Exploring antidiabetic drug targets as potential disease-modifying agents in osteoarthritis

Background: Osteoarthritis is a leading cause of disability, and disease-modifying osteoarthritis drugs (DMOADs) could represent a pivotal advancement in treatment. Identifying the potential of antidiabetic medications as DMOADs could impact patient care significantly. Methods: We designed a comprehensive analysis pipeline involving two-sample Mendelian Randomization (MR) (genetic proxies for antidiabetic drug targets), summary-based MR (SMR) (for mRNA), and colocalisation (for drug-target genes) to assess their causal relationship with 12 osteoarthritis phenotypes. Summary statistics from the largest genome-wide association meta-analysis (GWAS) of osteoarthritis and gene expression data from the eQTLGen consortium were utilised. Findings: Seven out of eight major types of clinical antidiabetic medications were identified, resulting in fourteen potential drug targets. Sulfonylurea targets ABCC8/KCNJ11 were associated with increased osteoarthritis risk at any site (odds ratio (OR): 2.07, 95% confidence interval (CI): 1.50–2.84, P &lt; 3 × 10−4), while PPARG, influenced by thiazolidinediones (TZDs), was associated with decreased risk of hand (OR: 0.61, 95% CI: 0.48–0.76, P &lt; 3 × 10−4), finger (OR: 0.50, 95% CI: 0.35–0.73, P &lt; 3 × 10−4), and thumb (OR: 0.49, 95% CI: 0.34–0.71, P &lt; 3 × 10−4) osteoarthritis. Metformin and GLP1-RA, targeting GPD1 and GLP1R respectively, were associated with reduced risk of knee and finger osteoarthritis. In the SMR analyses, gene expression of KCNJ11, GANAB, ABCA1, and GSTP1, targeted by antidiabetic drugs, was significantly linked to at least one osteoarthritis phenotype and was replicated across at least two gene expression datasets. Additionally, increased KCNJ11 expression was related to decreased osteoarthritis risk and co-localised with at least one osteoarthritis phenotype. Interpretation: Our findings suggest a potential therapeutic role for antidiabetic drugs in treating osteoarthritis. The results indicate that certain antidiabetic drug targets may modify disease progression, with implications for developing targeted DMOADs. </p

Clinical Practice Guideline for Systemic Antifungal Prophylaxis in Pediatric Patients With Cancer and Hematopoietic Stem-Cell Transplantation Recipients

PURPOSE: To develop a clinical practice guideline for systemic antifungal prophylaxis in pediatric patients with cancer and hematopoietic stem-cell transplantation (HSCT) recipients. METHODS: Recommendations were developed by an international multidisciplinary panel that included a patient advocate. We conducted a systematic review of systemic antifungal prophylaxis in children and adults with cancer and HSCT recipients. The Grading of Recommendations Assessment, Development, and Evaluation approach was used to make strong or weak recommendations and to classify level of evidence as high, moderate, low, or very low. The panel considered directness of the data to pediatric patients. RESULTS: There were 68 randomized trials included in the systematic review, of which 6 (9%) were conducted in a solely pediatric population. Strong recommendations were made to administer systemic antifungal prophylaxis to children and adolescents receiving treatment of acute myeloid leukemia, to those undergoing allogeneic HSCT pre-engraftment, and to those receiving systemic immunosuppression for graft-versus-host disease treatment. A strong recommendation was made to administer a mold-active agent with an echinocandin or a mold-active azole when systemic antifungal prophylaxis is warranted. For children younger than 13 years of age, an echinocandin, voriconazole, or itraconazole is suggested. Posaconazole may also be used in those age 13 years or older. A strong recommendation against routine administration of amphotericin as systemic antifungal prophylaxis was made. CONCLUSION: We developed a clinical practice guideline for systemic antifungal prophylaxis administration in pediatric patients with cancer and HSCT recipients. Implementation and assessment of guideline-concordant rates and impacts are important future steps

The osteoarthritis prevention study (TOPS) - A randomized controlled trial of diet and exercise to prevent Knee Osteoarthritis:Design and rationale

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.</p

MedShapeNet -- A Large-Scale Dataset of 3D Medical Shapes for Computer Vision

Prior to the deep learning era, shape was commonly used to describe the objects. Nowadays, state-of-the-art (SOTA) algorithms in medical imaging are predominantly diverging from computer vision, where voxel grids, meshes, point clouds, and implicit surface models are used. This is seen from numerous shape-related publications in premier vision conferences as well as the growing popularity of ShapeNet (about 51,300 models) and Princeton ModelNet (127,915 models). For the medical domain, we present a large collection of anatomical shapes (e.g., bones, organs, vessels) and 3D models of surgical instrument, called MedShapeNet, created to facilitate the translation of data-driven vision algorithms to medical applications and to adapt SOTA vision algorithms to medical problems. As a unique feature, we directly model the majority of shapes on the imaging data of real patients. As of today, MedShapeNet includes 23 dataset with more than 100,000 shapes that are paired with annotations (ground truth). Our data is freely accessible via a web interface and a Python application programming interface (API) and can be used for discriminative, reconstructive, and variational benchmarks as well as various applications in virtual, augmented, or mixed reality, and 3D printing. Exemplary, we present use cases in the fields of classification of brain tumors, facial and skull reconstructions, multi-class anatomy completion, education, and 3D printing. In future, we will extend the data and improve the interfaces. The project pages are: https://medshapenet.ikim.nrw/ and https://github.com/Jianningli/medshapenet-feedbackComment: 16 page

Adherence to core treatments in osteoarthritis

Osteoarthritis (OA) is a prevalent and disabling joint condition. Despite numerous treatments for OA, the clinical benefits of core treatments such as exercise remain modest. Adherence (the extent to which treatments have been completed as prescribed) is an important factor influencing outcomes in OA. However, understanding of adherence remains poor. This thesis aims to investigate adherence to core treatments for OA. Chapter One provides a background of OA and presents a narrative review of adherence. Chapter Two presents a systematic review of adherence measures of core treatments in knee OA. Chapter Three investigates the relationship between adherence, pain, and function in thumb base OA participants. Those with higher baseline pain were more likely to be adherent to a home management program. Chapter Four investigates predictors of adherence to a step count intervention following total knee replacement (TKR). Younger age, higher patient activation, and higher technology self-efficacy were associated with higher adherence. Chapter Five investigates the correlation between self-reported and objective adherence measurements of step count following TKR. One-third of participants underestimated their step count adherence when comparing self-reported to objective measures. Chapter Six examined the presence of different trajectories of step count adherence following TKR using latent class analyses. Three distinct trajectories were identified. Baseline BMI and pain levels differed between groups. Taken together, the findings of this thesis provide greater insight into adherence in OA. The results of this work may be used to 1) make recommendations for reporting adherence in clinical practice and research; 2) identify those at risk of low adherence; 3) support the use of objective measures of adherence, and the need for valid and reliable tools of adherence measurement; 4) better understand how adherence varies between individuals and how to best support them

Does weather affect daily pain intensity levels in patients with acute low back pain? A prospective cohort study

The aim of this study was to investigate the influence of various weather parameters on pain intensity levels in patients with acute low back pain (LBP). We performed a secondary analysis using data from the PACE trial that evaluated paracetamol (acetaminophen) in the treatment of acute LBP. Data on 1604 patients with LBP were included in the analysis. Weather parameters (precipitation, temperature, relative humidity, and air pressure) were obtained from the Australian Bureau of Meteorology. Pain intensity was assessed daily on a 0–10 numerical pain rating scale over a 2-week period. A generalised estimating equation analysis was used to examine the relationship between daily pain intensity levels and weather in three different time epochs (current day, previous day, and change between previous and current days). A second model was adjusted for important back pain prognostic factors. The analysis did not show any association between weather and pain intensity levels in patients with acute LBP in each of the time epochs. There was no change in strength of association after the model was adjusted for prognostic factors. Contrary to common belief, the results demonstrated that the weather parameters of precipitation, temperature, relative humidity, and air pressure did not influence the intensity of pain reported by patients during an episode of acute LBP.6 page(s

Use of online information in musculoskeletal conditions - an analysis of Google Trends data

Background: The use of online searches to provide disease information appears to be proliferating, but we have little knowledge of its use or content for musculoskeletal conditions.Aims: We aimed to investigate the yearly online public interest for gout, low back pain, neck pain, osteoarthritis, and rheumatoid arthritis.Methods: We analysed data on global online searches in Google Trends for the above-mentioned conditions, between 2004 and 2020. The search volumes for each condition (relative to all searches conducted worldwide in that period), the top related queries, and topics were downloaded and summarised. The Annual Percent Change (APC) of the online interest for each condition was calculated. The topics and queries related to each condition were classified using thematic approach analysis and annual change in interest for each theme was calculated.Results: There was a rise in the relative volume of online searches for low back pain (APC 7.4; 95% CI 7.1-7.7), neck pain (APC 7.2; 95%CI 6.9-7.5), gout (APC 4.2; 95%CI 3.3-5.0), osteoarthritis (APC 4.0; 95%CI 3.5-4.5), and rheumatoid arthritis (APC 2.5; 95%CI 2.2-2.9) between 2008 and 2020. The interest for the cause and symptoms of all conditions, except gout, significantly increased over time, whilst the interest in topics related to treatment decreased. There seemed to be no interest in the prevention of the conditions.Conclusions: The global online interest in musculoskeletal conditions increased between 2008 and 2020. We observed an increase in interest for causes and symptoms of musculoskeletal conditions, but very limited interest in their treatment and prevention

Efficacy of combined conservative therapies on clinical outcomes in patients with thumb base osteoarthritis: protocol for a randomised, controlled trial (COMBO)

Management of thumb base osteoarthritis (OA) using a combination of therapies is common in clinical practice; however, evidence for the efficacy of this approach is lacking. The aim of this study is to determine the effect of a combination of conservative therapies for the treatment of thumb base OA compared with an education control group.This is a randomised, controlled, single-centre, two-arm superiority trial with 1:1 allocation ratio; with assessor and statistician blinded. Participants are blinded to the trial's hypothesis and to the interventions received by the opposite group. A total of 204 participants will be recruited from the community and randomised using a computer-generated schedule. The intervention group will receive education for joint protection and OA, a splint for the base of the thumb, hand exercises and topical diclofenac sodium 1% gel over 6 weeks. The control group will receive education for joint protection and OA alone. Main inclusion criteria are pain ≥40 mm (Visual Analogue Scale, 0-100) at the base of the thumb, impairment in hand function ≥6 (Functional Index for Hand Osteoarthritis, 0-30) and radiographic thumb base OA (Kellgren Lawrence grade ≥2). Participants currently receiving any of the intervention components will be excluded. Outcomes will be measured at 2, 6 and 12 weeks. The primary outcome is change in pain and hand function from baseline to 6 weeks. Other outcomes include changes in grip and pinch strength, quality of life, presence of joint swelling and tenderness, duration of joint stiffness, patient's global assessment and use of rescue medication. Analysis will be performed according to the intention-to-treat principle. Adverse events will be monitored throughout the study.This protocol is approved by the local ethics committee (HREC/15/HAWKE/479). Dissemination will occur through presentations at international conferences and publication in peer-reviewed journals.ACTRN12616000353493; Pre-results