT deficiency variant genotype (ZZ, SZ, MZ, SS, and MS) diagnoses were reviewed for BC and AB. The regional diagnostic rates for A1AT deficiency variants in these two provinces, normalized for the predicted population prevalence of each variant genotype, was defined as the annual provincial diagnostic rate (APDR) for a given variant genotype. Sex specific variations in the mean age at diagnosis for the five variant genotypes were compared both within and between provinces., Results: The SZ and MZ genotype APDRs were significantly increased in the AB population compared to the BC population. The SS and MS APDRs were similar between AB and BC. There was a significantly decreased mean age of diagnosis for AB males, as compared to BC males (for the SZ, MS, and MZ genotypes) and as compared to AB females (for the MS, MZ, and SS genotypes). There were no significant differences in the mean age of diagnosis between the females and males in BC, or between females in AB and BC, for any genotype., Conclusion: The notably higher APDR for more severe A1AT deficiency genotypes, and lower mean age of diagnosis for most variant genotypes in AB males, deserves further investigation to determine the explanation(s) for these differences., (Copyright © 2021 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.)

Understanding the role of endogenous cannabinoids (endocannabinoids) in disease is of increasing importance. However, tools to investigate endocannabinoid levels in humans are limited. In the current study, we report a simplified sample preparation method for quantifying endocannabinoids and steroid hormones in hair using liquid-liquid extraction combined with ultra performance liquid chromatography coupled to tandem mass spectrometry. The fully validated method is at least R 2  = 0.99 linear between 5 and 1,000 pg/mg for each analyte and the detection limits are at or below 0.50 pg/mg for cortisol, progesterone, oleoylethanolamide, and arachidonoyl ethanolamide, and 2.65 pg/mg for 2-arachidonoyl glycerol. Sequential extraction of hair samples revealed that multiple extractions may be required for quantitative recovery of steroids. However endogenous cannabinoids were efficiently recovered using a single sample extraction. The method was applied to a psychosocial stress study where participants provided samples of both hair and saliva. Endogenous hair arachidonoyl ethanolamide levels were negatively associated with resting, but not stressed, salivary cortisol levels in healthy participants. This simplified method enables the detailed study of hormonal and endocannabinoids in human hair with high sensitivity., Competing Interests: Declaration of Competing Interest The authors report no declarations of interest., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Streptococcus pneumoniae is an opportunistic pathogen that is a common cause of serious invasive diseases such as pneumonia, bacteremia, meningitis, and otitis media. Transmission of this bacterium has classically been thought to occur through inhalation of respiratory droplets and direct contact with nasal secretions. However, the demonstration that S. pneumoniae is desiccation tolerant and, therefore, environmentally stable for extended periods of time opens up the possibility that this pathogen is also transmitted via contaminated surfaces (fomites). To better understand the molecular mechanisms that enable S. pneumoniae to survive periods of desiccation, we performed a high-throughput transposon sequencing (Tn-seq) screen in search of genetic determinants of desiccation tolerance. We identified 42 genes whose disruption reduced desiccation tolerance and 45 genes that enhanced desiccation tolerance. The nucleotide excision repair pathway was the most enriched category in our Tn-seq results, and we found that additional DNA repair pathways are required for desiccation tolerance, demonstrating the importance of maintaining genome integrity after desiccation. Deletion of the nucleotide excision repair gene uvrA resulted in a delay in transmission between infant mice, indicating a correlation between desiccation tolerance and pneumococcal transmssion. Understanding the molecular mechanisms that enable pneumococcal persistence in the environment may enable targeting of these pathways to prevent fomite transmission, thereby preventing the establishment of new colonization and any resulting invasive disease.

Background: Human placental DNA methylation (DNAme) data is a valuable resource for studying sex differences during gestation, as DNAme profiles after delivery reflect the cumulative effects of gene expression patterns and exposures across gestation. Here, we present an analysis of sex differences in autosomal DNAme in the uncomplicated term placenta (n = 343) using the Illumina 450K array., Results: At a false discovery rate < 0.05 and a mean sex difference in DNAme beta value of > 0.10, we identified 162 autosomal CpG sites that were differentially methylated by sex and replicated in an independent cohort of samples (n = 293). Several of these differentially methylated CpG sites were part of larger correlated regions of sex differential DNAme. Although global DNAme levels did not differ by sex, the majority of significantly differentially methylated CpGs were more highly methylated in male placentae, the opposite of what is seen in differential methylation analyses of somatic tissues. Patterns of autosomal DNAme at these 162 CpGs were significantly associated with maternal age (in males) and newborn birthweight standard deviation (in females)., Conclusions: Our results provide a comprehensive analysis of sex differences in autosomal DNAme in the term human placenta. We report a list of high-confidence autosomal sex-associated differentially methylated CpGs and identify several key features of these loci that suggest their relevance to sex differences observed in normative and complicated pregnancies.

There currently exist few frameworks for common neurobiology between reexperiencing and negative cognitions and mood symptoms of PTSD. Adopting a dopaminergic framework for PTSD unites many aspects of unique symptom clusters, and this approach also links PTSD symptomology to common comorbidities with a common neurobiological deficiency. Here we review the dopamine literature and incorporate it with a growing field of research that describes both the contribution of endocannabinoids to fear extinction and PTSD, as well as the interactions between dopaminergic and endocannabinoid systems underlying this disorder. Based on current evidence, we outline an early, preliminary model that links re-experiencing and negative cognitions and mood in PTSD by invoking the interaction between endocannabinoid and dopaminergic signalling in the brain. These interactions between PTSD, dopamine and endocannabinoids may have implications for future therapies for treatment-resistant and comorbid PTSD patients., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The endogenous cannabinoid (eCB) system has been shown in animal models to regulate the initiation and termination of central nervous responses to stress. In human studies, the role of peripherally measured eCBs is much less clear and the effect in salivary eCBs has not been studied. In this study, we use a novel method to quantify cortisol and eCBs arachidonoyl ethanolamide (AEA) and 2-arachidonoyl glycerol (2-AG) in human saliva, as well as in plasma samples. Forty-five females and 32 males completed a mixed physiological/psychosocial stress-induction study where saliva, and blood samples in males, were collected at baseline, immediately following, 30-minutes following, and 45-minutes following stress induction. Cortisol significantly increased after stress, but there were sex differences in the cortisol response to stress, with females having higher cortisol after stress compared to males. There was a significant increase in salivary levels of 2-AG immediately following stress induction, but no effect of AEA. Salivary AEA was higher in males compared to females. Surprisingly, there was no effect of stress on plasma AEA or 2-AG levels in the male cohort, though small effect sizes for 2-AG were observed, which is consistent with most other human literature. This study is the first to show that the eCB system is active in human saliva and is responsive to acute stress, possibly as part of the sympathetic nervous system response., (Copyright © 2021 Elsevier B.V. All rights reserved.)

There is now significant literature suggesting that increasing brain-derived neurotropic factor (BDNF) signalling may improve memory-related disorders such as Alzheimer's disease. However, the effects of BDNF on short-term and working memory are not clear and existing evidence is inconsistent. Here we measured plasma BDNF and salivary cortisol levels, as well as working memory, on an N-Back task before and after mixed psychosocial/physiological stress induction in healthy males (N = 29). Stress induction was associated with higher circulating cortisol, but not BDNF levels. Higher cortisol and BDNF levels were significantly associated with poorer accuracy before and after stress induction. There was also a significant interaction, such that higher BDNF was associated with a buffering effect on the negative association between high cortisol and working memory. Future studies should replicate this data in larger samples, with emphasis on cortisol/BDNF interactions in determining working memory performance., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Endogenous cannabinoids are an increasingly intriguing target for biological research, given the changing legal status of medicinal cannabinoid-based products throughout the world. However, studying the endogenous cannabinoid system is a relatively new field, with few research teams attempting to develop quantitative methods for these important modulatory analytes in human matrices, other than blood. Here we develop and validate simultaneous methods for quantifying arachidonoyl-ethanolamide, 2-arachidonoyl glycerol, oleoylethanolamide, cortisol and progesterone in human plasma and saliva using liquid-liquid extraction combined with ultra-high performance liquid chromatography coupled to tandem mass spectrometry. The method was fully validated over the linear concentration range 1-20 ng/mL for each analyte in plasma (R 2  = 0.98-0.99) and saliva (R 2  = 0.99). We find that salivary endogenous cannabinoids and cortisol are acutely responsive to exercise, suggesting that targeting the saliva system may present a convenient way for future research of endogenous cannabinoids. This finding also encourages a broader understanding of the endogenous cannabinoid system during stress responses, and our method may consequently lead to a better understanding of the role of endogenous cannabinoids in peripheral tissues., Competing Interests: Declaration of Competing Interest The authors declared that there is no conflict of interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Despite research advances, it remains unclear if long-term, regular cannabis use harms cognition once intoxication has passed. Our meta-analysis aimed to investigate the association between cognitive functioning and long-term (mean ≥2 years), regular (mean ≥4 days/week), recreational cannabis use in adults during abstinence (mean ≥12 hr). We searched PubMed, PsycINFO, CINAHL, Scopus, and Dissertations and Theses International for English-language articles from the date each database began until May 22, 2019. We identified study inclusion by completing abstract and full text screening using predetermined criteria and Preferred Reporting Items for Systematic Review and Meta-Analysis guidelines. We classified cognitive performance into 6 cognitive domains (attention, executive function, learning and memory, decision making, information processing, and working memory), and included a global measure. Effect sizes were calculated for each domain using univariate meta-analyses. There were 30 studies with a total 849 participants who used cannabis (M = 30.7-years-old, SD = 5.5-years-old) and 764 control participants (M = 30.3-years-old, SD = 5.9-years-old). Cannabis was associated with significant but small-magnitude deficits in executive function, learning and memory, and global cognition, while decision making had moderate deficits. There were small-magnitude and nonsignificant group differences for information processing, working memory, and attention. Cannabis use duration, age of onset, and prolonged abstinence (≥25 days) did not influence outcomes, except group differences in executive function were nonsignificant in analyses of prolonged abstinence. Our results suggest that long-term, regular cannabis use is associated with small to moderate deficits in some cognitive domains. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Cannabinoids are a promising method for pharmacological treatment of post-traumatic stress disorder (PTSD). Despite considerable research devoted to the effect of cannabinoid modulation on PTSD symptomology, there is not a currently agreed way by which the cannabinoid system should be targeted in humans. In this review, we present an overview of recent research identifying neurological pathways by which different cannabinoid-based treatments may exert their effects on PTSD symptomology. We evaluate the strengths and weaknesses of each of these different approaches, including recent challenges presented to favourable options such as fatty acid amide hydrolase (FAAH) inhibitors. This article makes the strengths and challenges of different potential cannabinoid treatments accessible to psychological researchers interested in cannabinoid therapeutics and aims to aid selection of appropriate tools for future clinical trials., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Purpose: The presentation and etiology of cerebral palsy (CP) are heterogeneous. Diagnostic evaluation can be a prolonged and expensive process that might remain inconclusive. This study aimed to determine the diagnostic yield and impact on management of next-generation sequencing (NGS) in 50 individuals with atypical CP (ACP)., Methods: Patient eligibility criteria included impaired motor function with onset at birth or within the first year of life, and one or more of the following: severe intellectual disability, progressive neurological deterioration, other abnormalities on neurological examination, multiorgan disease, congenital anomalies outside of the central nervous system, an abnormal neurotransmitter profile, family history, brain imaging findings not typical for cerebral palsy. Previous assessment by a neurologist and/or clinical geneticist, including biochemical testing, neuroimaging, and chromosomal microarray, did not yield an etiologic diagnosis., Results: A precise molecular diagnosis was established in 65% of the 50 patients. We also identified candidate disease genes without a current OMIM disease designation. Targeted intervention was enabled in eight families (~15%)., Conclusion: NGS enabled a molecular diagnosis in ACP cases, ending the diagnostic odyssey, improving genetic counseling and personalized management, all in all enhancing precision medicine practices.

Study Design: Retrospective case analysis., Objectives: Evaluate the cost difference between magnetically controlled growing rod (MCGR) and traditional growing rod (TGR) surgeries at initial implantation and determine the recipient of cost savings., Summary of Background Data: Treatment of early-onset scoliosis is challenging and costly, with growing rods (GRs) becoming a standard treatment. Although both effectively control deformity, TGR requires repeat surgical lengthening and MCGR does not. Previous cost analyses have suggested that MCGR results in lower overall cost after 3 years because of the elimination of repeat surgeries; however, the benefactor of these savings is unclear., Methods: All patients who underwent initial GR implantation from May 2011 to January 2016 at a tertiary care children's hospital were included (37 cases: 16 MCGR and 21 TGR; 4 TGR to MCGR conversions). Financial information was analyzed including insurance provider, and amount billed to and reimbursed from payer. Charges at the time of implantation were divided into categories (surgery time, room/board, anesthesia, implant cost, lab, radiology, therapy, medications, neuromonitoring, operating room materials, and recovery room). Variables were compared using t-tests to determine differences overall and per category., Results: The average overall charge for MCGR implantation was 1.5 times greater than TGR implementation (p = .04). Average charges were statistically similar across all categories, except implant costs, which were significantly higher for MCGR (MCGR: $31,621 vs. TGR: $8,966, p < .0001). The average percentage reimbursement of total charges were similar between surgeries (MCGR 43% vs. TGR 46%, p = .26)., Conclusions: MCGR implantation has a significantly higher charge than TGR, secondary to the higher expense of MCGR implants. Despite this, total institutional reimbursement is similar between the two procedures. Although MCGRs have been shown to be "cost effective" after 3 years, our findings suggest health care institutions bear the cost of this new technology while payers gain the long-term financial benefit., Level of Evidence: Level III, economic analysis., (Copyright © 2018 Scoliosis Research Society. Published by Elsevier Inc. All rights reserved.)

Background: In 2009, the American Academy of Orthopedic Surgeons published clinical practice guidelines (CPGs) on the treatment of pediatric diaphyseal femur fractures, which recommended a nonaccidental trauma (NAT) evaluation for all patients below 36 months of age. A recent study of these guidelines found <50% clinical compliance with this treatment recommendation. We aimed to identify areas for improvement in compliance with this guideline., Methods: A retrospective review was performed of all patients presenting to a single pediatric tertiary care hospital with a diaphyseal femur fracture from January 2007 to June 2013 who were below 36 months old. Medical records were reviewed for documentation of a NAT evaluation, patient characteristics, presence of other fractures or injuries, and hospital of presentation. Radiographs were reviewed for fracture pattern. Statistical analysis was performed to assess for differences overall and before and after CPG publication., Results: During the study period, 281 children below 36 months presented with femur fractures; 41% were evaluated for NAT. Overall, the following factors were significantly associated with receipt of a NAT evaluation: younger age (P<0.001), transfer from an outside facility (P=0.027), and identification of another fracture (P=0.004). Before publication of the CPG, nonwhite patients were much more likely to undergo NAT evaluation compared with white patients (43% vs. 19%; P=0.014). After publication of the CPGs, this differential disappeared (43% vs. 47%; P=0.685). Fracture pattern and patient sex did not influence receipt of NAT evaluation., Conclusions: We found poor utilization of NAT evaluation for patients below 36 months old presenting with femur fracture. Despite CPG publication, only modest improvements in this evaluation occurred over the study period, with less than half of all patients being evaluated. Younger children, patients transferred from other institutions, and patients presenting with concomitant fractures were more likely to undergo NAT evaluation. Compliance with the CPG may be improved by focusing on older children, patients who initially present to tertiary care centers, and those with an isolated femur fracture., Level of Evidence: Level III-retrospective comparative study.

The endocannabinoid system is an increasingly recognised pharmacological target for treating stress and anxiety disorders, including post-traumatic stress disorder (PTSD). Recent preclinical developments have implicated the endocannabinoid system in stress responses, emotional memories and fear extinction, all critical to PTSD aetiology. However, preclinical research in endocannabinoid biology has neglected the influential role of sex hormone differences on PTSD symptomology, which is particularly important given that PTSD is twice as common in women as in men. In this review, we compile and consider the evidence that the endocannabinoid system is influenced by ovarian hormones, with application to stress disorders such as PTSD. It is clear that therapeutic modulation of the endocannabinoid system needs to be approached with awareness of ovarian hormonal influences, and knowledge of these influences may enhance treatment outcomes for female PTSD populations., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

In this work, we report a systematic study on temperature-dependent local structural evolution, oxygen stoichiometry, and electrochemical properties of an oxygen-deficient perovskite Sr 0.7 Y 0.3 CoO 3-δ (SYC30) for oxygen electrocatalysis. The obtained results are then closely compared with its analogue Sr 0.9 Y 0.1 CoO 3-δ (SYC10) of different crystal structures to establish structure-activity relationships. The comparison shows that both SYC30 and SYC10 consist of alternate layers of oxygen-deficient Co1-polyhedra and oxygen-saturated Co2-octahedra with Co1-polyhedra being responsible for V o •• migration. It is also found that the distribution and concentration of oxygen vacancies within the Co1-layer are, respectively, less symmetrical and lower in SYC30 than those in SYC10, making the former unfavorable for oxygen transport. A molecular orbital energy analysis reveals that the energy gap between Fermi level and O 2p level in the active Co1-polyhedra is larger in SYC30 than that in SYC10, further suggesting that SYC10 is a better oxide-ion conductor and thus a better electrocatalyst for oxygen reduction reaction, which is unambiguously confirmed by the subsequent electrochemical measurements.

Introduction: The dangers of radiation exposure in children have been well studied, with assessment of adolescent idiopathic scoliosis (AIS) documented as having the potential for notable patient exposure. The purposes of this study were to evaluate a consecutive series of patients referred to a tertiary care pediatric hospital for AIS and to assess the type and quality of imaging obtained before referral for specialist evaluation., Methods: We performed a prospective study of consecutive patients referred over a 6-month period to a pediatric orthopaedic practice at a large, free-standing, urban children's hospital for evaluation of AIS. We assessed prereferral radiographic exposure, evaluating the utilization and adequacy of these radiographs., Results: Of a total of 131 patients enrolled in the study, 79 had received radiographs before the visit; of these, only 59 patients (75%) brought the previously obtained radiographs to the specialist consultation, and 45 patients (76%) of this subset were found to be adequate for evaluation of AIS. Of the total cohort, 56 patients (43%) required repeat radiographs because of missing or inadequate radiographs., Discussion: We found a large number of missing or inadequate radiographs, leading to repeat radiation exposure in this cohort. Improvements in the utilization of radiographs before orthopaedic referral could decrease unnecessary patient radiation exposure.

Many inborn errors of metabolism (IEMs) are amenable to treatment; therefore, early diagnosis and treatment is imperative. Despite recent advances, the genetic basis of many metabolic phenotypes remains unknown. For discovery purposes, whole exome sequencing (WES) variant prioritization coupled with clinical and bioinformatics expertise is the primary method used to identify novel disease-causing variants; however, causation is often difficult to establish due to the number of plausible variants. Integrated analysis of untargeted metabolomics (UM) and WES or whole genome sequencing (WGS) data is a promising systematic approach for identifying disease-causing variants. In this review, we provide a literature-based overview of UM methods utilizing liquid chromatography mass spectrometry (LC-MS), and assess approaches to integrating WES/WGS and LC-MS UM data for the discovery and prioritization of variants causing IEMs. To embed this integrated -omics approach in the clinic, expansion of gene-metabolite annotations and metabolomic feature-to-metabolite mapping methods are needed.

Study Design: Comparative cohort study., Objective: To compare coronal deformity control, lengthening efficacy, and sagittal alignment between distraction-based growing rod constructs utilizing tandem versus wedding band connectors., Summary of Background Data: Different construct designs exist for growing rod treatment of early-onset scoliosis. All use a version of a rod connector, with the two main types being tandem and wedding band. Little data exist to quantify the impact of connector choice on radiographic outcomes of treatment., Methods: A multicenter database of prospectively and retrospectively collected data on early-onset scoliosis patients was reviewed. Patients of any thoracic or thoracolumbar coronal plane deformity whose initial growing rod treatment was initiated before age 10 years and underwent at least 3 years of dual growing rod treatment with either tandem or wedding band connectors were included. Preoperative, immediate postoperative, and prefinal radiographs were reviewed and compared in regard to major curve magnitude, T1-T12 and T1-S1 spinal length, length of instrumentation, and sagittal plane measures., Results: A total of 209 patients were included. The overall percent change from preoperative to prefinal in all radiographic parameters was not different between the two groups indicating similar efficacy in treatment. After controlling for institutional variation, the improvement of the major coronal Cobb angle from preoperative to prefinal was statistically improved for the tandem group (34° vs. 29°, p = .002) and the difference in T5-T12 kyphosis from preoperative to prefinal was significantly different between the groups (-6° vs. +1.3°, p = .008)., Conclusion: We identified little difference in the effects of connector type on radiographic outcomes of patients treated with traditional growing rod, which indicates that both wedding band and tandem connectors function similarly. The small differences detected suggest that tandem connectors may improve major Cobb correction, and wedding band connectors may maintain thoracic kyphosis over time., Level of Evidence: Level III., (Copyright © 2017 Scoliosis Research Society. Published by Elsevier Inc. All rights reserved.)

Research reports show increased prevalence of habitual khat chewing among various parts of the community in Ethiopia. Some users experience problems controlling their use; withdrawal symptoms may be adding to difficulties with reducing or ceasing use. We aimed to describe the nature and the time course of any withdrawal syndrome in relation to the cessation of khat use over the first 2 weeks of a quit attempt. Fifty-nine participants between the ages of 18 and 35 and who have already chewed ≥1 bundle of khat in their life with a chewing frequency of ≥3 days per week were recruited from Adama Science and Technology University campus. Participants were predominantly male (n = 45, 75%) and had the mean age of 24.8 years (range = 20-32; SD = 2.8). Participants used smart phones to monitor withdrawal symptoms and cravings. The total assessments were divided in to 3 prequit and 14 postquit days. The development of withdrawal symptoms was evident, and all withdrawal symptoms followed similar overall patterns, with salient elevations after the quit day and curvatures around the first week of postquit period. Depression, craving, nervousness, tiredness, restlessness, poor motivation, irritability, and negative affect substantially increased and reached peak on the first week around Day 7 and remained higher compared with the level at baseline indicating the persistence and severity of these symptoms over time. In addition, craving, irritability, and restlessness had significantly reverted to their baseline level during the second week of the postquit duration. We have demonstrated low rates of success during unaided quite attempts from khat and that the withdrawal syndrome is not trivial. Interventions are necessary to support individuals during the period of increased symptoms of dysphoria and to reduce the risk of relapse. (PsycINFO Database Record, ((c) 2018 APA, all rights reserved).)

Attentional bias towards threat can be demonstrated by enhanced processing of threat-related targets and/or greater interference when threat-related distractors are present. These effects are argued to reflect processing within the orienting and executive control networks of the brain respectively. This study investigated behavioural (RT) and electrophysiological correlates of early selective attention and top-down attentional control among females with high (n = 16) or low (n = 16) spider fear (Mean age = 22 years). Participants completed a novel flanker go/nogo task in which a central schematic flower or spider stimulus was flanked by either congruent or incongruent distractors. Participants responded to green stimuli (go trials) and withheld response to yellow stimuli (nogo trials). High fear participants demonstrated significantly shorter reaction times and greater P1 amplitude to spider targets, suggesting specific hypervigilance towards threat-relevant stimuli. In contrast to predictions, there was little evidence for behavioural interference effects or differences in N2 amplitude when distractor stimuli were threat-relevant.

A cascade of alternative sigma factors directs developmental gene expression during spore formation by the bacterium Bacillus subtilis. As the spore develops, a tightly regulated switch occurs in which the early-acting sigma factor σF is replaced by the late-acting sigma factor σG. The gene encoding σG (sigG) is transcribed by σF and by σG itself in an autoregulatory loop; yet σG activity is not detected until σF-dependent gene expression is complete. This separation in σF and σG activities has been suggested to be due at least in part to a poorly understood intercellular checkpoint pathway that delays sigG expression by σF. Here we report the results of a careful examination of sigG expression during sporulation. Unexpectedly, our findings argue against the existence of a regulatory mechanism to delay sigG transcription by σF and instead support a model in which sigG is transcribed by σF with normal timing, but at levels that are very low. This low-level expression of sigG is the consequence of several intrinsic features of the sigG regulatory and coding sequence-promoter spacing, secondary structure potential of the mRNA, and start codon identity-that dampen its transcription and translation. Especially notable is the presence of a conserved hairpin in the 5' leader sequence of the sigG mRNA that occludes the ribosome-binding site, reducing translation by up to 4-fold. Finally, we demonstrate that misexpression of sigG from regulatory and coding sequences lacking these features triggers premature σG activity in the forespore during sporulation, as well as inappropriate σG activity during vegetative growth. Altogether, these data indicate that transcription and translation of the sigG gene is tuned to prevent vegetative expression of σG and to ensure the precise timing of the switch from σF to σG in the developing spore.

Introduction and Aims: Despite the adverse effects of khat use and chewers interest in cessation, there are few studies that have reported on the outcome of khat cessation attempts, and limited resources available for potential quitters. We used electronic diaries to monitor the outcomes of an unassisted quit attempt among daily and near daily khat consumers, and examine predictors of success., Design and Methods: Sixty participants between the ages of 18 and 35 years who regularly chewed khat and who were attempting to quit were purposively recruited from an Ethiopian University campus. Real-time prospective daily recording of khat use was obtained for an average of 10 days prior to quit day (range 6-13) and 28 post-quit days (range 9-31), using an electronic diary., Results: Almost all (95%) achieved initial abstinence. Of these, 80% reached at least seven continuous days of abstinence; 7% maintained continuous abstinence for 28 days post-quit. While 93% lapsed (average 11 days post-quit, SD = 7), only a smaller proportion relapsed (41%: chewed for at least three consecutive days after at least 5 days of abstinence). No demographic factors were predictive of successful abstinence., Discussion and Conclusions: Regular khat chewers have difficulties in maintaining abstinence despite having motivation and desire to quit. This implies that treatment aids may be needed to assist chewers' in their quit attempts. Controlled experimental trial through the use of available low cost quit aids and behavioural resources is crucial in order to increase success rates for those seeking to desist from khat use., (© 2017 Australasian Professional Society on Alcohol and other Drugs.)

Objective: This study aimed to determine the efficacy of the Severity of Dependence Scale (SDS) as a screening tool for Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition-defined khat use disorder., Methods: Cross-sectional, purposive sample of past-year khat consumers aged 16 and above were recruited from khat markets and cafes from university and general community in Adama, Ethiopia. Participants self-completed a survey comprising current substance use disorder., Results: The SDS formed a unifactorial structure, consistent with the dependence construct. Almost three quarters (73%) of the sample were identified as experiencing Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition khat use disorder. The SDS demonstrated excellent discrimination (area under the curve = 0.92) and an optimal cut-off as a score of 3 or greater, with sensitivity of 81% and specificity of 96%. This classification validly identified a group with more frequent and higher dose khat use than participants that did not screen positive., Conclusion: Although khat is a mild stimulant, there is clear evidence that some consumers are both concerned with their use and experience problems associated with their use. Consistent with its application for other drugs, the SDS is a brief and simple screening tool that appears to validly identify individuals experiencing a khat use disorder syndrome and experiencing high rates of adverse consequences in association with use., (Copyright © 2018 John Wiley & Sons, Ltd.)

Aims: Long-term heavy use of cannabis and alcohol are known to be associated with memory impairments. In this study, we used event-related potentials to examine verbal learning and memory processing in a commonly used behavioral task. Method: We conducted two studies: first, a small pilot study of adolescent males, comprising 13 Drug-Naive Controls (DNC), 12 heavy drinkers (HD) and 8 cannabis users (CU). Second, a larger study of young adults, comprising 45 DNC (20 female), 39 HD (16 female), and 20 CU (9 female). In both studies, participants completed a modified verbal learning task (the Rey Auditory Verbal Learning Test, RAVLT) while brain electrical activity was recorded. ERPs were calculated for words which were subsequently remembered vs. those which were not remembered, and for presentations of learnt words, previously seen words, and new words in a subsequent recognition test. Pre-planned principal components analyses (PCA) were used to quantify the ERP components in these recall and recognition phases separately for each study. Results: Memory performance overall was slightly lower than published norms using the standardized RAVLT delivery, but was generally similar and showed the expected changes over trials. Few differences in performance were observed between groups; a notable exception was markedly poorer delayed recall in HD relative to DNC (Study 2). PCA identified components expected from prior research using other memory tasks. At encoding, there were no between-group differences in the usual P2 recall effect (larger for recalled than not-recalled words). However, alcohol-related differences were observed in a larger P540 (indexing recollection) in HD than DNC, and cannabis-related differences were observed in a smaller N340 (indexing familiarity) and a lack of previously seen > new words effect for P540 in Study 2. Conclusions: This study is the first examination of ERPs in the RAVLT in healthy control participants, as well as substance-using individuals, and represents an important advance in methodology. The results indicate alterations in recognition memory processing, which even if not manifesting in overt behavioral impairment, underline the potential for brain dysfunction with early exposure to alcohol and cannabis.

PurposeWe analyzed the Exome Aggregation Consortium (ExAC) data set for the presence of individuals with pathogenic genotypes implicated in Mendelian pediatric disorders.MethodsClinVar likely/pathogenic variants supported by at least one peer-reviewed publication were assessed within the ExAC database to identify individuals expected to exhibit a childhood disorder based on concordance with disease inheritance modes: heterozygous (for dominant), homozygous (for recessive) or hemizygous (for X-linked recessive conditions). Variants from 924 genes reported to cause Mendelian childhood disorders were considered.ResultsWe identified ExAC individuals with candidate pathogenic genotypes for 190 previously published likely/pathogenic variants in 128 genes. After curation, we determined that 113 of the variants have sufficient support for pathogenicity and identified 1,717 ExAC individuals (~2.8% of the ExAC population) with corresponding possible/disease-associated genotypes implicated in rare Mendelian disorders, ranging from mild (e.g., due to SCN2A deficiency) to severe pediatric conditions (e.g., due to FGFR1 deficiency).ConclusionLarge-scale sequencing projects and data aggregation consortia provide unprecedented opportunities to determine the prevalence of pathogenic genotypes in unselected populations. This knowledge is crucial for understanding the penetrance of disease-associated variants, phenotypic variability, somatic mosaicism, as well as published literature curation for variant classification procedures and predicted clinical outcomes.

Introduction: Driving following illicit drug consumption ('drug-driving') is a potential road safety risk. Roadside drug testing (RDT) is conducted across Australia with the dual aims of prosecuting drivers with drugs in their system and deterring drug-driving. We examined trends over time in self-reported past six-month drug-driving among sentinel samples of regular drug users and assessed the impact of experiences of RDT on drug-driving among these participants., Methods: Data from 1913 people who inject drugs (PWID) and 3140 regular psychostimulant users (RPU) who were first-time participants in a series of repeat cross-sectional sentinel studies conducted in Australian capital cities from 2007 to 2013 and reported driving in the past six months were analysed. Trends over time were assessed using the χ 2 test for trend. Multivariable logistic regressions assessed the relationship between experiences of RDT and recent drug-driving, adjusting for survey year, jurisdiction of residence and socio-demographic and drug use characteristics., Results: The percentage of participants reporting recent (past six months) drug-driving decreased significantly over time among both samples (PWID: 83% [2007] vs. 74% [2013], p<0.001; RPU: 72% vs. 56%, p<0.001), but drug-driving remained prevalent. Lifetime experience of RDT increased significantly over time (PWID: 6% [2007] vs. 32% [2013], p<0.001; RPU: 2% vs. 11%, p<0.001). There were no significant associations between experiencing RDT and drug-driving among either PWID or RPU., Conclusion: Although there is some evidence that drug-driving among key risk groups of regular drug users is declining in Australia, possibly reflecting a general deterrent effect of RDT, experiencing RDT appears to have no specific deterrent effect on drug-driving. Further intervention, with a particular focus on changing attitudes towards drug-driving, may be needed to further reduce this practice among these groups., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: Examine the motivations for new psychoactive substance (NPS) use amongst a sample of regular psychostimulant users (RPU) in Australia, and determine whether motivations differ across substances., Method: Data were obtained from 419 RPU interviewed for the 2014 Ecstasy and related Drugs Reporting System who reported lifetime NPS use. Based on the most recent NPS used, motivations for use were rated on an 11-point scale (0 'no influence'-10 'maximum influence')., Results: For NPS overall, value for money was found to be the most highly endorsed motivation for use, scoring a median of five out of ten. However, there was substantial variation in motivations for use across substance types. Availability (i.e. no other drug was available to me at the time; 6/10) was the most highly endorsed motivation for the use of synthetic cathinones, which was significantly higher than reported for DMT. Perceived legality and availability were the most highly endorsed motivations for synthetic cannabinoids (5/10); perceived legality scored higher for synthetic cannabinoids than for all the other NPS, whilst in regards to availability synthetic cannabinoids scored significantly higher than DMT only. Value for money was the most highly endorsed motivation for NBOMe (8/10) and 2C-family substances (5/10); in regards to NBOMe this scored significantly higher than all other NPS. Short effect duration was the most highly endorsed motivation for DMT (7/10), which was significantly higher than for all other NPS., Conclusion: Synthetic cathinones and cannabinoids appear to be largely motivated by 'opportunistic' reasons (i.e. availability, legality), while NBOMe, 2C-family substances and DMT appear to be motivated by particular desirable qualities of a substance (i.e. value for money, short effect duration). Providing a nuanced understanding of why individuals use particular NPS improves our ability to understand the NPS phenomenon and to tailor harm reduction messages to the appropriate target groups., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Clinical and laboratory data were collected from three Finnish patients including a sibling pair and another unrelated child with unexplained childhood hypoglycemia. Transient elevation of alanine transaminase, lactate and tricarboxylic acid cycle intermediates, especially fumarate, were noticed in urine organic acid analysis. Exome sequencing was performed for the patients and their parents. A novel homozygous PCK1 c.925G>A (p.G309R) mutation was detected in all affected individuals. COS-1 cells transfected with mutant PCK1 transcripts were used to study the pathogenic nature of the detected variant. The COS-1 transfected cells showed the mutant gene to be incapable of producing a normally functioning cytosolic phosphoenolpyruvate carboxykinase (PEPCK) enzyme. This report further delineates the clinical phenotype of isolated cytosolic PEPCK deficiency and offers a metabolic pattern helping to recognize these patients. Cytosolic PEPCK deficiency should be considered in the differential diagnosis of children presenting with hypoglycemia, hepatic dysfunction and elevated tricarboxylic acid intermediates in urinary organic acid analysis., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background and Objectives: The aim of the study was to examine habituation of subjective anxiety and electrophysiological correlates of cortical hyper-vigilance during exposure to spider images among high (n = 12) and low (n = 11) spider fear groups., Methods: Participants viewed a six-stage hierarchy of spider images. The images used at stage 1 and stage 6 were the same. Subjective anxiety was rated at four intervals during each three-minute exposure stage (0, 60, 120, and 180 s) and event-related potentials (ERPs) were averaged across these epochs (0-60, 60-120, 120-180)., Results: High spider fearfuls demonstrated greater habituation of self-reported anxiety within and between exposure stages compared to low fearfuls. Consistent with attentional hyper-vigilance, the high-fear group also demonstrated greater P1 amplitude in response to spider images. In both groups, habituation of P1 amplitude was found at later relative to earlier stages, but increased at stage six when the stage 1 image was re-presented, despite low subjective anxiety., Limitations: While the passive viewing paradigm mirrored image-based exposure, it was not possible to determine whether participants engaged in avoidance strategies. In addition, further research is needed to assess the relevance of habituation and reinstatement of P1 amplitude to therapeutic outcome., Conclusions: Habituation of subjective anxiety during image-based exposure is not necessarily accompanied by a reduction in measures of cortical hyper-vigilance. The reinstatement of the P1 response may indicate either re-activation of previous associations, less avoidance, or a more generalised dishabituation mechanism., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background and Objectives: Computer-aided vicarious exposure (CAVE) for obsessive-compulsive disorder (OCD) is an intervention in which participants learn and rehearse exposure with response prevention (ERP) by directing a character around a virtual world. This study aimed to pilot an online CAVE program for OCD in a community sample with high OCD symptomatology., Methods: Participants (n = 78) were allocated to an intervention group (three 45-min weekly CAVE sessions) or to a waitlist control group. The treatment group were asked to complete three 45-min sessions over a four week period., Results: Those who completed at least one CAVE session showed greater improvement on measures of OCD symptomatology at one-month post-treatment (d = 0.49-0.81) compared to waitlist (d = 0.01-0.1). Older age, past treatment and higher symptom severity were associated with non-adherence., Limitations: These findings should be considered preliminary due to sample size limitations and an absence of an active control group. However, the findings suggest that further development and evaluation of the program is warranted., Conclusions: Preliminary findings suggest that online CAVE programs have potential to bridge treatment gaps among those reluctant to attend treatment or engage with in vivo exposure exercises. These programs may also have potential applications as an adjunct to face-to-face or online cognitive behavioural therapy., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background: Over the past decade, monitoring systems have identified the rapid emergence of new psychoactive substances (NPS). While the use of many NPS is minimal and transitory, little is known about which products have potential for capturing the attention of significant proportions of the drug consuming market. The aim of this study was to explore self-reported experiences of three commonly used NPS classes within the Australian context (synthetic cathinones, hallucinogenic phenethylamines and hallucinogenic tryptamines) relative to traditional illicit drug counterparts., Methods: Frequent psychostimulant consumers interviewed for the Australian Ecstasy and related Drugs Reporting System (EDRS) (n=1208) provided subjective ratings of the pleasurable and negative (acute and longer-term) effects of substances used in the last six months on the last occasion of use, and the likelihood of future use., Results: Stimulant-type NPS (e.g., mephedrone, methylone) were rated less favourably than ecstasy and cocaine in terms of pleasurable effects and likelihood of future use. DMT (a hallucinogenic tryptamine) showed a similar profile to LSD in terms of pleasurable effects and the likelihood of future use, but negative effects (acute and comedown) were rated lower. Hallucinogenic phenethylamines (e.g., 2C-B) showed a similar negative profile to LSD, but were rated as less pleasurable and less likely to be used again., Conclusion: The potential for expanded use of stimulant-type NPS may be lower compared to commonly used stimulants such as ecstasy and cocaine. In contrast, the potential of DMT may be higher relative to LSD given the comparative absence of negative effects., (Copyright © 2016 Elsevier B.V. All rights reserved.)