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  Endemic Burkitt lymphoma avatar mouse models for exploring inter-patient tumor variation and testing targeted therapies

  Saikumar Lakshmi, Priya; Oduor, Cliff I; Forconi, Catherine S; M'Bana, Viriato; Bly, Courtney; Gerstein, Rachel M; Otieno, Juliana A; Ong'echa, John M; Münz, Christian; Luftig, Micah A; et al. (2023-03-06)

  Endemic Burkitt lymphoma (BL) is a childhood cancer in sub-Saharan Africa characterized by Epstein-Barr virus and malaria-associated aberrant B-cell activation and MYC chromosomal translocation. Survival rates hover at 50% after conventional chemotherapies; therefore, clinically relevant models are necessary to test additional therapies. Hence, we established five patient-derived BL tumor cell lines and corresponding NSG-BL avatar mouse models. Transcriptomics confirmed that our BL lines maintained fidelity from patient tumors to NSG-BL tumors. However, we found significant variation in tumor growth and survival among NSG-BL avatars and in Epstein-Barr virus protein expression patterns. We tested rituximab responsiveness and found one NSG-BL model exhibiting direct sensitivity, characterized by apoptotic gene expression counterbalanced by unfolded protein response and mTOR pro-survival pathways. In rituximab-unresponsive tumors, we observed an IFN-α signature confirmed by the expression of IRF7 and ISG15. Our results demonstrate significant inter-patient tumor variation and heterogeneity, and that contemporary patient-derived BL cell lines and NSG-BL avatars are feasible tools to guide new therapeutic strategies and improve outcomes for these children.
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  Career self-efficacy disparities in underrepresented biomedical scientist trainees

  Chatterjee, Deepshikha; Jacob, Gabrielle A; Varvayanis, Susi Sturzenegger; Wefes, Inge; Chalkley, Roger; Nogueira, Ana T; Fuhrmann, Cynthia N; Varadarajan, Janani; Hubbard, Nisaan M; Gaines, Christiann H; et al. (2023-03-01)

  The present study examines racial, ethnic, and gender disparities in career self-efficacy amongst 6077 US citizens and US naturalized graduate and postdoctoral trainees. Respondents from biomedical fields completed surveys administered by the National Institutes of Health Broadening Experiences in Scientific Training (NIH BEST) programs across 17 US institutional sites. Graduate and postdoctoral demographic and survey response data were examined to evaluate the impact of intersectional identities on trainee career self-efficacy. The study hypothesized that race, ethnicity and gender, and the relations between these identities, would impact trainee career self-efficacy. The analysis demonstrated that racial and ethnic group, gender, specific career interests (academic principal investigator vs. other careers), and seniority (junior vs. senior trainee level) were, to various degrees, all associated with trainee career self-efficacy and the effects were consistent across graduate and postdoctoral respondents. Implications for differing levels of self-efficacy are discussed, including factors and events during training that may contribute to (or undermine) career self-efficacy. The importance of mentorship for building research and career self-efficacy of trainees is discussed, especially with respect to those identifying as women and belonging to racial/ethnic populations underrepresented in biomedical sciences. The results underscore the need for change in the biomedical academic research community in order to retain a diverse biomedical workforce.
• Performance of Rapid Antigen Tests Based on Symptom Onset and Close Contact Exposure: A secondary analysis from the Test Us At Home prospective cohort study [preprint]

  Herbert, Carly; Wang, Biqi; Lin, Honghuang; Hafer, Nathaniel; Pretz, Caitlin; Stamegna, Pamela; Tarrant, Seanan; Hartin, Paul; Ferranto, Julia; Behar, Stephanie; et al. (2023-02-24)

  Background: The performance of rapid antigen tests for SARS-CoV-2 (Ag-RDT) in temporal relation to symptom onset or exposure is unknown, as is the impact of vaccination on this relationship. Objective: To evaluate the performance of Ag-RDT compared with RT-PCR based on day after symptom onset or exposure in order to decide on 'when to test'. Design setting and participants: The Test Us at Home study was a longitudinal cohort study that enrolled participants over 2 years old across the United States between October 18, 2021 and February 4, 2022. All participants were asked to conduct Ag-RDT and RT-PCR testing every 48 hours over a 15-day period. Participants with one or more symptoms during the study period were included in the Day Post Symptom Onset (DPSO) analyses, while those who reported a COVID-19 exposure were included in the Day Post Exposure (DPE) analysis. Exposure: Participants were asked to self-report any symptoms or known exposures to SARS-CoV-2 every 48-hours, immediately prior to conducting Ag-RDT and RT-PCR testing. The first day a participant reported one or more symptoms was termed DPSO 0, and the day of exposure was DPE 0. Vaccination status was self-reported. Main outcome and measures: Results of Ag-RDT were self-reported (positive, negative, or invalid) and RT-PCR results were analyzed by a central laboratory. Percent positivity of SARS-CoV-2 and sensitivity of Ag-RDT and RT-PCR by DPSO and DPE were stratified by vaccination status and calculated with 95% confidence intervals. Results: A total of 7,361 participants enrolled in the study. Among them, 2,086 (28.3%) and 546 (7.4%) participants were eligible for the DPSO and DPE analyses, respectively. Unvaccinated participants were nearly twice as likely to test positive for SARS-CoV-2 than vaccinated participants in event of symptoms (PCR+: 27.6% vs 10.1%) or exposure (PCR+: 43.8% vs. 22.2%). The highest proportion of vaccinated and unvaccinated individuals tested positive on DPSO 2 and DPE 5-8. Performance of RT-PCR and Ag-RDT did not differ by vaccination status. Ag-RDT detected 78.0% (95% Confidence Interval: 72.56-82.61) of PCR-confirmed infections by DPSO 4. For exposed participants, Ag-RDT detected 84.9% (95% CI: 75.0-91.4) of PCR-confirmed infections by day five post-exposure (DPE 5). Conclusions and relevance: Performance of Ag-RDT and RT-PCR was highest on DPSO 0-2 and DPE 5 and did not differ by vaccination status. These data suggests that serial testing remains integral to enhancing the performance of Ag-RDT.
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  Epigenetic and chromosomal features drive transposon insertion in Drosophila melanogaster

  Cao, Jichuan; Yu, Tianxiong; Xu, Bo; Hu, Zhongren; Zhang, Xiao-Ou; Theurkauf, William E; Weng, Zhiping (2023-02-10)

  Transposons are mobile genetic elements prevalent in the genomes of most species. The distribution of transposons within a genome reflects the actions of two opposing processes: initial insertion site selection, and selective pressure from the host. By analyzing whole-genome sequencing data from transposon-activated Drosophila melanogaster, we identified 43 316 de novo and 237 germline insertions from four long-terminal-repeat (LTR) transposons, one LINE transposon (I-element), and one DNA transposon (P-element). We found that all transposon types favored insertion into promoters de novo, but otherwise displayed distinct insertion patterns. De novo and germline P-element insertions preferred replication origins, often landing in a narrow region around transcription start sites and in regions of high chromatin accessibility. De novo LTR transposon insertions preferred regions with high H3K36me3, promoters and exons of active genes; within genes, LTR insertion frequency correlated with gene expression. De novo I-element insertion density increased with distance from the centromere. Germline I-element and LTR transposon insertions were depleted in promoters and exons, suggesting strong selective pressure to remove transposons from functional elements. Transposon movement is associated with genome evolution and disease; therefore, our results can improve our understanding of genome and disease biology.
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  Large-scale organoid study suggests effects of trisomy 21 on early fetal neurodevelopment are more subtle than variability between isogenic lines and experiments

  Czerminski, Jan T; King, Oliver D; Lawrence, Jeanne B (2023-02-03)

  This study examines cortical organoids generated from a panel of isogenic trisomic and disomic iPSC lines (subclones) as a model of early fetal brain development in Down syndrome (DS). An initial experiment comparing organoids from one trisomic and one disomic line showed many genome-wide transcriptomic differences and modest differences in cell-type proportions, suggesting there may be a neurodevelopmental phenotype that is due to trisomy of chr21. To better control for multiple sources of variation, we undertook a highly robust study of ∼1,200 organoids using an expanded panel of six all-isogenic lines, three disomic, and three trisomic. The power of this experimental design was indicated by strong detection of the ∼1.5-fold difference in chr21 genes. However, the numerous expression differences in non-chr21 genes seen in the smaller experiment fell away, and the differences in cell-type representation between lines did not correlate with trisomy 21. Results suggest that the initial smaller experiment picked up differences between small organoid samples and individual isogenic lines, which "averaged out" in the larger panel of isogenic lines. Our results indicate that even when organoid and batch variability are better controlled for, variation between isogenic cell lines (even subclones) may obscure, or be conflated with, subtle neurodevelopmental phenotypes that may be present in ∼2nd trimester DS brain development. Interestingly, despite this variability between organoid batches and lines, and the "fetal stage" of these organoids, an increase in secreted Aβ40 peptide levels-an Alzheimer-related cellular phenotype-was more strongly associated with trisomy 21 status than were neurodevelopmental shifts in cell-type composition.
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  Quality improvements in radiation oncology clinical trials

  Smith, Koren; Ulin, Kenneth; Knopp, Michael; Kry, Stephan; Xiao, Ying; Rosen, Mark; Michalski, Jeff; Iandoli, Matthew; Laurie, Fran; Quigley, Jean; et al. (2023-01-26)

  Clinical trials have become the primary mechanism to validate process improvements in oncology clinical practice. Over the past two decades there have been considerable process improvements in the practice of radiation oncology within the structure of a modern department using advanced technology for patient care. Treatment planning is accomplished with volume definition including fusion of multiple series of diagnostic images into volumetric planning studies to optimize the definition of tumor and define the relationship of tumor to normal tissue. Daily treatment is validated by multiple tools of image guidance. Computer planning has been optimized and supported by the increasing use of artificial intelligence in treatment planning. Informatics technology has improved, and departments have become geographically transparent integrated through informatics bridges creating an economy of scale for the planning and execution of advanced technology radiation therapy. This serves to provide consistency in department habits and improve quality of patient care. Improvements in normal tissue sparing have further improved tolerance of treatment and allowed radiation oncologists to increase both daily and total dose to target. Radiation oncologists need to define a priori dose volume constraints to normal tissue as well as define how image guidance will be applied to each radiation treatment. These process improvements have enhanced the utility of radiation therapy in patient care and have made radiation therapy an attractive option for care in multiple primary disease settings. In this chapter we review how these changes have been applied to clinical practice and incorporated into clinical trials. We will discuss how the changes in clinical practice have improved the quality of clinical trials in radiation therapy. We will also identify what gaps remain and need to be addressed to offer further improvements in radiation oncology clinical trials and patient care.
• Interactions between FUS and the C-terminal Domain of Nup62 are Sufficient for their Co-phase Separation into Amorphous Assemblies

  Kumar, Meenakshi Sundaram; Stallworth, Karly M; Murthy, Anastasia C; Lim, Su Min; Li, Nan; Jain, Aastha; Munro, James B; Fawzi, Nicolas L; Lagier-Tourenne, Clotilde; Bosco, Daryl A (2023-01-21)

  Deficient nucleocytoplasmic transport is emerging as a pathogenic feature of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), including in ALS caused by mutations in Fused in Sarcoma (FUS). Recently, both wild-type and ALS-linked mutant FUS were shown to directly interact with the phenylalanine-glycine (FG)-rich nucleoporin 62 (Nup62) protein, where FUS WT/ Nup62 interactions were enriched within the nucleus but ALS-linked mutant FUS/ Nup62 interactions were enriched within the cytoplasm of cells. Nup62 is a central channel Nup that has a prominent role in forming the selectivity filter within the nuclear pore complex and in regulating effective nucleocytoplasmic transport. Under conditions where FUS phase separates into liquid droplets in vitro, the addition of Nup62 caused the synergistic formation of amorphous assemblies containing both FUS and Nup62. Here, we examined the molecular determinants of this process using recombinant FUS and Nup62 proteins and biochemical approaches. We demonstrate that the structured C-terminal domain of Nup62 containing an alpha-helical coiled-coil region plays a dominant role in binding FUS and is sufficient for inducing the formation of FUS/Nup62 amorphous assemblies. In contrast, the natively unstructured, F/G repeat-rich N-terminal domain of Nup62 modestly contributed to FUS/Nup62 phase separation behavior. Expression of individual Nup62 domain constructs in human cells confirmed that the Nup62 C-terminal domain is essential for localization of the protein to the nuclear envelope. Our results raise the possibility that interactions between FUS and the C-terminal domain of Nup62 can influence the function of Nup62 under physiological and/or pathological conditions.
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  The Role of Wearable Technology in Measuring and Supporting Patient Outcomes Following Total Joint Replacement: Review of the Literature

  Iovanel, Gregory; Ayers, David; Zheng, Hua (2023-01-12)

  Background: The incidence rate of total joint replacement (TJR) continues to increase due to the aging population and the surgery that is very successful in providing pain relief to and improving function among patients with advanced knee or hip arthritis. Improving patient outcomes and patient satisfaction after TJR remain important goals. Wearable technologies provide a novel way to capture patient function and activity data and supplement clinical measures and patient-reported outcome measures in order to better understand patient outcomes after TJR. Objective: We examined the current literature to evaluate the potential role of wearable devices and compare them with existing methods for monitoring and improving patient rehabilitation and outcomes following TJR. Methods: We performed a literature search by using the research databases supported by the University of Massachusetts Chan Medical School's Lamar Soutter Library, including PubMed and Scopus, supplemented with the Google Scholar search engine. A specific search strategy was used to identify articles discussing the use of wearable devices in measuring and affecting postoperative outcomes of patients who have undergone TJR. Selected papers were organized into a spreadsheet and categorized for our qualitative literature review to assess how wearable data correlated with clinical measures and patient-reported outcome measures. Results: A total of 9 papers were selected. The literature showed the impact of wearable devices on evaluating and improving postoperative functional outcomes. Wearable-collected data could be used to predict postoperative clinical measures, such as range of motion and Timed Up and Go times. When predicting patient-reported outcomes, specifically Hip Disability and Osteoarthritis Outcome Scores/Knee Injury and Osteoarthritis Outcome Scores and Veterans RAND 12-Item Health Survey scores, strong associations were found between changes in sensor-collected data and changes in patient-reported outcomes over time. Further, the step counts of patients who received feedback from a wearable improved over time when compared to those of patients who did not receive feedback. Conclusions: These findings suggest that wearable technology has the potential to remotely measure and improve postoperative orthopedic patient outcomes. We anticipate that this review will facilitate further investigation into whether wearable devices are viable tools for guiding the clinical management of TJR rehabilitation.
• Chemically Crosslinked Amphiphilic Degradable Shape Memory Polymer Nanocomposites with Readily Tuned Physical, Mechanical, and Biological Properties

  Xu, Xiaowen; Skelly, Jordan D; Song, Jie (2023-01-06)

  Facile surgical delivery and stable fixation of synthetic scaffolds play roles just as critically as degradability and bioactivity in ensuring successful scaffold-guided tissue regeneration. Properly engineered shape memory polymers (SMPs) may meet these challenges. Polyhedral oligomeric silsesquioxanes (POSSs) can be covalently integrated with urethane-crosslinked polylactide (PLA) to give high-strength, degradable SMPs around physiological temperatures. To explore their potential for guided bone regeneration, here we tune their hydrophilicity, degradability, cytocompatibility, and osteoconductivity/osteoinductivity by crosslinking star-branched POSS-PLA with hydrophilic polyethylene glycol diisocyanates of different lengths and up to 60 wt % hydroxyapatite (HA). The composites exhibit high compliance, toughness, up to gigapascal storage moduli, and excellent shape recovery (>95%) at safe triggering temperatures. Water swelling ratios and hydrolytic degradation rates positively correlated with the hydrophilic crosslinker lengths, while the negative impact of degradation on the proliferation and osteogenesis of bone marrow stromal cells was mitigated with HA incorporation. Macroporous composites tailored for a rat femoral segmental defect were fabricated, and their ability to stably retain and sustainedly release recombinant osteogenic bone morphogenetic protein-2 and support cell attachment and osteogenesis was demonstrated. These properties combined make these amphiphilic osteoconductive degradable SMPs promising candidates as next-generation synthetic bone grafts.
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  High bacillary burden and the ESX-1 type VII secretion system promote MHC class I presentation by Mycobacterium tuberculosis infected macrophages to CD8 T-cells [preprint]

  Mott, Daniel; Yang, Jason; Baer, Christina; Papavinasasundaram, Kadamba; Sassetti, Christopher M.; Behar, Samuel M. (2023-01-02)

  Mycobacterium tuberculosis (Mtb) subverts host defenses to persist in macrophages despite immune pressure. CD4 T-cells can recognize macrophages infected with a single bacillus in vitro. Under identical conditions, CD8 T-cells inefficiently recognize infected macrophages and fail to restrict Mtb growth, although they can inhibit Mtb growth during high burden intracellular infection. We show that high intracellular Mtb numbers cause macrophage death, leading other macrophages to scavenge cellular debris and cross-present the TB10.4 antigen to CD8 T-cells. Presentation by infected macrophages requires Mtb to have a functional ESX-1 type VII secretion system. These data indicate that phagosomal membrane damage and cell death promote class I MHC presentation of the immunodominant antigen TB10.4 by macrophages. Although this mode of antigen-presentation stimulates cytokine production that we presume would be host beneficial; killing of uninfected cells could worsen immunopathology. We suggest that shifting the focus of CD8 T-cell recognition to uninfected macrophages would limit the interaction of CD8 T-cells with infected macrophages and impair CD8 T-cell mediated resolution of tuberculosis.
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  Video-based communication assessment for weight management counseling training in medical residents: a mixed methods study

  Faro, Jamie M; D'Addario, Angelo; King, Ann M; Mazor, Kathleen M; Pbert, Lori; Sadasivam, Rajani S; Geller, Alan C; Murphy, Elizabeth A; Ockene, Judith K (2022-12-28)

  Background: Physician delivered weight management counseling (WMC) occurs infrequently and physicians report lack of training and poor self-efficacy. The purpose of this study was to develop and test the Video-based Communication Assessment (VCA) for weight management counseling (WMC) training in medical residents. Methods: This study was a mixed methods pilot conducted in 3 phases. First, we created five vignettes based on our prior data and expert feedback, then administered the vignettes via the VCA to Internal Medicine categorical residents (n = 16) from a University Medical School. Analog patients rated responses and also provided comments. We created individualized feedback reports which residents were able to view on the VCA. Lastly, we conducted debriefing interviews with the residents (n = 11) to obtain their feedback on the vignettes and personalized feedback. Interviews were transcribed, and we used thematic analysis to generate and apply codes, followed by identifying themes. Results: Descriptive statistics were calculated and learning points were created for the individualized feedback reports. In VCA debriefing interviews with residents, five themes emerged: 1) Overall the VCA was easy to use, helpful and more engaging than traditional learning and assessment modes, 2) Patient scenarios were similar to those encountered in the clinic, including diversity, health literacy and different stages of change, 3) The knowledge, skills, and reminders from the VCA can be transferred to practice, 4) Feedback reports were helpful, to the point and informative, including the exemplar response of how to best respond to the scenario, and 5) The VCA provide alternatives and practice scenarios to real-life patient situations when they aren't always accessible. Conclusions: We demonstrated the feasibility and acceptability of the VCA, a technology delivered platform, for delivering WMC to residents. The VCA exposed residents to diverse patient experiences and provided potential opportunities to tailor providers responses to sociological and cultural factors in WMC scenarios. Future work will examine the effect of the VCA on WMC in actual clinical practice.
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  Comanagement with rheumatology and prescription biologics filled during pregnancy in women with rheumatic diseases: a retrospective analysis of US administrative claims data

  Shridharmurthy, Divya; Lapane, Kate L; Baek, Jonggyu; Nunes, Anthony; Kay, Jonathan; Liu, Shao-Hsien (2022-12-22)

  Objectives: To evaluate comanagement with rheumatology and biological prescriptions filled during pregnancy among women with axial spondyloarthritis (axSpA), rheumatoid arthritis (RA) or psoriatic arthritis (PsA) and to examine factors associated with receiving comanagement with rheumatology during pregnancy. Design: A retrospective analysis of US claims data. Setting: Commercially insured enrollees using data from the 2013-2018 IBM MarketScan Commercial Claims and Encounters Database. Participants: We identified 4131 pregnant women aged ≤55 years from the 2013-2018 IBM MarketScan Commercial Claims and Encounters Database with an International Classification of Disease, 9th Revision/10th Revision codes for RA, axSpA or PsA, with continuous enrolment at ≥3 months before the date of the last menstrual period (LMP) (index date) and throughout pregnancy. Primary outcomes: Filled biologics (prescriptions and infusions) claims were categorised by 90 days before the LMP and trimester, as were primary care, obstetrician and rheumatological claims. Results: The prevalence of axSpA, RA and PsA was 0.7%, 0.2% and 0.04% among reproductive age women. The average maternal age was 32.7 years (SD 5.7). During pregnancy, 9.1% of those with axSpA (n=2,410) and 56.4% of those with RA/PsA (n=1,721) had a rheumatological claim. Biologics claims were less common among those with axSpA (90 days before LMP: 1.6%, during pregnancy: 1.1%) than those with RA/PsA (90 days before LMP: 11.9%, during pregnancy: 6.9%). Medications during pregnancy included corticosteroids (axSpA: 0.3%, RA/PsA: 2.2%), non-biological disease-modifying antirheumatic drugs (axSpA: 0.2%, RA/PsA: 1.7%), non-steroidal anti-inflammatory drugs (axSpA: 0.2%, RA/PsA: 1.3%) and opioids (axSpA: 0.2%, RA/PsA: 0.6%). Established rheumatological care and biologics claims during the 90 days before LMP showed good prediction accuracy for receiving comanagement with rheumatology during pregnancy (axSpA: area under the receiver operator curve (AUC) 0.73, RA/PsA: AUC 0.70). Conclusion: Comanagement with rheumatology during pregnancy occurs infrequently, especially for women with axSpA. Biologics claims during pregnancy may not align with published guidelines. Future research is warranted to improve comanagement with rheumatology during pregnancy.
• US clinicians' perspectives on advance care planning for persons with dementia: A qualitative study

  Tjia, Jennifer; D'Arcangelo, Noah; Carlston, Daniel; Bronzi, Olivia; Gazarian, Priscilla; Reich, Amanda; Porteny, Thalia; Gonzales, Kristina; Perez, Stephen; Weissman, Joel S; et al. (2022-12-22)

  Background: Although advance care planning (ACP) for persons with dementia (PWD) can promote patient-centered care by aligning future healthcare with patient values, few PWD have documented ACPs for reasons incompletely understood. The objective of this paper is to characterize the perceived value of, barriers to, and successful strategies for completing ACP for PWD as reported by frontline clinicians. Methods: Qualitative study using semi-structured interviews (August 2018-December 2019) with clinicians (physicians, nurse practitioners, nurses, social workers) at 11 US health systems. Interviews asked clinicians about their approaches to ACP with PWDs, including how ACP was initiated, what was discussed, how carepartners were involved, how decision-making was approached, and how decision-making capacity was assessed. Results: Of 75 participating generalist and specialty clinicians from across the United States, 61% reported conducting ACP with PWD, of whom 19% conducted ACP as early as possible with PWD. Three themes emerged: value of early ACP preserves PWD's autonomy in cases of differing PWD carepartner values, acute medical crises, and clinician paternalism; barriers to ACP with PWD including the dynamic and subjective assessment of patient decision-making capacity, inconsistent awareness of cognitive impairment by clinicians, and the need to balance patient and family carepartner involvement; and strategies to support ACP include clarifying clinicians' roles in ACP, standardizing clinicians' approach to PWD and their carepartners, and making time for ACP and decision-making assessments that allow PWD and carepartner involvement regardless of the patients' capacity. Conclusions: Clinicians found early ACP for PWD valuable in promoting patient-centered care among an at-risk population. In sharing their perspectives on conducting ACP for PWD, clinicians described challenges that are amenable to changes in training, workflow, and material support for clinician time. Clinical practices need sustainable scheduling and financial support models.
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  SnapFISH: a computational pipeline to identify chromatin loops from multiplexed DNA FISH data [preprint]

  Lee, Lindsay; Yu, Hongyu; Jia, Bojing Blair; Jussila, Adam; Zhu, Chenxu; Chen, Jiawen; Xie, Liangqi; Hafner, Antonina; Strambio-De-Castillia, Caterina; Boettiger, Alistair; et al. (2022-12-19)

  Multiplexed DNA fluorescence in situ hybridization (FISH) imaging technologies have been developed to map the folding of chromatin fibers at tens of nanometer and tens of kilobase resolution in single cells. However, computational methods to reliably identify chromatin loops from such imaging datasets are still lacking. Here we present a Single-Nucleus Analysis Pipeline for multiplexed DNA FISH (SnapFISH), to process the multiplexed DNA FISH data and identify chromatin loops. SnapFISH can identify known chromatin loops from mouse embryonic stem cells with high sensitivity and accuracy. In addition, SnapFISH obtained comparable results of chromatin loops across datasets generated from diverse imaging technologies.
• Discrimination and Sleep: Differential Effects by Type and Coping Strategy

  Majeno, Angelina; Molina, Kristine M; Frisard, Christine F; Lemon, Stephenie C; Rosal, Milagros C (2022-12-19)

  Background: Discrimination has been posited as a contributor of sleep disparities for Latinxs. The strategy used to cope with discrimination may reduce or exacerbate its effects on sleep. This study examined whether different types of discrimination (everyday and major lifetime discrimination) were associated with sleep indices (quality, disturbances, efficiency) and whether coping strategy used moderated associations. Method: Data of Latinx adults (N = 602; 51% women, 65% Dominican, Mage = 46.72 years) come from the Latino Health and Well-being Project, a community-based, cross-sectional study of Latinxs in Lawrence, MA. Multiple linear regressions were estimated separately for each sleep outcome. Results: Everyday discrimination was significantly associated with poorer sleep quality and greater disturbances; major lifetime discrimination was significantly associated with worse sleep across the three sleep indices. Coping strategy moderated associations between discrimination and sleep. Compared with Latinxs who used passive coping, those who used passive-active coping strategies had poorer sleep quality the more they experienced everyday discrimination. Latinxs who used any active coping strategy, compared with passive coping, had greater sleep disturbances the more frequently they experienced major lifetime discrimination. Conclusions: Findings show that everyday discrimination and major lifetime discrimination are associated with different dimensions of sleep and suggest that coping with discrimination may require the use of different strategies depending on the type of discrimination experienced.
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  Peer support and whole health coaching to address the healthcare needs of homeless veterans: a pilot study

  Blonigen, Daniel; Smelson, David; Smith, Jennifer; Baldwin, Nicole; McInnes, D Keith; Raikov, Ivan; Weber, Jillian; Hyde, Justeen (2022-12-19)

  Background: Homelessness is a robust social determinant of acute care service utilization among veterans. Although intensive outpatient programs have been developed for homeless veterans who are high utilizers of acute care ("super utilizers"), few scalable programs have been implemented to address their needs. Objective: Describe the development and pilot testing of a novel intervention that integrates the roles of a peer and whole health coach ("Peer-WHC") in coordination with primary care teams to reduce homeless veterans' frequent use of acute care. Design: Single-arm trial in three outpatient primary care clinics at a Veterans Health Administration (VHA) medical center; pre/post design using mixed-methods. Participants: Twenty veterans from VHA's homeless registry who were super-utilizers of acute care and enrolled in primary care. Intervention: Weekly health coaching sessions with a peer over 12 weeks, including discussions of patients' health care utilization patterns and coordination with primary care. Main measures: Rates of session attendance and intervention fidelity, patient-reported satisfaction and changes in patient engagement and perceptions of health, pre/post utilization of acute and supportive care services, and qualitative interviews with multiple stakeholders to identify barriers and facilitators to implementation. Key results: On average, patients attended 6.35 sessions (SD = 3.5, Median = 7). Satisfaction scores (M = 28.75 out of 32; SD = 2.79) exceeded a priori benchmarks. Patients' perceptions of health improved from pre to post [t(df)=-2.26(14), p = 0.04]. In the 3-months pre/post, 45% (n = 9) and 15% (n = 3) of patients, respectively, were hospitalized. Qualitative feedback from patients, providers, and peers and fidelity metrics suggested value in increasing the length of the intervention to facilitate goal-setting with patients and coordination with primary care. Conclusion: Findings support the feasibility, acceptability, and utility of Peer-WHC to address the healthcare needs of homeless veterans. A future trial is warranted to test the impact of Peer-WHC on reducing these patients' frequent use of acute care.
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  Pre-implementation formative evaluation of cooperative pain education and self-management expanding treatment for real-world access: A pragmatic pain trial

  Mattocks, Kristin M; LaChappelle, Kathryn M; Krein, Sarah L; DeBar, Lynn L; Martino, Steve; Edmond, Sara; Ankawi, Brett; MacLean, R Ross; Higgins, Diana M; Murphy, Jennifer L; et al. (2022-12-16)

  Objective: Cognitive behavioral therapy for chronic pain (CBT-CP) is an evidence-based treatment for improving functioning and pain intensity for people with chronic pain with extensive evidence of effectiveness. However, there has been relatively little investigation of the factors associated with successful implementation and uptake of CBT-CP, particularly clinician and system level factors. This formative evaluation examined barriers and facilitators to the successful implementation and uptake of CBT-CP from the perspective of CBT-CP clinicians and referring primary care clinicians. Methods: Qualitative interviews guided by the Consolidated Framework for Implementation Research were conducted at nine geographically diverse Veterans Affairs sites as part of a pragmatic clinical trial comparing synchronous, clinician-delivered CBT-CP and remotely delivered, technology-assisted CBT-CP. Analysis was informed by a grounded theory approach. Results: Twenty-six clinicians (CBT-CP clinicians = 17, primary care clinicians = 9) from nine VA medical centers participated in individual qualitative interviews conducted by telephone from April 2019 to August 2020. Four themes emerged in the qualitative interviews: (1) the complexity and variability of referral pathways across sites, (2) referring clinician's lack of knowledge about CBT-CP, (3) referring clinician's difficulty identifying suitable candidates for CBT-CP, and (4) preference for interventions that can be completed from home. Conclusions: This formative evaluation identified clinician and system barriers to widespread implementation of CBT-CP and allowed for refinement of the subsequent implementation of two forms of CBT-CP in an ongoing pragmatic trial. Identification of relative difference in barriers and facilitators in the two forms of CBT-CP may emerge more clearly in a pragmatic trial that evaluates how treatments perform in real-world settings and may provide important information to guide future system-wide implementation efforts.
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  Anti-SOD1 Nanobodies That Stabilize Misfolded SOD1 Proteins Also Promote Neurite Outgrowth in Mutant SOD1 Human Neurons

  Kumar, Meenakshi Sundaram; Fowler-Magaw, Megan E; Kulick, Daniel; Boopathy, Sivakumar; Gadd, Del Hayden; Rotunno, Melissa; Douthwright, Catherine; Golebiowski, Diane; Yusuf, Issa; Xu, Zuoshang; et al. (2022-12-16)

  ALS-linked mutations induce aberrant conformations within the SOD1 protein that are thought to underlie the pathogenic mechanism of SOD1-mediated ALS. Although clinical trials are underway for gene silencing of SOD1, these approaches reduce both wild-type and mutated forms of SOD1. Here, we sought to develop anti-SOD1 nanobodies with selectivity for mutant and misfolded forms of human SOD1 over wild-type SOD1. Characterization of two anti-SOD1 nanobodies revealed that these biologics stabilize mutant SOD1 in vitro. Further, SOD1 expression levels were enhanced and the physiological subcellular localization of mutant SOD1 was restored upon co-expression of anti-SOD1 nanobodies in immortalized cells. In human motor neurons harboring the SOD1 A4V mutation, anti-SOD1 nanobody expression promoted neurite outgrowth, demonstrating a protective effect of anti-SOD1 nanobodies in otherwise unhealthy cells. In vitro assays revealed that an anti-SOD1 nanobody exhibited selectivity for human mutant SOD1 over endogenous murine SOD1, thus supporting the preclinical utility of anti-SOD1 nanobodies for testing in animal models of ALS. In sum, the anti-SOD1 nanobodies developed and presented herein represent viable biologics for further preclinical testing in human and mouse models of ALS.
• Clinical Practice Guidelines on Interventional Management of Low Back Pain: A Synthesis of Recommendations

  Olivier, Timothy J; Konda, Chaitanya; Pham, Tri; Baltich Nelson, Becky; Patel, Ankit; Sharma, G Sunny; Trivedi, Kavita; Annaswamy, Thiru M (2022-12-12)

  Objective: To summarize the recommendations on the interventional management of subacute and chronic non-radicular low back pain (LBP) from the 21 quality-appraised CPGs identified in the previously published paper: "Quality of Clinical Practice Guidelines on Interventional Management of Low Back Pain: A Systematic Review". By disseminating this information, we aim to facilitate the implementation of these recommendations into clinical practice. Literature survey: Electronic bibliographic databases, guideline databases and grey literature were searched from January 2016 to January 2020 to identify CPGs that met study criteria. Methodology: 21 CPGs were quality-appraised and interventional management recommendations were extracted and organized into several treatment categories including epidural steroid injections (ESIs), radiofrequency procedures (RF), facet injections, sacroiliac injections (SI), and prolotherapy. Within each treatment category, the recommendations were organized based on 2 factors: quality of CPG and strength of recommendation. Synthesis: Overall, there was no consistency in recommendations for or against any interventional procedure, even when accounting for the quality of the CPG. In all of the CPGs reviewed, the most common strength of recommendation was weakly-for. The second, third and fourth most common strength of recommendations were inconclusive, weakly-against and strongly-against respectively and the least common was strongly-for. The treatment categories with the greatest number of recommendations were RF procedures (most common strength of recommendation-weakly for) and facet procedures. Among the high-quality CPGs, the most common strength of recommendation was inconclusive. Conclusions: Most of the interventional management recommendations for management of non-radicular LBP in the 21 CPGs appraised in this review were either weakly-for, weakly-against or inconclusive, with several recommendations within each treatment category contradicting each other. AGREE II quality appraisals of CPGs on interventional management of LBP were of unclear utility in guiding clinical implementation.
• Lessons Learned from Clinicians in a Federally Qualified Health Center: Steps Toward Eliminating Burnout

  Cauley, Andrew W; Green, Alexander R; Gardiner, Paula M (2022-12-12)

  Background: Burnout continues to impact health care workers and its effect takes a toll on their lives and wellbeing, especially in primary care. Relatively few studies have focused specifically on the perspective of clinicians in Federally Qualified Health Centers (FQHCs), which offer crucial, preventative health care services to vulnerable and underserved patient populations. Objective: To examine the perspectives of clinicians working at an FQHC in the Northeast United States after the implementation of a year-long wellness initiative. Design: A qualitative analysis of clinician's discussion during focus groups conducted after the wellness initiative. Subjects and Setting/Location: A total of 28 clinicians (primary care physicians and nurse practitioners) in an FQHC in the Northeast United States. Interventions: A one-year wellness initiative with programs and activities designed to bolster wellness. Outcome Measures: Analyzed NVIVO-coded transcripts of focus group discussion to generate codes and used modified grounded theory to extrapolate meaningful themes. Results: Five key themes emerged from the qualitative analysis: (1) clinicians often felt burdened by their workload and personally responsible when they were not able to provide optimal care to patients; (2) burnout was exacerbated by systemic problems at the FQHC; (3) medical assistants, medical scribes, schedulers, and other support staff played a crucial role in the wellness of the entire team; (4) perceived differences in priorities between administration and health care workers may have contributed to burnout; and (5) a communicative and stable team helped clinicians effectively care for their patients. Conclusions: Clinician burnout is a complex problem at FQHCs with many root causes. Addressing burnout and improving clinician wellness at FQHCs will require a multifaceted approach encompassing systemic, team, and individual components. The perspectives from the clinicians at our FQHC may inform wellness strategies for other safety net, clinical institutions in the primary care setting.

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