Genome-wide association meta-analysis of knee and hip osteoarthritis uncovers genetic differences between patients treated with joint replacement and patients without joint replacement.

OBJECTIVES: Osteoarthritis is a common and severe, multifactorial disease with a well-established genetic component. However, little is known about how genetics affect disease progression, and thereby the need for joint placement. Therefore, we aimed to investigate whether the genetic associations of knee and hip osteoarthritis differ between patients treated with joint replacement and patients without joint replacement. METHODS: We included knee and hip osteoarthritis cases along with healthy controls, altogether counting >700 000 individuals. The cases were divided into two groups based on joint replacement status (surgical vs non-surgical) and included in four genome-wide association meta-analyses: surgical knee osteoarthritis (N = 22 525), non-surgical knee osteoarthritis (N = 38 626), surgical hip osteoarthritis (N = 20 221) and non-surgical hip osteoarthritis (N = 17 847). In addition, we tested for genetic correlation between the osteoarthritis groups and the pain phenotypes intervertebral disc disorder, dorsalgia, fibromyalgia, migraine and joint pain. RESULTS: We identified 52 sequence variants associated with knee osteoarthritis (surgical: 17, non-surgical: 3) or hip osteoarthritis (surgical: 34, non-surgical: 1). For the surgical phenotypes, we identified 10 novel variants, including genes involved in autophagy (rs2447606 in ATG7) and mechanotransduction (rs202127176 in PIEZO1). One variant, rs13107325 in SLC39A8, associated more strongly with non-surgical knee osteoarthritis than surgical knee osteoarthritis. For all other variants, significance and effect sizes were higher for the surgical phenotypes. In contrast, genetic correlations with pain phenotypes tended to be stronger in the non-surgical groups. CONCLUSIONS: Our results indicate differences in genetic associations between knee and hip osteoarthritis depending on joint replacement status.

Medial unicompartmental knee arthroplasty: increasingly uniform patient demographics despite differences in surgical volume and usage-a descriptive study of 8,501 cases from the Danish Knee Arthroplasty Registry.

Background and purpose - Using contemporary indications, up to 50% of patients undergoing knee arthroplasty are eligible for unicompartmental knee arthroplasty (UKA), and lower UKA use likely reflects a restrictive approach to patient selection. Since broader indications have been successfully introduced, and low surgical volume and UKA percentage (usage) are associated with higher revision rates, it is of interest whether the actual use of UKA has changed accordingly. We explored this by assessing time trends in patient demographics and whether these are associated with center UKA volume and usage. Patients and methods - From the Danish Knee Arthroplasty Registry, we included 8,501 medial UKAs performed for primary osteoarthritis during 2002-2016. Using locally weighted regression, we examined changes-both overall and by center volume and usage (low vs high)-in sex distribution, age, weight, and preoperative American Knee Society Score (AKSS-O). Results - Over the last 20 years, UKA use in Denmark has been increasing steadily. Age, weight, and proportion of men all increased regardless of volume and usage. AKSS-O showed an initial increase followed by a decrease. In low-usage and low-volume centers, the proportion of women was higher, patients were younger, weighed less, and had higher AKSS-O scores; however, for age and AKSS-O, the groups were converging during the last part of the period. Interpretation - Characteristics of UKA patients have changed in the last 15 years irrespective of center volume and usage. We found between-group differences for both volume and usage, though with convergence for age and AKSS-O, which suggests an increasingly uniform approach to patient selection.

Patient attitudes towards day-case hip and knee arthroplasty.

Aims: This study aimed to investigate patients' attitudes towards day-case hip and knee arthroplasty and to describe patient characteristics associated with different attitudes, with the purpose of providing an insight into the information requirements for patients that surgeons should address when informing patients about day-case surgery. Methods: A total of 5,322 patients scheduled for hip or knee arthroplasty between 2016 and 2022 were included in the study. Preoperatively, patients were asked if they were interested in day-case surgery ('Yes', 'Do not know', 'No'). Patient demographics including age, BMI, sex, and patient-reported outcome measures (PROMs) such as the EuroQol five-dimension three-level questionnaire (EQ-5D-3L) were examined within each attitude group. Additionally, changes in attitude were assessed among patients who had completed the questionnaire in association with prior hip or knee arthroplasty. Results: Of the surveyed patients, 41.8% were interested in day-case surgery (n = 2,222), 20.8% responded 'Do not know' (n = 1,105), and 37.5% were not interested (n = 1,995). Patients who were not interested had a higher mean age ('No', 70.2 years (SD 10.0) vs 'Yes', 65.2 years (SD 10.7)), with a majority being female ('No', 71.9% female (n = 1,434) vs 'Yes', 48.6% female (n = 1,081)). Approximately 20% of patients responded 'Do not know' regardless of age, sex, and PROMs. Patients reporting anxiety/depression based on EQ-5D-3L more frequently answered 'No' (56.9%; 66/116) compared to those not experiencing anxiety/depression (34.9%; 1,356/3,890). Among patients who responded 'Do not know' before their first surgery, over 70% changed their attitude to either 'Yes' (29.9%; 38/127) or 'No' (40.9%; 52/127) at their subsequent surgery. Conclusion: From 2016 to 2022, 58.3% of hip and knee arthroplasty patients expressed uncertainty or no interest in day-case surgery. In connection with current initiatives to increase the number of day-case arthroplasty procedures, there should be a focus on informing patients to address the prevalent negative or uncertain attitude. Further research is needed to investigate what preoperative information patients consider crucial in their decision-making process regarding day-case surgery.

Genetics may affect the risk of undergoing surgery for rhizarthrosis.

Osteoarthritis is a prevalent and severe disease. Involvement of the trapeziometacarpal joint is common and can lead to both pain and disability. Genetics are known to affect the risk of osteoarthritis, but it remains unclear how genetics affect disease trajectories. In this study, we investigated whether the genetic associations of trapeziometacarpal osteoarthritis (rhizarthrosis) vary with the need for surgical treatment. The study was conducted as a case-control genome-wide association study using individuals from the Copenhagen Hospital Biobank pain and degenerative musculoskeletal disease study and the Danish Blood Donor Study (N = 208,342). We identified patients diagnosed with rhizarthrosis and grouped them by treatment status, resulting in two case groups: surgical (N = 1083) and nonsurgical (N = 1888). The case groups were tested against osteoarthritis-free controls in two genome-wide association studies. We then compared variants suggestive of association (p < 10-6) in either of these analyses directly between the treatment groups (surgical vs. nonsurgical rhizarthrosis). We identified 10 variants suggestive of association with either surgical (seven variants) or nonsurgical (three variants) rhizarthrosis. None of the variants reached nominal significance in the opposite treatment group (p ≥ 0.14), and all 10 variants were significantly different between the treatment groups at a false discovery rate of 5%. These results suggest possible differences in the genetic associations of rhizarthrosis depending on surgical treatment. Clinical significance: Uncovering genetic differences between clinically distinct patient groups can reveal biological determinants of disease trajectories.

A genome-wide meta-analysis identifies 50 genetic loci associated with carpal tunnel syndrome.

Carpal tunnel syndrome (CTS) is the most common entrapment neuropathy and has a largely unknown underlying biology. In a genome-wide association study of CTS (48,843 cases and 1,190,837 controls), we found 53 sequence variants at 50 loci associated with the syndrome. The most significant association is with a missense variant (p.Glu366Lys) in SERPINA1 that protects against CTS (P = 2.9 × 10-24, OR = 0.76). Through various functional analyses, we conclude that at least 22 genes mediate CTS risk and highlight the role of 19 CTS variants in the biology of the extracellular matrix. We show that the genetic component to the risk is higher in bilateral/recurrent/persistent cases than nonrecurrent/nonpersistent cases. Anthropometric traits including height and BMI are genetically correlated with CTS, in addition to early hormonal-replacement therapy, osteoarthritis, and restlessness. Our findings suggest that the components of the extracellular matrix play a key role in the pathogenesis of CTS.

Lower tendon stiffness in very old compared with old individuals is unaffected by short-term resistance training of skeletal muscle.

Aging negatively affects collagen-rich tissue, like tendons, but in vivo tendon mechanical properties and the influence of physical activity after the 8th decade of life remain to be determined. This study aimed to compare in vivo patellar tendon mechanical properties in moderately old (old) and very old adults and the effect of short-term resistance training. Twenty old (9 women, 11 men, >65 yr) and 30 very old (11 women, 19 men, >83 yr) adults were randomly allocated to heavy resistance training (HRT) or no training (CON) and underwent testing of in vivo patellar tendon (PT) mechanical properties and PT dimensions before and after a 3-mo intervention. Previous measurements of muscle properties, blood parameters, and physical activity level were included in the analysis. Data from 9 old HRT, 10 old CON, 14 very old CON, and 12 old HRT adults were analyzed. In addition to lower quadriceps muscle strength and cross-sectional area (CSA), we found lower PT stiffness and Young's modulus ( P < 0.001) and a trend toward the lower mid-portion PT-CSA ( P = 0.09) in very old compared with old subjects. Daily step count was also lower in very old subjects ( P < 0.001). Resistance training improved muscle strength and cross-sectional area equally in old and very old subjects ( P < 0.05) but did not affect PT mechanical properties or dimension. We conclude that PT material properties are reduced in very old age, and this may likely be explained by reduced physical activity. Three months of resistance training however, could not alter PT mechanical properties in very old individuals. NEW & NOTEWORTHY This research is the first to quantify in vivo tendon mechanical properties in a group of very old adults in their eighties. Patellar tendon stiffness was lower in very old (87 yr on average) compared with moderately old (68 yr on average) individuals. Reduced physical activity with aging may explain some of the loss in tendon stiffness, but regular heavy resistance training for 3 mo was not sufficient to change tendon mechanical properties.

Electrical somatosensory stimulation followed by motor training of the paretic upper limb in acute stroke: study protocol for a randomized controlled trial.

BACKGROUND: Upper limb paresis is one of the most frequent and persistent impairments following stroke. Only 12-34% of stroke patients achieve full recovery of upper limb functioning, which seems to be required to habitually use the affected arm in daily tasks. Although the recovery of upper limb functioning is most pronounced during the first 4 weeks post stroke, there are few studies investigating the effect of rehabilitation during this critical time window. The purpose of this trial is to determine the effect of electrical somatosensory stimulation (ESS) initiated in the acute stroke phase on the recovery of upper limb functioning in a nonselected sample of stroke patients. METHODS/DESIGN: A sample of 102 patients with upper limb paresis of varying degrees of severity is assigned to either the intervention or the control group using stratified random sampling. The intervention group receives ESS plus usual rehabilitation and the control group receives sham ESS plus usual rehabilitation. The intervention is applied as 1 h of ESS/sham ESS daily, followed by motor training of the affected upper limb. The ESS/sham ESS treatment is initiated within 7 days from stroke onset and it is delivered during hospitalization, but no longer than 4 weeks post stroke. The primary outcome is hand dexterity assessed by the Box and Block Test; secondary outcomes are the Fugl-Meyer Assessment, hand grip strength, pinch strength, perceptual threshold of touch, degree of pain, and modified Rankin Scale score. Outcome measurements are conducted at baseline, post intervention and at 6-month follow-up. DISCUSSION: Because of the wide inclusion criteria, we believe that the results can be generalized to the larger population of patients with a first-ever stroke who present with an upper limb paresis of varying severity. On the other hand, the sample size (n = 102) may preclude subgroup analyses in such a heterogeneous sample. The sham ESS treatment totals a mere 2% of the active ESS treatment delivered to the intervention group per ESS session, and we consider that this dose is too small to induce a treatment effect. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02250365 . Registered on 18 September 2014.