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Abstract Research on climate anxiety is rapidly growing, with ongoing exploration of population prevalence, contributing factors, and mitigation strategies that transform anxiety into helpful action. What remains unclear is whether and how to delineate climate anxiety from mental ill health. A limited conceptualization of climate anxiety restricts efforts to identify and support those adversely affected. This paper draws on psychological and existential theories to propose a theoretical model of climate anxiety and coping, extending previous conceptualizations. The model theorizes that climate change evokes an existential conflict that manifests affectively as climate anxiety (and other emotional experiences), wherein cognitive and behavioral coping processes are activated. These processes fall on a continuum of adaptivity, depending on functional impact. Responses might range from meaningful engagement with activities that address climate change to maladaptive strategies that negatively impact personal, social, and occupational functioning. Applications of this model in research and practice are proposed.

ABSTRACTChildhood obesity is linked to maternal smoking during pregnancy. Gut microbiota may partially mediate this association and could be potential targets for intervention; however, its role is understudied. We included 1,592 infants from the Canadian Healthy Infants Longitudinal Development Cohort. Data on environmental exposure and lifestyle factors were collected prenatally and throughout the first three years. Weight outcomes were measured at one and three years of age. Stool samples collected at 3 and 12 months were analyzed by sequencing the V4 region of 16S rRNA to profile microbial compositions and magnetic resonance spectroscopy to quantify the metabolites. We showed that quitting smoking during pregnancy did not lower the risk of offspring being overweight. However, exclusive breastfeeding until the third month of age may alleviate these risks. We also reported that maternal smoking during pregnancy significantly increased Firmicutes abundance and diversity. We further revealed that Firmicutes diversity mediates the elevated risk of childhood overweight and obesity linked to maternal prenatal smoking. This effect possibly occurs through excessive microbial butyrate production. These findings add to the evidence that women should quit smoking before their pregnancies to prevent microbiome-mediated childhood overweight and obesity risk, and indicate the potential obesogenic role of excessive butyrate production in early life.

Abstract Targeting the estrogen receptor alpha (ERα) pathway is validated in the clinic as an effective means to treat ER+ breast cancers. Here we present the development of a VHL-targeting and orally bioavailable proteolysis-targeting chimera (PROTAC) degrader of ERα. In vitro studies with this PROTAC demonstrate excellent ERα degradation and ER antagonism in ER+ breast cancer cell lines. However, upon dosing the compound in vivo we observe an in vitro-in vivo disconnect. ERα degradation is lower in vivo than expected based on the in vitro data. Investigation into potential causes for the reduced maximal degradation reveals that metabolic instability of the PROTAC linker generates metabolites that compete for binding to ERα with the full PROTAC, limiting degradation. This observation highlights the requirement for metabolically stable PROTACs to ensure maximal efficacy and thus optimisation of the linker should be a key consideration when designing PROTACs.

The nests of mound-building ants are unexplored reservoirs of fungal diversity. A previous assessment of this diversity in the nests of Formica ulkei suggested that water availability may be a determinant of the composition of this mycota. To investigate this question, we recovered 3594 isolates of filamentous Ascomycota from the nests of Formica obscuripes and adjacent, non-nest sites, employing Dichloran Rose Bengal agar (DRBA), Dichloran Rose Bengal agar containing glycerol (DRBAG), and malt extract agar containing sucrose (MEA20S). Higher numbers of fungi were isolated from the tops of mounds than from within mounds and non-mound sites. Mound nest soils were dominated by members of the family Aspergillaceae, and up to 50% of the colonies isolated on DRBAG belonged to the genus Aspergillus. Pseudogymnoascus pannorum and species of Talaromyces were also present in higher numbers in mound soils. Species of Penicillium were more abundant in non-nest soils, where they accounted for over 66% of isolates on DRBA. All Aspergillaceae assessed for xerotolerance on a medium augmented with glycerol or sucrose were xerophilic. These results, and our observation that the nests of F. obscuripes are low-water environments, indicate that water availability influences the structure of the fungal communities in these animal-modified habitats.

Attachment styles influence mental health and relationships through life. Few studies examine the adolescent factors associated with adult attachment styles. This paper examines the association between adolescent emotional and behavioral problems and maternal-adolescent communication with attachment style in early adulthood. Data from 3423 participants in a birth cohort study were examined. At 14-years, participants' mothers completed the Parent-Adolescent Communication Scale. Participants completed the Youth Self-Report at 14-years which measures internalizing and externalizing symptoms, and the Attachment Style Questionnaire (ASQ) at 21-years. The ASQ comprises five domains of internal working models of interpersonal relationships and attachment style: confidence (security), discomfort with closeness and relationships as secondary (avoidance), need for approval and preoccupation with relationships (anxiety). Associations were examined using general linear models. After adjustments, internalizing symptoms score was associated with all domains of attachment and externalizing symptoms score was associated with four domains of attachment insecurity, but not attachment security. Low openness in maternal-adolescent communication was most strongly associated with decreased confidence and high problem maternal-adolescent communication was associated with viewing relationships as secondary. Adolescents with emotional and behavioral problems and maternal-adolescent communication may benefit from attachment-based interventions to support the development of healthy relationships and attachments in young adulthood.

Abstract Background Idiopathic Anaphylaxis (IA) is the most common anaphylactic syndrome in adults. Mental health problems associated with IA are not well recognised. We aimed to assess if patients diagnosed with IA were more likely to experience mental health problems compared to a normative Australian population. We additionally hypothesised that the number of anaphylactic episodes would correlate with symptoms of anxiety. Methods A total of 34 patients with at least one episode of IA were recruited from an adult immunology clinic. Patients were recruited as part of a separate study evaluating alternative aetiologies in IA. Mental health problems were measured using the Depression, Anxiety and Stress Scale (DASS-21). An extension of the survey included questions specifically focused on the psychological impact of IA. Results Compared to population norms, those with IA had significantly higher levels of mental health problems. Statistically significant DASS-21 scores were identified for depression 4.24 vs. 2.57 (p

Place is of central significance to urban planning processes that specifically target community involvement and co-ownership of development decisions. Consequently, the intriguing but often daunting task of understanding how a sense of place emerges, develops, and evolves has been a subject of interdisciplinary study that links the social sciences, humanities, and more recently, cognitive sciences. Since Kevin Lynch’s classic study of urban images and mental maps, borders within cities have either directly or indirectly featured as vital meaning-making elements of place identities. However, despite some remarkable precedents, analysis of political and socio-cultural borders has only begun to link place-making and bordering processes in ways that resonate with urban planning studies. In this article, we will suggest that borders emerge in the embodied creation of social space as a means to interpret the environment and stabilise ways of knowing the wider world. Building on our own previous research on participatory place-making initiatives in Berlin, we will indicate how border stories (i.e., the social communication of neighbourhood distinction, relationality, and transformation) represent vital knowledges of place. These knowledges reflect embodied experiences of place as well as contestations and tensions that characterise place development processes. Perhaps most importantly in terms of planning, the salience of urban borders lies in broadening understanding of how and why places function—or fail to function—as communities.

A commonly suggested strategy for addressing bullying is for victims to seek help from a trusted person. Despite this recommendation, there are a group of adolescent victims who choose not to seek help. This study aimed to identify factors associated with not seeking help among adolescents who experienced bullying victimisation. A sub-sample of youth who self-reported being bullied (N = 652) was drawn from an Australian nationally representative household survey of adolescents aged 11-17 years (N = 2,967). Adolescent participants and their parents completed survey items on demographics, bullying experiences, mental health, school, and family characteristics. Overall, 45.3% of bullied adolescents did not seek help. Neither the type, frequency, nor levels of distress caused by the bullying victimisation were associated with help-seeking. Age was no longer associated with increased odds of "not" seeking help for bullying victimisation, after controlling for mental health, social, and interpersonal functioning. In a multivariate logistic regression model examining demographic, mental health, social, and interpersonal factors, those with poorer prosocial skills, lower perceived social support, and higher internet use had increased odds of "not" seeking help for bullying victimisation (OR = 2.81, 95% CI = 1.00, 7.93; OR = 2.70, 95% CI = 1.32, 5.52; and OR = 2.19, 95% CI = 1.11, 4.33, respectively). Identifying and supporting young people who are socially isolated and/or have poorer prosocial skills may improve help-seeking among adolescents who experience bullying victimisation. This approach has the potential to address victimisation earlier in its course thereby reducing consequent harm.

We describe a case of a 31-year-old man with a history of ocular non-Hodgkin's lymphoma who presented with a large 12-cm non-resolving traumatic skin lesion on his back. Biopsy showed fungal elements, and on fungal culture, Rhizopus arrhizus (formerly R. oryzae) was isolated. Cutaneous mucormycosis is an important diagnostic consideration for a non-resolving skin lesion in an immunocompromised host. Early tissue sampling is key, and diagnostic certainty is particularly important because first line therapy, liposomal amphotericin B, has significant systemic toxicities, notable renal toxicity, and is therefore challenging to continue empirically. Surgical debridement is an integral part of therapy, highlighting the need for early multidisciplinary care in patients with cutaneous mucormycosis.

Introduction A rise in premature mortality—defined here as death during the most productive years of life, between adolescence and middle adulthood (15–60 years)—is contributing to stalling life expectancy in high-income countries. Causes of mortality vary, but often include substance misuse, suicide, unintentional injury and non-communicable disease. The development of evidence-informed policy frameworks to guide new approaches to prevention require knowledge of early targets for intervention, and interactions between higher level drivers. Here, we aim to: (1) identify systematic reviews with or without meta-analyses focused on intervention targets for premature mortality (in which intervention targets are causes of mortality that can, at least hypothetically, be modified to reduce risk); (2) evaluate the review quality and risk of bias; (3) compare and evaluate each review’s, and their relevant primary studies, findings to identify existing evidence gaps.Methods and analysis In May 2023, we searched electronic databases (MEDLINE, PubMed, Embase, Cochrane Library) for peer-reviewed papers published in the English language in the 12 years from 2012 to 2023 that examined intervention targets for mortality. Screening will narrow these papers to focus on systematic reviews with or without meta-analyses, and their primary papers. Our outcome is death between ages 15 and 60 years; with potential intervention targets measured prior to death. A MeaSurement Tool to Assess systematic Reviews (AMSTAR 2) will be used to assess quality and risk of bias within included systematic reviews. Results will be synthesised narratively due to anticipated heterogeneity between reviews and between primary studies contained within included reviews.Ethics and dissemination This review will synthesise findings from published systematic reviews and meta-analyses, and their primary reviewed studies, meaning ethics committee approval is not required. Our findings will inform cross-cohort consortium development, be published in a peer-reviewed journal, and be presented at national and international conferences.PROSPERO registration number CRD42022355861.

The National Strategic Framework for Aboriginal and Torres Strait Islander Peoples’ Mental Health and Social and Emotional Wellbeing identifies building a strong Aboriginal and Torres Strait Islander led evidence-base to inform care as a key priority. Aboriginal and/or Torres Strait Islander adolescents in contact with the criminal justice system are a highly vulnerable group of Australians, with substantial unmet needs. There is limited evidence to inform culturally appropriate models of care that meet the social and emotional wellbeing needs of justice-involved Aboriginal and/or Torres Strait Islander adolescents. This project aims to develop, implement and evaluate an in-reach and community transitional model of social and emotional wellbeing care for Aboriginal and/or Torres Strait Islander adolescents (10–17 years old) who experience detention through close engagement with Aboriginal and/or Torres Strait Islander youth, Elders, researchers, practitioners and community members, and by drawing on culturally informed practice and knowledge systems. The project is based on a multi-level mixed methods design, with a strong focus on ongoing project evaluation (based on the Ngaa-bi-nya framework) and co-design. Co-design is facilitated through culturally safe and trauma informed participatory processes based on development of strong partnerships from project initiative, design, implementation and evaluation. Application of the landscape domain of the Ngaa-bi-nya framework for Aboriginal and Torres Strait Islander program evaluation will be explored in Phase one. Aboriginal and Torres Strait Islander adolescents with experience in detention will be engaged through one-on-one interviews with data collection through the Growth and Empowerment Measure (GEM) Youth (which will be adapted from the adult version and validated as part of this study), the Kessler Psychological Distress Scale (K-10), questions around alcohol and drug use, and narrative interviews exploring experience. Qualitative data will be analyzed using an inductive thematic approach, structured within the framework of the Ngaa-bi-nya landscape prompts. Quantitative data will be analyzed using descriptive statistics to provide a profile of the cohort. Findings from Phase one will be used to inform the development of a model of social and emotional wellbeing care that will be implemented and evaluated in Phase two.

The authors investigate marine heatwaves on the ocean bottom in the shallow waters surrounding North America. Relative to their surface counterparts, bottom marine heatwaves are often more intense, more persistent, and can occur independently.

ABSTRACT The environment plays an instrumental role in the developmental origins of health and disease. Protective features of the environment in the development of asthma and atopy have been insufficiently studied. We used data from the CHILD (Canadian Healthy Infant Longitudinal Development) Cohort Study to examine relationships between living near natural green spaces in early infancy in Edmonton, AB, Canada and the development of atopic sensitization at 1 year and 3 years of age in a cohort of 699 infants, and whether these associations were mediated by infant gut microbiota (measured using 16s V4 amplicon sequencing) at 4 months. The Urban Planning Land Vegetation Index (uPLVI) map of the City of Edmonton was used to assess infants’ exposure to natural spaces based on their home postal codes, and atopic sensitization was assessed using skin prink testing (SPTs) for common food and inhalant allergens. Our findings suggest there is a protective effect of natural green space proximity on the development of multiple inhalant atopic sensitizations at 3 years (odds ratio = 0.28 [95% CI 0.09, 0.90]). This relationship was mediated by changes to Actinobacteria diversity in infant fecal samples taken at 4 months. We also found a positive association between nature proximity and sensitization to at least one food or inhaled allergen; this association was not mediated by gut microbiota. Together, these findings underscore the importance of promoting natural urban greenspace preservation to improve child health by reducing atopic disease susceptibility. IMPORTANCE Our findings highlight the importance of preserving natural green space in urban settings to prevent sensitization to environmental allergens and promote early-life gut microbiota pathways to this health benefit. These findings support a mediating role of gut microbiome compositions in health and disease susceptibility. This study used unique, accurate, and comprehensive methodology to classify natural space exposure via a high-resolution topographical map of foliage subtypes within the City of Edmonton limits. These methods are improvements from other methods previously used to classify natural space exposure, such as the normalized density vegetation index from satellite imagery, which is not able to distinguish anthropogenic from green space. The use of these methods and the associations found between natural green space exposure and atopic sensitization outcomes support their use in future studies. Our findings also provide many avenues for future research including longer term follow up of this cohort and investigation of a causal role of reduced Actinobacteria diversity on atopic sensitization development.

Identifying magmatic rock associations in a subduction zone is substantial for understanding the related geodynamic evolution. The final closure time of the Paleo-Asian Ocean and the exact subduction processes have continuously been controversial, hindering our recognition of the tectonic evolution of the Central Asian Orogenic Belt (CAOB). Here we investigated the Early Permian gabbros-granodiorites from Xi Ujimqin in the northern Inner Mongolian region. The gabbros have slightly depleted light rare-earth elements [(La/Yb)N = 0.8] and flat heavy rare earth elements (HREE) [(Gd/Yb)N = 1.1] that are comparable to those of N-MORB. They show depletion in Nb and Ta, positive whole-rock εNd(t) values of +7.7 to +8.7 and zircon εHf(t) values of +8.7 to +10.6. These mafic rocks are interpreted to be products of partial melting of depleted mantle that had been metasomatized by slab-derived fluids, with subsequent fractional crystallization and minor crustal contamination. These granodiorites chemically resemble typical adakites and have MORB-like whole-rock SrNd isotopic compositions (87Sr/86Sri = 0.7028–0.7029; εNd(t) = +8.2–+8.5) and positive zircon εHf(t) (+13.4–+15.9) values, suggesting that they originated from the subducted slab-melts and reacted with mantle wedge peridotite. UPb zircon dating shows emplacement of N-MORB-type gabbros and adakitic granodiorites at ∼297 Ma and ∼290 Ma, respectively. Our new data indicate the presence coeval slab-derived adakites and slab fluid-metasomatized asthenosphere-derived N-MORB-type rocks, indicating that subduction lasted until at least the Early Permian. Such an association along with the extension-related magmatism in northern Mongolia recorded the northward ridge subduction of the Paleo-Asian Ocean during the Late Carboniferous–Early Permian. This model is consistent with the spatial distribution and the ages of magmatic activity with positive εNd(t)–εHf(t) values from this region. Ridge subduction and induced slab windows probably played a key role in Paleozoic crustal growth of CAOB, and by inference in the other accretionary orogens throughout Earth history.

Abstract Background Schizophrenia is a persistent psychotic disorder often accompanied by severe disability and premature mortality. New pharmacological treatments are urgently needed. Sodium benzoate, a common food preservative holds potential to be an effective, accessible treatment for schizophrenia, though the optimal dosing and mechanism of action of the compound requires further investigation. Methods Individuals with persistent treatment-refractory schizophrenia (n=52) will be recruited. Patients will be randomised in a 1:1:1:1 ratio to receive treatment of one of three active doses (1000, 2000 or 4000 mg daily) of sodium benzoate or placebo for 6 weeks duration. The primary outcome measurement is change in the Positive and Negative Syndrome Scale (PANSS) total score. Secondary outcome measurements are PANSS subscales, Global Assessment of Function (GAF), Clinical Global Impression (CGI) and Patient Global Impression (PGI-I). Change in concentrations of peripheral amino acids (D-alanine, L-alanine, D-serine, L-serine, glycine and glutamate), plasma sodium benzoate, plasma catalase, 3-nitrotyrosine, malondialdehyde and high-sensitivity C-reactive protein (hs-CRP) will be determined as tertiary measures. Discussion This trial seeks to build upon previous research indicating potential efficacy of sodium benzoate for reduction of symptoms in individuals with treatment-refractory schizophrenia. The trial aims to improve the understanding of the mechanism of action of the compound. Trial registration Australian New Zealand Clinical Trials Registry (ANZCTR) ACTRN12621000327886 . Registered on 23 March 2021.

Abstract Executive dysfunctions in early psychosis (EP) are subtle but persistent, hindering recovery. We asked whether changes in the cognitive control system (CCS) disrupt the response to increased cognitive load in persons with EP. In all, 30 EP and 30 control participants undertook multimodal MRI. Computational models of structural and effective connectivity amongst regions in the CCS were informed by cortical responses to the multi-source interference task, a paradigm that selectively introduces stimulus conflict. EP participants showed greater activation of CCS regions, including the superior parietal cortex, and were disproportionately slower at resolving stimulus conflict in the task. Computational models of the effective connectivity underlying this behavioral response suggest that the normative (control) group resolved stimulus conflict through an efficient and direct modulation of gain between the visual cortex and the anterior insula (AI). In contrast, the EP group utilized an indirect path, with parallel and multi-region hops to resolve stimulus conflict at the AI. Individual differences in task performance were dependent on initial linear gain modulations in the EP group versus a single nonlinear modulation in the control group. Effective connectivity in the EP group was associated with reduced structural integration amongst those connections critical for task execution. CCS engagement during stimulus conflict is hampered in EP owing to inefficient use of higher-order network interactions, with high tonic gain impeding task-relevant (phasic) signal amplification.

Abstract The UK and Sweden have among the worst per-capita COVID-19 mortality in Europe. Sweden stands out for its greater reliance on voluntary, rather than mandatory, control measures. We explore how the timing and effectiveness of control measures in the UK, Sweden and Denmark shaped COVID-19 mortality in each country, using a counterfactual assessment: what would the impact have been, had each country adopted the others’ policies? Using a Bayesian semi-mechanistic model without prior assumptions on the mechanism or effectiveness of interventions, we estimate the time-varying reproduction number for the UK, Sweden and Denmark from daily mortality data. We use two approaches to evaluate counterfactuals which transpose the transmission profile from one country onto another, in each country’s first wave from 13th March (when stringent interventions began) until 1st July 2020. UK mortality would have approximately doubled had Swedish policy been adopted, while Swedish mortality would have more than halved had Sweden adopted UK or Danish strategies. Danish policies were most effective, although differences between the UK and Denmark were significant for one counterfactual approach only. Our analysis shows that small changes in the timing or effectiveness of interventions have disproportionately large effects on total mortality within a rapidly growing epidemic.

Abstract Background There is concern that rates of mental disorders may be increasing although findings disagree. Using an innovative design with a daughter-mother data set we assess whether there has been a generational increase in lifetime ever rates of major depressive disorder, generalised anxiety disorder, panic disorder, and post-traumatic stress disorder (PTSD) experienced prior to 30 years of age. Methods Pregnant women were recruited during 1981–1983 and administered the Composite International Diagnostic Interview (CIDI) at the 27-year follow-up (2008–11). Offspring were administered the CIDI at the 30-year follow-up (2010–2014). Comparisons for onset of diagnosis are restricted to daughter and mother dyads up to 30 years of age. To address recall bias, disorders were stratified into more (≥12 months duration) and less persistent episodes (

Abstract Childhood aggressive behavior (AGG) has a substantial heritability of around 50%. Here we present a genome-wide association meta-analysis (GWAMA) of childhood AGG, in which all phenotype measures across childhood ages from multiple assessors were included. We analyzed phenotype assessments for a total of 328 935 observations from 87 485 children aged between 1.5 and 18 years, while accounting for sample overlap. We also meta-analyzed within subsets of the data, i.e., within rater, instrument and age. SNP-heritability for the overall meta-analysis (AGGoverall) was 3.31% (SE = 0.0038). We found no genome-wide significant SNPs for AGGoverall. The gene-based analysis returned three significant genes: ST3GAL3 (P = 1.6E–06), PCDH7 (P = 2.0E–06), and IPO13 (P = 2.5E–06). All three genes have previously been associated with educational traits. Polygenic scores based on our GWAMA significantly predicted aggression in a holdout sample of children (variance explained = 0.44%) and in retrospectively assessed childhood aggression (variance explained = 0.20%). Genetic correlations (r g ) among rater-specific assessment of AGG ranged from r g = 0.46 between self- and teacher-assessment to r g = 0.81 between mother- and teacher-assessment. We obtained moderate-to-strong r g s with selected phenotypes from multiple domains, but hardly with any of the classical biomarkers thought to be associated with AGG. Significant genetic correlations were observed with most psychiatric and psychological traits (range $$\left| {r_g} \right|$$ r g : 0.19–1.00), except for obsessive-compulsive disorder. Aggression had a negative genetic correlation (r g = ~−0.5) with cognitive traits and age at first birth. Aggression was strongly genetically correlated with smoking phenotypes (range $$\left| {r_g} \right|$$ r g : 0.46–0.60). The genetic correlations between aggression and psychiatric disorders were weaker for teacher-reported AGG than for mother- and self-reported AGG. The current GWAMA of childhood aggression provides a powerful tool to interrogate the rater-specific genetic etiology of AGG.

Introduction The increasing prevalence of developmental disorders in early childhood poses a significant global health burden. Early detection of developmental problems is vital to ensure timely access to early intervention, and universal developmental surveillance is recommended best practice for identifying issues. Despite this, there is currently considerable variation in developmental surveillance and screening between Australian states and territories and low rates of developmental screening uptake by parents. This study aims to evaluate an innovative web-based developmental surveillance programme and a sustainable approach to referral and care pathways, linking primary care general practice (GP) services that fall under federal policy responsibility and state government-funded child health services.Methods and analysis The proposed study describes a longitudinal cluster randomised controlled trial (c-RCT) comparing a ‘Watch Me Grow Integrated’ (WMG-I) approach for developmental screening, to Surveillance as Usual (SaU) in GPs. Forty practices will be recruited across New South Wales and Queensland, and randomly allocated into either the (1) WMG-I or (2) SaU group. A cohort of 2000 children will be recruited during their 18-month vaccination visit or opportunistic visit to GP. At the end of the c-RCT, a qualitative study using focus groups/interviews will evaluate parent and practitioner views of the WMG-I programme and inform national and state policy recommendations.Ethics and dissemination The South Western Sydney Local Health District (2020/ETH01625), UNSW Sydney (2020/ETH01625) and University of Queensland (2021/HE000667) Human Research Ethics Committees independently reviewed and approved this study. Findings will be reported to the funding bodies, study institutes and partners; families and peer-reviewed conferences/publications.Trial registration number ANZCTR12621000680864.

Invariant natural killer T cells are known to be composed of a number of phenotypic and functionally distinct populations. Here the authors use transcriptomic and epigenomic analysis to further characterize the peripheral iNKT compartment before and after antigenic stimulation.

A systematic comparison of lipophilicity modulations upon fluorination of isopropyl, cyclopropyl and 3-oxetanyl substituents, at a single carbon atom, is provided using directly comparable, and easily accessible model compounds. In addition, comparison with relevant linear chain derivatives is provided, as well as lipophilicity changes occurring upon chain extension of acyclic precursors to give cyclopropyl containing compounds. For the compounds investigated, fluorination of the isopropyl substituent led to larger lipophilicity modulation compared to fluorination of the cyclopropyl substituent.

Background and Objective: Dementia is a broad term for a complex range of conditions that affect the brain, such as Alzheimer’s disease (AD). Dementia affects a lot of people in the elderly community, hence there is a huge demand to better understand this condition by using cost effective and quick methods, such as neuropsychological tests, since pathological assessments are invasive and demand expensive resources. One of the promising initiatives that deals with dementia and Mild Cognitive Impairment (MCI) is the Alzheimer’s Disease Neuroimaging Initiative (ADNI), which includes cognitive tests, such as Clinical Dementia Rating (CDR) scores. The aim of this research is to investigate non-invasive dementia indicators, such as cognitive features, that are typically diagnosed by clinical assessment within ADNI’s data to understand their effect on dementia. Methods: To achieve the aim, machine learning techniques have been utilized to classify patients into Cognitively Normal (CN), MCI, or having dementia, based on the sum of CDR scores (CDR-SB) besides demographic variables. Particularly, the performance of Support Vector Machine (SVM), K-nearest neighbors (KNN), Decision Trees (C4.5), Probabilistic Naïve Bayes (NB), and Rule Induction (RIPPER) is measured with respect to different evaluation measures, including specificity, sensitivity, and harmonic mean (F-measure), among others, on a large number of cases and controls from the ADNI dataset. Results: The results indicate competitive performance when classifying subjects from the baseline selected variables using machine learning technology. Though we observed fairly good results across all machine learning algorithms utilized, there was still variation in the performance ability, indicating that some algorithms, such as NB and C4.5, are better suited to the task of classifying dementia status based on our baseline data. Conclusions: Using cognitive tests, such as CDR-SB scores, with demographic attributes to pinpoint to dementia using machine learning can be seen a less invasive approach that could be good for clinical use to aid in the diagnosis of dementia. This study gives an indication that a comprehensive assessment tool, such as CDR, may be adequate in assessing and assigning a dementia class to patients, upon their visit, in order to speed further clinical procedures.

How gut immunity in early life is shaped by birth in relation to delivery mode, intrapartum antibiotic prophylaxis (IAP) and labor remains undetermined. We aimed to address this gap with a study of secretory Immunoglobulin A (SIgA) in the infant gut that also tested SIgA-stimulating pathways mediated by gut microbiota and metabolites. Among 1017 Canadian full-term infants, gut microbiota of fecal samples collected at 3 and 12 months were profiled using 16S rRNA sequencing; C. difficile was quantified by qPCR; fecal metabolites and SIgA levels were measured by NMR and SIgA enzyme-linked immunosorbent assay, respectively. We assessed the putative causal relationships from birth events to gut microbiota and metabolites, and ultimately to SIgA, in statistical sequential mediation models, adjusted for maternal gravida status in 551 infants. As birth mode influences the ability to breastfeed, the statistical mediating role of breastfeeding status and milk metabolites was also evaluated. Relative to vaginal birth without maternal IAP, cesarean section (CS) after labor was associated with reduced infant gut SIgA levels at 3 months (6.27 vs. 4.85 mg/g feces, p < 0.05); this association was sequentially mediated through gut microbiota and metabolites of microbial or milk origin. Mediating gut microbiota included Enterobacteriaceae, C. difficile, and Streptococcus. The milk or microbial metabolites in CS-SIgA mediating pathways were galactose, fucose, GABA, choline, lactate, pyruvate and 1,2-propanediol. This cohort study documented the impact of birth on infant gut mucosal SIgA. It is the first to characterize gut microbe-metabolite mediated pathways for early-life SIgA maturation, pathways that require experimental verification.

Infant vitamin D liquid formulations often contain non-medicinal excipients such as glycerin (ie. glycerol) and 1,2-propanediol (1,2-PD). We examined whether infant vitamin D supplementation is associated with fecal glycerol and 1,2-PD concentrations at 3 months of age and characterized associations between these two molecules, and gut microbiota and their metabolites. Fecal metabolites and microbiota were quantified using Nuclear Magnetic Resonance Spectroscopy and 16S rRNA sequencing, respectively, in 575 infants from the CHILD Study at 3 months of age. Vitamin D supplement use was determined using questionnaires. Vitamin D supplementation was associated with greater odds of high 1,2-PD (adjusted OR 1.65 95% CI: 1.06, 2.53) and with decreased odds of high fecal glycerol (adjusted OR: 0.62 95% CI: 0.42, 0.90) after adjustment for breastfeeding and other covariates. Our findings were confirmed in linear regression models; vitamin D supplementation was positively associated with fecal 1,2-PD and inversely associated with glycerol (aβ: 0.37, 95% CI 0.03, 0.71 & aβ: −0.23 95% CI −0.44, −0.03, respectively). Fecal 1,2-PD and glycerol concentrations were negatively correlated with each other. Positive correlations between fecal 1,2-PD, Bifidobacteriaceae, Lactobacillaceae, Enterobacteriaceae and acetate levels were observed. Our research demonstrates that infant vitamin D supplement administration may differentially and independently influence infant gut microbiota metabolites.

Background: Existing evidence regarding the association between hypertensive disorders of pregnancy (HDP) and the risk of maternal mental illness is inconclusive. This study sought to investigate (a) whether HDP (pre-eclampsia and gestational hypertension) are independently associated with depressive and anxiety symptoms during pregnancy and in the postpartum period, and (b) whether parity moderates any observed associations. Methods: The study cohort consisted of more than 8300 mothers who participated in the Avon Longitudinal Study of Parents and Children (ALSPAC). Maternal antenatal and postnatal depressive and anxiety symptoms were assessed using the Edinburgh Postnatal Depression Scale (EPDS) and the Crown-Crisp Experiential Index (CCEI), respectively. Univariable and multivariable logistic and linear regression analyses were used to examine the associations. Results: Mothers with pre-eclampsia had a 53% (aOR = 1.53; 95% CI, 1.06–2.23) increased risk of antenatal depressive symptoms compared with those without pre-eclampsia. Having pre-eclampsia and being a nulliparous woman resulted in the highest risk of antenatal depressive symptoms (aOR = 2.75; 95% CI, 1.09–6.96). Pre-eclampsia was associated with a 56% increased risk of antenatal anxiety symptoms among nulliparous women. We also found associations between gestational hypertension and antenatal depressive and anxiety symptoms. No associations between pre-eclampsia and/or gestational hypertension and postnatal anxiety and depressive symptoms were observed.Conclusions: Mothers with HDP were at higher risk of clinically significant antenatal depressive and anxiety symptoms. Nulliparous women with pre-eclampsia are a higher risk group for mental ill-health and should be routinely screened for anxiety and depressive symptoms and provided with interventions when indicated.

Background: There is limited evidence on interventions to minimise weight gain at clozapine commencement. We compared the effect of adjunctive metformin versus placebo at clozapine initiation. Methods: People with schizophrenia commencing on clozapine were randomised to either metformin or placebo for 24 weeks. The primary outcome was difference in the change of body weight. Secondary outcomes included comparative rates of weight gain of more than 5%, overall weight gain/loss, and differences in metabolic and psychosis outcomes. Results: The study was closed prematurely in March 2020 due to COVID-19 restrictions. Ten participants were randomised to each of the metformin and placebo groups. Eight metformin group and five placebo group participants completed the trial and were included in the analysis. The study was insufficiently powered to detect difference between the metformin and placebo groups for the primary outcome of change in weight (0.09 kg vs 2.88 kg, p = 0.231). In terms of secondary outcomes, people in the metformin group were significantly less likely to gain >5% of their body weight (12.5% vs 80%, p = 0.015) and were more likely to lose weight (37.5% vs 0% p = 0.024) compared to placebo. There was no difference between the groups in terms of adverse drug reactions (ADRs). Conclusion: While limited by the forced premature closure of the trial due to COVID19, the findings from this randomised controlled trial are promising. Clozapine and metformin co-commencement may be a promising treatment to prevent clozapine-associated weight gain, especially given the low rates of ADRs associated with metformin. This supports the consideration of use of metformin to prevent weight gain in people initiated on clozapine; however, further studies are needed to confirm this finding. Trial registration: ACTRN12617001547336

Background Cannabis use has been associated with increased risk of psychiatric disorders. However, associations between adolescent cannabis use, depression and anxiety disorders are inconsistently reported in longitudinal samples. Aims To study associations of adolescent cannabis use with depression and anxiety disorders. Method We used data from the Northern Finland Birth Cohort 1986, linked to nationwide registers, to study the association between adolescent cannabis use and depression and anxiety disorders until 33 years of age (until 2018). Results We included 6325 participants (48.8% male) in the analyses; 352 (5.6%) participants reported cannabis use until 15–16 years of age. By the end of the follow-up, 583 (9.2%) participants were diagnosed with unipolar depression and 688 (10.9%) were diagnosed with anxiety disorder. Cannabis use in adolescence was associated with an increased risk of depression and anxiety disorders in crude models. After adjusting for parental psychiatric disorder, baseline emotional and behavioural problems, demographic factors and other substance use, using cannabis five or more times was associated with increased risk of anxiety disorders (hazard ratio 2.01, 95% CI 1.15–3.82), and using cannabis once (hazard ratio 1.93, 95% CI 1.30–2.87) or two to four times (hazard ratio 2.02, 95% CI 1.24–3.31) was associated with increased risk of depression. Conclusions Cannabis use in adolescence was associated with an increased risk of future depression and anxiety disorders. Further research is needed to clarify if this is a causal association, which could then inform public health messages about the use of cannabis in adolescence.