Chronic opioid usage not only causes addiction behavior through the central nervous system, but also modulates the peripheral immune system. However, how opioid impacts the immune system is still ...barely characterized systematically. In order to understand the immune modulatory effect of opioids in an unbiased way, here we perform single-cell RNA sequencing (scRNA-seq) of peripheral blood mononuclear cells from opioid-dependent individuals and controls to show that chronic opioid usage evokes widespread suppression of antiviral gene program in naive monocytes, as well as in multiple immune cell types upon stimulation with the pathogen component lipopolysaccharide. Furthermore, scRNA-seq reveals the same phenomenon after a short in vitro morphine treatment. These findings indicate that both acute and chronic opioid exposure may be harmful to our immune system by suppressing the antiviral gene program. Our results suggest that further characterization of the immune modulatory effects of opioid is critical to ensure the safety of clinical opioids.
We report a genome-wide association study for open-angle glaucoma (OAG) blindness using a discovery cohort of 590 individuals with severe visual field loss (cases) and 3,956 controls. We identified ...associated loci at TMCO1 (rs4656461G odds ratio (OR) = 1.68, P = 6.1 × 10(-10)) and CDKN2B-AS1 (rs4977756A OR = 1.50, P = 4.7 × 10(-9)). We replicated these associations in an independent cohort of cases with advanced OAG (rs4656461 P = 0.010; rs4977756 P = 0.042) and two additional cohorts of less severe OAG (rs4656461 combined discovery and replication P = 6.00 × 10(-14), OR = 1.51, 95% CI 1.35-1.68; rs4977756 combined P = 1.35 × 10(-14), OR = 1.39, 95% CI 1.28-1.51). We show retinal expression of genes at both loci in human ocular tissues. We also show that CDKN2A and CDKN2B are upregulated in the retina of a rat model of glaucoma.
It is common practice in genome-wide association studies (GWAS) to focus on the relationship between disease risk and genetic variants one marker at a time. When relevant genes are identified it is ...often possible to implicate biological intermediates and pathways likely to be involved in disease aetiology. However, single genetic variants typically explain small amounts of disease risk. Our idea is to construct allelic scores that explain greater proportions of the variance in biological intermediates, and subsequently use these scores to data mine GWAS. To investigate the approach's properties, we indexed three biological intermediates where the results of large GWAS meta-analyses were available: body mass index, C-reactive protein and low density lipoprotein levels. We generated allelic scores in the Avon Longitudinal Study of Parents and Children, and in publicly available data from the first Wellcome Trust Case Control Consortium. We compared the explanatory ability of allelic scores in terms of their capacity to proxy for the intermediate of interest, and the extent to which they associated with disease. We found that allelic scores derived from known variants and allelic scores derived from hundreds of thousands of genetic markers explained significant portions of the variance in biological intermediates of interest, and many of these scores showed expected correlations with disease. Genome-wide allelic scores however tended to lack specificity suggesting that they should be used with caution and perhaps only to proxy biological intermediates for which there are no known individual variants. Power calculations confirm the feasibility of extending our strategy to the analysis of tens of thousands of molecular phenotypes in large genome-wide meta-analyses. We conclude that our method represents a simple way in which potentially tens of thousands of molecular phenotypes could be screened for causal relationships with disease without having to expensively measure these variables in individual disease collections.
Abstract
Prostate-specific membrane antigen (PSMA) positron emission tomography (PET)/computed tomography (CT) is a molecular and functional imaging modality with better restaging accuracy over ...conventional imaging for detecting prostate cancer in men suspected of lymph node (LN) progression after definitive therapy. However, the availability of PSMA PET/CT is limited in both low-resource settings and for repeating imaging surveillance. In contrast, CT is widely available, cost-effective, and routinely performed as part of patient follow-up or radiotherapy workflow. Compared with the molecular activities, the morphological and texture changes of subclinical LNs in CT are subtle, making manual detection of positive LNs infeasible. Instead, we harness the power of artificial intelligence for automated LN detection on CT. We examined
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Ga-PSMA-11 PET/CT images from 88 patients (including 739 PSMA PET/CT-positive pelvic LNs) who experienced a biochemical recurrence after radical prostatectomy and presented for salvage radiotherapy with prostate-specific antigen < 1 ng/mL. Scans were divided into a training set (nPatient = 52, nNode = 400), a validation set (nPatient = 18, nNode = 143), and a test set (nPatient = 18, nNodes = 196). Using PSMA PET/CT as the ground truth and consensus pelvic LN clinical target volumes as search regions, a 2.5-dimensional (2.5D) Mask R-CNN based object detection framework was trained. The entire framework contained whole slice imaging pretraining, masked-out region fine-tuning, prediction post-processing, and “window bagging”. Following an additional preprocessing step—pelvic LN clinical target volume extraction, our pipeline located positive pelvic LNs solely based on CT scans. Our pipeline could achieve a sensitivity of 83.351%, specificity of 58.621% out of 196 positive pelvic LNs from 18 patients in the test set, of which most of the false positives can be post-removable by radiologists. Our tool may aid CT-based detection of pelvic LN metastasis and triage patients most unlikely to benefit from the PSMA PET/CT scan.
Coordination-induced desolvation or ligand displacement by cosolvents and additives is a key feature responsible for the reactivity of Sm(II)-based reagent systems. High-affinity proton donor ...cosolvents such as water and glycols also demonstrate coordination-induced bond weakening of the O–H bond, facilitating reduction of a broad range of substrates. In the present work, the coordination of ammonia to SmI2 was examined using Born–Oppenheimer molecular dynamics simulations and mechanistic studies, and the SmI2-ammonia system is compared to the SmI2-water system. The coordination number and reactivity of the SmI2-ammonia solvent system were found to be similar to those of SmI2-water but exhibited an order of magnitude greater rate of arene reduction by SmI2-ammonia than by SmI2-water at the same concentrations of cosolvent. In addition, upon coordination of ammonia to SmI2, the Sm(II)-ammonia solvate demonstrates one of the largest degrees of N–H bond weakening reported in the literature compared to known low-valent transition metal ammonia complexes.
We conducted a genome-wide association meta-analysis of 4,604 endometriosis cases and 9,393 controls of Japanese and European ancestry. We show that rs12700667 on chromosome 7p15.2, previously found ...to associate with disease in Europeans, replicates in Japanese (P = 3.6 × 10(-3)), and we confirm association of rs7521902 at 1p36.12 near WNT4. In addition, we establish an association of rs13394619 in GREB1 at 2p25.1 with endometriosis and identify a newly associated locus at 12q22 near VEZT (rs10859871). Excluding cases of European ancestry of minimal or unknown severity, we identified additional previously unknown loci at 2p14 (rs4141819), 6p22.3 (rs7739264) and 9p21.3 (rs1537377). All seven SNP effects were replicated in an independent cohort and associated at P <5 × 10(-8) in a combined analysis. Finally, we found a significant overlap in polygenic risk for endometriosis between the genome-wide association cohorts of European and Japanese descent (P = 8.8 × 10(-11)), indicating that many weakly associated SNPs represent true endometriosis risk loci and that risk prediction and future targeted disease therapy may be transferred across these populations.
Contemporary mortality data for myectomy are well known to experts in dedicated HCM centers but may not have penetrated sufficiently into the practicing general cardiology community. ...this is an ...opportune time to tabulate the most recent operative mortality data from 5 major high-volume HCM myectomy centers in North America (Table 1). ...perceptions of HCM and myectomy have been contaminated by older obsolete published reports skewed to a grim portrayal of outcome, including high operative mortality (1,2). ...a contemporary understanding of the safety (and efficacy) (1,2) attributable to myectomy is crucial to assessing the role of surgery in the management armamentarium for this disease.
Purpose The purpose of this study was to systematically evaluate the technique and tests used in the physical examination of the adult hip performed by multiple clinicians who regularly treat ...patients with hip problems and identify common physical examination patterns. Methods The subjects included 5 men and 6 women with a mean age (±SD) of 29.8 ± 9.4 years. They underwent physical examination of the hip by 6 hip specialists with a strong interest in hip-related problems. All examiners were blind to patient radiographs and diagnoses. Patient examinations were video recorded and reviewed. Results It was determined that 18 tests were most frequently performed (≥40%) by the examiners, 3 standing, 11 supine, 3 lateral, and 1 prone. Of the most frequently performed tests, 10 were performed more than 50% of the time. The tests performed in the supine position were as follows: flexion range of motion (ROM) (percentage of use, 98%), flexion internal rotation ROM (98%), flexion external rotation ROM (86%), passive supine rotation test (76%), flexion/adduction/internal rotation test (70%), straight leg raise against resistance test (61%), and flexion/abduction/external rotation test (52%). The tests performed in the standing position were the gait test (86%) and the single-leg stance phase test (77%). The 1 test in the prone position was the femoral anteversion test (58%). Conclusions There are variations in the testing that hip specialists perform to examine and evaluate their patients, but there is enough commonality to form the basis to recommend a battery of physical examination maneuvers that should be considered for use in evaluating the hip. Clinical Relevance Patients presenting with groin, abdominal, back, and/or hip pain need to have a basic examination to ensure that the hip is not overlooked. A comprehensive physical examination of the hip will benefit the patient and the physician and serve as the foundation for future multicenter clinical studies.
The Diagnostic and Statistical Manual of Mental Disorders (DSM; 5th ed.) reassignment of gambling disorder as an addictive disorder alongside the substance-related addictive disorders encourages ...research into their shared etiologies. The aims of this study were to examine: (a) the associations of Big Five personality dimensions with alcohol, nicotine, cannabis, and gambling disorders, (b) the comorbidity between these disorders, (c) the extent to which common personality underpinnings explain comorbidity, (d) whether results differed for men and women, and (e) the magnitude of personality differences corresponding to the 4 disorders. Participants were 3,785 twins and siblings (1,365 men, 2,420 women; Mage = 32 years, range = 21-46 years) from the Australian Twin Registry who completed psychiatric interviews and Big Five personality inventories. The personality profile of high neuroticism, low agreeableness, and low conscientiousness was associated with all 4 addictive disorders. All but 1 of the pairwise associations between the disorders were significant. After accounting for Big Five traits, the associations were attenuated to varying degrees but remained significant. The results were generally similar for men and women. The results suggest that the Big Five traits of neuroticism, agreeableness, and conscientiousness are associated with the general propensity to develop an addictive disorder and may in part explain their co-occurrence; however, they may be more broadly associated with the propensity for any psychiatric disorder. The effect sizes of the personality associations suggest that the diagnosis of gambling disorder as operationalized by the DSM may be more severe than the other addictive disorders. Calibration of the diagnosis of gambling disorder to the other addictive disorders may be warranted.
The bidirectional relationship between depression and chronic pain is well-recognized, but their clinical management remains challenging. Here we characterize the shared risk factors and outcomes for ...their comorbidity in the Australian Genetics of Depression cohort study (
= 13,839). Participants completed online questionnaires about chronic pain, psychiatric symptoms, comorbidities, treatment response and general health. Logistic regression models were used to examine the relationship between chronic pain and clinical and demographic factors. Cumulative linked logistic regressions assessed the effect of chronic pain on treatment response for 10 different antidepressants. Chronic pain was associated with an increased risk of depression (OR = 1.86 1.37-2.54), recent suicide attempt (OR = 1.88 1.14-3.09), higher use of tobacco (OR = 1.05 1.02-1.09) and misuse of painkillers (e.g., opioids; OR = 1.31 1.06-1.62). Participants with comorbid chronic pain and depression reported fewer functional benefits from antidepressant use and lower benefits from sertraline (OR = 0.75 0.68-0.83), escitalopram (OR = 0.75 0.67-0.85) and venlafaxine (OR = 0.78 0.68-0.88) when compared to participants without chronic pain. Furthermore, participants taking sertraline (OR = 0.45 0.30-0.67), escitalopram (OR = 0.45 0.27-0.74) and citalopram (OR = 0.32 0.15-0.67) specifically for chronic pain (among other indications) reported lower benefits compared to other participants taking these same medications but not for chronic pain. These findings reveal novel insights into the complex relationship between chronic pain and depression. Treatment response analyses indicate differential effectiveness between particular antidepressants and poorer functional outcomes for these comorbid conditions. Further examination is warranted in targeted interventional clinical trials, which also include neuroimaging genetics and pharmacogenomics protocols. This work will advance the delineation of disease risk indicators and novel aetiological pathways for therapeutic intervention in comorbid pain and depression as well as other psychiatric comorbidities.
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