Efficacy and Safety of Vamorolone Over 48 Weeks in Boys With Duchenne Muscular Dystrophy: A Randomized Controlled Trial.

BACKGROUND AND OBJECTIVES: Vamorolone is a dissociative agonist of the glucocorticoid receptor that has shown similar efficacy and reduced safety concerns in comparison with prednisone in Duchenne muscular dystrophy (DMD). This study was conducted to determine the efficacy and safety of vamorolone over 48 weeks and to study crossover participants (prednisone to vamorolone; placebo to vamorolone). METHODS: A randomized, double-blind, placebo-controlled and prednisone-controlled clinical trial of 2 doses of vamorolone was conducted in participants with DMD, in the ages from 4 years to younger than 7 years at baseline. The interventions were 2 mg/kg/d of vamorolone and 6 mg/kg/d of vamorolone for 48 weeks (period 1: 24 weeks + period 2: 24 weeks) and 0.75 mg/kg/d of prednisone and placebo for the first 24 weeks (before crossover). Efficacy was evaluated through gross motor outcomes and safety through adverse events, growth velocity, body mass index (BMI), and bone turnover biomarkers. This analysis focused on period 2. RESULTS: A total of 121 participants with DMD were randomized. Vamorolone at a dose of 6 mg/kg/d showed maintenance of improvement for all motor outcomes to week 48 (e.g., for primary outcome, time to stand from supine [TTSTAND] velocity, week 24 least squares mean [LSM] [SE] 0.052 [0.0130] rises/s vs week 48 LSM [SE] 0.0446 [0.0138]). After 48 weeks, vamorolone at a dose of 2 mg/kg/d showed similar improvements as 6 mg/kg/d for North Star Ambulatory Assessment (NSAA) (vamorolone 6 mg/kg/d-vamorolone 2 mg/kg/d LSM [SE] 0.49 [1.14]; 95% CI -1.80 to 2.78, p = 0.67), but less improvement for other motor outcomes. The placebo to vamorolone 6 mg/kg/d group showed rapid improvements after 20 weeks of treatment approaching benefit seen with 48-week 6 mg/kg/d of vamorolone treatment for TTSTAND, time to run/walk 10 m, and NSAA. There was significant improvement in linear growth after crossover in the prednisone to vamorolone 6 mg/kg/d group, and rapid reversal of prednisone-induced decline in bone turnover biomarkers in both crossover groups. There was an increase in BMI after 24 weeks of treatment that then stabilized for both vamorolone groups. DISCUSSION: Improvements of motor outcomes seen with 6 mg/kg/d of vamorolone at 24 weeks of treatment were maintained to 48 weeks of treatment. Vamorolone at a dose of 6 mg/kg/d showed better maintenance of effect compared with vamorolone at a dose of 2 mg/kg/d for most (3/5) motor outcomes. Bone morbidities of prednisone (stunting of growth and declines in serum bone biomarkers) were reversed when treatment transitioned to vamorolone. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov Identifier: NCT03439670. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that for boys with DMD, the efficacy of vamorolone at a dose of 6 mg/kg/d was maintained over 48 weeks.

DNA repair in tumor radioresistance: insights from fruit flies genetics.

BACKGROUND: Radiation therapy (RT) is a key anti-cancer treatment that involves using ionizing radiation to kill tumor cells. However, this therapy can lead to short- and long-term adverse effects due to radiation exposure of surrounding normal tissue. The type of DNA damage inflicted by radiation therapy determines its effectiveness. High levels of genotoxic damage can lead to cell cycle arrest, senescence, and cell death, but many tumors can cope with this damage by activating protective mechanisms. Intrinsic and acquired radioresistance are major causes of tumor recurrence, and understanding these mechanisms is crucial for cancer therapy. The mechanisms behind radioresistance involve processes like hypoxia response, cell proliferation, DNA repair, apoptosis inhibition, and autophagy. CONCLUSION: Here we briefly review the role of genetic and epigenetic factors involved in the modulation of DNA repair and DNA damage response that promote radioresistance. In addition, leveraging our recent results on the effects of low dose rate (LDR) of ionizing radiation on Drosophila melanogaster we discuss how this model organism can be instrumental in the identification of conserved factors involved in the tumor resistance to RT.

Oral splint therapy in patients with Menière's disease and temporomandibular disorder: a long-term, controlled study.

PURPOSE: To assess the effect of oral splint therapy on audio-vestibular symptoms in patients with Menière's disease (MD) and temporomandibular disorder (TMD). METHODS: Retrospective case-control study. Treatment group: 37 patients with MD and TMD who received gnatological treatment. CONTROL GROUP: 26 patients with MD and TMD who had never received gnatological treatment. The number of vertigo spells in 6 months (primary endpoint), pure-tone audiometry average (PTA), MD stage, functional level, Dizziness handicap Index (DHI), Tinnitus handicap Index (THI) and Aural Fullness Scale (AFS) were compared at baseline and after 24 months according to groups. Analysis of Covariance was used to determine the treatment effect. RESULTS: Groups were comparable for demographic, clinical data, baseline PTAs and the number of vertigo spells. Analysis of covariance showed a significant effect of gnathological treatment on number of vertigo spells ([Formula: see text] = 0.258, p < 0.001), PTA ([Formula: see text] = 0.201, p < 0.001), MD stage ([Formula: see text] = 0.224, p < 0.001), functional level ([Formula: see text] = 0.424, p < 0.001), DHI ([Formula: see text] = 0.421, p < 0.001), THI ([Formula: see text] = 0.183, p < 0.001), but not for AFS ([Formula: see text] = 0.005, p = 0.582). The treatment group showed vertigo control of class A in 86.5% and class B in 13.5% of patients. In the control group, vertigo control was of class A in 19.2% of patients and class B in 11.5%, class C in 30.8%, class D in 11.5%, class E in 19.2% and class F in 7.7%. Classes of vertigo control differed significantly (X2 test, p < 0.001). CONCLUSIONS: Oral splint therapy could represent a viable treatment in patients with TMD and uncontrolled MD disease. The effects are maintained at least after 2 years.

Potential Circumstances Associated With Moral Injury and Moral Distress in Healthcare Workers and Public Safety Personnel Across the Globe During COVID-19: A Scoping Review.

Healthcare workers (HCWs) and public safety personnel (PSP) across the globe have continued to face ethically and morally challenging situations during the COVID-19 pandemic that increase their risk for the development of moral distress (MD) and moral injury (MI). To date, however, the global circumstances that confer risk for MD and MI in these cohorts have not been systematically explored, nor have the unique circumstances that may exist across countries been explored. Here, we sought to identify and compare, across the globe, potentially morally injurious or distressful events (PMIDEs) in HCWs and PSP during the COVID-19 pandemic. A scoping review was conducted to identify and synthesize global knowledge on PMIDEs in HCWs and select PSP. Six databases were searched, including MEDLINE, EMBASE, Web of Science, PsychInfo, CINAHL, and Global Health. A total of 1,412 articles were retrieved, of which 57 articles were included in this review. These articles collectively described the experiences of samples from 19 different countries, which were comprised almost exclusively of HCWs. Given the lack of PSP data, the following results should not be generalized to PSP populations without further research. Using qualitative content analysis, six themes describing circumstances associated with PMIDEs were identified: (1) Risk of contracting or transmitting COVID-19; (2) Inability to work on the frontlines; (3) Provision of suboptimal care; (4) Care prioritization and resource allocation; (5) Perceived lack of support and unfair treatment by their organization; and (6) Stigma, discrimination, and abuse. HCWs described a range of emotions related to these PMIDEs, including anxiety, fear, guilt, shame, burnout, anger, and helplessness. Most PMIDE themes appeared to be shared globally, particularly the 'Risk of contracting or transmitting COVID-19' and the 'Perceived lack of support and unfair treatment by their organization.' Articles included within the theme of 'Stigma, discrimination, and abuse' represented the smallest global distribution of all PMIDE themes. Overall, the present review provides insight into PMIDEs encountered by HCWs across the globe during COVID-19. Further research is required to differentiate the experience of PSP from HCWs, and to explore the impact of social and cultural factors on the experience of MD and MI.

Listen to the Children: Elementary School Students' Perspectives on a Mindfulness Intervention.

In recent years, mindfulness-based practices in grade schools have been associated with students' improved cognitive skills and general classroom behavior. In the majority of studies, however, only teacher and parent feedback are elicited, omitting a considerably significant voice - that of the students. Our study aims to fill this gap by exploring student opinions and perceptions regarding the implementation of a classroom-based mindfulness program. Elementary school students (N = 51) took part in teacher-facilitated mindfulness activities which were incorporated into their daily classroom routines. Over the course of the 8-week intervention period, students participated in focus groups about their perceptions of the program. Through qualitative content analysis, two major findings emerged from the focus group data: student opinions about the mindfulness program varied substantially and the mindfulness activities were not always liked and enjoyed. Critically, if students do not enjoy classroom-based mindfulness programs, they may be less motivated to engage in mindful activities and in turn may not experience the benefits that mindfulness has to offer. To maximize student engagement with mindfulness while addressing their concerns, the following recommendations are made: A balance between the entertaining and educational aspects of the program, flexible program delivery, and encouraging students to pursue mindful living outside of the classroom. This research is important to educational and clinical practitioners as student insight will benefit the development and modification of classroom-based mindfulness programs to ensure that students are better able to engage with and benefit from these programs.

Different inflammatory blood markers correlate with specific outcomes in incident HPV-negative head and neck squamous cell carcinoma: a retrospective cohort study.

BACKGROUND: Inflammatory blood markers have been associated with oncological outcomes in several cancers, but evidence for head and neck squamous cell carcinoma (HNSCC) is scanty. Therefore, this study aims at investigating the association between five different inflammatory blood markers and several oncological outcomes. METHODS: This multi-centre retrospective analysis included 925 consecutive patients with primary HPV-negative HNSCC (median age: 68 years) diagnosed between April 2004 and June 2018, whose pre-treatment blood parameters were available. Neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), lymphocyte to monocyte ratio (LMR), systemic inflammatory marker (SIM), and systemic immune-inflammation index (SII) were calculated; their associations with local, regional, and distant failure, disease-free survival (DFS), and overall survival (OS) was calculated. RESULTS: The median follow-up was 53 months. All five indexes were significantly associated with OS; the highest accuracy in predicting patients' survival was found for SIM (10-year OS = 53.2% for SIM < 1.40 and 40.9% for SIM ≥ 2.46; c-index = 0.569) and LMR (10-year OS = 60.4% for LMR ≥ 3.76 and 40.5% for LMR < 2.92; c-index = 0.568). While LMR showed the strongest association with local failure (HR = 2.16; 95% CI:1.22-3.84), PLR showed the strongest association with regional (HR = 1.98; 95% CI:1.24-3.15) and distant failure (HR = 1.67; 95% CI:1.08-2.58). CONCLUSION: Different inflammatory blood markers may be useful to identify patients at risk of local, regional, or distant recurrences who may benefit from treatment intensification or intensive surveillance programs.

Self-reported smell and taste recovery in coronavirus disease 2019 patients: a one-year prospective study.

PURPOSE: The aim of the present study was to estimate the 1 year prevalence and recovery rate of self-reported chemosensory dysfunction in a series of subjects with previous mild-to-moderate symptomatic COVID-19. METHODS: Prospective study based on the SNOT-22, item "sense of smell or taste" and additional outcomes. RESULTS: 268/315 patients (85.1%) completing the survey at baseline also completed the follow-up interview. The 12 months prevalence of self-reported COVID-19 associated chemosensory dysfunction was 21.3% (95% CI 16.5-26.7%). Of the 187 patients who complained of COVID-19 associated chemosensory dysfunction at baseline, 130 (69.5%; 95% CI 62.4-76.0%) reported complete resolution of smell or taste impairment, 41 (21.9%) reported a decrease in the severity, and 16 (8.6%) reported the symptom was unchanged or worse 1 year after onset. The risk of persistence was higher for patients reporting a baseline SNOT-22 score ≥ 4 (OR = 3.32; 95% CI 1.32-8.36) as well as for those requiring ≥ 22 days for a negative swab (OR = 2.18; 95% CI 1.12-4.27). CONCLUSION: A substantial proportion of patients with previous mild-to-moderate symptomatic COVID-19 characterized by new onset of chemosensory dysfunction still complained on altered sense of smell or taste 1 year after the onset.

Six-Month Psychophysical Evaluation of Olfactory Dysfunction in Patients with COVID-19.

This study prospectively assessed the 6-month prevalence of self-reported and psychophysically measured olfactory dysfunction in subjects with mild-to-moderate COVID-19. Self-reported smell or taste impairment was prospectively evaluated by SNOT-22 at diagnosis, 4-week, 8-week, and 6-month. At 6 months from the diagnosis, psychophysical evaluation of olfactory function was also performed using the 34-item culturally adapted University of Pennsylvania Smell Identification Test (CA-UPSIT). 145 completed both the 6-month subjective and psychophysical olfactory evaluation. According to CA-UPSIT, 87 subjects (60.0%) exhibited some smell dysfunction, with 10 patients being anosmic (6.9%) and seven being severely microsmic (4.8%). At the time CA-UPSIT was administered, a weak correlation was observed between the self-reported alteration of the sense of smell or taste and olfactory test scores (Spearman's r = -0.26). Among 112 patients who self-reported normal sense of smell at last follow-up, CA-UPSIT revealed normal smell in 46 (41.1%), mild microsmia in 46 (41.1%), moderate microsmia in 11 (9.8%), severe microsmia in 3 (2.3%), and anosmia in 6 (5.4%) patients; however, of those patients self-reporting normal smell but who were found to have hypofunction on testing, 62 out of 66 had a self-reported reduction in sense of smell or taste at an earlier time point. Despite most patients report a subjectively normal sense of smell, we observed a high percentage of persistent smell dysfunction at 6 months from the diagnosis of syndrome coronavirus 2 (SARS-CoV-2) infection, with 11.7% of patients being anosmic or severely microsmic. These data highlight a significant long-term rate of smell alteration in patients with previous SARS-COV-2 infection.

Healthcare Workers and COVID-19-Related Moral Injury: An Interpersonally-Focused Approach Informed by PTSD.

The COVID-19 pandemic has resulted in a still-unfolding series of novel, potentially traumatic moral and ethical challenges that place many healthcare workers at risk of developing moral injury. Moral injury is a type of psychological response that may arise when one transgresses or witnesses another transgress deeply held moral values, or when one feels that an individual or institution that has a duty to provide care has failed to do so. Despite knowledge of this widespread exposure, to date, empirical data are scarce as to how to prevent and, where necessary, treat COVID-19-related moral injury in healthcare workers. Given the relation between moral injury and post-traumatic stress disorder (PTSD), we point here to social and interpersonal factors as critical moderators of PTSD symptomology and consider how this knowledge may translate to interventions for COVID-19-related moral injury. Specifically, we first review alterations in social cognitive functioning observed among individuals with PTSD that may give rise to interpersonal difficulties. Drawing on Nietlisbach and Maercker's 2009 work on interpersonal factors relevant to survivors of trauma with PTSD, we then review the role of perceived social support, social acknowledgment and social exclusion in relation to potential areas of targeted intervention for COVID-19-related moral injury in healthcare workers. Finally, building on existing literature (e.g., Phoenix Australia-Centre for Posttraumatic Mental Health and the Canadian Centre of Excellence-PTSD, 2020) we conclude with individual and organizational considerations to bolster against the development of moral injury in healthcare workers during the pandemic.