Hematologic Cancer after Gene Therapy for Cerebral Adrenoleukodystrophy.

BACKGROUND: Gene therapy with elivaldogene autotemcel (eli-cel) consisting of autologous CD34+ cells transduced with lentiviral vector containing ABCD1 complementary DNA (Lenti-D) has shown efficacy in clinical studies for the treatment of cerebral adrenoleukodystrophy. However, the risk of oncogenesis with eli-cel is unclear. METHODS: We performed integration-site analysis, genetic studies, flow cytometry, and morphologic studies in peripheral-blood and bone marrow samples from patients who received eli-cel therapy in two completed phase 2-3 studies (ALD-102 and ALD-104) and an ongoing follow-up study (LTF-304) involving the patients in both ALD-102 and ALD-104. RESULTS: Hematologic cancer developed in 7 of 67 patients after the receipt of eli-cel (1 of 32 patients in the ALD-102 study and 6 of 35 patients in the ALD-104 study): myelodysplastic syndrome (MDS) with unilineage dysplasia in 2 patients at 14 and 26 months; MDS with excess blasts in 3 patients at 28, 42, and 92 months; MDS in 1 patient at 36 months; and acute myeloid leukemia (AML) in 1 patient at 57 months. In the 6 patients with available data, predominant clones contained lentiviral vector insertions at multiple loci, including at either MECOM-EVI1 (MDS and EVI1 complex protein EVI1 [ecotropic virus integration site 1], in 5 patients) or PRDM16 (positive regulatory domain zinc finger protein 16, in 1 patient). Several patients had cytopenias, and most had vector insertions in multiple genes within the same clone; 6 of the 7 patients also had somatic mutations (KRAS, NRAS, WT1, CDKN2A or CDKN2B, or RUNX1), and 1 of the 7 patients had monosomy 7. Of the 5 patients with MDS with excess blasts or MDS with unilineage dysplasia who underwent allogeneic hematopoietic stem-cell transplantation (HSCT), 4 patients remain free of MDS without recurrence of symptoms of cerebral adrenoleukodystrophy, and 1 patient died from presumed graft-versus-host disease 20 months after HSCT (49 months after receiving eli-cel). The patient with AML is alive and had full donor chimerism after HSCT; the patient with the most recent case of MDS is alive and awaiting HSCT. CONCLUSIONS: Hematologic cancer developed in a subgroup of patients who were treated with eli-cel; the cases are associated with clonal vector insertions within oncogenes and clonal evolution with acquisition of somatic genetic defects. (Funded by Bluebird Bio; ALD-102, ALD-104, and LTF-304 ClinicalTrials.gov numbers, NCT01896102, NCT03852498, and NCT02698579, respectively.).

Lentiviral Gene Therapy for Cerebral Adrenoleukodystrophy.

BACKGROUND: Cerebral adrenoleukodystrophy is a severe form of X-linked adrenoleukodystrophy characterized by white-matter disease, loss of neurologic function, and early death. Elivaldogene autotemcel (eli-cel) gene therapy, which consists of autologous CD34+ cells transduced with Lenti-D lentiviral vector containing ABCD1 complementary DNA, is being tested in persons with cerebral adrenoleukodystrophy. METHODS: In a phase 2-3 study, we evaluated the efficacy and safety of eli-cel therapy in boys with early-stage cerebral adrenoleukodystrophy and evidence of active inflammation on magnetic resonance imaging (MRI). The primary efficacy end point was survival without any of six major functional disabilities at month 24. The secondary end points included overall survival at month 24 and the change from baseline to month 24 in the total neurologic function score. RESULTS: A total of 32 patients received eli-cel; 29 patients (91%) completed the 24-month study and are being monitored in the long-term follow-up study. At month 24, none of these 29 patients had major functional disabilities; overall survival was 94%. At the most recent assessment (median follow-up, 6 years), the neurologic function score was stable as compared with the baseline score in 30 of 32 patients (94%); 26 patients (81%) had no major functional disabilities. Four patients had adverse events that were directly related to eli-cel. Myelodysplastic syndrome (MDS) with excess blasts developed in 1 patient at month 92; the patient underwent allogeneic hematopoietic stem-cell transplantation and did not have MDS at the most recent follow-up. CONCLUSIONS: At a median follow-up of 6 years after lentiviral gene therapy, most patients with early cerebral adrenoleukodystrophy and MRI abnormalities had no major functional disabilities. However, insertional oncogenesis is an ongoing risk associated with the integration of viral vectors. (Funded by Bluebird Bio; ALD-102 and LTF-304 ClinicalTrials.gov numbers NCT01896102 and NCT02698579, respectively.).

Self-guided digital behavioural therapy versus active control for fibromyalgia (PROSPER-FM): a phase 3, multicentre, randomised controlled trial.

BACKGROUND: International guidelines have recommended cognitive behavioural therapy, including acceptance and commitment therapy (ACT), as it offers validated benefits for managing fibromyalgia; however, it is inaccessible to most patients. We aimed to evaluate the effect of a 12-week, self-guided, smartphone-delivered digital ACT programme on fibromyalgia management. METHODS: In the PROSPER-FM randomised clinical trial conducted at 25 US community sites, adult participants aged 22-75 years with fibromyalgia were recruited and randomly assigned (1:1) to the digital ACT group or an active control group that offered daily symptom tracking and monitoring and access to health-related and fibromyalgia-related educational materials. Randomisation was done with a web-based system in permuted blocks of four at the site level. We used a blind-to-hypothesis approach in which participants were informed they would be randomly assigned to one of two potentially effective therapies under evaluation. Research staff were not masked to group allocation, with the exception of a masked statistics group while preparing statistical programming for the interim analysis. The primary endpoint was patient global impression of change (PGIC) response rate at week 12. Analyses were by intention to treat. The trial was registered with ClinicalTrials.gov, NCT05243511 (now fully closed). FINDINGS: Between Feb 8, 2022, and Feb 2, 2023, 590 individuals were screened, of whom 275 (257 women and 18 men) were randomly assigned to the digital ACT group (n=140) and the active control group (n=135). At 12 weeks, 99 (71%) of 140 ACT participants reported improvement on PGIC versus 30 (22%) of 135 active control participants, corresponding to a difference in proportions of 48·4% (95% CI 37·9-58·9; p<0·0001). No device-related safety events were reported. INTERPRETATION: Digital ACT was safe and efficacious compared with digital symptom tracking in managing fibromyalgia in adult patients. FUNDING: Swing Therapeutics.

Outcomes of hematopoietic stem cell gene therapy for Wiskott-Aldrich syndrome.

Wiskott-Aldrich syndrome (WAS) is a rare X-linked disorder characterized by combined immunodeficiency, eczema, microthrombocytopenia, autoimmunity, and lymphoid malignancies. Gene therapy (GT) to modify autologous CD34+ cells is an emerging alternative treatment with advantages over standard allogeneic hematopoietic stem cell transplantation for patients who lack well-matched donors, avoiding graft-versus-host-disease. We report the outcomes of a phase 1/2 clinical trial in which 5 patients with severe WAS underwent GT using a self-inactivating lentiviral vector expressing the human WAS complementary DNA under the control of a 1.6-kB fragment of the autologous promoter after busulfan and fludarabine conditioning. All patients were alive and well with sustained multilineage vector gene marking (median follow-up: 7.6 years). Clinical improvement of eczema, infections, and bleeding diathesis was universal. Immune function was consistently improved despite subphysiologic levels of transgenic WAS protein expression. Improvements in platelet count and cytoskeletal function in myeloid cells were most prominent in patients with high vector copy number in the transduced product. Two patients with a history of autoimmunity had flares of autoimmunity after GT, despite similar percentages of WAS protein-expressing cells and gene marking to those without autoimmunity. Patients with flares of autoimmunity demonstrated poor numerical recovery of T cells and regulatory T cells (Tregs), interleukin-10-producing regulatory B cells (Bregs), and transitional B cells. Thus, recovery of the Breg compartment, along with Tregs appears to be protective against development of autoimmunity after GT. These results indicate that clinical and laboratory manifestations of WAS are improved with GT with an acceptable safety profile. This trial is registered at clinicaltrials.gov as #NCT01410825.

Post-Transcriptional Genetic Silencing of BCL11A to Treat Sickle Cell Disease.

BACKGROUND: Sickle cell disease is characterized by hemolytic anemia, pain, and progressive organ damage. A high level of erythrocyte fetal hemoglobin (HbF) comprising α- and γ-globins may ameliorate these manifestations by mitigating sickle hemoglobin polymerization and erythrocyte sickling. BCL11A is a repressor of γ-globin expression and HbF production in adult erythrocytes. Its down-regulation is a promising therapeutic strategy for induction of HbF. METHODS: We enrolled patients with sickle cell disease in a single-center, open-label pilot study. The investigational therapy involved infusion of autologous CD34+ cells transduced with the BCH-BB694 lentiviral vector, which encodes a short hairpin RNA (shRNA) targeting BCL11A mRNA embedded in a microRNA (shmiR), allowing erythroid lineage-specific knockdown. Patients were assessed for primary end points of engraftment and safety and for hematologic and clinical responses to treatment. RESULTS: As of October 2020, six patients had been followed for at least 6 months after receiving BCH-BB694 gene therapy; median follow-up was 18 months (range, 7 to 29). All patients had engraftment, and adverse events were consistent with effects of the preparative chemotherapy. All the patients who could be fully evaluated achieved robust and stable HbF induction (percentage HbF/(F+S) at most recent follow-up, 20.4 to 41.3%), with HbF broadly distributed in red cells (F-cells 58.9 to 93.6% of untransfused red cells) and HbF per F-cell of 9.0 to 18.6 pg per cell. Clinical manifestations of sickle cell disease were reduced or absent during the follow-up period. CONCLUSIONS: This study validates BCL11A inhibition as an effective target for HbF induction and provides preliminary evidence that shmiR-based gene knockdown offers a favorable risk-benefit profile in sickle cell disease. (Funded by the National Institutes of Health; ClinicalTrials.gov number, NCT03282656).

Contemporary management of pain in cirrhosis: Toward precision therapy for pain.

Chronic pain is highly prevalent in patients with cirrhosis and is associated with poor health-related quality of life and poor functional status. However, there is limited guidance on appropriate pain management in this population, and pharmacologic treatment can be harmful, leading to adverse outcomes, such as gastrointestinal bleeding, renal injury, falls, and hepatic encephalopathy. Chronic pain can be categorized mechanistically into three pain types: nociceptive, neuropathic, and nociplastic, each responsive to different therapies. By discussing the identification, etiology, and treatment of these three mechanistic pain descriptors with a focus on specific challenges in patients with cirrhosis, we provide a framework for better tailoring treatments, including nonpharmacologic therapies, to patients' needs.

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.

Replication competent retrovirus testing (RCR) in the National Gene Vector Biorepository: No evidence of RCR in 1,595 post-treatment peripheral blood samples obtained from 60 clinical trials.

The clinical impact of any therapy requires the product be safe and effective. Gammaretroviral vectors pose several unique risks, including inadvertent exposure to replication competent retrovirus (RCR) that can arise during vector manufacture. The US FDA has required patient monitoring for RCR, and the National Gene Vector Biorepository is an NIH resource that has assisted eligible investigators in meeting this requirement. To date, we have found no evidence of RCR in 338 pre-treatment and 1,595 post-treatment blood samples from 737 patients associated with 60 clinical trials. Most samples (75%) were obtained within 1 year of treatment, and samples as far out as 9 years after treatment were analyzed. The majority of trials (93%) were cancer immunotherapy, and 90% of the trials used vector products produced with the PG13 packaging cell line. The data presented here provide further evidence that current manufacturing methods generate RCR-free products and support the overall safety profile of retroviral gene therapy.

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.

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.

'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.

[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.

Expanded phenotypic and hematologic abnormalities beyond bone marrow failure in MECOM-associated syndromes.

The MECOM gene encodes multiple protein isoforms that are essential for hematopoietic stem cell self-renewal and maintenance. Germline MECOM variants have been associated with congenital thrombocytopenia, radioulnar synostosis and bone marrow failure; however, the phenotypic spectrum of MECOM-associated syndromes continues to expand and novel pathogenic variants continue to be identified. We describe eight unrelated patients who add to the previously known phenotypes and genetic defects of MECOM-associated syndromes. As each subject presented with unique MECOM variants, the series failed to demonstrate clear genotype-to-phenotype correlation but may suggest a role for additional modifiers that affect gene expression and subsequent phenotype. Recognition of the expanded hematologic and non-hematologic clinical features allows for rapid molecular diagnosis, early identification of life-threatening complications, and improved genetic counseling for families. A centralized international publicly accessible database to share annotated MECOM variants would advance their clinical interpretation and provide a foundation to perform functional MECOM studies.

Transient neonatal hemolytic anemia due to the novel gamma globin gene mutation HBG2:C.290T>C, p.Leu97Pro (hemoglobin Wareham).

Unstable gamma globin variants can cause transient neonatal hemolytic anemia. We have identified a novel variant in a newborn who presented with jaundice and anemia requiring phototherapy and red blood cell transfusion. The patient was found to be heterozygous for the mutation HGB2:c.290T>C, p.Leu97Pro, which we have termed hemoglobin (Hb) Wareham. This substitution is expected to generate an unstable hemoglobin with increased oxygen affinity based on the homologous mutation previously described in the beta globin gene, which is termed as Hb Debrousse. The patient fully recovered by 9 months of age as expected with the transition from fetal to adult hemoglobin.

Rac1 activation controls nuclear localization of beta-catenin during canonical Wnt signaling.

Canonical Wnt signaling critically regulates cell fate and proliferation in development and disease. Nuclear localization of beta-catenin is indispensable for canonical Wnt signaling; however, the mechanisms governing beta-catenin nuclear localization are not well understood. Here we demonstrate that nuclear accumulation of beta-catenin in response to Wnt requires Rac1 activation. The role of Rac1 depends on phosphorylation of beta-catenin at Ser191 and Ser605, which is mediated by JNK2 kinase. Mutations of these residues significantly affect Wnt-induced beta-catenin nuclear accumulation. Genetic ablation of Rac1 in the mouse embryonic limb bud ectoderm disrupts canonical Wnt signaling and phenocopies deletion of beta-catenin in causing severe truncations of the limb. Finally, Rac1 interacts genetically with beta-catenin and Dkk1 in controlling limb outgrowth. Together these results uncover Rac1 activation and subsequent beta-catenin phosphorylation as a hitherto uncharacterized mechanism controlling canonical Wnt signaling and may provide additional targets for therapeutic intervention of this important pathway.

Biobehavioral Assessments in BACPAC: Recommendations, Rationale, and Methods.

The Biobehavioral Working Group of BACPAC was charged to evaluate a range of psychosocial, psychophysical, and behavioral domains relevant to chronic low back pain, and recommend specific assessment tools and procedures to harmonize biobehavioral data collection across the consortium. Primary references and sources for measure selection were the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials, the Minimum Data Set from the National Institutes of Health (NIH) Research Task Force on Standards for Chronic Low Back Pain, the Patient-Reported Outcomes Measurement Information System, and NeuroQOL. The questionnaire's recommendations supplemented the NIH HEAL Common Data Elements and BACPAC Minimum Data Set. Five domains were identified for inclusion: Pain Characteristics and Qualities; Pain-Related Psychosocial/Behavioral Factors; General Psychosocial Factors; Lifestyle Choices; and Social Determinants of Health/Social Factors. The Working Group identified best practices for required and optional Quantitative Sensory Testing of psychophysical pain processing for use in BACPAC projects.

Development of a double shmiR lentivirus effectively targeting both BCL11A and ZNF410 for enhanced induction of fetal hemoglobin to treat ß-hemoglobinopathies.

A promising treatment for ß-hemoglobinopathies is the de-repression of γ-globin expression leading to increased fetal hemoglobin (HbF) by targeting BCL11A. Here, we aim to improve a lentivirus vector (LV) containing a single BCL11A shmiR (SS) to further increase γ-globin induction. We engineered a novel LV to express two shmiRs simultaneously targeting BCL11A and the γ-globin repressor ZNF410. Erythroid cells derived from human HSCs transduced with the double shmiR (DS) showed up to a 70% reduction of both BCL11A and ZNF410 proteins. There was a consistent and significant additional 10% increase in HbF compared to targeting BCL11A alone in erythroid cells. Erythrocytes differentiated from SCD HSCs transduced with the DS demonstrated significantly reduced in vitro sickling phenotype compared to the SS. Erythrocytes differentiated from transduced HSCs from ß-thalassemia major patients demonstrated improved globin chain balance by increased γ-globin with reduced microcytosis. Reconstitution of DS-transduced cells from Berkeley SCD mice was associated with a statistically larger reduction in peripheral blood hemolysis markers compared with the SS vector. Overall, these results indicate that the DS LV targeting BCL11A and ZNF410 can enhance HbF induction for treating ß-hemoglobinopathies and could be used as a model to simultaneously and efficiently target multiple gene products.

A 4-week morning light treatment with stable sleep timing for individuals with fibromyalgia: a randomized controlled trial.

OBJECTIVES: Fibromyalgia is characterized by chronic widespread pain, mood, and sleep disturbance. Pharmacological treatments have modest efficacy and are associated with negative side effects, and alternative approaches are needed. Morning bright light treatment may assist in the management of fibromyalgia as it can reduce depressive symptoms, improve sleep, and advance circadian timing. METHODS: Sixty people with fibromyalgia (58 women, mean age 41.8 ± 13.3 years) were enrolled in a study comparing 4 weeks of a 1-hour daily morning bright light treatment (active treatment) to a morning dim light treatment (comparison treatment). Both light treatments included behavioral procedures to stabilize sleep timing. The morning bright light treatment was expected to produce larger improvements in pain and function than the dim light treatment and larger improvements in potential mediators (mood, sleep, and circadian timing). RESULTS: Both the bright and dim light treatment groups achieved significant but similar levels of improvement in pain intensity, pain interference, physical function, depressive symptoms, and sleep disturbance. Overall, the sample on average displayed a clinically meaningful improvement in the Fibromyalgia Impact Questionnaire-Revised score (mean reduction of 11.2 points), comparable to that reported following physical exercise treatments. Minimal side effects were observed. CONCLUSIONS: Findings indicate that the effects of a morning bright light treatment did not exceed those of a comparison dim light treatment; yet the changes on average in both conditions revealed clinically meaningful improvements. Future research is warranted to identify what elements of this trial may have contributed to the observed effects.

The Back Pain Consortium (BACPAC) Research Program Data Harmonization: Rationale for Data Elements and Standards.

OBJECTIVE: One aim of the Back Pain Consortium (BACPAC) Research Program is to develop an integrated model of chronic low back pain that is informed by combined data from translational research and clinical trials. We describe efforts to maximize data harmonization and accessibility to facilitate Consortium-wide analyses. METHODS: Consortium-wide working groups established harmonized data elements to be collected in all studies and developed standards for tabular and nontabular data (eg, imaging and omics). The BACPAC Data Portal was developed to facilitate research collaboration across the Consortium. RESULTS: Clinical experts developed the BACPAC Minimum Dataset with required domains and outcome measures to be collected by use of questionnaires across projects. Other nonrequired domain-specific measures are collected by multiple studies. To optimize cross-study analyses, a modified data standard was developed on the basis of the Clinical Data Interchange Standards Consortium Study Data Tabulation Model to harmonize data structures and facilitate integration of baseline characteristics, participant-reported outcomes, chronic low back pain treatments, clinical exam, functional performance, psychosocial characteristics, quantitative sensory testing, imaging, and biomechanical data. Standards to accommodate the unique features of chronic low back pain data were adopted. Research units submit standardized study data to the BACPAC Data Portal, developed as a secure cloud-based central data repository and computing infrastructure for researchers to access and conduct analyses on data collected by or acquired for BACPAC. CONCLUSIONS: BACPAC harmonization efforts and data standards serve as an innovative model for data integration that could be used as a framework for other consortia with multiple, decentralized research programs.