Strategies Utilized to Transfer Weight During Knee Flexion and Extension With Rotation for Individuals With a Total Knee Replacement

Functional activities in daily life can require squatting and shifting body weight during transverse plane rotations. Stability of the knee can be challenging for people with a total knee replacement (TKR) due to reduced proprioception, nonconforming articular geometry, muscle strength, and soft tissue weakness. The objective of this study was to identify strategies utilized by individuals with TKR in double-stance transferring load during rotation and flexion. Twenty-three subjects were recruited for this study: 11 TKR subjects (age: 65 6 6 years; BMI 27.4 6 4.1) and 12 healthy subjects (age: 63 6 7; BMI 24.6 6 3.8). Each subject completed a novel crossover button push task where rotation, flexion, and extension of the knee were utilized. Each subject performed two crossover reaching tasks where the subject used the opposite hand to cross over their body and press a button next to either their shoulder (high) or knee (low), then switched hands and rotated to press the opposite button, either low or high. The two tasks related to the order they pressed the buttons while crossing over, either low-to-high (L2H) or high-to-low (H2L). Force platforms measured ground reaction forces under each foot, which were then converted to lead force ratios (LFRs) based on the total force. Knee flexion angles were also measured. No statistical differences were found in the LFRs during the H2L and L2H tasks for the different groups, although differences in the variation of the loading within subjects were noted. A significant difference was found between healthy and unaffected knee angles and a strong trend between healthy and affected subject's knee angles in both H2L and L2H tasks. Large variations in the LFR at mid-task in the TKR subjects suggested possible difficulties in maintaining positional stability during these tasks. The TKR subjects maintained more of an extended knee, which is a consistent quadriceps avoidance strategy seen by other researchers in different tasks. These outcomes suggest that individuals with a TKR utilize strategies, such as keeping an extended knee, to achieve rotary tasks during knee flexion and extension. Repeated compensatory movements could result in forces that may cause difficulty over time in the hip joints or low back. Early identification of these strategies could improve TKR success and the return to activities of daily living that involve flexion and rotation

A Comparison of Chief Complaints, Specific Diagnoses, and Demographics of Pediatric Urgent Care Visits Before and During the COVID-19 Pandemic: A Retrospective Study

There was an increased incidence of pediatric patients who presented with injuries caused by falls not related to sports or other recreational activities, as well as for animal bites, during the early pandemic period of April 2020. Education of parents and caregivers of young children is warranted to raise awareness of the even greater potential for falls and animal bites when children are confined at home for longer than typical periods of time, as occurred with the stay-at-home government orders during the initial period of the COVID-19 pandemic

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Genomic epidemiology of SARS-CoV-2 in a UK university identifies dynamics of transmission

AbstractUnderstanding SARS-CoV-2 transmission in higher education settings is important to limit spread between students, and into at-risk populations. In this study, we sequenced 482 SARS-CoV-2 isolates from the University of Cambridge from 5 October to 6 December 2020. We perform a detailed phylogenetic comparison with 972 isolates from the surrounding community, complemented with epidemiological and contact tracing data, to determine transmission dynamics. We observe limited viral introductions into the university; the majority of student cases were linked to a single genetic cluster, likely following social gatherings at a venue outside the university. We identify considerable onward transmission associated with student accommodation and courses; this was effectively contained using local infection control measures and following a national lockdown. Transmission clusters were largely segregated within the university or the community. Our study highlights key determinants of SARS-CoV-2 transmission and effective interventions in a higher education setting that will inform public health policy during pandemics.</jats:p

Electrostatic and Hydrophobic Interactions Mediate Single-Stranded DNA Recognition and <i>Acta2</i> Repression by Purine-Rich Element-Binding Protein B

Myofibroblast differentiation is characterized by an increased level of expression of cytoskeletal smooth muscle α-actin. In human and murine fibroblasts, the gene encoding smooth muscle α-actin (<i>Acta2</i>) is tightly regulated by a network of transcription factors that either activate or repress the 5′ promoter–enhancer in response to environmental cues signaling tissue repair and remodeling. Purine-rich element-binding protein B (Purβ) suppresses the expression of <i>Acta2</i> by cooperatively interacting with the sense strand of a 5′ polypurine sequence containing an inverted MCAT <i>cis</i> element required for gene activation. In this study, we evaluated the chemical basis of nucleoprotein complex formation between the Purβ repressor and the purine-rich strand of the MCAT element in the mouse <i>Acta2</i> promoter. Quantitative single-stranded DNA (ssDNA) binding assays conducted in the presence of increasing concentrations of monovalent salt or anionic detergent suggested that the assembly of a high-affinity nucleoprotein complex is driven by a combination of electrostatic and hydrophobic interactions. Consistent with the results of pH titration analysis, site-directed mutagenesis revealed several basic amino acid residues in the intermolecular (R267) and intramolecular (K82 and R159) subdomains that are essential for Purβ transcriptional repressor function in <i>Acta2</i> promoter–reporter assays. In keeping with their diminished <i>Acta2</i> repressor activity in fibroblasts, purified Purβ variants containing an R267A mutation exhibited reduced binding affinity for purine-rich ssDNA. Moreover, certain double and triple-point mutants were also defective in binding to the <i>Acta2</i> corepressor protein, Y-box-binding protein 1. Collectively, these findings establish the repertoire of noncovalent interactions that account for the unique structural and functional properties of Purβ

Efficacy of platinum rechallenge in metastatic urothelial carcinoma after previous platinum-based chemotherapy for metastatic disease

BACKGROUND: Fit patients with metastatic urothelial carcinoma (mUC) receive first-line platinum-based combination chemotherapy (fPBC) as standard of care and may receive additional later-line chemotherapy after progression. Our study compares outcomes with subsequent platinum-based chemotherapy (sPBC) versus subsequent non-platinum-based chemotherapy (sNPBC).MATERIALS AND METHODS: Patients from 27 international centers in the Retrospective International Study of Cancers of the Urothelium (RISC) who received fPBC for mUC and at least two cycles of subsequent chemotherapy were included in this study. A multivariable Cox proportional hazards model compared overall survival (OS) and progression-free survival (PFS).RESULTS: One hundred thirty-five patients received sPBC and 161 received sNPBC. Baseline characteristics were similar between groups, except patients who received sPBC had higher baseline hemoglobin, higher disease control rate with fPBC, and longer time since fPBC. OS was superior in the sPBC group (median 7.9 vs 5.5 months) in a model adjusting for comorbidity burden, performance status, liver metastases, number of fPBC cycles received, best response to fPBC, and time since fPBC (hazard ratio, 0.72; 95% confidence interval, 0.53-0.98; p = .035). There was no difference in PFS. More patients in the sPBC group achieved disease control than in the sNPBC group (57.4% vs 44.8%; p = .041). Factors associated with achieving disease control in the sPBC group but not the sNPBC group included longer time since fPBC, achieving disease control with fPBC, and absence of liver metastases.CONCLUSION: After receiving fPBC for mUC, patients who received sPBC had better OS and disease control. This may help inform the choice of subsequent chemotherapy in patients with mUC.IMPLICATIONS FOR PRACTICE: Patients with progressive metastatic urothelial carcinoma after first-line platinum-based combination chemotherapy may now receive immuno-oncology agents, erdafitinib, enfortumab vedotin, or sacituzumab govitecan-hziy; however, those ineligible for these later-line therapies or who progress after receiving them may be considered for subsequent chemotherapy. In this retrospective study of 296 patients, survival outcomes and disease control rates were better in those receiving subsequent platinum-based rechallenge compared with non-platinum-based chemotherapy, suggesting that patients should receive platinum rechallenge if clinically able. Disease control with platinum rechallenge was more likely with prior first-line platinum having achieved disease control, longer time since first-line platinum, and absence of liver metastases.</p

American College of Rheumatology Clinical Guidance for Multisystem Inflammatory Syndrome in Children Associated With SARS-CoV-2 and Hyperinflammation in Pediatric COVID-19: Version 1.

ObjectiveTo provide guidance on the management of multisystem inflammatory syndrome in children (MIS-C), a condition characterized by fever, inflammation, and multiorgan dysfunction that manifests late in the course of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, and to provide recommendations for children with hyperinflammation during coronavirus disease 2019 (COVID-19), the acute, infectious phase of SARS-CoV-2 infection.MethodsA multidisciplinary task force was convened by the American College of Rheumatology (ACR) to provide guidance on the management of MIS-C associated with SARS-CoV-2 and hyperinflammation in COVID-19. The task force was composed of 9 pediatric rheumatologists, 2 adult rheumatologists, 2 pediatric cardiologists, 2 pediatric infectious disease specialists, and 1 pediatric critical care physician. Preliminary statements addressing clinical questions related to MIS-C and hyperinflammation in COVID-19 were developed based on evidence reports. Consensus was built through a modified Delphi process that involved 2 rounds of anonymous voting and 2 webinars. A 9-point scale was used to determine the appropriateness of each statement (median scores of 1-3 for inappropriate, 4-6 for uncertain, and 7-9 for appropriate), and consensus was rated as low, moderate, or high based on dispersion of the votes along the numeric scale. Approved guidance statements were those that were classified as appropriate with moderate or high levels of consensus, as prespecified prior to voting.ResultsThe ACR task force approved a total of 128 guidance statements addressing the management of MIS-C and hyperinflammation in pediatric COVID-19. These statements were refined into 40 final clinical guidance statements, accompanied by a flow diagram depicting the diagnostic pathway for MIS-C.ConclusionOur understanding of SARS-CoV-2-related syndromes in the pediatric population continues to evolve. The guidance provided in this "living document" reflects currently available evidence, coupled with expert opinion, and will be revised as further evidence becomes available