Search

Background: Osteoarthritis (OA), the leading cause of disability among adults, has no cure and is associated with significant comorbidities. The premise of this randomized clinical trial is that, in a population at risk, a 48-month program of dietary weight loss and exercise will result in less incident structural knee OA compared to control. Methods/design: The Osteoarthritis Prevention Study (TOPS) is a Phase III, assessor-blinded, 48-month, parallel 2 arm, multicenter randomized clinical trial designed to reduce the incidence of structural knee OA. The study objective is to assess the effects of a dietary weight loss, exercise, and weight-loss maintenance program in preventing the development of structural knee OA in females at risk for the disease. TOPS will recruit 1230 ambulatory, community dwelling females with obesity (Body Mass Index (BMI) ​≥ ​30 ​kg/m2) and aged ≥50 years with no radiographic (Kellgren-Lawrence grade ≤1) and no magnetic resonance imaging (MRI) evidence of OA in the eligible knee, with no or infrequent knee pain. Incident structural knee OA (defined as tibiofemoral and/or patellofemoral OA on MRI) assessed at 48-months from intervention initiation using the MRI Osteoarthritis Knee Score (MOAKS) is the primary outcome. Secondary outcomes include knee pain, 6-min walk distance, health-related quality of life, knee joint loading during gait, inflammatory biomarkers, and self-efficacy. Cost effectiveness and budgetary impact analyses will determine the value and affordability of this intervention. Discussion: This study will assess the efficacy and cost effectiveness of a dietary weight loss, exercise, and weight-loss maintenance program designed to reduce incident knee OA. Trial registration: ClinicalTrials.gov Identifier: NCT05946044.

Background: For patients with acute myocardial infarction (AMI), direct coronary angiography (CA) is recommended, while for non-AMI patients, the diagnostic work-up depends on clinical criteria. This analysis provides initial prospective German data for the degree of guideline-adherence (GL) in the use of CA on non-AMI patients presenting at the emergency department (ED) with suspected acute coronary syndrome (ACS) according to the 2015 ESC-ACS-GL. Furthermore the implications of the application of the 2020 ESC-ACS-GL recommendations were evaluated. Methods: Patient symptoms were identified using a standardized questionnaire; medical history and diagnostic work-up were acquired from health records. In accordance with the 2015 ESC-ACS-GL, CA was considered GL-adherent if intermediate risk criteria (IRC) were present or non-invasive, image-guided testing (NIGT) was pathological. Results: Between January 2019 and August 2021, 229 patients were recruited across seven centers. Patients presented with chest pain, dyspnea, and other symptoms in 66.7%, 16.2% and 17.1%, respectively, were in mean 66.3 ± 10.5 years old, and 36.3% were female. In accordance with the 2015 ESC-ACS-GL, the use of CA was GL-adherent for 64.0% of the patients. GL-adherent compared to non-adherent use of CA resulted in revascularization more often (44.5% vs. 17.1%, p

Objective: To assess the value of a morphine Patient Controlled Intravenous Analgesia (PCIA) after Tonsillectomies (TE). Methods: 30 adult patients were treated with oral analgesics (protocol group) and compared to 30 patients treated with a morphine PCIA for the first 3 Postoperative Days (PODs) after TE. Average and maximum pain severities (Numeric Rating Scale – NRS: 0–10) on PODs 1–3, analgesic score, quality of life, patient satisfaction and side effects were defined as outcome measures. Results: Average pain severities of the protocol and the PCIA group were of similar magnitude (NRS) (POD1: 4.48 vs. 4.71 [p = 0.68], POD2: 4.75 vs. 4.22 [p = 0.32] and POD3: 4.44 vs. 4.25 [p = 0.71]). Maximum pain intensities on POD1 (p = 0.92), POD2 (p = 0.51) and POD3 (p = 0.36) were also comparable between both groups. Patients with a PCIA consumed significantly more opioids (p = 0.001) without significant more side-effects. Conclusion: The PCIA did not provide a superior pain control compared to oral analgesics. In view of the considerable effort and the high opioid consumption, it cannot be recommended as a standardized application for pain control after TE.

Background: With 900′000 coronary angiographies (CA) per year, Germany has the highest annual per capita volume in Europe. Until now there are no prospective clinical data on the degree of guideline-adherence in the use of CA in patients with suspected chronic coronary syndrome (CCS) in Germany. Methods: Between January 2019 and August 2021, 458 patients with suspected CCS were recruited in nine German centres. Guideline-adherence was evaluated according to the current European Society of Cardiology and German guidelines. Pre-test probability (PTP) for CAD was determined using age, gender, and a standardized patient questionnaire to identify symptoms. Data on the diagnostic work-up were obtained from health records. Results: Patients were in mean 66.6 years old, male in 57.3 %, had known CAD in 48.4 % and presented with typical, atypical, non-anginal chest pain or dyspnoea in 35.7 %, 41.3 %, 23.0 % and 25.4 %, respectively. PTP according to the European guidelines was in mean 24.2 % (11.9 %-36.5 % 95 % CI). 20.9 % of the patients received guideline-recommended preceding non-invasive image guided testing. The use of CA was adherent to the European and German guideline recommendations in 20.4 % and 25.4 %, respectively. In multivariate-analysis, arterial hypertension and prior revascularization were predictors of guideline non-adherence. Conclusion: These are the first prospective clinical data which demonstrated an overall low degree of guideline-adherence in the use of CA in patients with suspected CCS in the German health care setting. To improve adherence rates, the availability of and access to non-invasive image guided testing needs to be strengthened. (German Clinical Trials Registry DRKS00015638 – Registration Date: 19.02.2019)

Objective: To examine the plasma microbiome for differences between obese individuals with and without osteoarthritis (OA) and its association with serum lipopolysaccharide (LPS). Design: Blood samples from 70 participants with body mass index (BMI) ​≥ ​30kg/m2 and age ≥55 years, with (cases) or without (controls) hand plus knee OA, were analyzed for serum LPS and composition of the plasma microbiome. The Dirichlet-multinominal recursive partitioning model (DM-RPart) was applied to microbiome compositional data to test the hypothesis that LPS levels distinguish plasma microbiome, accounting for BMI and age. Results: No significant differences in alpha diversity, or compositional differences between groups at the genus level, were seen between cases and controls (p ​= ​0.11). β-Diversity was significantly associated with serum LPS levels (p ​= ​0.01). DM-RPart resulted in an optimal tree with 3 divisions: 1) based on age (split at 69 years); 2) those older than 69 were split based on BMI; 3) those with BMI

Objective: To evaluate the degree of symmetry of knee osteoarthritis (OA) structural severity and progression of participants with a mean follow-up time of 3.8 years. Design: Participants from the Genetics of Generalized Osteoarthritis (GOGO) study (n ​= ​705) were selected on the basis of radiographic evidence of OA in at least 1 knee, availability of radiographs at baseline and follow-up, and no history of prior knee injury or surgery. Incidence and progression of osteoarthritis were determined by radiographic Kellgren-Lawrence (KL) grade; compartmental OA progression was determined by change in joint space width of lateral and medial tibiofemoral compartments. Total OA progression was the sum of change in KL grade of both knees. Results: Compared with left knees, right knees had more severe KL grades at baseline (p ​= ​0.0002) and follow-up (p ​= ​0.0004), McNemar's χ2 ​= ​34.16 and 26.08, respectively; however, both knees progressed similarly (p ​= ​0.121, McNemar's χ2 ​= ​10.09). Compartmental changes were symmetric across knees: medial r ​= ​0.287, p ​= ​0.0002; lateral r ​= ​0.593, p ​= ​0.0002. Change in joint space width in the medial compartment was negatively correlated with change in the lateral compartment of the same knee (left knees: r ​= ​−0.293, p ​= ​0.021; right knees: r ​= ​−0.195, p ​= ​0.0002). Conclusions: Although right knees tended to have more severe OA at both baseline and follow-up, radiographic progression did not differ by knee and compartmental progression correlated across knees. Given this trend in generalized OA, the risk of progression for both knees should be considered, even if only one knee has radiographic OA at baseline.

Gene amplifications of PIK3CA or KRAS induce a downstream activation of the AKT-mTOR or RAF-ERK-pathways. Interactions of the active AKT pathway have been implicated in the inflammatory tumor microenvironment. Nothing is known about these interactions or prognostic power in esophageal adenocarcinoma (EAC). We retrospectively analyzed a large cohort of 685 EAC considering KRAS and PIK3CA gene amplification using fluorescence in situ hybridization (FISH) and immunohistochemistry. These results were correlated with clinical and molecular data as well as the inflammatory tumor microenvironment. Amplifications of KRAS were seen in 94 patients (17.1%), PIK3CA amplifications in 23 patients (5.0%). KRAS amplifications significantly correlated with nodal positive patients and poorer overall survival (OS) in the subgroup without neoadjuvant treatment (p = 0.004), coamplifications of Her2 (p = 0.027), and TP53 mutations (p = 0.016). PIK3CA amplifications significantly correlated with a high amount of tumor infiltrating T cells (p = 0.003) and showed a tendency to better OS (p = 0.068). A correlation with checkpoint makers (PD-L1, LAG3, VISTA, TIM3, IDO) could not be revealed. Our findings are the first to link the KRAS amplified genotype with lymphonodal positivity and poor prognosis and the PIK3CA-amplified genotype with a T cell–rich microenvironment in EAC. Future studies must show whether these two genotype subgroups can be therapeutically influenced. A dual inhibition of MEK and SHP2T could be effective in the subgroup of KRAS amplified EACs and an immune checkpoint blockade may prove to be particularly promising in the subgroup of PIK3CA-amplified EACs.

Up to 40% of esophageal carcinomas have a biallelic intact TP53 gene. It is largely unclear how these carcinoma cells prevent apoptosis, what is the kind of pathway alterations, or whether therapeutically relevant alterations exist in this subgroup. We evaluated The Cancer Genome Atlas (TCGA) data to compare TP53-mutated with TP53–wild-type tumors regarding copy number variations, gene mutations, and expression patterns of protein-coding genes and miRNAs. Additionally, we analyzed up to 428 esophageal adenocarcinomas (EACs) in total using an ultra-deep parallel sequencing panel, immunohistochemistry, as well as fluorescence in situ hybridization. In the TCGA cohort, 17.3% has a biallelic intact TP53 gene. This group has a smaller average total size of somatic copy number variations. Some protein coding genes and miRNAs were differentially expressed between the TP53-wild-type and TP53-mutated group to emphasize mdm2, CCND2, TP73, or miRNA 150, 488, or 4662a. In addition, 50% of the TP53–wild-type tumors carry somatic mutations in at least one of the genes involved in the TP53 pathway. Our patient cohort revealed 41.3% TP53–wild-type tumors; 5.6% were MDM2 amplified. In accordance with the TCGA data, we did not find a prognostic relevance of TP53 in our tumor cohort as well. The mutation status of TP53 defines an important subtype in esophageal carcinoma. Our comprehensive molecular analysis revealed important and potentially therapeutically relevant genomic alterations in this subgroup.

Objective: In previous studies, we determined an association between increased serum and articular cartilage levels of CCL2 with osteoarthritis (OA) progression, cartilage damage and increased MMP13 in cartilage. Here we analyzed CCL2 downstream signaling mediators that lead to gene expression of cartilage catabolic markers, in healthy and OA human articular chondrocytes. Design: Human articular chondrocytes obtained from healthy or OA subjects were treated with or without recombinant human CCL2; cell lysates or mRNA were collected for immunoblotting or qRT-PCR. For pathway analysis, chondrocytes were pre-incubated with an inhibitor of CCR2 (the unique CCL2 receptor), ERK inhibitor or p38 inhibitor prior to CCL2 treatment. Results: CCL2 treatment of both healthy and OA chondrocytes activated ERK and p38 via CCR2. In healthy chondrocytes, short (6h) and prolonged (24–72h) CCL2 treatments led to Ccr2, Mmp-1, Mmp-3, Mmp-13 and Timp1 upregulation. In OA chondrocytes, CCL2 induced expression of Ccr2, Mmp-1 and Mmp-3, but not Mmp1 and Timp1, and only following longer treatments (72h). In both healthy and OA chondrocytes, the CCL2-mediated upregulation of Ccr2 and cartilage catabolic markers was mediated by ERK and p38 signaling. Conclusions: The triggering of the CCL2/CCR2 axis in articular chondrocytes activates specific MAPK pathways leading to gene expression of cartilage degrading enzymes. However, some differences in the response to CCL2 stimulation are detected in healthy vs OA chondrocytes with respect to the number of activated genes and to the time of exposure to CCL2, suggesting that CCL2 action in articular cartilage may be dependent on OA stage and severity.

Summary: Objective: While a role for vitamin K in maintaining joint tissue homeostasis has been proposed based on the presence of vitamin K dependent proteins in cartilage and bone, it is not clear if low vitamin K intake is causally linked to joint tissue degeneration. To address this gap, we manipulated vitamin K status in aging mice to test its effect on age-related changes in articular cartilage and sub-chondral bone. Methods: Eleven-month old male C57BL6 mice were randomly assigned to a low vitamin K diet containing 120 mcg phylloquinone/kg diet (n = 32) or a control diet containing 1.5 mg phylloquinone/kg diet (n = 30) for 6 months. Knees were evaluated histologically using Safranin O and H&E staining, as well as using micro-CT. Results: Eleven mice in the low vitamin K diet group and three mice in the control group died within the first 100 days of the experiment (p = 0.024). Mice fed the low vitamin K diet had higher Safranin-O scores, indicative of more proteoglycan loss, compared to mice fed the control diet (p ≤ 0.026). The articular cartilage structure scores did not differ between the two groups (p ≥ 0.190). The sub-chondral bone parameters measured using micro CT also did not differ between the two groups (all p ≥ 0.174). Conclusion: Our findings suggest low vitamin K status can promote joint tissue proteoglycan loss in older male mice. Future studies are needed to confirm our findings and obtain a better understanding of the molecular mechanisms underlying the role of vitamin K in joint tissue homeostasis.

Summary: Objective: To stimulate future research directions that seek solutions for osteoarthritis (OA) at the interface between diverse disciplines and address osteoarthritis (OA) as a serious disease with a complexity that has presented a barrier to finding safe effective solutions. Methods: Sessions were conducted at the 2019 meetings of the Orthopaedic Research Society (ORS) and Osteoarthritis Research Society International (OARSI) that included presentations and questions/comments submitted from leading OA researchers representing imaging, mechanics, biomarkers, phenotyping, clinical, epidemiology, inflammation and exercise. Results: Solutions for OA require a paradigm shift in research and clinical methods in which OA is contextualized as a complex whole-body/person disease. New OA definition(s)/phenotype(s) and OA markers/signals are needed to address the interplay between genetic and environmental factors of the disease as well as capture the mechanosensitivity of the disease. The term “Mechanokines” was proposed to highlight the importance of incorporating whole body mechanics as a marker of early OA. New interventions and apparent paradoxical observations/questions (e.g. exercise vs. load modification) were also discussed in the context of considering OA as a complex system. Conclusion: To advance new OA treatments that are safe and effective, OA should be considered as a “Whole Person” disease. This approach requires a concerted effort to bridge disciplines and include interactions across scales from the molecule to the whole body, including psychosocial aspects.

Management of domesticated ungulates on grasslands has the potential to affect ecosystem function at landscape to global scales. In the southwestern United States, introduction of livestock in the 1800s corresponded with grassland degradation and dramatic shifts in vegetation, including the rapid spread of invasive plant species. In contemporary grasslands, however, evidence increasingly suggests that responsible grazing may enhance plant diversity in the region, though positive effects on diversity may or may not offer corresponding benefits to ecosystem function. Here, we examined the effects of grazing on land cover and functional composition of a semiarid grassland over a 20-year period. We found that high intensity grazing increased exposed soil and shifted community composition toward a greater proportion of annual and exotic species. This was particularly apparent following a severe drought event that initiated a significant loss of perennial plant cover, especially forbs, and was followed by a nearly 4-fold expansion of exotic species. Plots that were grazed at moderate levels consistently exhibited the lowest proportion of exotic species and were similar in functional group composition to exclosure plots. However, moderate grazing did increase soil exposure relative to exclosure plots. These findings suggest that moderate grazing could provide benefits to grassland ecosystem diversity and correlated ecosystem services like invasive species control and pollination services, while simultaneously increasing erosion, reducing water infiltration and altering nutrient cycling, due to increased soil exposure and disturbance. The potential for grazing to exert antagonistic effects on ecosystem services, depending on site conditions and grazing intensity, suggests that livestock management decisions should be tailored to individual management and conservation goals that address the inherent spatiotemporal variability of arid grasslands. Keywords: Plant functional groups, Climate change, Southwestern United States, Exotic species, Ecosystem services, Livestock management