These collections showcase journal articles, preprints, book chapters, and other publications and presentations produced by faculty, postdocs, and researchers at UMass Chan Medical School, including a dedicated collection for research on COVID-19 and related viruses.

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  • The mobile vaccine equity enhancement program–a model program for enhancing equity in vaccine availability based at a large health care system

    Broach, John; Brown, Olga; McEachern, Caitlin; Forget, Janell; Lancette, Peter; Soucie, Norman; Inzerillo, Julie; Klugman, Robert; Tosi, Stephen; Haddad, Abraham; et al. (2023-10-17)
    The SARS CoV-2 (COVID-19) pandemic presented unprecedented challenges as communities attempted to respond to the administration of a novel vaccine that faced cold chain logistical requirements and vaccine hesitancy among many, as well as complicated phased rollout plans that changed frequently as availability of the vaccine waxed and waned. The COVID-19 pandemic also disproportionately affected communities of color and communities with barriers to accessing healthcare. In the setting of these difficulties, a program was created specifically to address inequity in vaccine administration with a focus on communities of color and linguistic diversity as well as those who had technological barriers to online sign-up processes common at mass vaccination sites. This effort, the Mobile Vaccine Equity Enhancement Program (MVeeP), delivered over 12,000 vaccines in 24 months through a reproducible set of practices that can inform equity-driven vaccine efforts in future pandemics.
  • The Importance of Quality Assurance in Radiation Oncology Clinical Trials

    FitzGerald, Thomas J; Bishop-Jodoin, Maryann; Laurie, Fran; Iandoli, Matthew; Smith, Koren; Ulin, Kenneth; Ding, Linda; Moni, Janaki; Cicchetti, M Giulia; Knopp, Michael; et al. (2023-10-01)
    Clinical trials have been the center of progress in modern medicine. In oncology, we are fortunate to have a structure in place through the National Clinical Trials Network (NCTN). The NCTN provides the infrastructure and a forum for scientific discussion to develop clinical concepts for trial design. The NCTN also provides a network group structure to administer trials for successful trial management and outcome analyses. There are many important aspects to trial design and conduct. Modern trials need to ensure appropriate trial conduct and secure data management processes. Of equal importance is the quality assurance of a clinical trial. If progress is to be made in oncology clinical medicine, investigators and patient care providers of service need to feel secure that trial data is complete, accurate, and well-controlled in order to be confident in trial analysis and move trial outcome results into daily practice. As our technology has matured, so has our need to apply technology in a uniform manner for appropriate interpretation of trial outcomes. In this article, we review the importance of quality assurance in clinical trials involving radiation therapy. We will include important aspects of institution and investigator credentialing for participation as well as ongoing processes to ensure that each trial is being managed in a compliant manner. We will provide examples of the importance of complete datasets to ensure study interpretation. We will describe how successful strategies for quality assurance in the past will support new initiatives moving forward.
  • Group Acupuncture Therapy With Yoga Therapy for Chronic Neck, Low Back, and Osteoarthritis Pain in Safety Net Settings for an Underserved Population: A Feasibility Pilot Study

    Teets, Raymond; Nielsen, Arya; Moonaz, Steffany; Anderson, Belinda J; Mah, Donna M; Walter, Eve; Milanes, Mirta; Jyung, Hyowoun; Soto Cossio, Luz E; Meissner, Paul; et al. (2023-09-28)
    Background: Acupuncture and yoga have both been shown to be effective in chronic pain. Underrepresented populations have poorer pain outcomes with less access to effective pain care. Objective: To assess the feasibility of bundling group acupuncture with yoga therapy for chronic neck, back or osteoarthritis pain in safety net settings. Methods: This was a feasibility pilot in Bronx and Harlem primary care community health centers. Participants with chronic neck, back or osteoarthritis pain received acupuncture and yoga therapy over a 10-week period. Participants received 10 weekly acupuncture treatments in group setting; with Yoga therapy sessions beginning immediately following the 3rd session. Primary outcome was pain interference and pain intensity on the Brief Pain Inventory (BPI); Outcomes were measured at baseline, 10-week close of intervention, and 24-week follow-up. Results: 93 patients were determined to be eligible and completed the baseline interview. The majority of participants were non-White and Medicaid recipients. 78 (84%) completed the intervention and 10-week survey, and 58 (62%) completed the 24-week post intervention survey. Participants received an average number of 6.5 acupuncture sessions (out of a possible 10), and 4 yoga sessions (out of a possible 8) over the 10-week intervention. Patients showed statistically significant improvements in pain at the close of the intervention and at a somewhat lesser rate, at 24-weeks post intervention. Challenges included telephone outreach and site coordination integrating acupuncture with yoga therapy. The trial also had to be stopped early due to the COVID-19 pandemic. Conclusions: Bundling acupuncture therapy and yoga therapy is feasible for an underrepresented population with chronic pain in urban community health centers with preliminary indications of acceptability and benefit to participants.
  • Multicomponent Pharmacist Intervention Did Not Reduce Clinically Important Medication Errors for Ambulatory Patients Initiating Direct Oral Anticoagulants

    Kapoor, Alok; Patel, Parth; Mbusa, Daniel; Pham, Thu; Cicirale, Carrie; Tran, Wenisa; Beavers, Craig; Javed, Saud; Wagner, Joann; Swain, Dawn; et al. (2023-09-27)
    Background: Anticoagulants including direct oral anticoagulants (DOACs) are among the highest-risk medications in the United States. We postulated that routine consultation and follow-up from a clinical pharmacist would reduce clinically important medication errors (CIMEs) among patients beginning or resuming a DOAC in the ambulatory care setting. Objective: To evaluate the effectiveness of a multicomponent intervention for reducing CIMEs. Design: Randomized controlled trial. Participants: Ambulatory patients initiating a DOAC or resuming one after a complication. Intervention: Pharmacist evaluation and monitoring based on the implementation of a recently published checklist. Key elements included evaluation of the appropriateness of DOAC, need for DOAC affordability assistance, three pharmacist-initiated telephone consultations, access to a DOAC hotline, documented hand-off to the patient's continuity provider, and monitoring of follow-up laboratory tests. Control: Coupons and assistance to increase the affordability of DOACs. Main measure: Anticoagulant-related CIMEs (Anticoagulant-CIMEs) and non-anticoagulant-related CIMEs over 90 days from DOAC initiation; CIMEs identified through masked assessment process including two physician adjudication of events presented by a pharmacist distinct from intervention pharmacist who reviewed participant electronic medical records and interview data. Analysis: Incidence and incidence rate ratio (IRR) of CIMEs (intervention vs. control) using multivariable Poisson regression modeling. Key results: A total of 561 patients (281 intervention and 280 control patients) contributed 479 anticoagulant-CIMEs including 31 preventable and ameliorable ADEs and 448 significant anticoagulant medication errors without subsequent documented ADEs (0.95 per 100 person-days). Failure to perform required blood tests and concurrent, inappropriate usage of a DOAC with aspirin or NSAIDs were the most common anticoagulant-related CIMEs despite pharmacist documentation systematically identifying these issues when present. There was no reduction in anticoagulant-related CIMEs among intervention patients (IRR 1.17; 95% CI 0.98-1.42) or non-anticoagulant-related CIMEs (IRR 1.05; 95% CI 0.80-1.37). Conclusion: A multi-component intervention in which clinical pharmacists implemented an evidence-based DOAC Checklist did not reduce CIMEs. Nih trial number: NCT04068727.
  • Beyond genome-wide association studies: Investigating the role of noncoding regulatory elements in primary sclerosing cholangitis

    Pratt, Henry E; Wu, Tong; Elhajjajy, Shaimae I; Zhou, Jeffrey Y.; Fitzgerald, Kate; Fazzio, Tom; Weng, Zhiping; Pratt, Daniel S (2023-09-27)
    Background: Genome-wide association studies (GWAS) have identified 30 risk loci for primary sclerosing cholangitis (PSC). Variants within these loci are found predominantly in noncoding regions of DNA making their mechanisms of conferring risk hard to define. Epigenomic studies have shown noncoding variants broadly impact regulatory element activity. The possible association of noncoding PSC variants with regulatory element activity has not been studied. We aimed to (1) determine if the noncoding risk variants in PSC impact regulatory element function and (2) if so, assess the role these regulatory elements have in explaining the genetic risk for PSC. Methods: Available epigenomic datasets were integrated to build a comprehensive atlas of cell type-specific regulatory elements, emphasizing PSC-relevant cell types. RNA-seq and ATAC-seq were performed on peripheral CD4+ T cells from 10 PSC patients and 11 healthy controls. Computational techniques were used to (1) study the enrichment of PSC-risk variants within regulatory elements, (2) correlate risk genotype with differences in regulatory element activity, and (3) identify regulatory elements differentially active and genes differentially expressed between PSC patients and controls. Results: Noncoding PSC-risk variants are strongly enriched within immune-specific enhancers, particularly ones involved in T-cell response to antigenic stimulation. In total, 250 genes and >10,000 regulatory elements were identified that are differentially active between patients and controls. Conclusions: Mechanistic effects are proposed for variants at 6 PSC-risk loci where genotype was linked with differential T-cell regulatory element activity. Regulatory elements are shown to play a key role in PSC pathophysiology.
  • Awake intracerebroventricular delivery and safety assessment of oligonucleotides in a large animal model

    Benatti, Hector Ribeiro; Prestigiacomo, Rachel D; Taghian, Toloo; Miller, Rachael; King, Robert; Gounis, Matthew J; Celik, Ugur; Bertrand, Stephanie; Tuominen, Susan; Bierfeldt, Lindsey; et al. (2023-09-26)
    Oligonucleotide therapeutics offer great promise in the treatment of previously untreatable neurodegenerative disorders; however, there are some challenges to overcome in pre-clinical studies. (1) They carry a well-established dose-related acute neurotoxicity at the time of administration. (2) Repeated administration into the cerebrospinal fluid may be required for long-term therapeutic effect. Modifying oligonucleotide formulation has been postulated to prevent acute toxicity, but a sensitive and quantitative way to track seizure activity in pre-clinical studies is lacking. The use of intracerebroventricular (i.c.v.) catheters offers a solution for repeated dosing; however, fixation techniques in large animal models are not standardized and are not reliable. Here we describe a novel surgical technique in a sheep model for i.c.v. delivery of neurotherapeutics based on the fixation of the i.c.v. catheter with a 3D-printed anchorage system composed of plastic and ceramic parts, compatible with magnetic resonance imaging, computed tomography, and electroencephalography (EEG). Our technique allowed tracking electrical brain activity in awake animals via EEG and video recording during and for the 24-h period after administration of a novel oligonucleotide in sheep. Its anchoring efficiency was demonstrated for at least 2 months and will be tested for up to a year in ongoing studies.
  • Effectiveness of various COVID-19 vaccine regimens among 10.4 million patients from the National COVID Cohort Collaborative during Pre-Delta to Omicron periods - United States, 11 December 2020 to 30 June 2022

    Fu, Yuanyuan; Wu, Kaipeng; Wang, Zhanwei; Yang, Hua; Chen, Yu; Wu, Lang; Yanagihara, Richard; Hedges, Jerris R; Wang, Hongwei; Deng, Youping (2023-09-22)
    Objective: This study reports the vaccine effectiveness (VE) of COVID-19 vaccine regimens in the United States, based on the National COVID Cohort Collaborative (N3C) database. Methods: Data from 10.4 million adults, enrolled in the N3C from 11 December 2020 to 30 June 2022, were analyzed. VE against infection and death outcomes were evaluated across 13 vaccine regimens in recipient cohorts during the Pre-Delta, Delta, and Omicron periods. VE was estimated as (1-odds ratio) × 100% by multivariate logistic regression, using the unvaccinated cohort as reference. Results: Natural immunity showed a highly protective effect (70.33%) against re-infection, but the mortality risk among the unvaccinated population was increased after re-infection; vaccination following infection reduced the risk of re-infection and death. mRNA-1273 full vaccination plus mRNA-1273 booster showed the highest anti-infection effectiveness (47.59%) (95% CI, 46.72-48.45) in the overall cohort. In the type 2 diabetes cohort, VE against infection was highest with BNT162b2 full vaccination plus mRNA-1273 booster (61.19%) (95% CI, 53.73-67.75). VE against death was also highest with BNT162b2 full vaccination plus mRNA-1273 booster (89.56%) (95% CI, 85.75-92.61). During the Pre-Delta period, all vaccination regimens showed an anti-infection effect; during the Delta period, only boosters, mixed vaccines, and Ad26.COV2.S vaccination exhibited an anti-infection effect; during the Omicron period, none of the vaccine regimens demonstrated an anti-infection effect. Irrespective of the variant period, even a single dose of mRNA vaccine offered protection against death, thus demonstrating survival benefit, even in the presence of infection or re-infection. Similar patterns were observed in patients with type 2 diabetes. Conclusions: Although the anti-infection effect declined as SARS-CoV-2 variants evolved, all COVID-19 mRNA vaccines had sustained effectiveness against death. Vaccination was crucial for preventing re-infection and reducing the risk of death following SARS-CoV-2 infection.
  • Association of neighborhood-level sociodemographic factors with Direct-to-Consumer (DTC) distribution of COVID-19 rapid antigen tests in 5 US communities

    Herbert, Carly; Shi, Qiming; Baek, Jonggyu; Wang, Biqi; Kheterpal, Vik; Nowak, Christopher; Suvarna, Thejas; Singh, Aditi; Hartin, Paul; Durnam, Basyl; et al. (2023-09-22)
    Background: Many interventions for widescale distribution of rapid antigen tests for COVID-19 have utilized online, direct-to-consumer (DTC) ordering systems; however, little is known about the sociodemographic characteristics of home-test users. We aimed to characterize the patterns of online orders for rapid antigen tests and determine geospatial and temporal associations with neighborhood characteristics and community incidence of COVID-19, respectively. Methods: This observational study analyzed online, DTC orders for rapid antigen test kits from beneficiaries of the Say Yes! Covid Test program from March to November 2021 in five communities: Louisville, Kentucky; Indianapolis, Indiana; Fulton County, Georgia; O'ahu, Hawaii; and Ann Arbor/Ypsilanti, Michigan. Using spatial autoregressive models, we assessed the geospatial associations of test kit distribution with Census block-level education, income, age, population density, and racial distribution and Census tract-level Social Vulnerability Index. Lag association analyses were used to measure the association between online rapid antigen kit orders and community-level COVID-19 incidence. Results: In total, 164,402 DTC test kits were ordered during the intervention. Distribution of tests at all sites were significantly geospatially clustered at the block-group level (Moran's I: p < 0.001); however, education, income, age, population density, race, and social vulnerability index were inconsistently associated with test orders across sites. In Michigan, Georgia, and Kentucky, there were strong associations between same-day COVID-19 incidence and test kit orders (Michigan: r = 0.89, Georgia: r = 0.85, Kentucky: r = 0.75). The incidence of COVID-19 during the current day and the previous 6-days increased current DTC orders by 9.0 (95% CI = 1.7, 16.3), 3.0 (95% CI = 1.3, 4.6), and 6.8 (95% CI = 3.4, 10.2) in Michigan, Georgia, and Kentucky, respectively. There was no same-day or 6-day lagged correlation between test kit orders and COVID-19 incidence in Indiana. Conclusions: Our findings suggest that online ordering is not associated with geospatial clustering based on sociodemographic characteristics. Observed temporal preferences for DTC ordering can guide public health messaging around DTC testing programs.
  • A single neuron in C. elegans orchestrates multiple motor outputs through parallel modes of transmission

    Huang, Yung-Chi; Luo, Jinyue; Huang, Wenjia; Baker, Casey M; Gomes, Matthew A; Meng, Bohan; Byrne, Alexandra B; Flavell, Steven W (2023-09-21)
    Animals generate a wide range of highly coordinated motor outputs, which allows them to execute purposeful behaviors. Individual neurons in the circuits that generate behaviors have a remarkable capacity for flexibility as they exhibit multiple axonal projections, transmitter systems, and modes of neural activity. How these multi-functional properties of neurons enable the generation of adaptive behaviors remains unknown. Here, we show that the HSN neuron in C. elegans evokes multiple motor programs over different timescales to enable a suite of behavioral changes during egg laying. Using HSN activity perturbations and in vivo calcium imaging, we show that HSN acutely increases egg laying and locomotion while also biasing the animals toward low-speed dwelling behavior over minutes. The acute effects of HSN on egg laying and high-speed locomotion are mediated by separate sets of HSN transmitters and different HSN axonal compartments. The long-lasting effects on dwelling are mediated in part by HSN release of serotonin, which is taken up and re-released by NSM, another serotonergic neuron class that directly evokes dwelling. Our results show how the multi-functional properties of a single neuron allow it to induce a coordinated suite of behaviors and also reveal that neurons can borrow serotonin from one another to control behavior.
  • Dual Residency Training in Neurology and Psychiatry: History and Current Practice

    Benjamin, Sheldon (2023-09-20)
    In the early 20th century, neurology training included more experience in psychiatry, and psychiatry training included more training in neurology than what is currently required. After World War I, the increased need for differential diagnosis of what might now be called functional neurological disorders resulted in the military encouraging combined residency training in neurology and psychiatry and the promulgation of the term "neuropsychiatry" for this specialty. Thirty-six percent of physicians certified by the American Board of Psychiatry and Neurology in its first decade (1935-1945) held certification in both neurology and psychiatry. However, the term neuropsychiatry gradually became used interchangeably with general psychiatry-to distinguish it from psychoanalysis-and lost its specificity. It is widely held that the popularity of psychoanalysis resulted in psychiatrists perceiving less need for neurological knowledge, and inclusion of neurology content in psychiatry training decreased. Dual residency training programs in neurology and psychiatry began to increase in popularity again in the 1980s as advances in neuroscience, neuroimaging, and pharmacology, paired with the growth of behavioral neurology, laid the foundation for meaningful practice of neuropsychiatry. The author surveyed 207 physicians who graduated from both a neurology and psychiatry residency and 18 current trainees in combined neuropsychiatry residency programs to collect information on their current practice, academic activity, and opinions about their training. The response rate was 64%. Respondents' attitudes toward the value of their dual neurology and psychiatry training were overwhelmingly positive. Reasons for the lack of growth of combined residency programs in neurology and psychiatry are examined.
  • Outpatient Treatment of Confirmed COVID-19: Living, Rapid Practice Points From the American College of Physicians (Version 2)

    Qaseem, Amir; Yost, Jennifer; Abraham, George M; Andrews, Rebecca; Jokela, Janet A; Miller, Matthew C; Humphrey, Linda L; Dunn, Andrew; Haeme, Ray; Lee, Rachael; et al. (2023-09-19)
    Description: Evidence for the use of outpatient treatments in adults with confirmed COVID-19 continues to evolve with new data. This is version 2 of the American College of Physicians (ACP) living, rapid practice points focusing on 22 outpatient treatments for COVID-19, specifically addressing the dominant SARS-CoV-2 Omicron variant. Methods: The Population Health and Medical Science Committee (formerly the Scientific Medical Policy Committee) developed this version of the living, rapid practice points on the basis of a living, rapid review done by the ACP Center for Evidence Reviews at Cochrane Austria at the University for Continuing Education Krems (Danube University Krems). This topic will be maintained as living and rapid by continually monitoring and assessing the impact of new evidence. Practice point 1: Consider molnupiravir to treat symptomatic patients with confirmed mild to moderate COVID-19 in the outpatient setting who are within 5 days of the onset of symptoms and at a high risk for progressing to severe disease. Practice point 2: Consider nirmatrelvir-ritonavir combination therapy to treat symptomatic patients with confirmed mild to moderate COVID-19 in the outpatient setting who are within 5 days of the onset of symptoms and at a high risk for progressing to severe disease. Practice point 3: Do not use ivermectin to treat patients with confirmed mild to moderate COVID-19 in the outpatient setting. Practice point 4: Do not use sotrovimab to treat patients with confirmed mild to moderate COVID-19 in the outpatient setting.
  • On a path toward a broad-spectrum anti-viral: inhibition of HIV-1 and coronavirus replication by SR kinase inhibitor harmine

    Dahal, Subha; Clayton, Kiera; Cabral, Tyler; Cheng, Ran; Jahanshahi, Shahrzad; Ahmed, Choudhary; Koirala, Amrit; Villasmil Ocando, Alonso; Malty, Ramy; Been, Terek; et al. (2023-09-14)
    RNA processing plays a key role in gene expression, allowing for increased protein diversity and functional complexity. Consequently, modulating RNA processing can impact gene function. Given HIV-1's reliance on host RNA processing machinery for viral protein production/replication, modulators of this process could serve as novel anti-virals to complement and/or enhance existing therapies. In this study, screening of several serine-arginine-rich (SR) kinase inhibitors for their impact on HIV-1 gene expression identified harmine as an inhibitor of HIV-1 gene expression in several cell lines and primary CD4+ T cells/macrophages at low micromolar concentrations with limited cell toxicity. Harmine induced a loss of viral structural protein expression associated with reduced HIV-1 unspliced and singly-spliced HIV-1 RNA levels but limited impact on multiply spliced RNAs. Although harmine is a known inhibitor of both DYRK1A and monoaminoxidase A (MAO A), neither DYRK1A depletion nor other MAO A inhibitors had any effect on HIV-1 expression. However, the compound altered the expression of several other SR kinases in primary CD4+ T cells, increasing CLK1 and reducing CLK2 kinase levels, effects known to regulate HIV-1 expression. Harmine was also unique among the SR kinase inhibitors tested for its ability to suppress replication of a seasonal coronavirus, human coronavirus (HCoV)-229E, and multiple severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants, reducing viral protein expression and virus release. Harmine acts post-entry, arresting virus replication even after the onset of viral protein production. At doses required to suppress HIV-1 replication, harmine had limited impact on the host transcriptome, alternative splicing, or alterative polyadenylation as assessed by RNA-Seq. Together, our study demonstrates the feasibility of targeting host RNA processing to inhibit a range of viruses with minimal impact on the host cell. IMPORTANCE This study highlights the crucial role RNA processing plays in regulating viral gene expression and replication. By targeting SR kinases, we identified harmine as a potent inhibitor of HIV-1 as well as coronavirus (HCoV-229E and multiple SARS-CoV-2 variants) replication. Harmine inhibits HIV-1 protein expression and reduces accumulation of HIV-1 RNAs in both cell lines and primary CD4+ T cells. Harmine also suppresses coronavirus replication post-viral entry by preferentially reducing coronavirus sub-genomic RNA accumulation. By focusing on host factors rather than viral targets, our study offers a novel approach to combating viral infections that is effective against a range of unrelated viruses. Moreover, at doses required to inhibit virus replication, harmine had limited toxicity and minimal effect on the host transcriptome. These findings support the viability of targeting host cellular processes as a means of developing broad-spectrum anti-virals.
  • Perceptions of social media utilization among orthopaedic foot and ankle surgeons

    Salimy, Mehdi S; Narain, Ankur S; Curtin, Patrick B; Bellinger, Eric C; Patel, Abhay R (2023-09-08)
    Background: The growing social media presence in healthcare has provided physicians with new ways to engage with patients. However, foot and ankle orthopaedic surgeons have been found to underuse social media platforms despite their known benefits for patients and surgeons. Thus, this study sought to investigate the reasons for this phenomenon and to identify potential barriers to social media utilization in clinical practice. Methods: A 19-question survey was distributed to active attending physicians identified through the American Orthopaedic Foot & Ankle Society membership database. The survey included demographic, practice characteristics, and social media use questions assessed by a 5-point Likert scale. Logistic regression was used to identify predictors of positive attitudes toward social media. Results: Fifty-eight surgeons were included. Most respondents were male (n = 43, 74.1%), in private practice (n = 31, 53.5%), and described their practice to be greater than 51% elective procedures (n = 46, 79.4%). The average years in practice was 14.8 years (standard deviation, SD: 10.0 years). A total of 32.8% (n = 19) of surgeons reported using social media as part of their clinical practice. Facebook (n = 19, 32.8%), a professional website or blog (n = 18, 31.0%), and LinkedIn (n = 15, 25.9%) were the most used platforms-primarily for practice marketing or brand development (n = 19, 32.8%). A total of 58.6% (n = 34) of surgeons reported they did not use social media. The primary reasons were the time commitment (n = 31, 53.5%), concerns about obscuring professional boundaries (n = 22, 37.9%), and concerns regarding confidentiality (n = 11, 19.0%). Many surgeons reported that social media positively influences foot and ankle surgery (n = 23, 39.7%), although no individual predictors for these views could be identified. Conclusions: Foot and ankle orthopaedic surgeons tended to view social media use positively, but the time investment and concerns over professionalism and confidentiality pose challenges to its use. Given the influence of a surgeon's social media identity on patient satisfaction and practice building, efforts should be made to streamline social media use for foot and ankle surgeons to establish their online presence. Level of evidence: Level IV, cross-sectional study.
  • Translation of dipeptide repeat proteins in ALS/FTD through unique and redundant AUG initiation codons

    Sonobe, Yoshifumi; Lee, Soojin; Krishnan, Gopinath; Gu, Yuanzheng; Kwon, Deborah Y; Gao, Fen-Biao; Roos, Raymond P; Kratsios, Paschalis (2023-09-07)
    A hexanucleotide repeat expansion in C9ORF72 is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). A hallmark of ALS/FTD pathology is the presence of dipeptide repeat (DPR) proteins, produced from both sense GGGGCC (poly-GA, poly-GP, poly-GR) and antisense CCCCGG (poly-PR, poly-PG, poly-PA) transcripts. Translation of sense DPRs, such as poly-GA and poly-GR, depends on non-canonical (non-AUG) initiation codons. Here, we provide evidence for canonical AUG-dependent translation of two antisense DPRs, poly-PR and poly-PG. A single AUG is required for synthesis of poly-PR, one of the most toxic DPRs. Unexpectedly, we found redundancy between three AUG codons necessary for poly-PG translation. Further, the eukaryotic translation initiation factor 2D (EIF2D), which was previously implicated in sense DPR synthesis, is not required for AUG-dependent poly-PR or poly-PG translation, suggesting that distinct translation initiation factors control DPR synthesis from sense and antisense transcripts. Our findings on DPR synthesis from the C9ORF72 locus may be broadly applicable to many other nucleotide repeat expansion disorders.
  • Bacteroides Fragilis in the gut microbiomes of Alzheimer's disease activates microglia and triggers pathogenesis in neuronal C/EBPβ transgenic mice

    Xia, Yiyuan; Xiao, Yifan; Wang, Zhi-Hao; Liu, Xia; Alam, Ashfaqul M; Haran, John P; McCormick, Beth A; Shu, Xiji; Wang, Xiaochuan; Ye, Keqiang (2023-09-06)
    Gut dysbiosis contributes to Alzheimer's disease (AD) pathogenesis, and Bacteroides strains are selectively elevated in AD gut microbiota. However, it remains unknown which Bacteroides species and how their metabolites trigger AD pathologies. Here we show that Bacteroides fragilis and their metabolites 12-hydroxy-heptadecatrienoic acid (12-HHTrE) and Prostaglandin E2 (PGE2) activate microglia and induce AD pathogenesis in neuronal C/EBPβ transgenic mice. Recolonization of antibiotics cocktail-pretreated Thy1-C/EBPβ transgenic mice with AD patient fecal samples elicits AD pathologies, associated with C/EBPβ/Asparaginyl endopeptidase (AEP) pathway upregulation, microglia activation, and cognitive disorders compared to mice receiving healthy donors' fecal microbiota transplantation (FMT). Microbial 16S rRNA sequencing analysis shows higher abundance of proinflammatory Bacteroides fragilis in AD-FMT mice. Active components characterization from the sera and brains of the transplanted mice revealed that both 12-HHTrE and PGE2 activate primary microglia, fitting with poly-unsaturated fatty acid (PUFA) metabolites enrichment identified by metabolomics. Strikingly, recolonization with live but not dead Bacteroides fragilis elicited AD pathologies in Thy1-C/EBPβ transgenic mice, so did 12-HHTrE or PGE2 treatment alone. Collectively, our findings support a causal role for Bacteroides fragilis and the PUFA metabolites in activating microglia and inducing AD pathologies in Thy1- C/EBPβ transgenic mice.
  • Neighborhood Disadvantage and Neural Correlates of Threat and Reward Processing in Survivors of Recent Trauma

    Webb, E Kate; Ely, Timothy D; Rowland, Grace E; Lebois, Lauren A M; van Rooij, Sanne J H; Bruce, Steven E; Jovanovic, Tanja; House, Stacey L; Beaudoin, Francesca L; An, Xinming; et al. (2023-09-05)
    Importance: Differences in neighborhood socioeconomic characteristics are important considerations in understanding differences in risk vs resilience in mental health. Neighborhood disadvantage is associated with alterations in the function and structure of threat neurocircuitry. Objective: To investigate associations of neighborhood disadvantage with white and gray matter and neural reactivity to positive and negative stimuli in the context of trauma exposure. Design, setting, and participants: In this cross-sectional study, survivors of trauma who completed sociodemographic and posttraumatic symptom assessments and neuroimaging were recruited as part of the Advancing Understanding of Recovery After Trauma (AURORA) study between September 2017 and June 2021. Data analysis was performed from October 25, 2022, to February 15, 2023. Exposure: Neighborhood disadvantage was measured with the Area Deprivation Index (ADI) for each participant home address. Main outcomes and measures: Participants completed separate threat and reward tasks during functional magnetic resonance imaging. Diffusion-weighted and high-resolution structural images were also collected. Linear models assessed the association of ADI with reactivity, microstructure, and macrostructure of a priori regions of interest after adjusting for income, lifetime trauma, sex at birth, and age. A moderated-mediation model tested whether ADI was associated with neural activity via microstructural changes and if this was modulated by PTSD symptoms. Results: A total of 280 participants (183 females [65.4%]; mean [SD] age, 35.39 [13.29] years) completed the threat task and 244 participants (156 females [63.9%]; mean [SD] age, 35.10 [13.26] years) completed the reward task. Higher ADI (per 1-unit increase) was associated with greater insula (t274 = 3.20; β = 0.20; corrected P = .008) and anterior cingulate cortex (ACC; t274 = 2.56; β = 0.16; corrected P = .04) threat-related activity after considering covariates, but ADI was not associated with reward reactivity. Greater disadvantage was also associated with altered microstructure of the cingulum bundle (t274 = 3.48; β = 0.21; corrected P = .001) and gray matter morphology of the ACC (cortical thickness: t273 = -2.29; β = -0.13; corrected P = .02; surface area: t273 = 2.53; β = 0.13; corrected P = .02). The moderated-mediation model revealed that ADI was associated with ACC threat reactivity via cingulum microstructural changes (index of moderated mediation = -0.02). However, this mediation was only present in individuals with greater PTSD symptom severity (at the mean: β = -0.17; standard error = 0.06, t= -2.28; P = .007; at 1 SD above the mean: β = -0.28; standard error = 0.08; t = -3.35; P < .001). Conclusions and relevance: In this study, neighborhood disadvantage was associated with neurobiology that supports threat processing, revealing associations of neighborhood disadvantage with neural susceptibility for PTSD and suggesting how altered structure-function associations may complicate symptoms. Future work should investigate specific components of neighborhood disadvantage that may be associated with these outcomes.
  • Topical treatments for atopic dermatitis (eczema): systematic review and network meta-analysis of randomized trials

    Chu, Derek K; Chu, Alexandro W L; Rayner, Daniel G; Guyatt, Gordon H; Yepes-Nuñez, Juan José; Gomez-Escobar, Luis; Pérez-Herrera, Lucia C; Díaz Martinez, Juan Pablo; Brignardello-Petersen, Romina; Sadeghirad, Behnam; et al. (2023-09-05)
    Background: Atopic dermatitis (AD) is a common skin condition with multiple topical treatment options, but uncertain comparative effects. Objectives: We systematically synthesized the benefits and harms of AD prescription topical treatments. Methods: For the 2023 AAAAI/ACAAI JTFPP AD guidelines, we searched MEDLINE, EMBASE, CENTRAL, CINAHL, LILACS, ICTRP, and GREAT to September 5, 2022 for randomized trials addressing AD topical treatments. Paired reviewers independently screened records, extracted data, and assessed risk of bias. Random-effects network meta-analyses addressed AD severity, itch, sleep, AD-quality of life, flares, and harms. The GRADE approach informed certainty of evidence ratings. We classified topical corticosteroids (TCS) using seven classes-group 1 being most potent. OSF: https://osf.io/q5m6s. Results: 219 included trials (43,123 patients) evaluated 68 interventions. With high-certainty, pimecrolimus improved six of seven outcomes-among the best for two; high-dose tacrolimus (0.1%) improved five-among the best for two; low-dose tacrolimus (0.03%) improved five-among the best for one. With moderate-to-high certainty, group 5 TCS improved six-among the best for three; group 4 TCS and delgocitinib improved four-among the best for two; ruxolitinib improved four-among the best for one; group 1 TCS improved three-among the best for two. These interventions did not increase harms. Crisaborole and difamilast were intermediately effective, but uncertain harm. Topical antibiotics alone or in combination may be among the least effective. To maintain AD control, group 5 TCS were among the most effective, followed by tacrolimus and pimecrolimus. Conclusions: For individuals with AD, pimecrolimus, tacrolimus, and moderate-potency TCS are among the most effective in improving and maintaining multiple AD outcomes. Topical antibiotics may be among the least effective.
  • Systemic treatments for atopic dermatitis (eczema): systematic review and network meta-analysis of randomized trials

    Chu, Alexandro W L; Wong, Melanie M; Rayner, Daniel G; Guyatt, Gordon H; Martinez, Juan Pablo Díaz; Ceccacci, Renata; Zhao, Irene X; McMullen, Eric; Srivastava, Archita; Wang, Jason; et al. (2023-09-05)
    Background: Atopic dermatitis (AD) is an inflammatory skin condition with multiple systemic treatments and uncertainty regarding their comparative impact on AD outcomes. Objective: We systematic synthesized the benefits and harms of AD systemic treatments. Methods: For the 2023 AAAAI/ACAAI JTFPP AD guidelines, we searched MEDLINE, EMBASE, CENTRAL, Web of Science, and GREAT, from inception to November 29, 2022, for randomized trials addressing systemic treatments and phototherapy for AD. Paired reviewers independently screened records, extracted data, and assessed risk of bias. Random-effects network meta-analyses addressed AD severity, itch, sleep, AD-quality of life, flares, and harms. The GRADE approach informed certainty of evidence ratings. OSF: https://osf.io/e5sna. Results: 149 included trials (28,686 patients with moderate-to-severe AD) evaluated 75 interventions. With high-certainty, high-dose upadacitinib was among the most effective for five of six patient-important outcomes; high-dose abrocitinib and low-dose upadacitinib were among the most effective for two outcomes. These JAK inhibitors were among the most harmful in increasing adverse events. With high-certainty, dupilumab, lebrikizumab, and tralokinumab were of intermediate effectiveness and among the safest-modestly increasing conjunctivitis. Low-dose baricitinib was among the least effective. The efficacy and safety of azathioprine, oral corticosteroids, cyclosporine, methotrexate, mycophenolate, phototherapy, and many novel agents are less certain. Conclusions: Among individuals with moderate-to-severe AD, high-certainty evidence demonstrates that high-dose upadacitinib is among the most effective in addressing multiple patient-important outcomes but also among the most harmful. High-dose abrocitinib and low-dose upadacitinib are effective, but also among the most harmful. Dupilumab, lebrikizumab, and tralokinumab are of intermediate effectiveness and favorable safety.
  • Clinician commentary on adapting psychotherapy in collaborative care for treating opioid use disorder and co-occurring psychiatric conditions in primary care

    Mullin, Daniel J; Mitton, Ashley (2023-09-01)
    Comments on the original article by French, et al. (see record 2023-74550-001) regarding adapting psychotherapy in collaborative care for treating opioid use disorder and co-occurring psychiatric conditions in primary care. This article provided a potential treatment pathway for certain patients. However, it has left the question: What options are available for patients who decline to participate in this collaborative care approach? It is important to emphasize that we do not want to deny them access to treatment for their (opioid use disorder) OUD. Are there alternative interventions with a lower intensity that may still hold value for patients who opt out of this particular approach? In future research, the current authors would like to see expanded treatment pathways that match patients at all levels of engagement. By offering a more diverse range of options, we can better meet the needs of a broader spectrum of patients, ultimately improving treatment outcomes for individuals with OUD and psychiatric symptoms. (PsycInfo Database Record (c) 2023 APA, all rights reserved).
  • Reliable multiplex generation of pooled induced pluripotent stem cells

    Smullen, Molly; Olson, Meagan N; Reichert, Julia M; Dawes, Pepper; Murray, Liam F; Baer, Christina E; Wang, Qi; Readhead, Benjamin; Church, George M; Lim, Elaine T; et al. (2023-08-31)
    Reprogramming somatic cells into pluripotent stem cells (iPSCs) enables the study of systems in vitro. To increase the throughput of reprogramming, we present induction of pluripotency from pooled cells (iPPC)-an efficient, scalable, and reliable reprogramming procedure. Using our deconvolution algorithm that employs pooled sequencing of single-nucleotide polymorphisms (SNPs), we accurately estimated individual donor proportions of the pooled iPSCs. With iPPC, we concurrently reprogrammed over one hundred donor lymphoblastoid cell lines (LCLs) into iPSCs and found strong correlations of individual donors' reprogramming ability across multiple experiments. Individual donors' reprogramming ability remains consistent across both same-day replicates and multiple experimental runs, and the expression of certain immunoglobulin precursor genes may impact reprogramming ability. The pooled iPSCs were also able to differentiate into cerebral organoids. Our procedure enables a multiplex framework of using pooled libraries of donor iPSCs for downstream research and investigation of in vitro phenotypes.

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