Strength of Excitatory Inputs to Layer 3 Pyramidal Neurons During Synaptic Pruning in the Monkey Prefrontal Cortex: Relevance for the Pathogenesis of Schizophrenia.

BACKGROUND: In schizophrenia, layer 3 pyramidal neurons (L3PNs) of the dorsolateral prefrontal cortex exhibit deficits in markers of excitatory synaptic inputs that are thought to disrupt the patterns of neural network activity essential for cognitive function. These deficits are usually interpreted under Irwin Feinberg's hypothesis of altered synaptic pruning, which postulates that normal periadolescent pruning, thought to preferentially eliminate weak/immature synapses, is altered in schizophrenia. However, it remains unknown whether periadolescent pruning on L3PNs in the primate dorsolateral prefrontal cortex selectively eliminates weak excitatory synapses or uniformly eliminates excitatory synapses across the full distribution of synaptic strengths. METHODS: To distinguish between these alternative models of synaptic pruning, we assessed the densities of dendritic spines, the site of most excitatory inputs to L3PNs, and the distributions of excitatory synaptic strengths in dorsolateral prefrontal cortex L3PNs from male and female monkeys across the periadolescent period of synaptic pruning. We used patch-clamp methods in acute brain slices to record miniature excitatory synaptic currents and intracellular filling with biocytin to quantify dendritic spines. RESULTS: On L3PNs, dendritic spines exhibited the expected age-related decline in density, but mean synaptic strength and the shape of synaptic strength distributions remained stable with age. CONCLUSIONS: The absence of age-related differences in mean synaptic strength and synaptic strength distributions supports the model of a uniform pattern of synaptic pruning across the full range of synaptic strengths. The implications of these findings for the pathogenesis and functional consequences of dendritic spine deficits in schizophrenia are discussed.

Renal impairment associated with tenofovir disoproxil fumarate for antiretroviral therapy and HIV pre-exposure prophylaxis: An observational cohort study.

BACKGROUND: Tenofovir disoproxil fumarate (TDF) is associated with adverse renal outcomes when prescribed for HIV infection. There are few data concerning real-world renal outcomes amongst patients prescribed TDF for pre-exposure prophylaxis (PrEP). METHODS AND FINDINGS: Data were extracted from 52 sexual health clinics across Australia from 2009-2019. All patients prescribed TDF-containing antiretroviral therapy and PrEP were included. Rates of renal impairment (a fall in eGFR to <60 ml/min/1·73m2) were calculated for people living with HIV (PLWHIV) prescribed TDF and HIV negative PrEP-users. Risk factors were assessed using Cox-proportional hazards models. Sensitivity analysis of risk using 1:1 propensity-score matching to adjust for potential imbalance in HIV and PrEP cohorts was conducted. 5,973 patients on PrEP and 1,973 PLWHIV were included. There were 39 (0.7%) instances of renal impairment in the PrEP group and 81 (4.1%) in the PLWHIV cohort (hazard ratio [HR]:0.35 95% confidence interval [CI]: 0.22-0.56). Rates of renal impairment were 4.01/1000 person-years (95%CI:2.93-5.48) in the PrEP cohort and 16.18/1000 person-years (95%CI:13.01-20.11) in the PLWHIV cohort (p<0.001). Predictors of renal impairment were: older age (40-49 years (HR:5.09 95%CI: 2.12-12.17) and 50-82 years (HR:13.69 95%CI: 5.92-31.67) (compared with 30-39 years) and baseline eGFR<90ml/min (HR:61.19 95%CI: 19.27-194.30). After adjusting for age and baseline eGFR the rate of renal impairment remained lower in the PrEP cohort (aHR:0.62 95%CI: 0.40-0.94, p = 0.023). In propensity-matched analysis using 1,622 patients per cohort the risk of renal impairment remained higher in the PLWHIV cohort (log-rank p = 0.001). CONCLUSION: Patients prescribed TDF-based PrEP had lower rates of renal impairment than patients prescribed TDF for HIV infection. In propensity analysis, after matching for some risk factors, rates of renal impairment remained higher amongst patients with HIV.

Altered expression of microglial markers of phagocytosis in schizophrenia.

BACKGROUND: Cognitive disturbances in schizophrenia have been linked to a lower density of dendritic spines on pyramidal neurons in the prefrontal cortex (PFC). Complement component C4, which has previously been found at higher levels in schizophrenia, marks synapses for phagocytosis by microglia. Thus, elevated consumption of dendritic spines by microglia mediated through excessive complement activity may play a role in lower spine density in schizophrenia. However, it is unclear if microglia themselves have the molecular capacity for enhanced phagocytosis of spines in schizophrenia. METHODS: Transcript levels for complement components and microglia-specific phagocytic markers were quantified using quantitative PCR in the PFC of 62 matched pairs of schizophrenia and unaffected comparison subjects and in antipsychotic-exposed monkeys. RESULTS: Relative to comparison subjects, schizophrenia subjects had higher mRNA levels for C4 (+154 %); C1q (+69 %), which initiates the classical complement pathway that includes C4; and for microglia-specific markers that enable phagocytic activity including TAM receptor tyrosine kinases Axl (+27 %) and MerTK (+27 %) and lysosome-associated glycoprotein CD68 (+27 %) (all p ≤ .042). Transcript levels for microglial phagocytic markers were correlated with C4 mRNA levels in schizophrenia subjects (all r ≥ 0.31, p ≤ .015). We also found further evidence consistent with microglial activation in schizophrenia, including higher mRNA levels for THIK1 (TWIK-related halothane-inhibited potassium channel: +30 %) and lower mRNA levels for the purinergic receptor P2Y12 (-27 %) (all p ≤ .016). Transcript levels were unchanged in antipsychotic-exposed monkeys. CONCLUSIONS: These results are consistent with the presence of increased complement activity and an elevated molecular capacity of microglia for phagocytosis in the same schizophrenia subjects.

A pilot study to show that asymptomatic sexually transmitted infections alter the foreskin epithelial proteome.

There is limited data on the role of asymptomatic STIs (aSTIs) on the risk of human immunodeficiency virus (HIV) acquisition in the male genital tract (MGT). The impact of foreskin removal on lowering HIV acquisition is well described, but molecular events leading to HIV acquisition are unclear. Here, in this pilot study, we show that asymptomatic urethral infection with Chlamydia trachomatis (CT) significantly impacts the foreskin proteome composition. We developed and optimized a shotgun liquid chromatography coupled tandem mass spectrometry (MS)-based proteomics approach and utilized this on foreskins collected at medical male circumcision (MMC) from 16 aSTI+ men and 10 age-matched STI- controls. We used a novel bioinformatic metaproteomic pipeline to detect differentially expressed (DE) proteins. Gene enrichment ontology analysis revealed proteins associated with inflammatory and immune activation function in both inner and outer foreskin from men with an aSTI. Neutrophil activation/degranulation and viral-evasion proteins were significantly enriched in foreskins from men with aSTI, whereas homotypic cell-cell adhesion proteins were enriched in foreskin tissue from men without an aSTI. Collectively, our data show that asymptomatic urethral sexually transmitted infections result in profound alterations in epithelial tissue that are associated with depletion of barrier integrity and immune activation.

Optimisation of treatments for oral Neisseria gonorrhoeae infection: Pharmacokinetics Study (STI-PK project) - study protocol for non-randomised clinical trial.

INTRODUCTION: Neisseria gonorrhoeae infections are common and incidence increasing. Oropharyngeal infections are associated with greater treatment failure compared with other sites and drive transmission to anogenital sites through saliva. Gonococcal resistance is increasing and new treatments are scarce, therefore, clinicians must optimise currently available and emerging treatments in order to have efficacious therapeutic options. This requires pharmacokinetic data from the oral cavity/oropharynx, however, availability of such information is currently limited. METHODS AND ANALYSIS: Healthy male volunteers (participants) recruited into the study will receive single doses of either ceftriaxone 1 g, cefixime 400 mg or ceftriaxone 500 mg plus 2 g azithromycin. Participants will provide samples at 6-8 time points (treatment regimen dependent) from four oral sites, two oral fluids, one anorectal swab and blood. Participants will complete online questionnaires about their medical history, sexual practices and any side effects experienced up to days 5-7. Saliva/oral mucosal pH and oral microbiome analysis will be undertaken. Bioanalysis will be conducted by liquid chromatography-mass spectrometry. Drug concentrations over time will be used to develop mathematical models for optimisation of drug dosing regimens and to estimate pharmacodynamic targets of efficacy. ETHICS AND DISSEMINATION: This study was approved by Royal Melbourne Hospital Human Research Ethics Committee (60370/MH-2021). The study results will be submitted for publication in peer-reviewed journals and reported at conferences. Summary results will be sent to participants requesting them. All data relevant to the study will be included in the article or uploaded as supplementary information. TRIAL REGISTRATION NUMBER: ACTRN12621000339853.

Diurnal Alterations in Gene Expression Across Striatal Subregions in Psychosis.

BACKGROUND: Psychosis is a defining feature of schizophrenia and highly prevalent in bipolar disorder. Notably, individuals with these illnesses also have major disruptions in sleep and circadian rhythms, and disturbances of sleep and circadian rhythms can precipitate or exacerbate psychotic symptoms. Psychosis is associated with the striatum, though to our knowledge, no study to date has directly measured molecular rhythms and determined how they are altered in the striatum of subjects with psychosis. METHODS: We performed RNA sequencing and both differential expression and rhythmicity analyses to investigate diurnal alterations in gene expression in human postmortem striatal subregions (nucleus accumbens, caudate, and putamen) in subjects with psychosis (n = 36) relative to unaffected comparison subjects (n = 36). RESULTS: Across regions, we found differential expression of immune-related transcripts and a substantial loss of rhythmicity in core circadian clock genes in subjects with psychosis. In the nucleus accumbens, mitochondrial-related transcripts had decreased expression in subjects with psychosis, but only in those who died at night. Additionally, we found a loss of rhythmicity in small nucleolar RNAs and a gain of rhythmicity in glutamatergic signaling in the nucleus accumbens of subjects with psychosis. Between-region comparisons indicated that rhythmicity in the caudate and putamen was far more similar in subjects with psychosis than in matched comparison subjects. CONCLUSIONS: Together, these findings reveal differential and rhythmic gene expression differences across the striatum that may contribute to striatal dysfunction and psychosis in psychotic disorders.

Advancing Sexual Harassment Prevention and Elimination in the Sciences: "Every ... Health Organization Must Do Something Similar".

BACKGROUND: Sexual harassment is pervasive in science. A 2018 report found that the prevalence of sexual harassment in academia in the United States is 58%. An activity held at an international scientific congress was designed to advance sexual harassment prevention and elimination and empower binary and nonbinary persons at risk for harassment, discrimination, and violence. The objective is to describe the activity and outcomes to provide a promising model for other scientific communities. METHODS: A description of the plenary and key components as well as the data collection and analysis of selected outcomes are provided. RESULTS: Among 1338 congress participants from 61 countries, 526 (39%) attended the #MeToo plenary, and the majority engaged in some way during the plenary session. Engagement included standing for the pledge (~85%), participating in the question and answer session (n = 5), seeking counseling (n = 3), and/or providing written post-it comments (n = 96). Respondents to a postcongress survey (n = 388 [24% of all attendees]) ranked the plenary as number 1 among 14 congressional plenaries. In postanalysis, the written post-it comments were sorted into 14 themes within 6 domains, including: (1) emotional responses, (2) barriers to speaking out, (3) public health priorities, (4) reframing narratives about the issue, (5) allyship, and (6) moving the issue forward. CONCLUSIONS: Scientific organizations, agencies, and institutions have an important role to play in setting norms and changing enabling policies toward a zero-tolerance culture of sexual harassment. The activity presented offers a promising model for scientific communities with similar goals. The outcomes suggest that the plenary successfully engaged participants and had a measurable impact on the participants.

Engaging hard-to-reach men-who-have-sex-with-men with sexual health screening: Qualitative interviews in an Australian sex-on-premises-venue and sexual health service.

CONTEXT: Compared with the general population in Australia, men-who-have-sex-with-men (MSM) have higher rates of HIV and sexually transmissible infections (STIs). Despite widespread advice to test regularly, a minority of these men remain "hard to reach." We undertook qualitative interviews with a group of such men in Sydney to better understand their views and experiences in relation to sexual health screening. METHODS: We conducted semi-structured interviews with men engaging with HIV/STI screening services at a sex-on-premises-venue and the local Sexual Health Service in Greater Western Sydney. We analyzed these data for content and themes. RESULTS: Sexual behaviors and identities were diverse, often discordant and compartmentalized from everyday lives. Overall, reported HIV/STI knowledge was poor and men did not see themselves at risk of HIV/STIs regardless of sexual behavior. Men took calculated risks and balanced with pleasure and escapism. Reasons for avoidance of testing included fear, unwillingness to disclose behavior, privacy concerns, and perceived low risk. Men viewed sexual health care as distinct from general health care. Service delivery preferences varied by service venue. Participants highlighted convenience, confidentiality, and trust as critical factors for a testing service. CONCLUSION: A variety of testing options are needed to engage hard-to-reach MSM. Opportunities to enhance testing may include expanding health messaging, demystifying testing, and delinking sexual identity from sexual behavior and risk, thus promoting advantages of testing and establishing testing as standard of care.

Schizophrenia-associated differential DNA methylation in brain is distributed across the genome and annotated to MAD1L1, a locus at which DNA methylation and transcription phenotypes share genetic variation with schizophrenia risk.

DNA methylation (DNAm), the addition of a methyl group to a cytosine in DNA, plays an important role in the regulation of gene expression. Single-nucleotide polymorphisms (SNPs) associated with schizophrenia (SZ) by genome-wide association studies (GWAS) often influence local DNAm levels. Thus, DNAm alterations, acting through effects on gene expression, represent one potential mechanism by which SZ-associated SNPs confer risk. In this study, we investigated genome-wide DNAm in postmortem superior temporal gyrus from 44 subjects with SZ and 44 non-psychiatric comparison subjects using Illumina Infinium MethylationEPIC BeadChip microarrays, and extracted cell-type-specific methylation signals by applying tensor composition analysis. We identified SZ-associated differential methylation at 242 sites, and 44 regions containing two or more sites (FDR cutoff of q = 0.1) and determined a subset of these were cell-type specific. We found mitotic arrest deficient 1-like 1 (MAD1L1), a gene within an established GWAS risk locus, harbored robust SZ-associated differential methylation. We investigated the potential role of MAD1L1 DNAm in conferring SZ risk by assessing for colocalization among quantitative trait loci for methylation and gene transcripts (mQTLs and tQTLs) in brain tissue and GWAS signal at the locus using multiple-trait-colocalization analysis. We found that mQTLs and tQTLs colocalized with the GWAS signal (posterior probability >0.8). Our findings suggest that alterations in MAD1L1 methylation and transcription may mediate risk for SZ at the MAD1L1-containing locus. Future studies to identify how SZ-associated differential methylation affects MAD1L1 biological function are indicated.

Cell type specific cannabinoid CB1 receptor distribution across the human and non-human primate cortex.

Alterations in cannabinoid CB1 receptor (CB1R) are implicated in various psychiatric disorders. CB1R participates in both depolarization induced suppression of inhibition (DSI) and depolarization induced suppression of excitation (DSE), suggesting its involvement in regulating excitatory and inhibitory (E/I) balance. Prior studies examining neuronal cell type specific CB1R distribution have been conducted near exclusively within rodents. Identification of these distribution patterns within the human and non-human primate cortex is essential to increase our insight into its function. Using co-labeling immunohistochemistry and fluorescent microscopy, we examined CB1R protein levels within excitatory and inhibitory boutons of male human and non-human primate prefrontal cortex and auditory cortices, regions involved in the behavioral effects of exogenous cannabinoid exposures. We found that CB1R was present in both bouton populations within all brain regions examined in both species. Significantly higher CB1R levels were found within inhibitory than within excitatory boutons across all regions in both species, although the cell type by brain region interactions differed between the two species. Our results support the importance of conducting more in-depth CB1R examinations to understand how cell type and brain region dependent differences contribute to regional E/I balance regulation, and how aberrations in CB1R distribution may contribute to pathology.

Surveillance systems to monitor antimicrobial resistance in Neisseria gonorrhoeae: a global, systematic review, 1 January 2012 to 27 September 2020.

BackgroundEffective surveillance of antimicrobial resistance (AMR) in Neisseria gonorrhoeae is required for the early detection of resistant strains and to ensure that treatment guidelines are appropriate for the setting in which they are implemented. AMR in N. gonorrhoeae has been identified as a global health threat.AimWe performed a systematic review to identify and describe surveillance systems targeting AMR in N. gonorrhoeae.MethodsWe searched Medline, PubMed, Global Health, EMBASE, CINAHL, Web of Science and ProQuest databases and grey literature between 1 January 2012 and 27 September 2020. Surveillance systems were defined as the continuous, systematic collection, analysis and interpretation of N. gonorrhoeae resistance data. The key components of surveillance systems were extracted, categorised, described and summarised.ResultsWe found 40 publications reporting on N. gonorrhoeae AMR surveillance systems in 27 countries and 10 multi-country or global surveillance reports. The proportion of countries with surveillance systems in each of the WHO's six regions ranged from one of 22 countries in the Eastern Mediterranean and five of 54 in Africa, to three of 11 countries in South East Asia. Only four countries report systems which are both comprehensive and national. We found no evidence of a current surveillance system in at least 148 countries. Coverage, representativeness, volume, clinical specimen source, type and epidemiological information vary substantially and limit interpretability and comparability of surveillance data for public health action.ConclusionGlobally, surveillance for N. gonorrhoeae AMR is inadequate and leaves large populations vulnerable to a major public health threat.

Cognitive Dysfunction and Prefrontal Cortical Circuit Alterations in Schizophrenia: Developmental Trajectories.

Individuals with schizophrenia (SZ) exhibit cognitive performance below expected levels based on familial cognitive aptitude. One such cognitive process, working memory (WM), is robustly impaired in SZ. These WM impairments, which emerge over development during the premorbid and prodromal stages of SZ, appear to reflect alterations in the neural circuitry of the dorsolateral prefrontal cortex. Within the dorsolateral prefrontal cortex, a microcircuit formed by reciprocal connections between excitatory layer 3 pyramidal neurons and inhibitory parvalbumin basket cells (PVBCs) appears to be a key neural substrate for WM. Postmortem human studies indicate that both layer 3 pyramidal neurons and PVBCs are altered in SZ, suggesting that levels of excitation and inhibition are lower in the microcircuit. Studies in monkeys indicate that features of both cell types exhibit distinctive postnatal developmental trajectories. Together, the results of these studies suggest a model in which 1) genetic and/or early environmental insults to excitatory signaling in layer 3 pyramidal neurons give rise to cognitive impairments during the prodromal phase of SZ and evoke compensatory changes in inhibition that alter the developmental trajectories of PVBCs, and 2) synaptic pruning during adolescence further lowers excitatory activity to a level that exceeds the compensatory capacity of PVBC inhibition, leading to a failure of the normal maturational improvements in WM during the prodromal and early clinical stages of SZ. Findings that support as well as challenge this model are discussed.

Synaptic Variability and Cortical Gamma Oscillation Power in Schizophrenia.

OBJECTIVE: Cognitive impairments in schizophrenia are associated with lower gamma oscillation power in the prefrontal cortex (PFC). Gamma power depends in part on excitatory drive to fast-spiking parvalbumin interneurons (PVIs). Excitatory drive to cortical neurons varies in strength, which could affect how these neurons regulate network oscillations. The authors investigated whether variability in excitatory synaptic strength across PVIs could contribute to lower prefrontal gamma power in schizophrenia. METHODS: In postmortem PFC from 20 matched pairs of comparison and schizophrenia subjects, levels of vesicular glutamate transporter 1 (VGlut1) and postsynaptic density 95 (PSD95) proteins were quantified to assess variability in excitatory synaptic strength across PVIs. A computational model network was then used to simulate how variability in excitatory synaptic strength across fast-spiking (a defining feature of PVIs) interneurons (FSIs) regulates gamma power. RESULTS: The variability of VGlut1 and PSD95 levels at excitatory inputs across PVIs was larger in schizophrenia relative to comparison subjects. This alteration was not influenced by schizophrenia-associated comorbid factors, was not present in monkeys chronically exposed to antipsychotic medications, and was not present in calretinin interneurons. In the model network, variability in excitatory synaptic strength across FSIs regulated gamma power by affecting network synchrony. Finally, greater synaptic variability interacted synergistically with other synaptic alterations in schizophrenia (i.e., fewer excitatory inputs to FSIs and lower inhibitory strength from FSIs) to robustly reduce gamma power. CONCLUSIONS: The study findings suggest that greater variability in excitatory synaptic strength across PVIs, in combination with other modest synaptic alterations in these neurons, can markedly lower PFC gamma power in schizophrenia.

Differential gene expression between callosal and ipsilateral projection neurons in the monkey dorsolateral prefrontal and posterior parietal cortices.

Reciprocal connections between primate dorsolateral prefrontal (DLPFC) and posterior parietal (PPC) cortices, furnished by subsets of layer 3 pyramidal neurons (PNs), contribute to cognitive processes including working memory (WM). A different subset of layer 3 PNs in each region projects to the homotopic region of the contralateral hemisphere. These ipsilateral (IP) and callosal (CP) projections, respectively, appear to be essential for the maintenance and transfer of information during WM. To determine if IP and CP layer 3 PNs in each region differ in their transcriptomes, fluorescent retrograde tracers were used to label IP and CP layer 3 PNs in the DLPFC and PPC from macaque monkeys. Retrogradely-labeled PNs were captured by laser microdissection and analyzed by RNAseq. Numerous differentially expressed genes (DEGs) were detected between IP and CP neurons in each region and the functional pathways containing many of these DEGs were shared across regions. However, DLPFC and PPC displayed opposite patterns of DEG enrichment between IP and CP neurons. Cross-region analyses indicated that the cortical area targeted by IP or CP layer 3 PNs was a strong correlate of their transcriptome profile. These findings suggest that the transcriptomes of layer 3 PNs reflect regional, projection type and target region specificity.

Molecular rhythm alterations in prefrontal cortex and nucleus accumbens associated with opioid use disorder.

Severe and persistent disruptions to sleep and circadian rhythms are common in people with opioid use disorder (OUD). Preclinical evidence suggests altered molecular rhythms in the brain modulate opioid reward and relapse. However, whether molecular rhythms are disrupted in the brains of people with OUD remained an open question, critical to understanding the role of circadian rhythms in opioid addiction. Using subjects' times of death as a marker of time of day, we investigated transcriptional rhythms in the brains of subjects with OUD compared to unaffected comparison subjects. We discovered rhythmic transcripts in both the dorsolateral prefrontal cortex (DLPFC) and nucleus accumbens (NAc), key brain areas involved in OUD, that were largely distinct between OUD and unaffected subjects. Fewer rhythmic transcripts were identified in DLPFC of subjects with OUD compared to unaffected subjects, whereas in the NAc, nearly double the number of rhythmic transcripts was identified in subjects with OUD. In NAc of subjects with OUD, rhythmic transcripts peaked either in the evening or near sunrise, and were associated with an opioid, dopamine, and GABAergic neurotransmission. Associations with altered neurotransmission in NAc were further supported by co-expression network analysis which identified OUD-specific modules enriched for transcripts involved in dopamine, GABA, and glutamatergic synaptic functions. Additionally, rhythmic transcripts in DLPFC and NAc of subjects with OUD were enriched for genomic loci associated with sleep-related GWAS traits, including sleep duration and insomnia. Collectively, our findings connect transcriptional rhythm changes in opioidergic, dopaminergic, GABAergic signaling in the human brain to sleep-related traits in opioid addiction.

Chromatin domain alterations linked to 3D genome organization in a large cohort of schizophrenia and bipolar disorder brains.

Chromosomal organization, scaling from the 147-base pair (bp) nucleosome to megabase-ranging domains encompassing multiple transcriptional units, including heritability loci for psychiatric traits, remains largely unexplored in the human brain. In this study, we constructed promoter- and enhancer-enriched nucleosomal histone modification landscapes for adult prefrontal cortex from H3-lysine 27 acetylation and H3-lysine 4 trimethylation profiles, generated from 388 controls and 351 individuals diagnosed with schizophrenia (SCZ) or bipolar disorder (BD) (n = 739). We mapped thousands of cis-regulatory domains (CRDs), revealing fine-grained, 104-106-bp chromosomal organization, firmly integrated into Hi-C topologically associating domain stratification by open/repressive chromosomal environments and nuclear topography. Large clusters of hyper-acetylated CRDs were enriched for SCZ heritability, with prominent representation of regulatory sequences governing fetal development and glutamatergic neuron signaling. Therefore, SCZ and BD brains show coordinated dysregulation of risk-associated regulatory sequences assembled into kilobase- to megabase-scaling chromosomal domains.

Barriers and enablers for young Aboriginal people in accessing public sexual health services: A mixed method systematic review.

BACKGROUND: A mixed method systematic review was undertaken to address the research question, Do young Australian Aboriginal people barriers in accessing public sexual health services? Aboriginal people are disproportionally affected by significantly higher incidence rates of sexually transmissible infections (STIs), compared to the rest of the Australian population. This problem is particularly acute for young people under 30 years of age who suffer from the consequences of STIs due to the number of sexual partners and challenges faced in accessing healthcare. METHODS: The study inclusion criteria were: papers published between January 1999 and September 2019 inclusive; published in any language, discussed healthcare barriers and facilitators; included people under 30 years of age; contained research with one or more of the following terms; Aboriginal, Health, Access, Barriers and Sexual Health; was published or discussed Australia research. Articles were extracted from MEDLINE, Embase, PsychINFO, Proquest Social Sciences, Open Grey and NLM Bookshelf. An initial search identified 770 articles; 23 duplicate articles were removed. 642 were excluded for not meeting inclusion criteria following a title and abstract review of articles. 60 articles underwent full text review by two reviewers and 15 articles were included in analysis. RESULTS: This review found that novel approaches to service delivery such as incorporating STI testing into other targeted initiatives, providing self-testing kits and achieving high levels of cultural competency were key facilitators to access. Whereas location of services, inconsistent service provision, shame and differing levels of knowledge about the effects of STIs were key barriers. CONCLUSIONS: This systematic review identified barriers and facilitators of access to sexual health services for Aboriginal young people. System level changes are needed to improve physical environments, service integration and consistent provision of culturally competent services. This review highlights the need for further research focussed on assessing the real-world pressures of young Aboriginal people and how healthcare providers can better offer a person-centred service.

Differential gene expression in layer 3 pyramidal neurons across 3 regions of the human cortical visual spatial working memory network.

Visual spatial working memory (vsWM) is mediated by a distributed cortical network composed of multiple nodes, including primary visual (V1), posterior parietal (PPC), and dorsolateral prefrontal (DLPFC) cortices. Feedforward and feedback information is transferred among these nodes via projections furnished by pyramidal neurons (PNs) located primarily in cortical layer 3. Morphological and electrophysiological differences among layer 3 PNs across these nodes have been reported; however, the transcriptional signatures underlying these differences have not been examined in the human brain. Here we interrogated the transcriptomes of layer 3 PNs from 39 neurotypical human subjects across 3 critical nodes of the vsWM network. Over 8,000 differentially expressed genes were detected, with more than 6,000 transcriptional differences present between layer 3 PNs in V1 and those in PPC and DLPFC. Additionally, over 600 other genes differed in expression along the rostral-to-caudal hierarchy formed by these 3 nodes. Moreover, pathway analysis revealed enrichment of genes in V1 related to circadian rhythms and in DLPFC of genes involved in synaptic plasticity. Overall, these results show robust regional differences in the transcriptome of layer 3 PNs, which likely contribute to regional specialization in their morphological and physiological features and thus in their functional contributions to vsWM.

Expression of actin- and oxidative phosphorylation-related transcripts across the cortical visuospatial working memory network in unaffected comparison and schizophrenia subjects.

Visuospatial working memory (vsWM), which is impaired in schizophrenia (SZ), is mediated by a distributed cortical network. In one node of this network, the dorsolateral prefrontal cortex (DLPFC), altered expression of transcripts for actin assembly and mitochondrial oxidative phosphorylation (OXPHOS) have been reported in SZ. To understand the relationship between these processes, and the extent to which similar alterations are present in other regions of vsWM network in SZ, a subset of actin- (CDC42, BAIAP2, ARPC3, and ARPC4) and OXPHOS-related (ATP5H, COX4I1, COX7B, and NDUFB3) transcripts were quantified in DLPFC by RNA sequencing in 139 SZ and unaffected comparison (UC) subjects, and in DLPFC and three other regions of the cortical vsWM network by qPCR in 20 pairs of SZ and UC subjects. By RNA sequencing, levels of actin- and OXPHOS-related transcripts were significantly altered in SZ, and robustly correlated in both UC and SZ subject groups. By qPCR, cross-regional expression patterns of these transcripts in UC subjects were consistent with greater actin assembly in DLPFC and higher OXPHOS activity in primary visual cortex (V1). In SZ, CDC42 and ARPC4 levels were lower in all regions, BAIAP2 levels higher only in V1, and ARPC3 levels unaltered across regions. All OXPHOS-related transcript levels were lower in SZ, with the disease effect decreasing from posterior to anterior regions. The differential alterations in markers of actin assembly and energy production across regions of the cortical vsWM network in SZ suggest that each region may make specific contributions to vsWM impairments in the illness.