Can genetics guide exercise prescriptions in osteoarthritis?

Osteoarthritis (OA) is the most common form of arthritis and has a multifactorial etiology. Current management for OA focuses on minimizing pain and functional loss, typically involving pharmacological, physical, psychosocial, and mind-body interventions. However, there remain challenges in determining which patients will benefit most from which interventions. Although exercise-based interventions are recommended as first-line treatments and are known to be beneficial for managing both the disease and illness of OA, the optimal exercise prescription is unknown, due in part to our limited understanding of the precise mechanisms underlying its action. Here we present our perspective on the potential role of genetics in guiding exercise prescription for persons with OA. We describe key publications in the areas of exercise and OA, genetics and OA, and exercise and genetics, and point to a paucity of knowledge at the intersection of exercise, genetics, and OA. We suggest there is emerging evidence to support the use of genetics and epigenetics to explain the beneficial effects of exercise for OA. We identify missing links in the existing research relating to exercise, genetics, and OA, and highlight epigenetics as a promising mechanism through which environmental exposures such as exercise may impact OA outcomes. We anticipate future studies will improve our understanding of how genetic and epigenetic factors mediate exercise-based interventions to support implementation and ultimately improve OA patient care

Concurrent validity and reliability of a semi-automated approach to measuring the magnetic resonance imaging morphology of the knee joint in active youth

Post-traumatic knee osteoarthritis is attributed to alterations in joint morphology, alignment, and biomechanics triggered by injury. While magnetic resonance (MR) imaging-based measures of joint morphology and alignment are relevant to understanding osteoarthritis risk, time consuming manual data extraction and measurement limit the number of outcomes that can be considered and deter widespread use. This paper describes the development and evaluation of a semi-automated software for measuring tibiofemoral and patellofemoral joint architecture using MR images from youth with and without a previous sport-related knee injury. After prompting users to identify and select key anatomical landmarks, the software can calculate 37 (14 tibiofemoral, 23 patellofemoral) relevant geometric features (morphology and alignment) based on established methods. To assess validity and reliability, 11 common geometric features were calculated from the knee MR images (proton density and proton density fat saturation sequences; 1.5 T) of 76 individuals with a 3-10-year history of youth sport-related knee injury and 76 uninjured controls. Spearman's or Pearson's correlation coefficients (95% CI) and Bland-Altman plots were used to assess the concurrent validity of the semi-automated software (novice rater) versus expert manual measurements, while intra-class correlation coefficients (ICC 2,1; 95%CI), standard error of measurement (95%CI), 95% minimal detectable change, and Bland-Altman plots were used to assess the inter-rater reliability of the semi-automated software (novice vs resident radiologist rater). Correlation coefficients ranged between 0.89 (0.84, 0.92; Lateral Trochlear Inclination) and 0.97 (0.96, 0.98; Patellar Tilt Angle). ICC estimates ranged between 0.79 (0.63, 0.88; Lateral Patellar Tilt Angle) and 0.98 (0.95, 0.99; Bisect Offset). Bland-Altman plots did not reveal systematic bias. These measurement properties estimates are equal, if not better than previously reported methods suggesting that this novel semi-automated software is an accurate, reliable, and efficient alternative method for measuring large numbers of geometric features of the tibiofemoral and patellofemoral joints from MR studies. </p

Patellofemoral joint geometry and osteoarthritis features 3–10 years after knee injury compared with uninjured knees

In this cross-sectional study, we compared patellofemoral geometry in individuals with a youth-sport-related intra-articular knee injury to uninjured individuals, and the association between patellofemoral geometry and magnetic resonance imaging (MRI)-defined osteoarthritis (OA) features. In the Youth Prevention of Early OA (PrE-OA) cohort, we assessed 10 patellofemoral geometry measures in individuals 3–10 years following injury compared with uninjured individuals of similar age, sex, and sport, using mixed effects linear regression. We also dichotomized geometry to identify extreme (&gt;1.96 standard deviations) features and assessed likelihood of having extreme values using Poisson regression. Finally, we evaluated the associations between patellofemoral geometry with MRI-defined OA features using restricted cubic spline regression. Mean patellofemoral geometry did not differ substantially between groups. However, compared with uninjured individuals, injured individuals were more likely to have extremely large sulcus angle (prevalence ratio [PR] 3.9 [95% confidence interval, CI: 2.3, 6.6]), and shallow lateral trochlear inclination (PR 4.3 (1.1, 17.9)) and trochlear depth (PR 5.3 (1.6, 17.4)). In both groups, high bisect offset (PR 1.7 [1.3, 2.1]) and sulcus angle (PR 4.0 [2.3, 7.0]) were associated with cartilage lesion, and most geometry measures were associated with at least one structural feature, especially cartilage lesions and osteophytes. We observed no interaction between geometry and injury. Certain patellofemoral geometry features are correlated with higher prevalence of structural lesions compared with injury alone, 3–10 years following knee injury. Hypotheses generated in this study, once further evaluated, could contribute to identifying higher-risk individuals who may benefit from targeted treatment aimed at preventing posttraumatic OA.</p

Imaging with ultrasound in physical therapy: What is the PT’s scope of practice? A competency-based educational model and training recommendations.

Physical therapists employ ultrasound (US) imaging technology for a broad range of clinical and research purposes. Despite this, few physical therapy regulatory bodies guide the use of US imaging, and there are limited continuing education opportunities for physical therapists to become proficient in using US within their professional scope of practice. Here, we (i) outline the current status of US use by physical therapists; (ii) define and describe four broad categories of physical therapy US applications (ie, rehabilitation, diagnostic, intervention and research US); (iii) discuss how US use relates to the scope of high value physical therapy practice and (iv) propose a broad framework for a competency-based education model for training physical therapists in US. This paper only discusses US imaging— not ’therapeutic’ US. Thus, ’imaging’ is implicit anywhere the term ’ultrasound’ is used.pre-print847 K

Exploring the use of ultrasound imaging by physiotherapists: An international survey

Background: National surveys in New Zealand, Australia and the United Kingdom suggest ultrasound imaging (USI) use by physiotherapists is increasing. However, concerns exist regarding clarity for scopes of practice, and availability and standardisation of training. Objectives: To investigate physiotherapists' understanding of scopes of practice for the use of USI; clarify the professional contexts, clinical uses and levels of training; and identify barriers preventing physiotherapists' USI use. Design: A cross-sectional, observational survey. Methods: An Internet-based survey, offered in 20 different languages, was used including items covering five domains: (1) demographic and professional characteristics; (2) knowledge of scope of practice; (3) USI use; (4) USI training content and duration; and (5) perceived barriers to physiotherapists' use of USI. Results: 1307 registered physiotherapists from 49 countries responded; 30% were unsure of the scope of practice for physiotherapists' USI use. 38% of participants were users of USI, reporting varied contexts and clinical uses, reflected in the broader categories of: (i) biofeedback; (ii) diagnosis; (iii) assessment; (iv) injection guidance; (v) research; (vi) and teaching. The training users received varied, with formal training more comprehensive. 62% were non-users, the most common barrier was lack of training (76%). Conclusion: These findings suggest physiotherapists' USI use is increasing in various contexts; however, there is uncertainty regarding scopes of practice. There are discrepancies in training offered, with a lack of training the most common barrier to physiotherapists' use of USI. International guidelines, including a USI training framework, are needed to support the consistent and sustainable use of USI in physiotherapy

Toward designing human intervention studies to prevent osteoarthritis after knee injury: A report from an interdisciplinary OARSI 2023 workshop

Objective: The global impact of osteoarthritis is growing. Currently no disease modifying osteoarthritis drugs/therapies exist, increasing the need for preventative strategies. Knee injuries have a high prevalence, distinct onset, and strong independent association with post-traumatic osteoarthritis (PTOA). Numerous groups are embarking upon research that will culminate in clinical trials to assess the effect of interventions to prevent knee PTOA despite challenges and lack of consensus about trial design in this population. Our objectives were to improve awareness of knee PTOA prevention trial design and discuss state-of-the art methods to address the unique opportunities and challenges of these studies. Design: An international interdisciplinary group developed a workshop, hosted at the 2023 Osteoarthritis Research Society International Congress. Here we summarize the workshop content and outputs, with the goal of moving the field of PTOA prevention trial design forward. Results: Workshop highlights included discussions about target population (considering risk, homogeneity, and possibility of modifying osteoarthritis outcome); target treatment (considering delivery, timing, feasibility and effectiveness); comparators (usual care, placebo), and primary symptomatic outcomes considering surrogates and the importance of knee function and symptoms other than pain to this population. Conclusions: Opportunities to test multimodal PTOA prevention interventions across preclinical models and clinical trials exist. As improving symptomatic outcomes aligns with patient and regulator priorities, co-primary symptomatic (single or aggregate/multidimensional outcome considering function and symptoms beyond pain) and structural/physiological outcomes may be appropriate for these trials. To ensure PTOA prevention trials are relevant and acceptable to all stakeholders, future research should address critical knowledge gaps and challenges

Establishing outcome measures in early knee osteoarthritis

The classification and monitoring of individuals with early knee osteoarthritis (OA) are important considerations for the design and evaluation of therapeutic interventions and require the identification of appropriate outcome measures. Potential outcome domains to assess for early OA include patient-reported outcomes (such as pain, function and quality of life), features of clinical examination (such as joint line tenderness and crepitus), objective measures of physical function, levels of physical activity, features of imaging modalities (such as of magnetic resonance imaging) and biochemical markers in body fluid. Patient characteristics such as adiposity and biomechanics of the knee could also have relevance to the assessment of early OA. Importantly, research is needed to enable the selection of outcome measures that are feasible, reliable and validated in individuals at risk of knee OA or with early knee OA. In this Perspectives article, potential outcome measures for early symptomatic knee OA are discussed, including those measures that could be of use in clinical practice and/or the research setting

Population genomics of cardiometabolic traits: design of the University College London-London School of Hygiene and Tropical Medicine-Edinburgh-Bristol (UCLEB) Consortium.

Substantial advances have been made in identifying common genetic variants influencing cardiometabolic traits and disease outcomes through genome wide association studies. Nevertheless, gaps in knowledge remain and new questions have arisen regarding the population relevance, mechanisms, and applications for healthcare. Using a new high-resolution custom single nucleotide polymorphism (SNP) array (Metabochip) incorporating dense coverage of genomic regions linked to cardiometabolic disease, the University College-London School-Edinburgh-Bristol (UCLEB) consortium of highly-phenotyped population-based prospective studies, aims to: (1) fine map functionally relevant SNPs; (2) precisely estimate individual absolute and population attributable risks based on individual SNPs and their combination; (3) investigate mechanisms leading to altered risk factor profiles and CVD events; and (4) use Mendelian randomisation to undertake studies of the causal role in CVD of a range of cardiovascular biomarkers to inform public health policy and help develop new preventative therapies

HMG-coenzyme A reductase inhibition, type 2 diabetes, and bodyweight: evidence from genetic analysis and randomised trials.

BACKGROUND: Statins increase the risk of new-onset type 2 diabetes mellitus. We aimed to assess whether this increase in risk is a consequence of inhibition of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), the intended drug target. METHODS: We used single nucleotide polymorphisms in the HMGCR gene, rs17238484 (for the main analysis) and rs12916 (for a subsidiary analysis) as proxies for HMGCR inhibition by statins. We examined associations of these variants with plasma lipid, glucose, and insulin concentrations; bodyweight; waist circumference; and prevalent and incident type 2 diabetes. Study-specific effect estimates per copy of each LDL-lowering allele were pooled by meta-analysis. These findings were compared with a meta-analysis of new-onset type 2 diabetes and bodyweight change data from randomised trials of statin drugs. The effects of statins in each randomised trial were assessed using meta-analysis. FINDINGS: Data were available for up to 223 463 individuals from 43 genetic studies. Each additional rs17238484-G allele was associated with a mean 0·06 mmol/L (95% CI 0·05-0·07) lower LDL cholesterol and higher body weight (0·30 kg, 0·18-0·43), waist circumference (0·32 cm, 0·16-0·47), plasma insulin concentration (1·62%, 0·53-2·72), and plasma glucose concentration (0·23%, 0·02-0·44). The rs12916 SNP had similar effects on LDL cholesterol, bodyweight, and waist circumference. The rs17238484-G allele seemed to be associated with higher risk of type 2 diabetes (odds ratio [OR] per allele 1·02, 95% CI 1·00-1·05); the rs12916-T allele association was consistent (1·06, 1·03-1·09). In 129 170 individuals in randomised trials, statins lowered LDL cholesterol by 0·92 mmol/L (95% CI 0·18-1·67) at 1-year of follow-up, increased bodyweight by 0·24 kg (95% CI 0·10-0·38 in all trials; 0·33 kg, 95% CI 0·24-0·42 in placebo or standard care controlled trials and -0·15 kg, 95% CI -0·39 to 0·08 in intensive-dose vs moderate-dose trials) at a mean of 4·2 years (range 1·9-6·7) of follow-up, and increased the odds of new-onset type 2 diabetes (OR 1·12, 95% CI 1·06-1·18 in all trials; 1·11, 95% CI 1·03-1·20 in placebo or standard care controlled trials and 1·12, 95% CI 1·04-1·22 in intensive-dose vs moderate dose trials). INTERPRETATION: The increased risk of type 2 diabetes noted with statins is at least partially explained by HMGCR inhibition. FUNDING: The funding sources are cited at the end of the paper

Association between alcohol and cardiovascular disease: Mendelian randomisation analysis based on individual participant data.

OBJECTIVE: To use the rs1229984 variant in the alcohol dehydrogenase 1B gene (ADH1B) as an instrument to investigate the causal role of alcohol in cardiovascular disease. DESIGN: Mendelian randomisation meta-analysis of 56 epidemiological studies. PARTICIPANTS: 261 991 individuals of European descent, including 20 259 coronary heart disease cases and 10 164 stroke events. Data were available on ADH1B rs1229984 variant, alcohol phenotypes, and cardiovascular biomarkers. MAIN OUTCOME MEASURES: Odds ratio for coronary heart disease and stroke associated with the ADH1B variant in all individuals and by categories of alcohol consumption. RESULTS: Carriers of the A-allele of ADH1B rs1229984 consumed 17.2% fewer units of alcohol per week (95% confidence interval 15.6% to 18.9%), had a lower prevalence of binge drinking (odds ratio 0.78 (95% CI 0.73 to 0.84)), and had higher abstention (odds ratio 1.27 (1.21 to 1.34)) than non-carriers. Rs1229984 A-allele carriers had lower systolic blood pressure (-0.88 (-1.19 to -0.56) mm Hg), interleukin-6 levels (-5.2% (-7.8 to -2.4%)), waist circumference (-0.3 (-0.6 to -0.1) cm), and body mass index (-0.17 (-0.24 to -0.10) kg/m(2)). Rs1229984 A-allele carriers had lower odds of coronary heart disease (odds ratio 0.90 (0.84 to 0.96)). The protective association of the ADH1B rs1229984 A-allele variant remained the same across all categories of alcohol consumption (P=0.83 for heterogeneity). Although no association of rs1229984 was identified with the combined subtypes of stroke, carriers of the A-allele had lower odds of ischaemic stroke (odds ratio 0.83 (0.72 to 0.95)). CONCLUSIONS: Individuals with a genetic variant associated with non-drinking and lower alcohol consumption had a more favourable cardiovascular profile and a reduced risk of coronary heart disease than those without the genetic variant. This suggests that reduction of alcohol consumption, even for light to moderate drinkers, is beneficial for cardiovascular health