Supplementary Figure S2. Mutation profiles obtained from LC-WES using SOLiD 5500xl sequencer.

BACKGROUND:Individuals with bipolar disorder (BD) often have co-occurring substance use disorders (SUDs), which substantially impoverish the course of illness. Despite the importance of this dual diagnosis, the evidence of the efficacy and safety of adjuvant treatments is mostly unknown. OBJECTIVE:To perform a meta-analysis to evaluate the efficacy and safety of adjuvant drugs in patients with co-occurring BD and SUD. METHODS:We searched PubMed, Scopus, and Web of Knowledge until 30th April 2022 for randomized clinical trials (RCT) evaluating the efficacy and safety of adjuvant drugs compared to placebo in patients with a dual diagnosis of BD and SUD. We meta-analyzed the effect of adjuvant drugs on general outcomes (illness severity, mania, depression, anxiety, abstinence, substance craving, substance use, gamma-GT, adherence, and adverse events) and used the results to objectively assess the quality of the evidence according to the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach. For completeness, we also report the specific effects of specific adjuvant drugs in patients with specific substance disorders. RESULTS:We included 15 RCT studies (9 alcohol, 3 cocaine, 2 nicotine, and 1 cannabis) comprising 628 patients allocated to treatment and 622 to placebo. There was low-quality evidence that adjuvant drugs may reduce illness severity (g=-0.25, 95% CI: -0.44, -0.06), and very-low quality evidence that they may decrease substance use (g=-0.23, 95% CI: -0.44, -0.02) and increase substance abstinence (g=0.21, 95% CI: 0.04, 0.38). DISCUSSION:There is low-quality evidence that adjuvant drugs may help reduce illness severity, probably via facilitating abstinence and lower substance use. However, the evidence is weak; thus, these results should be considered cautiously until better evidence exists.

Background: Schizophrenia patients often show obsessive-compulsive symptoms (OCS) and obsessive-compulsive disorder (OCD) and their presence has been associated with poorer prognosis. However, the impact of OCS/OCD on psychotic severity remains unclear. The aim of this study is twofold: 1) to investigate the effect of OCS/OCD on the severity of positive, negative, and global psychotic symptoms of schizophrenia patients and 2) to analyze the effect of patient and study-related covariates on moderating this relationship.Methods: A systematic review and meta-analysis (SRMA) of studies comparing the severity of psychotic symptoms among schizophrenia patients with and without OCS/OCD was performed. Standardized mean difference (SMD) was calculated for positive, negative, and global psychotic symptoms. The difference of SMD (Diff SMD) was calculated to analyze the effect of covariates on study outcomes using meta-regression.Results: Sixty-seven studies involving 7740 patients were included. Patients with schizophrenia and OCS/OCD showed a slightly higher severity of positive (SMD = 0.17, p value = 0.0089) and global psychotic symptoms (SMD = 0.24, p value = 0.0104) than patients without OCS/OCD but no differences in negative symptoms were found between groups (SMD = 0.11, p value = 0.0367). Only one covariate "proportion of patients without antipsychotics (AP)" was found to modify the effect on psychotic severity (Diff SMD = -0.008, p value = 0.002).Conclusions: Comorbid OCS/OCD in schizophrenia has, at most, a minor impact on psychotic severity. Variability in this effect was considerable and was poorly explained by the covariates analyzed.

Supplementary Table S1: Clinicopathological and epidemiological patient data and urothelial tumor sample description. Supplementary Table S2: Complete list of annotated SBS identified in all LC-WES analyzed urothelial tumors (HiSeq2500 data only). Supplementary Table S3: GO and KEGG Classification of genes mutated by non-synonymous A:T>T:A mutations. Supplementary Table S4: List of cancer driver genes found recurrently mutated in the EN and Taiwan UTUC sample sets. Supplementary Table S5: GO and KEGG classification of the recurrently mutated cancer driver genes (see Figure 3B).

Among the available literature on electromagnetic interference between high voltage power lines and nearby pipelines, the topic of transient induced voltage on the pipelines are rarely discussed. Fault in high voltage transmission systems is usually cleared in several cycles, sometimes even before the fault current reaches the steady state. This paper proposes an analytical approach for calculating the transient induced voltage and current on a pipeline due to inductive coupling using a circuit model. A numerical example is studied to demonstrate the waveforms of transient induced voltage and current on the pipeline. Simulation results show that the transient peak of the induced voltage is greater than steady state values. Therefore, it is necessary to study the induced voltage and current during the transient period.

The present study aims to draw attention to the fact that endurance sport could be a risk factor for dural arteriovenous fistula (DAVF) development. DAVFs have been correlated with acquired dural venous sinus anomalies owing to trauma, infection, neoplasia, or other classic risk thrombogenic factors. Here we report 3 cases of intracranial DAVF in young healthy patients who had no known thrombogenic risk factors other than amateur intensive sports practice.Three young healthy individuals not fitting into the classical clinical picture of a DAVF patient presented to our institution. One was a 40-year-old man with an acute subdural hematoma secondary to an ethmoidal DAVF. Another 41-year-old man presented with a cerebellar hematoma due to a tentorial DAVF. A third 41-year-old man presented with numbness of his right arm in relationship to a superior sagittal sinus DAVF. None of them had a relevant medical history. All the usual thrombogenic risk factors for DAVF development were ruled out. Interestingly, the 3 patients had outstanding training and practice routines for endurance sports.Dehydration, microfractures, muscular contractures, low heart rate, long distance travel, and high altitudes are all well documented thrombogenic risk factors affecting endurance sports amateur athletes and might represent a plausible mechanism for the development of DAVF. Despite its limitations, to our knowledge, this is the first work suggesting a possible link between such sport practice and DAVF development. Further prospective research from larger dedicated vascular centers might shed further light on this hypothetic but intriguing link.

Youth with family history (FH+) of substance use disorders (SUDs) are at increased risk for developing SUDs. Similarly, childhood attention deficit hyperactivity disorder (ADHD) is considered to be a risk factor for developing SUDs. Recent research has suggested a close association between SUDs and impaired inhibitory control. As such, it is crucial to examine common and distinct neural alterations associated with inhibitory control in these at-risk groups, particularly prior to the initiation of heavy substance use. This paper reviews the functional magnetic resonance imaging (fMRI) literature of inhibitory control in these two at-risk youth populations (FH+ and ADHD), specifically considering studies that used motor response inhibition tasks (Go/No-Go or Stop Signal). Across the selected fMRI studies, we discovered no common alteration in the at-risk groups, but found neural alterations specific to each at-risk group. In FH+ youth and youth who transitioned into heavy substance use, blunted activation in the lateral part of the frontal pole (FP-lat) was most reliably observed. Importantly, longitudinal studies indicate that the blunted FP-lat activation may predict later SUDs, irrespective of the presence of FH+. In regards to ADHD, blunted activation was observed in the right dorsal anterior cingulate cortex (dACC) and left caudate. Of note, similar blunted dACC activation was also reported by one FH+ study, and thus, we cannot preclude a possibility that the right dACC activity may be a potential common alteration in both at-risk groups, particularly given a limited number of FH+ studies in the current review. Research challenges remain, and large-scale, longitudinal efforts will help determine the neurobiological markers predictive of SUDs among at-risk adolescents, including those with FH+, as well as those with ADHD and other psychiatric disorders.

Abstract Exposure to aristolochic acid (AA, IARC Group 1 carcinogen) present in some traditional herbal medicines leads to aristolochic acid nephropathy (AAN), often complicated by development of multiple urothelial carcinomas of sequential onset. We used genome-scale mutational signature analysis of multiple urinary tract tumors of AAN cases from a unique patient group to determine the relationships of the patients’ late-onset second cancers to the AA exposure as well as to the first cancers. Aristolactam-DNA adduct-positive AAN patients (n=4) who developed cancer within 8 years following the initial exposure to AA were chosen for analysis of their first cancers (upper tract urothelial carcinomas, UTUC) and second cancers of delayed onset (1-9 years after first-cancer diagnosis, involving the bladder or ureteral meatus). All patients had received a kidney transplant before developing the second cancers and had a functional renal graft prior to prophylactic nephroureterectomy. Genomic DNAs were isolated from FFPE sections of the renal cortex and from the upper and lower tract tumors of each patient using laser capture micro-dissection or macro-dissection of the tumor areas. Low-coverage (~15x) exome 100-bp paired-end sequencing was performed using Illumina HiSeq2500. Customized variant calling identified somatic variants absent in non-tumor tissues. Non-negative matrix factorization was applied to extract mutational signatures in the tumor tissues. In all cases, we established the mutational signature of AA (the COSMIC signature 22) in the first UTUC as well as second cancers involving the bladder or lower ureter (meatus). Additionally, the first and second cancers harbored considerable overlaps in exposure-specific (A>T) somatic mutations. This finding provides evidence that the delayed onset of bladder urothelial carcinomas in AAN patients is likely due to distal seeding of cancer cells originating from the primary UTUC tumors. Our first-of-its-kind study addresses the risk as well as mechanistic factors leading to the second, late-onset bladder urothelial carcinomas following kidney transplantation and primary UTUC development. Our results underline the importance of long-term bladder follow-up in high-risk populations with established or suspected AA exposure. Funding: IARC; NYU Genome Technology Center is partially supported by the NIH/NCI (P30CA016087) grant. Citation Format: Xavier Castells, Maude Ardin, Sandrine Rorive, Nilufer Broeders, Yan Song, Stephanie Villar, Christine Carreira, Pierre-Paul Bringuier, Adriana Heguy, Thierry Quackels, Thierry Roumeguere, Joelle Nortier, Jiri Zavadil. Tracking the genetic relationship between first and late-onset second urothelial cancers by mutational signature analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5738. doi:10.1158/1538-7445.AM2017-5738

The risk-benefit balance of pharmacological treatment for children and adolescents with ADHD and the factors that moderate this relationship are unclear.

The factors underlying the variability in the results of randomized, placebo-controlled clinical trials (RPCCT) assessing pharmacological interventions for adults with attention deficit hyperactivity disorder (ADHD) are not fully understood.

Background The nature of somatic mutations observed in human tumors at single gene or genome-wide levels can reveal information on past carcinogenic exposures and mutational processes contributing to tumor development. While large amounts of sequencing data are being generated, the associated analysis and interpretation of mutation patterns that may reveal clues about the natural history of cancer present complex and challenging tasks that require advanced bioinformatics skills. To make such analyses accessible to a wider community of researchers with no programming expertise, we have developed within the web-based user-friendly platform Galaxy a first-of-its-kind package called MutSpec. Results MutSpec includes a set of tools that perform variant annotation and use advanced statistics for the identification of mutation signatures present in cancer genomes and for comparing the obtained signatures with those published in the COSMIC database and other sources. MutSpec offers an accessible framework for building reproducible analysis pipelines, integrating existing methods and scripts developed in-house with publicly available R packages. MutSpec may be used to analyse data from whole-exome, whole-genome or targeted sequencing experiments performed on human or mouse genomes. Results are provided in various formats including rich graphical outputs. An example is presented to illustrate the package functionalities, the straightforward workflow analysis and the richness of the statistics and publication-grade graphics produced by the tool. Conclusions MutSpec offers an easy-to-use graphical interface embedded in the popular Galaxy platform that can be used by researchers with limited programming or bioinformatics expertise to analyse mutation signatures present in cancer genomes. MutSpec can thus effectively assist in the discovery of complex mutational processes resulting from exogenous and endogenous carcinogenic insults.