Biomechanical regulation of articular cartilage metabolism of proteoglycan 4 and articular surface integrity

Articular cartilage provides a low-friction, load bearing surface that allows the bones of diarthrodial joints to slide smoothly against each other, with the zonal variations in cartilage matrix structure imparting different functions to each zone. The ability of mechanical stimuli to regulate chondrocyte production of matrix molecules involved in load-bearing has been well documented. Recently it has been suggested that chondrocyte metabolism of specialized molecules secreted by the superficial zone, such as proteoglycan 4, that mediate the lubrication function of the articular surface, may also depend on biomechanical cues. The overall motivation of this dissertation was to contribute to the understanding of the role of biomechanical stimulation in maintaining boundary lubrication of the articular surface by investigating the effects of various loading protocols in vitro (explanted cartilage disks), ex vivo (intact cartilage during whole-joint culture), and in vivo, on PRG4 metabolism and articular surface integrity. In vitro studies demonstrated that static and dynamic compression and dynamic shear stimulation regulate PRG4 biosynthesis, both during loading and after unloading. Similarly, continuous rehabilitative motion applied to whole joints during culture stimulated PRG4 biosynthesis, in a manner dependent on region within the joint, as different regions experienced different loading environments. Marked site- associated variation in cartilage surface integrity was also shown to exist in vivo, likely due to variation in biomechanical environments with joint region. Finally, it was shown that PRG4 molecules can be removed from and re- attached to the articular cartilage surface, which suggests a mechanism by which secreted PRG4 molecules might maintain lubrication function. Elucidating the role of mechanical stimuli, both in vitro and in vivo, in regulating cartilage metabolism of PRG4 and articular surface integrity could lead to an understanding of the processes involved in joint health and degeneration, and possible techniques for tissue-engineering of cartilage tissue with a functional surface laye

Risk of COVID-19 after natural infection or vaccinationResearch in context

Background: While vaccines have established utility against COVID-19, phase 3 efficacy studies have generally not comprehensively evaluated protection provided by previous infection or hybrid immunity (previous infection plus vaccination). Individual patient data from US government-supported harmonized vaccine trials provide an unprecedented sample population to address this issue. We characterized the protective efficacy of previous SARS-CoV-2 infection and hybrid immunity against COVID-19 early in the pandemic over three-to six-month follow-up and compared with vaccine-associated protection. Methods: In this post-hoc cross-protocol analysis of the Moderna, AstraZeneca, Janssen, and Novavax COVID-19 vaccine clinical trials, we allocated participants into four groups based on previous-infection status at enrolment and treatment: no previous infection/placebo; previous infection/placebo; no previous infection/vaccine; and previous infection/vaccine. The main outcome was RT-PCR-confirmed COVID-19 >7–15 days (per original protocols) after final study injection. We calculated crude and adjusted efficacy measures. Findings: Previous infection/placebo participants had a 92% decreased risk of future COVID-19 compared to no previous infection/placebo participants (overall hazard ratio [HR] ratio: 0.08; 95% CI: 0.05–0.13). Among single-dose Janssen participants, hybrid immunity conferred greater protection than vaccine alone (HR: 0.03; 95% CI: 0.01–0.10). Too few infections were observed to draw statistical inferences comparing hybrid immunity to vaccine alone for other trials. Vaccination, previous infection, and hybrid immunity all provided near-complete protection against severe disease. Interpretation: Previous infection, any hybrid immunity, and two-dose vaccination all provided substantial protection against symptomatic and severe COVID-19 through the early Delta period. Thus, as a surrogate for natural infection, vaccination remains the safest approach to protection. Funding: National Institutes of Health

Risk of COVID-19 after natural infection or vaccinationResearch in context

Summary: Background: While vaccines have established utility against COVID-19, phase 3 efficacy studies have generally not comprehensively evaluated protection provided by previous infection or hybrid immunity (previous infection plus vaccination). Individual patient data from US government-supported harmonized vaccine trials provide an unprecedented sample population to address this issue. We characterized the protective efficacy of previous SARS-CoV-2 infection and hybrid immunity against COVID-19 early in the pandemic over three-to six-month follow-up and compared with vaccine-associated protection. Methods: In this post-hoc cross-protocol analysis of the Moderna, AstraZeneca, Janssen, and Novavax COVID-19 vaccine clinical trials, we allocated participants into four groups based on previous-infection status at enrolment and treatment: no previous infection/placebo; previous infection/placebo; no previous infection/vaccine; and previous infection/vaccine. The main outcome was RT-PCR-confirmed COVID-19 >7–15 days (per original protocols) after final study injection. We calculated crude and adjusted efficacy measures. Findings: Previous infection/placebo participants had a 92% decreased risk of future COVID-19 compared to no previous infection/placebo participants (overall hazard ratio [HR] ratio: 0.08; 95% CI: 0.05–0.13). Among single-dose Janssen participants, hybrid immunity conferred greater protection than vaccine alone (HR: 0.03; 95% CI: 0.01–0.10). Too few infections were observed to draw statistical inferences comparing hybrid immunity to vaccine alone for other trials. Vaccination, previous infection, and hybrid immunity all provided near-complete protection against severe disease. Interpretation: Previous infection, any hybrid immunity, and two-dose vaccination all provided substantial protection against symptomatic and severe COVID-19 through the early Delta period. Thus, as a surrogate for natural infection, vaccination remains the safest approach to protection. Funding: National Institutes of Health