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Emerging evidence indicates periostin (POSTN) is upregulated in patients with OA, and studies have shown that it can induce the activation of inflammatory cytokines and catabolic enzymes, making it a potential therapeutic target. Link N (LN) is a peptide fragment derived from the link protein and has been demonstrated as an anabolic-like factor and anti-catabolic and anti-inflammatory factors both in vitro and in vivo. This study aims to determine if LN can regulate POSTN expression and function in OA cartilage. Articular cartilage was recovered from donors undergoing total knee replacements to isolate chondrocytes and prepare osteochondral explants. Cells and explants were treated with POSTN and LN (1 and 100 μg) and measured for changes in POSTN expression and various matrix proteins, catabolic and proinflammatory factors, and signaling. To determine the effects of POSTN expression in vivo, a rabbit OA model was used. Immunoprecipitation and in silico modeling were used to determine peptide/POSTN interactions. Western blotting, PCR, and immunohistochemistry demonstrated that LN decreased POSTN expression both in vitro and in vivo. LN was also able to directly inhibit POSTN signaling in OA chondrocytes. In silico docking suggested the direct interaction of LN with POSTN at residues responsible for its oligomerization. Immunoprecipitation experiments confirmed the direct interaction of LN with POSTN and the destabilization of its oligomerization. This study demonstrates the ability of a peptide, LN, to suppress the overexpression and function of POSTN in OA cartilage.

Intervertebral disc degeneration and pain are associated with the nucleotide-binding domain, leucine-rich repeat, and pyrin domain-containing 3 (NLRP3) inflammasome activation and the processing of interleukin-1 beta (IL-1β). Activation of thehm inflammasome is triggered by Toll-like receptor stimulation and requires the cofactor receptor cluster of differentiation 14 (CD14). Short Link N (sLN), a peptide derived from link protein, has been shown to modulate inflammation and pain in discs in vitro and in vivo; however, the underlying mechanisms remain elusive. This study aims to assess whether sLN modulates IL-1β and inflammasome activity through interaction with CD14. Disc cells treated with lipopolysaccharides (LPS) with or without sLN were used to assess changes in Caspase-1, IL-1β, and phosphorylated nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB). Peptide docking of sLN to CD14 and immunoprecipitation were performed to determine their interaction. The results indicated that sLN inhibited LPS-induced NFκB and Caspase-1 activation, reducing IL-1β maturation and secretion in disc cells. A significant decrease in inflammasome markers was observed with sLN treatment. Immunoprecipitation studies revealed a direct interaction between sLN and the LPS-binding pocket of CD14. Our results suggest that sLN could be a potential therapeutic agent for discogenic pain by mitigating IL-1β and inflammasome activity within discs.

The Coronavirus disease 2019 (COVID-19) outbreak impacted health care. We investigated its impact on the time to referral and diagnosis for symptomatic cancer patients in The Netherlands. We performed a national retrospective cohort study utilizing primary care records linked to The Netherlands Cancer Registry. For patients with symptomatic colorectal, lung, breast, or melanoma cancer, we manually explored free and coded texts to determine the durations of the primary care (IPC) and secondary care (ISC) diagnostic intervals during the first COVID-19 wave and pre-COVID-19. We found that the median IPC duration increased for colorectal cancer from 5 days (Interquartile Range (IQR) 1-29 days) pre-COVID-19 to 44 days (IQR 6-230, p < 0.01) during the first COVID-19 wave, and for lung cancer, the duration increased from 15 days (IQR) 3-47) to 41 days (IQR 7-102, p < 0.01). For breast cancer and melanoma, the change in IPC duration was negligible. The median ISC duration only increased for breast cancer, from 3 (IQR 2-7) to 6 days (IQR 3-9, p < 0.01). For colorectal cancer, lung cancer, and melanoma, the median ISC durations were 17.5 (IQR (9-52), 18 (IQR 7-40), and 9 (IQR 3-44) days, respectively, similar to pre-COVID-19 results. In conclusion, for colorectal and lung cancer, the time to primary care referral was substantially prolonged during the first COVID-19 wave. In such crises, targeted primary care support is needed to maintain effective cancer diagnosis.

Introduction: In the Netherlands, the onset of the coronavirus pandemic saw shifts in primary health service provision away from physical consultations, cancer-screening programs were temporarily halted, and government messaging focused on remaining at home. In March and April 2020, weekly cancer diagnoses decreased to 73% of their pre-COVID levels, and 39% for skin cancer. This study aims to explore the effect of the COVID pandemic on patient presentations for cancer-related symptoms in primary care in The Netherlands. Methods: Retrospective cohort study using routine clinical primary care data. Monthly incidences of patient presentations for cancer-related symptoms in five clinical databases in The Netherlands were analysed from March 2018 to February 2021. Results: Data demonstrated reductions in the incidence of cancer-related symptom presentations to primary care during the first COVID wave (March-June 2020) of -34% (95% CI: -43 to -23%) for all symptoms combined. In the second wave (October 2020-February 2021) there was no change in incidence observed (-8%, 95% CI -20% to 6%). Alarm-symptoms demonstrated decreases in incidence in the first wave with subsequent incidences that continued to rise in the second wave, such as: first wave: breast lump -17% (95% CI: -27 to -6%) and haematuria -15% (95% CI -24% to -6%); and second wave: rectal bleeding +14% (95% CI: 0 to 30%) and breast lump +14% (95% CI: 2 to 27%). Presentations of common non-alarm symptom such as tiredness and naevus demonstrated decreased in-cidences in the first wave of 45% (95% CI: -55% to -33%) and 37% (95% CI -47% to -25%). In the second wave, tiredness incidence was reduced by 20% (95% CI: -33% to -3%). Subgroup analy-sis did not demonstrate difference in incidence according to sex, age groups, comorbidity status, or previous history of cancer. Conclusions: These data describe large-scale primary care avoidance that did not increase until the end of the first COVID year for many cancer-related symptoms, suggestive that substantial numbers of patients delayed presenting to primary care. For those patients who had underlying cancer, this may have had impacted the cancer stage at diagnosis, treatment, and mortality.

This study evaluated the efficacy of an integrated Total Worker Health ® program, "All the Right Moves", designed to target the conditions of work and workers' health behaviors through an ergonomics program combined with a worksite-based health promotion Health Week intervention. A matched-pair cluster randomized controlled trial was conducted on ten worksites (five intervention ( n = 324); five control sites ( n = 283)). Worker surveys were collected at all sites pre- and post- exposure at one- and six-months. Linear and logistic regression models evaluated the effect of the intervention on pain and injury, dietary and physical activity behaviors, smoking, ergonomic practices, and work limitations. Worker focus groups and manager interviews supplemented the evaluation. After controlling for matched intervention and control pairs as well as covariates, at one-month following the ergonomics program we observed a significant improvement in ergonomic practices (B = 0.20, p = 0.002), and a reduction in incidences of pain and injury (OR = 0.58, p = 0.012) in the intervention group. At six months, we observed differences in favor of the intervention group for a reduction in physically demanding work (B = -0.25, p = 0.008), increased recreational physical activity (B = 35.2, p = 0.026) and higher consumption of fruits and vegetables (B = 0.87, p = 0.008). Process evaluation revealed barriers to intervention implementation fidelity and uptake, including a fissured multiemployer worksite, the itinerant nature of workers, competing production pressures, management support, and inclement weather. The All the Right Moves program had a positive impact at the individual level on the worksites with the program. For the longer term, the multi-organizational structure in the construction work environment needs to be considered to facilitate more upstream, long-term changes.