Amiloride Reduces Urokinase/Plasminogen-Driven Intratubular Complement Activation in Glomerular Proteinuria.

SIGNIFICANCE STATEMENT: Proteinuria predicts accelerated decline in kidney function in CKD. The pathologic mechanisms are not well known, but aberrantly filtered proteins with enzymatic activity might be involved. The urokinase-type plasminogen activator (uPA)-plasminogen cascade activates complement and generates C3a and C5a in vitro / ex vivo in urine from healthy persons when exogenous, inactive, plasminogen, and complement factors are added. Amiloride inhibits uPA and attenuates complement activation in vitro and in vivo . In conditional podocin knockout (KO) mice with severe proteinuria, blocking of uPA with monoclonal antibodies significantly reduces the urine excretion of C3a and C5a and lowers tissue NLRP3-inflammasome protein without major changes in early fibrosis markers. This mechanism provides a link to proinflammatory signaling in proteinuria with possible long-term consequences for kidney function. BACKGROUND: Persistent proteinuria is associated with tubular interstitial inflammation and predicts progressive kidney injury. In proteinuria, plasminogen is aberrantly filtered and activated by urokinase-type plasminogen activator (uPA), which promotes kidney fibrosis. We hypothesized that plasmin activates filtered complement factors C3 and C5 directly in tubular fluid, generating anaphylatoxins, and that this is attenuated by amiloride, an off-target uPA inhibitor. METHODS: Purified C3, C5, plasminogen, urokinase, and urine from healthy humans were used for in vitro / ex vivo studies. Complement activation was assessed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, immunoblotting, and ELISA. Urine and plasma from patients with diabetic nephropathy treated with high-dose amiloride and from mice with proteinuria (podocin knockout [KO]) treated with amiloride or inhibitory anti-uPA antibodies were analyzed. RESULTS: The combination of uPA and plasminogen generated anaphylatoxins C3a and C5a from intact C3 and C5 and was inhibited by amiloride. Addition of exogenous plasminogen was sufficient for urine from healthy humans to activate complement. Conditional podocin KO in mice led to severe proteinuria and C3a and C5a urine excretion, which was attenuated reversibly by amiloride treatment for 4 days and reduced by >50% by inhibitory anti-uPA antibodies without altering proteinuria. NOD-, LRR- and pyrin domain-containing protein 3-inflammasome protein was reduced with no concomitant effect on fibrosis. In patients with diabetic nephropathy, amiloride reduced urinary excretion of C3dg and sC5b-9 significantly. CONCLUSIONS: In conditions with proteinuria, uPA-plasmin generates anaphylatoxins in tubular fluid and promotes downstream complement activation sensitive to amiloride. This mechanism links proteinuria to intratubular proinflammatory signaling. In perspective, amiloride could exert reno-protective effects beyond natriuresis and BP reduction. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: Increased Activity of a Renal Salt Transporter (ENaC) in Diabetic Kidney Disease, NCT01918488 and Increased Activity of ENaC in Proteinuric Kidney Transplant Recipients, NCT03036748 .

Conversions between metabolically unhealthy and healthy obesity from midlife to late-life.

INTRODUCTION: Metabolically healthy obesity may be a transient phenotype, but studies with long follow-up, especially covering late-life, are lacking. We describe conversions between cross-categories of body mass index (BMI) and metabolic health in 786 Swedish twins with up to 27 years of follow-up, from midlife to late-life. METHODS: Metabolic health was defined as the absence of metabolic syndrome (MetS). We first visualized conversions between BMI-metabolic health phenotypes in 100 individuals with measurements available at ages 50-64, 65-79, and ≥80. Next, we modeled conversion in metabolic health status by BMI category in the full sample using Cox proportional hazards regression. RESULTS: The proportion of individuals with MetS and with overweight or obesity increased with age. However, one-fifth maintained a metabolically healthy overweight or obesity across all three age categories. Among those metabolically healthy at baseline, 59% converted to MetS during follow-up. Conversions occurred 56% more often among individuals with metabolically healthy obesity, but not overweight, compared to normal weight. Among those with MetS at baseline, 60% regained metabolic health during follow-up, with no difference between BMI categories. CONCLUSIONS: Conversions between metabolically healthy and unhealthy status occurred in both directions in all BMI categories. While conversions to MetS were more common among individuals with obesity, many individuals maintained or regained metabolic health during follow-up.

Erosive hand osteoarthritis and sarcopenia: data from Osteoarthritis Initiative cohort.

OBJECTIVES: There is no evidence linking specific osteoarthritis (OA) types, such as erosive hand OA (EHOA), with distant generalised changes in muscle composition (sarcopenia), which can potentially be modified. This study pioneers the exploration of the association between EHOA and sarcopenia, both of which are predominantly observed in the older adults. METHODS: Using the Osteoarthritis Initiative cohort, we selected hand OA (modified Kellgren and Lawrence (grade ≥2 in ≥1 hand joint) participants with radiographic central erosions in ≥1 joints (EHOA group) and propensity score-matched hand OA participants with no erosion (non-EHOA group). MRI biomarkers of thigh muscles were measured at baseline, year 2 and year 4 using a validated deep-learning algorithm. To adjust for 'local' effects of coexisting knee OA (KOA), participants were further stratified according to presence of radiographic KOA. The outcomes were the differences between EHOA and non-EHOA groups in the 4-year rate of change for both intramuscular adipose tissue (intra-MAT) deposition and contractile (non-fat) area of thigh muscles. RESULTS: After adjusting for potential confounders, 844 thighs were included (211 EHOA:633 non-EHOA; 67.1±7.5 years, female/male:2.9). Multilevel mixed-effect regression models showed that EHOA is associated a different 4-year rate of change in intra-MAT deposition (estimate, 95% CI: 71.5 mm2/4 years, 27.9 to 115.1) and contractile area (estimate, 95% CI: -1.8%/4 years, -2.6 to -1.0) of the Quadriceps. Stratified analyses showed that EHOA presence is associated with adverse changes in thigh muscle quality only in participants without KOA. CONCLUSIONS: EHOA is associated with longitudinal worsening of thigh muscle composition only in participants without concomitant KOA. Further research is needed to understand the systemic factors linking EHOA and sarcopenia, which unlike EHOA is modifiable through specific interventions.

2023 EULAR classification criteria for hand osteoarthritis.

OBJECTIVES: The objective of this study is to develop classification criteria for overall hand osteoarthritis (OA), interphalangeal OA and thumb base OA based on self-reported data and radiographic features. METHODS: The classification criteria sets were developed in three phases. In phase 1, we identified criteria that discriminated hand OA from controls. In phase 2, we used a consensus-based decision analysis approach to derive a clinician-based evaluation of the relative importance of the criteria. In phase 3, we refined the scoring system, determined the cut-offs for disease classification and compared the sensitivity and specificity of the European Alliance of Associations for Rheumatology (EULAR) criteria with the 1990 American College of Rheumatology (ACR) criteria. RESULTS: In persons with hand symptoms and no other disease (including psoriasis) or acute injury that can explain the hand symptoms (mandatory criteria), hand OA can be classified based on age, duration of morning stiffness, number of joints with osteophytes and joint space narrowing, and concordance between symptoms and radiographic findings. Using a sum of scores based on each diagnostic element, overall hand OA can be classified if a person achieves 9 or more points on a 0-15 scale. The cut-off for interphalangeal OA and thumb base OA is 8 points. While the EULAR criteria demonstrated better sensitivity than the ACR criteria in the phase 1 data set, the performance of the two criteria sets was similar in two external cohorts. CONCLUSIONS: International experts developed the EULAR criteria to classify overall hand OA, interphalangeal OA and thumb base OA in clinical studies using a rigorous methodology.

A perspective on the evolution of semi-quantitative MRI assessment of osteoarthritis: Past, present and future.

OBJECTIVE: This perspective describes the evolution of semi-quantitative (SQ) magnetic resonance imaging (MRI) in characterizing structural tissue pathologies in osteoarthritis (OA) imaging research over the last 30 years. METHODS: Authors selected representative articles from a PubMed search to illustrate key steps in SQ MRI development, validation, and application. Topics include main scoring systems, reading techniques, responsiveness, reliability, technical considerations, and potential impact of artificial intelligence (AI). RESULTS: Based on original research published between 1993 and 2023, this article introduces available scoring systems, including but not limited to Whole-Organ Magnetic Resonance Imaging Score (WORMS) as the first system for whole-organ assessment of the knee and the now commonly used MRI Osteoarthritis Knee Score (MOAKS) instrument. Specific systems for distinct OA subtypes or applications have been developed as well as MRI scoring instruments for other joints such as the hip, the fingers or thumb base. SQ assessment has proven to be valid, reliable, and responsive, aiding OA investigators in understanding the natural history of the disease and helping to detect response to treatment. AI may aid phenotypic characterization in the future. SQ MRI assessment's role is increasing in eligibility and safety evaluation in knee OA clinical trials. CONCLUSIONS: Evidence supports the validity, reliability, and responsiveness of SQ MRI assessment in understanding structural aspects of disease onset and progression. SQ scoring has helped explain associations between structural tissue damage and clinical manifestations, as well as disease progression. While AI may support human readers to more efficiently perform SQ assessment in the future, its current application in clinical trials still requires validation and regulatory approval.

Assessing the association of epigenetic age acceleration with osteoarthritis in the Multicenter Osteoarthritis Study (MOST).

PURPOSE: Advancing age is one of the strongest risk factors for osteoarthritis (OA). DNA methylation-based measures of epigenetic age acceleration may provide insights into mechanisms underlying OA. METHODS: We analyzed data from the Multicenter Osteoarthritis Study in a subset of 671 participants ages 45-69 years with no or mild radiographic knee OA. DNA methylation was assessed with the Illumina Infinium MethylationEPIC 850K array. We calculated predicted epigenetic age according to Hannum, Horvath, PhenoAge, and GrimAge epigenetic clocks, then regressed epigenetic age on chronological age to obtain the residuals. Associations between the residuals and knee, hand, and multi-joint OA were assessed using logistic regression, adjusted for chronological age, sex, clinical site, smoking status, and race. RESULTS: Twenty-three percent met criteria for radiographic hand OA, 25% met criteria for radiographic knee OA, and 8% met criteria for multi-joint OA. Mean chronological age (SD) was 58.4 (6.7) years. Mean predicted epigenetic age (SD) according to Horvath, Hannum, PhenoAge, and GrimAge epigenetic clocks was 64.9 (6.4), 68.6 (5.9), 50.5 (7.7), and 67.0 (6.2), respectively. Horvath epigenetic age acceleration was not associated with an increased odds of hand OA, odds ratio (95% confidence intervals) = 1.03 (0.99-1.08), with similar findings for knee and multi-joint OA. We found similar magnitudes of associations for Hannum epigenetic age, PhenoAge, and GrimAge acceleration compared to Horvath epigenetic age acceleration. CONCLUSIONS: Epigenetic age acceleration as measured by various well-validated epigenetic clocks based on DNA methylation was not associated with increased risk of knee, hand, or multi-joint OA independent of chronological age.

Hand osteoarthritis phenotypes based on a biopsychosocial approach, and their associations with cross-sectional and longitudinal pain.

OBJECTIVE: Hand osteoarthritis (OA) pain is characterized as heterogeneous and multifactorial. Differences in pain may be explained by underlying phenotypes, which have not been previously explored DESIGN: Latent class analysis determined classes of participants with hand OA from the Nor-Hand study baseline examination (2016-17) based on a biopsychosocial framework. Outcomes were hand and overall bodily pain intensity (Numeric Rating Scale, 0-10) at baseline and follow-up (2019-21), The relations of the classes to pain outcomes at baseline, follow-up, and change over time were analysed in separate models by linear regression, using the overall healthiest class as reference. RESULTS: Five classes differing in radiographic hand OA burden and OA burden in the lower extremities by ultrasound, demographic factors, psychosocial burden and pain sensitization was identified. Persons with the least severe OA but higher burden of biopsychosocial factors reported the most hand pain (beta 3.65, 95% CI 2.53, 4.75). Pain was less pronounced in persons with the most severe hand OA but low burden of biopsychosocial factors (beta 1.03, 95% CI 0.41, 1.65). Results were similar for overall bodily pain and at follow-up. Changes in pain were small, but the association between a separate class defined by higher levels of biopsychosocial burden and pain changes was significant. CONCLUSION: The five hand OA phenotypes were associated with pain at baseline and 3.5 years later. The phenotype with the least OA severity, but higher burden of biopsychosocial factors reported more pain than the phenotype with the most severe OA, reflecting the symptom-structure discordance of the hand OA pain experience.

Associations of inflammatory and metabolic biomarkers with incident erosive hand osteoarthritis in the osteoarthritis initiative cohort.

OBJECTIVE: Erosive hand osteoarthritis (eHOA) is a subtype of hand osteoarthritis (OA) that develops in finger joints with pre-existing OA and is differentiated by clinical characteristics (hand pain/disability, inflammation, and erosions) that suggest inflammatory or metabolic processes. METHOD: This was a longitudinal nested case-cohort design among Osteoarthritis Initiative participants who had hand radiographs at baseline and 48-months, and biospecimens collected at baseline. We classified incident radiographic eHOA in individuals with ≥1 joint with Kellgren-Lawrence ≥2 and a central erosion present at 48-months but not at baseline. We used a random representative sample (n = 1282) for comparison. We measured serum biomarkers of inflammation, insulin resistance and dysglycemia, and adipokines using immunoassays and enzymatic colorimetric procedures, blinded to case status. RESULTS: Eighty-six participants developed incident radiographic eHOA. In the multivariate analyses adjusted for age, gender, race, smoking, and body mass index, and after adjustment for multiple analyses, incident radiographic eHOA was associated with elevated levels of interleukin-7 (risk ratio (RR) per SD = 1.30 [95% confidence interval (CI) 1.09, 1.55] p trend 0.01). CONCLUSION: This exploratory study suggests an association of elevated interleukin-7, an inflammatory cytokine, with incident eHOA, while other cytokines or biomarkers of metabolic inflammation were not associated. Interleukin-7 may mediate inflammation and tissue damage in susceptible osteoarthritic finger joints and participate in erosive progression.

Turbulence Transition in Magnetically Confined Hydrogen and Deuterium Plasmas.

In this study, we discovered a turbulence transition in a large helical device. The turbulence level and turbulence-driven energy transport decrease to a specific transition density and increase above it. The ruling turbulences below and above the transition density were ion-temperature gradient (ITG) and resistive-interchange (RI) turbulences, consistent with the predictions of gyrokinetic theory and two-fluid MHD model, respectively. Isotope experiments on hydrogen (H) and deuterium (D) clarified the role of transitions. In the ITG regime, turbulence levels and energy transport were comparable in the H and D plasmas. In contrast, in the RI regime, they were clearly suppressed in the D plasma. The results provide crucial knowledge for understanding isotope effects and future optimization of stellarator and heliotron devices.

Associations between Sleep Disorders and Impulsive-Compulsive Behaviors in Parkinson's Disease: A Prospective Cohort Study.

OBJECTIVE: To examine the associations of excessive daytime sleepiness (EDS) and probable rapid eye movement sleep behavior disorder (pRBD), respectively, with impulsive-compulsive behaviors (ICB) over a 5-year follow-up in patients with early Parkinson's disease (PD). METHODS: The Parkinson's Progression Markers Initiative is a multicenter cohort study based on an ongoing and open-ended registry. Longitudinal associations of sleep disorders with ICB over 5-year follow-up visits were estimated using generalized linear mixed-effects models among PD participants. RESULTS: A total of 825 PD participants were enrolled at baseline. The study sample had a median baseline age of 63.1 (interquartile range [IQR]: 55.6-69.3) years and comprised 496 (61.5%) men. Among them, 201 (24.9%) had ICB at baseline. In the generalized mixed-effects models, EDS (odds ratio [OR] =1.09, 95% confidence interval [CI] 1.05, 1.12) and RBD (OR=1.07, 95% CI 1.03, 1.12) were substantially associated with higher odds of developing ICB over time in PD patients, after multivariate adjustment including age, gender, family history, GDS score, STAI-Y score, MDS-UPDRS part III score, LEDD, and disease duration. Consistent results were observed when stratifying by age at baseline, gender, and PD family history. CONCLUSIONS: The study findings suggest a longitudinal association between EDS and pRBD with an increased risk of developing ICB in patients with Parkinson's disease. The findings emphasize the significance of evaluating and addressing sleep disorders in PD patients as a potential approach to managing ICB.

Advanced biological ageing predicts future risk for neurological diagnoses and clinical examination findings.

Age is a dominant risk factor for some of the most common neurological diseases. Biological ageing encompasses interindividual variation in the rate of ageing and can be calculated from clinical biomarkers or DNA methylation data amongst other approaches. Here, we tested the hypothesis that a biological age greater than one's chronological age affects the risk of future neurological diagnosis and the development of abnormal signs on clinical examination. We analysed data from the Swedish Adoption/Twin Study of Aging (SATSA): a cohort with 3175 assessments of 802 individuals followed-up over several decades. Six measures of biological ageing were generated: two physiological ages (created from bedside clinical measurements and standard blood tests) and four blood methylation age measures. Their effects on future stroke, dementia or Parkinson's disease diagnosis, or development of abnormal clinical signs, were determined using survival analysis, with and without stratification by twin pairs. Older physiological ages were associated with ischaemic stroke risk; for example one standard deviation advancement in baseline PhenoAgePhys or KDMAgePhys residual increased future ischaemic stroke risk by 29.2% [hazard ratio (HR): 1.29, 95% confidence interval (CI) 1.06-1.58, P = 0.012] and 42.9% (HR 1.43, CI 1.18-1.73, P = 3.1 × 10-4), respectively. In contrast, older methylation ages were more predictive of future dementia risk, which was increased by 29.7% (HR 1.30, CI 1.07-1.57, P = 0.007) per standard deviation advancement in HorvathAgeMeth. Older physiological ages were also positively associated with future development of abnormal patellar or pupillary reflexes, and the loss of normal gait. Measures of biological ageing can predict clinically relevant pathology of the nervous system independent of chronological age. This may help to explain variability in disease risk between individuals of the same age and strengthens the case for trials of geroprotective interventions for people with neurological disorders.

Nerve Transfer After Cervical Spinal Cord Injury: Who Has a "Time Sensitive" Injury Based on Electrodiagnostic Findings?

OBJECTIVE: To use the ulnar compound muscle action potential (CMAP) to abductor digiti minimi (ADM) to identify the proportion of individuals with cervical spinal cord injury (SCI) who have lower motor neuron (LMN) abnormalities involving the C8-T1 spinal nerve roots, within 3-6 months, and thus may influence the response to nerve transfer surgery. DESIGN: Retrospective analysis of prospectively collected data. Data were analyzed from European Multicenter Study About SCI database. SETTING: Multi-center, academic hospitals. PARTICIPANTS: We included 79 subjects (age=41.4±17.7, range:16-75; 59 men; N=79), who were classified as cervical level injuries 2 weeks after injury and who had manual muscle strength examinations that would warrant consideration for nerve transfer (C5≥4, C8<3). INTERVENTIONS: None. MAIN OUTCOME MEASURES: The ulnar nerve CMAP amplitude to ADM was used as a proxy measure for C8-T1 spinal segment health. CMAP amplitude was stratified into very abnormal (<1.0 mV), sub-normal (1.0-5.9 mV), and normal (>6.0 mV). Analysis took place at 3 (n=148 limbs) and 6 months (n=145 limbs). RESULTS: At 3- and 6-month post-injury, 33.1% and 28.3% of limbs had very abnormal CMAP amplitudes, respectively, while in 54.1% and 51.7%, CMAPs were sub-normal. Median change in amplitude from 3 to 6 months was 0.0 mV for very abnormal and 1.0 mV for subnormal groups. A 3-month ulnar CMAP <1 mV had a positive predictive value of 0.73 (95% CI 0.69-0.76) and 0.78 (95% CI 0.75-0.80) for C8 and T1 muscle strength of 0 vs 1 or 2. CONCLUSION: A high proportion of individuals have ulnar CMAPs below the lower limit of normal 3- and 6-month post cervical SCI and may also have intercurrent LMN injury. Failure to identify individuals with LMN denervation could result in a lost opportunity to improve hand function through timely nerve transfer surgeries.

Dementia and mortality in older adults: A twin study.

INTRODUCTION: Dementia predicts increased mortality. We used case-control and co-twin control models to investigate genetic and shared environmental influences on this association. METHODS: Case-control design, including 987 twins with dementia and 2938 age- and sex-matched controls in the Swedish Twin Registry. Co-twin control design, including 90 monozygotic (MZ) and 288 dizygotic (DZ) twin pairs discordant for dementia. To test for genetic and environmental confounding, differences were examined in mortality risk between twins with dementia and their matched or co-twin controls. RESULTS: Twins with dementia showed greater mortality risk than age- and sex-matched controls (HR = 2.02 [1.86, 2.18]). Mortality risk is significantly elevated but attenuated substantially in discordant twin pairs, for example, comparing MZ twins with dementia to their co-twin controls (HR = 1.48 [1.08, 2.04]). DISCUSSION: Findings suggest that genetic factors partially confound the association between dementia and mortality and provide an alternative hypothesis to increased mortality due to dementia itself. Highlights We studied dementia and mortality in twin pairs discordant for dementia. People without dementia outlived people with dementia. Identical twins with dementia and their co-twin controls had similar survival time. Findings suggest genotype may explain the link between dementia and mortality.

Associations between pain sensitization and measures of physical function in people with hand osteoarthritis: Results from the Nor-Hand study.

OBJECTIVE: To examine whether pain sensitization is associated with hand and lower extremity function in people with hand osteoarthritis (OA) in the Nor-Hand study. DESIGN: Pain sensitization was assessed by pressure pain thresholds (PPTs) and temporal summation (TS). Hand function was assessed by Australian/Canadian Osteoarthritis Hand Index (AUSCAN) (range: 0-36), grip strength and Moberg pick-up test, and lower extremity function was assessed by Western Ontario and McMaster Universities Osteoarthritis Index (range: 0-68), 30-s chair stand test, and 40-m walk test. We examined whether sex-standardized PPT and TS values were cross-sectionally associated with measures of physical function using linear regression analyses. Beta coefficients were presented per sex-specific standard deviation of PPT and TS. The mediating effect of pain was examined by causal-inference based mediation analysis. RESULTS: In 206 participants, higher PPTs at/near the hand, indicative of less peripheral and/or central pain sensitization, were associated with greater grip strength and better self-reported hand function (beta for PPT at finger joint on AUSCAN function: -1.41, 95% CI -2.40, -0.42). Higher PPTs at/near the hand, near the knee and at trapezius were associated with lower extremity function, although not statistically significant for all outcomes. Self-reported pain severity mediated the effect of PPT on self-reported function. TS was not associated with hand or lower extremity function. CONCLUSION: Peripheral sensitization, and possibly central sensitization, was associated with impaired function. Effects of PPTs on self-reported function were mediated by self-reported pain, whereas there might be a direct effect of sensitization or effects through other mediators on performance-based function.

A scoping review of how early-stage knee osteoarthritis has been defined.

BACKGROUND: Early-stage knee osteoarthritis (KOA) classification criteria will enable consistent identification and trial recruitment of individuals with knee osteoarthritis (OA) at an earlier stage of the disease when interventions may be more effective. Toward this goal, we identified how early-stage KOA has been defined in the literature. METHODS: We performed a scoping literature review in PubMed, EMBASE, Cochrane, and Web of Science, including human studies where early-stage KOA was included as a study population or outcome. Extracted data included demographics, symptoms/history, examination, laboratory, imaging, performance-based measures, gross inspection/histopathologic domains, and the components of composite early-stage KOA definitions. RESULTS: Of 6142 articles identified, 211 were included in data synthesis. An early-stage KOA definition was used for study inclusion in 194 studies, to define study outcomes in 11 studies, and in the context of new criteria development or validation in six studies. The element most often used to define early-stage KOA was Kellgren-Lawrence (KL) grade (151 studies, 72%), followed by symptoms (118 studies, 56%), and demographic characteristics (73 studies, 35%); 14 studies (6%) used previously developed early-stage KOA composite criteria. Among studies defining early-stage KOA radiographically, 52 studies defined early-stage KOA by KL grade alone; of these 52, 44 (85%) studies included individuals with KL grade 2 or higher in their definitions. CONCLUSION: Early-stage KOA is variably defined in the published literature. Most studies included KL grades of 2 or higher within their definitions, which reflects established or later-stage OA. These findings underscore the need to develop and validate classification criteria for early-stage KOA.

Hand joints without radiographic osteoarthritis maintain their joint space width over 4 years despite what's happening elsewhere in the hand.

OBJECTIVES: We aimed to determine if hand osteoarthritis is characterized by systemic cartilage loss by assessing if radiographically normal joints had greater joint space width (JSW) loss during four years in hands with incident or prevalent osteoarthritis elsewhere in the hand compared with hands without osteoarthritis. METHODS: We used semi-automated software to measure JSW in the distal and proximal interphalangeal joints of 3,368 participants in the Osteoarthritis Initiative who had baseline and 48-month hand radiographs. A reader scored 16 hand joints (including the thumb-base) for Kellgren-Lawrence (KL) Grade. A joint had osteoarthritis if scored as KL ≥ 2. We identified three groups based on longitudinal hand osteoarthritis status: 1) no hand osteoarthritis (KL < 2 in all 16 joints) at the baseline and 48-month visits, 2) incident hand osteoarthritis (KL < 2in all 16 joints at baseline and then ≥1 joint with KL ≥ 2 at 48-months), and 3) prevalent hand osteoarthritis (≥1 joint with KL ≥ 2 at baseline and 48-months). We then assessed if JSW in radiographically normal joints (KL = 0) differed across these three groups. We calculated unpooled effect sizes to help interpret the differences between groups. RESULTS: We observed small differences in JSW loss that are unlikely to be clinically important between radiographically normal joints between those without hand osteoarthritis (n = 1054) and those with incident (n = 102) or prevalent hand osteoarthritis (n = 2212) (effect size range: -0.01 to 0.24). These findings were robust when examining JSW loss dichotomized based on meaningful change and in other secondary analyses. CONCLUSIONS: Hand osteoarthritis is not a systemic disease of cartilage.

Sexual communication patterns in couples with vulvodynia-a case-control behavioral observation study.

BACKGROUND: Sexual communication is a common target in psychological treatments for vulvodynia, and associations with sexual function and distress, as well as pain intensity, have been demonstrated. However, structured observations of the communication patterns of couples with vulvodynia are lacking, as these are needed to guide treatment efforts. AIM: To explore (1) the sexual communication patterns in couples with vulvodynia in terms of observed communication quality (operationalized as validating and invalidating responses), self-reported sexual assertiveness, and self-disclosure and (2) associations between sexual communication quality and pain intensity. METHODS: In a case-control design with within- and between-group comparisons, 62 couples engaged in videotaped discussions about their sexual relationship. Trained coders assessed the discussions by rating sexual communication (validation and invalidation) according to a structured behavioral coding scheme. Group differences in sexual communication quality were examined with parametric and nonparametric tests. Dyadic associations among observed communication quality, self-rated sexual assertiveness, and self-disclosure were examined within the actor-partner interdependence model. Multiple regression was used to test the predictive value of partners' validation/invalidation on the pain intensity of the women with vulvodynia. OUTCOMES: Observed communication quality (ie, validation and invalidation), self-reported sexual assertiveness, self-disclosure, and pain intensity. RESULTS: Partners of women with vulvodynia were more invalidating toward their partners than those of women without pain. There were no significant differences in validating/invalidating communication between women in the 2 groups or in validation between partners. Partners' validating communication were significantly associated with women's lower pain intensity. The sexual communication patterns differed between couples with and without vulvodynia, and the associations between validating/invalidating responses and sexual assertiveness were stronger in the vulvodynia group than in the group without pain. Results on validation/invalidation and self-disclosure were inconclusive. CLINICAL IMPLICATIONS: The results indicate a need to direct treatment interventions toward couples' sexual communication quality (ie, levels of validation and invalidation). STRENGTHS AND LIMITATIONS: Strengths include systematic behavioral coding and dyadic analyses. Limitations include the cross-sectional design and self-selection of participants. CONCLUSION: This study demonstrated sexual communication patterns specific to couples with vulvodynia, and we conclude that validation and invalidation are important components of the sexual communication of couples with vulvodynia as they relate to sexual assertiveness, women's self-disclosure, and pain intensity.

Effects of prenatal exercise on gestational weight gain, obstetric and neonatal outcomes: FitMum randomized controlled trial.

BACKGROUND: To investigate the effects of two different exercise interventions during pregnancy on gestational weight gain (GWG) and obstetric and neonatal outcomes compared to standard care. Additionally, we aimed to improve standardization of GWG measurements by developing a model to estimate GWG for a standardized pregnancy period of 40 weeks and 0 days accounting for individual differences in gestational age (GA) at delivery. METHODS: In a randomized controlled trial we compared the effects of structured supervised exercise training (EXE) three times per week throughout pregnancy versus motivational counselling on physical activity (MOT) seven times during pregnancy with standard care (CON) on GWG and obstetric and neonatal outcomes. Uniquely, to estimate GWG for a standardized pregnancy period, we developed a novel model to predict GWG based on longitudinally observed body weights during pregnancy and at admission for delivery. Observed weights were fitted to a mixed effects model that was used to predict maternal body weight and estimate GWG at different gestational ages. Obstetric and neonatal outcomes, among them gestational diabetes mellitus (GDM) and birth weight, were obtained after delivery. GWG and the investigated obstetric and neonatal outcomes are secondary outcomes of the randomized controlled trial, which might be underpowered to detect intervention effects on these outcomes. RESULTS: From 2018-2020, 219 healthy, inactive pregnant women with median pre-pregnancy BMI of 24.1 (21.8-28.7) kg/m2 were included at median GA 12.9 (9.4-13.9) weeks and randomized to EXE (n = 87), MOT (n = 87) or CON (n = 45). In total 178 (81%) completed the study. GWG at GA 40 weeks and 0 days did not differ between groups (CON: 14.9 kg [95% CI, 13.6;16.1]; EXE: 15.7 kg [14.7;16.7]; MOT: 15.0 kg [13.6;16.4], p = 0.538), neither did obstetric nor neonatal outcomes. For example, there were no differences between groups in the proportions of participants developing GDM (CON: 6%, EXE: 7%, MOT: 7%, p = 1.000) or in birth weight (CON: 3630 (3024-3899), EXE: 3768 (3410-4069), MOT: 3665 (3266-3880), p = 0.083). CONCLUSIONS: Neither structured supervised exercise training nor motivational counselling on physical activity during pregnancy affected GWG or obstetric and neonatal outcomes compared to standard care. TRIAL REGISTRATION: ClinicalTrials.gov; NCT03679130; 20/09/2018.

Exploring the differences between radiographic joint space width and MRI cartilage thickness changes using data from the IMI-APPROACH cohort.

OBJECTIVE: Longitudinal weight-bearing radiographic joint space width (JSW) and non-weight-bearing MRI-based cartilage thickness changes often show weak correlations. The current objective was to investigate these correlations, and to explore the influence of different factors that could contribute to longitudinal differences between the two methods. METHODS: The current study included 178 participants with medial osteoarthritis (OA) out of the 297 knee OA participants enrolled in the IMI-APPROACH cohort. Changes over 2 years in medial JSW (ΔJSWmed), minimum JSW (ΔJSWmin), and medial femorotibial cartilage thickness (ΔMFTC) were assessed using linear regression, using measurements from radiographs and MRI acquired at baseline, 6 months, and 1 and 2 years. Pearson R correlations were calculated. The influence of cartilage quality (T2 mapping), meniscal extrusion (MOAKS scoring), potential pain-induced unloading (difference in knee-specific pain scores), and increased loading (BMI) on the correlations was analyzed by dividing participants in groups based on each factor separately, and comparing correlations (slope and strength) between groups using linear regression models. RESULT: Correlations between ΔMFTC and ΔJSWmed and ΔJSWmin were statistically significant (p < 0.004) but weak (R < 0.35). Correlations were significantly different between groups based on cartilage quality and on meniscal extrusion: only patients with the lowest T2 values and with meniscal extrusion showed significant moderate correlations. Pain-induced unloading or BMI-induced loading did not influence correlations. CONCLUSIONS: While the amount of loading does not seem to make a difference, weight-bearing radiographic JSW changes are a better reflection of non-weight-bearing MRI cartilage thickness changes in knees with higher quality cartilage and with meniscal extrusion.

Quantifying Tenodesis Hand Function in Cervical Spinal Cord Injury: Implications for Function.

PURPOSE: Cervical spinal cord injury (SCI) has a profound effect on upper-extremity function. Individuals with stiffness and/or spasticity may have more, or less, useful tenodesis function. This study examined the variability present before any reconstructive surgery. METHODS: Tenodesis pinch and grasp were measured with the wrist in maximal active extension. Tenodesis pinch was the contact point of the thumb with the index finger proximal phalanx (T-IF:P1), middle phalanx (T-IF:P2), distal phalanx (T-IF:P3), or absent (T-IF:absent). Tenodesis grasp was the distance from the long finger to the distal palmar crease (LF-DPC). Activities of daily living function was assessed using the Spinal Cord Independence Measure (SCIM). RESULTS: The study included 27 individuals (4 females, 23 males; mean age 36 years, mean time since SCI 6.8 years). The mean International Classification for Surgery of the Hand in Tetraplegia (ICSHT) group classification was 3. In the dominant hand, individuals with a T-IF tenodesis pinch to P1 or P2 had significantly higher total SCIM scores (43.7 and 34.2, respectively) compared to those with absent T-IF tenodesis pinch (SCIM 17.8). Shorter LF-DPC distance with tenodesis grasp (improved finger closing) also correlated with improved SCIM mobility and total scores. No association was found between the ICSHT group and SCIM score or tenodesis measures. CONCLUSIONS: Quantifying tenodesis with pinch (T-IF) and grasp (LF-DPC) is a simple method to characterize hand movement in individuals with cervical SCI. Better tenodesis pinch and grasp were associated with improved activities of daily living performance. CLINICAL RELEVANCE: Differences in grasp function have implications for mobility, and differences in pinch function have implications for all functions, particularly self-care. These physical measurements could be used to assess movement changes after nonsurgical and surgical treatment in tetraplegia.