"A little bit of hope goes a long way": Exploring the role of peer workers in alcohol and other drug rehabilitation services.

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.

Psychological and attentional outcomes following acute mindfulness induction among high anxiety individuals: A systematic review and meta-analysis.

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.

Identification of Streptococcus pneumoniae genes associated with hypothiocyanous acid tolerance through genome-wide screening.

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 ΔahpD, 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.

Relationship between attentional bias and stimulus control: An observational study of real-world eating patterns.

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.

Psychological Outcomes and Mechanisms of Mindfulness-Based Training for Generalised Anxiety Disorder: A Systematic Review and Meta-Analysis.

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.

Human germline heterozygous gain-of-function STAT6 variants cause severe allergic disease.

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.

Who's afraid of the X? Incorporating the X and Y chromosomes into the analysis of DNA methylation array data.

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.

Safety Evaluation of a Novel Algal Feed Additive for Poultry Production.

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.

Evaluación de seguridad de un nuevo aditivo alimentario con base en algas para la producción avícola. Los aditivos alimentarios son componentes críticos para la salud avícola y la viabilidad económica de la producción avícola libre de antibióticos. El objetivo del presente estudio es evaluar la seguridad de un nuevo aditivo alimentario derivado de algas, un polvo de biomasa seca producido a partir de la cepa crAL082 de Chlamydomonas reinhardtii, que fue modificado para expresar una N-acetilmuramoil-Lalanina amidasa (EC 3.5.1.28) y una enzima tipo lisozima (EC 3.2.1.17). Un estudio de toxicidad oral de 42 días mostró que el polvo de biomasa seca crAL082 fue totalmente tolerado por los pollos de engorde con base a la ausencia de efectos perjudiciales encontrados en el rendimiento, la mortalidad, la hematología, la química clínica sanguínea y los resultados histopatológicos en comparación con los del grupo de control no tratado, lo que resultó en un "Nivel sin efecto adverso observado" ("No Observed Adverse Effect Level" = de 5000 ppm, la dosis más alta probada. El estudio demuestra el primer resultado de seguridad de un polvo de biomasa seca de microalgas C. reinhardtii utilizado como aditivo alimentario en pollos de engorde. Además, se muestra la seguridad de las dos enzimas adicionales expresadas dentro de la cepa crAL082 de C. reinhardtii e ingeridas por las aves.

Exploring the Patient Experience with Patient-Reported Outcomes: A Qualitative, Multistakeholder Study.

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 and the clinical diagnosis of genetic disease: The CAUSES study.

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.

Translation of animal endocannabinoid models of PTSD mechanisms to humans: Where to next?

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.

The effects of acute stress on attentional networks and working memory in females.

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 (Mage = 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.

BDNF genotype Val66Met interacts with acute plasma BDNF levels to predict fear extinction and recall.

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.

Secondary biogenic amine deficiencies: genetic etiology, therapeutic interventions, and clinical effects.

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.

Cannabinoid polymorphisms interact with plasma endocannabinoid levels to predict fear extinction learning.

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.

Chloroform-based liquid-liquid extraction and LC-MS/MS quantification of endocannabinoids, cortisol and progesterone in human hair.

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 R2 = 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.

A cross-cohort analysis of autosomal DNA methylation sex differences in the term placenta.

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.

Is the diagnostic rate for the common subtypes of A1AT deficiency consistent across two Canadian Provinces?

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.

A Tn-seq Screen of Streptococcus pneumoniae Uncovers DNA Repair as the Major Pathway for Desiccation Tolerance and Transmission.

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.