Description of a novel splice site variant in UBA1 gene causing VEXAS syndrome.

OBJECTIVE: The vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome is a complex immune disorder consequence of somatic UBA1 variants. Most reported pathogenic UBA1 variants are missense or splice site mutations directly impairing the translational start site at p. Met41, with recent studies showing that these variants are frequent causes of recurrent inflammation in older individuals. Here we aimed to characterize a novel UBA1 variant found in two patients clinically presenting with VEXAS syndrome. METHODS: Patients' data were collected from direct assessments and from their medical charts. Genomics analyses were performed by both Sanger and amplicon-based deep sequencing, mRNA studies were performed by both cDNA subcloning and mRNA sequencing. RESULTS: We report a novel, somatic variant in a canonical splice site of the UBA1 gene (c.346-2A>G), which was identified in two unrelated adult male patients with late-onset, unexplained inflammatory manifestations including recurrent fever, Sweet syndrome-like neutrophilic dermatosis, and lung inflammation responsive only to glucocorticoids. RNA analysis from patients' samples demonstrated aberrant mRNA splicing leading to multiple in-frame transcripts, including a transcript retaining the full sequence of intron 4 and a different transcript with the deletion of the first 15 nucleotides of exon 5. CONCLUSION: Here we describe the abnormal UBA1 transcription as a consequence of the novel c.346-2A>G variant identified in two patients with clinical features compatible with VEXAS syndrome. Overall, these results further demonstrate the expanding spectrum of variants in UBA1 leading to pathology and support for a complete gene evaluation in those candidate patients for VEXAS syndrome.

Therapeutic biomarkers in acute myeloid leukemia: functional and genomic approaches.

Acute myeloid leukemia (AML) is clinically and genetically a heterogeneous disease characterized by clonal expansion of abnormal hematopoietic progenitors. Genomic approaches to precision medicine have been implemented to direct targeted therapy for subgroups of AML patients, for instance, IDH inhibitors for IDH1/2 mutated patients, and FLT3 inhibitors with FLT3 mutated patients. While next generation sequencing for genetic mutations has improved treatment outcomes, only a fraction of AML patients benefit due to the low prevalence of actionable targets. In recent years, the adoption of newer functional technologies for quantitative phenotypic analysis and patient-derived avatar models has strengthened the potential for generalized functional precision medicine approach. However, functional approach requires robust standardization for multiple variables such as functional parameters, time of drug exposure and drug concentration for making in vitro predictions. In this review, we first summarize genomic and functional therapeutic biomarkers adopted for AML therapy, followed by challenges associated with these approaches, and finally, the future strategies to enhance the implementation of precision medicine.

Virtual Bioequivalence Assessment of Ritlecitinib Capsules with Incorporation of Observed Clinical Variability Using a Physiologically Based Pharmacokinetic Model.

Ritlecitinib, an orally available Janus kinase 3 and tyrosine kinase inhibitor being developed for the treatment of alopecia areata (AA), is highly soluble across the physiological pH range at the therapeutic dose. As such, it is expected to dissolve rapidly in any in vitro dissolution conditions. However, in vitro dissolution data showed slower dissolution for 100-mg capsules, used for the clinical bioequivalence (BE) study, compared with proposed commercial 50-mg capsules. Hence, a biowaiver for the lower 50-mg strength using comparable multimedia dissolution based on the f2 similarity factor was not possible. The in vivo relevance of this observed in vitro dissolution profile was evaluated with a physiologically based pharmacokinetic (PBPK) model. This report describes the development, verification, and application of the ritlecitinib PBPK model to translate observed in vitro dissolution data to an in vivo PK profile for ritlecitinib capsule formulations. Virtual BE (VBE) trials were conducted using the Simcyp VBE module, including the model-predicted within-subject variability or intra-subject coefficient of variation (ICV). The results showed the predicted ICV was predicted to be smaller than observed clinical ICV, resulting in a more optimistic BE risk assessment. Additional VBE assessment was conducted by incorporating clinically observed ICV. The VBE trial results including clinically observed ICV demonstrated that proposed commercial 50-mg capsules vs clinical 100-mg capsules were bioequivalent, with > 90% probability of success. This study demonstrates a PBPK model-based biowaiver for a clinical BE study while introducing a novel method to integrate clinically observed ICV into VBE trials with PBPK models. Trial registration: NCT02309827, NCT02684760, NCT04004663, NCT04390776, NCT05040295, NCT05128058.

Mental Health of Children With Special Educational Needs and the Return to In-Person Learning After the COVID-19 Pandemic.

Importance: There is limited evidence on whether the quality of life and behavior of children with special educational needs (SEN) have improved or worsened since schools reopened after COVID-19-related school closures. Objective: To describe the changes in the mental well-being of children and adolescents with SEN during the initial 6 months of resuming in-person learning after COVID-19-related school closures. Design, Setting, and Participants: This repeated cross-sectional study reported data from surveys completed by parents and caregivers of children and adolescents aged 3 to 18 years with SEN studying at special schools in Hong Kong. The first cohort was obtained during COVID-19-related school closure in April 2020 (wave 1) and the second cohort was obtained 6 months after school resumption with data collection between July and October 2021 (wave 2). Data analysis occurred from January to June 2022. Exposure: Diagnosis of a disability or disorder that required school-based special educational programming. Main Outcomes and Measures: Children's emotional and behavioral difficulties (measured with the Strengths and Difficulties Questionnaire [SDQ]), quality of life (measured with the Pediatric Quality of Life Inventory [PedsQL]), lifestyle habits, parental stress, and parental well-being (measured with the PedsQL Family Impact Module) were assessed. Cross-sectional comparisons of well-being between the 2 waves were conducted using analysis of covariance, and multiple regression analysis was performed to identify factors associated with mental health outcomes in wave 2. Results: In wave 1, a total of 456 parents and caregivers of children with SEN (mean [SD] age, 7.44 [3.98] years; 315 boys [69.1%]; 141 girls [30.9%]) responded to the surveys. In wave 2, 519 parents and caregivers of children with SEN (mean [SD] age, 8.16 [4.47] years; 365 boys [70.3%]; 154 girls [29.7%]) responded. After school resumption, preschoolers aged 3 to 5 years with SEN had significantly fewer emotional difficulties (mean [SD] SDQ score, 3.26 [2.39] vs 2.68 [2.03]; standardized mean difference [SMD] = 0.26; 95% CI, 0.07-0.46; Bonferroni-corrected P = .04) and conduct difficulties (mean [SD] SDQ score, 2.88 [1.89] vs 2.41 [1.91]; SMD = 0.25; 95% CI, 0.05-0.44; Bonferroni-corrected P = .01), whereas adolescents had more conduct difficulties (mean [SD] SDQ score, 1.62 [1.50] vs 2.37 [3.02]; SMD = 0.41; 95% CI, 0.13-0.70; Bonferroni-corrected P = .049). The overall quality of life of school-aged children with SEN aged 6 to 11 years worsened after school resumption (mean [SD] PedsQL score, 67.52 [17.45] vs 60.57 [16.52]; SMD = 0.41; 95% CI, 0.19-0.62; Bonferroni-corrected P = .002). Conclusions and Relevance: The findings of this repeated cross-sectional study suggest that preschoolers with SEN had improved emotional and behavioral functioning when school resumed after COVID-19-related closures. School-aged children with SEN, adolescents with SEN, and children with intellectual disabilities were at risk of reduced quality of life, indicating that additional support should be offered to vulnerable groups as they return to schools.

An Environmental Scan of Advanced Practice Radiation Therapy in the United States: A PESTEL Analysis.

PURPOSE: In 2021, the Advanced Practice Radiation Therapy Working Group (APRTWG) was established in the United States as a grassroots alliance of multidisciplinary radiation oncology professionals-radiation therapists, physicians, dosimetrists, and administrators-located across the country, interested in studying and establishing the Advanced Practice Radiation Therapist (APRT) level of practice in the United States. The APRT model has shown success in the United Kingdom, Canada, Australia, Singapore, and other countries, documenting the value of the APRT to the quality and advancement of clinical care. In the United States, the APRTWG seeks to coordinate activities, align resources, and drive the national agenda to collectively develop and define novel models of care using APRT in line with the evolving needs of patients and the radiation therapy profession. This environmental scan aims to examine the context of radiation oncology medical practice in the United States to inform pathways ahead for a proposed APRT model through a Political, Economic, Social, Technological, Environmental, and Legal (PESTEL) analysis. METHODS AND MATERIALS: A literature search was conducted to understand the chronological timeline of the development of APRT during the past 25 years. Items that included the activities, scope of practice, and implementation of APRT nationally and internationally were identified. Papers describing advanced practitioner roles that are commonly found in the multidisciplinary team in radiation oncology both in the United States and internationally, such as physician assistants and nurse practitioners, were excluded. RESULTS: Despite the environmental scan outcome, it is acknowledged that data collation and analysis was not as robust as that anticipated by undertaking a systematic review. Papers were identified by the lead author that aligned with each of the PESTEL factors. Defined broadly, a new care model can adjust how health services are delivered by incorporating best practices in patient care for a specific population, person, or patient cohort. As patients enter different stages of their disease, the purpose of a new model is to provide individuals with the right care, at the right time, by the right team, in the right place. It is clear that the opportunity for positive change and impact on the current state of practice in radiation oncology exists. CONCLUSION: The environmental scan findings demonstrate the complexities associated with implementing APRT in the United States, with multifactorial political, environmental, societal, technological, economic, and legal aspects to consider. The APRTWG will continue to lead and participate in such activities to demonstrate and identify APRT role opportunities in the United States and drive the nationwide implementation of the APRT level of practice in this country.

Validation of the traditional Chinese version of the diabetes eating problem survey-revised and study of the prevalence of disordered eating patterns in Chinese patients with type 1 DM.

BACKGROUND: Disordered eating behaviours (DEBs) in patients with type 1 diabetes mellitus (T1DM) are associated with an increased risk of complications and mortality. The Diabetes Eating Problem Survey-Revised (DEPS-R) was developed to screen for DEBs in T1DM patients. The objectives of this study were to develop a traditional Chinese version DEPS-R (electronic version) and to measure the prevalence of DEBs in a local population sample. METHODS: The DEPS-R was translated into traditional Chinese, modified and developed into an electronic version. The psychometric properties of the C-DEPS-R were tested on T1DM patients from 15 to 64 years old. The factor structure of the traditional C-DEPS-R was examined by confirmatory factor analysis (CFA). The C-EDE-Q and the C-DES-20 were used for convergent and divergent validity testing, respectively. Module H of the CB-SCID-I/P was used as a diagnostic tool for eating disorders. A correlation study was conducted with the C-DEPS-R scores obtained and the clinical characteristics. Type 2 diabetic (T2DM) patients on insulin treatment were recruited as controls. RESULTS: In total, 228 T1DM patients and 58 T2DM patients were recruited. There was good internal consistency of the traditional C-DEPS-R (electronic version), with the McDonald's omega of 0.825 and test-retest reliability of 0.991. A three-factor model of the traditional C-DEPS-R was confirmed by CFA. The cut-off score for the traditional C-DEPS-R was determined to be 24; 13.2% (95% CI 8.8%-17.5%) of T1DM patients were found to score above the cut-off score, while 7.5% (95% CI 4-10.9%) scored above the cut-off by the C-EDE-Q, and 4.4% (95% CI 2.1%-7.9%) were diagnosed with eating disorders by the CB-SCID-I/P Module H. Females with T1DM scored higher on the traditional C-DEPS-R. There was a significant correlation of the C-DEPS-R with BMI, occurrence of DKA, use of a continuous glucose monitoring system and positive diagnosis by the CB-SCID-I/P module H (p < 0.05). CONCLUSION: The traditional Chinese-DEPS-R (electronic version) demonstrated good psychometric properties. It is a self-rated, time-efficient and reliable tool for the screening of disordered eating behaviours in T1DM patients in the Chinese population of Hong Kong. Disordered eating behaviours, such as insulin omission, are associated with an increased risk of diabetes mellitus-related complications and mortality. Generic screening tools for eating disorders may over- or underestimate such problems in diabetic patients. Type 1 diabetes mellitus patients are at particular risk of developing disordered eating behaviours or eating disorders, yet studies in Chinese populations are limited. This study developed and validated the traditional Chinese (electronic) version of the Diabetes Eating Problem Survey-Revised (DEPS-R). The traditional Chinese-DEPS-R is a self-rated, time-efficient and reliable tool for the screening of disordered eating behaviours in Type 1 diabetes mellitus patients in the Chinese population of Hong Kong. The study also estimated the prevalence of disordered eating behaviours in diabetic patients from the local Chinese population, and the clinical correlations of the symptoms and clinical parameters were explored. The study reflected a higher prevalence of eating problems in the Type 1 diabetes mellitus population and demonstrated significant correlations of eating problems with BMI as well as the occurrence of diabetic ketoacidosis. Correspondence: lcw891@ha.org.hk.

Evaluation of cannabidiol nanoparticles and nanoemulsion biodistribution in the central nervous system after intrathecal administration for the treatment of pain.

We investigated how the biodistribution of cannabidiol (CBD) within the central nervous system (CNS) is influenced by two different formulations, an oil-in-water (O/W) nanoemulsion and polymer-coated nanoparticles (PCNPs). We observed that both CBD formulations administered were preferentially retained in the spinal cord, with high concentrations reaching the brain within 10 min of administration. The CBD nanoemulsion reached Cmax in the brain at 210 ng/g within 120 min (Tmax), whereas the CBD PCNPs had a Cmax of 94 ng/g at 30 min (Tmax), indicating that rapid brain delivery can be achieved through the use of PCNPs. Moreover, the AUC0-4h of CBD in the brain was increased 3.7-fold through the delivery of the nanoemulsion as opposed to the PCNPs, indicating higher retention of CBD at this site. Both formulations exhibited immediate anti-nociceptive effects in comparison to the respective blank formulations.

A Pilot Randomized Controlled Trial of an Online Educational Program for Primiparous Women to Improve Breastfeeding.

BACKGROUND: There are different approaches to breastfeeding interventions, but the global 6-month exclusive breastfeeding rates remain suboptimal. The COVID-19 pandemic has brought extra difficulties in promoting breastfeeding. RESEARCH AIM: To test the feasibility and effectiveness of a theory-based, real-time online educational and support program for breastfeeding related outcomes. METHODS: An assessor-blinded, prospective pilot randomized controlled trial with parallel-group, repeated-measures design was used. The sample was low-risk primiparous mothers (N = 40) who delivered in the local public hospitals. Study outcomes consisted of exclusive breastfeeding rate, breastfeeding self-efficacy, and other breastfeeding outcomes measured by a self-reported questionnaire, including the Breastfeeding Self-Efficacy Scale and the Edinburgh Postnatal Depression Scale. Comparisons between the differences in the intervention and control groups were carried out. RESULTS: Thirteen participants in the intervention group successfully completed the program. They had a higher exclusive breastfeeding rate, breastfeeding self-efficacy, breastfeeding initiation rate, and longer exclusive breastfeeding duration than the control group. Additionally, the intervention group had a lower partial breastfeeding rate, and a higher maternal postnatal depression score and infant's morbidity at postnatal 2 months. However, all the results were not statistically significant (p > .050). Overall, the intervention was highly valued by all participants who appreciated the regular postnatal follow-ups. CONCLUSIONS: Despite showing the satisfactory feasibility of the program, no significant improvements were found in all study outcomes. Considering the participants' comments, we suggest refining and further testing the intervention with a larger sample size over a longer-term follow-up to confirm its effectiveness.This study has been registered at ClinicalTrials.gov (NCT04741425).

Nuclear stabilization of p53 requires a functional nucleolar surveillance pathway.

The nucleolar surveillance pathway monitors nucleolar integrity and responds to nucleolar stress by mediating binding of ribosomal proteins to MDM2, resulting in p53 accumulation. Inappropriate pathway activation is implicated in the pathogenesis of ribosomopathies, while drugs selectively activating the pathway are in trials for cancer. Despite this, the molecular mechanism(s) regulating this process are poorly understood. Using genome-wide loss-of-function screens, we demonstrate the ribosome biogenesis axis as the most potent class of genes whose disruption stabilizes p53. Mechanistically, we identify genes critical for regulation of this pathway, including HEATR3. By selectively disabling the nucleolar surveillance pathway, we demonstrate that it is essential for the ability of all nuclear-acting stresses, including DNA damage, to induce p53 accumulation. Our data support a paradigm whereby the nucleolar surveillance pathway is the central integrator of stresses that regulate nuclear p53 abundance, ensuring that ribosome biogenesis is hardwired to cellular proliferative capacity.

Feasibility of a telephone-delivered educational intervention for knowledge transfer of COVID-19-related information to older adults in Hong Kong: a pre-post-pilot study.

BACKGROUND: During the COVID-19 pandemic, educational interventions have become necessary to prevent the spread of health-related misinformation among Hong Kong older adults. The primary objective of this study was to assess the feasibility of a student-led, telephone-delivered intervention to improve COVID-19-related health knowledge among Hong Kong older adults. The secondary objective was to evaluate the impact of the intervention on the student volunteers. METHODS: Twenty-five participants aged 65 or above who were able to communicate in Cantonese and had no hearing or cognitive impairments were recruited for this longitudinal pre-post-study from a community center in Hong Kong. The pilot telephone-delivered intervention consisted of five telephone call sessions conducted by 25 student volunteers. Each participant was paired with the same volunteer throughout the intervention. The first four sessions included pre-tests that assessed the participants' understanding of three COVID-19-related themes: medication safety, healthcare voucher scheme, and COVID-19 myth-busting. Standardized explanations of the pre-test questions were offered to participants during the phone calls. In the last session, a post-test on all the themes was conducted. The intervention's feasibility was assessed based on (a) percentage changes in the participants' test scores, (b) attrition rate, and (c) the acceptability of the intervention by the participants. The impact of the intervention on the student volunteers was evaluated based on a student feedback survey. There was no control group. RESULTS: Significant improvements in the participants' test scores (out of 100%) for all themes were observed after the intervention: from 76 to 95.2% for medication safety, from 64.0 to 88.8% for the healthcare voucher scheme, and from 78.0 to 93.2% for COVID-19 myth-busting. The average improvement in test scores of the three themes was 18.4% (95% CI 12.2 to 24.6%). Most participants were satisfied with the program. The student feedback survey suggested that the intervention enhanced students' communication skills and understanding of Hong Kong older adults. CONCLUSION: This pilot study offers initial evidence of the potential and feasibility of student-led, telephone-delivered educational interventions for the transfer of COVID-19-related knowledge to older adults and their benefits for the student volunteers. Future studies should include larger samples and a control group.

High-definition transcranial direct current stimulation (HD-tDCS) as augmentation therapy in late-life depression (LLD) with suboptimal response to treatment-a study protocol for a double-blinded randomized sham-controlled trial.

BACKGROUND: Late-life depression (LLD) has a poorer prognosis and higher relapse rate than younger adults, with up to one third of patients with LLD showing suboptimal response to antidepressant therapy. LLD has been associated with significant impairment in cognition and daily functioning. Few studies have evaluated the therapeutic effects of high-definition transcranial direct current stimulation (HD-tDCS) on depressive and cognitive symptoms of LLD. The current randomized controlled trial assesses the efficacy of HD-tDCS as an augmentation therapy with antidepressants compared to sham-control in subjects with LLD. METHODS: Fifty-eight patients with LLD will be recruited and randomly assigned to the active HD-tDCS or sham HD-tDCS group. In both groups, patients will receive the active or sham intervention in addition to their pre-existing antidepressant therapy, for 2 weeks with 5 sessions per week, each lasting 30 min. The primary outcome measures will be the change of depressive symptoms, clinical response and the remission rate as measured with the Hamilton Depression Rating scale (HAMD-17) before and after the intervention, and at the 4th and 12th week after the completed intervention. Secondary outcome measures include cognitive symptoms, anxiety symptoms, daily functioning and adverse effects.  DISCUSSION: Older adults with depression are associated with poorer outcomes or unsatisfactory responses to antidepressant therapy, and significant cognitive decline. Therefore, a new effective treatment option is needed. This randomized control trial aims at assessing the efficacy of HD-tDCS on ameliorating the depressive, cognitive and anxiety symptoms, and improving the daily functioning of subjects with LLD. TRIAL REGISTRATION: ClinicalTrials.gov NCT05322863. Registered on 11 April 2022.

Effectiveness of table salt versus copper sulphate in treating umbilical granuloma: A pilot randomized controlled trial.

BACKGROUND: Umbilical granuloma is a common infantile condition which usually responds to non operative management. Copper sulphate (CuSO4) is often used as chemical cauterization but can cause superficial skin burns. An alternative is table salt (NaCl), which osmotically dehydrates wet granulation tissue causing necrosis. We aimed to compare the effectiveness of NaCl versus CuSO4 in treating umbilical granuloma. METHOD: We performed a multi centerrandomized controlled trial involving three regional pediatricsurgical units. We included children who presented with umbilical granuloma from December 2018 to May 2020. Children who received treatment prior to index visit were excluded. They were randomly allocated to receive NaCl (twice/day application for 5 days by caregiver) or CuSO4 (single application by clinician). Demographic data, compliance in the NaCl group by pill counting method, treatment outcomes, and complications were recorded. Treatment success was defined as complete lesion resolution. Partial or no response was considered treatment failure. Subsequent treatment then reverted to the respective center's routine management. RESULT: We recruited 70 participants with 6 dropouts (2 defaulters, 1 vitellointestinal duct, 3 urachal remnants), leaving 64 subjects for final analysis: 31 NaCl, 33 CuSO4. Compliance rate of 77.4% was recorded for NaCl, with 6 (20%) 'poor compliance' participants stopping therapy before completion owing to complete resolution. NaCl group had a significantly higher complete resolution rate (90.4%) compared to CuSO4 (69.7%), p = 0.040. No NaCl participant developed complications versus 9% (n = 3) in CuSO4 (periumbilical superficial skin burn). CONCLUSION: Table salt is an ideal treatment choice for umbilical granuloma as it is effective, safe, and readily available. LEVEL OF EVIDENCE: II.

Gathering Global Perspectives to Establish the Research Priorities and Minimum Data Sets for Degenerative Cervical Myelopathy: Sampling Strategy of the First Round Consensus Surveys of AO Spine RECODE-DCM.

STUDY DESIGN: Survey. INTRODUCTION: AO Spine Research Objectives and Common Data Elements for Degenerative Cervical Myelopathy (AO Spine RECODE-DCM) is an international initiative that aims to accelerate knowledge discovery and improve outcomes by developing a consensus framework for research. This includes defining the top research priorities, an index term and a minimum data set (core outcome set and core data elements set - core outcome set (COS)/core data elements (CDE)). OBJECTIVE: To describe how perspectives were gathered and report the detailed sampling characteristics. METHODS: A two-stage, electronic survey was used to gather and seek initial consensus. Perspectives were sought from spinal surgeons, other healthcare professionals and people with degenerative cervical myelopathy (DCM). Participants were allocated to one of two parallel streams: (1) priority setting or (2) minimum dataset. An email campaign was developed to advertise the survey to relevant global stakeholder individuals and organisations. People with DCM were recruited using the international DCM charity Myelopathy.org and its social media channels. A network of global partners was recruited to act as project ambassadors. Data from Google Analytics, MailChimp and Calibrum helped optimise survey dissemination. RESULTS: Survey engagement was high amongst the three stakeholder groups: 208 people with DCM, 389 spinal surgeons and 157 other healthcare professionals. Individuals from 76 different countries participated; the United States, United Kingdom and Canada were the most common countries of participants. CONCLUSION: AO Spine RECODE-DCM recruited a diverse and sufficient number of participants for an international PSP and COS/CDE process. Whilst PSP and COS/CDE have been undertaken in other fields, to our knowledge, this is the first time they have been combined in one process.