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  Implications of Non-Specific Effects for Testing, Approving, and Regulating Vaccines

  Benn, Christine Stabell; Amenyogbe, Nelly; Björkman, Anders; Domínguez-Andrés, Jorge; Fish, Eleanor N; Flanagan, Katie L; Klein, Sabra L; Kollmann, Tobias R; Kyvik, Kirsten Ohm; Netea, Mihai G; et al. (2023-04-19)

  The current framework for testing and regulating vaccines was established before the realization that vaccines, in addition to their effect against the vaccine-specific disease, may also have "non-specific effects" affecting the risk of unrelated diseases. Accumulating evidence from epidemiological studies shows that vaccines in some situations can affect all-cause mortality and morbidity in ways that are not explained by the prevention of the vaccine-targeted disease. Live attenuated vaccines have sometimes been associated with decreases in mortality and morbidity that are greater than anticipated. In contrast, some non-live vaccines have in certain contexts been associated with increases in all-cause mortality and morbidity. The non-specific effects are often greater for female than male individuals. Immunological studies have provided several mechanisms that explain how vaccines might modulate the immune response to unrelated pathogens, such as through trained innate immunity, emergency granulopoiesis, and heterologous T-cell immunity. These insights suggest that the framework for the testing, approving, and regulating vaccines needs to be updated to accommodate non-specific effects. Currently, non-specific effects are not routinely captured in phase I-III clinical trials or in the post-licensure safety surveillance. For instance, an infection with Streptococcus pneumoniae occurring months after a diphtheria-tetanus-pertussis vaccination would not be considered an effect of the vaccination, although evidence indicates it might well be for female individuals. Here, as a starting point for discussion, we propose a new framework that considers the non-specific effects of vaccines in both phase III trials and post-licensure.
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  Atypical Fragility Fractures due to Bony or Soft Tissue Phosphaturic Mesenchymal Tumors: A Report of Two Cases

  Clegg, Stephanie M; Eiel, Emily S; Fine, Sara; Gafni, Rachel I; Most, Mathew J (2023-04-12)

  Introduction: Tumor-induced osteomalacia (TIO) is a rare paraneoplastic disorder where patients present with hypophosphatemia, chronic diffuse bone pain, and occasionally fractures. Benign phosphaturic mesenchymal tumors (PMT) are responsible for the TIO and are largely soft tissue tumors. Cases: Two male patients with TIO secondary to PMT were reported-one in the bony scapula and the other in the plantar foot soft tissue. The first case describes a 63-year-old Caucasian male, who sustained an intertrochanteric proximal femur stress fracture and approximately two years of diffuse bone pain and hypophosphatemia. Wide excision of a left scapula boney lesion resulted in immediate resolution of his electrolyte abnormalities and bone pain. Case 2 describes a 58-year-old male with four years of multifocal bone pain and atraumatic fractures. A 68Ga-DOTATATE-positron emission tomography/computed tomography (PET/CT) scan identified a soft tissue tumor in his plantar foot, which was ultimately excised. He also experienced near immediate resolution of his pain and no additional fractures. Conclusion: TIO is a rare condition presenting with chronic multifocal bone pain, stress fractures, and hypophosphatemia. These two cases highlight that the causative tumor may originate in soft tissue or bone. Furthermore, a high index of suspicion, along with fibroblast growth factor-23 testing and DOTATATE-PET/CT localization, can help with diagnosis and minimize treatment delays.
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  Advancing Maternal Health Equity Among Migrant Communities

  Johnson-Agbakwu, Crista (2023-04-06)

  Crista Johnson-Agbakwu, MD, is the inaugural executive director of the new UMass Chan Medical School Collaborative in Health Equity. Dr. Johnson-Agbawku, professor of obstetrics & gynecology and population & quantitative health sciences, is an accomplished physician who has focused her career on reducing the disparities between social determinants of health and health care. This talk was planned in conjunction with the National Library of Medicine traveling exhibit, "Outside/Inside: Immigration, Migration, and Health Care in the United States," hosted at the UMass Chan Medical School Lamar Soutter Library March 13 - April 22, 2023.
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  Improved Performance of ChatGPT-4 on the OKAP Exam: A Comparative Study with ChatGPT-3.5 [preprint]

  Teebagy, Sean; Colwell, Lauren; Wood, Emma; Yaghy, Antonio; Faustina, Misha (2023-04-03)

  This study aims to evaluate the performance of ChatGPT-4, an advanced Artificial Intelligence (AI) language model, on the Ophthalmology Knowledge Assessment Program (OKAP) examination compared to its predecessor, ChatGPT-3.5. Both models were tested on 180 OKAP practice questions covering various ophthalmology subject categories. Results showed that ChatGPT-4 significantly outperformed ChatGPT-3.5 (81% vs. 57%; p<0.001), indicating improvements in medical knowledge assessment. The superior performance of ChatGPT-4 suggests potential applicability in ophthalmologic education and clinical decision support systems. Future research should focus on refining AI models, ensuring a balanced representation of fundamental and specialized knowledge, and determining the optimal method of integrating AI into medical education and practice.
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  Synthesis and validation of click-modified of NOD1/2 agonists [preprint]

  Bharadwaj, Ravi; Anonick, Madison V.; Mashayekh, Siavash; Brown, Ashley; Wodzanowski, Kimberly A.; Okuda, Kendi; Silverman, Neal; Grimes, Catherine L. (2023-03-28)

  NOD1 and NOD2 sense small bacterial peptidoglycan fragments often called muropeptides. These muropeptides include iE-DAP and MDP, the minimal agonists for NOD1 and NOD2, respectively. Here, we synthesized and validated alkyne-modified muropeptides, iE-DAP-Alk and MDP-Alk, for use in click-chemistry reactions. While it has long been known that many cell types respond to extracellular exposure to muropeptides, it is unclear how these innate immune activators access their cytosolic innate immune receptors, NOD1 and NOD2. The subcellular trafficking and transport mechanisms by which muropeptides access these cytosolic innate immune receptors are a major gap in our understanding of these critical host responses. The clickchemistry-enabled agonists developed here will be particularly powerful to decipher the underlying cell biology and biochemistry of NOD1 and NOD2 innate immune sensing.
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  Cryo-EM structure of the human Sirtuin 6-nucleosome complex [preprint]

  Chio, Un Seng; Rechiche, Othman; Bryll, Alysia R; Zhu, Jiang; Feldman, Jessica L; Peterson, Craig L; Tan, Song; Armache, Jean-Paul (2023-03-18)

  Sirtuin 6 (SIRT6) is a multifaceted protein deacetylase/deacylase and a major target for small-molecule modulators of longevity and cancer. In the context of chromatin, SIRT6 removes acetyl groups from histone H3 in nucleosomes, but the molecular basis for its nucleosomal substrate preference is unknown. Our cryo-electron microscopy structure of human SIRT6 in complex with the nucleosome shows that the catalytic domain of SIRT6 pries DNA from the nucleosomal entry-exit site and exposes the histone H3 N-terminal helix, while the SIRT6 zinc-binding domain binds to the histone acidic patch using an arginine anchor. In addition, SIRT6 forms an inhibitory interaction with the C-terminal tail of histone H2A. The structure provides insights into how SIRT6 can deacetylate both H3 K9 and H3 K56. Teaser: The structure of the SIRT6 deacetylase/nucleosome complex suggests how the enzyme acts on both histone H3 K9 and K56 residues.
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  De novo lipogenesis fuels adipocyte autophagosome and lysosome membrane dynamics

  Rowland, Leslie A; Guilherme, Adilson; Henriques, Felipe; DiMarzio, Chloe; Munroe, Sean; Wetoska, Nicole; Kelly, Mark; Reddig, Keith; Hendricks, Gregory; Pan, Meixia; et al. (2023-03-13)

  Adipocytes robustly synthesize fatty acids (FA) from carbohydrate through the de novo lipogenesis (DNL) pathway, yet surprisingly DNL contributes little to their abundant triglyceride stored in lipid droplets. This conundrum raises the hypothesis that adipocyte DNL instead enables membrane expansions to occur in processes like autophagy, which requires an abundant supply of phospholipids. We report here that adipocyte Fasn deficiency in vitro and in vivo markedly impairs autophagy, evident by autophagosome accumulation and severely compromised degradation of the autophagic substrate p62. Our data indicate the impairment occurs at the level of autophagosome-lysosome fusion, and indeed, loss of Fasn decreases certain membrane phosphoinositides necessary for autophagosome and lysosome maturation and fusion. Autophagy dependence on FA produced by Fasn is not fully alleviated by exogenous FA in cultured adipocytes, and interestingly, imaging studies reveal that Fasn colocalizes with nascent autophagosomes. Together, our studies identify DNL as a critical source of FAs to fuel autophagosome and lysosome maturation and fusion in adipocytes.
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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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  Cross-reactivity influences changes in human influenza A virus and Epstein Barr virus specific CD8 memory T cell receptor alpha and beta repertoires between young and old

  Clark, Fransenio; Gil, Anna; Thapa, Ishwor; Aslan, Nuray; Ghersi, Dario; Selin, Liisa K. (2023-02-24)

  Older people have difficulty controlling infection with common viruses such as influenza A virus (IAV), RNA virus which causes recurrent infections due to a high rate of genetic mutation, and Epstein Barr virus (EBV), DNA virus which persists in B cells for life in the 95% of people that become acutely infected. We questioned whether changes in epitope-specific memory CD8 T cell receptor (TCR) repertoires to these two common viruses could occur with increasing age and contribute to waning immunity. We compared CD8 memory TCR alpha and beta repertoires in two HLA-A2+ EBV- and IAV-immune donors, young (Y) and older (O) donors to three immunodominant epitopes known to be cross-reactive, IAV-M158-66 (IAV-M1), EBV-BMLF1280-288 (EBV-BM), and EBV-BRLF1109-117 (EBV-BR). We, therefore, also designed these studies to examine if TCR cross-reactivity could contribute to changes in repertoire with increasing age. TCR high throughput sequencing showed a significant difference in the pattern of TRBV usage between Y and O. However, there were many more differences in AV and AJ usage, between the age groups suggesting that changes in TCRα usage may play a greater role in evolution of the TCR repertoire emphasizing the importance of studying TRAV repertoires. With increasing age there was a preferential retention of TCR for all three epitopes with features in their complementarity-determining region (CDR3) that increased their ease of generation, and their cross-reactive potential. Young and older donors differed in the patterns of AV/AJ and BV/BJ pairings and usage of dominant CDR3 motifs specific to all three epitopes. Both young and older donors had cross-reactive responses between these 3 epitopes, which were unique and differed from the cognate responses having features that suggested they could interact with either ligand. There was an increased tendency for the classic IAV-M1 specific clone BV19-IRSS-JB2.7/AV27-CAGGGSQGNLIF-AJ42 to appear among the cross-reactive clones, suggesting that the dominance of this clone may relate to its cross-reactivity with EBV. These results suggest that although young and older donors retain classic TCR features for each epitope their repertoires are gradually changing with age, maintaining TCRs that are cross-reactive between these two common human viruses, one with recurrent infections and the other a persistent virus which frequently reactivates.
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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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  The role of RNA-binding proteins in orchestrating germline development in Caenorhabditis elegans

  Albarqi, Mennatallah M Y; Ryder, Sean P (2023-01-04)

  RNA passed from parents to progeny controls several aspects of early development. The germline of the free-living nematode Caenorhabditis elegans contains many families of evolutionarily conserved RNA-binding proteins (RBPs) that target the untranslated regions of mRNA transcripts to regulate their translation and stability. In this review, we summarize what is known about the binding specificity of C. elegans germline RNA-binding proteins and the mechanisms of mRNA regulation that contribute to their function. We examine the emerging role of miRNAs in translational regulation of germline and embryo development. We also provide an overview of current technology that can be used to address the gaps in our understanding of RBP regulation of mRNAs. Finally, we present a hypothetical model wherein multiple 3'UTR-mediated regulatory processes contribute to pattern formation in the germline to ensure the proper and timely localization of germline proteins and thus a functional reproductive system.
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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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