Multimodal regulatory elements within a hormone-specific super enhancer control a heterogeneous transcriptional response.

The hormone-stimulated glucocorticoid receptor (GR) modulates transcription by interacting with thousands of enhancers and GR binding sites (GBSs) throughout the genome. Here, we examined the effects of GR binding on enhancer dynamics and investigated the contributions of individual GBSs to the hormone response. Hormone treatment resulted in genome-wide reorganization of the enhancer landscape in breast cancer cells. Upstream of the DDIT4 oncogene, GR bound to four sites constituting a hormone-dependent super enhancer. Three GBSs were required as hormone-dependent enhancers that differentially promoted histone acetylation, transcription frequency, and burst size. Conversely, the fourth site suppressed transcription and hormone treatment alleviated this suppression. GR binding within the super enhancer promoted a loop-switching mechanism that allowed interaction of the DDIT4 TSS with the active GBSs. The unique functions of each GR binding site contribute to hormone-induced transcriptional heterogeneity and demonstrate the potential for targeted modulation of oncogene expression.

Unlocking cellular plasticity: Enhancing human iPSC reprogramming through bromodomain inhibition and extracellular matrix gene expression regulation.

The transformation from a fibroblast mesenchymal cell state to an epithelial-like state is critical for Induced Pluripotent Stem Cell (iPSC) reprogramming. In this report, we describe studies with PFI-3, a small molecule inhibitor that specifically targets the bromodomains of SMARCA2/4 and PBRM1 subunits of SWI/SNF complex, as an enhancer of iPSC reprogramming efficiency. Our findings reveal that PFI-3 induces cellular plasticity in multiple human dermal fibroblasts, leading to a mesenchymal-epithelial transition (MET) during iPSC formation. This transition is characterized by the upregulation of E-cadherin expression, a key protein involved in epithelial cell adhesion. Additionally, we identified COL11A1 as a reprogramming barrier and demonstrated COL11A1 knockdown increased reprogramming efficiency. Notably, we found that PFI-3 significantly reduced the expression of numerous extracellular matrix (ECM) genes, particularly those involved in collagen assembly. Our research provides key insights into the early stages of iPSC reprogramming, highlighting the crucial role of ECM changes and cellular plasticity in this process.

Effects of sEH inhibition on the eicosanoid and cytokine storms in SARS-CoV-2-infected mice.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection involves an initial viral infection phase followed by a host-response phase that includes an eicosanoid and cytokine storm, lung inflammation and respiratory failure. While vaccination and early anti-viral therapies are effective in preventing or limiting the pathogenic host response, this latter phase is poorly understood with no highly effective treatment options. Inhibitors of soluble epoxide hydrolase (sEH) increase levels of anti-inflammatory molecules called epoxyeicosatrienoic acids (EETs). This study aimed to investigate the impact of sEH inhibition on the host response to SARS-CoV-2 infection in a mouse model with human angiotensin-converting enzyme 2 (ACE2) expression. Mice were infected with SARS-CoV-2 and treated with either vehicle or the sEH inhibitor 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea (TPPU). At day 5 post-infection, SARS-CoV-2 induced weight loss, clinical signs, a cytokine storm, an eicosanoid storm, and severe lung inflammation with ~50% mortality on days 6-8 post-infection. SARS-CoV-2 infection induced lung expression of phospholipase A2 (PLA2), cyclooxygenase (COX) and lipoxygenase (LOX) pathway genes, while suppressing expression of most cytochrome P450 genes. Treatment with the sEH inhibitor TPPU delayed weight loss but did not alter clinical signs, lung cytokine expression or overall survival of infected mice. Interestingly, TPPU treatment significantly reversed the eicosanoid storm and attenuated viral-induced elevation of 39 fatty acids and oxylipins from COX, LOX and P450 pathways, which suggests the effects at the level of PLA2 activation. The suppression of the eicosanoid storm by TPPU without corresponding changes in lung cytokines, lung inflammation or mortality reveals a surprising dissociation between systemic oxylipin and cytokine signaling pathways during SARS-CoV-2 infection and suggests that the cytokine storm is primarily responsible for morbidity and mortality in this animal model.

Enablers and barriers to primary health care access for Indigenous adolescents: a systematic review and meta-aggregation of studies across Australia, Canada, New Zealand, and USA.

BACKGROUND: Indigenous adolescents access primary health care services at lower rates, despite their greater health needs and experience of disadvantage. This systematic review identifies the enablers and barriers to primary health care access for Indigenous adolescents to inform service and policy improvements. METHODS: We systematically searched databases for publications reporting enablers or barriers to primary health care access for Indigenous adolescents from the perspective of adolescents, their parents and health care providers, and included studies focused on Indigenous adolescents aged 10-24 years from Australia, Canada, New Zealand, and United States of America. Results were analyzed against the WHO Global standards for quality health-care services for adolescents. An additional ninth standard was added which focused on cultural safety. RESULTS: A total of 41 studies were included. More barriers were identified than enablers, and against the WHO Global standards most enablers and barriers related to supply factors - providers' competencies, appropriate package of services, and cultural safety. Providers who built trust, respect, and relationships; appropriate package of service; and culturally safe environments and care were enablers to care reported by adolescents, and health care providers and parents. Embarrassment, shame, or fear; a lack of culturally appropriate services; and privacy and confidentiality were common barriers identified by both adolescent and health care providers and parents. Cultural safety was identified as a key issue among Indigenous adolescents. Enablers and barriers related to cultural safety included culturally appropriate services, culturally safe environment and care, traditional and cultural practices, cultural protocols, Indigenous health care providers, cultural training for health care providers, and colonization, intergenerational trauma, and racism. Nine recommendations were identified which aim to address the enablers and barriers associated with primary health care access for Indigenous adolescents. CONCLUSION: This review provides important evidence to inform how services, organizations and governments can create accessible primary health care services that specifically meet the needs of Indigenous adolescents. We identify nine recommendations for improving the accessibility of primary health care services for Indigenous adolescents.

Sexual risk and testing for sexually transmissible infections in Aboriginal and Torres Strait Islander peoples and non-Indigenous young South Australians: results of an online survey.

Background Disproportionate rates of sexually transmissible infections (STIs) among Aboriginal and Torres Strait Islander young people are often attributed to risk-taking behaviours, but research rarely conducts direct comparison with their non-Indigenous peers to address this negative discourse. Methods 'Let's Talk About It 2019' was a cross-sectional online survey of South Australians (16-29 years). It prioritised recruitment of Aboriginal and Torres Strait Islander respondents to compare behaviours with non-Indigenous peers using multivariable Poisson regression models. Results Aboriginal and Torres Strait Islander (n =231) and non-Indigenous (n =2062) respondents reported similar condom use (40% vs 43%, P =0.477) and sexual debut median ages (16 years vs 17 years). Higher proportions of Aboriginal and/or Torres Strait Islander respondents reported a recent health check (48% vs 38%, P =0.002), STIs (60% vs 49%, P P =0.006) testing, STI diagnosis (29% vs 21%, P =0.042), and intoxication during last sex (30% vs 18%, P Conclusions Behaviours associated with STI transmission were mostly similar among Aboriginal and Torres Strait Islander and non-Indigenous respondents. Higher STI/HIV testing among Aboriginal and Torres Strait Islander respondents suggests effectiveness of targeted programs. Interventions targeting substance use and condom use among all young people are needed. Future interventions need to focus beyond behaviours and explore social determinants of health and sexual networks as contributors to disproportionate STI rates.

Impact of Anti-EGFR Therapies on HER2-Positive Metastatic Colorectal Cancer: A Systematic Literature Review and Meta-Analysis of Clinical Outcomes.

BACKGROUND: HER2 overexpression/amplification in patients with RAS wild-type (WT) metastatic colorectal cancer (mCRC) may be associated with resistance to standard-of-care anti-EGFR therapies. Given the lack of comprehensive investigations into this association, we assessed the prognostic or predictive effect of HER2 amplification/overexpression on anti-EGFR treatment outcomes. METHODS: A systematic review of MEDLINE, Embase, and Cochrane Library (2001-2021) identified studies evaluating progression-free survival (PFS), overall response rate (ORR), and overall survival (OS) in HER2-positive vs. HER2-negative patients with RAS WT mCRC who received anti-EGFR treatments and whose HER2 status was known. Meta-analyses of proportions (ORR) and hazard ratios (PFS, OS) were performed using random-effect models with pre-specified sensitivity analyses. RESULTS: Five high-quality retrospective cohort studies were included in the meta-analyses representing 594 patients with mCRC. All patients received anti-EGFR treatment, either as monotherapy or in combination with chemotherapy. Meta-analysis of PFS demonstrated a 2.84-fold higher risk of death or progression (95% CI, 1.44-5.60) in patients with HER2-positive (vs. HER2-negative) RAS WT mCRC treated with anti-EGFR regimens. The odds of response to anti-EGFR treatment were 2-fold higher in HER2-negative vs. HER2-positive (odds ratio, 1.96 [95% CI, 1.10-3.48]). Differences in OS were not statistically significant. Sensitivity analyses confirmed the robustness of the base-case estimates. CONCLUSIONS: While this study could not account for all confounding factors, in patients with RAS WT mCRC who received anti-EGFR therapy, HER2 overexpression/amplification was associated with worse PFS and ORR and may therefore predict poorer outcomes. HER2 testing is important to inform treatment decisions and could optimize outcomes for patients.

A HIV diagnosis and treatment cascade for Aboriginal and Torres Strait Islander peoples of Australia.

Aboriginal and Torres Strait Islander (hereafter Aboriginal) people are a priority population for HIV care in Australia; however, no HIV cascade exists for this population. We developed annual HIV cascades for 2010-2017 specific to Aboriginal peoples. By 2017, an estimated 595 Aboriginal people were living with HIV (PLWH); however, 14% remained undiagnosed. Cascade steps below global targets were: PLWH aware of their diagnosis (86%), and retention in care (81% of those who had received any care in previous two years in a sentinel network of clinics). For people retained in care, treatment outcomes surpassed global targets (92% receiving treatment, 93% viral suppression). Increases occurred across all HIV cascade steps over time; however, the least improvement was for retention in care, while the greatest improvement was achieving viral suppression. The HIV cascade for Aboriginal peoples highlights both gaps and strengths in the Australian HIV care system, and importantly highlights where potential interventions may be required to achieve the global UNAIDS targets.

Infectious syphilis in women and heterosexual men in major Australian cities: sentinel surveillance data, 2011-2019.

OBJECTIVES: To examine changes in the positive infectious syphilis test rate among women and heterosexual men in major Australian cities, and rate differences by social, biomedical, and behavioural determinants of health. DESIGN, SETTING: Analysis of data extracted from de-identified patient records from 34 sexual health clinics participating in the Australian Collaboration for Coordinated Enhanced Sentinel Surveillance of Sexually Transmissible Infections and Blood Borne Viruses (ACCESS). PARTICIPANTS: First tests during calendar year for women and heterosexual men aged 15 years or more in major cities who attended ACCESS sexual health clinics during 2011-2019. MAIN OUTCOME MEASURES: Positive infectious syphilis test rate; change in annual positive test rate. RESULTS: 180 of 52 221 tested women (0.34%) and 239 of 36 341 heterosexual men (0.66%) were diagnosed with infectious syphilis. The positive test rate for women was 1.8 (95% confidence interval [CI], 0.9-3.2) per 1000 tests in 2011, 3.0 (95% CI, 2.0-4.2) per 1000 tests in 2019 (change per year: rate ratio [RR], 1.12; 95% CI, 1.01-1.25); for heterosexual men it was 6.1 (95% CI, 3.8-9.2) per 1000 tests in 2011 and 7.6 (95% CI, 5.6-10) per 1000 tests in 2019 (RR, 1.10; 95% CI, 1.03-1.17). In multivariable analyses, the positive test rate was higher for women (adjusted RR [aRR], 1.85; 95% CI, 1.34-2.55) and heterosexual men (aRR, 2.39; 95% CI, 1.53-3.74) in areas of greatest socio-economic disadvantage than for those in areas of least socio-economic disadvantage. It was also higher for Indigenous women (aRR, 2.39; 95% CI, 1.22-4.70) and for women who reported recent injection drug use (aRR, 4.87; 95% CI, 2.18-10.9) than for other women; it was lower for bisexual than heterosexual women (aRR, 0.48; 95% CI, 0.29-0.81) and for women who reported recent sex work (aRR, 0.35; 95% CI, 0.29-0.44). The positive test rate was higher for heterosexual men aged 40-49 years (aRR, 2.11; 95% CI, 1.42-3.12) or more than 50 years (aRR, 2.36; 95% CI, 1.53-3.65) than for those aged 15-29 years. CONCLUSION: The positive test rate among both urban women and heterosexual men tested was higher in 2019 than in 2011. People who attend reproductive health or alcohol and drug services should be routinely screened for syphilis.

Pulmonary Function and Blood DNA Methylation: A Multiancestry Epigenome-Wide Association Meta-analysis.

Rationale: Methylation integrates factors present at birth and modifiable across the lifespan that can influence pulmonary function. Studies are limited in scope and replication. Objectives: To conduct large-scale epigenome-wide meta-analyses of blood DNA methylation and pulmonary function. Methods: Twelve cohorts analyzed associations of methylation at cytosine-phosphate-guanine probes (CpGs), using Illumina 450K or EPIC/850K arrays, with FEV1, FVC, and FEV1/FVC. We performed multiancestry epigenome-wide meta-analyses (total of 17,503 individuals; 14,761 European, 2,549 African, and 193 Hispanic/Latino ancestries) and interpreted results using integrative epigenomics. Measurements and Main Results: We identified 1,267 CpGs (1,042 genes) differentially methylated (false discovery rate, <0.025) in relation to FEV1, FVC, or FEV1/FVC, including 1,240 novel and 73 also related to chronic obstructive pulmonary disease (1,787 cases). We found 294 CpGs unique to European or African ancestry and 395 CpGs unique to never or ever smokers. The majority of significant CpGs correlated with nearby gene expression in blood. Findings were enriched in key regulatory elements for gene function, including accessible chromatin elements, in both blood and lung. Sixty-nine implicated genes are targets of investigational or approved drugs. One example novel gene highlighted by integrative epigenomic and druggable target analysis is TNFRSF4. Mendelian randomization and colocalization analyses suggest that epigenome-wide association study signals capture causal regulatory genomic loci. Conclusions: We identified numerous novel loci differentially methylated in relation to pulmonary function; few were detected in large genome-wide association studies. Integrative analyses highlight functional relevance and potential therapeutic targets. This comprehensive discovery of potentially modifiable, novel lung function loci expands knowledge gained from genetic studies, providing insights into lung pathogenesis.

Integrating testing for sexually transmissible infections into annual health assessments for Aboriginal and Torres Strait Islander young people: a cross-sectional analysis.

BACKGROUND: In the context of an expanding syphilis epidemic, we assessed the integration of sexually transmissible infection (STI) testing within annual health assessments for Aboriginal and Torres Strait Islander young people aged 16-29years in Aboriginal Community Controlled Health Services between 2018 and 2020. METHODS: Using routinely collected electronic medical record data from a national sentinel surveillance system (ATLAS), we performed a cross-sectional analysis to calculate the proportion of assessments that integrated any or all of the tests for chlamydia, gonorrhoea, syphilis, and HIV. We used logistic regression to identify correlates of integration of any STI test. RESULTS: Of the 13 892 assessments, 23.8% (95% CI 23.1, 24.6) integrated a test for any STI and 11.5% (95% CI 10.9, 12.0) included all four STIs. Of assessments that included a chlamydia/gonorrhoea test, 66.9% concurrently included a syphilis test. Integration of any STI test was associated with patients aged 20-24years (OR 1.2, 95% CI 1.1-1.4) and 25-29years (OR 1.1, 95% CI 1.0-1.2) compared to 16-19years and patients residing in very remote (OR 4.2, 95% CI 3.7-4.8), remote (OR 2.4, 95% CI 2.1-2.8), and regional areas (OR 2.5, 95% CI 2.2-2.8) compared to metropolitan areas. There was no association with patient sex. CONCLUSIONS: Integration of STI testing into annual health assessments for Aboriginal and Torres Strait Islander young people was higher in remote areas where disease burden is greatest. Integration is similar in men and women, which contrasts with most studies that have found higher testing in women.

APOBEC3G Is a p53-Dependent Restriction Factor in Respiratory Syncytial Virus Infection of Human Cells Included in the p53/Immune Axis.

Identifying and understanding genetic factors that influence the propagation of the human respiratory syncytial virus (RSV) can lead to health benefits and possibly augment recent vaccine approaches. We previously identified a p53/immune axis in which the tumor suppressor p53 directly regulates the expression of immune system genes, including the seven members of the APOBEC3 family of DNA cytidine deaminases (A3), which are innate immune sentinels against viral infections. Here, we examined the potential p53 and A3 influence in RSV infection, as well as the overall p53-dependent cellular and p53/immune axis responses to infection. Using a paired p53 model system of p53+ and p53- human lung tumor cells, we found that RSV infection activates p53, leading to the altered p53-dependent expression of A3D, A3F, and A3G, along with p53 site-specific binding. Focusing on A3G because of its 10-fold-greater p53 responsiveness to RSV, the overexpression of A3G can reduce RSV viral replication and syncytial formation. We also observed that RSV-infected cells undergo p53-dependent apoptosis. The study was expanded to globally address at the transcriptional level the p53/immune axis response to RSV. Nearly 100 genes can be directly targeted by the p53/immune axis during RSV infection based on our p53BAER analysis (Binding And Expression Resource). Overall, we identify A3G as a potential p53-responsive restriction factor in RSV infection. These findings have significant implications for RSV clinical and therapeutic studies and other p53-influenced viral infections, including using p53 adjuvants to boost the response of A3 genes.

Sarcopenia and Myosteatosis Predict Adverse Outcomes After Emergency Laparotomy: A Multi-center Observational Cohort Study.

OBJECTIVE: To determine the relationship between BC, specifically low skeletal muscle mass (sarcopenia) and poor muscle quality (myosteatosis) and outcomes in emergency laparotomy patients. BACKGROUND: Emergency laparotomy has one of the highest morbidity and mortality rates of all surgical interventions. BC objectively identifies patients at risk of adverse outcomes in elective cancer cohorts, however, evidence is lacking in emergency surgery. METHODS: An observational cohort study of patients undergoing emergency laparotomy at ten English hospitals was performed. BC analyses were performed at the third lumbar vertebrae level using preoperative computed tomography images to quantify skeletal muscle index (SMI) and skeletal muscle radiation attenuation (SM-RA). Sex-specific SMI and SM-RA were determined, with the lower tertile splits defining sarcopenia (low SMI) and myosteatosis (low SM-RA). Accuracy of mortality risk prediction, incorporating SMI and SM-RA variables into risk models was assessed with regression modeling. RESULTS: Six hundred ten patients were included. Sarcopenia and myosteatosis were both associated with increased risk of morbidity (52.1% vs 45.1%, P = 0.028; 57.5% vs 42.6%, P = 0.014), 30-day (9.5% vs 3.6%, P = 0.010; 14.9% vs 3.4%, P < 0.001), and 1-year mortality (27.4% vs 11.5%, P < 0.001; 29.7% vs 12.5%, P < 0.001). Risk-adjusted 30-day mortality was significantly increased by sarcopenia [OR 2.56 (95% CI 1.12-5.84), P = 0.026] and myosteatosis [OR 4.26 (2.01-9.06), P < 0.001], similarly at 1-year [OR 2.66 (95% CI 1.57-4.52), P < 0.001; OR2.08 (95%CI 1.26-3.41), P = 0.004]. BC data increased discrimination of an existing mortality risk-prediction model (AUC 0.838, 95% CI 0.835-0.84). CONCLUSION: Sarcopenia and myosteatosis are associated with increased adverse outcomes in emergency laparotomy patients.

Genetic regulation of liver lipids in a mouse model of insulin resistance and hepatic steatosis.

To elucidate the contributions of specific lipid species to metabolic traits, we integrated global hepatic lipid data with other omics measures and genetic data from a cohort of about 100 diverse inbred strains of mice fed a high-fat/high-sucrose diet for 8 weeks. Association mapping, correlation, structure analyses, and network modeling revealed pathways and genes underlying these interactions. In particular, our studies lead to the identification of Ifi203 and Map2k6 as regulators of hepatic phosphatidylcholine homeostasis and triacylglycerol accumulation, respectively. Our analyses highlight mechanisms for how genetic variation in hepatic lipidome can be linked to physiological and molecular phenotypes, such as microbiota composition.

Hospitalisations for pelvic inflammatory disease in young Aboriginal women living in remote Australia: the role of chlamydia and gonorrhoea.

OBJECTIVE: Aboriginal women living in remote Australia experience a high burden of both chlamydia and gonorrhoea infections and disproportionately high rates of pelvic inflammatory disease (PID). We estimated for the first time the fraction of PID attributable to these infections in young Aboriginal women living in these settings. METHODS: Using published data from two large Australian studies (2002-2013; 2010-2014), we calculated the fraction of emergency department presentations and hospitalisations for PID attributable to chlamydia and/or gonorrhoea infection in Aboriginal women aged 16-29 years living in remote Australia. We used a Monte Carlo simulation to estimate the mean and 95% CIs for the assumed prevalence and population attributable fractions for PID for infection stratifications (chlamydia only, gonorrhoea only and dual infection) as well as for any infection (chlamydia and/or gonorrhoea). Additional outputs were calculated for chlamydia infection with/without gonorrhoea coinfection, and vice versa. RESULTS: The prevalence of chlamydia only was 12.9% (95% CI: 11.6% to 14.2%), gonorrhoea only was 7.8% (95% CI: 6.6% to 8.9%) and dual infection was 6.5% (95% CI: 5.8% to 7.2%); rate ratios of PID were 1.9 (95% CI: 1.5 to 2.3), 5.2 (95% CI: 4.3 to 6.4) and 4.6 (95% CI: 3.8 to 5.5), respectively. The overall fraction of PID attributable to chlamydia and/or gonorrhoea was 40.2% (95% CI: 36.0% to 44.4%); any gonorrhoea was 33.4% (95% CI: 29.2% to 37.8%) and any chlamydia was 20.6% (95% CI: 16.9% to 24.6%). CONCLUSION: Our study demonstrates the importance of calculating the fraction of PID related to chlamydia and gonorrhoea in the local context, demonstrating the major contribution gonorrhoea makes to PID hospitalisations among Australian Aboriginal women living in remote settings. To significantly and sustainably reduce the unacceptable rate of PID in this population, strategies are urgently needed to improve timely testing and treatment and recognition and management of PID in primary care.

Benthic Dissolved Silicon and Iron Cycling at Glaciated Patagonian Fjord Heads.

Glacier meltwater supplies silicon (Si) and iron (Fe) sourced from weathered bedrock to downstream ecosystems. However, the extent to which these nutrients reach the ocean is regulated by the nature of the benthic cycling of dissolved Si and Fe within fjord systems, given the rapid deposition of reactive particulate fractions at fjord heads. Here, we examine the benthic cycling of the two nutrients at four Patagonian fjord heads through geochemical analyses of sediment pore waters, including Si and Fe isotopes (δ30Si and δ56Fe), and reaction-transport modeling for Si. A high diffusive flux of dissolved Fe from the fjord sediments (up to 0.02 mmol m-2 day-1) compared to open ocean sediments (typically <0.001 mmol m-2 day-1) is supported by both reductive and non-reductive dissolution of glacially-sourced reactive Fe phases, as reflected by the range of pore water δ56Fe (-2.7 to +0.8‰). In contrast, the diffusive flux of dissolved Si from the fjord sediments (0.02-0.05 mmol m-2 day-1) is relatively low (typical ocean values are >0.1 mmol m-2 day-1). High pore water δ30Si (up to +3.3‰) observed near the Fe(II)-Fe(III) redox boundary is likely associated with the removal of dissolved Si by Fe(III) mineral phases, which, together with high sedimentation rates, contribute to the low diffusive flux of Si at the sampled sites. Our results suggest that early diagenesis promotes the release of dissolved Fe, yet suppresses the release of dissolved Si at glaciated fjord heads, which has significant implications for understanding the downstream transport of these nutrients along fjord systems.

Hepatitis C treatment outcomes for Australian First Nations Peoples: equivalent SVR rate but higher rates of loss to follow-up.

BACKGROUND: First Nations Peoples of Australia are disproportionally affected by hepatitis C (HCV) infection. Through a prospective study we evaluated the outcome of direct-acting antiviral (DAA) therapy among First Nations Peoples with HCV infection. METHODS: Adults who initiated DAA therapy at one of 26 hospitals across Australia, 2016-2019 were included in the study. Clinical data were obtained from medical records and the Pharmaceutical and Medicare Benefits Schemes. Outcomes included sustained virologic response (SVR) and loss to follow-up (LTFU). A multivariable analysis assessed factors associated with LTFU. RESULTS: Compared to non-Indigenous Australians (n = 3206), First Nations Peoples (n = 89) were younger (p < 0.001), morel likely to reside in most disadvantaged (p = 0.002) and in regional/remote areas (p < 0.001), and had similar liver disease severity. Medicines for mental health conditions were most commonly dispensed among First Nations Peoples (55.2% vs. 42.8%; p = 0.022). Of 2910 patients with follow-up data, both groups had high SVR rates (95.3% of First Nations Peoples vs. 93.2% of non-Indigenous patients; p = 0.51) and 'good' adherence (90.0% vs. 86.9%, respectively; p = 0.43). However, 28.1% of First Nations Peoples were LTFU vs. 11.2% of non-Indigenous patients (p < 0.001). Among First Nations Peoples, younger age (adj-OR = 0.93, 95% CI 0.87-0.99) and treatment initiation in 2018-2019 vs. 2016 (adj-OR = 5.14, 95% CI 1.23-21.36) predicted LTFU, while higher fibrosis score was associated with better engagement in HCV care (adj-OR = 0.71, 95% CI 0.50-0.99). CONCLUSIONS: Our data showed that First Nations Peoples have an equivalent HCV cure rate, but higher rates of LTFU. Better strategies to increase engagement of First Nations Peoples with HCV care are needed.

SIRT1-mediated deacetylation of CRABPII regulates cellular retinoic acid signaling and modulates embryonic stem cell differentiation.

Retinoid homeostasis is critical for normal embryonic development. Both the deficiency and excess of these compounds are associated with congenital malformations. Here we demonstrate that SIRT1, the most conserved mammalian NAD⁺-dependent protein deacetylase, contributes to homeostatic retinoic acid (RA) signaling and modulates mouse embryonic stem cell (mESC) differentiation in part through deacetylation of cellular retinoic acid binding protein II (CRABPII). We show that RA-mediated acetylation of CRABPII at K102 is essential for its nuclear accumulation and subsequent activation of RA signaling. SIRT1 interacts with and deacetylates CRABPII, regulating its subcellular localization. Consequently, SIRT1 deficiency induces hyperacetylation and nuclear accumulation of CRABPII, enhancing RA signaling and accelerating mESC differentiation in response to RA. Consistently, SIRT1 deficiency is associated with elevated RA signaling and development defects in mice. Our findings reveal a molecular mechanism that regulates RA signaling and highlight the importance of SIRT1 in regulation of ESC pluripotency and embryogenesis.

Lrp1 Regulation of Pulmonary Function. Follow-Up of Human GWAS in Mice.

Human genome-wide association studies (GWASs) have identified more than 270 loci associated with pulmonary function; however, follow-up studies to determine causal genes at these loci are few. SNPs in low-density lipoprotein receptor-related protein 1 (LRP1) are associated with human pulmonary function in GWASs. Using murine models, we investigated the effect of genetic disruption of the Lrp1 gene in smooth muscle cells on pulmonary function in naive animals and after exposure to bacterial LPS or house dust mite extract. Disruption of Lrp1 in smooth muscle cells leads to an increase in tissue resistance, elastance, and tissue elastance at baseline. Furthermore, disruption of Lrp1 in smooth muscle increases airway responsiveness as measured by increased total lung resistance and airway resistance after methacholine. Immune cell counts in BAL fluid were increased in animals with Lrp1 disruption. The difference in airway responsiveness by genotype observed in naive animals was not observed after LPS or house dust mite extract exposure. To further explore the mechanisms contributing to changes in pulmonary function, we identified several ligands dysregulated with Lrp1 disruption in smooth muscle cells. These data suggest that dysregulation of LRP1 in smooth muscle cells affects baseline pulmonary function and airway responsiveness and helps establish LRP1 as the causal gene at this GWAS locus.

Vascular origins of low-frequency oscillations in the cerebrospinal fluid signal in resting-state fMRI: Interpretation using photoplethysmography.

In vivo mapping of cerebrovascular oscillations in the 0.05-0.15 Hz remains difficult. Oscillations in the cerebrospinal fluid (CSF) represent a possible avenue for noninvasively tracking these oscillations using resting-state functional MRI (rs-fMRI), and have been used to correct for vascular oscillations in rs-fMRI functional connectivity. However, the relationship between low-frequency CSF and vascular oscillations remains unclear. In this study, we investigate this relationship using fast simultaneous rs-fMRI and photoplethysmogram (PPG), examining the 0.1 Hz PPG signal, heart-rate variability (HRV), pulse-intensity ratio (PIR), and the second derivative of the PPG (SDPPG). The main findings of this study are: (a) signals in different CSF regions are not equivalent in their associations with vascular and tissue rs-fMRI signals; (b) the PPG signal is maximally coherent with the arterial and CSF signals at the cardiac frequency, but coherent with brain tissue at ~0.2 Hz; (c) PIR is maximally coherent with the CSF signal near 0.03 Hz; and (d) PPG-related vascular oscillations only contribute to ~15% of the CSF (and arterial) signal in rs-fMRI. These findings caution against averaging all CSF regions when extracting physiological nuisance regressors in rs-fMRI applications, and indicate the drivers of the CSF signal are more than simply cardiac. Our study is an initial attempt at the refinement and standardization of how the CSF signal in rs-fMRI can be used and interpreted. It also paves the way for using rs-fMRI in the CSF as a potential tool for tracking cerebrovascular health through, for instance, the potential relationship between PIR and the CSF signal.

Current issues in the prevalence, diagnosis and management of hepatocellular carcinoma in Australia.

Hepatocellular carcinoma (HCC) is the commonest primary liver cancer encountered in the community and a leading cause of cancer morbidity and mortality. In Australia, there are several current important issues that need to be addressed in HCC management. There is a dramatically rising incidence of HCC in Australia with comparatively poorer outcomes in remote regions and in socioeconomic disadvantaged groups. Aboriginal people have a greater incidence of HCC on a background of increased liver disease prevalence and face several barriers to delivery of better healthcare outcomes compared to other Australians. The previously adopted use of imaging alone to diagnose HCC is now being challenged with biopsy likely to become increasingly necessary with the increased uptake of personalised medicine management. Managing HCC is complex involving many disciplines with the multidisciplinary team approach being the current accepted standard of care for patients. New immunotherapy combinations promise to offer patients with advanced HCC promising novel management options. However, the Australian inequities in prevalence, diagnosis and service provision, especially in Aboriginal people, need to be redressed concurrently with the adoption of new HCC management options.