Peripheral serotonin levels as a predictor of antidepressant treatment response: A systematic review.

There are currently no reliable biomarkers to predict clinical response to pharmacological treatments of depressive disorders. Peripheral blood 5-hydroxytryptamine (5-HT; serotonin) has been suggested as a biomarker of antidepressant treatment response, but there has not been an attempt to systematically summarize and evaluate the scientific evidence of this hypothesis. In this systematic review we searched MEDLINE, Embase, PsycINFO, and the Cochrane Central Register of Controlled Trials. Twenty-six relevant studies investigating peripheral 5-HT as an antidepressant biomarker were identified. In all, we did not find robust support for an association between baseline 5-HT and treatment response. Several larger studies with lower risk of bias, however, showed that higher baseline 5-HT was associated with a greater antidepressant response to SSRIs, prompting future studies to investigate this hypothesis. Our results also confirm previous reports that SSRI treatment is associated with a decrease in peripheral 5-HT levels; however, we were not able to confirm that larger decreases of 5-HT are associated with better treatment outcome as results were inconclusive.

Professional Standards for Specialist Medical Administrators: Over-the-top Downunder?

In Australia, there are only two publicly reported disciplinary cases against specialist medical administrators. In the most recent decision of Medical Board of Australia v Gruner, the Victorian Civil and Administrative Tribunal confirmed that specialist medical administrators owe patients and the public the same professional obligations as medical practitioners with direct patient contact. More controversially, the Tribunal also held that medical administrators have a professional obligation only to accept roles with clear position descriptions that afford them sufficient time and resources to ensure the safe delivery of health services. We argue that this imposes unrealistic expectations on medical administrators engaged by rural, regional, or private health services that already struggle to attract and retain specialist medical expertise. This may exacerbate existing health inequalities by disincentivising specialist medical administrators from seeking fractional appointments that assist under-funded areas of workforce shortage.

Pharmacological inhibition of α-synuclein aggregation within liquid condensates.

Aggregated forms of α-synuclein constitute the major component of Lewy bodies, the proteinaceous aggregates characteristic of Parkinson's disease. Emerging evidence suggests that α-synuclein aggregation may occur within liquid condensates formed through phase separation. This mechanism of aggregation creates new challenges and opportunities for drug discovery for Parkinson's disease, which is otherwise still incurable. Here we show that the condensation-driven aggregation pathway of α-synuclein can be inhibited using small molecules. We report that the aminosterol claramine stabilizes α-synuclein condensates and inhibits α-synuclein aggregation within the condensates both in vitro and in a Caenorhabditis elegans model of Parkinson's disease. By using a chemical kinetics approach, we show that the mechanism of action of claramine is to inhibit primary nucleation within the condensates. These results illustrate a possible therapeutic route based on the inhibition of protein aggregation within condensates, a phenomenon likely to be relevant in other neurodegenerative disorders.

Pharmacological induction of chromatin remodeling drives chemosensitization in triple-negative breast cancer.

Targeted therapies have improved outcomes for certain cancer subtypes, but cytotoxic chemotherapy remains a mainstay for triple-negative breast cancer (TNBC). The epithelial-to-mesenchymal transition (EMT) is a developmental program co-opted by cancer cells that promotes metastasis and chemoresistance. There are no therapeutic strategies specifically targeting mesenchymal-like cancer cells. We report that the US Food and Drug Administration (FDA)-approved chemotherapeutic eribulin induces ZEB1-SWI/SNF-directed chromatin remodeling to reverse EMT that curtails the metastatic propensity of TNBC preclinical models. Eribulin induces mesenchymal-to-epithelial transition (MET) in primary TNBC in patients, but conventional chemotherapy does not. In the treatment-naive setting, but not after acquired resistance to other agents, eribulin sensitizes TNBC cells to subsequent treatment with other chemotherapeutics. These findings provide an epigenetic mechanism of action of eribulin, supporting its use early in the disease process for MET induction to prevent metastatic progression and chemoresistance. These findings warrant prospective clinical evaluation of the chemosensitizing effects of eribulin in the treatment-naive setting.

Serum brain-derived neurotrophic factor, Val66Met polymorphism and open-label SSRI treatment response in Major Depressive Disorder.

BACKGROUND: Brain-derived neurotrophic factor (BDNF) has been implicated in the therapeutic action of antidepressants and possibly in the pathophysiology of Major Depressive Disorder (MDD). Clinical studies of peripheral blood levels of BDNF in MDD have provided conflicting results, and there are also conflicting reports regarding the predictive value of peripheral BDNF levels for antidepressant treatment response. The present study investigated the association between serum BDNF levels, the BDNF Val66Met polymorphism (rs6265), clinical characteristics and SSRI treatment response. METHODS: This open-label clinical trial included 99 physically healthy, unmedicated MDD participants and 70 healthy controls. Following a baseline assessment, 53 of the MDD participants completed an eight-week, open-label course of SSRI antidepressant treatment. Serum BDNF levels and Hamilton Rating Scale for Depression (HDRS) ratings were examined at baseline and after eight weeks of treatment. Antidepressant response was defined as a decrease in HDRS ratings of > 50% from baseline to the end-of-treatment. Finally, serum BDNF levels and SSRI treatment response were compared between MDD participants who were heterozygous or homozygous for the Met allele ("Met-carriers") and individuals homozygous for the Val allele. RESULTS: Serum BDNF levels at baseline were significantly higher in the unmedicated MDD participants compared to healthy controls (15.90 ng/ml vs 13.75 ng/ml, t (167) = -2.041, p = 0.043). In a post-hoc analysis, this difference was seen in the female but not male participants (16.85 ng/ml vs 14.06 ng/ml, t (91) = -2.067, p = 0.042; 14.86 ng/ml vs 13.31 ng/ml, t (74) = -0.923, p = 0.359). Baseline serum BDNF levels were not associated with treatment responder status or with absolute change in depression ratings over the course of 8-week SSRI treatment (p = 0.599). In both Responders and Non-responders, no significant changes in serum BDNF levels were found over the 8-week period of SSRI-treatment (16.32 ng/ml vs 16.23 ng/ml, t (18) = 0.060, p = 0.953; 16.04 ng/ml vs 15.61 ng/ml, t (29) = 0.438, p = 0.665, respectively). Further, no differences were found in serum BDNF levels prior to treatment between MDD Met-carriers and MDD Val/Val homozygotes (15.32 ng/ml vs 16.36 ng/ml, t (85) = 0.747, p = 0.457), and no differences were found in post-treatment serum BDNF (F1,42= 0.031, p = 0.862). However, MDD Val/Val homozygotes showed significantly greater antidepressant responses at week 8 than did MDD Met-carriers (F1,46 = 4.366, p = 0.043). CONCLUSION: Our results do not support sufficient reliability of using peripheral BDNF to characterize depression or to predict antidepressant response in clinical use. The role of sex in moderating BDNF differences in depression, and the role of BDNF gene polymorphisms in predicting antidepressant response, remain to be further investigated. We conclude that, while central nervous system BDNF is likely involved in antidepressant efficacy and in aspects of MDD pathophysiology, its reflection in serum BDNF levels is of limited diagnostic or prognostic utility.

Polygenic Risk Scores Driving Clinical Change in Glaucoma.

Glaucoma is a clinically heterogeneous disease and the world's leading cause of irreversible blindness. Therapeutic intervention can prevent blindness but relies on early diagnosis, and current clinical risk factors are limited in their ability to predict who will develop sight-threatening glaucoma. The high heritability of glaucoma makes it an ideal substrate for genetic risk prediction, with the bulk of risk being polygenic in nature. Here, we summarize the foundations of glaucoma genetic risk, the development of polygenic risk prediction instruments, and emerging opportunities for genetic risk stratification. Although challenges remain, genetic risk stratification will significantly improve glaucoma screening and management.

Deep Learning-Based Identification of Intraocular Pressure-Associated Genes Influencing Trabecular Meshwork Cell Morphology.

Purpose: Genome-wide association studies have recently uncovered many loci associated with variation in intraocular pressure (IOP). Artificial intelligence (AI) can be used to interrogate the effect of specific genetic knockouts on the morphology of trabecular meshwork cells (TMCs) and thus, IOP regulation. Design: Experimental study. Subjects: Primary TMCs collected from human donors. Methods: Sixty-two genes at 55 loci associated with IOP variation were knocked out in primary TMC lines. All cells underwent high-throughput microscopy imaging after being stained with a 5-channel fluorescent cell staining protocol. A convolutional neural network was trained to distinguish between gene knockout and normal control cell images. The area under the receiver operator curve (AUC) metric was used to quantify morphological variation in gene knockouts to identify potential pathological perturbations. Main Outcome Measures: Degree of morphological variation as measured by deep learning algorithm accuracy of differentiation from normal controls. Results: Cells where LTBP2 or BCAS3 had been perturbed demonstrated the greatest morphological variation from normal TMCs (AUC 0.851, standard deviation [SD] 0.030; and AUC 0.845, SD 0.020, respectively). Of 7 multigene loci, 5 had statistically significant differences in AUC (P < 0.05) between genes, allowing for pathological gene prioritization. The mitochondrial channel most frequently showed the greatest degree of morphological variation (33.9% of cell lines). Conclusions: We demonstrate a robust method for functionally interrogating genome-wide association signals using high-throughput microscopy and AI. Genetic variations inducing marked morphological variation can be readily identified, allowing for the gene-based dissection of loci associated with complex traits. Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

pH-responsive i-motif-conjugated nanoparticles for MRI analysis.

Gadolinium (Gd)-based contrast agents (CAs) are widely used to enhance anatomical details in magnetic resonance imaging (MRI). Significant research has expanded the field of CAs into bioresponsive CAs by modulating the signal to image and monitor biochemical processes, such as pH. In this work, we introduce the modular, dynamic actuation mechanism of DNA-based nanostructures as a new way to modulate the MRI signal based on the rotational correlation time, τR. We combined a pH-responsive oligonucleotide (i-motif) and a clinical standard CA (Gd-DOTA) to develop a pH-responsive MRI CA. The i-motif folds into a quadruplex under acidic conditions and was incorporated onto gold nanoparticles (iM-GNP) to achieve increased relaxivity, r1, compared to the unbound i-motif. In vitro, iM-GNP resulted in a significant increase in r1 over a decreasing pH range (7.5-4.5) with a calculated pKa = 5.88 ± 0.01 and a 16.7% change per 0.1 pH unit. In comparison, a control CA with a non-responsive DNA strand (T33-GNP) did not show a significant change in r1 over the same pH range. The iM-GNP was further evaluated in 20% human serum and demonstrated a 28.14 ± 11.2% increase in signal from neutral pH to acidic pH. This approach paves a path for novel programmable, dynamic DNA-based complexes for τR-modulated bioresponsive MRI CAs.

Omega-3 fatty acids for inflamed depression - A match/mismatch study.

Despite decades of research on the pathophysiology of depression, the development of new therapeutic interventions has been slow, and no biomarkers of treatment response have been clinically implemented. Several lines of evidence suggest that the clinical and biological heterogeneity among patients with major depressive disorder (MDD) has hampered progress in this field. MDD with low-grade inflammation - "inflamed depression" - is a subtype of depression that may be associated with a superior antidepressant treatment response to anti-inflammatory compounds. Omega-3 fatty acid eicosapentaenoic acid (EPA) has anti-inflammatory properties, and preliminary data suggest that it may be particularly efficacious in inflamed depression. In this study we tested the hypothesis that add-on EPA has greater antidepressant efficacy in MDD patients with high baseline high-sensitivity C-reactive protein (hs-CRP) compared to MDD patients with low hs-CRP. All subjects received 2.2 g EPA, 400 mg docosahexaenoic acid and 800 mg of other fatty acids daily for 8 weeks, added to stable ongoing antidepressant treatment. The primary outcome was change in the 17-item Hamilton Depression Rating Scale (HAMD-17). Patients and raters were blind to baseline hs-CRP status. In an intention-to-treat analysis including all subjects with at least one post baseline visit (n = 101), ahs-CRPcut-off of ≥1 mg/L, but not ≥3 mg/L, was associated with a greater improvement in HAMD-17 total score. In addition to a general antidepressant effect among patients with hs-CRP ≥ 1 mg/L, adjuvant EPA treatment improved symptoms putatively related to inflamed depression such as fatigue and sleep difficulties. This adds to the mounting evidence that delineation of MDD subgroups based on inflammation may be clinically relevant to predict treatment response to anti-inflammatory interventions.

Painful physical symptoms and antidepressant treatment outcome in depression: a systematic review and meta-analysis.

BACKGROUND: Painful physical symptoms (PPS) are highly prevalent in patients with major depressive disorder (MDD). Presence of PPS in depressed patients are potentially associated with poorer antidepressant treatment outcome. We aimed to evaluate the association of baseline pain levels and antidepressant treatment outcomes. METHODS: We searched PubMed, Embase and Cochrane Library databases from inception through February 2023 based on a pre-registered protocol (PROSPERO: CRD42022381349). We included original studies that reported pretreatment pain measures in antidepressant treatment responder/remitter and non-responder/non-remitter among patients with MDD. Data extraction and quality assessment were performed following the Preferred Reporting Items for Systematic Reviews and Meta-analyses by two reviewers independently. The primary outcome was the difference of the pretreatment pain levels between antidepressant treatment responder/remitter and non-responder/non-remitter. Random-effects meta-analysis was used to calculate effect sizes (Hedge's g) and subgroup and meta-regression analyses were used to explore sources of heterogeneity. RESULTS: A total of 20 studies were included. Six studies reported significantly higher baseline pain severity levels in MDD treatment non-responders (Hedge's g = 0.32; 95% CI, 0.13-0.51; P = 0.0008). Six studies reported the presence of PPS (measured using a pain severity scale) was significantly associated with poor treatment response (OR = 1.46; 95% CI, 1.04-2.04; P = 0.028). Five studies reported significant higher baseline pain interference levels in non-responders (Hedge's g = 0.46; 95% CI, 0.32-0.61; P < 0.0001). Four studies found significantly higher baseline pain severity levels in non-remitters (Hedge's g = 0.27; 95% CI, 0.14-0.40; P < 0.0001). Eight studies reported the presence of PPS significantly associated with treatment non-remission (OR = 1.70; 95% CI, 1.24-2.32; P = 0.0009). CONCLUSIONS: This study suggests that PPS are negatively associated with the antidepressant treatment outcome in patients with MDD. It is possible that better management in pain conditions when treating depression can benefit the therapeutic effects of antidepressant medication in depressed patients.

Quantification of follicles in human ovarian tissue using image processing software and trained artificial intelligence.

Cancer survival rates in prepubertal girls and young women have risen in recent decades due to increasingly efficient treatments. However, many such treatments are gonadotoxic, causing premature ovarian insufficiency (POI), loss of fertility and ovarian endocrine function. Implantation of donor ovarian tissue encapsulated in immune-isolating capsules is a promising method to restore physiological endocrine function without immunosuppression or risk of reintroducing cancer cells harbored by the tissue. The success of this approach is largely determined by follicle density (FD) in the implanted ovarian tissue, which is analyzed manually from histologic sections and necessitates specialized, time-consuming labor. To address this limitation, we developed a fully automated method to quantify FD that does not require additional coding. We first analyzed ovarian tissue from 12 human donors between 16 to 37 years old using semi-automated image processing with manual follicle annotation and then trained artificial intelligence program based on follicle identification and object classification. One operator manually analyzed 102 whole slide images (WSIs) from serial histologic sections. Of those, 77 images were assessed by a second manual operator, followed with an automated method utilizing artificial intelligence (AI). Of the 1181 follicles the control operator counted, the comparison operator counted 1178, and the AI counted 927 follicles with 80% of those being correctly identified as follicles. The three-stage AI pipeline finished 33% faster than manual annotation. Collectively, this report supports the use of artificial intelligence and automation to select tissue donors and grafts with the greatest FD to ensure graft longevity for POI treatment.

Effect of Camera Parallax Angle on the Accuracy of Static Contact Angle Measurements.

Measuring the contact angle at the solid/liquid/vapor triple point in sessile drop experiments is one of the most popular and simple ways to quantify the wettability of surfaces and determine the surface free energy. Despite decades of technical advancements in contact angle measurements, which allowed for improving the precision of sessile drop measurements below ±1°, an often overlooked source of experimental error in these measurements originates from the camera's parallax angle (PA) - the angle between the camera optical axis and the sample stage surface. Here, we quantified the systematic errors in the measurement of contact angles due to the acquisition of drop images at finite PA values by simulating sessile drop experiments in which synthetic drops were created using the Young-Laplace equation. The absolute contact angle error induced by imaging drops at nonzero PAs was found to increase as the true contact angle (TCA) deviates from 90° and resulted in an overestimation (underestimation) of the contact angle for drops having TCAs lower (higher) than 90°. The computed absolute contact angle error reaches values as high as -20° (+12.2°) for drops having a TCA of 175° (5°) when imaged with a PA of 10°, thus indicating the importance of considering the PA when accurately quantifying contact angles in sessile drop experiments. The shape and, by extension, volume of the sessile drop was also found to affect the magnitude of the absolute contact angle error as sessile drops with higher apex curvatures exhibited lower absolute error than those with lower curvatures at any given PA. The outcomes of this work provide guidelines for minimizing systematic errors in sessile drop measurements due to the collection of drop images at nonzero PAs.

Substitution of Met-38 to Ile in γ-synuclein found in two patients with amyotrophic lateral sclerosis induces aggregation into amyloid.

α-, ß-, and γ-Synuclein are intrinsically disordered proteins implicated in physiological processes in the nervous system of vertebrates. α-synuclein (αSyn) is the amyloidogenic protein associated with Parkinson's disease and certain other neurodegenerative disorders. Intensive research has focused on the mechanisms that cause αSyn to form amyloid structures, identifying its NAC region as being necessary and sufficient for amyloid assembly. Recent work has shown that a 7-residue sequence (P1) is necessary for αSyn amyloid formation. Although γ-synuclein (γSyn) is 55% identical in sequence to αSyn and its pathological deposits are also observed in association with neurodegenerative conditions, γSyn is resilient to amyloid formation in vitro. Here, we report a rare single nucleotide polymorphism (SNP) in the SNCG gene encoding γSyn, found in two patients with amyotrophic lateral sclerosis (ALS). The SNP results in the substitution of Met38 with Ile in the P1 region of the protein. These individuals also had a second, common and nonpathological, SNP in SNCG resulting in the substitution of Glu110 with Val. In vitro studies demonstrate that the Ile38 variant accelerates amyloid fibril assembly. Contrastingly, Val110 retards fibril assembly and mitigates the effect of Ile38. Substitution of residue 38 with Leu had little effect, while Val retards, and Ala increases the rate of amyloid formation. Ile38 γSyn also results in the formation of γSyn-containing inclusions in cells. The results show how a single point substitution can enhance amyloid formation of γSyn and highlight the P1 region in driving amyloid formation in another synuclein family member.

High throughput functional profiling of genes at intraocular pressure loci reveals distinct networks for glaucoma.

INTRODUCTION: Primary open angle glaucoma (POAG) is a leading cause of blindness globally. Characterized by progressive retinal ganglion cell degeneration, the precise pathogenesis remains unknown. Genome-wide association studies (GWAS) have uncovered many genetic variants associated with elevated intraocular pressure (IOP), one of the key risk factors for POAG. We aimed to identify genetic and morphological variation that can be attributed to trabecular meshwork cell (TMC) dysfunction and raised IOP in POAG. METHODS: 62 genes across 55 loci were knocked-out in a primary human TMC line. Each knockout group, including five non-targeting control groups, underwent single-cell RNA-sequencing (scRNA-seq) for differentially-expressed gene (DEG) analysis. Multiplexed fluorescence coupled with CellProfiler image analysis allowed for single-cell morphological profiling. RESULTS: Many gene knockouts invoked DEGs relating to matrix metalloproteinases and interferon-induced proteins. We have prioritized genes at four loci of interest to identify gene knockouts that may contribute to the pathogenesis of POAG, including ANGPTL2, LMX1B, CAV1, and KREMEN1. Three genetic networks of gene knockouts with similar transcriptomic profiles were identified, suggesting a synergistic function in trabecular meshwork cell physiology. TEK knockout caused significant upregulation of nuclear granularity on morphological analysis, while knockout of TRIOBP, TMCO1 and PLEKHA7 increased granularity and intensity of actin and the cell-membrane. CONCLUSION: High-throughput analysis of cellular structure and function through multiplex fluorescent single-cell analysis and scRNA-seq assays enabled the direct study of genetic perturbations at the single-cell resolution. This work provides a framework for investigating the role of genes in the pathogenesis of glaucoma and heterogenous diseases with a strong genetic basis.

Pharmacology of Veratrum californicum Alkaloids as Hedgehog Pathway Antagonists.

Veratrum californicum contains steroidal alkaloids that function as inhibitors of hedgehog (Hh) signaling, a pathway involved in the growth and differentiation of cells and normal tissue development. This same Hh pathway is abnormally active for cell proliferation in more than 20 types of cancer. In this current study, alkaloids have been extracted from the root and rhizome of V. californicum, followed by their separation into five fractions using high performance liquid chromatography. Mass spectrometry was used to identify the presence of twenty-five alkaloids, nine more than are commonly cited in literature reports, and the Bruker Compass Data Analysis software was used to predict the molecular formula for every detected alkaloid. The Gli activity of the raw extract and each fraction were compared to 0.1 µM cyclopamine, and fractions 1, 2, and 4 showed increased bioactivity through suppression of the Hh signaling pathway. Fractions 2 and 4 had enhanced bioactivity, but fraction 1 was most effective in inhibiting Hh signaling. The composition of fraction 1 consisted of veratrosine, cycloposine, and potential isomers of each.

SVR Chemometrics to Quantify ß-Lactoglobulin and α-Lactalbumin in Milk Using MIR.

Protein content variation in milk can impact the quality and consistency of dairy products, necessitating access to in-line real time monitoring. Here, we present a chemometric approach for the qualitative and quantitative monitoring of ß-lactoglobulin and α-lactalbumin, using mid-infrared spectroscopy (MIR). In this study, we employed Hotelling T2 and Q-residual for outlier detection, automated preprocessing using nippy, conducted wavenumber selection with genetic algorithms, and evaluated four chemometric models, including partial least squares, support vector regression (SVR), ridge, and logistic regression to accurately predict the concentrations of ß-lactoglobulin and α-lactalbumin in milk. For the quantitative analysis of these two whey proteins, SVR performed the best to interpret protein concentration from 197 MIR spectra originating from 42 Cornell University samples of preserved pasteurized modified milk. The R2 values obtained for ß-lactoglobulin and α-lactalbumin using leave one out cross-validation (LOOCV) are 92.8% and 92.7%, respectively, which is the highest correlation reported to date. Our approach introduced a combination of preprocessing automation, genetic algorithm-based wavenumber selection, and used Optuna to optimize the framework for tuning hyperparameters of the chemometric models, resulting in the best chemometric analysis of MIR data to quantitate ß-lactoglobulin and α-lactalbumin to date.

Circulating cell-free mitochondrial DNA levels and glucocorticoid sensitivity in a cohort of male veterans with and without combat-related PTSD.

Circulating cell-free mitochondrial DNA (ccf-mtDNA) is a biomarker of cellular injury or cellular stress and is a potential novel biomarker of psychological stress and of various brain, somatic, and psychiatric disorders. No studies have yet analyzed ccf-mtDNA levels in post-traumatic stress disorder (PTSD), despite evidence of mitochondrial dysfunction in this condition. In the current study, we compared plasma ccf-mtDNA levels in combat trauma-exposed male veterans with PTSD (n = 111) with those who did not develop PTSD (n = 121) and also investigated the relationship between ccf mt-DNA levels and glucocorticoid sensitivity. In unadjusted analyses, ccf-mtDNA levels did not differ significantly between the PTSD and non-PTSD groups (t = 1.312, p = 0.191, Cohen's d = 0.172). In a sensitivity analysis excluding participants with diabetes and those using antidepressant medication and controlling for age, the PTSD group had lower ccf-mtDNA levels than did the non-PTSD group (F(1, 179) = 5.971, p = 0.016, partial η2 = 0.033). Across the entire sample, ccf-mtDNA levels were negatively correlated with post-dexamethasone adrenocorticotropic hormone (ACTH) decline (r = -0.171, p = 0.020) and cortisol decline (r = -0.149, p = 0.034) (viz., greater ACTH and cortisol suppression was associated with lower ccf-mtDNA levels) both with and without controlling for age, antidepressant status and diabetes status. Ccf-mtDNA levels were also significantly positively associated with IC50-DEX (the concentration of dexamethasone at which 50% of lysozyme activity is inhibited), a measure of lymphocyte glucocorticoid sensitivity, after controlling for age, antidepressant status, and diabetes status (ß = 0.142, p = 0.038), suggesting that increased lymphocyte glucocorticoid sensitivity is associated with lower ccf-mtDNA levels. Although no overall group differences were found in unadjusted analyses, excluding subjects with diabetes and those taking antidepressants, which may affect ccf-mtDNA levels, as well as controlling for age, revealed decreased ccf-mtDNA levels in PTSD. In both adjusted and unadjusted analyses, low ccf-mtDNA levels were associated with relatively increased glucocorticoid sensitivity, often reported in PTSD, suggesting a link between mitochondrial and glucocorticoid-related abnormalities in PTSD.

Identifying the real-world challenges of dysplasia surveillance in inflammatory bowel disease: a retrospective cohort study in a tertiary health network.

BACKGROUND: Dysplasia surveillance in inflammatory bowel disease (IBD) is often suboptimal and deviates from guidelines. AIMS: To assess dysplasia surveillance behaviours and adherence to guidelines amongst a large tertiary teaching health network with a specialised IBD unit to identify areas where dysplasia surveillance could be improved. METHODS: A retrospective audit of IBD surveillance colonoscopy practice over an 18-month period was performed using the Provation Endoscopy Database and the hospital's primary sclerosing cholangitis database. RESULTS: The audit identified 115 dysplasia surveillance colonoscopies. A total of 37% of index dysplasia colonoscopies were outside recommended guidelines. A total of 10% had inadequate bowel preparation and only 40% had excellent bowel preparation. A total of 28% of patients underwent dye-based chromoendoscopy and 69% underwent high-definition white-light endoscopy. Dye chromoendoscopy was more likely to be used by IBD specialists than interventional endoscopists (P = 0.008) and other endoscopists (P = 0.004). Only IBD specialists and interventional endoscopists used dye chromoendoscopy. Dysplasia or colorectal cancer was detected in 3.4% of the colonoscopies. Overall, the several dysplasia examinations were lower than expected. CONCLUSIONS: Dysplasia surveillance in the IBD population remains an area of improvement given the current national guidelines. IBD specialists are more likely to perform dye chromoendoscopy than other endoscopists/gastroenterologists. Dysplasia rates in this real-world contemporary setting are less than expected in historical studies and may represent improvements in IBD management principles and medications.

The landscape of genomic structural variation in Indigenous Australians.

Indigenous Australians harbour rich and unique genomic diversity. However, Aboriginal and Torres Strait Islander ancestries are historically under-represented in genomics research and almost completely missing from reference datasets1-3. Addressing this representation gap is critical, both to advance our understanding of global human genomic diversity and as a prerequisite for ensuring equitable outcomes in genomic medicine. Here we apply population-scale whole-genome long-read sequencing4 to profile genomic structural variation across four remote Indigenous communities. We uncover an abundance of large insertion-deletion variants (20-49 bp; n = 136,797), structural variants (50 b-50 kb; n = 159,912) and regions of variable copy number (>50 kb; n = 156). The majority of variants are composed of tandem repeat or interspersed mobile element sequences (up to 90%) and have not been previously annotated (up to 62%). A large fraction of structural variants appear to be exclusive to Indigenous Australians (12% lower-bound estimate) and most of these are found in only a single community, underscoring the need for broad and deep sampling to achieve a comprehensive catalogue of genomic structural variation across the Australian continent. Finally, we explore short tandem repeats throughout the genome to characterize allelic diversity at 50 known disease loci5, uncover hundreds of novel repeat expansion sites within protein-coding genes, and identify unique patterns of diversity and constraint among short tandem repeat sequences. Our study sheds new light on the dimensions and dynamics of genomic structural variation within and beyond Australia.

Using collective intelligence methods to improve government data infrastructures and promote the use of complex data: The example of the Northern Ireland Longitudinal Study.

BACKGROUND: This paper discusses how collective intelligence (CI) methods can be implemented to improve government data infrastructures, not only to support understanding and primary use of complex national data but also to increase the dissemination and secondary impact of research based on these data. The case study uses the Northern Ireland Longitudinal Study (NILS), a member of the UK family of census/administrative data longitudinal studies (UKLS). METHODS: A stakeholder-engaged CI approach was applied to inform the transformation of the NILS Research Support Unit (RSU) infrastructure to support researchers in their use of government data, including collaborative decision-making and better dissemination of research outputs. RESULTS: We provide an overview of NILS RSU infrastructure design changes that have been implemented to date, focusing on a website redesign to meet user information requirements and the formation of better working partnerships between data users and providers within the Northern Ireland data landscape. We also discuss the key challenges faced by the design team during this project of transformation. CONCLUSION: Our primary objective to improve government data infrastructure and to increase dissemination and the impact of research based on data was a complex and multifaceted challenge due to the number of stakeholders involved and their often conflicting perspectives. Results from this CI approach have been pivotal in highlighting how NILS RSU can work collaboratively with users to maximize the potential of this data, in terms of forming multidisciplinary networks to ensure the research is utilized in policy and in the literature and providing academic support and resources to attract new researchers.