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Immunomodulatory imide drugs (IMiDs) are central components of therapy for multiple myeloma (MM). IMiDs bind cereblon (CRBN), an adaptor for the CUL4-DDB1-RBX1 E3 ligase to change its substrate specificity and induce degradation of 'neosubstrate' transcription factors that are essential to MM cells. Mechanistic studies to date have largely focussed on mediators of therapeutic activity and insight into clinical IMiD toxicities is less developed. We adopted BioID2-dependent proximity labelling (BioID2-CRBN) to characterise the CRBN interactome in the presence and absence of various IMiDs and the proteasome inhibitor, bortezomib. We aimed to leverage this technology to further map CRBN interactions beyond what has been achieved by conventional proteomic techniques. In support of this approach, analysis of cells expressing BioID2-CRBN following IMiD treatment displayed biotinylation of known CRBN interactors and neosubstrates. We observed that bortezomib alone significantly modifies the CRBN interactome. Proximity labelling also suggested that IMiDs augment the interaction between CRBN and proteins that are not degraded, thus designating 'neointeractors' distinct from previously disclosed 'neosubstrates'. Here we identify Non-Muscle Myosin Heavy Chain IIA (MYH9) as a putative CRBN neointeractor that may contribute to the haematological toxicity of IMiDs. These studies provide proof of concept for proximity labelling technologies in the mechanistic profiling of IMiDs and related E3-ligase-modulating drugs., (© 2024 The Author(s). The FEBS Journal published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

Background: Minor ischemic stroke, defined as National Institute of Health Stroke Scale score of 0-5 on admission, represents half of all acute ischemic strokes. The role of intravenous alteplase (IVA) among patients with minor stroke is inconclusive; therefore, we evaluated clinical outcomes of these patients treated with or without IVA., Materials and Methods: We searched Medline, Embase, Scopus, and the Cochrane library until August 1, 2023. Inclusion was restricted to the English literature of studies that reported on minor nondisabling stroke patients treated with or without IVA. Odds ratios (ORs) with their corresponding 95% CIs were utilized using a random-effects model. Efficacy outcomes included rates of excellent (modified Rankin scale [mRS] of 0-1) and good (mRS of 0-2) functional outcome at 90 days. The main safety outcome was symptomatic intracerebral hemorrhage (sICH)., Results: Five eligible studies, two RCTs and three observational studies, comprising 2764 patients (31.8% female) met inclusion criteria. IVA was administered to 1559 (56.4%) patients. Pooled analysis of the two RCTs revealed no difference between the two groups in terms of 90-days excellent functional outcomes (OR 0.76 [95% CI, 0.51-1.13]; I 2  = 0%) and sICH rates (OR 3.76 [95% CI, 0.61-23.20]). No significant differences were observed between the groups in terms of good functional outcomes, 90-day mortality, and 90-day stroke recurrence., Conclusion: This meta-analysis of minor nondisabling stroke suggests that IVA did not prove more beneficial compared to no-IVA., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Abstract ., Introduction: Sleep disturbances and elevated stress levels are commonly reported among individuals seeking treatment for substance use disorders (SUDs). However, it remains unclear whether the relationship between sleep and stress differs based on the primary substance of use or if there are commonalities across different substances. This study aimed to investigate the association between sleep disturbances and perceived stress among individuals in SUD treatment and examine whether primary substance influences this relationship., Method: A sample of 4,201 individuals from 59 SUD treatment programs completed assessments including the Insomnia Severity Index and Perceived Stress Scale in 2021. Cross-sectional and longitudinal analyses were conducted to evaluate the relationship between sleep and stress across different primary substances during treatment., Results: The results demonstrated that higher stress was associated with more severe insomnia, and vice versa, both at treatment intake and over the course of treatment, regardless of primary substance. Persons using heroin/ fentanyl evidenced a stronger association of sleep on stress, and persons using cocaine evidenced a stronger relationship of stress on sleep., Discussion: The findings suggest that sleep/stress associations are ubiquitous across different classes of drugs, although sleep might have more influence on stress in persons primarily using heroin/ fentanyl, and stress might have more influence on sleep in persons primarily using cocaine, relative to other substances. Interventions targeting either sleep or stress could have positive effects on SUD outcomes, but further research is needed to investigate the underlying neurobiological mechanisms and inform the development of effective interventions for sleep and stress in SUD populations., (© Copyright 2024 Physicians Postgraduate Press, Inc.)

Exposure to certain chemicals prenatally and in childhood can impact development and may increase risk for attention-deficit/hyperactivity disorder (ADHD). Leveraging a larger set of literature searches conducted to synthesize results from longitudinal studies of potentially modifiable risk factors for childhood ADHD, we present meta-analytic results from 66 studies that examined the associations between early chemical exposures and later ADHD diagnosis or symptoms. Studies were eligible for inclusion if the chemical exposure occurred at least 6 months prior to measurement of ADHD diagnosis or symptomatology. Included papers were published between 1975 and 2019 on exposure to anesthetics (n = 5), cadmium (n = 3), hexachlorobenzene (n = 4), lead (n = 22), mercury (n = 12), organophosphates (n = 7), and polychlorinated biphenyls (n = 13). Analyses are presented for each chemical exposure by type of ADHD outcome reported (categorical vs. continuous), type of ADHD measurement (overall measures of ADHD, ADHD symptoms only, ADHD diagnosis only, inattention only, hyperactivity/impulsivity only), and timing of exposure (prenatal vs. childhood vs. cumulative), whenever at least 3 relevant effect sizes were available. Childhood lead exposure was positively associated with ADHD diagnosis and symptoms in all analyses except for the prenatal analyses (odds ratios (ORs) ranging from 1.60 to 2.62, correlation coefficients (CCs) ranging from 0.14 to 0.16). Other statistically significant associations were limited to organophosphates (CC = 0.11, 95% confidence interval (CI): 0.03-0.19 for continuous measures of ADHD outcomes overall), polychlorinated biphenyls (CC = 0.08, 95% CI: 0.02-0.14 for continuous measures of inattention as the outcome), and both prenatal and childhood mercury exposure (CC = 0.02, 95% CI: 0.00-0.04 for continuous measures of ADHD outcomes overall for either exposure window). Our findings provide further support for negative impacts of prenatal and/or childhood exposure to certain chemicals and raise the possibility that primary prevention and targeted screening could prevent or mitigate ADHD symptomatology. Furthermore, these findings support the need for regular review of regulations as our scientific understanding of the risks posed by these chemicals evolves., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Although neurobiologic and genetic factors figure prominently in the development of attention deficit/hyperactivity disorder (ADHD), adverse physical health experiences and conditions encountered during childhood may also play a role. Poor health is known to impact the developing brain with potential lifelong implications for behavioral issues. In attempt to better understand the relationship between childhood physical health and the onset and presence of ADHD symptoms, we summarized international peer-reviewed articles documenting relationships between a select group of childhood diseases or health events (e.g., illnesses, injuries, syndromes) and subsequent ADHD outcomes among children ages 0-17 years. Drawing on a larger two-phase systematic review, 57 longitudinal or retrospective observational studies (1978-2021) of childhood allergies, asthma, eczema, head injury, infection, or sleep problems and later ADHD diagnosis or symptomatology were identified and subjected to meta-analysis. Significant associations were documented between childhood head injuries, infections, and sleep problems with both dichotomous and continuous measures of ADHD, and between allergies with dichotomous measures of ADHD. We did not observe significant associations between asthma or eczema with ADHD outcomes. Heterogeneity detected for multiple associations, primarily among continuously measured outcomes, underscores the potential value of future subgroup analyses and individual studies. Collectively, these findings shed light on the importance of physical health in understanding childhood ADHD. Possible etiologic links between physical health factors and ADHD are discussed, as are implications for prevention efforts by providers, systems, and communities., (© 2022. Society for Prevention Research.)

Previous studies have shown mixed results on the relationship between prenatal, birth, and postnatal ("pregnancy-related") risk factors and attention-deficit/hyperactivity disorder (ADHD). We conducted meta-analyses to identify potentially modifiable pregnancy-related factors associated with ADHD. A comprehensive search of PubMed, Web of Science, and EMBASE in 2014, followed by an updated search in January 2021, identified 69 articles published in English on pregnancy-related risk factors and ADHD for inclusion. Risk factors were included in the meta-analysis if at least three effect sizes with clear pregnancy-related risk factor exposure were identified. Pooled effect sizes were calculated for ADHD overall, ADHD diagnosis, inattention, and hyperactivity/impulsivity. Odds ratios (OR) were calculated for dichotomous measures and correlation coefficients (CC) for continuous measures. Prenatal factors (pre-pregnancy weight, preeclampsia, pregnancy complications, elevated testosterone exposure), and postnatal factors (Apgar score, neonatal illness, no breastfeeding) were positively associated with ADHD overall; the findings for ADHD diagnosis were similar with the exception that there were too few effect sizes available to examine pre-pregnancy weight and lack of breastfeeding. Prenatal testosterone was significantly associated with inattention and hyperactivity/impulsivity. Effect sizes were generally small (range 1.1-1.6 ORs, -0.16-0.11 CCs). Risk factors occurring at the time of birth (perinatal asphyxia, labor complications, mode of delivery) were not significantly associated with ADHD. A better understanding of factors that are consistently associated with ADHD may inform future prevention strategies. The findings reported here suggest that prenatal and postnatal factors may serve as potential targets for preventing or mitigating the symptoms of ADHD., (© 2022. This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.)

Poor parental mental health and stress have been associated with children's mental disorders, including attention-deficit/hyperactivity disorder (ADHD), through social, genetic, and neurobiological pathways. To determine the strength of the associations between parental mental health and child ADHD, we conducted a set of meta-analyses to examine the association of parent mental health indicators (e.g., parental depression, antidepressant usage, antisocial personality disorder, and stress and anxiety) with subsequent ADHD outcomes in children. Eligible ADHD outcomes included diagnosis or symptoms. Fifty-eight articles published from 1980 to 2019 were included. We calculated pooled effect sizes, accounting for each study's conditional variance, separately for test statistics based on ADHD as a dichotomous (e.g., diagnosis or clinical cutoffs) or continuous measurement (e.g., symptoms of ADHD subtypes of inattentiveness and hyperactivity/impulsivity). Parental stress and parental depression were significantly associated with increased risk for ADHD overall and both symptoms and diagnosis. Specifically, maternal stress and anxiety, maternal prenatal stress, maternal depression, maternal post-partum depression, and paternal depression were positively associated with ADHD. In addition, parental depression was associated with symptoms of ADHD inattentive and hyperactive/impulsive subtypes. Parental antisocial personality disorder was also positively associated with ADHD overall and specifically ADHD diagnosis. Prenatal antidepressant usage was associated with ADHD when measured dichotomously only. These findings raise the possibility that prevention strategies promoting parental mental health and addressing parental stress could have the potential for positive long-term impacts on child health, well-being, and behavioral outcomes., (© 2022. This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.)

Parenting and family environment have significant impact on child development, including development of executive function, attention, and self-regulation, and may affect the risk of developmental disorders including attention-deficit/hyperactivity disorder (ADHD). This paper examines the relationship of parenting and family environment factors with ADHD. A systematic review of the literature was conducted in 2014 and identified 52 longitudinal studies. A follow-up search in 2021 identified 7 additional articles, for a total of 59 studies that examined the association of parenting factors with ADHD outcomes: ADHD overall (diagnosis or symptoms), ADHD diagnosis specifically, or presence of the specific ADHD symptoms of inattention and hyperactivity/impulsivity. For parenting factors that were present in three or more studies, pooled effect sizes were calculated separately for dichotomous or continuous ADHD outcomes, accounting for each study's conditional variance. Factors with sufficient information for analysis were parenting interaction quality (sensitivity/warmth, intrusiveness/reactivity, and negativity/harsh discipline), maltreatment (general maltreatment and physical abuse), parental relationship status (divorce, single parenting), parental incarceration, and child media exposure. All factors showed a significant direct association with ADHD outcomes, except sensitivity/warmth which had an inverse association. Parenting factors predicted diagnosis and overall symptoms as well as inattentive and hyperactive symptoms when measured, but multiple factors showed significant heterogeneity across studies. These findings support the possibility that parenting and family environment influences ADHD symptoms and may affect a child's likelihood of being diagnosed with ADHD. Prevention strategies that support parents, such as decreasing parenting challenges and increasing access to parent training in behavior management, may improve children's long-term developmental health., (© 2022. This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.)

Endoscopic Ultrasound (EUS) stands as a remarkable innovation in the realm of gastroenterology and its allied disciplines. EUS has evolved to such an extent that it now assumes a pivotal role in both diagnosis and therapeutics. In addition, it has developed as a tool which is also capable of addressing complications arising from endoscopic and surgical procedures. This minimally invasive technique combines endoscopy with high-frequency ultrasound, facilitating, high-resolution images of the gastrointestinal tract and adjacent structures. Complications within the gastrointestinal tract, whether stemming from endoscopic or surgical procedures, frequently arise due to disruption in the integrity of the gastrointestinal tract wall. While these complications are usually promptly detected, there are instances where their onset is delayed. EUS plays a dual role in the management of these complications. Firstly, in its ability to assess and increasingly to definitively manage complications through drainage procedures. It is increasingly employed to manage post-surgical collections, abscesses biliary strictures and bleeding. Its high-resolution imaging capability allows precise real-time visualisation of these complications., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Nadeem Tehami reports was provided by University Hospital Southampton NHS Foundation Trust. Nadeem Tehami reports a relationship with University Hospital Southampton NHS Foundation Trust that includes: employment. Nadeem Tehami has patent NA pending to NA. None If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

One aim of roadside green infrastructure (GI) is to mitigate exposure to local, traffic-generated pollutants. Here, we determine the efficacy of roadside GI in improving local air quality through the deposition and/or dispersion of airborne particulate matter (PM). PM was collected on both pumped air filters and on the leaves of a recently installed 'tredge' (trees managed as a head-high hedge) at an open road environment next to a primary school in Manchester, U.K. The magnetic properties of PM deposited on leaves and filters (size fractions PM 10 and PM 2.5 ) were deduced from hysteresis loops, first-order reversal curves (FORCs), and low-temperature remanence measurements. These were complemented with electron microscopy to identify changes in magnetic PM concentration downwind of the tredge/GI. We show that the tredge is permeable to airflow using a simple CO 2 tracer experiment; hence, it allows interception and subsequent deposition of PM on its leaves. Magnetic loadings per m 3 of air from filters (PM 10 saturation magnetisation, M s , at 5 K) were reduced by 40 % behind the tredge and a further 63 % in the playground; a total reduction of 78 % compared to roadside air. For the PM 2.5 fraction, the reduction in magnetic loading behind the tredge was remarkable (82 %), reflecting efficient diffusional capture of sub-5 nm Fe-oxide particles by the tredge. Some direct mixing of roadside and playground air occurs at the back of the playground, caused by air flow over, and/or through gaps in, the slowly-permeable tredge. The magnetic loading on tredge leaves increased over successive days, capturing ~23 % of local, traffic-derived PM 10 . Using a heuristic two-dimensional turbulent mixing model, we assess the limited dispersion of PM < 22.5 μm induced by eddies in the tredge wake. This study demonstrates that PM deposition on leaves reduces exposure significantly in this school playground setting; hence, providing a cost-effective mitigation strategy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Targeted inhibitors of bromodomain and extraterminal (BET)-bromodomains and phosphatidylinositol-3-kinase (PI3K) signaling demonstrate potent but self-limited antilymphoma activity as single agents in the context of cellular Myelocytomatosis ( cMYC ) oncogene-dysregulation. However, combined PI3K and BET inhibition imparts synergistic anticancer activity with the potential for more sustained disease responses due to the mutual antagonism of compensatory epigenetic and signaling networks. Here, we describe the mechanistic and therapeutic validation of rationally designed dual PI3K/BET bromodomain inhibitors, built by linkage of established PI3K and BET inhibitor pharmacophores. The lead candidate demonstrates high selectivity, nanomolar range cellular potency, and compelling in vivo efficacy, including curative responses in the aggressive Eµ- Myc lymphoma model. These studies further support the therapeutic strategy of combined PI3K and BET inhibition and provide a potential step-change in approach to orthogonal MYC antagonism using optimized chimeric small-molecule technology.

Background: We aimed to identify distinct trajectories of tobacco, cannabis, and their co-use among African Americans, and to investigate whether these patterns were associated with polygenic risk scores (PRS) for tobacco and cannabis use., Method: Participants (N=428 participants; 50.9% male) were initially recruited for an elementary school-based prevention in a Mid-Atlantic city when they were in first grade. From ages 14-26, participants reported on their frequency of tobacco and cannabis use in the past year during annual assessments. DNA was collected from participants at age 21. PRS for smoking heaviness (i.e., cigarettes per day) and lifetime cannabis use were created based on genome-wide association study results derived from Liu et al. (2019) and Pasman et al. (2018), respectively., Results: We identified five distinct trajectories of tobacco and cannabis co-use, including (1) Low Tobacco and Cannabis Use, (2) Adolescent Limited Tobacco and Cannabis Use, (3) Experimental Cannabis, Young Adult Increasing Tobacco, (4) Experimental Tobacco, Young Adult Increasing Cannabis, and (5) High, Chronic Tobacco and Cannabis Use. Compared to the Low Tobacco and Cannabis Use subgroup, individuals in the High, Chronic Tobacco and Cannabis Use subgroup had greater PRS for smoking heaviness, and individuals in the Experimental Cannabis, Young Adult Increasing Tobacco subgroup had higher PRS for lifetime cannabis use., Conclusions: Polygenic risk for lifetime cannabis use and smoking heaviness is associated with the developmental progression of tobacco and cannabis co-use among African Americans, furthering knowledge on the etiology of co-use in this population., Competing Interests: Declaration of Competing Interest The authors report no conflicts of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Solid pseudopapillary neoplasm (SPN) is an uncommon pathology of the pancreas with unpredictable malignant potential. Endoscopic ultrasound (EUS) assessment plays a vital role in lesion characterization and confirmation of the tissue diagnosis. However, there is a paucity of data regarding the imaging assessment of these lesions., Aim: To determine the characteristic EUS features of SPN and define its role in preoperative assessment., Methods: This was an international, multicenter, retrospective, observational study of prospective cohorts from 7 large hepatopancreaticobiliary centers. All cases with postoperative histology of SPN were included in the study. Data collected included clinical, biochemical, histological and EUS characteristics., Results: One hundred and six patients with the diagnosis of SPN were included. The mean age was 26 years (range 9 to 70 years), with female predominance (89.6%). The most frequent clinical presentation was abdominal pain (80/106; 75.5%). The mean diameter of the lesion was 53.7 mm (range 15 to 130 mm), with the slight predominant location in the head of the pancreas (44/106; 41.5%). The majority of lesions presented with solid imaging features (59/106; 55.7%) although 33.0% (35/106) had mixed solid/cystic characteristics and 11.3% (12/106) had cystic morphology. Calcification was observed in only 4 (3.8%) cases. Main pancreatic duct dilation was uncommon, evident in only 2 cases (1.9%), whilst common bile duct dilation was observed in 5 (11.3%) cases. One patient demonstrated a double duct sign at presentation. Elastography and Doppler evaluation demonstrated inconsistent appearances with no emergence of a predictable pattern. EUS guided biopsy was performed using three different types of needles: Fine needle aspiration (67/106; 63.2%), fine needle biopsy (37/106; 34.9%), and Sonar Trucut (2/106; 1.9%). The diagnosis was conclusive in 103 (97.2%) cases. Ninety-seven patients were treated surgically (91.5%) and the post-surgical SPN diagnosis was confirmed in all cases. During the 2-year follow-up period, no recurrence was observed., Conclusion: SPN presented primarily as a solid lesion on endosonographic assessment. The lesion tended to be located in the head or body of the pancreas. There was no consistent characteristic pattern apparent on either elastography or Doppler assessment. Similarly SPN did not frequently cause stricture of the pancreatic duct or common bile duct. Importantly, we confirmed that EUS-guided biopsy was an efficient and safe diagnostic tool. The needle type used does not appear to have a significant impact on the diagnostic yield. Overall SPN remains a challenging diagnosis based on EUS imaging with no pathognomonic features. EUS guided biopsy remains the gold standard in establishing the diagnosis., Competing Interests: Conflict-of-interest statement: All the authors declare that they have no conflict of interest., (©The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved.)

Background: Endoscopic ultrasound guided gastrojejunostomy (EUS-GJ) with lumen apposing metal stents has recently emerged as a viable option, as an alternative to surgical gastrojejunostomy and endoscopic enteral stenting, for managing gastric outlet obstruction (GOO). We aim to perform a retrospective analysis of the efficacy, safety and outcomes of EUS-GJ performed at three tertiary institutions in the United Kingdom., Methods: Consecutive patients who underwent EUS-GJ between August 2018 and March 2021 were identified from a prospectively maintained database. Data were obtained from interrogation of electronic health records., Results: Twenty five patients (15 males) with a median age of 63 years old (range 29-80) were included for analysis. 88% (22/25) of patients had GOO due to underlying malignant disease. All patients were deemed surgically inoperable or at high surgical risk. Both technical and clinical success were achieved in 92% (23/25) of patients. There was an improvement in the mean Gastric Outlet Obstruction Scoring System scores following a technically successful EUS-GJ (2.52 vs 0.68, p < 0.01). Adverse events occurred in 2/25 patients (8%), both due to stent maldeployment necessitating endoscopic closure of the gastric defect with clips. Long-term follow-up data were available for 21 of 23 patients and the re-intervention rate was 4.8% (1/21) over a median follow-up period of 162 (range 5-474) days., Conclusion: EUS-GJ in carefully selected patients is an effective and safe procedure when performed by experienced endoscopists., (© 2022. Crown.)

Purpose: To explore whether coil embolization of penile collateral arteries to prevent nontarget embolization during prostatic artery embolization (PAE) negatively affects erectile function., Materials and Methods: Retrospective analysis was performed on a prospectively maintained multicenter PAE database on all patients with benign prostatic hyperplasia (January 2014 to July 2016). International Index of Erectile Function (IIEF-5) scores were collected at baseline and within 12 months after the procedure. A logistic regression and nearest neighbor propensity-matched analysis (matched for age, baseline IIEF-5 scores, and use of 5α-reductase inhibitors) and paired t test were used to evaluate for differential impact on IIEF-5 scores between the group of patients who underwent (unilateral) penile collateral coil embolization and a matched control group of patients who did not., Results: Of a total of 216 patients, 26 underwent coil protection of an accessory pudendal vessel/penile collateral. After exclusions, 22 propensity-matched pairs were identified. The mean IIEF-5 score at baseline for the coil-embolized group was 14.8 ± 8.3 (out of a possible score of 30) and that for the matched control group was 14.0 ± 7.8. At the 12-month follow-up after the procedure, the mean follow-up IIEF-5 score was 15.5 ± 8.0 for the coil-embolized group and 14.2 ± 8.2 for the matched control group. The change in IIEF-5 scores after PAE was not significantly different between the 2 groups (0.66 ± 3.8 vs 0.20 ± 2.0; P = .64; 95% CI, -1.53 to 2.44)., Conclusions: When penile collateral arteries were identified, protective coil embolization of penile collateral/accessory pudendal vessels during PAE was unlikely to affect erectile function negatively., (Copyright © 2022 SIR. Published by Elsevier Inc. All rights reserved.)

Backgrounds/aims: Gallstone disease is a recognized complication of bariatric surgery. Subsequent management of choledocholithiasis may be challenging due to altered anatomy which may include Roux-en-Y gastric bypass (RYGB). We conducted a retrospective service evaluation study to assess the safety and efficacy of endoscopic ultrasound-directed transgastric endoscopic retrograde cholangiopancreatography (EDGE) in patients with RYGB anatomy., Methods: All the patients who underwent EDGE for endoscopic retrograde cholangiopancreatography after RYGB at two tertiary care centers in the United Kingdom between January 2020 and October 2021 were included in the study. Clinical and demographic details were recorded for all patients. The primary outcome measures were technical and clinical success. Adverse events were recorded. Hot Axios lumen apposing metal stents measuring 20 mm in diameter and 10 mm in length were used in all the patients for creation of a gastro-gastric or gastro-jejunal fistula., Results: A total of 14 patients underwent EDGE during the study period. The majority of the patients were female (85.7%) and the mean age of patients was 65.8 ± 9.8 years. Technical success was achieved in all but one patient at the first attempt (92.8%) and clinical success was achieved in 100% of the patients. Complications arose in 3 patients with 1 patient experiencing persistent fistula and weight gain., Conclusions: In patients with RYGB anatomy, EDGE facilitated biliary access has a high rate of clinical success with an acceptable safety profile. Adverse events are uncommon and can be managed endoscopically.

Researchers have documented that being an LGBTQ+-identifying teacher can present particular challenges and marginalizing experiences. This longitudinal, qualitative study is a follow-up to a year-long endeavor documenting the experiences of one gay and one lesbian-identifying preservice teachers as they navigated school and a professional job search. In this study, we followed these same two teachers as they entered their first year of professional teaching in academic year 2015-2016, and we present the experiences, difficulties, challenges, and navigation of these two LGTBQ+-identifying elementary teachers. The two participants also recently (2020) reflected back on their first year of professional teaching some four years prior, and we used their insights to chronicle another layer of reflection on their professional experiences. With these elementary teachers' experiences at the center, this study offers implications for school systems about how to recognize, support, and advocate for LGBTQ+-identifying teachers, particularly those new to the profession.

Peripheral T-cell lymphoma (PTCL) is a rare, heterogenous malignancy with dismal outcomes at relapse. Hypomethylating agents (HMA) have an emerging role in PTCL, supported by shared mutations with myelodysplasia (MDS). Response rates to azacitidine in PTCL of follicular helper cell origin are promising. Guadecitabine is a decitabine analogue with efficacy in MDS. In this phase II, single-arm trial, PTCL patients received guadecitabine on days 1-5 of 28-day cycles. Primary end points were overall response rate (ORR) and safety. Translational sub-studies included cell free plasma DNA sequencing and functional genomic screening using an epigenetically-targeted CRISPR/Cas9 library to identify response predictors. Among 20 predominantly relapsed/refractory patients, the ORR was 40% (10% complete responses). Most frequent grade 3-4 adverse events were neutropenia and thrombocytopenia. At 10 months median follow-up, median progression free survival (PFS) and overall survival (OS) were 2.9 and 10.4 months respectively. RHOA G17V mutations associated with improved PFS (median 5.47 vs. 1.35 months; Wilcoxon p = 0.02, Log-Rank p = 0.06). 4/7 patients with TP53 variants responded. Deletion of the histone methyltransferase SETD2 sensitised to HMA but TET2 deletion did not. Guadecitabine conveyed an acceptable ORR and toxicity profile; decitabine analogues may provide a backbone for future combinatorial regimens co-targeting histone methyltransferases., (© 2022. The Author(s).)

Background/aims: Cholangiogram interpretation is not used as a key performance indicator (KPI) of endoscopic retrograde cholangiopancreatography (ERCP) training, and national societies recommend different minimum numbers per annum to maintain competence. This study aimed to determine the relationship between correct ERCP cholangiogram interpretation and experience., Methods: One hundred fifty ERCPists were surveyed to appropriately interpret ERCP cholangiographic findings. There were three groups of 50 participants each: "Trainees," "Consultants group 1" (performed >75 ERCPs per year), and "Consultants group 2" (performed >100 ERCPs per year)., Results: Trainees was inferior to Consultants groups 1 and 2 in identifying all findings except choledocholithiasis outside the intrahepatic duct on the initial or completion/occlusion cholangiogram. Consultants group 1 was inferior to Consultants group 2 in identifying Strasberg type A bile leaks (odds ratio [OR], 0.86; 95% confidence interval [CI], 0.77-0.96), Strasberg type B (OR, 0.84; 95% CI, 0.74-0.95), and Bismuth type 2 hilar strictures (OR, 0.81; 95% CI, 0.69-0.95)., Conclusion: This investigation supports the notion that cholangiogram interpretation improves with increased annual ERCP case volumes. Thus, a higher annual volume of procedures performed may improve the ability to correctly interpret particularly difficult findings. Cholangiogram interpretation, in addition to bile duct cannulation, could be considered as another KPI of ERCP training.

Introduction: Paediatric varicocele embolization has many benefits over surgical ligation, but lacks published long-term data. We investigated technical and clinical outcomes in this under reported patient group., Objective: To evaluate technical success, complications and recurrence rates following varicocele embolization in paediatric patients., Materials and Methods: A single-centre retrospective review of procedural data and electronic notes of consecutive patients referred for varicocele embolization over a 10-year period was performed (February 2010-March 2020). The primary outcomes were technical success and clinical efficacy (lack of symptom recurrence). Secondary outcomes included complications, testicular vein size reduction and procedural parameters including radiation exposure. Chi-square analysis was used to identify predictors of clinical success. Follow-up involved outpatient clinical assessment and telephone interview., Results: 40 patients (median age 15) were referred for left-sided symptomatic varicocele. Technical embolization success was achieved in 36/40 patients (90%), with 4 procedures abandoned (inaccessible vein). Embolization technique was platinum-based coils ± sclerosant. There were no immediate or long-term procedural complications. 32/36 patients completed short term follow-up at a median interval of 2.8 months. 30/32 (93.78%) experienced early clinical success. We found a significant reduction in peritesticular vein size following embolization (pre-3.70 vs post-2.56 mm, p = 0.00017) and a significant relationship between varicocele grade and early clinical success (χ2 = 4.2, p = 0.04), but not pre-treatment peritesticular vein size (χ2 = 0.02, p = 0.88). 33/36 patients completed long-term follow-up (median 4.2 years, range 0.36-9.9 years) producing a late clinical success rate of 93.9% (31/33). No post procedural complications including hydroceles were identified., Discussion: This study demonstrates technical success, matching rates described in adult patients which is reassuring and in support of embolization in the younger patient cohort. More importantly, the overall clinical success rate is comparable with previous embolization studies. Reassuringly, all symptom recurrences occurred early in follow-up, and there is a cogent argument for a single follow-up appointment at this juncture. Our long-term average follow-up duration, primarily gained via telephone interview, exceeds other studies. Although our study has the longest follow-up for varicocele embolization in children, it is limited by a few patients being lost to early and long-term follow-up. This is a recognised issue faced by studies attempting to follow-up benign conditions with a high clinical success rate., Conclusion: Paediatric varicocele embolization is a successful alternative to surgical ligation, with no complications and good clinical outcomes over a long-term follow-up., Competing Interests: Conflict of interest None., (Copyright © 2021 Journal of Pediatric Urology Company. Published by Elsevier Ltd. All rights reserved.)

Objective: The aims of this study were to determine whether physical rehabilitation intervention for individuals who required extracorporeal membrane oxygenation (ECMO) is associated with clinical outcomes and to assess whether the patient mobility response over initial rehabilitation sessions early in the intensive care unit (ICU) course predicts or is associated with survival, lengths of stay, discharge disposition, and 30-day readmissions., Methods: This study was a 10-year retrospective practice analysis of adults who were critically ill and required ECMO for >72 hours in the cardiothoracic ICU at an academic medical center. Physical rehabilitation implemented during or following the initiation of ECMO was quantified on the basis of timing, frequency, and change in mobility level in response to the intervention over the first 4 consecutive sessions. The primary dependent outcome was in-hospital mortality. Secondary outcomes included 30-day readmission and discharge disposition ranked on an ordinal scale., Results: Three hundred fifteen individuals (mean age = 50 years [SD = 15 years]; 63% men; mean Sequential Organ Failure Assessment score = 11.6 [SD = 3.3]) met the inclusion criteria. Two hundred eighteen individuals (69%) received at least 1 physical rehabilitation session while requiring ECMO, 70 (22%) received rehabilitation after ECMO was discontinued, and 27 (9%) never received rehabilitation. Individuals discharged alive achieved higher mobility levels and had a steeper, more positive rate of change in mobility over the first 4 sessions than individuals who died in the hospital (2.8 vs 0.38; degrees of freedom = 199, t = 8.24). Those who received rehabilitation and achieved the milestones of sitting on the edge of the bed and walking for >45 m were more likely to survive (47% vs 13%; χ2 = 156) than those who did not (26% vs 3.5%; χ2 = 80)., Conclusion: A positive rate of change in mobility and the ability to achieve mobility milestones with rehabilitation were associated with improved clinical outcomes., Impact: An individual's mobility response to physical rehabilitation early in the ICU course is an important indicator of illness and should be used with clinical presentation to guide clinical decision-making and predict outcomes., (© The Author(s) 2021. Published by Oxford University Press on behalf of the American Physical Therapy Association. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Dengue virus (DENV) threatens almost 70% of the world's population, with no effective therapeutic currently available and controversy surrounding the one approved vaccine. A key factor in dengue viral replication is the interaction between DENV nonstructural proteins (NS) 5 and 3 (NS3) in the infected cell. Here, we perform a proof-of-principle high-throughput screen to identify compounds targeting the NS5-NS3 binding interface. We use a range of approaches to show for the first time that two small molecules-repurposed drugs I-OMe tyrphostin AG538 (I-OMe-AG238) and suramin hexasodium (SHS)-inhibit NS5-NS3 binding at low μM concentration through direct binding to NS5 that impacts thermostability. Importantly, both have strong antiviral activity at low μM concentrations against not only DENV-2, but also Zika virus (ZIKV) and West Nile virus (WNV). This work highlights the NS5-NS3 binding interface as a viable target for the development of anti-flaviviral therapeutics.

Issue Addressed: Health outcomes linked to men's relationships have the potential to both promote and risk the well-being of males and their families. The current scoping review provides a synthesis of men's relationship programs (excluding criminal court mandated services) in Australia, Canada and the United Kingdom to distil predominant program designs, access points, delivery modes and evaluative strategies., Methods: Databases CINAHL, Medline, PsycInfo and Web of Science were searched for eligible articles published January 2010 and June 2020. The inclusion criteria consisted of empirical studies focussed on relationship programs for men., Results: The review identified 21 articles comprising eight focussed on Fathering Identities as the Catalyst for Relationship Building and 13 targeting Men's Behaviour Change in Partner Relationships. Findings highlight the prevalence of group-based, in-person programs which men accessed via third party or self-referrals. Fathering programs highlighted the impact of men's violence on their children in appealing to attendees to strategise behavioural adjustments. Men's partner relationship programs emphasised self-control amid building strategies for proactively dealing with distress and conflict. Program evaluations consistently reported attendee feedback to gauge the acceptability and usefulness of services., Conclusions: That most men attending fathering and partner relationship programs were referred as a result of domestic violence and/or intimate partner violence underscores men's reticence for proactively seeking help as well as the absence of upstream relationship programs. There are likely enormous gains to be made by norming boys and men's relationship programs to prevent rather than correct violent and/or abusive behaviours., (© 2021 Australian Health Promotion Association.)

Backgrounds/aims: Post-operative pancreatic fistulas (POPF) and fluid collections (POPFC) remain significant sources of morbidity and mortality after pancreatic resections. There remains a paucity of literature describing endoscopic ultrasound (EUS) guided drainage of POPFC using a Hot AXIOS™ lumen apposing metal stent (LAMS)., Methods: We conducted a retrospective study, encompassing all consecutive patients with POPFC managed using Hot AXIOS™ LAMS at our institution between January 2017 and December 2019. Primary outcome measures were technical and clinical success. Secondary outcome measures were adverse events and recurrence rates., Results: Five patients underwent EUS guided drainage using Hot AXIOS™ LAMS during the study period. Mean age of patients was 67.8 ± 2.16 years. The majority (60.0%) of patients were males. Median duration of symptom onset after surgery was 9 days. All patients presented with abdominal pain. Median size of the collection measured on computed tomography was 91 mm. Median interval time between symptom onset and EUS drainage was 30 days. Two patients required percutaneous drainage prior to EUS guided drainage. Technical and clinical success were achieved for all patients. No adverse events were observed. Median duration of follow-up was 90 days. No recurrence of collection occurred during the follow-up period., Conclusions: EUS guided drainage of POPFC using Hot AXIOS™ LAMS is a safe and effective treatment modality with technical and clinical success rates of 100% in our experience.

Pitt-Hopkins syndrome (PTHS) is a rare autism spectrum-like disorder characterized by intellectual disability, developmental delays, and breathing problems involving episodes of hyperventilation followed by apnea. PTHS is caused by functional haploinsufficiency of the gene encoding transcription factor 4 (Tcf4). Despite the severity of this disease, mechanisms contributing to PTHS behavioral abnormalities are not well understood. Here, we show that a Tcf4 truncation (Tcf4 tr/+ ) mouse model of PTHS exhibits breathing problems similar to PTHS patients. This behavioral deficit is associated with selective loss of putative expiratory parafacial neurons and compromised function of neurons in the retrotrapezoid nucleus that regulate breathing in response to tissue CO 2 /H + . We also show that central Nav1.8 channels can be targeted pharmacologically to improve respiratory function at the cellular and behavioral levels in Tcf4 tr/+ mice, thus establishing Nav1.8 as a high priority target with therapeutic potential in PTHS., (© 2021. The Author(s).)

LGBTQ+-identifying preservice teachers must navigate several different contexts, including the university and public schools, wherein they must make decisions about being open ("out") regarding their LGBTQ+ identities. However, the small amount of research to date has typically focused on the experiences of LGBTQ+ educators already actively working in public schools. In this year-long, qualitative case study, we present the experiences, perspectives, and challenges of two elementary preservice teachers who identify as gay and lesbian through their year-long student teaching placement. The study offers implications for teacher education programs about often overlooked ways to recruit, support, and advocate for LGBTQ+ preservice teachers.

Obsessive-compulsive disorder (OCD) affects 1-2% of the population, and, as with other complex neuropsychiatric disorders, it is thought that rare variation contributes to its genetic risk. In this study, we performed exome sequencing in the largest OCD cohort to date (1,313 total cases, consisting of 587 trios, 41 quartets and 644 singletons of affected individuals) and describe contributions to disease risk from rare damaging coding variants. In case-control analyses (n = 1,263/11,580), the most significant single-gene result was observed in SLITRK5 (odds ratio (OR) = 8.8, 95% confidence interval 3.4-22.5, P = 2.3 × 10 -6 ). Across the exome, there was an excess of loss of function (LoF) variation specifically within genes that are LoF-intolerant (OR = 1.33, P = 0.01). In an analysis of trios, we observed an excess of de novo missense predicted damaging variants relative to controls (OR = 1.22, P = 0.02), alongside an excess of de novo LoF mutations in LoF-intolerant genes (OR = 2.55, P = 7.33 × 10 -3 ). These data support a contribution of rare coding variants to OCD genetic risk., (© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Purpose: To compare the relative IPSS (International Prostate Symptom Score) improvement in storage and voiding symptoms between prostatic artery embolization (PAE) and transurethral resection of the prostate (TURP)., Method: Retrospective analysis of the UK-ROPE (UK Register of Prostate Embolization) multicentre database was conducted with inclusion of all patients with full IPSS questionnaire score data. The voiding and storage subscore improvement was compared between interventions. Student's t-test (paired and unpaired) and ANOVA (Analysis of variance) were used to identify significant differences between the groups., Results: 146 patients (121 PAE, 25 TURP) were included in the analysis. Storage symptoms were more frequently the most severe symptom ('storage' in 75 patients vs 'voiding' in 17 patients). Between groups, no significant difference was seen in raw storage subscore improvement (TURP 4.9 vs PAE 4.2; p = 0.34) or voiding subscore improvement (TURP 8.4 vs PAE 6.7; p = 0.1). ANOVA demonstrated a greater proportionate reduction (relative to total IPSS) towards voiding symptoms in the TURP group (27.3% TURP vs 9.9% PAE, p = 0.001)., Conclusion: Although both TURP and PAE improve voiding symptoms more than storage, a significantly larger proportion of total symptom reduction is due to voiding in the TURP cohort, with PAE providing a more balanced improvement between voiding and storage.

Background: Patients undergoing orthopedic surgery are at risk of post-operative complications and needing Medical Emergency Team (MET) review. We assessed the frequency of, and associations with MET calls in orthopedic patients, and whether this was associated with increased in-hospital morbidity and mortality., Methods: Retrospective cohort study of patients admitted over four years to a University teaching hospital using hospital administrative and MET call databases., Results: Amongst 6344 orthopedic patients, 55.8% were female, the median (IQR) age and Charlson comorbidity index were 66 years (47-79) and 3 (1-5), respectively. Overall, 54.5% of admissions were emergency admissions, 1130 (17.8%) were non-operative, and 605 (9.5%) patients received a MET call. The strongest independent associations with receiving a MET call was the operative procedure, especially hip and knee arthroplasty. Common MET triggers were hypotension (37.5%), tachycardia (25.0%) and tachypnoea (9.1%). Patients receiving a MET call were at increased risk of anemia, delirium, pressure injury, renal failure and wound infection. The mortality of patients who received a MET call was 9.8% compared with 0.8% for those who did not. After adjusting for pre-defined co-variates, requirement for a MET call was associated with an adjusted odd-ratio of 9.57 (95%CI 3.1-29.7) for risk of in-hospital death., Conclusions: Approximately 10% of orthopedic patients received a MET call, which was most strongly associated with major hip and knee arthroplasty. Such patients are at increased risk of morbidity and in-hospital mortality. Further strategies are needed to more pro-actively manage at-risk orthopedic patients., (Crown Copyright © 2020. Published by Elsevier B.V. All rights reserved.)

Background: Fluoroscopy during endoscopic retrograde cholangiopancreatography (ERCP) exposes staff and patients to potentially harmful ionizing radiation. We performed a UK survey to explore trainee and trainer attitudes to radiation protection and cholangiogram interpretation in ERCP., Methods: An electronic 10-point survey was prospectively distributed to endoscopy unit leads, training programme directors between October and November 2019. Only UK-based ERCP trainees and trainers with hands-on procedural exposure were eligible for the survey., Results: The survey was completed by 107 respondents (58 trainees and 49 trainers), with an estimated overall response rate of 46%. Overall, 49% of respondents were up to date with their radiation protection course, 38% were aware of European Basic safety standards directive (BSSD), 38% wore radiation protection goggles, and 40% were aware of the average radiation screening dose per ERCP procedure. Compared with trainers, trainees were less likely to routinely wear thyroid protection shields (76% vs 92%; p=0.028), have awareness of the BSSD (20% vs 49%; p=0.037) or know their average procedural radiation dosages (21% vs 63%; p<0.001). With regard to cholangiogram interpretation, only 26% had received formal training, with 97% of trainees expressing a desire for further training., Conclusion: This survey highlights a relative complacency in safety attitudes to radiation protection during ERCP. These data provide impetus to improve training and quality assurance in radiation protection, which should be regarded as a mandatory safety aspect prior to commencing hands-on ERCP training., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Although much of the attention surrounding the opioid epidemic has focused on rural and suburban Whites and prescription opioids, heroin overdoses among urban Blacks are on the rise. While some argue that legalization of cannabis will combat the epidemic, there are concerns it ignores the shift in the epidemic and could increase vulnerability to opioid misuse. The goal of this study is to examine the association between cannabis use from adolescence to young adulthood with opioid misuse in a primarily urban Black cohort., Methods: Data are from a study of 580 youth (87 % Black and 71 % low SES) residing in Baltimore City followed from ages 6-26. Cannabis trajectories were identified between ages 14-26 using group-based trajectory modeling. Logistic regressions were conducted to examine the impact of trajectories on opioid misuse in young adulthood adjusting for individual, neighborhood and peer factors. Opioid misuse was defined as using heroin or narcotics or painkillers without a prescription between ages 19-26., Results: Four cannabis trajectories were identified: Low/Non-Users (59.7 %), Adolescent Onset Limited (19.5 %), Young Adult Onset (10.8 %), and Adolescent Onset Chronic (10.0 %). Adolescent Onset Chronic cannabis users had the highest rate of opioid misuse (44.8 %) followed by Adolescent Onset Limited (18.8 %), Young Adult Onset (14.8 %) and Low/Non-Users (8.3 %). Prevalences were significantly higher for Adolescent Onset groups relative to Low/Non-Users even after adjustment for individual, neighborhood and peer factors., Conclusions: Adolescent onset cannabis use is associated with opioid misuse in young adulthood among urban Blacks even after adjustment for socioecological factors associated with opioid misuse., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Autosomal dominant mutations in transcription factor 4 (TCF4) are associated with a rare syndromic form of Autism Spectrum Disorder (ASD) called Pitt-Hopkins Syndrome (PTHS). Here, we report the generation of a collection of induced pluripotent stem cells (iPSCs) from 5 patients diagnosed with PTHS and 5 familial controls. These patient-derived iPSCs contain a variety of mutations within the TCF4 gene, possess a normal karyotype and express all the appropriate pluripotent stem cell markers. These novel patient lines will be a useful resource for the research community to study PTHS and the function of TCF4., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 The Author(s). Published by Elsevier B.V. All rights reserved.)

Objectives: Face masks are an important component of personal protection equipment employed in preventing the spread of diseases such as COVID-19. As the supply of mass-produced masks has decreased, the use of homemade masks has become more prevalent. It is important to quantify the effectiveness of different types of materials to provide useful information, which should be considered for homemade masks., Methods: Filtration effects of different types of common materials were studied by measuring the aerosol droplet concentrations in the upstream and downstream regions. Flow-field characteristics of surrounding regions of tested materials were investigated using a laser-diagnostics technique, i.e., particle image velocimetry. The pressure difference across the tested materials was measured., Results: Measured aerosol concentrations indicated a breakup of large-size particles into smaller particles. Tested materials had higher filtration efficiency for large particles. Single-layer materials were less efficient, but they had a low pressure-drop. Multilayer materials could produce greater filtering efficiency with an increased pressure drop, which is an indicator of comfort level and breathability. The obtained flow-fields indicated a flow disruption downstream of the tested materials as the velocity magnitude noticeably decreased., Conclusions: The obtained results provide an insight into flow-field characteristics and filtration efficiency of different types of household materials commonly used for homemade masks. This study allows comparison with mass-produced masks under consistent test conditions while employing several well-established techniques., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Exposure to particulate air pollution is a major environmental risk factor for cardiovascular mortality and morbidity, on a global scale. Both acute and chronic cardiovascular impacts have so far been attributed to particulate-mediated oxidative stress in the lung and/or via 'secondary' pathways, including endothelial dysfunction, and inflammation. However, increasing evidence indicates the translocation of inhaled nanoparticles to major organs via the circulation. It is essential to identify the composition and intracellular targets of such particles, since these are likely to determine their toxicity and consequent health impacts. Of potential major concern is the abundant presence of iron-rich air pollution nanoparticles, emitted from a range of industry and traffic-related sources. Bioreactive iron can catalyse formation of damaging reactive oxygen species, leading to oxidative stress and cell damage or death. Here, we identify for the first time, in situ, that exogenous nanoparticles (~15-40 nm diameter) within myocardial mitochondria of young, highly-exposed subjects are dominantly iron-rich, and co-associated with other reactive metals including aluminium and titanium. These rounded, electrodense nanoparticles (up to ~ 10 x more abundant than in lower-pollution controls) are located within abnormal myocardial mitochondria (e.g. deformed cristae; ruptured membranes). Measurements of an oxidative stress marker, PrP C and an endoplasmic reticulum stress marker, GRP78, identify significant ventricular up-regulation in the highly-exposed vs lower-pollution controls. In shape/size/composition, the within-mitochondrial particles are indistinguishable from the iron-rich, combustion- and friction-derived nanoparticles prolific in roadside/urban environments, emitted from traffic/industrial sources. Incursion of myocardial mitochondria by inhaled iron-rich air pollution nanoparticles thus appears associated with mitochondrial dysfunction, and excess formation of reactive oxygen species through the iron-catalyzed Fenton reaction. Ventricular oxidative stress, as indicated by PrP C and GRP78 up-regulation, is evident even in children/young adults with minimal risk factors and no co-morbidities. These new findings indicate that myocardial iron overload resulting from inhalation of airborne, metal-rich nanoparticles is a plausible and modifiable environmental risk factor for cardiac oxidative stress and cardiovascular disease, on an international scale., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Introduction: In recent years there has been an increasing application of advanced EVAR techniques to tackle complex clinical and anatomical scenarios. In a bid to overcome the limitations of the traditional stent-grafts, newer EVAR endografts and techniques have been developed and introduced into clinical practice, permitting endovascular management of difficult infrarenal, juxta-renal and thoracoabdominal aneurysms for which previously there was no endovascular solution. As a consequence, we are now confronted with unique patterns of endoleak requiring customized clinical-radiological assessment and treatment. Despite the increasing body of evidence regarding new EVAR techniques and related endoleaks, current guidelines do not specifically address these issues., Objectives: Our review aims to assess risk factors, development, and management strategies of these endoleaks, in the most recent infrarenal EVAR devices and in more complex fenestrated EVAR (FEVAR) and Chimney EVAR (Ch-EVAR)., Expert Opinion: Most new devices have demonstrated types of endoleaks that need specific imaging and treatment, as in EVAS, FEVAR, and ChEVAR. Knowledge of specific stent-graft characteristics and the nature of endoleaks associated with the various procedures facilitates the application of relevant useful imaging. In addition, it should aid development of a customized and practically relevant approach to patient management during intervention and follow-up.

Introduction: FTND (Fagerstrӧm test for nicotine dependence) and TTFC (time to smoke first cigarette in the morning) are common measures of nicotine dependence (ND). However, genome-wide meta-analysis for these phenotypes has not been reported., Methods: Genome-wide meta-analyses for FTND (N = 19,431) and TTFC (N = 18,567) phenotypes were conducted for adult smokers of European ancestry from 14 independent cohorts., Results: We found that SORBS2 on 4q35 (p = 4.05 × 10-8), BG182718 on 11q22 (p = 1.02 × 10-8), and AA333164 on 14q21 (p = 4.11 × 10-9) were associated with TTFC phenotype. We attempted replication of leading candidates with independent samples (FTND, N = 7010 and TTFC, N = 10 061), however, due to limited power of the replication samples, the replication of these new loci did not reach significance. In gene-based analyses, COPB2 was found associated with FTND phenotype, and TFCP2L1, RELN, and INO80C were associated with TTFC phenotype. In pathway and network analyses, we found that the interconnected interactions among the endocytosis, regulation of actin cytoskeleton, axon guidance, MAPK signaling, and chemokine signaling pathways were involved in ND., Conclusions: Our analyses identified several promising candidates for both FTND and TTFC phenotypes, and further verification of these candidates was necessary. Candidates supported by both FTND and TTFC (CHRNA4, THSD7B, RBFOX1, and ZNF804A) were associated with addiction to alcohol, cocaine, and heroin, and were associated with autism and schizophrenia. We also identified novel pathways involved in cigarette smoking. The pathway interactions highlighted the importance of receptor recycling and internalization in ND., Implications: Understanding the genetic architecture of cigarette smoking and ND is critical to develop effective prevention and treatment. Our study identified novel candidates and biological pathways involved in FTND and TTFC phenotypes, and this will facilitate further investigation of these candidates and pathways., (© The Author(s) 2019. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved.For permissions, please e-mail: journals.permissions@oup.com.)

General personality dimensions are associated with clinical severity and treatment response in individuals with depression and many anxiety disorders, but little is known about these relationships in individuals with obsessive-compulsive disorder (OCD). Individuals in the current study included 705 adults with OCD who had participated in family and genetic studies of the disorder. Participants self-completed the Neuroticism, Extraversion, Openness Personality Inventory or Neuroticism, Extraversion, Openness Five-Factor Inventory-3. Relationships between personality scores, and subjective impairment and OCD treatment response, were evaluated. The odds of subjective impairment increased with (unit increase in) the neuroticism score (odds ratio, OR = 1.03; 95% CI = 1.01-1.04; p < 0.01) and decreased with extraversion scores (OR = 0.98; 95% CI = 0.96-0.99; p < 0.01). The odds of reporting a good response to serotonin/selective serotonin reuptake inhibitors (OR = 1.02; 95% CI = 1.01-1.04; p < 0.01) or cognitive behavioural therapy (OR = 1.03; 95% CI = 1.01-1.05; p < 0.01) increased with the extraversion score. The magnitude of these relationships did not change appreciably after adjusting for other clinical features related to one or more of the personality dimensions. The findings suggest that neuroticism and extraversion are associated with subjective impairment, and that extraversion is associated with self-reported treatment response, in individuals with OCD. © 2019 John Wiley & Sons, Ltd., (© 2019 John Wiley & Sons, Ltd.)

Background: Hypotension following orthopaedic surgery has been associated with increased morbidity and mortality. Rapid response teams (RRT) review patients on hospital wards with hypotension., Aim: To evaluate the epidemiology of hypotensive RRT activations in adult orthopaedic patients to identify contributing factors and areas for future quality improvement., Methods: Timing of RRT activations, presumed causes of hypotension and associated treatments were assessed., Results: Among 963 RRT activations in 605 patients over 3 years, the first calls of 226 of 605 patients were due to hypotension, and 213 (94.2%) of 226 had sufficient data for analysis. The median age was 79 (interquartile range 66-87) years; 58 (27.2%) were male, and comorbidities were common. Most (68%) surgery was emergent, and 75.1% received intraoperative vasopressors for hypotension. Most activations occurred within 24 h of surgery, and hypovolaemia, infection and arrhythmias were common presumed causes. Fluid boluses occurred in 173 (81.2%), and the time between surgery and RRT activation was 10 (4.0-26.5) h. in cases where fluid boluses were given, compared with 33 (15.5-61.5) h. where they were not (P < 0.001). Blood transfusion (30, 14.1%) and withholding of medications were also common. Hospital mortality was 8.5% (18), and 13.6% (29) were admitted to critical care at some stage. In-hospital death was associated with older age, functional dependence, arrhythmia and presumed infection., Conclusions: Hypotension-related RRT calls in orthopaedic patients are common. Future interventional studies might focus on perioperative fluid therapy and vaso-active medications, as well as withholding of anti-hypertensive medications preoperatively., (© 2019 Royal Australasian College of Physicians.)

DSM-V-defined substance use disorder comprises four groups of symptoms: impaired control, social impairment, risky use, and pharmacological reactions. Behavioral patterns of impaired control, including impulsivity and risk taking, are associated with HIV risk behaviors. Substance users with stronger craving symptoms are more likely to use drugs via intravenous injection than other routes because of the faster drug effect and the higher bioavailability; thus, they are at high risk of HIV infection. HIV risk behaviors such as unprotected sex and intravenous injection facilitate HIV disease spread. Public health policies such as Needle and Syringe Exchange Programs and medication-assisted treatment are proven to reduce HIV risk behaviors such as the frequency of intravenous injection and even the incidence of HIV infection, but both of them have limitations. While intravenous injection is a frequently discussed issue in public policies and the HIV-related literature, it is a much less frequent topic in the addiction literature. We believed that understanding the mental substrate behind impulsivity/risk taking and the possible biological mechanism of intravenous injection may help in creating more effective strategies to slow down HIV infection.

Dengue virus (DENV) threatens almost 70% of the world's population, with no effective vaccine or therapeutic currently available. A key contributor to infection is nuclear localisation in the infected cell of DENV nonstructural protein 5 (NS5) through the action of the host importin (IMP) α/β1 proteins. Here, we used a range of microscopic, virological and biochemical/biophysical approaches to show for the first time that the small molecule GW5074 has anti-DENV action through its novel ability to inhibit NS5⁻IMPα/β1 interaction in vitro as well as NS5 nuclear localisation in infected cells. Strikingly, GW5074 not only inhibits IMPα binding to IMPβ1, but can dissociate preformed IMPα/β1 heterodimer, through targeting the IMPα armadillo (ARM) repeat domain to impact IMPα thermal stability and α-helicity, as shown using analytical ultracentrifugation, thermostability analysis and circular dichroism measurements. Importantly, GW5074 has strong antiviral activity at low µM concentrations against not only DENV-2, but also zika virus and West Nile virus. This work highlights DENV NS5 nuclear targeting as a viable target for anti-flaviviral therapeutics.

Objective: Research on the heterogeneity in drinking patterns of urban minorities within a socioecological framework is rare. The purpose of this study was to explore multiple, distinct patterns of drinking from adolescence to young adulthood in a sample of urban minority youth and to examine the influence of neighborhood, family, and peers on these trajectories., Method: Data are from a longitudinal study of 584 (56% male) primarily Black (87%) youth who were first sampled in childhood based on their residence in low-income neighborhoods in Baltimore City and followed up annually through age 26. Data were analyzed using group-based trajectory modeling and multinomial logistic regression., Results: Modeling revealed six trajectories from ages 14 to 26: abstainer, experimenter, adult increasing, young adult increasing, adolescent limited, and adolescent increasing. Neighborhood disadvantage was a risk factor for drinking regardless of the timing of onset. Perceptions of availability, peer drinking, and parental approval for drinking were risk factors for underage drinking trajectories, whereas parental supervision was a significant protective factor. Positive social activities in neighborhoods was protective against increased drinking, whereas a decline in perceptions of peer drinking was associated with adolescent-limited drinking., Conclusions: Our findings uniquely highlight the importance of developing interventions involving parents for urban minority youth for whom family is particularly relevant in deterring underage drinking. Perhaps most importantly, our data suggest that interventions that support positive social activities in disadvantaged neighborhoods are protective against adolescent drinking and altering perceptions of peer drinking may reduce adolescent drinking among low-income, urban minority youth.