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Endoplasmic reticulum stress activates the unfolded protein response (UPR). The authors show that glucose extends the lifespan of aged animals by activating the otherwise quiescent UPR while causing a UPR-dependent reduced longevity in young animals

Abstract Background Psychosocial interventions are needed to enhance patient engagement and retention in medication treatment within opioid treatment programs. Measurement-based care (MBC), an evidence-based intervention structure that involves ongoing monitoring of treatment progress over time to assess the need for treatment modifications, has been recommended as a flexible and low-cost intervention for opioid treatment program use. The MBC2OTP Project is a two-phase pilot hybrid type 1 effectiveness-implementation trial that has three specific aims: (1) to employ Rapid Assessment Procedure Informed Clinical Ethnography (RAPICE) to collect mixed methods data to inform MBC implementation; (2) to use RAPICE data to adapt an MBC protocol; and (3) to conduct a hybrid type 1 trial to evaluate MBC’s preliminary effectiveness and implementation potential in opioid treatment programs. Methods This study will be conducted in two phases. Phase 1 will include RAPICE site visits, qualitative interviews (N = 32–48 total), and quantitative surveys (N = 64–80 total) with staff at eight programs to build community partnerships and evaluate contextual factors impacting MBC implementation. Mixed methods data will be analyzed using immersion/crystallization and thematic analysis to inform MBC adaptation and site selection. Four programs selected for Phase 2 will participate in MBC electronic medical record integration, training, and ongoing support. Chart reviews will be completed in the 6 months prior-to and following MBC integration (N = 160 charts, 80 pre and post) to evaluate effectiveness (patient opioid abstinence and treatment engagement) and implementation outcomes (counselor MBC exposure and fidelity). Discussion This study is among the first to take forward recommendations to implement and evaluate MBC in opioid treatment programs. It will also employ an innovative RAPICE approach to enhance the quality and rigor of data collection and inform the development of an MBC protocol best matched to opioid treatment programs. Overall, this work seeks to enhance treatment provision and clinical outcomes for patients with opioid use disorder. Trial registration This study will be registered with Clinicaltrials.gov within 21 days of first participant enrollment in Phase 2. Study Phase 1 (RAPICE) does not qualify as a clinical trial, therefore Phase 2 clinical trial registration has not yet been pursued because all elements of Phase 2 will be dependent on Phase 1 outcomes.

Manual measurement of snow water equivalent (SWE) is still important today for several applications such as hydrological model validation. This measurement can be performed with different types of snow tube sampler or by a snow pit. Although these methods have been performed for several decades, there is an apparent lack of information required to have a consensus regarding the best reference for “true” SWE. We define and estimate the uncertainty and measurement error of different methods of snow pits and snow samplers used in a boreal biome. Analysis was based upon measurements taken over five consecutive winters (2016–2020) from the same flat and open area. This study compares two snow pit methods and three snow samplers. In addition to including the Standard Federal sampler (SFS), this study documents the first use of two new large diameter samplers, the Hydro-Québec sampler (HQS) and Université Laval sampler (ULS). Large diameter samplers had the lowest uncertainty (2.6 % to 4.0 %). Snow pit methods had higher uncertainty due to instruments (7.1 % to 11.4 %), close to that of the SFS (mean = 10.4 %). Given its larger collected snow volume for estimating SWE and its lower uncertainty, we posit that ULS represents the most appropriate method of reference for “true” SWE. By considering ULS as the reference in calculating mean bias error (MBE), different snow pit methods overestimated SWE by 16.6 % to 26.2 %, which was much higher than SFS (8.4 %). This study suggests that large diameter samplers are the best method for estimating “true” SWE in a boreal biome.

Abstract Visual components of trauma memories are often vividly re-experienced by survivors with deleterious consequences for normal function. Neuroimaging research on trauma has primarily focused on threat-processing circuitry as core to trauma-related dysfunction. Conversely, limited attention has been given to visual circuitry which may be particularly relevant to posttraumatic stress disorder (PTSD). Prior work suggests that the ventral visual stream is directly related to the cognitive and affective disturbances observed in PTSD and may be predictive of later symptom expression. The present study used multimodal magnetic resonance imaging data (n = 278) collected two weeks after trauma exposure from the AURORA study, a longitudinal, multisite investigation of adverse posttraumatic neuropsychiatric sequelae. Indices of gray and white matter were combined using data fusion to identify a structural covariance network (SCN) of the ventral visual stream 2 weeks after trauma. Participant’s loadings on the SCN were positively associated with both intrusion symptoms and intensity of nightmares. Further, SCN loadings moderated connectivity between a previously observed amygdala-hippocampal functional covariance network and the inferior temporal gyrus. Follow-up MRI data at 6 months showed an inverse relationship between SCN loadings and negative alterations in cognition in mood. Further, individuals who showed decreased strength of the SCN between 2 weeks and 6 months had generally higher PTSD symptom severity over time. The present findings highlight a role for structural integrity of the ventral visual stream in the development of PTSD. The ventral visual stream may be particularly important for the consolidation or retrieval of trauma memories and may contribute to efficient reactivation of visual components of the trauma memory, thereby exacerbating PTSD symptoms. Potentially chronic engagement of the network may lead to reduced structural integrity which becomes a risk factor for lasting PTSD symptoms.

Gastrointestinal stromal tumors (GISTs) account for 1% of GI neoplasms in adults, and epidemiological data suggest an even lower occurrence in pregnant women. The majority of GISTs are caused by KIT and PDGFRA mutations. This is not the case in women of childbearing age. Some GISTs do not have a KIT/PDGFRA mutation and are classified as wild-type (WT) GISTs. WT-GIST includes many molecular subtypes including SDH deficiencies. In this paper, we present the first case report of a metastatic SDH-deficient GIST in a 23-year-old pregnant patient and the challenges encountered given her concurrent pregnancy. Our patient underwent a surgical tumor resection of her gastric GIST as well as a lymphadenectomy a week after induction of labor at 37 + 1 weeks. She received imatinib, sunitinib as well as regorafenib afterward. These drugs were discontinued because of disease progression despite treatment or after side effects were reported. Hence, she is currently under treatment with ripretinib. Her last FDG-PET showed a stable disease. This case highlights the complexity of GI malignancy care during pregnancy, and the presentation and management particularities of metastatic WT-GISTs. This case also emphasizes the need for a multidisciplinary approach and better clinical guidelines for offering optimal management to women in this specific context.

ABSTRACTBackground Pharmacological management of fibromyalgia is complex. Chronic pain management is characterized by off-label prescribing and use, multimorbidity, and polypharmacy.Aims This study aimed to describe pain medications use and perceived risk among people living with fibromyalgia and compare this use to evidence-based recommendations.Methods Directive telephone interviews were conducted with 63 individuals self-reporting a diagnosis of fibromyalgia (Quebec, Canada). The questionnaire addressed specific questions about their pain and pharmacological treatments currently used for pain management (prescribed and over-the-counter). Collected data were compared to the Canadian Fibromyalgia Clinical Practice Guidelines and to evidence reports published by recognized organizations.Results Despite a lack of robust scientific evidence to support opioids use to manage pain in fibromyalgia, 33% of our sample reported using them. Nonsteroidal anti-inflammatory drugs were used by 54.0% of participants, although this medication is not recommended due to lack of efficacy. Tramadol, which is recommended, was used by 23.8% of participants. Among the medications strongly recommended, anticonvulsants were used by 36.5%, serotonin norepinephrine reuptake inhibitor antidepressants by 55.6%, and tricyclic antidepressants by 22.2%. Cannabinoids (17.5%) and medical cannabis (34.9%) use were also reported. For all of these medication subclasses, no differences were found between participants not reporting (n = 35) or reporting (n = 28) more than one pain diagnosis (P

Introduction: Extensive investigation has been undertaken regarding drug delivery systems for the management of glioblastoma multiforme (GBM). The infiltrative behavior of GBM cells within the brain tissue is primarily attributed to their heterogeneity, the movement of interstitial fluid (IFF), and the presence of chemokines. These factors contribute to the limited effectiveness of current conventional treatments. To address the dissemination of GBM cells, a proposed therapeutic approach involves utilizing a controlled release gradient of CXC-chemokine-ligand-12 (CXCL12). However, the impact of IFF on GBM cell migration within the brain underscores its critical importance as a significant parameter, which, surprisingly, has not been extensively studied in the context of localized drug delivery targeting the brain.Methods: Hydrogels are known for their inherent capacity to entrap various agents and exert precise control over their subsequent release. In the present investigation, we aimed to elucidate the release kinetics of CXCL12, whether in its free form or encapsulated within nanoparticles, from alginate-based hydrogels, both under static and dynamic conditions. To investigate the impact of convective forces mimicking the interstitial fluid flow (IFF) within the peritumoral environment of the brain, a three-dimensional in vitro model was developed. This model enabled the evaluation of CXCL12 release as a function of time and position, specifically accounting for the contribution of simulated IFF on the release behavior.Results: We first demonstrated that the release kinetic profiles under static culture conditions were independent of the initial mass loading and the predominant phenomenon occurring was diffusion. Subsequently, we investigated the release of CXCL12, which was loaded into Alginate/Chitosan-Nanoparticles (Alg/Chit-NPs) and embedded within an alginate hydrogel matrix. Mathematical modeling results also indicated the presence of electrostatic interactions between alginate and CXCL12. The Alg/Chit-NPs effectively slowed down the initial burst release, leading to a reduction in the diffusion coefficient of CXCL12. To further study the release behavior, we developed a perfusion bioreactor with a unique culture chamber designed to recapitulate the peritumoral environment and varied the fluid flow rates at 0.5 µL/min, 3 µL/min, 6.5 µL/min, and 10 µL/min. As the flow rate increased, the cumulative amount of released CXCL12 also increased for all three initial mass loadings. Beyond 3 µL/min, convection became the dominant mechanism governing CXCL12 release, whereas below this threshold, diffusion played a more prominent role.Conclusion: The indirect perfusion flow had a crucial impact on CXCL12 release and distribution inside the hydrogel in and against its direction. This system highlights the importance of considering the IFF in brain targeting delivery system and will be used in the future to study GBM cell behaviors in response to CXCL12 gradient.

Background: New Delhi Metallo-β-lactamase (NDM)–producing Escherichia coli are highly resistant organisms that spread quickly. In the United States, organisms with blaNDM are rare and mostly associated with healthcare settings. However, in other countries, blaNDM can be relatively common and are found in community settings. State veterinary and public health partners detected NDM E. coli in a dog from Iran living at a Wisconsin animal rescue facility (ARF), where 40% of dogs had international origins. We investigated to determine spread among dog and human contacts and prevent further transmission. Methods: We screened dogs and humans at the ARF, a local veterinary clinic (clinic A), and ARF staff homes (homes A and B) for colonization with blaNDM. We reviewed veterinary records and conducted a case–control analysis to identify risk factors for blaNDM acquisition among dogs. We evaluated ARF infection control practices. Screening specimens that were positive for blaNDM were cultured. We conducted an analysis of short- and long-read whole-genome sequencing data to evaluate isolate relatedness. We compared NDM E. coli sequences from dogs to all NDM E. coli sequences from humans collected in Wisconsin and nearby states. Results: Screening identified blaNDM colonization in 27 (37%) of 73 ARF dogs and 4 (56%) of 7 dogs in home A, but not in ARF or staff in clinic A. Among ARF dogs with blaNDM, 20 (74%) 27 had international origins and 22 (81%) had ≥1 medical condition. Dogs sharing the same space (OR, 5.1; 95% CI, 1.8–14.7) were associated with blaNDM acquisition. We observed high animal density, soiled environments, and insufficient hand hygiene. ARF staff wore workwear and work shoes off site, including to home A. Sequencing identified 3 multilocus sequence types (STs) using the Achtman scheme among 27 isolates with blaNDM-5. Most isolates were ST361 (20 of 27, 74%) followed by ST167 (6 of 27, 22%) and ST1163 (1 of 27, 4%). Within-MLST cluster variability was

Background: Nationally, >30% of all outpatient antibiotics are unnecessary or inappropriate, and only 52% of outpatients with sinusitis, otitis media, or pharyngitis receive recommended first-line antibiotics. The Minnesota All Payer Claims Database (MN APCD) collects medical claims, pharmacy claims, and eligibility files from private and public healthcare payers. We analyzed claims to describe overall and firstline antibiotic prescribing for acute bronchitis, adult acute sinusitis, and pediatric patients. Results: We analyzed 3,502,013 respiratory events from 1,612,501 members. Acute bronchitis accounted for 179,723 events (5.1%), acute sinusitis accounted for 236,901 adult events (10%), and otitis media accounted for 232,226 pediatric events (19%). Also, 73,385 bronchitis diagnoses (~40%) had no associated antibiotic. Antibiotics were associated with 199,445 adult sinusitis events (84.2%), of which 89,386 (44.8%) were firstline antibiotics, and 190,962 pediatric otitis media events (82.2%), of which 126,859 (66.4%) were firstline antibiotics. Common antibiotic classes used when a firstline drug was not selected were macrolides (28.9%) and tetracyclines (26.8%) for adult acute sinusitis and cephalosporins (61.4%) and macrolides (30.6%) for pediatric otitis media. Compared to the least vulnerable quartile, the most vulnerable social vulnerability index (SVI) quartile had lower odds of receiving firstline antibiotics for adult acute sinusitis if antibiotics were prescribed (OR, 0.90; 95% CI, 0.87–0.94) and higher odds of receiving firstline antibiotics for pediatric otitis media if antibiotics were prescribed (OR, 1.16; 95% CI, 1.12–1.21). Conclusions: Improvement is needed in avoiding antibiotics for acute bronchitis and selecting firstline drugs for sinusitis and otitis media. Additional analyses adjusting for demographic, geographic, and prescriber factors are planned to better understand differences in prescribing appropriateness among Minnesotans.

This study examined the experience of contraceptive counseling and care in a Federally Qualified Health Center in Maryland. Patients attending medical visits in 2021 were surveyed using the Interpersonal Quality of Family Planning scale to assess the quality of contraceptive counseling. Medical chart reviews were performed to identify alignment between contraceptive care received, and preferences patients had expressed. Primary care providers, reproductive health providers, and a subgroup of patients were interviewed to further contextualize survey and chart review findings. The average item score for the 94 survey participants was 4.39 (SD: 0.9) out of 5. Factor analysis showed high internal consistency reliability (alpha = 0.96). Eighty percent of patients received contraceptive care that aligned with their preferences, 4% did not, and 16% lacked clear contraceptive preferences. Qualitative analysis revealed that patients desired more guidance from providers in selecting a contraceptive method, while providers noted logistical and insurance-related barriers to care. While the quality of contraceptive counseling was high, patient experience of care may be improved by implementing team-based care.

Cet article présente les résultats d’une recherche visant à explorer l’importance qu’accordent les étudiantes en formation en enseignement, au Québec et en France, quant à la mise en relation de la didactique et de la gestion de la classe. L’hypothèse de cette recherche est que les futures enseignantes ont de la difficulté à faire des liens entre ces deux dimensions parce qu’elles sont abordées séparément dans la formation. Les résultats présentés portent sur les données issues d’un questionnaire sur les liens entre la didactique et la gestion de la classe, développé dans le cadre de cette recherche et distribué auprès de 313 étudiantes. Cette première analyse descriptive permet de constater que les étudiantes semblent établir peu de liens entre la didactique et la gestion de la classe, particulièrement concernant les étapes de planification et d’évaluation. Ces constats soulèvent plusieurs questionnements sur la conception qu’elles ont de l’acte d’enseigner et sur le rôle de la formation en enseignement.

Drug targets are the main focus of drug discovery due to their key role in disease pathogenesis. Computational approaches are widely applied to drug development because of the increasing availability of biological molecular datasets. Popular generative approaches can create new drug molecules by learning the given molecule distributions. However, these approaches are mostly not for target-specific drug discovery. We developed an energy-based probabilistic model for computational target-specific drug discovery. Results show that our proposed TagMol can generate molecules with similar binding affinity scores as real molecules. GAT-based models showed faster and better learning relative to Graph Convolutional Network baseline models.

Objectives: Our objective is to determine if specific sociodemographic characteristics were associated with perceived drug-related discrimination among people who use drugs (PWUD) presenting for care in the emergency department (ED). Methods: We conducted a secondary analysis of data from the Navigator trial, a randomized control trial of two behavioral interventions in the ED for people at risk of an opioid overdose. Participants included adult patients presenting to two Rhode Island EDs. Eligible participants included those high risk for an opioid overdose, resided or received most of their healthcare in Rhode Island, and were able to provide consent. The primary outcome of this analysis was self-reported feelings of drug-related discrimination by the medical community. The independent variables of interest included race/ethnicity, gender identity, and sexual orientation. Log-binomial multivariable regression models were constructed with all three independent variables of interest and a selection of sociodemographic covariates. Results: Of 620 eligible participants, 251 (40.5%) reported ever experiencing drug-related discrimination in their lifetime. In the adjusted model, participants who identified as women and participants who identified as LGBQIA+ were more likely to report experiencing drug-related discrimination from the medical community in EDs. Racial/ethnic minority groups were less likely than White (non-Hispanic) participants to report drug-related discrimination. Discussion: In this study population, White participants reported more drug-related discrimination than their minority counterparts, although female and LGBQIA+ patients reported more discrimination. Future studies should further assess the significance of these intersecting identities on self-reported discrimination. This knowledge could improve ED-based interventions, policies, and services for PWUD.

Objectives: To determine associations between primary provider specialty and the contraceptive care that patients receive in a Federally Qualified Health Center setting in Maryland. Methods: A study of reproductive-age patients and their providers was performed from January 2018 to December 2021. A pooled crosssectional survey of electronic medical record data for 44 127 encounters of 22 828 patients was performed to calculate the odds of contraceptive care being addressed by patients who had General Practitioner, OB/GYN, pediatrician, or infectious disease (ID) specialists as their primary providers. Results: In 19 041 encounters (43%), contraception was addressed through either counseling alone, documentation of a contraceptive prescription, or long-acting reversible contraceptive (LARC) placement procedure. After adjusting for insurance status and race/ethnicity, the odds ratio (OR) of contraceptive care delivery was statistically significantly higher for OB/GYN providers compared to General Practitioners—OR 2.42 (CI 2.29-2.53) and statistically significantly lower for ID providers—OR 0.69 (CI 0.61-0.79). There was a non-statistically significant difference for Pediatricians—OR 0.88 (CI 0.77-1.01). Conclusion: The provision of contraceptive care, a critical aspect of comprehensive primary care delivered in an FQHC setting, varies by provider specialty, and may be negatively influenced by Ryan White funding related structures. There is a need to intentionally design robust referral and tracking systems to ensure contraceptive care is equitably accessible to all, regardless of assigned primary care provider specialty or HIV status.

Glycine receptors (GlyRs) are glycine-gated inhibitory pentameric ligand-gated ion channels composed of α or α + β subunits. A number of structures of these proteins have been reported, but to date, these have only revealed details of the extracellular and transmembrane domains, with the intracellular domain (ICD) remaining uncharacterised due to its high flexibility. The ICD is a region that can modulate function in addition to being critical for receptor localisation and clustering via proteins such as gephyrin. Here, we use modelling and molecular dynamics (MD) to reveal details of the ICDs of both homomeric and heteromeric GlyR. At their N and C ends, both the α and β subunit ICDs have short helices, which are major sites of stabilising interactions; there is a large flexible loop between them capable of forming transient secondary structures. The α subunit can affect the β subunit ICD structure, which is more flexible in a 4α2:1β than in a 4α1:1β GlyR. We also explore the effects of gephyrin binding by creating GlyR models bound to the gephyrin E domain; MD simulations suggest these are more stable than the unbound forms, and again there are α subunit-dependent differences, despite the fact the gephyrin binds to the β subunit. The bound models also suggest that gephyrin causes compaction of the ICD. Overall, the data expand our knowledge of this important receptor protein and in particular clarify features of the underexplored ICD.

The Guaymas Basin in the Gulf of California is characterized by active seafloor spreading, the rapid deposition of organic-rich sediments, steep geothermal gradients, and abundant methane of mixed thermogenic and microbial origin. Subsurface sediment samples from eight drilling sites with distinct geochemical and thermal profiles were selected for DNA extraction and PCR amplification to explore the diversity of methane-cycling archaea in the Guaymas Basin subsurface. We performed PCR amplifications with general (mcrIRD), and ANME-1 specific primers that target the alpha (α) subunit of methyl coenzyme M reductase (mcrA). Diverse ANME-1 lineages associated with anaerobic methane oxidation were detected in seven out of the eight drilling sites, preferentially around the methane-sulfate interface, and in several cases, showed preferences for specific sampling sites. Phylogenetically, most ANME-1 sequences from the Guaymas Basin subsurface were related to marine mud volcanoes, seep sites, and the shallow marine subsurface. The most frequently recovered methanogenic phylotypes were closely affiliated with the hyperthermophilic Methanocaldococcaceae, and found at the hydrothermally influenced Ringvent site. The coolest drilling site, in the northern axial trough of Guaymas Basin, yielded the greatest diversity in methanogen lineages. Our survey indicates the potential for extensive microbial methane cycling within subsurface sediments of Guaymas Basin.

There is an increasing recognition of the crucial role of the right ventricle (RV) in determining the functional status and prognosis in multiple conditions. In the past decade, the epigenetic regulation (DNA methylation, histone modification, and non-coding RNAs) of gene expression has been raised as a critical determinant of RV development, RV physiological function, and RV pathological dysfunction. We thus aimed to perform an up-to-date review of the literature, gathering knowledge on the epigenetic modifications associated with RV function/dysfunction. Therefore, we conducted a systematic review of studies assessing the contribution of epigenetic modifications to RV development and/or the progression of RV dysfunction regardless of the causal pathology. English literature published on PubMed, between the inception of the study and 1 January 2023, was evaluated. Two authors independently evaluated whether studies met eligibility criteria before study results were extracted. Amongst the 817 studies screened, 109 studies were included in this review, including 69 that used human samples (e.g., RV myocardium, blood). While 37 proposed an epigenetic-based therapeutic intervention to improve RV function, none involved a clinical trial and 70 are descriptive. Surprisingly, we observed a substantial discrepancy between studies investigating the expression (up or down) and/or the contribution of the same epigenetic modifications on RV function or development. This exhaustive review of the literature summarizes the relevant epigenetic studies focusing on RV in human or preclinical setting.

Abstract Introduction Foot involvement is a significant concern in psoriatic arthritis (PsA) as it can lead to severe levels of foot pain and disability and reduced mobility and quality of life. Previous studies have shown moderate efficacy for custom-made foot orthoses (CFO) in reducing foot pain and disability in people with rheumatoid arthritis. However, evidence on the efficacy of CFO in people with PsA is lacking. Objectives To explore the effects of CFO on foot function, foot and lower limb pain, gait function, and free-living walking activities (FWA) in people with PsA. Methods A pre-experimental study including twenty participants with PsA (mean age: 54.10 ± 9.06 years and disease duration: 11.53 ± 10.22 years) was carried out. All the participants received and wore CFO for 7 weeks. Foot and lower limb pain and foot function were measured before and after the intervention using the numerical rating scale (NRS) and the foot function index (FFI). Gait function was assessed by recording spatiotemporal parameters (STPs) during a 10-m walk test using an instrumented gait analysis system (Mobility Lab). Free-living walking activities (step count, free-living cadence, time spent in different ambulatory physical activities (APA)) were recorded over 7 days using an accelerometer-instrumented sock. Results The FFI reported scores demonstrated severe baseline levels of foot pain (54.46 ± 14.58 %) and disability (46.65 ± 16.14%). Statistically and clinically significant improvements in foot pain and foot function and large effect sizes (Cohen’s effect size > 1, p < 0.005) were observed after the intervention period. A strong correlation (r = −0.64, p < 0.01) between the CFO wearing time and foot function was demonstrated. However, no significant changes were found for gait STP or free-living walking activities after 7 weeks of CFO use. Conclusion Results support the clinical and biomechanical plausibility of using CFO in people with PsA to reduce pain and improve foot function. Large-scale and controlled studies are needed to confirm these findings. Moreover, a multidisciplinary approach including the prescription of exercise therapy and physiotherapy combined with CFO could be required to improve STP and promote APA in people with PsA. Trial registration ClinicalTrials.gov , NCT05075343 . Retrospectively registered on September 29, 2021

IntroductionBehavioral and cerebral dissociation has been now clearly established in some patients with acquired disorders of consciousness (DoC). Altogether, these studies mainly focused on the preservation of high-level cognitive markers in prolonged DoC, but did not specifically investigate lower but key-cognitive functions to consciousness emergence, such as the ability to take a first-person perspective, notably at the acute stage of coma. We made the hypothesis that the preservation of self-recognition (i) is independent of the behavioral impairment of consciousness, and (ii) can reflect the ability to recover consciousness.MethodsHence, using bedside Electroencephalography (EEG) recordings, we acquired, in a large cohort of 129 severely brain damaged patients, the brain response to the passive listening of the subject’s own name (SON) and unfamiliar other first names (OFN). One hundred and twelve of them (mean age ± SD = 46 ± 18.3 years, sex ratio M/F: 71/41) could be analyzed for the detection of an individual and significant discriminative P3 event-related brain response to the SON as compared to OFN (‘SON effect’, primary endpoint assessed by temporal clustering permutation tests).ResultsPatients were either coma (n = 38), unresponsive wakefulness syndrome (UWS, n = 30) or minimally conscious state (MCS, n = 44), according to the revised version of the Coma Recovery Scale (CRS-R). Overall, 33 DoC patients (29%) evoked a ‘SON effect’. This electrophysiological index was similar between coma (29%), MCS (23%) and UWS (34%) patients (p = 0.61). MCS patients at the time of enrolment were more likely to emerged from MCS (EMCS) at 6 months than coma and UWS patients (p = 0.013 for comparison between groups). Among the 72 survivors’ patients with event-related responses recorded within 3 months after brain injury, 75% of the 16 patients with a SON effect were EMCS at 6 months, while 59% of the 56 patients without a SON effect evolved to this favorable behavioral outcome.DiscussionAbout 30% of severely brain-damaged patients suffering from DoC are capable to process salient self-referential auditory stimuli, even in case of absence of behavioral detection of self-conscious processing. We suggest that self-recognition covert brain ability could be an index of consciousness recovery, and thus could help to predict good outcome.

Introduction Being bullied in adolescence has been associated with developing depressive symptoms in adulthood. Objectives We sought to describe the trajectories of peer victimization across adolescence and their relationships with grey matter volumes and depression outcomes in young adulthood. Methods Community adolescents from the IMAGEN database (n = 724) with both peer victimization and neuroimaging data were included. A longitudinal clusterization method (normal mixture model) was used to analyze the bullying scores at baseline (age 14), and at follow-ups at age 16, 18 and 22. Relations between clusters and brain volumes or depression diagnosis were examined using logistic and linear multivariate regression models. Results Three victimization trajectories were observed. A first trajectory included participants who were never bullied and had no depression outcome, a second trajectory identified participants who were bullied at age 14 and 16 only, and had no depression outcome, and finally, a third trajectory of continuous bullying throughout adolescence to young adulthood (age 22) that was significantly associated with depression outcomes (r=0.87, p=0.0004). In addition, the continuously bullied participants displayed larger volumes of bilateral hippocampus, posterior cingulate cortex and right putamen at age 22. Conclusions These data confirm that chronic peer victimization throughout adolescence is associated with brain structure changes and might increase vulnerability to depressive disorders. They highlight the need for preventive school interventions in early adolescents. Disclosure of InterestNone Declared

Introduction Recent longitudinal studies point towards the existence of a positive relationship between cannabis use and violence in people with severe mental disorders. However, the existence of a dose-response relationship between the frequency and/or the severity of cannabis use and violence has seldom been investigated. Objectives This study aimed to determine if a dose-response relationship between cannabis use and violence exists in a psychiatric population. Methods This observational study was conducted at the Institut universitaire de santé mentale de Montréal (Montréal, Canada). A total of 98 outpatients (81 males and 17 females, all over 18 years of age) with severe mental disorders were included in the analyses. Clinical evaluations were conducted every 3 months for a year. Substance use, violent behaviors, and potential covariables were assessed through self-reported assessments, urinary testing, as well as clinical, criminal, and police records. Using generalized estimating equations, the association between cannabis use frequency (non-users, occasional, regular, and frequent users, assessed using the Time-Line Follow-Back and confirmed with urinary testing) and violence was investigated, as well as the association between the severity of cannabis use (measured using the Cannabis Use Problems Identification Test – CUPIT) and violent behaviors. Results Cannabis use frequency and severity were significant predictors of violent behaviors. After adjustment for time, age, sex, ethnicity, psychiatric diagnoses, impulsivity and use of alcohol and stimulants, odds ratios were of 1.91 (p

Introduction VR-Assisted Therapy (VRT) for auditory verbal hallucinations has been demonstrated to have a significant impact on the symptoms, beliefs, and quality of life of patients with treatment-resistant schizophrenia. However, little is known about how these changes are implemented into their lives and on which aspects these improvements occur. Objectives This study aimed to qualitatively explore changes in the quality of life of patients who underwent VRT in the context of an ongoing clinical trial. Methods Ten consecutive patients enrolled in an ongoing clinical trial were assessed using semi-guided interviews before as well as 3 months after VRT. These encounters have been recorded and transcribed. Then, the content of the participants’ discourse was thoroughly analyzed, leading to the generation of an extensive theme grid. Each utterance was then coded by at least two members of the research team, and each disagreement was then discussed in a group format until a consensus was reached. As the cases were analyzed, the grid was adapted in a back and forth manner. New participants were included until data saturation occurred. Results The content analysis allowed the identification of nine main themes representing different aspects of the patients’ quality of life: psychiatric symptomatology, identity, occupations, wishes, interpersonal relationships, lifestyle, psychiatric follow-up, life events, and attitudes/behaviors during the interview. Each theme was then subdivided into more specific codes. By analyzing the evolution of the frequency of each subtheme, it was observed that, following therapy, patients presented with less psychotic symptoms, which were also perceived more positively, a better self-esteem, more hobbies and projects, as well as an overall improved lifestyle and mood. Conclusions Investigating how VRT impacts the patients’ quality of life allows for a deeper understanding of how people with treatment-resistant schizophrenia can achieve meaningful changes and move towards a certain recovery process. Disclosure of InterestNone Declared

Introduction Auditory verbal hallucinations (AVH), which often present in individuals with schizophrenia, can cause great psychological distress. Although antipsychotic medication can reduce AVH, 30% of patients will be resistant. Treatment resistance could be associated with important consequences, and there are only few treatment alternatives. Unfortunately, more than 50% of patients will not respond favorably to the best available psychological therapy, cognitive-behavioral therapy (CBT). However, using virtual reality (VR), our research team has adapted a therapy whose goal is to recreate the faces and voices of the patients’ persecutory voices as avatars. By interacting with an external representation of their hallucinations, patients implement new strategies to control their voices and to regulate their emotions. A small clinical trial (proof of concept) has demonstrated the safety and validity of this therapy as well as its superiority compared to the usual treatment. Objectives (1) To verify whether VR-Assisted Therapy (VRT) is superior to CBT for the treatment of AVH; and (2) to examine the effects of VRT and CBT on the symptomatology and quality of life. Methods For this single-blind randomized controlled clinical trial, 136 patients will by recruited (68/intervention) The effects on psychotic symptomatology as well as on quality of life is assessed using standardized questionnaires. Patients are included if they hear persecutory voices and have not responded to at least 2 trials of antipsychotics. Both groups are randomized from an external site and begin with an initial clinical assessment prior to randomization. Participants then receive 9 weekly one-hour therapy sessions (CBT or VRT), beginning the following week. A second clinical evaluation is carried out one week after the last session. A linear mixed effects model will be used to compare the effects of the 2 interventions. Results Results from a pilot randomized comparative trial evaluating the short- and long-term efficacy of VRT over CBT for patients with treatment-resistant schizophrenia (N=37/group) showed that both interventions produced significant improvements in AVH severity and depressive symptoms. Although results did not show a statistically significant superiority of VRT over CBT for AVH, VRT did achieve larger effects particularly on overall AVH (d = 1.080 for VRT and d = 0.555 for CBT). The recruitment of the current clinical trial is in progress. Image: Conclusions VRT, which is currently under clinical investigation, presents itself as an interesting complement to existing pharmacological treatments. Since VR technologies allow the recreation of scenarios that are nearly impossible to reproduce in real life, VR-assisted psychotherapy could eventually become an integral part of our clinical practices. Disclosure of InterestNone Declared

Genome-wide association studies have identified >250 genetic variants associated with coronary artery disease (CAD), but the causal variants, genes and molecular mechanisms remain unknown at most loci. We performed pooled CRISPR screens to test the impact of sequences at or near CAD-associated genetic variants on vascular endothelial cell functions. Using CRISPR knockout, inhibition and activation, we targeted 1998 variants at 83 CAD loci to assess their effect on three adhesion proteins (E-selectin, ICAM1, VCAM1) and three key endothelial functions (nitric oxide and reactive oxygen species production, calcium signalling). At a false discovery rate ≤10%, we identified significant CRISPR perturbations near 42 variants located within 26 CAD loci. We used base editing to validate a putative causal variant in the promoter of the FES gene. Although a few of the loci include genes previously characterized in endothelial cells (e.g. AIDA, ARHGEF26, ADAMTS7), most are implicated in endothelial dysfunction for the first time. Detailed characterization of one of these new loci implicated the RNA helicase DHX38 in vascular endothelial cell senescence. While promising, our results also highlighted several limitations in using CRISPR perturbations to functionally dissect GWAS loci, including an unknown false negative rate and potential off-target effects.

The use of transcatheter edge-to-edge mitral valve repair (TEER) in symptomatic patients with severe mitral regurgitation (MR) has dramatically increased over the last few years. Current guidelines consider TEER as a reasonable option in symptomatic patients with primary or chronic secondary severe MR with high or prohibitive surgical risk and favorable anatomy. However, several anatomical and morphological mitral features have restricted the use of this mini-invasive technique in its early experience. The latest fourth generation (G4) of the MitraClip system has been recently introduced and includes the possibility of independent leaflet grasping and 4 different sizes. This technical update offers the possibility of selecting and combining multiple devices for complex mitral valve anatomies and challenging procedures, which helps expand the applications of TEER. The present review describes the potential advantages and the help of the MitraClip G4 devices to overcome various anatomic and morphologic issues in challenging cases with complex primary and secondary MR procedures.

In the immersive environment of an online serious video game designed to depict social norms about excessive alcohol consumption, this study examines the effects of real-world and virtual-world social norms on alcohol use outcomes, centering on the persuasive elements of the One Shot game and its social psychological effects. This study implements a one-group, pretest-posttest, quasi-experimental design. Using a national sample of young adults aged 21–25 (N = 550) who reported recent binge drinking, OLS regression analyses documented that virtual-world norms were more predictive of alcohol-related outcomes than real-world norms. Specifically, virtual-world descriptive norms paired with severe consequences of hazardous drinking predicted improvements from pre-game to post-game in drinking refusal self-efficacy and attitudes toward drinking. Likewise, virtual-world social disapproval had a similar effect on drinking refusal self-efficacy, but not on attitudes toward drinking. Neither measure of virtual-world social norms had a significant effect on changes in intention to drink less from pre-game to post-game. Real-world descriptive norms and social disapproval had no significant effects on any of the alcohol use outcomes. Each of the three alcohol use outcomes improved significantly from pre-game to post-game. Implications for norms-based research and online serious video games are discussed.

Abstract Objective The objective of this study was to estimate the association between receipt of specific post‐overdose care services in the emergency department (ED) and subsequent engagement in treatment for opioid use disorder (OUD) after discharge. Methods This was a retrospective cohort study of Rhode Island residents treated at 1 of 4 EDs for opioid overdose who were not engaged in OUD treatment and were discharged home (May 2016–April 2021). Electronic health record data were used to identify ED services received, and state administrative data were used to define subsequent engagement in OUD treatment within 30 days. Multivariable conditional logistic regression was used to estimate the association between ED services received and subsequent treatment engagement. Results Overall, 1008 people not engaged in OUD treatment were treated at study EDs for opioid overdose and discharged home, of whom 146 (14%) subsequently engaged in OUD treatment within 30 days. Most patients were aged 25 to 44 years (59%) and non‐Hispanic White (69%). Receipt of behavioral counseling in the ED (adjusted odds ratio [aOR] = 1.79, 95% confidence interval [CI] = 1.18–2.71) and initiation of buprenorphine treatment in/from the ED (aOR = 5.86, 95% CI = 2.70–12.71) were associated with treatment engagement. Receipt of a take‐home naloxone kit or naloxone prescription and referral to treatment at discharge were not associated with treatment engagement. Overall, 49% of patients received behavioral counseling in the ED, and 3% initiated buprenorphine in/from the ED. Conclusion Strategies for increasing provision of behavioral counseling and initiation of buprenorphine in the ED may be useful for improving subsequent engagement in OUD treatment after discharge.

Few studies have examined teachers' natural use of praise and reprimand in the absence of training, possibly due to the challenges of live data collection. This study sought to determine the feasibility of using technology to examine teachers' use of praise and reprimand during class-wide and small group instruction in four elementary classrooms. In both settings, teachers used more general praise than behavior-specific praise and these differences were statistically significant. No differences were found between reprimand type, regardless of instructional context. During class-wide instruction, praise was delivered more frequently to individual students. No significant difference in praise or reprimand rates were observed between instructional contexts. Implications for training teachers to increase their praise-to-reprimand use and future research via video data collection are offered.

Polar research plays a vital role in developing our understanding of Earth's climate system. It is intrinsically interdisciplinary, lending itself to integration into existing undergraduate courses. Here we explore introducing undergraduates to polar research through computational guided inquiry (CGI) modules taught in a variety of courses and disciplines. Students apply course disciplinary techniques to analysis of polar data or research, in the context of climate change, by working through educational modules that include spreadsheets (Excel[superscript TM]) or interactive computer programing (Python in a Jupyter Notebook), over a few class or lab periods. The goals of this exploratory curriculum project are to determine instructor perceptions of effectiveness of the educational modules for teaching preexisting disciplinary course objectives, as well as student perceptions of enjoyment and learning. Evaluation consisted of a student questionnaire and interviews with instructors by an external evaluator. Students and instructors overall reported positive experiences with the modules, highlighted the importance of polar data and climate literacy, and noted increases in student understanding of course learning goals and comfort with the computational tools. Professors further reported that students found the modules motivating, fun and engaging. Taken together, this suggests that the modules are an effective means of bringing polar research into undergraduate classrooms while satisfying instructor goals for course learning objectives. Lessons learned include the importance of providing material such as videos to help transition to the topics of polar research and climate change and of supporting widely varying computational fluency.