Cocaine Use Disorder

DETAILED METHODOLOGY Phase I: * Research Design: Qualitative * Research Setting: Selected public schools of Pokhara, Nepal * Population: Teachers, Parents, and Students of Pokhara, Nepal * Samples: Selected Teachers, Parents \& students * Sample Size: 38 (The sample will be collected till data Saturation) * Data collection Technique: Focus group discussion * Data collection Tool: Focus group lead questions * Data Analysis: Thematic analysis (Atlas.ti) Phase II Research design: Cluster Randomized Trial Randomization method: Cluster Randomization Research Setting: Selected public schools of Pokhara, Nepal Population: Adolescent students of Pokhara, Nepal Sample: Selected Adolescents, who are in the age group 13-15 years old and studying in 8th \& 9th grades Variables * Independent variables: School-based Substance abuse Prevention Programme (SSPP) * Dependent variables: awareness, attitudes, peer pressure, and life skills related to prevention of substance abuse. * Demographic variables: age in years, gender, religion, education/grade, family type, residence, number of siblings, education of parents, occupation of parents, sources of information, history of substance abuse in the family. Sample size: 210 The expected outcomes of the study is to enhance awareness towards prevention of substance abuse,develop a positive attitude towards the prevention of substance abuse,develop drug refusal skills among adolescents,improve life skills and helps in th reduction of drug abuse behaviour adolescents

The proposed study will be a non-pharmacological, two arm parallel, Prospective, single blind clinical trial to evaluate if there is a difference in retentive characteristics of dentition in two group of post orthodontic treatment patients with vertical growth pattern patients in one group and horizontal growth pattern patients in other group of patients. The present study will be conducted in the Department of Orthodontic and Dentofacial Orthopedics, P.G.I.D.S, Pt. B.D Sharma University of health sciences, Rohtak. The study will be carried out after the institutional approval obtained from ethical committee. Patient will be allocated to two different study group by the investigator. the data analyst will be blinded regarding the intervention group. The sample size for the proposed study was calculated by using the formula. Total sample size = N = 2σ 2 (Zβ + Zα/2) 2 / (difference of mean )2. sample size of 20 patients was calculated by using the above formula at confidence interval 95% with power 99%. GROUP 1: patient with vertical growth pattern have who had undergone, fixed orthodontic cases having FMA of 26 0 or more for hyperdivergent cases. GROUP 2 patient with horizontal growth pattern who had undergone , Fixed orthodontic cases having FMA of 24 o or less for hypodivergent cases. Changes in levels of bone turnover markers CTX-bone resorption and BALP-bone formation using ELISA. These parameters will be charted at T0, T1, T2, T3,T4 for each patient. T0 - Records will be obtained at the time of retainer delivery T1 - Records will be obtained after 1month of retainer delivery T2 - Records will be obtained after 3 month of retainer delivery T3- Records will be obtained after 6 months of retainer delivery T4- Records will be obtained after 12 months of retainer delivery Assessment of bite force will be done using bite force measuring device at T0 - Records will be obtained at the time of retainer delivery T1 - Records will be obtained after 1month of retainer delivery T2 - Records will be obtained after3month of retainer delivery T3- Records will be obtained after 6 months of retainer delivery T4- Records will be obtained after 12 months of retainer delivery

Cocaine use disorder (CUD) is a chronic disorder associated with numerous relapses and periods of abstinence. Studies in CUD suggest that \~ 60 to 75% of abstinent addicts relapse over twelve months. Documenting specific neurochemical abnormalities that lead to relapse in individuals with CUD has the potential to accelerate the development of medications to prevent relapse. Basic investigations postulate an imbalance between brain stress and anti-stress/resilience systems as the underlying mechanism that drives negative reinforcement, craving, and relapse in addiction.. Nociceptin (N/OFQ), which binds to the nociceptive opioid peptide receptors (NOP) is a critical component of the brain's anti-stress system. N/OFQ exerts its anti-stress effect by counteracting the functional effects of the primary stress-promoting neuropeptide corticotrophin releasing factor (CRF) in the brain. Studies have also shown that acute increases in CRF and stress are countered by increased NOP receptor expression (\~ 10% ) in brain regions that regulate stress such as bed nucleus of the stria terminalis. PET studies with the NOP radiotracer \[11C\]NOP-1A show increased binding to NOP in CUD compared to HC. PET studies also show NOP receptors to upregulate (\~ 15%) in response to an acute intravenous hydrocortisone challenge (1 mg/Kg). NOP upregulation may represent an adaptive mechanism in the brain to counteract stress-induced increases in cortisol and CRF. Here, we postulate a failure in this adaptive mechanism as a reason that leads to relapse in CUD. CUD subjects and HC will be studied with \[11C\]NOP-1A before and after an intravenous hydrocortisone challenge (aim 1). Hydrocortisone is used as a challenge because it increases cortisol and CRF in brain regions that regulate stress. We hypothesize that hydrocortisone-induced increases in \[11C\]NOP-1A binding (DELTA VT) will be smaller in CUD relative to HC, and this will be associated with less time to relapse in a 12-week follow up. Mechanistic studies have also shown N/OFQ to act on ventral tegmental area/midbrain NOP receptors to inhibit the firing of dopamine neurons and limit reward to cocaine. Imaging amphetamine-induced dopamine release in a subset of CUD subjects who participate in aim 1 will allow us to link midbrain NOP receptor expression with ventral striatum (VST) dopamine release and examine its role in reinforcement (aim 2). The aims proposed in this study have the potential to clarify the role of N/OFQ and NOP in stress, reward, and relapse in CUD.

The clinical significance of retained needle fragments remains unknown. Needle retentions can be asymptomatic, cause local symptoms, and can sometimes even lead to dangerous complications such as needle emboli to the heart or lungs. The most common injection sites are likely the peripheral veins of the arms. However, continuous IVD use leads to vein sclerosis, and patients with long-term use may therefore also use peripheral veins of their lower limbs and even the central veins of the groin or neck. Subcutaneously retained needles can pose a risk of needlestick injury to medical staff during clinical examination and treatment procedures. Unrecognized retained needles can also cause hazards during magnetic resonance imaging. The study protocol received a positive review from the Tampere University Hospital Ethics Committee (study code: R22037). The researchers subsequently received the organizational permissions necessary to conduct the study. PWIDs will be asked to give written informed consent prior to any study procedures. Participants will be asked to fill in a questionnaire about their basic information, drug use history, previous injection sites, and whether they have had any local complications due to injecting drugs. After the completion of the questionnaire, participants will undergo targeted X-ray imaging of the injection sites. As metallic objects, needle fragments can be visualized with standard X-ray imaging. Female participants of childbearing potential (\< 50 years) will undergo urine sample pregnancy testing prior to X-ray imaging. A pilot study with 20 participants will be conducted first. Experiences from the pilot will be used to refine the study protocol if needed. If modifications are made, they will be subjected to ethics review and will be provided on ClinicalTrials.gov. After the pilot study, the researchers aim to recruit an additional 80 patients (totaling up to 100 participants). Our research questions are 1) What is the prevalence of radiologically confirmed needle retention among PWIDs\*? The secondary research questions are 1. Do patient-reported symptoms and the suspicion of a retained needle fragments correspond to radiologically confirmed needle retention? 2. What are the predisposing factors to needle fragmentation? 3. Have PWIDs sought medical attention prior to the study for possible symptoms in the injection sites? 4. How frequently are verified needle fragments surgically removed within five years after their detection, and are verified needle fragments a proxy or a risk factor for mortality? \*As only patients in outpatient care will be recruited, the sample is not entirely representative of all PWIDs in the study area (e.g., people who are hospitalized or imprisoned are not recruited).

This is a single arm, open-label, dose escalation investigator initiated (IIT) study, the primary objective is to evaluate the safety and tolerability of CD19/ CD22/BCMA CAR-T therapy in patients with relapsed/refractory multiple myeloma, and determine the maximum tolerated dose (MTD). For the secondary objectives,pharmacokinetics(PK), survival of CAR-T cells in vivo,pharmacodynamics (PD) and efficacy in R/R MM will be evaluated. This study flow comprises of a screening phase( 30 to10 days prior to infusion), apheresis phase (9 to 8 days prior to infusion), lymphodepletion phase (5 to 3 days prior to infusion) , infusion of CD19/CD22/BCMA CAR-T cells on Day0, DLT assessments phase (from Day1 to Day 28) and post- treatment follow-up phase (Day 29 and up to end of the study).

This study will be a two-arm, assessor-blind, randomized controlled trial enrolling approximately 300 middle and high school students who have recently violated a school substance use policy. Participants will be followed over a one-year period. Participants will be randomly assigned to either four-weeks of iDECIDE or a waitlist control group. Participants assigned to receive iDECIDE will receive a drug education curriculum developed to provide behavioral support and psychoeducation via videoconference or in-person visits. The purpose of iDECIDE is to provide students with the knowledge and skills they need to make healthy decisions regarding substance use. Participants in the waitlist control group will undergo symptom and substance use monitoring only, until completion of the one-month follow-up visit at which point they will be offered the opportunity to enroll in the iDECIDE curriculum, if desired. Data collection will occur during nine visits over the span of approximately one year, including one randomization baseline visit, four weekly visits during the intervention phase of the study during which time participants will participate in either iDECIDE or monitoring, and then four follow-up visits. The follow-up visits will occur at approximately one week, one month, six months, and one year following the end-of-intervention. Participants in both arms will complete questionnaires and assessments conducted by raters blinded to study arm assignment. Primary outcomes (knowledge of drug effects, knowledge of brain development and neurobiology of addiction, readiness to quit, perceptions of harm, and frequency of substance use) will be assessed at visit 1 (baseline), visit 5 (end-of-intervention), visit 6 (one week follow-up), and visit 7 (one month follow-up). Participants will be compensated for session attendance and provision of urine samples.

Montefiore will engage fathers in families at risk of substance misuse in the Bronx and neighboring communities. Families will be referred from Bronx and neighboring community-based child welfare systems, substance use disorder (SUD) treatment providers, and medical providers if identified at risk of substance use concerns and will be randomly assigned to receive services as usual as part of the comparison group, or to receive enhanced services as part of the program group. Enhanced services include: (1) Motivational Enhancement; (2) referral to Healthy, Empowered, Resilient, and Open (HERO) Dads fatherhood engagement program; (3) Contingency Management; and (4) Case Management.

Healthy controls (HC) will be studied as outpatients and undergo one MRI and one 11C-UCB-J PET scan, along with neurocognitive tasks. Individuals with Cocaine Use Disorder (CUD) will complete the study as inpatients on our unit and undergo one MRI and two 11C-UCB-J PET scans, along with neurocognitive tasks. Participants will complete sleep studies (to evaluate sleep architecture); the first two nights after admission and the last two nights before discharge. Cocaine users will be asked to complete outpatient follow-ups twice a week for up to nine weeks following their inpatient stay.

The goal of this study is to understand how Bright Horizons impacts adolescents who have a recent binge substance use event. Participants will receive a lesson on binge substance use and answer questions at three different time points: when participants enroll in the study; 4 weeks later; and 4 weeks after that visit. Evaluation questions will ask about participants' substance use, family and peer relationships, and other emotions and behaviors. Control participants will receive the Bright Horizons intervention after enrollment of all intervention participants is complete.

ATTACH™ is well established and positioned for transition to an online format as the clinic visit program has: 1) been tested and found to be effective in seven rapid-cycling RCT's; 2) been named a Frontiers of Innovation Project of the Harvard Center of the Developing Child; 3) attained a CIHR Innovative Clinical Trial (ICT) grant to scale and spread the program across Canada; 4) three agencies already independently delivering the clinic program (Discovery House, CUPS and Alcove Addictions Recovery); and 5) agency health-service providers and families have requested an online ATTACH™ program. As building on this sound foundation requires less validation than a newly formed program, ATTACH™ online is poised for rapid uptake by the community partners, and tremendous impact. Methods: Using participatory design and iKT approaches, the multidisciplinary team (Nursing and Software Engineering) will work collaboratively with mothers enrolled in the ongoing ATTACH™ pilot studies along with health-service providers and professional facilitators, to co-design the user interfaces for virtual delivery of ATTACH™. The goal is to develop and test a functioning minimum viable product (MVP) that is robust and reliable. We propose to undertake a four-phase study as follows: Phases 1 and 2: Exploratory - user engagement to identify content and explore design challenges and user preferences, followed by prototyping of interface designs; Phase 3: Software Development - iterative design sessions with users to develop MVPs; and Phase 4: Pilot Test - beta test MVPs and refine user interface designs. System Design (Phases 1-4) In Phase 1, content and delivery protocols for ATTACH™ will be determined with each program's Health-Service Provider Advisory Committee (H-SPAC), comprised of service providers who deliver the program. Further, 6 parents recruited from the ongoing or past intervention program studies and 6 H-SPAC members will take part in separate recorded Zoom focus group sessions and a REDcap survey (open and close-ended questions) to explore their experiences with online delivery of the parenting intervention and user-interface design preferences. Data will be transcribed verbatim and reviewed by design team for key design elements to be incorporated into interface prototypes (e.g., mobile app, web-based application) for co-design sessions. In Phase 2, a series of weekly design sessions (3-4) will be conducted with 6 Phase 1 parents and 6 H-SPAC members who will co-design prototypes of user interfaces for virtual intervention programs. Design sessions will be conducted via Zoom, using a whiteboard application to facilitate the co-design process, and recorded for later analysis by the design team. In Phase 3, an agile iterative software design approach will be used to integrate user feedback into design prototypes for 3-4 weekly design sessions, resulting in MVPs for ATTACH™. In Phase 4, two unique MVPs will be pilot (beta) tested with parents and a brief REDcap survey will assess user satisfaction. Refinements will be made to the final MVPs based on user feedback, resulting in the final web-interface. Pilot Testing to Examine Child Mental, Emotional and Behavioural (MEB) Health and Development Outcomes (Phase 4). Parents will be recruited from Discovery House and CUPS for ATTACH™ (n=20; fewer as more sessions). Quasi-experimental design methods (pre/post-test) will evaluate the impact of the MVPs, for both programs, on the primary outcome of children's MEB health and development (Ages and Stages-3rd Ed. and Socio-emotional 2nd d.). Secondary outcomes include parent-infant interaction quality (via the Parent-Child Interaction Teaching Scale) and RF (in ATTACH™). As this new research program is built upon existing CIHR grant designed to test the clinic visit programs, we will determine both within group changes from the virtual program versions and compare virtual to clinic visit versions, once studies resume. Outcomes will be assessed with parametric (e.g. paired and independent t-tests), non-parametric equivalent tests, and effect size statistics as appropriate.