Genome-Wide Association Study of Lithium-Induced Dry Mouth in Bipolar I Disorder

Dry mouth is a rather common unpleasant adverse drug reaction (ADR) to lithium treatment in bipolar disorders that often lead to poor adherence or early dropout. The aim of this study was to identify the genetic variants of dry mouth associated with lithium treatment in patients with bipolar I (BPI) disorder. In total, 1242 BPI patients who had ever received lithium treatment were identified by the Taiwan Bipolar Consortium for this study. The proportions of patients who experienced impaired drug compliance during lithium medication were comparable between those only with dry mouth and those with any other ADR (86% and 93%, respectively). Dry mouth appeared to be the most prevalent (47.3%) ADR induced by lithium treatment. From the study patients, 921 were included in a genome-wide association study (GWAS), and replication was conducted in the remaining 321 patients. The SNP rs10135918, located in the immunoglobulin heavy chain locus (IGH), showed the strongest associations in the GWAS (p = 2.12 × 10−37) and replication groups (p = 6.36 × 10−13) (dominant model) for dry mouth with a sensitivity of 84.9% in predicting dry mouth induced by lithium. Our results may be translated into clinical recommendation to help identify at-risk individuals for early identification and management of dry mouth, which will improve medication adherence.

Moderate Exercise Protects Against Joint Disease in a Murine Model of Osteoarthritis

Exercise is recommended as a non-pharmacological therapy for osteoarthritis (OA). Clinical studies investigating the impact of exercise on OA have primarily focussed on the assessment of joint pain and mobilisation, where positive outcomes have been demonstrated. Clinical imaging studies provide limited information on the impact of exercise (positive or negative) on the actual bone and soft tissue pathology. Various exercise regimes, with differing intensities and duration, have been used in a range of OA models, with disparate results. The present study provides definitive insight into the effect of moderate exercise on early joint pathology in the destabilisation of the medial meniscus (DMM) mouse model of OA. Exercise was induced by forced treadmill walking for 3 or 7 weeks. Joints were analysed by microcomputed tomography and histology. Exercise offered protection against cartilage damage and joint inflammation, and a temporary protection against osteosclerosis. Furthermore, exercise modified the metaphyseal trabecular microarchitecture of the osteoarthritic leg. Collectively, our findings provide scientific support for the clinical recommendation of moderate exercise as a physical therapy in OA. In addition to indirect benefit via positive physiological effects of weight loss, our data suggest direct short-term benefits in ameliorating pathology of cartilage, synovitis and bone.

Molecular profiling of advanced soft-tissue sarcomas: the MULTISARC randomized trial

Background Soft-tissue sarcomas (STS) represent a heterogeneous group of rare tumors including more than 70 different histological subtypes. High throughput molecular analysis (next generation sequencing exome [NGS]) is a unique opportunity to identify driver mutations that can change the usual one-size-fits-all treatment paradigm to a patient-driven therapeutic strategy. The primary objective of the MULTISARC trial is to assess whether NGS can be conducted for a large proportion of metastatic STS participants within a reasonable time, and, secondarily to determine whether a NGS-guided therapeutic strategy improves participant’s outcome. Methods This is a randomized, multicentre, phase II/III trial inspired by the design of umbrella and biomarker-driven trials. The setting plans up to 17 investigational centres across France and the recruitment of 960 participants. Participants aged at least 18 years, with unresectable locally advanced and/or metastatic STS confirmed by the French sarcoma pathological reference network, are randomized according to 1:1 allocation ratio between the experimental arm “NGS” and the standard “No NGS”. NGS will be considered feasible if (i) NGS results are available and interpretable, and (ii) a report of exome sequencing including a clinical recommendation from a multidisciplinary tumor board is provided to investigators within 7 weeks from reception of the samples on the biopathological platform. A feasibility rate of more than 70% is expected (null hypothesis: 70% versus alternative hypothesis: 80%). In terms of care, participants randomized in “No NGS” arm and who fail treatment will be able to switch to the NGS arm at the request of the investigator. Discussion The MULTISARC trial is a prospective study designed to provide high-level evidence to support the implementation of NGS in routine clinical practice for advanced STS participants, on a large scale. Trial registration clinicaltrial.gov NCT03784014.

859. Suboptimal Uptake, Retention, and Adherence of Daily Oral PrEP Among People with OUD Receiving HCV Treatment

Background Daily oral pre-exposure prophylaxis (PrEP) with tenofovir/emtricitabine (TDF/FTC) effectively prevents HIV among people who use drugs (PWUD). Despite rising rates of HIV incidence and injection drug use, PrEP use remains low and limited research exists on PrEP adherence and retention in this population. Methods Based in Washington, DC and Baltimore, the ANCHOR investigation evaluated a community-based model of care collocating hepatitis C (HCV) therapy, medication for opioid use disorder (OUD), and PrEP in people with chronic HCV, OUD, and drug use within 1 year. PrEP counseling was offered from HCV treatment Day 0 until Week 24 and subjects could start any time during this window. PrEP patients were followed for 48 weeks and assessed for adherence by self-report and dried blood spot analysis of TDF. ANCHOR PrEP study enrollment and participant retention along the PrEP continuum. Results 198 participants enrolled in ANCHOR, of whom 185 (93%) were HIV-negative. 29 subjects (16% of HIV-negative group) initiated PrEP. 116 subjects (63%) met 2014 CDC criteria for PrEP initiation due to IDU (82, 44%), sex (9, 5%), or both (25, 14%). Those who initiated were more likely to meet both CDC sexual and IDU risk criteria than those who declined PrEP (P=0.006). Providers recommended PrEP to 94 subjects (51%), which was associated with uptake (P=0.02). While median treatment duration was 104 days (IQR 28, 276), only 8 subjects were retained through Week 48. The most common reason for discontinuation was side effects in 7 subjects or 24% of PrEP subgroup. Treatment interruptions occurred in one-third of the PrEP subgroup. Adherence of 4 to 7 pills per week was variable over time by self-report and declined by TDF analysis. No HIV seroconversions occurred. Demographic and epidemiological background of the ANCHOR study population. Total duration, in days, on PrEP in the ANCHOR study. Discontinued participants are grouped by reason for cessation of therapy. PrEP Adherence Adherence to PrEP by ANCHOR study timepoint, assessed via self-report (above) and dried bloodspot analysis of tenofovir level (below). Conclusion In this cohort of people with OUD and HCV, 16% of subjects started PrEP. While clinical recommendation was associated with uptake, high rates of disruption and discontinuation, compounded by variable pill adherence, made daily oral TDF/FTC a suboptimal preventive strategy in this cohort. Emerging PrEP modalities like long-acting injectables have potential to address these barriers, but PWUD have been excluded from their research and development to date. Additional work to identify vulnerable individuals and to promote use, adherence, and retention will be critical in implementing PrEP more effectively in this key population. Disclosures Sarah Kattakuzhy, MD, Gilead Sciences (Scientific Research Study Investigator, Research Grant or Support) Elana S. Rosenthal, MD, Gilead Sciences (Research Grant or Support)Merck (Research Grant or Support)

Treatment of acute lymphoblastic leukemia in children by ALL IC-BFM 2002 protocol: results of multicenter retrospective study

By the whole history of pediatric acute lymphoblastic leukemia (ALL) treatment protocols development, one of the World ideologist of original science-based therapeutic approaches was German group BFM (Berlin–Frankfurt–Münster). It is not surprisingly that modern ALL treatment protocols, developed by BFM group are high-effective and use in many countries. Understanding the probability of recovery of overwhelming ALL patients majority treated by ALL IC-BFM 2002 protocol, the Scientific-Practical Board of Ministry of Health of Russia in 2020 adopted a protocol as clinical recommendation for pediatric ALL treatment (ID:529).It the current issue BFM ALL treatment protocols evolution is presented and first Russian multicenter experience in pediatric ALL treatment by ALL IC-BFM 2002 protocol. It was 408 pediatric and adolescents patients with primary ALL included the study. All of them were treated by ALL IC-BFM 2002 protocol from 01.11.2003 to 12.05.2021. Survival rate was estimated on 01.06.2021.ALL IC-BFM 2002 demonstrated a high efficiency in multicenter retrospective study. 15-year event-free survival was 83.7 ± 2.1 %, relapsefree survival – 88 ± 1.8 % and overall survival – 93.4 ± 1.4 %. So, ALL IC-BFM 2002 protocol could be realized in Russian clinics and give results similar to world’s leading medical centers.

A COMPARATIVE MODEL STUDY BETWEEN THE SURVIVABILITY OF DENTAL IMPLANTS VERSUS DENTAL AUTOTRANSPLANTS, LEADING TO A SYSTEMATIC REVIEW

Aim: The aim of this Systematic Review is to compare the survival rate of teeth autotransplantation with immediate implant placement in cases of singular loss of teeth and obtain a clinical recommendation for similar cases. Materials And Methods: The research will be conducted by two independent reviewers in PubMed search and it will include studies from January 2017 to December 2020.The survival rate of both immediate implant placement and tooth autotransplantation will be evaluated in different follow-up times and the information compiled in several metaanalyses.

Physical Exercise: An Overview of Benefits From Psychological Level to Genetics and Beyond

Any form of physical activity, including exercise, is linked with preventing several diseases including metabolic disorders, cancer, and mood disorders. Beyond benefits, its therapeutic activity is inconclusive in terms of types, intensity, and individual training status, and this could be a major research for prescribing exercise as a therapeutic strategy. Exercise and its myriad forms occupy the space on clinical recommendation, which implies that quantifiable benefits of the same have been proven. Further, the benefits of exercise and its impact have also been found to have a genetic underlying interaction, which has created a niche of personal genomics, wherein apart from diet, an exercise regimen also becomes tailorable for every individual. Many subjective well-being reports highlighted daily exercise to keep mental and general health in excellent conditions, and the uncertainties around it. Thus, adopting an exercise behavior and inculcating it as a routine has been recommended. Further, the kind of benefit that can be extracted out of exercise and training is to a great extent influenced by genetic markers around fat, obesity, hunger, as well as satiety. Genetic markers can also impact the body temperature during exercise, making the entire experience of training either comfortable or unpleasant. Thus, there is an overwhelming amount of scientific evidence that has gathered around the benefits of exercise, which has become a pressing need from the 21st century when the belief in the value of exercise started waning, and that spiked up the era of lifestyle and noncommunicable ailments.

THE EFFICACY OF LASER THERAPY AND IBUPROFEN ON PAIN AFTER ELASTOMERIC SEPARATOR PLACEMENT: RAPID REVIEW

Background: Separator placement is the first step in orthodontic treatment, which aims to create space between teeth before molar band placement. This procedure can cause pain for the patient. Pain management after separator placement can be done through pharmacological and non-pharmacological approaches.Method: The aim of this rapid review was to determine the efficacy of laser therapy and ibuprofen for pain management after elastomeric separator placement in orthodontic treatment.Result: Ten articles were included in this review, four articles gave laser therapy interventions and six articles gave ibuprofen therapy interventions. The result of the quality assessment using Strength of Recommendation Taxonomy (SORT) was laser therapy intervention has one good quality articles and three limited-quality articles, while ibuprofen therapy has two good quality articles and four limited-quality articles.Conclusion: The efficacy of laser therapy and the efficacy of ibuprofen on pain after separator placement is good, with the strength of the clinical recommendation of ibuprofen is better than laser therapy.

Sepsis in children: federal clinical guideline (draft)

The article publishes a draft clinical recommendation on sepsis in children, developed by specialists of the Association of Pediatric Anesthesiologists and Resuscitators (ADAR) of Russia and approved at the 2nd Russian Congress of Pediatric Anesthesiologists and Resuscitators in April 2021. The definitions of sepsis and septic shock in pediatric patients and their criteria are proposed and substantiated. Data on etiology and pathogenesis, epidemiology, clinical picture and diagnosis of shock are presented. The recommendations are based on a large clinical material of intensive care for sepsis and septic shock in children. The paper provides data on the rehabilitation, prevention and organization of medical services for sepsis in children. The editorial staff of the journal accepts all comments and additions to this project for transmission to the developers.

Applications of Ketogenic Diets in Patients with Headache: Clinical Recommendations

Headaches are among the most prevalent and disabling neurologic disorders and there are several unmet needs as current pharmacological options are inadequate in treating patients with chronic headache, and a growing interest focuses on nutritional approaches as non-pharmacological treatments. Among these, the largest body of evidence supports the use of the ketogenic diet (KD). Exactly 100 years ago, KD was first used to treat drug-resistant epilepsy, but subsequent applications of this diet also involved other neurological disorders. Evidence of KD effectiveness in migraine emerged in 1928, but in the last several year’s different groups of researchers and clinicians began utilizing this therapeutic option to treat patients with drug-resistant migraine, cluster headache, and/or headache comorbid with metabolic syndrome. Here we describe the existing evidence supporting the potential benefits of KDs in the management of headaches, explore the potential mechanisms of action involved in the efficacy in-depth, and synthesize results of working meetings of an Italian panel of experts on this topic. The aim of the working group was to create a clinical recommendation on indications and optimal clinical practice to treat patients with headaches using KDs. The results we present here are designed to advance the knowledge and application of KDs in the treatment of headaches.