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Additional file 1: Table S1. Read codes used for covid-19 vaccination records and diagnosed SARS-CoV-2 infection. Figure S1. A directed acyclic graph of the comparative effectiveness of BNT162b2 and ChAdOx1 nCoV-19 vaccines against COVID-19 and potential confounders.

BACKGROUND: Findings of observational studies investigating the impact of transfusions are at odds with those of randomised controlled trials, raising concern that observational studies may be inappropriate to inform transfusion decisions. We examined whether observational data could replicate evidence from randomised controlled trials on restrictive transfusion in cardiac and orthopaedic surgery, and be generalised to broader specialties as well as to a lower haemoglobin transfusion threshold (7 g/dL). MATERIAL AND METHODS: A multicentre, prospective cohort study was performed at three representative regional hospitals in China between 2015 and 2016. Participants were surgical inpatients (≥18 years; hospital stay ≥24 h) in six specialties: cardiac, cerebral, vascular (CCV), and orthopaedic, general, thoracic (non-CCV). Patients with a stable haemoglobin (7–10 g/dL) constituted the primary analytic sample, while patients with ≥500 mL intra-operative bleeding were analysed separately to avoid haemoglobin instability. The association of transfusion with surgical outcomes (death, in-hospital complications) was evaluated. RESULTS: The transfusion rate was 10.7% in 36,607 patients (mean age, 52.5±14.3 years; 52.3% female). After restriction, stratification, and propensity score matching to reduce patients’ heterogeneity, transfusion was unrelated to death (CCV: odds ratio [OR]=0.74, 95% confidence interval [CI]: 0.16–3.39; non-CCV: OR 0.83, 95% CI: 0.36–1.94) and the composite complication (CCV: OR 1.31, 95% CI: 0.63–2.72; non-CCV: OR=1.24, 95% CI: 0.81–1.90). The results were consistent in subgroups (elderly, coronary heart disease, malignant tumour, severe illness) and applicable to patients with significant bleeding after restoration of a stable haemoglobin. DISCUSSION: Transfusion at a stable haemoglobin concentration of 7–10 g/dL did not alter surgical outcomes. Our results show the feasibility of observational data to expand restrictive transfusion to broader specialties and a lower transfusion threshold in surgical practice.

Additional file 2: Supplemental Figure 2. Sox9, Col2a1, Acan and Mmp-13 genes expression. Mouse chondrocytes were cultured under different magnesium conditions (0.7mM, 0,4mM and 0.1mM) with or without treatment of Rapa. Sox9, Col2a1, Acan and Mmp-13 genes expression were assessed by qRT-PCR (n = 5). Hprt1 was used as housekeeping gene. Data were expressed as the mean ± SD and analyzed by one-way ANOVA test. (*P

Additional file 5: Supplemental Figure 5. Catenin, Wnt3a, Wnt5a, Wnt5b and Wnt16 genes expression. Mouse chondrocytes were cultured under different magnesium conditions (0.7mM, 0,4mM and 0.1mM). mRNA levels of Catenin, Wnt3a, Wnt5a, Wnt5b and Wnt16 were investigated by qRT-PCR (n = 5). Hprt1 was used as housekeeping gene. Data were expressed as the mean ± SD and analyzed by one-way ANOVA test. (*P

Additional file 6: Supplemental Table 1. Ct values of Wnt ligands normalized to β-actin in qRT-PCR.

Additional File 1 .

Additional file 4: Supplemental Figure 4. Immunohistochemistry analysis of Beclin-1. (A, B) Immunostaining and quantitative analysis of cells positive for Beclin-1 in sham and DMM-induced OA mice fed with diets containing different content of magnesium (500 mg/kg, 300 mg/kg, 100 mg/kg) (n = 9). Scale bar: 100 μm. Data were expressed as the mean ± SEM and analyzed by one-way ANOVA test (*P

Additional file 1: Supplemental Figure 1. Body weight of mice over time. Body weight of sham and DMM-induced OA mice fed with diets containing different content of magnesium (500 mg/kg, 300 mg/kg, 100 mg/kg) measured weekly. No statistical significance was observed between different groups at the same age.

Additional file 3: Supplemental Figure 3. Immunohistochemistry analysis of LC3-II. (A, B) Immunostaining and quantitative analysis of cells positive for LC3-II in sham and DMM-induced OA mice fed with diets containing different content of magnesium (500 mg/kg, 300 mg/kg, 100 mg/kg) (n = 9). Scale bar: 100 μm. Data were expressed as the mean ± SEM and analyzed by one-way ANOVA test (*P

Additional file 1: Supplemental Figure 1. Recruitment and enrollment of study participants in Xiangya Osteoarthritis Study (XO Study). Supplemental Figure 2. Longitudinal ultrasonographic scan of suprapatellar recess (B mode). SH, synovial hypertrophy; E, joint effusion. Supplemental Figure 3. Longitudinal ultrasonographic scan of suprapatellar recess (Power Doppler mode). Power Doppler signal (PDS) at synovial membrane was scored using a semi-quantitative grading system, from 0 to 3 (0=absent, 1=mild, 2=moderate, 3=marked or severe). (A) grade 0, (B) grade 1, (C) grade 2. We did not detected grade 3 PDS in knee joints of participants of our study. Supplemental Figure 4. Bilateral weight-bearing posterior-anterior tibio-femoral radiographs, assessed according to Kellgren and Lawrence (KL) criteria: (A) grade 0, (B) grade 1, (C) grade 2, (D) grade 3 and (E) grade 4. Supplemental Figure 5. Skyline views of patellofemoral radiographs, assessed according to Kellgren and Lawrence (KL) criteria: (A) grade 0, (B) grade 1, (C) grade 2, (D) grade 3 and (E) grade 4. Supplemental Table 1. The intra- and inter-rater reliability for ultrasound-detected synovial abnormalities and Kellgren-Lawrence grade of knee radiography. Supplemental Table 2. Prevalence of knee synovial abnormalities on ultrasound among middle-aged and elderly persons, according to age group and sex. Supplemental Table 3. Association of knee synovial abnormalities on ultrasound and knee pain. Supplemental Table 4. Association of knee synovial abnormalities on ultrasound and knee pain among people with two knees discordant for knee pain. Supplemental Table 5. Association of knee synovial abnormalities on ultrasound and knee radiographic osteoarthritis. Supplemental Table 6. Association of knee pain stratified by knee synovial abnormalities on ultrasound and radiographic osteoarthritis status among people with two knees discordant for knee pain.

Several professional organizations have recommended tramadol as one of the first-line or second-line therapies for patients with chronic noncancer pain and its prescription has been increasing rapidly worldwide; however, the safety profile of tramadol, such as risk of fracture, remains unclear. This study aimed to examine the association of tramadol with risk of hip fracture. Among individuals age 50 years or older without a history of hip fracture, cancer, or opioid use disorder in The Health Improvement Network (THIN) database in the United Kingdom general practice (2000-2017), five sequential propensity score-matched cohort studies were assembled, ie, participants who initiated tramadol or those who initiated one of the following medications: codeine (n = 146,956) (another commonly used weak opioid), naproxen (n = 115,109) or ibuprofen (n = 107,438) (commonly used nonselective nonsteroidal anti-inflammatory drugs [NSAIDs]), celecoxib (n = 43,130), or etoricoxib (n = 27,689) (cyclooxygenase-2 inhibitors). The outcome was incident hip fracture over 1 year. After propensity-score matching, the included participants had a mean age of 65.7 years and 56.9% were women. During the 1-year follow-up, 518 hip fracture (3.7/1000 person-years) occurred in the tramadol cohort and 401 (2.9/1000 person-years) occurred in the codeine cohort. Compared with codeine, hazard ratio (HR) of hip fracture for tramadol was 1.28 (95% confidence interval [CI] 1.13 to 1.46). Risk of hip fracture was also higher in the tramadol cohort than in the naproxen (2.9/1000 person-years for tramadol, 1.7/1000 person-years for naproxen; HR = 1.69, 95% CI 1.41 to 2.03), ibuprofen (3.4/1000 person-years for tramadol, 2.0/1000 person-years for ibuprofen; HR = 1.65, 95% CI 1.39 to 1.96), celecoxib (3.4/1000 person-years for tramadol, 1.8/1000 person-years for celecoxib; HR = 1.85, 95% CI 1.40 to 2.44), or etoricoxib (2.9/1000 person-years for tramadol, 1.5/1000 person-years for etoricoxib; HR = 1.96, 95% CI 1.34 to 2.87) cohort. In this population-based cohort study, the initiation of tramadol was associated with a higher risk of hip fracture than initiation of codeine and commonly used NSAIDs, suggesting a need to revisit several guidelines on tramadol use in clinical practice. © 2020 American Society for Bone and Mineral Research.