Pediatric Gastrointestinal Outcomes During the Post-Acute Phase of COVID-19.

Background: The impact of COVID-19 on gastrointestinal (GI) outcomes in children during the post-acute and chronic phases of the disease is not well understood. Methods: We conducted a retrospective cohort study across twenty-nine healthcare institutions from March 2020 to September 2023, including 413,455 pediatric patients with confirmed SARS-CoV-2 infection and 1,163,478 controls without infection. Infection was confirmed via polymerase chain reaction (PCR), serology, antigen tests, or clinical diagnosis of COVID-19 and related conditions. We examined the incidence of predefined GI symptoms and disorders during the post-acute (28 to 179 days post-infection) and chronic (180 to 729 days post-infection) phases. The adjusted risk ratios (aRRs) were calculated using stratified Poisson regression, with stratification based on propensity scores. Results: Our cohort comprised 1,576,933 patients, with females representing 48.0% of the sample. The analysis revealed that children with SARS-CoV-2 infection had an increased risk of developing at least one GI symptom or disorder in both the post-acute (8.64% vs. 6.85%; aRR 1.25, 95% CI 1.24-1.27) and chronic phases (12.60% vs. 9.47%; aRR 1.28, 95% CI 1.26-1.30) compared to uninfected peers. Specifically, the risk of abdominal pain was higher in COVID-19 positive patients during the post-acute phase (2.54% vs. 2.06%; aRR 1.14, 95% CI 1.11-1.17) and chronic phase (4.57% vs. 3.40%; aRR 1.24, 95% CI 1.22-1.27). Interpretation: Children with a history of SARS-CoV-2 infection are at an increased risk of GI symptoms and disorders during the post-acute and chronic phases of COVID-19. This highlights the need for ongoing monitoring and management of GI outcomes in this population. Research in Context: Evidence before this study: We searched PubMed, Scopus, and Google Scholar databases up to September 2023 for studies assessing the incidence and risk of gastrointestinal (GI) symptoms and disorders in children following viral infections, including COVID-19. We included studies published in any language and involving various methodologies (observational studies, cohort studies, and clinical trials). Our search terms included "COVID-19," "SARS-CoV-2," "gastrointestinal symptoms," "children," "post-acute," and "chronic." The evidence prior to this study suggested an increased risk of GI disorders in adults after viral infections but was less definitive for the pediatric population.Added value of this study: This study significantly extends the existing literature by specifically examining the risk of GI symptoms and disorders in the pediatric population during the post-acute and chronic phases of COVID-19. Using a large retrospective cohort design encompassing over 1.5 million children and adolescents from 29 healthcare institutions, our analysis provides robust evidence of increased GI symptoms like abdominal pain, diarrhea, and constipation among COVID-19 positive patients compared to non-infected peers. It is one of the largest studies of its kind and the first to provide such comprehensive data for the U.S. pediatric population, with follow-up extending up to two years post-infection.Implications of all the available evidence: The findings underscore the importance of monitoring children and adolescents for persistent GI symptoms following COVID-19, suggesting that these symptoms may be more common and prolonged than previously recognized. These insights are crucial for pediatric healthcare providers and could influence guidelines for the follow-up care of children recovering from COVID-19. The study also highlights the need for future research to explore the underlying mechanisms of post-acute and chronic GI symptoms in children to develop targeted interventions and improve long-term outcomes. Authorship Statement: Authorship has been determined according to ICMJE recommendations.

A novel high-titer, bifunctional lentiviral vector for autologous hematopoietic stem cell gene therapy of sickle cell disease.

A major limitation of gene therapy for sickle cell disease (SCD) is the availability and access to a potentially curative one-time treatment, due to high treatment costs. We have developed a high-titer bifunctional lentiviral vector (LVV) in a vector backbone that has reduced size, high vector yields, and efficient gene transfer to human CD34+ hematopoietic stem and progenitor cells (HSPCs). This LVV contains locus control region cores expressing an anti-sickling ßAS3-globin gene and two microRNA-adapted short hairpin RNA simultaneously targeting BCL11A and ZNF410 transcripts to maximally induce fetal hemoglobin (HbF) expression. This LVV induces high levels of anti-sickling hemoglobins (HbAAS3 + HbF), while concurrently decreasing sickle hemoglobin (HbS). The decrease in HbS and increased anti-sickling hemoglobin impedes deoxygenated HbS polymerization and red blood cell sickling at low vector copy per cell in transduced SCD patient CD34+ cells differentiated into erythrocytes. The dual alterations in red cell hemoglobins ameliorated the SCD phenotype in the SCD Berkeley mouse model in vivo. With high titer and enhanced transduction of HSPC at a low multiplicity of infection, this LVV will increase the number of patient doses of vector from production lots to decrease costs and help improve accessibility to gene therapy for SCD.

Untargeted metabolomics reveals the effects of pre-analytic storage on serum metabolite profiles from healthy cats.

Untargeted metabolomics investigations have characterized metabolic disturbances associated with various diseases in domestic cats. However, the pre-analytic stability of serum metabolites in the species is unknown. Our objective was to compare serum metabolomes from healthy cats stored at -20°C for up to 12 months to samples stored at -80°C. Serum samples from 8 adult, healthy cats were stored at -20°C for 6 months, -20°C for 12 months, or -80°C for 12 months. Untargeted liquid chromatography-mass spectrometry was used to generate serum metabolite profiles containing relative abundances of 733 serum metabolites that were compared among storage conditions. Unsupervised analysis with principal component analysis and hierarchical clustering of Euclidian distances revealed separation of samples from individual cats regardless of storage condition. Linear mixed-effects models identified 75 metabolites that differed significantly among storage conditions. Intraclass correlation analysis (ICC) classified most serum metabolites as having excellent (ICC ≥ 0.9; 33%) or moderate (ICC 0.75-0.89; 33%) stability, whereas 13% had poor stability (ICC < 0.5). Biochemicals that varied significantly among storage conditions and classified with poor stability included glutathione metabolites, amino acids, gamma-glutamyl amino acids, and polyunsaturated fatty acids. The benzoate; glycine, serine and threonine; tryptophan; chemical (xenobiotics); acetylated peptide, and primary bile acid sub pathways were enriched among highly stable metabolites, whereas the monohydroxy fatty acid, polyunsaturated fatty, and monoacylglycerol sub-pathways were enriched among unstable metabolites. Our findings suggest that serum metabolome profiles are representative of the cat of origin, regardless of storage condition. However, changes in specific serum metabolites, especially glutathione, gamma-glutamyl amino acid, and fatty acid metabolites were consistent with increased sample oxidation during storage at -20°C compared with -80°C. By investigating the pre-analytic stability of serum metabolites, this investigation provides valuable insights that could aid other investigators in planning and interpreting studies of serum metabolomes in cats.

Post-Acute Cardiovascular Outcomes of COVID-19 in Children and Adolescents: An EHR Cohort Study from the RECOVER Project.

Background: The risk of cardiovascular outcomes in the post-acute phase of SARS-CoV-2 infection has been quantified among adults and children. This paper aimed to assess a multitude of cardiac signs, symptoms, and conditions, as well as focused on patients with and without congenital heart defects (CHDs), to provide a more comprehensive assessment of the post-acute cardiovascular outcomes among children and adolescents after COVID-19. Methods: This retrospective cohort study used data from the RECOVER consortium comprising 19 US children's hospitals and health institutions between March 2020 and September 2023. Every participant had at least a six-month follow-up after cohort entry. Absolute risks of incident post-acute COVID-19 sequelae were reported. Relative risks (RRs) were calculated by contrasting COVID-19-positive with COVID-19-negative groups using a Poisson regression model, adjusting for demographic, clinical, and healthcare utilization factors through propensity scoring stratification. Results: A total of 1,213,322 individuals under 21 years old (mean[SD] age, 7.75[6.11] years; 623,806 male [51.4%]) were included. The absolute rate of any post-acute cardiovascular outcome in this study was 2.32% in COVID-19 positive and 1.38% in negative groups. Patients with CHD post-SARS-CoV-2 infection showed increased risks of any cardiovascular outcome (RR, 1.63; 95% confidence interval (CI), 1.47-1.80), including increased risks of 11 of 18 post-acute sequelae in hypertension, arrhythmias (atrial fibrillation and ventricular arrhythmias), myocarditis, other cardiac disorders (heart failure, cardiomyopathy, and cardiac arrest), thrombotic disorders (thrombophlebitis and thromboembolism), and cardiovascular-related symptoms (chest pain and palpitations). Those without CHDs also experienced heightened cardiovascular risks after SARS-CoV-2 infection (RR, 1.63; 95% CI, 1.57-1.69), covering 14 of 18 conditions in hypertension, arrhythmias (ventricular arrhythmias and premature atrial or ventricular contractions), inflammatory heart disease (pericarditis and myocarditis), other cardiac disorders (heart failure, cardiomyopathy, cardiac arrest, and cardiogenic shock), thrombotic disorders (pulmonary embolism and thromboembolism), and cardiovascular-related symptoms (chest pain, palpitations, and syncope). Conclusions: Both children with and without CHDs showed increased risks for a variety of cardiovascular outcomes after SARS-CoV-2 infection, underscoring the need for targeted monitoring and management in the post-acute phase.

Withdrawal catastrophizing scale: initial psychometric properties and implications for the study of opioid use disorder and hyperkatifeia.

Background: Discovery of modifiable factors influencing subjective withdrawal experience might advance opioid use disorder (OUD) research and precision treatment. This study explores one factor - withdrawal catastrophizing - a negative cognitive and emotional orientation toward withdrawal characterized by excessive fear, worry or inability to divert attention from withdrawal symptoms.Objectives: We define a novel concept - withdrawal catastrophizing - and present an initial evaluation of the Withdrawal Catastrophizing Scale (WCS).Methods: Prospective observational study (n = 122, 48.7% women). Factor structure (exploratory factor analysis) and internal consistency (Cronbach's α) were assessed. Predictive validity was tested via correlation between WCS and next-day subjective opiate withdrawal scale (SOWS) severity. The clinical salience of WCS was evaluated by correlation between WCS and withdrawal-motivated behaviors including risk taking, OUD maintenance, OUD treatment delay, history of leaving the hospital against medical advice and buprenorphine-precipitated withdrawal.Results: WCS was found to have a two-factor structure (distortion and despair), strong internal consistency (α = .901), and predictive validity - Greater withdrawal catastrophizing was associated with next-day SOWS (rs (99) = 0.237, p = .017). Withdrawal catastrophizing was also correlated with risk-taking behavior to relieve withdrawal (rs (119) = 0.357, p < .001); withdrawal-motivated OUD treatment avoidance (rs (119) = 0.421, p < .001), history of leaving the hospital against medical advice (rs (119) = 0.373, p < .001) and buprenorphine-precipitated withdrawal (rs (119) = 0.369, p < .001).Conclusion: This study provides first evidence of withdrawal catastrophizing as a clinically important phenomenon with implications for the future study and treatment of OUD.

Fecal microbiome composition and diversity of cryopreserved canine stool at different duration and storage conditions.

Fresh-frozen stool banks intended for humans with gastrointestinal and metabolic disorders have been recently established and there are ongoing efforts to establish the first veterinary fresh-frozen stool bank. Fresh frozen stored feces provide an advantage of increased availability and accessibility to high-quality optimal donor fecal material. The stability of frozen canine feces regarding fecal microbiome composition and diversity has not been reported in dogs, providing the basis for this study. We hypothesized that fecal microbial composition and diversity of healthy dogs would remain stable when stored at -20°C and -80°C for up to 12 months compared to baseline samples evaluated before freezing. Stool samples were collected from 20 apparently healthy dogs, manually homogenized, cryopreserved in 20% glycerol and aliquoted, frozen in liquid nitrogen and stored at -20°C or -80°C for 3, 6, 9, and 12 months. At baseline and after period of storage, aliquots were thawed and treated with propidium monoazide before fecal DNA extraction. Following long-read 16S-rRNA amplicon sequencing, bacterial community composition and diversity were compared among treatment groups. We demonstrated that fresh-frozen canine stools collected from 20 apparently healthy dogs could be stored for up to 12 months at -80°C with minimal change in microbial community composition and diversity and that storage at -80°C is superior to storage at -20°C. We also found that differences between dogs had the largest effect on community composition and diversity. Relative abundances of certain bacterial taxa, including those known to be short-chain fatty acid producers, varied significantly with specific storage temperatures and duration. Further work is required to ascertain whether fecal donor material that differs in bacterial community composition and diversity across storage conditions and duration could lead to differences in clinical efficacy for specific clinical indications of fecal microbiota transplantation.

[Evidence-based interventions to treat chronic low back pain: treatment selection for a personalized medicine approach : German version]. / Evidenzbasierte Interventionen zur Behandlung von chronischem Schmerz im unteren Rücken ­ Therapieauswahl für einen personalisierten Behandlungsansatz : Deutsche Fassung.

INTRODUCTION: Chronic low back pain (cLBP) is highly prevalent in the United States and globally, resulting in functional impairment and lowered quality of life. While many treatments are available for cLBP, clinicians have little information about which specific treatment(s) will work best for individual patients or subgroups of patients. The Back Pain Research Consortium, part of the National Institutes of Health Helping to End Addiction Long-termSM (HEAL) Initiative, will conduct a collaborative clinical trial, which seeks to develop a personalized medicine algorithm to optimize patient and provider treatment selection for patients with cLBP. OBJECTIVE: The primary objective of this article is to provide an update on evidence-based cLBP interventions and describe the process of reviewing and selecting interventions for inclusion in the clinical trial. METHODS: A working group of cLBP experts reviewed and selected interventions for inclusion in the clinical trial. The primary evaluation measures were strength of evidence and magnitude of treatment effect. When available in the literature, duration of effect, onset time, carryover effect, multimodal efficacy, responder subgroups, and evidence for the mechanism of treatment effect or biomarkers were considered. CONCLUSION: The working group selected 4 leading, evidence-based treatments for cLBP to be tested in the clinical trial and for use in routine clinical treatment. These treatments include (1) duloxetine, (2) acceptance and commitment therapy, (3) a classification-based exercise and manual therapy intervention, and (4) a self-management approach. These interventions each had a moderate to high level of evidence to support a therapeutic effect and were from different therapeutic classes.

Vaccine Effectiveness Against Long COVID in Children.

OBJECTIVES: Vaccination reduces the risk of acute coronavirus disease 2019 (COVID-19) in children, but it is less clear whether it protects against long COVID. We estimated vaccine effectiveness (VE) against long COVID in children aged 5 to 17 years. METHODS: This retrospective cohort study used data from 17 health systems in the RECOVER PCORnet electronic health record program for visits after vaccine availability. We examined both probable (symptom-based) and diagnosed long COVID after vaccination. RESULTS: The vaccination rate was 67% in the cohort of 1 037 936 children. The incidence of probable long COVID was 4.5% among patients with COVID-19, whereas diagnosed long COVID was 0.8%. Adjusted vaccine effectiveness within 12 months was 35.4% (95 CI 24.5-44.7) against probable long COVID and 41.7% (15.0-60.0) against diagnosed long COVID. VE was higher for adolescents (50.3% [36.6-61.0]) than children aged 5 to 11 (23.8% [4.9-39.0]). VE was higher at 6 months (61.4% [51.0-69.6]) but decreased to 10.6% (-26.8% to 37.0%) at 18-months. CONCLUSIONS: This large retrospective study shows moderate protective effect of severe acute respiratory coronavirus 2 vaccination against long COVID. The effect is stronger in adolescents, who have higher risk of long COVID, and wanes over time. Understanding VE mechanism against long COVID requires more study, including electronic health record sources and prospective data.

Validation of a simple body map to measure widespread pain in urologic chronic pelvic pain syndrome: A MAPP Research Network study.

PURPOSE: In patients with urologic chronic pelvic pain syndrome (UCPPS), the presence of widespread pain appears to identify a distinct phenotype, with a different symptom trajectory and potentially different response to treatment than patients with pelvic pain only. MATERIALS AND METHODS: A 76-site body map was administered four times, at weekly intervals, to 568 male and female UCPPS participants in the MAPP Network protocol. The 76 sites were classified into 13 regions (1 pelvic region and 12 nonpelvic regions). The degree of widespread pain was scored from 0 to 12 based on the number of reported nonpelvic pain regions. This continuous body map score was regressed over other measures of widespread pain, with UCPPS symptom severity, and with psychosocial variables to measure level of association. These models were repeated using an updated body map score (0-12) that incorporated a threshold of pain ≥ 4 at each site. RESULTS: Body map scores showed limited variability over the 4 weekly assessments, indicating that a single baseline assessment was sufficient. The widespread pain score correlated highly with other measures of widespread pain and correlated with worsened UCPPS symptom severity and psychosocial functioning. Incorporating a pain severity threshold ≥4 resulted in only marginal increases in these correlations. CONCLUSIONS: These results support the use of this 13-region body map in the baseline clinical assessment of UCPPS patients. It provides reliable data about the presence of widespread pain and does not require measurement of pain severity, making it relatively simple to use for clinical purposes.

Limitations of Noninvasive Tests-Based Population-Level Risk Stratification Strategy for Nonalcoholic Fatty Liver Disease.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) are highly prevalent but underdiagnosed. AIMS: We used an electronic health record data network to test a population-level risk stratification strategy using noninvasive tests (NITs) of liver fibrosis. METHODS: Data were obtained from PCORnet® sites in the East, Midwest, Southwest, and Southeast United States from patients aged [Formula: see text] 18 with or without ICD-10-CM diagnosis codes for NAFLD, NASH, and NASH-cirrhosis between 9/1/2017 and 8/31/2020. Average and standard deviations (SD) for Fibrosis-4 index (FIB-4), NAFLD fibrosis score (NFS), and Hepatic Steatosis Index (HSI) were estimated by site for each patient cohort. Sample-wide estimates were calculated as weighted averages across study sites. RESULTS: Of 11,875,959 patients, 0.8% and 0.1% were coded with NAFLD and NASH, respectively. NAFLD diagnosis rates in White, Black, and Hispanic patients were 0.93%, 0.50%, and 1.25%, respectively, and for NASH 0.19%, 0.04%, and 0.16%, respectively. Among undiagnosed patients, insufficient EHR data for estimating NITs ranged from 68% (FIB-4) to 76% (NFS). Predicted prevalence of NAFLD by HSI was 60%, with estimated prevalence of advanced fibrosis of 13% by NFS and 7% by FIB-4. Approximately, 15% and 23% of patients were classified in the intermediate range by FIB-4 and NFS, respectively. Among NAFLD-cirrhosis patients, a third had FIB-4 scores in the low or intermediate range. CONCLUSIONS: We identified several potential barriers to a population-level NIT-based screening strategy. HSI-based NAFLD screening appears unrealistic. Further research is needed to define merits of NFS- versus FIB-4-based strategies, which may identify different high-risk groups.

Exocrine pancreatic insufficiency in dogs and cats.

Exocrine pancreatic insufficiency (EPI) is a malabsorptive syndrome caused by insufficient secretion of digestive enzymes from pancreatic acini. The most common causes of EPI in dogs and cats are pancreatic acinar atrophy and chronic pancreatitis. EPI is diagnosed by measurement of species-specific immunoassays for serum trypsin-like immunoreactivity, the concentration of which directly reflects the mass of functioning pancreatic acinar tissue. EPI is treated by pancreatic enzyme replacement therapy, nutritional management (low-residue diets with moderate fat content), and supplementation of cobalamin. Some dogs and cats have persistent clinical signs despite these treatments. Growing evidence suggests that these clinical signs may be due to enteric microbiota dysbiosis or the presence of concurrent diseases such as chronic enteropathies. Management of these abnormalities may improve outcome in dogs and cats with EPI. The long-term prognosis for dogs and cats with EPI is generally good if high-quality medical therapy is provided. Future studies are needed to further understand the causes of persistent dysbiosis in animals with EPI following initiation of pancreatic enzyme replacement therapy and assess the efficacy of treatments to ameliorate these abnormalities.

'I'm still here, I'm alive and breathing': The experience of Black Americans with long COVID.

AIMS AND OBJECTIVES: In this study, we aimed to characterize the impact of long COVID on quality of life and approaches to symptom management among Black American adults. BACKGROUND: As a novel condition, qualitative evidence concerning long COVID symptoms and their impact on quality of life can inform the refinement of diagnostic criteria and care plans. However, the underrepresentation of Black Americans in long COVID research is a barrier to achieving equitable care for all long COVID patients. DESIGN: We employed an interpretive description study design. METHODS: We recruited a convenience sample of 15 Black American adults with long COVID. We analysed the anonymized transcripts from race-concordant, semi-structured interviews using an inductive, thematic analysis approach. We followed the SRQR reporting guidelines. RESULTS: We identified four themes: (1) The impact of long COVID symptoms on personal identity and pre-existing conditions; (2) Self-management strategies for long COVID symptoms; (3) Social determinants of health and symptom management; and (4) Effects on interpersonal relationships. CONCLUSION: Findings demonstrate the comprehensive ramifications of long COVID on the lives of Black American adults. Results also articulate how pre-existing conditions, social risk factors, distrust due to systemic racism, and the nature of interpersonal relationships can complicate symptom management. RELEVANCE TO CLINICAL PRACTICE: Care approaches that support access to and implementation of integrative therapies may be best suited to meet the needs of long COVID patients. Clinicians should also prioritize eliminating patient exposure to discrimination, implicit bias, and microaggressions. This is of particular concern for long COVID patients who have symptoms that are difficult to objectively quantify, such as pain and fatigue. NO PATIENT OR PUBLIC CONTRIBUTION: While patient perspectives and experiences were the focus of this study, patients were not involved with the design or conduct of the study, data analysis or interpretation, or writing the manuscript.

Self-guided digital acceptance and commitment therapy for fibromyalgia management: results of a randomized, active-controlled, phase II pilot clinical trial.

Although empirically validated for fibromyalgia (FM), cognitive and behavioral therapies, including Acceptance and Commitment Therapy (ACT), are inaccessible to many patients. A self-guided, smartphone-based ACT program would significantly improve accessibility. The SMART-FM study assessed the feasibility of conducting a predominantly virtual clinical trial in an FM population in addition to evaluating preliminary evidence for the safety and efficacy of a digital ACT program for FM (FM-ACT). Sixty-seven patients with FM were randomized to 12 weeks of FM-ACT (n = 39) or digital symptom tracking (FM-ST; n = 28). The study population was 98.5% female, with an average age of 53 years and an average baseline FM symptom severity score of 8 out of 11. Endpoints included the Fibromyalgia Impact Questionnaire-Revised (FIQ-R) and the Patient Global Impression of Change (PGIC). The between-arm effect size for the change from baseline to Week 12 in FIQ-R total scores was d = 0.44 (least-squares mean difference, - 5.7; SE, 3.16; 95% CI, - 11.9 to 0.6; P = .074). At Week 12, 73.0% of FM-ACT participants reported improvement on the PGIC versus 22.2% of FM-ST participants (P < .001). FM-ACT demonstrated improved outcomes compared to FM-ST, with high engagement and low attrition in both arms. Retrospectively registered at ClinicalTrials.gov (NCT05005351) on August 13, 2021.

The Chronic Overlapping Pain Condition Screener.

Ten Chronic Overlapping Pain Conditions (COPCs) are currently recognized by the National Institutes of Health Pain Consortium (eg, irritable bowel syndrome, chronic migraine headache, and chronic low back pain). These conditions affect millions of Americans; however, assessing these conditions, their co-occurrence, and their relationship to treatment has proven challenging due to time constraints and a lack of standardized measures. We present a Chronic Overlapping Pain Condition-Screener (COPC-S) that is logic-driven, efficient, and freely available in electronic format to nonprofit entities. Thirty experts were convened to identify and modify self-report criteria for each COPC as well as criteria that trigger the administration of the diagnostic criteria from a body map and a brief series of questions. Their recommendations were then programmed into the Research Electronic Data Capture platform and refined for comprehensibility and ease of use by patient focus groups. The electronic screener and physician-administered criteria were both administered to patients with known COPCs in a counter-balanced fashion to determine the level of agreement between methods. The expert panel identified screening items/body map regions and diagnostic criteria for all 10 COPCs. Patients found the content comprehensible and the platform easy to use. Cohen's Kappa statistics suggested good agreement between the electronic COPC-S and criteria administered by a physician (κ = .813). The COPC-S is an efficient tool for screening multiple COPCs and has applicability to research studies, clinical trials, and clinical practice. PERSPECTIVE: Assessing COPCs remains a challenge for researchers and clinicians. The COPC-S is an efficient and logic-driven electronic tool that allows for the rapid screening assessment of 10 COPCs. The instrument may have utility in research and clinical settings.

Relationship Between Nociplastic Pain Involvement and Medication Use, Symptom Relief, and Adverse Effects Among People Using Medical Cannabis for Chronic Pain.

OBJECTIVES: Cannabis is increasingly being used for chronic pain management, but cannabis' effects remain poorly characterized in chronic nociplastic pain (NPP), which is posited to be caused by disturbances in nervous system pain processing. In this cross-sectional study (n=1213), we used the 2011 Fibromyalgia (FM) Survey Criteria as a surrogate measure for degree of NPP among individuals using medical cannabis for chronic pain. METHODS: Using a quartile-split, we investigated associations between the degree of NPP and medication use, cannabis use characteristics, and symptom relief. Continuous variables were assessed using one-way analysis of variance and categorical variables with Pearson χ 2 test and binomial logistic regression for calculation of odds ratios. RESULTS: Participants were predominately female (59%), with a mean ± SD age of 49.4±13.6 years. Higher FM scores were associated with less self-reported improvement in pain and health since initiating medical cannabis use, as well as more cannabis-related side effects. Paradoxically, higher FM scores were also associated with higher usage of concomitant medication use (including opioids and benzodiazepines) but also with substituting cannabis for significantly more medication classes, including opioids and benzodiazepines. DISCUSSION: This article presents evidence that individuals in higher NPP quartiles have higher analgesic intake, higher odds of substituting cannabis for medications, higher side effect burden, and lower therapeutic effect from cannabis. These seemingly contradictory findings may reflect higher symptom burden, polypharmacy at baseline, or that NPP may be challenging to treat with cannabis. Further research is necessary to further explain cannabinoid effects in NPP.

Clonal selection of hematopoietic stem cells after gene therapy for sickle cell disease.

Gene therapy (GT) provides a potentially curative treatment option for patients with sickle cell disease (SCD); however, the occurrence of myeloid malignancies in GT clinical trials has prompted concern, with several postulated mechanisms. Here, we used whole-genome sequencing to track hematopoietic stem cells (HSCs) from six patients with SCD at pre- and post-GT time points to map the somatic mutation and clonal landscape of gene-modified and unmodified HSCs. Pre-GT, phylogenetic trees were highly polyclonal and mutation burdens per cell were elevated in some, but not all, patients. Post-GT, no clonal expansions were identified among gene-modified or unmodified cells; however, an increased frequency of potential driver mutations associated with myeloid neoplasms or clonal hematopoiesis (DNMT3A- and EZH2-mutated clones in particular) was observed in both genetically modified and unmodified cells, suggesting positive selection of mutant clones during GT. This work sheds light on HSC clonal dynamics and the mutational landscape after GT in SCD, highlighting the enhanced fitness of some HSCs harboring pre-existing driver mutations. Future studies should define the long-term fate of mutant clones, including any contribution to expansions associated with myeloid neoplasms.

Vaccine Effectiveness Against Long COVID in Children: A Report from the RECOVER EHR Cohort.

Objective: Vaccination reduces the risk of acute COVID-19 in children, but it is less clear whether it protects against long COVID. We estimated vaccine effectiveness (VE) against long COVID in children aged 5-17 years. Methods: This retrospective cohort study used data from 17 health systems in the RECOVER PCORnet electronic health record (EHR) Program for visits between vaccine availability, and October 29, 2022. Conditional logistic regression was used to estimate VE against long COVID with matching on age group (5-11, 12-17) and time period and adjustment for sex, ethnicity, health system, comorbidity burden, and pre-exposure health care utilization. We examined both probable (symptom-based) and diagnosed long COVID in the year following vaccination. Results: The vaccination rate was 56% in the cohort of 1,037,936 children. The incidence of probable long COVID was 4.5% among patients with COVID-19, while diagnosed long COVID was 0.7%. Adjusted vaccine effectiveness within 12 months was 35.4% (95 CI 24.5 - 44.5) against probable long COVID and 41.7% (15.0 - 60.0) against diagnosed long COVID. VE was higher for adolescents 50.3% [36.3 - 61.0]) than children aged 5-11 (23.8% [4.9 - 39.0]). VE was higher at 6 months (61.4% [51.0 - 69.6]) but decreased to 10.6% (-26.8 - 37.0%) at 18-months. Discussion: This large retrospective study shows a moderate protective effect of SARS-CoV-2 vaccination against long COVID. The effect is stronger in adolescents, who have higher risk of long COVID, and wanes over time. Understanding VE mechanism against long COVID requires more study, including EHR sources and prospective data. Article Summary: Vaccination against COVID-19 has a protective effect against long COVID in children and adolescents. The effect wanes over time but remains significant at 12 months. What's Known on This Subject: Vaccines reduce the risk and severity of COVID-19 in children. There is evidence for reduced long COVID risk in adults who are vaccinated, but little information about similar effects for children and adolescents, who have distinct forms of long COVID. What This Study Adds: Using electronic health records from US health systems, we examined large cohorts of vaccinated and unvaccinated patients <18 years old and show that vaccination against COVID-19 is associated with reduced risk of long COVID for at least 12 months. Contributors' Statement: Drs. Hanieh Razzaghi and Charles Bailey conceptualized and designed the study, supervised analyses, drafted the initial manuscript, and critically reviewed and revised the manuscript.Drs. Christopher Forrest and Yong Chen designed the study and critically reviewed and revised the manuscript.Ms. Kathryn Hirabayashi, Ms. Andrea Allen, and Dr. Qiong Wu conducted analyses, and critically reviewed and revised the manuscript.Drs. Suchitra Rao, H Timothy Bunnell, Elizabeth A. Chrischilles, Lindsay G. Cowell, Mollie R. Cummins, David A. Hanauer, Benjamin D. Horne, Carol R. Horowitz, Ravi Jhaveri, Susan Kim, Aaron Mishkin, Jennifer A. Muszynski, Susanna Nagie, Nathan M. Pajor, Anuradha Paranjape, Hayden T. Schwenk, Marion R. Sills, Yacob G. Tedla, David A. Williams, and Ms. Miranda Higginbotham critically reviewed and revised the manuscript.All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work. Authorship statement: Authorship has been determined according to ICMJE recommendations.

Genetic reversal of the globin switch concurrently modulates both fetal and sickle hemoglobin and reduces red cell sickling.

We previously reported initial clinical results of post-transcriptional gene silencing of BCL11A expression (NCT03282656) reversing the fetal to adult hemoglobin switch. A goal of this approach is to increase fetal hemoglobin (HbF) expression while coordinately reducing sickle hemoglobin (HbS) expression. The resulting combinatorial effect should prove effective in inhibiting HbS polymerization at lower physiologic oxygen values thereby mitigating disease complications. Here we report results of exploratory single-cell analysis of patients in which BCL11A is targeted molecularly and compare results with cells of patients treated with hydroxyurea (HU), the current standard of care. We use single-cell assays to assess HbF, HbS, oxygen saturation, and hemoglobin polymer content in RBCs for nine gene therapy trial subjects (BCLshmiR, median HbF% = 27.9) and compare them to 10 HU-treated subjects demonstrating high and comparable levels of HbF (HU High Responders, median HbF% = 27.0). All BCL11A patients achieved the primary endpoint for NCT03282656, which was defined by an absolute neutrophil count greater than or equal to 0.5 × 109 cells/L for three consecutive days, achieved within 7 weeks following infusion. Flow cytometric assessment of single-RBC HbF and HbS shows fewer RBCs with high HbS% that would be most susceptible to sickling in BCLshmiR vs. HU High Responders: median 42% of RBCs with HbS%>70% in BCLshmiR vs. 61% in HU High Responders (p = 0.004). BCLshmiR subjects also demonstrate more RBCs resistant to HbS polymerization at lower physiologic oxygen tension: median 32% vs. 25% in HU High Responders (p = 0.006). Gene therapy-induced BCL11A down-regulation reverses the fetal-to-adult hemoglobin switch and induces RBCs with higher HbF%, lower HbS%, and greater resistance to deoxygenation-induced polymerization in clinical trial subjects compared with a cohort of highly responsive hydroxyurea-treated subjects.

Electronic Patient-Reported Outcome Data Collection Systems in Oncology Clinical Trials: A Survey of Clinical Research Professionals (an Alliance Study).

PURPOSE: To describe clinical research professionals (CRPs)' experiences with electronic patient-reported outcome (ePRO) data collection systems in oncology clinical trials and identify correlates of CRPs' attitude toward technology. METHODS: An online survey was conducted among 210 CRPs from 125 National Cancer Institute-funded research sites. Measures included CRPs' demographic characteristics, working years, employment locations, and previous experiences with various types of ePROs. Their attitude toward technology was measured by the Technology Attitude Scale-Adapted. The Wilcoxon signed-rank test was used to compare two subdomains of attitude (perceived usefulness [PU] and perceived ease of use [PEU]). Multiple linear regression was used to explore correlates of (1) overall attitude, (2) PU, and (3) PEU. The significance level was 5%. RESULTS: Participants' median age was 41 years (range, 21-67). Most were female (90%) and White (82%). More than half of the participants had previous experiences with web-based ePROs using patients' own devices (72%) or site-/sponsor-provided on-site devices (eg, kiosks or tablets; 64%). CRPs who were 60 years or older (ß = -0.32, P < .05) or worked for 10-20 years (ß = -0.11, P < .05) had relatively negative attitudes, controlling for other factors. Previous experiences with more ePRO types were associated with more positive attitudes (ß = 0.08, P = .02). Similar correlates were found with PU but not with PEU. CONCLUSION: This study revealed that CRPs had various experiences with ePRO systems and attitudes toward technology. Age, working years, and previous experiences with ePROs were correlates of overall attitude toward technology and PU. These findings suggest necessary targeted training to facilitate ePRO use in oncology clinical trials by improving CRPs' awareness and attitude toward technology.