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Traumatic brain injury (TBI) is one of the foremost causes of disability and mortality globally. While the scientific and medical emphasis is to save lives and avoid disability during acute period of injury, a severe health problem can manifest years after injury. For instance, TBI increases the risk of cognitive impairment in the elderly. Remote TBI history was reported to be a cause of the accelerated clinical trajectory of Alzheimer’s disease-related dementia (ADRD) resulting in earlier onset of cognitive impairment and increased AD-associated pathological markers like greater amyloid deposition and cortical thinning. It is not well understood whether a single TBI event may increase the risk of dementia. Moreover, the cellular signaling pathways remain elusive for the chronic effects of TBI on cognition. We have hypothesized that a single TBI induces sustained neuroinflammation and disrupts cellular communication in a way that results later in ADRD pathology. To test this, we induced TBI in young adult CD1 mice and assessed the behavioral outcomes after 11 months followed by pathological, histological, transcriptomic, and MRI assessment. On MRI scans, these mice showed significant loss of tissue, reduced CBF, and higher white matter injury compared to sham mice. We found these brains showed progressive atrophy, markers of ADRD, sustained astrogliosis, loss of neuronal plasticity, and growth factors even after 1-year post-TBI. Because of progressive neurodegeneration, these mice had motor deficits, showed cognitive impairments, and wandered randomly in open field. We, therefore, conclude that progressive pathology after adulthood TBI leads to neurodegenerative conditions such as ADRD and impairs neuronal functions.

Cannabis use disorder (CanUD) has increased with the legalization of the use of cannabis. Around 20% of individuals using cannabis develop CanUD, and the number of users has grown with increasing ease of access. CanUD and other substance use disorders (SUDs) are associated phenotypically and genetically. We leveraged new CanUD genomics data to undertake genetically-informed analyses with unprecedented power, to investigate the genetic architecture and causal relationships between CanUD and lifetime cannabis use with risk for developing SUDs and substance use traits. Analyses included calculating local and global genetic correlations, genomic structural equation modeling (genomicSEM), and Mendelian Randomization (MR). Results from the genetic correlation and genomicSEM analyses demonstrated that CanUD and cannabis use differ in their relationships with SUDs and substance use traits. We found significant causal effects of CanUD influencing all the analyzed traits: opioid use disorder (OUD) (Inverse variant weighted, IVW β= 0.925 ± 0.082), problematic alcohol use (PAU) (IVW β= 0.443 ± 0.030), drinks per week (DPW) (IVW β= 0.182 ± 0.025), Fagerström Test for Nicotine Dependence (FTND) (IVW β= 0.183 ± 0.052), cigarettes per day (IVW β= 0.150 ± 0.045), current versus former smokers (IVW β= 0.178 ± 0.052), and smoking initiation (IVW β= 0.405 ± 0.042). We also found evidence of bidirectionality showing that OUD, PAU, smoking initiation, smoking cessation, and DPW all increase risk of developing CanUD. For cannabis use, bidirectional relationships were inferred with PAU, smoking initiation, and DPW; cannabis use was also associated with a higher risk of developing OUD (IVW β= 0.785 ± 0.266). GenomicSEM confirmed that CanUD and cannabis use load onto different genetic factors. We conclude that CanUD and cannabis use can increase the risk of developing other SUDs. This has substantial public health implications; the move towards legalization of cannabis use may be expected to increase other kinds of problematic substance use. These harmful outcomes are in addition to the medical harms associated directly with CanUD.

Individuals suffering from chronic pain develop substance use disorders (SUDs) more often than others. Understanding the shared genetic influences underlying the comorbidity between chronic pain and SUDs will lead to a greater understanding of their biology. Genome-wide association statistics were obtained from the UK Biobank for multisite chronic pain (MCP, Neffective= 387,649) and from the Million Veteran Program and the Psychiatric Genomics Consortium meta-analyses for alcohol use disorder (AUD, Neffective= 296,974), cannabis use disorder (CanUD, Neffective= 161,053), opioid use disorder (OUD, Neffective= 57,120), and problematic tobacco use (PTU, Neffective= 270,120). SNP-based heritability was estimated for each of the traits and genetic correlation (rg) analyses were performed to assess MCP-SUD pleiotropy. Bidirectional Mendelian Randomization analyses evaluated possible causal relationships. Finally, to identify and characterize individual loci, we performed a genome-wide pleiotropy analysis and a brain-wide analysis using imaging phenotypes available from the UK Biobank. MCP was positively genetically correlated with AUD (rg= 0.26, p= 7.55 × 10−18), CanUD (rg= 0.37, p= 8.21 × 10−37), OUD (rg= 0.20, p= 1.50 × 10−3), and PTU (rg= 0.29, p= 8.53 × 10−12). Although the MR analyses supported bi-directional relationships, MCP had larger effects on AUD (pain-exposure: beta = 0.18, p= 8.21 × 10−4; pain-outcome: beta = 0.07, p= 0.018), CanUD (pain-exposure: beta = 0.58, p= 2.70 × 10−6; pain-outcome: beta = 0.05, p= 0.014) and PTU (pain-exposure: beta = 0.43, p= 4.16 × 10−8; pain-outcome: beta = 0.09, p= 3.05 × 10−6) than the reverse. The genome-wide analysis identified two SNPs pleiotropic between MCP and all SUD investigated: IHO1rs7652746 (ppleiotropy= 2.69 × 10−8), and CADM2rs1248857 (ppleiotropy= 1.98 × 10−5). In the brain-wide analysis, rs7652746 was associated with multiple cerebellum and amygdala imaging phenotypes. When analyzing MCP pleiotropy with each SUD separately, we found 25, 22, and 4 pleiotropic variants for AUD, CanUD, and OUD, respectively. To our knowledge, this is the first large-scale study to provide evidence of potential causal relationships and shared genetic mechanisms underlying MCP-SUD comorbidity.

Two themes are coming to the forefront in this decade: Cognitive impairment of an aging population and the quantum leap in developing artificial intelligence (AI). Both can be described as growing exponentially and presenting serious challenges. Although many questions have been addressed about the dangers of AI, we want to go beyond the fearful aspects of this topic and focus on the possible contribution of AI to solve the problem of chronic disorders of the elderly leading to cognitive impairment, like Alzheimer’s disease, Parkinson’s disease, and Lewy body dementia. Our second goal is to look at the ways in which modern neuroscience can influence the future design of computers and the development of AI. We wish to honor the memory of Dr. John von Neumann, who came up with many breakthrough details of the first electronic computer. Remarkably, Dr. von Neumann dedicated his last book to the comparison of the human brain and the computer as it stood in those years of the mid-1950s. We will point out how his ideas are more relevant than ever in the age of supercomputers, AI and brain implants.

DNA is damaged through various exogenous sources (e.g., automobile exhaust, tobacco smoke, and processed foods), which can yield diverse C8-dG bulky aryl adducts. Adducts are known to induce structural changes to DNA that can lead to various biological outcomes, ranging from cell death to diseases such as cancer. Unfortunately, the relationship between the chemical composition of the damaged product, the adducted DNA structure, and the biological consequences is not well understood, which limits the development of disease detection and prevention strategies. The present study uses density functional theory (DFT) calculations and quintuplicate 1 μs molecular dynamics (MD) simulations to characterize the structure of DNA containing 21 model C8-dG adducts that systematically differ in size (phenyl to pyrenyl), shape (α (2,3), β (3,4) fusion, or ring substitution), and nucleobase–aryl group linkage (N, O, and C-linked). DFT calculations reveal that the inherent structural features of the G nucleobase adducts are impacted by linker type and bulky moiety shape, but not size, with the conformational flexibility reducing with α-ring fusion and linker composition as N > O > C. These structural properties are maintained in nucleoside models, which also reveal an increased propensity for anti-to-synrotation about the glycosidic bond with N < O < C linker type. Although these diverse chemical features do not influence the global structure of adducted DNA, the adducts differentially impact the conformation local to the adducted site, including the relative populations of structures with the bulky moiety in the major groove (B conformer) and intercalated (stacked) into the helix (S conformer). Specifically, while the smallest phenyl adducts favor the B conformation and the largest pyrenyl-derived adducts stabilize the S conformation, the B/S ratio decreases with an increase in ring size and N > O > C linker composition. The shape and size (length) of the adduct can further finetune the B/S ratio, with β-fused naphthyl or α-fused phenanthryl N-linked adducts and O or C-linked adducts containing ring substitution increasing the prevalence of the S adducted DNA conformation. Overall, this work uncovers the significant effect of bulky moiety size and linker type, as well as the lesser impact of aryl group shape, on adducted DNA structure, which suggests differential replication and repair outcomes, and thereby represents an important step toward rationalizing connections between the structure and biological consequences of diverse DNA adducts.

This paper presents the first nationwide analysis detailing the scope and scale of labor-intensive forestry contracts performed on National Forest System lands and examines the businesses contracted, location and types of work performed, and distance traveled by businesses between 2001 and 2020. During the study period, 61,698 contracts were awarded to 7,896 businesses, totaling $12.9 billion, to perform labor-intensive forestry work, with most work being contracted for wildfire-related activities. Businesses were typically located in western states and non-minority owned businesses received the majority of contracts. Of minority-owned businesses, Hispanic American–owned businesses received the most contracts. The median distance that businesses traveled to accomplish work increased significantly through time but differed by business type. Understanding the scope and work of businesses awarded contracts provides insight into the workforce and its relationship to marginalized populations. Strategic investment in this workforce may have widespread impacts on federal, state, and local economies and the livelihoods of forest workers.Study Implications: Between 2001–2020, the USDA Forest Service spent billions of dollars on contracts with thousands of businesses to conduct labor-intensive forestry projects; however, project locations and awarded businesses were not evenly distributed through space and time. Emerging and minority businesses represented a small proportion of contracts awarded. Advancing understanding of the businesses conducting labor-intensive forestry work lays the foundation for inquiry into the working conditions forest workers experience as well as disparities in contract capture. Some regions may have benefitted more from contract capture than others. Understanding factors enabling places and businesses to capture these contract dollars may help identify others that may benefit from investment.

Objectives: To assess the agreement in evaluating optical coherence tomography (OCT) variables in the leading macular diseases such as neovascular age-related macular degeneration (nAMD), diabetic macular oedema (DMO) and retinal vein occlusion (RVO) among OCT-certified graders. Methods: SD-OCT volume scans of 356 eyes were graded by seven graders. The grading included presence of intra- and subretinal fluid (IRF, SRF), pigment epithelial detachment (PED), epiretinal membrane (ERM), conditions of the vitreomacular interface (VMI), central retinal thickness (CRT) at the foveal centre-point (CP) and central millimetre (CMM), as well as height and location of IRF/SRF/PED. Kappa statistics (κ) and intraclass correlation coefficient (ICC) were used to report categorical grading and measurement agreement. Results: The overall agreement on the presence of IRF/SRF/PED was κ = 0.82/0.85/0.81; κ of VMI condition was 0.77, that of ERM presence 0.37. ICC for CRT measurements at CP and CMM was excellent with an ICC of 1.00. Height measurements of IRF/SRF/PED showed robust consistency with ICC = 0.85–0.93. There was substantial to almost perfect agreement in locating IRF/SRF/PED with κ = 0.67–0.86. Between diseases, κ of IRF/SRF presence was 0.69/0.80 for nAMD, 0.64/0.83 for DMO and 0.86/0.89 for RVO. Conclusion: Even in the optimized setting, featuring certified graders, standardized image acquisition and the use of a professional reading platform, there is a disease dependent variability in biomarker evaluation that is most pronounced for IRF in nAMD as well as DMO. Our findings highlight the variability in the performance of human expert OCT grading and the need for AI-based automated feature analyses.

The paper first raised questions about the extraterritoriality issue on digital advertising services’ taxation. Moreover, it addresses the application of a sales tax with progressive rates for these services. The paper emphasizes that linking sales taxes and tax progression is doubtful. In cross-border cases, justification problems may restrict fundamental EU freedoms and effectuate the issue of discrimination against those multinationals that provide services like publishing ads over the internet in Hungarian consumer markets. Notably, the EU judicial authorities have acted in a formalistic manner. Specifically, they have matched the existing EU rules and principles with the advertising tax case without further consideration. Consequently, the Member States’ legislative objective of redistribution, which refers to the ability to pay, was not reviewed on its merits. While the government is seeking to hone the Hungarian advertising tax from 2023, the question is how long it will remain in force due to the international two-pillar agreement finalized by the OECD. The Hungarian tax has passed many tests, but the respective legal construction has remained unsecured and has not been intact from further challenges.

The paper first raised questions about the extraterritoriality issue on digital advertising services’ taxation. Moreover, it addresses the application of a sales tax with progressive rates for these services. The paper emphasizes that linking sales taxes and tax progression is doubtful. In cross-border cases, justification problems may restrict fundamental EU freedoms and effectuate the issue of discrimination against those multinationals that provide services like publishing ads over the internet in Hungarian consumer markets. Notably, the EU judicial authorities have acted in a formalistic manner. Specifically, they have matched the existing EU rules and principles with the advertising tax case without further consideration. Consequently, the Member States’ legislative objective of redistribution, which refers to the ability to pay, was not reviewed on its merits. While the government is seeking to hone the Hungarian advertising tax from 2023, the question is how long it will remain in force due to the international two-pillar agreement finalized by the OECD. The Hungarian tax has passed many tests, but the respective legal construction has remained unsecured and has not been intact from further challenges.

As recreational use of cannabis is being decriminalized in many places and medical use widely sanctioned, there are growing concerns about increases in cannabis use disorder (CanUD), which is associated with numerous medical comorbidities. Here we performed a genome-wide association study of CanUD in the Million Veteran Program (MVP), followed by meta-analysis in 1,054,365 individuals (ncases= 64,314) from four broad ancestries designated by the reference panel used for assignment (European n= 886,025, African n= 123,208, admixed American n= 38,289 and East Asian n= 6,843). Population-specific methods were applied to calculate single nucleotide polymorphism-based heritability within each ancestry. Statistically significant single nucleotide polymorphism-based heritability for CanUD was observed in all but the smallest population (East Asian). We discovered genome-wide significant loci unique to each ancestry: 22 in European, 2 each in African and East Asian, and 1 in admixed American ancestries. A genetically informed causal relationship analysis indicated a possible effect of genetic liability for CanUD on lung cancer risk, suggesting potential unanticipated future medical and psychiatric public health consequences that require further study to disentangle from other known risk factors such as cigarette smoking.

Purpose: To evaluate the reliability of automated fluid detection in identifying retinal fluid activity in OCT scans of patients treated with anti-VEGF therapy for neovascular age-related macular degeneration by correlating human expert and automated measurements with central retinal subfield thickness (CSFT) and fluid volume values. Methods: We utilized an automated deep learning approach to quantify macular fluid in SD-OCT volumes (Cirrus, Spectralis, Topcon) from patients of HAWK and HARRIER Studies. Three-dimensional volumes for IRF and SRF were measured at baseline and under therapy in the central millimeter and compared to fluid gradings, CSFT and foveal centerpoint thickness (CPT) values measured by the Vienna Reading Center. Results: 41.906 SD-OCT volume scans were included into the analysis. Concordance between human expert grading and automated algorithm performance reached AUC values of 0.93/0.85 for IRF and 0.87 for SRF in HARRIER/HAWK in the central millimeter. IRF volumes showed a moderate correlation with CSFT at baseline (HAWK: r = 0.54; HARRIER: r = 0.62) and weaker correlation under therapy (HAWK: r = 0.44; HARRIER: r = 0.34). SRF and CSFT correlations were low at baseline (HAWK: r = 0.29; HARRIER: r = 0.22) and under therapy (HAWK: r = 0.38; HARRIER: r = 0.45). The residual standard error (IRF: 75.90 µm; SRF: 95.26 µm) and marginal residual standard deviations (IRF: 46.35 µm; SRF: 44.19 µm) of fluid volume were high compared to the range of CSFT values. Conclusion: Deep learning-based segmentation of retinal fluid performs reliably on OCT images. CSFT values are weak indicators for fluid activity in nAMD. Automated quantification of fluid types, highlight the potential of deep learning-based approaches to objectively monitor anti-VEGF therapy.

Background/aimsTo establish a consensus in the nomenclature for reporting optical coherence tomography angiography (OCTA findings in uveitis.MethodsThe modified Delphi process consisted of two rounds of electronic questionnaires, followed by a face-to-face meeting conducted virtually. Twenty-one items were included for discussion. The three main areas of discussion were: wide field OCTA (WF-OCTA), nomenclature of OCTA findings and OCTA signal attenuation assessment and measurement. Seventeen specialists in uveitis and retinal imaging were selected by the executive committee to constitute the OCTA nomenclature in Uveitis Delphi Study Group. The study endpoint was defined by the degree of consensus for each question: ‘strong consensus’ was defined as >90% agreement, ‘consensus’ as 85%–90% and ‘near consensus’ as >80% but <85%.ResultsThere was a strong consensus to apply the term ‘wide field’ to OCTA images measuring over 70° of field of view, to use the terms ‘flow deficit’ and ‘non-detectable flow signal’ to describe abnormal OCTA flow signal secondary to slow flow and to vessels displacement respectively, to use the terms ‘loose’ and ‘dense’ to describe the appearance of inflammatory choroidal neovascularisation, and to use the percentage of flow signal decrease to measure OCTA ischaemia with a threshold greater than or equal to 30% as a ‘large area’.ConclusionsThis study sets up consensus recommendations for reporting OCTA findings in uveitis by an expert panel, which may prove suitable for use in routine clinical care and clinical trials.

Problematic alcohol use (PAU), a trait that combines alcohol use disorder and alcohol-related problems assessed with a questionnaire, is a leading cause of death and morbidity worldwide. Here we conducted a large cross-ancestry meta-analysis of PAU in 1,079,947 individuals (European, N= 903,147; African, N= 122,571; Latin American, N= 38,962; East Asian, N= 13,551; and South Asian, N= 1,716 ancestries). We observed a high degree of cross-ancestral similarity in the genetic architecture of PAU and identified 110 independent risk variants in within- and cross-ancestry analyses. Cross-ancestry fine mapping improved the identification of likely causal variants. Prioritizing genes through gene expression and chromatin interaction in brain tissues identified multiple genes associated with PAU. We identified existing medications for potential pharmacological studies by a computational drug repurposing analysis. Cross-ancestry polygenic risk scores showed better performance of association in independent samples than single-ancestry polygenic risk scores. Genetic correlations between PAU and other traits were observed in multiple ancestries, with other substance use traits having the highest correlations. This study advances our knowledge of the genetic etiology of PAU, and these findings may bring possible clinical applicability of genetics insights—together with neuroscience, biology and data science—closer.

Background: In patients with renal artery stenosis, revascularization was seen as a mean to improve outcomes, but large studies failed to show significant benefit in general population. However, data on benefits of renal artery stenting in patients with high-risk features, such as rapidly declining renal function and cardiac destabilization syndromes, are limited, as they were excluded from trials. In this descriptive study, we aimed to evaluate short- and long-term outcomes in high-risk patients with renal artery stenosis, treated by angioplasty and stenting. We have retrospectively interrogated our local databases for renal artery percutaneous interventions; patients at high-risk (rapidly declining renal function; stable chronic renal failure and bilateral renal artery disease; severe hypertensive crisis) were selected for the current analysis. Results: Of 30 patients undergoing renal artery stenting, 18 patients were deemed "high-risk." On short term, good in-hospital control of hypertension and cardiac stabilization were obtained in all patients. Renal function improved significantly only in patients admitted with rapidly declining renal function, with significant creatinine level fall from median 3.98 mg/dL to 2.02 mg/dL, p= 0.023. However, for the whole group, creatinine change was non-significant (− 0.12 mg/dL, p= NS). On the long term, five patients (27.8%) ended-up on chronic hemodialysis and six patients died (33.3%) after a median of 20 months. No death occurred during the first year after the procedure. Conclusions: Percutaneous procedures are feasible and safe in patients with high-risk renal artery stenosis, especially in those with rapidly declining renal function, probably saving some of them from the immediate need for renal replacement therapy, but long-term results are negatively influenced by the precarious general and cardio-vascular status of these patients and by the pre-existing significant renal parenchymal disease, non-related to the renal artery stenosis.

Our results of post hoc analysis of the DRCR Protocol T trial provides evidence that patients with diabetic macular edema presented with complete or partial vitreomacular adhesion at baseline may derive to better visual results under anti-VEGF treatment, compared with those with complete posterior vitreous detachment.

Expansion and differentiation of antigen-experienced PD-1+TCF-1+stem-like CD8+T cells into effector cells is critical for the success of immunotherapies based on PD-1 blockade1–4. Hashimoto et al. have shown that, in chronic infections, administration of the cytokine interleukin (IL)-2 triggers an alternative differentiation path of stem-like T cells towards a distinct population of ‘better effector’ CD8+T cells similar to those generated in an acute infection5. IL-2 binding to the IL-2 receptor α-chain (CD25) was essential in triggering this alternative differentiation path and expanding better effectors with distinct transcriptional and epigenetic profiles. However, constitutive expression of CD25 on regulatory T cells and some endothelial cells also contributes to unwanted systemic effects from IL-2 therapy. Therefore, engineered IL-2 receptor β- and γ-chain (IL-2Rβγ)-biased agonists are currently being developed6–10. Here we show that IL-2Rβγ-biased agonists are unable to preferentially expand better effector T cells in cancer models and describe PD1-IL2v, a new immunocytokine that overcomes the need for CD25 binding by docking in cisto PD-1. Cisbinding of PD1-IL2v to PD-1 and IL-2Rβγ on the same cell recovers the ability to differentiate stem-like CD8+T cells into better effectors in the absence of CD25 binding in both chronic infection and cancer models and provides superior efficacy. By contrast, PD-1- or PD-L1-blocking antibodies alone, or their combination with clinically relevant doses of non-PD-1-targeted IL2v, cannot expand this unique subset of better effector T cells and instead lead to the accumulation of terminally differentiated, exhausted T cells. These findings provide the basis for the development of a new generation of PD-1 cis-targeted IL-2R agonists with enhanced therapeutic potential for the treatment of cancer and chronic infections.

•Adolescent drinking-in-the-dark (DID) binge drinking does not increase adulthood consumption in a DID model or a two bottle choice model in male and female SST-Cre:Ai9 mice.•Adolescent pair-housed intermittent access consumption of alcohol does not increase adulthood consumption in an identical adulthood model in male and female C57BL/6 J mice.•Adolescent intermittent access to alcohol does not increase adulthood consumption in male and female Wistar or Fischer 344 rats.•These complementary datasets across murine models, labs and institutions highlight the need to consider human social factors as well as biological factors.

Retinal–choroidal anastomosis is an exclusive clinical finding of macular neovascularization Type 3 in eyes with neovascular age-related macular degeneration. Multifocal macular neovascularization Type 3 is usually bilateral, and the lesions develop simultaneously, but when the multifocal phenotype is unilateral, it appears before the development of the unifocal one in the contralateral eye.

Background/objectives: We aim to develop an objective fully automated Artificial intelligence (AI) algorithm for MNV lesion size and leakage area segmentation on fluorescein angiography (FA) in patients with neovascular age-related macular degeneration (nAMD). Subjects/methods: Two FA image datasets collected form large prospective multicentre trials consisting of 4710 images from 513 patients and 4558 images from 514 patients were used to develop and evaluate a deep learning-based algorithm to detect CNV lesion size and leakage area automatically. Manual segmentation of was performed by certified FA graders of the Vienna Reading Center. Precision, Recall and F1 score between AI predictions and manual annotations were computed. In addition, two masked retina experts conducted a clinical-applicability evaluation, comparing the quality of AI based and manual segmentations. Results: For CNV lesion size and leakage area segmentation, we obtained F1 scores of 0.73 and 0.65, respectively. Expert review resulted in a slight preference for the automated segmentations in both datasets. The quality of automated segmentations was slightly more often judged as good compared to manual annotations. Conclusions: CNV lesion size and leakage area can be segmented by our automated model at human-level performance, its output being well-accepted during clinical applicability testing. The results provide proof-of-concept that an automated deep learning approach can improve efficacy of objective biomarker analysis in FA images and will be well-suited for clinical application.

Despite the large toll of opioid use disorder (OUD), genome-wide association studies (GWAS) of OUD to date have yielded few susceptibility loci. We performed a large-scale GWAS of OUD in individuals of European (EUR) and African (AFR) ancestry, optimizing genetic informativeness by performing MTAG (Multi-trait analysis of GWAS) with genetically correlated substance use disorders (SUDs). Meta-analysis included seven cohorts: the Million Veteran Program, Psychiatric Genomics Consortium, iPSYCH, FinnGen, Partners Biobank, BioVU, and Yale-Penn 3, resulting in a total N= 639,063 (Ncases= 20,686;Neffective= 77,026) across ancestries. OUD cases were defined as having a lifetime OUD diagnosis, and controls as anyone not known to meet OUD criteria. We estimated SNP-heritability (h2SNP) and genetic correlations (rg). Based on genetic correlation, we performed MTAG on OUD, alcohol use disorder (AUD), and cannabis use disorder (CanUD). A leave-one-out polygenic risk score (PRS) analysis was performed to compare OUD and OUD-MTAG PRS as predictors of OUD case status in Yale-Penn 3. The EUR meta-analysis identified three genome-wide significant (GWS; p≤ 5 × 10−8) lead SNPs—one at FURIN(rs11372849; p= 9.54 × 10−10) and two OPRM1variants (rs1799971, p= 4.92 × 10−09; rs79704991, p= 1.11 × 10−08; r2= 0.02). Rs1799971 (p = 4.91 × 10−08) and another OPRM1variant (rs9478500; p= 1.95 × 10−08; r2= 0.03) were identified in the cross-ancestry meta-analysis. Estimated h2SNPwas 12.75%, with strong rgwith CanUD (rg= 0.82; p= 1.14 × 10−47) and AUD (rg= 0.77; p= 6.36 × 10−78). The OUD-MTAG resulted in a GWAS Nequivalent= 128,748 and 18 independent GWS loci, some mapping to genes or gene regions that have previously been associated with psychiatric or addiction phenotypes. The OUD-MTAG PRS accounted for 3.81% of OUD variance (beta = 0.61;s.e. = 0.066; p= 2.00 × 10−16) compared to 2.41% (beta = 0.45; s.e. = 0.058; p= 2.90 × 10−13) explained by the OUD PRS. The current study identified OUD variant associations at OPRM1, single variant associations with FURIN, and 18 GWS associations in the OUD-MTAG. The genetic architecture of OUD is likely influenced by both OUD-specific loci and loci shared across SUDs.

UK Biobank (UKB) is a key contributor in mental health genome-wide association studies (GWAS) but only ~31% of participants completed the Mental Health Questionnaire (“MHQ responders”). We predicted generalized anxiety disorder (GAD), posttraumatic stress disorder (PTSD), and major depression symptoms using elastic net regression in the ~69% of UKB participants lacking MHQ data (“MHQ non-responders”; NTraining= 50%; NTest= 50%), maximizing the informative sample for these traits. MHQ responders were more likely to be female, from higher socioeconomic positions, and less anxious than non-responders. Genetic correlation of GAD and PTSD between MHQ responders and non-responders ranged from 0.636 to 1.08; both were predicted by polygenic scores generated from independent cohorts. In meta-analyses of GAD (N= 489,579) and PTSD (N= 497,803), we discovered many novel genomic risk loci (13 for GAD and 40 for PTSD). Transcriptomic analyses converged on altered regulation of prenatal dorsolateral prefrontal cortex in these disorders. Our results provide one roadmap by which sample size and statistical power may be improved for gene discovery of incompletely ascertained traits in the UKB and other biobanks with limited mental health assessment.

We examined whether a polygenic score (PGS) for smoking measured genetic risk for general behavioral disinhibition by estimating its associations with externalizing and internalizing psychopathology and related personality traits at multiple time points in adolescence (ages 11, 14, and 17 years; N= 3,225). The smoking PGS had strong associations with the stable variance across time for all the externalizing measures (mean standardized β = 0.27), agreeableness (β = −0.22, 95% confidence interval [CI] = [−0.28, −0.16]), and conscientiousness (β = −0.19, 95% CI = [−0.24, −0.13]) but was not significantly associated with internalizing measures (mean β = 0.06) or extraversion (β = 0.01, 95% CI = [−0.05, 0.07]). After controlling for smoking at age 17 years, the associations with externalizing, low agreeableness, and low conscientiousness remained statistically significant. The smoking PGS measures genetic influences that contribute to a spectrum of phenotypes related to behavioral disinhibition, including externalizing psychopathology and normal-range personality traits related to behavioral control but not internalizing psychopathology.

Genomic tumor profiling by next-generation sequencing (NGS) allows for large-scale tumor testing to inform targeted cancer therapies and immunotherapies, and to identify patients for clinical trials. These tests are often underutilized in patients with late-stage solid tumors and are typically performed in centralized specialty laboratories, thereby limiting access to these complex tests. Personal Genome Diagnostics Inc., elio tissue complete NGS solution is a comprehensive DNA-to-report kitted assay and bioinformatics solution. Comparison of 147 unique specimens from >20 tumor types was performed using the elio tissue complete solution and Foundation Medicine's FoundationOne test, which is of similar size and gene content. The analytical performance of all genomic variant types was evaluated. In general, the overall mutational profile is highly concordant between the two assays, with agreement in sequence variants reported between panels demonstrating >95% positive percentage agreement for single-nucleotide variants and insertions/deletions in clinically actionable genes. Both copy number alterations and gene translocations showed 80% to 83% positive percentage agreement, whereas tumor mutation burden and microsatellite status showed a high level of concordance across a range of mutation loads and tumor types. The Personal Genome Diagnostics Inc., elio tissue complete assay is comparable to the FoundationOne test and will allow more laboratories to offer a diagnostic NGS assay in house, which will ultimately reduce time to result and increase the number of patients receiving molecular genomic profiling and personalized treatment.

Human exposure to aromatic amines (AAs) can result in carcinogenic DNA adducts. To complement previous work geared toward understanding the mutagenicity of AA-derived adducts, which has almost exclusively studied (monoadducted) DNA containing a single lesion, the present work provides the first in-depth comparison of the structure of monoadducted and diadducted DNA duplexes. Specifically, molecular dynamics (MD) simulations were initially performed on DNA containing the nonmutagenic single-ringed N-(deoxyguanosin-8-yl)-aniline (ANdG) or the mutagenic four-ringed N-(deoxyguanosin-8-yl)-1-aminopyrene (APdG) lesion at G1, G2, or G3in the AA deletion hotspot (5′-G1G2CG3CC) in the antior synglycosidic orientation (B/S duplex conformation). Subsequently, diadducted strands were assessed that span each combination of damaged sites (G1G2(nearest neighbors), G2G3(next-nearest neighbors), and G1G3(two intervening nucleotides)) and anti/synlesion glycosidic orientations. Despite other N-linked C8-dG adducts exhibiting sequence dependence conformational heterogeneity, a single ANdG or APdG lesion induces helical conformational homogeneity that is exclusively controlled by aryl moiety size. However, the preferred damaged DNA conformation can change upon the addition of a second adduct depending on lesion separation, with neighboring lesions stabilizing a nonmutagenic conformation and next-nearest damaged sites stabilizing a promutagenic conformation regardless of adduct size. As a result, diadducted DNA is found to adopt conformations that are unfavored for the corresponding monoadducted system, pointing to differential replication and repair outcomes for diadducted DNA compared to those for monoadducted DNA. Thus, although the toxicity of monoadducted DNA is most significantly dictated by lesion size, the toxicity can increase or decrease upon a second damaging event depending on lesion size and relative position. Overall, our work adds the number of lesions and their spatial separation to the growing list of factors that determine the structure and biological outcomes of adducted DNA.

Objective Feasibility of diagnosis of pneumothorax using handheld ultrasound by non-radiologists shows inconsistent results. The aim of this study is to evaluate the feasibility and accuracy of portable ultrasound for immediate diagnosis of pneumothorax by general surgery residents who underwent short training.Methods Patients who presented to the emergency department of a university hospital with suspected pneumothorax between 10/2018 and 12/2019 were included in the study. Patients underwent ultrasound in 2 points of each hemithorax. Sensitivity and specificity for pneumothorax diagnosis by ultrasound and physical examination were calculated and compared with chest computed tomography (CT). Patients in whom a chest tube was placed prior to ultrasound examination and those who did not undergo a CT scan were excluded from the study.Results A total of 85 patients met the inclusion criteria. Mean age was 40.7 ± 20.2 years. Pneumothorax was found among 46 patients (54%) per chest CT, and of these, 21 (46%) underwent chest tube placement following imaging. Ultrasound showed the highest sensitivity and specificity (95.6% [95% confidence interval {CI} 85.16% to 99.47%] and 97.44% [95% CI 86.40% to 99.67%], respectively). Chest x-ray had the lowest sensitivity (47.8% [95% CI 32.89% to 63.05%]) for pneumothorax detection. Physical examination showed a moderate sensitivity and specificity (82.6% [95% CI 68.58% to 92.18%] and 77.89% [95% CI 60.67% to 88.87%], respectively) for the diagnosis of pneumothorax.Conclusions We found high accuracy rates of 2-point ultrasound in immediate pneumothorax diagnosis when performed by surgical residents who underwent a short ultrasound training. This is a fast and repeatable test, and has the potential for successful implementation in prehospital and military scenarios as well, minimizing unnecessary chest tube placements.

PurposeTo report on patients with macular neovascularisation type III (MNV3) arising from cilioretinal arteries (CRAs) (cilioretinal macular neovascularisation type III (cMNV3)).MethodsWe reviewed baseline examinations of patients with neovascular age-related macular degeneration using multimodal imaging. We determined the type and distribution of MNV lesions in each cMNV3 case, the range of distances from the fovea, existence of exudative maculopathy, intraretinal haemorrhage and other morphological characteristics. 50 consecutive eyes with usual MNV3 without CRA were included as a control group.Results102 eyes of 102 patients were identified with MNV3 lesions. Among these, we found 12 eyes (12%) with cMNV3, 84 eyes (82%) with usual MNV3 without CRA and 6 eyes (6%) with usual MNV3 with CRA. Ten cases of cMNV3 had one lesion, and two cases had two lesions. The lesions were distributed equally between the superior and inferior halves of the macula, whereas in the nasal and temporal halves, there were 8 (57%) and 6 (43%) lesions, respectively. All cMNV3 lesions were located between 500 and 1500 µm from the central fovea except one, which was located between 1500 and 3000 µm. None of the lesions had macular neovascularisation type I (MNV1) or macular neovascularisation type II (MNV2) elsewhere in both groups. Exudative maculopathy and intraretinal haemorrhage were found in seven (88%) and five (63%) of the eight pure cMNV3 cases, respectively.ConclusioncMNV3 can be solitary or multiple, isolated or accompanied with usual MNV3 lesions, but not with concurrent MNV1 or MNV2. It is frequently associated with extensive exudative maculopathy, intraretinal haemorrhage and subretinal fluid.