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Background Thumb osteoarthritis (OA) is a common and disabling condition. Adherence to prescribed conservative interventions may affect outcomes of thumb OA trials. Purpose The aim of the study was to determine whether baseline pain and hand function is associated with treatment adherence over 12 weeks in participants with thumb base OA. Study design Observational cohort study nested within a randomized-controlled trial. Methods Ninety-four participants from the intervention group were included in the analysis. Baseline pain and function were assessed using a 100 mm Visual Analogue Scale and the Functional Index for Hand Osteoarthritis questionnaire (0-30), respectively. Participants received a combination of treatments including education, orthosis, hand exercises, and topical anti–inflammatory gel. Adherence was measured using a daily self-reported diary. Participants were classified as non–adherent, partially adherent or fully adherent if they completed none, 1 and/or 2 or all 3 of the interventions as prescribed. Ordinal logistic regression modelling was performed. Results At 12-week follow-up, half of the participants were fully adherent to the treatments (n = 46, 48.9%), 30.9% of participants were partially adherent (n = 29) and 20.2% were non–adherent (n = 19, 20.2%). High baseline pain was a significantly associated with better adherence in the unadjusted model [OR = 3.15, 95% CI (1.18, 8.42)] and adjusted model [OR = 3.20, 95% CI (1.13, 8.20)]. Baseline function was not associated with adherence [OR = 1.03, 95% CI (0.47, 2.23)]. Conclusion High baseline pain was associated with better adherence in participants with thumb base OA. Higher baseline functional impairment was not associated with better adherence.

To determine the optimal combination of imaging and biochemical biomarkers for use in the prediction of knee osteoarthritis (OA) progression.The present study was a nested case-control trial from the Foundation of the National Institutes of Health OA Biomarkers Consortium that assessed study participants with a Kellgren/Lawrence grade of 1-3 who had complete biomarker data available (n = 539 to 550). Cases were participants' knees that had radiographic and pain progression between 24 and 48 months compared to baseline. Radiographic progression only was assessed in secondary analyses. Biomarkers (baseline and 24-month changes) that had a P value of0.10 in univariate analysis were selected, including quantitative cartilage thickness and volume on magnetic resonance imaging (MRI), semiquantitative MRI markers, bone shape and area, quantitative meniscal volume, radiographic progression (trabecular bone texture [TBT]), and serum and/or urine biochemical markers. Multivariable logistic regression models were built using 3 different stepwise selection methods (complex models versus parsimonious models).Among baseline biomarkers, the number of locations affected by osteophytes (semiquantitative), quantitative central medial femoral and central lateral femoral cartilage thickness, patellar bone shape, and semiquantitative Hoffa-synovitis predicted OA progression in most models (C statistic 0.641-0.671). In most models, 24-month changes in semiquantitative MRI markers (effusion-synovitis, meniscal morphologic changes, and cartilage damage), quantitative central medial femoral cartilage thickness, quantitative medial tibial cartilage volume, quantitative lateral patellofemoral bone area, horizontal TBT (intercept term), and urine N-telopeptide of type I collagen predicted OA progression (C statistic 0.680-0.724). A different combination of imaging and biochemical biomarkers (baseline and 24-month change) predicted radiographic progression only, which had a higher C statistic of 0.716-0.832.The present study highlights the combination of biomarkers with potential prognostic utility in OA disease-modifying trials. Properly qualified, these biomarkers could be used to enrich future trials with participants likely to experience progression of knee OA.

Duloxetine is a treatment approved by the US Food and Drug Administration for both osteoarthritis (OA) pain and depression, though uptake of duloxetine in knee OA management varies. We examined the cost-effectiveness of adding duloxetine to knee OA care in the absence or presence of depression screening.We used the Osteoarthritis Policy Model, a validated computer microsimulation of knee OA, to examine the value of duloxetine for patients with knee OA who have moderate pain by comparing 3 strategies: 1) usual care, 2) usual care plus duloxetine for patients who screen positive for depression on the Patient Health Questionnaire 9 (PHQ-9), and 3) usual care plus universal duloxetine. Outcome measures included quality-adjusted life years (QALYs), lifetime direct medical costs, and incremental cost-effectiveness ratios (ICERs), discounted at 3% annually. Model inputs, drawn from the published literature and national databases, included annual cost of duloxetine ($721-937); average pain reduction for duloxetine (17.5 points on the Western Ontario and McMaster Universities Osteoarthritis Index pain scale [0-100]), and likelihood of depression remission with duloxetine (27.4%). We considered 2 willingness-to-pay (WTP) thresholds of $50,000/QALY and $100,000/QALY. We varied parameters related to the PHQ-9 and the cost of duloxetine, efficacy, and toxicities to address uncertainty in model inputs.The screening strategy led to an additional 17 QALYs per 1,000 subjects and increased costs by $289/subject (ICER = $17,000/QALY). Universal duloxetine led to an additional 31 QALYs per 1,000 subjects and $1,205 per subject (ICER = $39,300/QALY). Under the majority of sensitivity analyses, universal duloxetine was cost-effective at the $100,000/QALY threshold.The addition of duloxetine to usual care for knee OA patients with moderate pain, regardless of depressive symptoms, is cost-effective at frequently used WTP thresholds.

OBJECTIVE To determine whether long-term diet (D) and exercise (E) interventions, alone or in combination (D+E), have beneficial effects for older adults with knee osteoarthritis 3.5-years after the interventions end. METHODS This is a secondary analysis of a subset (N = 94) of the first 184 participants who had successfully completed the Intensive Diet and Exercise in Arthritis (IDEA) trial (N = 399) and who consented to follow-up testing. Participants were older (age ≥ 55 years), overweight and obese adults with radiographic and symptomatic knee osteoarthritis in at least one knee who completed 1.5-year D+E (N=27), D (N=35), or E (N=32) interventions and returned for 5-year follow-up testing an average of 3.5-years later. RESULTS During the 3.5-years following the interventions, weight regain in D+E and D was 5.9 kg (7%) and 3.1 kg (4%), respectively, with a 1 kg (1%) weight loss in E. Compared to baseline, weight (D+E, -3.7 kg, P=.0007; D, -5.8 kg, P

PURPOSE The prevalence of germline pathogenic variants (PVs) in established breast cancer predisposition genes in women in the general population over age 65 years is not well-defined. However, testing guidelines suggest that women diagnosed with breast cancer over age 65 years might have < 2.5% likelihood of a PV in a high-penetrance gene. This study aimed to establish the frequency of PVs and remaining risks of breast cancer for each gene in women over age 65 years. METHODS A total of 26,707 women over age 65 years from population-based studies (51.5% with breast cancer and 48.5% unaffected) were tested for PVs in germline predisposition gene. Frequencies of PVs and associations between PVs in each gene and breast cancer were assessed, and remaining lifetime breast cancer risks were estimated for non-Hispanic White women with PVs. RESULTS The frequency of PVs in predisposition genes was 3.18% for women with breast cancer and 1.48% for unaffected women over age 65 years. PVs in BRCA1, BRCA2, and PALB2 were found in 3.42% of women diagnosed with estrogen receptor (ER)–negative, 1.0% with ER-positive, and 3.01% with triple-negative breast cancer. Frequencies of PVs were lower among women with no first-degree relatives with breast cancer. PVs in CHEK2, PALB2, BRCA2, and BRCA1 were associated with increased risks (odds ratio = 2.9-4.0) of breast cancer. Remaining lifetime risks of breast cancer were ≥ 15% for those with PVs in BRCA1, BRCA2, and PALB2. CONCLUSION This study suggests that all women diagnosed with triple-negative breast cancer or ER-negative breast cancer should receive genetic testing and that women over age 65 years with BRCA1 and BRCA2 PVs and perhaps with PALB2 and CHEK2 PVs should be considered for magnetic resonance imaging screening.

Summary Objective To investigate heterogeneous effects of a combination of conservative therapies compared with an education comparator for thumb base (TB) osteoarthritis (OA) according to clinically relevant characteristics. Methods Pre-planned subgroup analysis of the COMBO trial (n = 204) which compared a combination of education on self-management and ergonomic principles, a prefabricated neoprene splint, hand exercises, and diclofenac sodium gel, with education alone for radiographic and symptomatic TB OA. Primary outcomes were change in pain (visual analogue scale [VAS], 0–100 mm) and hand function (Functional Index for Hand Osteoarthritis questionnaire, 0–30) from baseline to week-6. Other outcomes were grip and tip-pinch strength and patient's global assessment (PGA) (VAS, 0–100 mm). Possible treatment effect modifiers were the presence of interphalangeal joint pain, erosive hand OA, radiographic thumb carpometacarpal joint subluxation (higher vs equal or lower than the sample mean), and baseline radiographic OA severity (Kellgren Lawrence grade). Linear regression models were fitted, adding interaction terms for each subgroup of interest. Results The treatment effects of the combined intervention at 6 weeks were greater in participants with lower joint subluxation compared with those with greater subluxation (pain −11.6 [95%CI −22.2, −9.9] and 2.6 [−5.5, 10.7], respectively, difference between the subluxation groups 14.2 units (95% CI 2.3, 26.1), p-value 0.02; and PGA −14.0 [−22.4, −5.5] and 1.5 [−6.2, 9.3), respectively, difference between the subluxation groups 15.5 units (95% CI 4.2, 26.8), p-value 0.03). There was no statistically significant heterogeneity for the other subgroups. Conclusion A combination of conservative therapies may provide greater benefits over 6 weeks in individuals with lower joint subluxation, although the clinical relevance is uncertain given the wide confidence intervals. Treatment strategies may need to be customized for those with greater joint subluxation. Trial registration number ACTRN 12616000353493.

Introduction Due to the complex shape of the carpometacarpal (CMC) joint, a fixed joint collapse deformity of the thumb CMC (CMC1) and metacarpophalangeal (MCP1) joint can present in advanced stages of CMC1 osteoarthritis (OA), resulting in adduction of the first metacarpal (MC1) and hyperextension of the MCP1. Purpose of the Study To determine whether joint collapse deformity is associated with worse pain and/or functional impairment. Study Design Cross-sectional. Methods This study used the baseline data from 140 patients enrolled in a longitudinal study of treatment for CMC1 OA. (efficacy of combined conservative therapies on clinical outcomes in patients with CMC1 OA). Joint collapse was determined at baseline using a pinch gauge. Pain was assessed on a visual analog scale (0-100) and function was assessed using the Functional Index for Hand Osteoarthritis questionnaire (0-30). Pain and function and the presence of joint collapse were entered in a univariate logistic regression. The final adjusted model for pain and joint collapse included age and sex. The final adjusted model for function and joint collapse included Kellgren Lawrence grade and grip strength. Results About 20% of participants demonstrated joint collapse on the tip-pinch test. The presence of joint collapse was associated with increased pain in the unadjusted [P = .047, OR = 2.45, 95% CI (1.01, 5.910)] and adjusted model [P = .049, OR = 2.45, 95% CI (1.00, 5.98)]. Conclusion CMC1 patients with joint collapse reported increased pain compared with those without joint collapse. Future studies should determine the relationship between thumb hypermobility and joint collapse and how to manage these conditions effectively.

Objectives To examine whether a hip brace can improve hip health quality-of-life (QoL) and is well-tolerated in people with femoroacetabular impingement syndrome (FAIS) or symptomatic labral tears after 6 weeks of wear. Design Parallel, two-arm, exploratory randomized trial. Setting Hospital and private clinics of orthopaedic surgeons. Participants Individuals >18 years with FAIS or labral tears. Interventions Usual conservative care versus usual conservative care plus a hip brace. Main outcomes Patient-reported outcomes were assessed with the International Hip Outcome Tool (iHOT-33), and Copenhagen Hip and Groin Outcome Scores (HAGOS). Brace acceptability was measured using the Quebec User Evaluation of Satisfaction with Assistive Technology survey. Independent t-tests assessed between-group differences. Results Thirty-eight participants were recruited, 19 each group, 60% women, mean age 39.3 ± 11.8 years, body mass index 25.3 ± 4.4 kg/m2, iHOT-33 36.6 ± 24.8. Three participants dropped out (one usual care, 2 braced). The mean between-group difference for iHOT-33 was 19.4 (95% confidence interval [CI] 1.68-37.06, P = 0.03) favoring the brace. There were improvements in most HAGOS subscale scores favoring the brace. Issues with brace tolerability for some participants were perceived comfort and effectiveness. Three brace-related adverse events were reported. Conclusion Between-group differences favored the braced group for hip health QoL, pain, symptoms, and function. Although these were promising results, the CIs for the estimates were wide, the small sample size likely a contributing factor. Our results suggest that further investigation of the brace is warranted, we calculated sample sizes and made recommendations for the design of a future trial.

PURPOSE This study assessed the joint association of pathogenic variants (PVs) in breast cancer (BC) predisposition genes and polygenic risk scores (PRS) with BC in the general population. METHODS A total of 26,798 non-Hispanic white BC cases and 26,127 controls from predominately population-based studies in the Cancer Risk Estimates Related to Susceptibility consortium were evaluated for PVs in BRCA1, BRCA2, ATM, CHEK2, PALB2, BARD1, BRIP1, CDH1, and NF1. PRS based on 105 common variants were created using effect estimates from BC genome-wide association studies; the performance of an overall BC PRS and estrogen receptor–specific PRS were evaluated. The odds of BC based on the PVs and PRS were estimated using penalized logistic regression. The results were combined with age-specific incidence rates to estimate 5-year and lifetime absolute risks of BC across percentiles of PRS by PV status and first-degree family history of BC. RESULTS The estimated lifetime risks of BC among general-population noncarriers, based on 10th and 90th percentiles of PRS, were 9.1%-23.9% and 6.7%-18.2% for women with or without first-degree relatives with BC, respectively. Taking PRS into account, more than 95% of BRCA1, BRCA2, and PALB2 carriers had > 20% lifetime risks of BC, whereas, respectively, 52.5% and 69.7% of ATM and CHEK2 carriers without first-degree relatives with BC, and 78.8% and 89.9% of those with a first-degree relative with BC had > 20% risk. CONCLUSION PRS facilitates personalization of BC risk among carriers of PVs in predisposition genes. Incorporating PRS into BC risk estimation may help identify > 30% of CHEK2 and nearly half of ATM carriers below the 20% lifetime risk threshold, suggesting the addition of PRS may prevent overscreening and enable more personalized risk management approaches.

The present study was undertaken to assess whether the odds for incident radiographic osteoarthritis (OA) differ between men and women in regard to body mass index (BMI) and inflammatory magnetic resonance imaging (MRI) markers 1 and 2 years prior, and whether the presence of inflammation on MRI differs between normal-weight and overweight/obese individuals who develop radiographic OA up to 4 years prior. We studied 355 knees from the Osteoarthritis Initiative study that developed incident radiographic OA and 355 matched controls. MRIs were read for effusion-synovitis and Hoffa-synovitis for up to 4 consecutive annual time points. Subjects were classified as normal-weight (BMI

To determine whether pericruciate fat pad (PCFP) signal intensity alteration and maximal area are associated with incident radiographic osteoarthritis (ROA) over 4 years in the Osteoarthritis Initiative (OAI) study. Participants were from the Osteoarthritis Initiative (OAI) study. Case knees (n = 355) were defined by incident ROA between 12 and 48 months visits and were matched by sex, age, and radiographic status with control knees (n = 355). Magnetic resonance images (MRIs) were used to assess PCFP signal intensity alteration and PCFP maximal area at P0 (time of onset of ROA), P-1 (1 year prior to P0), and baseline. Conditional logistic regression analyses were applied to assess associations between PCFP measures and the risk of incident ROA. The mean age of participants was 60.1 years and 66.9% were women. In multivariable analyses, PCFP signal intensity alteration measured at three time points (OR [95%CI]: 1.28 [1.10–1.50], 1.52 [1.30–1.78], 1.50 [1.27–1.76], respectively) and PCFP maximal area (OR [95%CI]: 1.21 [1.03–1.42], 1.27 [1.07–1.52], 1.37 [1.15–1.62], respectively) were significantly associated with incident ROA. PCFP signal intensity alteration and maximal area were associated with incident ROA over 4 years, implying that they may have roles to play in ROA. • Pericruciate fat pad signal intensity alteration and maximal area were associated with incident ROA, implying that they may have roles to play in ROA.

Objective To assess whether quantitative changes in the meniscus predict progression from early knee osteoarthritis (OA) to knee replacement (KR). Methods A nested case-control study was conducted among Osteoarthritis Initiative participants: all 35 case knees with baseline Kellgren/Lawrence (K/L) grade ≤2 that had KR between 36 and 60 months were matched 1:1 by age, sex, and baseline K/L grade to 35 control knees without subsequent KR. Quantitative 3-dimensional medial meniscus position and morphologic measures were determined from magnetic resonance imaging at the visit just before KR and 2 years before. Paired t-tests and case-control odds ratios (ORs, standardized per SD of change in controls) were used to compare changes between groups. Results Cases (52% women, age 65 ± 7 years, body mass index [BMI] 30 ± 4 kg/m2 , K/L grades 0/1/2: 5/8/22 participants, respectively) and controls (52% women, age 64 ± 7 years, BMI 30 ± 5 kg/m2 , K/L grades 0/1/2: 9/4/22 participants, respectively) were similar. Compared to control knees, KR case knees displayed longitudinal changes, specifically, a decrease in tibial plateau coverage, an increase in meniscal extrusion, and a decrease in meniscal width. The odds for KR increased with greater reduction in the percentage of tibial plateau coverage (OR 2.28 [95% CI confidence interval (95% CI) 1.43, 3.64]), a greater increase in maximal extrusion (OR 1.40 [95% CI 1.12, 1.75]), and a greater reduction of mean meniscal width (OR 2.01 [95% CI 1.23, 3.26]). The odds for KR increased with medial compartment cartilage thickness loss (OR 2.86 [95% CI 1.51, 5.41]) for comparison. Conclusion Quantitative measures of meniscal position and morphology are associated with subsequent KR in knees with rapidly progressing knee OA. These findings show that structural changes of the meniscus are related to an important clinical and economic outcome of knee OA.

BackgroundPhysical activity (PA) is important to general health and knee osteoarthritis (OA). Excessive workplace PA is an established risk factor for knee OA however, appropriate methods of measurement are unclear. There is a need to examine and assess the utility of new methods of measuring workplace PA and estimating knee load prior to application to large-scale, knee OA cohorts. Our aims, therefore, were to monitor workplace PA and estimate lower-limb loading across different occupations in health participants.MethodsTwenty-four healthy adults, currently working full-time in a single occupation (≥ 35 h/week) and free of musculoskeletal disease, comorbidity and had no history of lower-limb injury/surgery (past 12-months) were recruited across New South Wales (Australia). A convenience sample was recruited with occupations assigned to levels of workload; sedentary, light manual and heavy manual. Metrics of workplace PA including tasks performed (i.e., sitting), step-count and lower-limb loading were monitored over 10 working days using a daily survey, smartwatch, and a smartphone.ResultsParticipants of light manual occupations had the greatest between-person variations in mean lower-limb load (from 2 to 59 kg*m/s3). Lower-limb load for most participants of the light manual group was similar to a single participant in heavy manual work (30 kg*m/s3) and was at least three times greater than the sedentary group (2 kg*m/s3). The trends of workplace PA over working hours were largely consistent, per individual, but rare events of extreme loads were observed across all participants (up to 760 kg*m/s3).ConclusionsThere are large interpersonal variations in metrics of workplace PA, particularly among light and heavy manual occupations. Our estimates of lower-limb loading were largely consistent with pre-conceived levels of physical demand. We present a new approach to monitoring PA and estimating lower-limb loading, which could be applied to future occupational studies of knee OA.

Background: It is not known whether modifiable lifestyle factors that predict survival after invasive breast cancer differ by subtype. Methods: We analyzed data for 121,435 women diagnosed with breast cancer from 67 studies in the Breast Cancer Association Consortium with 16,890 deaths (8,554 breast cancer specific) over 10 years. Cox regression was used to estimate associations between risk factors and 10-year all-cause mortality and breast cancer–specific mortality overall, by estrogen receptor (ER) status, and by intrinsic-like subtype. Results: There was no evidence of heterogeneous associations between risk factors and mortality by subtype (Padj > 0.30). The strongest associations were between all-cause mortality and BMI ≥30 versus 18.5–25 kg/m2 [HR (95% confidence interval (CI), 1.19 (1.06–1.34)]; current versus never smoking [1.37 (1.27–1.47)], high versus low physical activity [0.43 (0.21–0.86)], age ≥30 years versus 0– Conclusions: We confirm associations between modifiable lifestyle factors and 10-year all-cause mortality. There was no strong evidence that associations differed by ER status or intrinsic-like subtype. Impact: Given the large dataset and lack of evidence that associations between modifiable risk factors and 10-year mortality differed by subtype, these associations could be cautiously used in prognostication models to inform patient-centered care.

Objective To test the effectiveness of a 32-week, stepped-care intervention on disease remission rates in overweight and obese patients with medial tibiofemoral osteoarthritis (OA) compared to controls. Methods In this randomized controlled trial, eligible participants were ≥50 years of age with a body mass index of ≥28 kg/m2 and radiographic evidence of medial tibiofemoral OA. Participants were randomized to stepped-care (n = 87) or control group (n = 84). The stepped-care group received a 2-step intervention. The first step consisted of an 18-week diet and exercise program. The second step consisted of 4 treatment subgroups: 1) diet and exercise maintenance; 2) cognitive-behavioral therapy; 3) unloader knee brace; and 4) muscle strengthening exercises. Allocation into subgroups was based on disease remission state and clinical characteristics. The primary end point was the disease remission rate (yes/no) at 32 weeks, which was reached when participants achieved the Patient Acceptable Symptom State cutoff value for pain and for the patient global assessment of disease activity and/or functional impairment. Results Disease remission at 32 weeks was achieved by 18 of 68 (26%) in the control group and 32 of 82 (39%) in the stepped-care group (difference 12.6% [95% confidence interval -2.3, 27.4], P = 0.10). The stepped-care group showed an improvement in pain and function between baseline and 20 weeks. While functional improvement was maintained at 32 weeks, pain levels tended to get worse between weeks 20 and 32. Conclusion The proposed intervention did not promote a significant difference in the rate of disease remission in comparison to the control group for overweight or obese patients with medial tibiofemoral OA.

BACKGROUND: Population-based estimates of the risk of breast cancer associated with germline pathogenic variants in cancer-predisposition genes are critically needed for risk assessment and management in women with inherited pathogenic variants. METHODS: In a population-based case–control study, we performed sequencing using a custom multigene amplicon-based panel to identify germline pathogenic variants in 28 cancer-predisposition genes among 32,247 women with breast cancer (case patients) and 32,544 unaffected women (controls) from population-based studies in the Cancer Risk Estimates Related to Susceptibility (CARRIERS) consortium. Associations between pathogenic variants in each gene and the risk of breast cancer were assessed. RESULTS: Pathogenic variants in 12 established breast cancer–predisposition genes were detected in 5.03% of case patients and in 1.63% of controls. Pathogenic variants in BRCA1 and BRCA2 were associated with a high risk of breast cancer, with odds ratios of 7.62 (95% confidence interval [CI], 5.33 to 11.27) and 5.23 (95% CI, 4.09 to 6.77), respectively. Pathogenic variants in PALB2 were associated with a moderate risk (odds ratio, 3.83; 95% CI, 2.68 to 5.63). Pathogenic variants in BARD1, RAD51C, and RAD51D were associated with increased risks of estrogen receptor–negative breast cancer and triple-negative breast cancer, whereas pathogenic variants in ATM, CDH1, and CHEK2 were associated with an increased risk of estrogen receptor–positive breast cancer. Pathogenic variants in 16 candidate breast cancer–predisposition genes, including the c.657_661del5 founder pathogenic variant in NBN, were not associated with an increased risk of breast cancer. CONCLUSIONS: This study provides estimates of the prevalence and risk of breast cancer associated with pathogenic variants in known breast cancer–predisposition genes in the U.S. population. These estimates can inform cancer testing and screening and improve clinical management strategies for women in the general population with inherited pathogenic variants in these genes. (Funded by the National Institutes of Health and the Breast Cancer Research Foundation.)

Background: Use of menopausal hormone therapy (MHT) is associated with increased risk for breast cancer. However, the relevant mechanisms and its interaction with genetic variants are not fully understood. Methods: We conducted a genome-wide interaction analysis between MHT use and genetic variants for breast cancer risk in 27,585 cases and 34,785 controls from 26 observational studies. All women were post-menopausal and of European ancestry. Multivariable logistic regression models were used to test for multiplicative interactions between genetic variants and current MHT use. We considered interaction p-values-8 as genome-wide significant, and p-values-5 as suggestive. Linkage disequilibrium (LD)-based clumping was performed to identify independent candidate variants.Results: None of the 9.7 million genetic variants tested for interactions with MHT use reached genome-wide significance. Only 213 variants, representing 18 independent loci, had p-values5. The strongest evidence was found for rs4674019 (p-value=2.27x10-7), which showed genome-wide significant interaction (p-value=3.8x10-8) with current MHT use when analysis was restricted to population-based studies only. Limiting the analyses to combined estrogen-progesterone MHT use only or to estrogen receptor (ER) positive cases did not identify any genome-wide significant evidence of interactions. Conclusions: In this large genome-wide SNP-MHT interaction study of breast cancer, we found no strong support for common genetic variants modifying the effect of MHT on breast cancer risk. These results suggest that common genetic variation has limited impact on the observed MHT–breast cancer risk association.

Background Microsurgical free tissue transfer has become a reliable technique with success rates around 99% and around 5% requiring exploration for vascular compromise. Protocols for flap monitoring between plastic surgery units vary. We aimed to elucidate the time period when monitoring is crucial for flap salvage. Methods A systematic search of literature was performed in PubMed, Cochrane Library, Medline, and Scopus databases from 1966 to July 2018 according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, identifying 3,844 studies with mention of free flap and monitoring or timing or salvage or compromise. Studies were screened for relevance according to predetermined inclusion criteria. Data was extracted from included studies relating to flap type, monitoring, timing and reason for failure, and success of salvage intervention. Results A total of 109 studies featuring 44,031 free flaps were included. A total of 2,549 (5.8%) flaps required return to theater for compromise; 926 (2.1%) were lost and 1,654 (3.7%) were salvaged. In the first 24 hours postoperatively 93.8% of explored flaps are successfully salvaged, by day 2: 83.33%, day 3: 12.1%, and beyond day 4: none were successful. Of the 355 flaps where the cause of failure was reported, 59.5% was venous, 27.9% was arterial, 2.3% was a combination of both, and 10.2% was hematoma or infection. The proportion of flap failures at various recipient sites was highest in the trunk/viscera (7%, 95% confidence interval [CI] 0.00, 0.36), followed by limbs (5%, 95% CI 0.02, 0.08), head and neck (3%, 95% CI 0.02, 0.04), and breast ( Conclusion Close flap monitoring is of most value in the first 48 hours postoperatively, facilitating rapid detection of vascular compromise, early salvage, and better outcomes. The location of the flap has implications on its success and certain recipient sites may need particular attention to improve chances of success.

Background Knee osteoarthritis (OA) is a highly prevalent musculoskeletal condition causing pain, physical disability, and reduced quality of life. Exercise and patient education are non-pharmacological interventions for knee OA unanimously recommended as first-line treatments based on extensive research evidence. However, none of the numerous randomised controlled trials of exercise and education for knee OA has used adequate sham/placebo comparison groups because the ‘active’ ingredients are unknown. Designing and executing an adequate and ‘blindable placebo’ version of an exercise and education intervention is impossible. Therefore, using an open-label study design, this trial compares the efficacy of a widely used ‘state-of-art’ exercise and education intervention (Good Life with osteoarthritis in Denmark; GLAD) with presumably inert intra-articular saline injections on improvement in knee pain in patients with knee OA. Methods In this open-label randomised trial, we will include 200 patients with radiographically verified OA of the knee and randomly allocate them to one of two interventions: (i) 8 weeks of exercise and education (GLAD) or (ii) Intra-articular injections of 5 ml isotonic saline every second week for a total of 4 injections. Outcomes are taken at baseline, after 8 weeks of treatment (week 9; primary endpoint) and after an additional 4 weeks of follow-up (week 12). The primary outcome is change from baseline in the Knee Injury and Osteoarthritis Outcome Score questionnaire (KOOS) pain subscale score. Secondary outcomes include the Physical function in Activities of Daily Living, Symptoms, and Knee-related Quality of Life subscales of the KOOS, the patients’ global assessment of disease impact, physical performance tests, and presence of knee joint swelling. Discussion This current trial compares a presumably active treatment (GLAD) with a presumably inert treatment (IA saline injections). Both study interventions have well-established and anticipated similar effects on knee OA symptoms, but the underlying mechanisms are unknown. The interpretation of the results of this trial will likely be difficult and controversial but will contribute to a better understanding of the bias introduced in the effect estimation of classically unblindable exercise and education interventions for knee OA. Trial registration www.ClinicalTrials.govNCT03843931. Prospectively registered on 18 February 2019.

Objective Use of specific medications may accelerate the progression of radiographic knee OA (RKOA). Our aim was to examine the effect of medication use on the progression of RKOA. Methods We used longitudinal data from the Osteoarthritis Initiative (OAI), an observational study of risk factors for knee OA. At baseline, we selected participants with RKOA (Kellgren–Lawrence grade ≥2) and excluded those with a history of knee-related injury/surgery and other musculoskeletal disorders. Current medication use (use/non-use in the previous 30 days) and radiographic medial minimum joint space width (mJSW) data were available at baseline and annually up to 96 months follow-up. We used random effects, panel regression to assess the association between current medication use (non-users as reference group) and change in mJSW. Results Of 2054 eligible participants, 2003 participants with baseline mJSW data were included [55.7% female, mean age 63.3 (s.d. 8.98) years]. Of seven medication classes, at baseline NSAIDs were the most frequently used analgesia (14.7%), anti-histamine (10.4%) use was frequent and the following comorbidity medications were used most frequently: statins (27.4%), anti-hypertensives (up to 15.0%), anti-depressant/anxiolytics/psychotropics (14.0%), osteoporosis-related medication (10.9%) and diabetes-related medication (6.9%). Compared with current non-users, current use of NSAIDs was associated with a loss of mJSW (b = −0.042, 95% CI −0.08, −0.0004). No other associations were observed. Conclusions In current users of NSAIDs, mJSW loss was increased compared with current non-users in participants with RKOA. Clinical trials are required to assess the potential disease-modifying effects of these medications.

Background To assess the association of co-existing MRI lesions with knee pain at rest or on joint loading. Methods We included participants from Osteoarthritis Initiative whose pain score, measured by WOMAC sub-scales, differed by ≥1 point at rest (in bed at night, sitting/lying down) or on joint loading (walking, stairs) between two knees. Cartilage morphology, bone marrow lesions, meniscus extrusion, meniscus morphology, Hoffa’s synovitis and synovitis-effusion were assessed using the compartment-specific MRI Osteoarthritis Knee Score. We performed latent class analyses to identify subgroups of co-existing MRI lesions and fitted a conditional logistic regression model to examine their associations with knee pain. Results Among 130 eligible participants, we identified five subgroups of knees according to patterns of co-existing MRI lesions: I. minimal lesions; II. mild lesions; III. moderate morphological lesions; IV. moderate multiple reactive lesions; and V. severe lesions. Compared with subgroup I, the odds ratios (ORs) and 95% confidence intervals (CI) of greater pain in bed at night were 1.6 (0.3, 7.2), 2.2 (0.5, 9.5), 6.2 (1.3, 29.6) and 11.2 (2.1, 59.2) for subgroups II-V, respectively. A similar association was observed between aforementioned subgroups and pain with sitting/lying down. The ORs (95% CI) of greater pain with walking were 1.0 (reference), 1.7 (0.5, 6.1), 0.7 (0.2, 2.3), 5.0 (1.4, 18.6) and 7.9 (2.0, 31.5) for subgroup I-V, respectively. The corresponding analysis for pain on stairs showed similar results. Conclusions Distinct patterns of co-existing MRI lesions have different implications for the pathogenesis of osteoarthritic knee pain occurring with/without joint loading.

Genital lymphedema is a rare condition in males that can lead to difficulty in voiding, sexual function, hygiene, and mobility. Only several methods of treatment have been developed and studied, primarily focusing on restoring patency of diseased lymph channels or resection of affected tissue. We are the first to describe the surgical technique and our experience of using free submental and submandibular arterio-venous vascularized lymph node transfer specifically for the treatment of scrotal edema. We report on two patients who have undergone selective neck dissection of submental and submandibular lymph nodes based off the facial artery and vein. These vascularized lymph nodes were then transferred to the groin, with anastomosis to the deep inferior epigastric perforator artery and vein. The first patient, a 63 year old had initial pretreatment measurement of the anal verge to base of penis was 18 cm in length, and maximum circumference of scrotum 27 cm for the first patient, and 31-42 cm, respectively, for the second patient, a 66 year old. At 9-month review for the first patient and 6-month review for the second patient, both donor and recipient site wounds had healed. The anal verge to base of penis length had decreased to 16 cm, while maximum circumference of scrotum had decreased to 23 cm, and 25-38 cm, respectively, for the second patient. We have had good success with reducing the burden on patients using this novel technique, and hence it should be considered as a viable treatment methodology in appropriately selected patients.

BACKGROUND: Recommended first-line management of lower limb osteoarthritis (OA) includes support for self-management, exercise and weight loss. However, many Australians with OA do not receive these. A National Osteoarthritis Strategy (the Strategy) was developed to outline a national plan to achieve optimal health outcomes for people at risk of, or with, OA. OBJECTIVE: The aim of this article is to identify priorities for action for Australians living with OA. DISCUSSION: The Strategy was developed in consultation with a leadership group, thematic working groups, an implementation advisory committee, multisectoral stakeholders and the public. Two priorities were identified by the 'living well with OA' working group: 1) support primary care practitioners in the delivery of high-value care to Australians with OA, and 2) enhance the uptake of high-value care by Australians with OA. Evidence-informed strategies and implementation plans were developed through consultation to address these priorities.

Summary Objective To investigate whether baseline cartilage thickness and its longitudinal change are associated with incident widespread full-thickness cartilage loss (wsFTCL) in knee osteoarthritis, and whether there are optimal cut-off values for predicting wsFTCL. Methods Central medial tibial (cMT) and femoral (cMF) cartilage were assessed using quantitative magnetic resonance imaging data from the Osteoarthritis Initiative cohort (N = 600 knees). Cartilage thickness was measured at baseline and 12 months. wsFTCL was defined semi-quantitatively (scores 2 and 3 from the MRI Osteoarthritis Knee Score) and its incidence at 24 months recorded. Logistic regression was used to determine the odds of developing wsFTCL for baseline and for each 0.1 mm decrease in cartilage thickness. Cut-off values were investigated using the minimal-p method and area under the Receiver Operating Characteristic curves (AUC). Results Incident wsFTCL was observed in 66 (12%) and 73 (14%) knees in cMT and cMF, respectively. Lower baseline cMT and cMF cartilage thickness values were associated with wsFTCL (OR = 1.20; 95% CI: 1.11, 1.28 and OR = 1.15; 95% CI: 1.06 to 1.24, respectively). Optimal cut-off AUCs for the tibia and femur were 0.64 (0.57–0.70) and 0.63 (0.57–0.69), respectively. Longitudinal decrease in femoral, but not tibial, cartilage thickness was associated with incident wsFTCL (OR = 1.77; 95% CI: 1.30 to 2.40); optimal cut-off AUC 0.65 (95% CI: 0.58–0.72). Conclusion Lower baseline cMT and baseline/change (decrease) over 12 months in cMF cartilage thickness were associated with incident, location-specific, wsFTCL at 24 months. Optimal cut-off values were relatively low and of uncertain utility for predicting incident wsFTCL.

Introduction. Hypertension is a leading risk factor for cardiovascular mortality and an emerging public health concern in sub-Saharan Africa. Few studies have examined performance on the management of hypertension in this region, where the context may be distinct from other developing regions. Objectives. We aimed to determine the prevalence and correlates of hypertension, awareness, treatment, and control among adults in Botswana, a middle-income African country undergoing rapid demographic transition and with high HIV burden. Methods. In this 2014 cross-sectional survey of adults aged 15–69 years, information on sociodemographic characteristics, lifestyle behavior, and medical history was collected through in-person interviews and physical measurements (body mass index and triplicate blood pressure (BP)). Hypertension was defined as self-report of use of antihypertensives in the previous two weeks and/or having elevated BP (≥140/90 mmHg). Multivariable logistic regression was employed to explore factors associated with hypertension, awareness (report of previous diagnosis), treatment (antihypertensives), and control (BP Results. Our analysis (N = 4,007) yielded an age-standardized hypertension prevalence of 30% (95% CI: 28%–32%, N = 1,393). Among hypertensives, 54% (50–58%) were unaware of their condition, 45% (40–50%) of those aware were untreated, and 63% (55–70%) of those on medications were suboptimally treated (BP ≥ 140/90 mmHg). A fifth of hypertensives who were diagnosed but not on medications had BP ≥ 180/110 mmHg. Diabetes was the strongest correlate of hypertension and awareness (aOR 4.00, 1.86–8.59; aOR 3.30, 1.44–7.55, respectively). Males were less likely to be aware (aOR 0.62, 0.41–0.94) or controlled (aOR 0.36, 0.16–0.83). Obese individuals were more likely to be treated (aOR 2.17, 1.12–4.22), yet less likely to be controlled (aOR 0.32, 0.15–0.66). Conclusions. We report the first nationally representative estimates of the hypertension care cascade performance in Botswana, which will support planning and future policy evaluations. Findings contribute to the relatively sparse evidence on this subject and may inform development of innovations that improve quality of hypertension management and adherence support in similar settings.

Fat necrosis is a common complication for the deep inferior epigastric perforator (DIEP) flap. A thorough understanding of the factors associated with fat necrosis will aid operative planning for reconstructive surgeons. A systematic review of the literature was performed between January 1989 and April 2019. Studies were included if they reported on fat necrosis in DIEP flap or evaluated the perfusion of the DIEP flap. Twenty-eight out of 312 studies met the inclusion and exclusion criteria. Fat necrosis rates ranged from 12.0 to 45.0% on clinical examination within the literature. The four main perforator-specific factors identified included perforator perfusion zones, perforator location, perforator number and venous congestion. Medial row perforators have a wider perfusion zone, while lateral row perforators have a narrow perfusion zone. Holm zone III has a higher rate of fat necrosis compared to Holm zone II. One to two perforators and more than five perforators and a Type III atypical connection between the superficial and deep venous system had a higher rate of fat necrosis. The DIEP flap should incorporate between two and three perforators of a substantial calibre; Holm zone III should be excluded if able and careful review of the pre-operative imaging should be performed to analyse the connections between the deep and superficial venous system. There are multiple perfusion-related factors to consider when planning the DIEP flap and ultimately a patient-specific approach to the vascular anatomy is essential. This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Osteoarthritis is the most prevalent joint condition that continues to increase with an ever-aging population and the rising tide of obesity. There are multiple recommendations/guidelines for the management of osteoarthritis. The basis of management should focus on self-management and education, lifestyle modifications, exercise and when appropriate, weight loss. Pharmacotherapy is targeted toward pain palliation with no agents available presently to target prevention and disease modification. The selection of pharmacotherapy should be tailored to the individual, taking into account of personal preferences and interactions with underlying co-morbidities. This editorial provides a guide to the selection process of presently available pharmacotherapy in osteoarthritis.

Objective Hand osteoarthritis (OA) trials often target exclusively the thumb base joint, although concomitant widespread interphalangeal (IP) joint involvement is frequent. We aimed to compare hand strength and function between individuals with isolated thumb base OA and those with coexistent IP joint pain and erosive OA. Methods Baseline data from a thumb base OA trial were analyzed (n = 204). Participants were age ≥40 years with symptomatic and radiographic thumb base OA. Only the index hand was included. Self-reported IP joint pain (in any proximal, distal, or thumb IP joint), hand function score (Functional Index for Hand Osteoarthritis questionnaire [range 0-30]), and hand grip and tip-pinch strength test results were obtained at baseline. Radiographs were scored for OA severity at each joint (Kellgren/Lawrence grade) and for the presence of erosive OA at the thumb base or IP joints. Multiple linear regression was used adjusting for age, sex, body mass index, and radiographic thumb base OA severity. Results Compared to individuals with isolated thumb base OA (62%), those with concomitant IP joint pain (17%) and erosive OA (21%) had significantly worse hand function (β = 1.82 [95% confidence interval (95% CI) 0.36, 3.28] and β = 1.47 [95% CI 0.74, 2.88], respectively). In addition, coexistence of erosive OA was independently associated with lower grip and tip-pinch strength (β = -5.14 [95% CI -7.58, -2.70] and β = -0.61 [95% CI -1.05, -0.17], respectively). Conclusion Concomitant IP joint pain and erosive OA are associated with worse hand function in individuals with thumb base OA. Patient stratification based on these characteristics may improve the design of future thumb base OA trials.

Summary Objective To determine if qualitative and quantitative measures of prefemoral fat pad (PFP) and quadriceps fat pad (QFP) are associated with incident radiographic osteoarthritis (iROA) over 4 years in the Osteoarthritis Initiative (OAI) study. Design Participants in this nested case–control study were selected from the OAI study with knees that had Kellgren Lawrence grades (KLG) of 0 or 1 at baseline. Case knees were defined by iROA (KLG≥ 2) over 4 years. Control knees without iROA were matched 1:1 with case knees. Magnetic resonance images (MRIs) were read at P0 (time of onset of iROA), P-1 (1 year prior to P0) and baseline, and used to assess PFP (i.e., prefemoral hyperintensity alteration, patellofemoral hyperintensity alteration, maximum axial area) and QFP (i.e., hyperintensity alteration, mass effect, maximum axial area). Conditional logistic regression analyses were performed to study the associations between PFP/QFP measures and iROA, after adjustment for covariates. Results 354 case knees with iROA were matched to 354 control knees. 66.9% of the participants were female, with an average age of 60.1 years. PFP prefemoral hyperintensity alteration measured at three time points (OR [95%CI]: 1.46 [1.18–1.82], 1.50 [1.20–1.88], 1.52 [1.22–1.89] respectively), PFP maximum axial area (OR [95%CI]: 1.07 [1.01–1.14], 1.08 [1.01–1.15], 1.08 [1.02–1.15] respectively) and QFP hyperintensity alteration (OR [95%CI]: 1.59 [1.27–2.00], 1.44 [1.13–1.82], 1.38 [1.09–1.73] respectively) were significantly associated with iROA in multivariable conditional logistic analyses. QFP mass effect measured at BL and P-1 (OR [95%CI]: 1.42 [1.11–1.82], 1.33 [1.01–1.73] respectively) were significantly associated with iROA. Conclusions Qualitative and quantitative measures of PFP and QFP are associated with increased iROA over 4 years.

Osteoarthritis (OA) is the leading cause of pain, loss of function and disability in the elderly, with the knee being the most impactful joint affected. Currently, there is still no 'cure' in OA treatment.The authors review the current and emerging therapies for knee OA including traditional OA medications (oral and topical NSAIDs, acetaminophen, and opioids) and emerging treatments including disease-modifying OA drugs. The failures of agents that have been through clinical trials are also summarized. Furthermore, the authors provide their expert perspectives on the future of pharmacotherapy for knee osteoarthritis.Compared to traditional OA medications, new disease-modifying OA drugs that act by reducing inflammation and increasing cartilage repair show promise to address the unmet need of disease modification. Many of these new drugs, however, are in the preclinical stage. Long-term RCTs are expected to identify the safety and efficacy of novel OA pharmacotherapy medicines.

IntroductionKnee osteoarthritis (KOA) is a highly prevalent disabling joint disease. Intra-articular stem cell therapy is increasingly being used for treating KOA with little high-quality evidence to support its use. The aim of this study is to investigate the efficacy, safety and cost-effectiveness of allogeneic mesenchymal stem cells (Cymerus MSCs) for treating symptomatic tibiofemoral KOA and improving knee structure over 24 months.Methods and analysisThe Stem Cell injections for symptomatic relief and strUctural improvement in people with Tibiofemoral knee OsteoaRthritis study is a phase III, multi-centre, parallel, superiority, randomised, double-blind, placebo-controlled trial, which will be conducted in Sydney and Hobart, Australia. 440 participants (220 per arm) aged over 40 years with painful KOA and mild to moderate structural change on X-ray (Kellgren and Lawrence grade 2 or 3) with medial minimum joint space width between 1 and 4 mm in the study knee will be recruited from the community and randomly allocated to receive either intra-articular MSCs or saline at baseline, week 3 and week 52. The coprimary outcomes will be the proportion of participants achieving patient-acceptable symptom state for knee pain at 24 months and quantitative central medial femorotibial compartment cartilage thickness change from baseline to 24 months. Main secondary outcomes include change in knee pain, Patient Global Assessment, physical function, quality of life and other structural changes. Additional data for cost-effectiveness analysis will also be recorded. Adverse events will be monitored throughout the study. The primary analysis will be conducted using modified intention-to-treat.Ethics and disseminationThis protocol has been approved by The University of Sydney (USYD) Human Research Ethics Committee (HREC) #: 2020/119 and The University of Tasmania (UTAS) HREC #: H0021868. All participants will be required to provide informed consent. Dissemination will occur through conferences, social media, and scientific publications.Trial registration numbersAustralian New Zealand Clinical Trials Registry (ACTRN12620000870954); U1111-1234-4897.

Aim To investigate the associations of ultrasound and radiographic features of thumb-base osteoarthritis (OA) with thumb-base pain and hand function at baseline and 12 weeks. Method Data from a randomized controlled trial conducted in participants with symptomatic radiographic thumb-base OA were analyzed. Participants who finished follow up were included in this secondary analysis. Pain and hand function were assessed using self-reported measures. All participants underwent ultrasound examinations for synovitis, power Doppler signal (PDS), and osteophytes, and underwent radiography for osteophytes, joint space narrowing (JSN), and subchondral bone sclerosis at baseline. Hand pain and function were reassessed after the 12-week follow up. The associations of ultrasound and radiographic findings with clinical features were further evaluated, using linear regression analyses, after adjustment for relevant confounding factors. Results A total of 166 participants (average age 66.2 years; 76.5% female) were included. At baseline, radiographic JSN and subchondral bone sclerosis were associated with hand function. There was a significant association between ultrasound-detected PDS and patient's global assessment (PGA) at baseline. Baseline radiographic JSN was significantly associated with the changes in stiffness and PGA from baseline to 12 weeks. There was no association between ultrasound features and changes in the clinical outcomes over 12 weeks. Conclusion This study indicates that radiographic features significantly correlate with hand function, and ultrasound PDS is closely related to the PGA at baseline in thumb-base OA. Radiographic JSN may be a predictor for stiffness and PGA in thumb-base OA.

Musculoskeletal pain such as osteoarthritis (OA) and low back pain (LBP) are very common and contribute to enormous burden and societal costs, despite dramatic therapeutic advances over recent decades. Novel approaches and targeted therapies are required to satisfy the urgent unmet medical need of musculoskeletal pain relief in both conditions. Nerve growth factor (NGF) inhibitors have utilized novel mechanisms different from conventional drugs, which have a variety of gastrointestinal, cardiac, or renal adverse effects. Several phase 2/3 studies have been accomplished for these drugs, such as tanezumab, fasinumab, and tyrosine receptor kinase A (TrkA) inhibitors. We searched the literature using the PubMed database and clinical trials using ClinicalTrials.gov to identify original papers, meta-analyses as well as ongoing clinical trials assessing the efficacy and safety profile of these drugs. In this narrative review, we briefly overview the disease burden of musculoskeletal pain, the role of NGF signaling and its receptors in the genesis of pain, and the mechanisms of action of inhibitors of NGF signaling and downstream pathways, and then discuss the efficacy and safety of each investigational drug in OA and LBP. Finally, we briefly review two serious adverse effects of NGF inhibitors, namely rapidly progressive OA and sympathetic system effects, and conclude with possible barriers and potential research directions to overcome these.

AIMS: To determine: 1) inter-rater reliability of quantitative measurements of ultrasound-detected synovitis, meniscal extrusion, and osteophytes; and 2) construct (convergent) validity via correlations and absolute agreements between ultrasound- and gold-standard magnetic resonance imaging (MRI)-outcomes in knee osteoarthritis. METHODS: Dynamic ultrasound images for supra-patellar synovitis, meniscal extrusion, and osteophytes were acquired and quantified by a physician operator, musculoskeletal ultrasonographer, and medical student independently. On the same day, 3T MRI images were acquired. Effusion-synovitis, meniscal extrusion, and osteophytes were quantified on sagittal or coronal proton-density-weighted fat-suppressed noncontrast TSE sequences, respectively. Intra-class correlation coefficients (ICCs), Pearson's correlations (r), and Bland-Altman plots were used to analyze inter-rater reliability, and correlations, and agreements between the two imaging modalities. RESULTS: Eighty-nine participants [48 females (53.9%)] with mean (standard deviation) age of 61.5 ± 6.9 years were included. The inter-rater reliability was excellent for osteophytes (ICC range = 0.90-0.96), meniscal extrusion (ICC range = 0.90-0.93), and synovitis (ICC range = 0.86-0.88). The correlations between ultrasound pathologies and their MRI counterparts were very strong (ICC range = 0.85-0.98) except for lateral meniscal extrusion [0.66 (95% CI, 0.52-0.76)]. Bland-Altman plots showed 0.01, 0.05, 0.10, 0.53, and 0.60 mm larger size in ultrasound medial tibial and medial femoral osteophytes, medial meniscal extrusions, synovitis, and lateral meniscal extrusions with 95% limits of agreements [±0.39, ±0.44, ±0.85, ±0.70, and ±0.90 (SDs)] than MRI measures, respectively. The lines of equality were within 95% CI of the mean differences (bias) only for medial osteophytes and medial meniscal extrusion. CONCLUSION: The quantitative assessment of synovitis, meniscal extrusion, and osteophytes generally showed excellent inter-rater reliability and strong correlations with MRI-based measurements. Absolute agreement was strong for medial tibiofemoral pathologies.

Background: Bony morphology is central to the pathomechanism of femoroacetabular impingement syndrome (FAIS), however isolated radiographic measures poorly predict symptom onset and severity. More comprehensive morphology measurement considered together with patient factors may better predict symptom presentation. This study aimed to determine the morphological parameter(s) and patient factor(s) associated with symptom age of onset and severity in FAIS. Methods: 99 participants (age 32.9 ± 10.5 years; body mass index (BMI 24.3 ± 3.1 kg/m2; 42% females) diagnosed with FAIS received standardised plain radiographs and magnetic resonance scans. Alpha angle in four radial planes (superior to anterior), acetabular version (AV), femoral torsion, lateral centre-edge, anterior centre-edge (ACEA) and femoral neck-shaft angles were measured. Age of symptom onset (age at presentation minus duration of symptoms), international Hip Outcome Tool-33 (iHOT-33) and modified UCLA activity scores were recorded. Backward stepwise regression assessed morphological parameters and patient factors (age, sex, BMI, symptom duration, annual income, private/public healthcare system accessed) to determine variables independently associated with onset age and iHOT-33 score. Results: Earlier symptom onset was associated with larger superoanterior alpha angle ( p = 0.007), smaller AV ( p = 0.023), lower BMI ( p = 0.010) and public healthcare system access ( p = 0.041) (r2 = 0.320). Worse iHOT-33 score was associated with smaller ACEA ( p = 0.034), female sex ( p = 0.040), worse modified UCLA activity score ( p = 0.010) and public healthcare system access ( p 2 = 0.340). Conclusions: Age of symptom onset was chiefly predicted by femoral and acetabular bony morphology measures, whereas symptom severity predominantly by patient factors. Factors measured explained a small amount of variance in the data; additional unmeasured factors may be more influential.

BackgroundArthroscopic surgery for femoroacetabular impingement syndrome (FAI) is known to lead to self-reported symptom improvement. In the context of surgical interventions with known contextual effects and no true sham comparator trials, it is important to ascertain outcomes that are less susceptible to placebo effects. The primary aim of this trial was to determine if study participants with FAI who have hip arthroscopy demonstrate greater improvements in delayed gadolinium-enhanced magnetic resonance imaging (MRI) of cartilage (dGEMRIC) index between baseline and 12 months, compared to participants who undergo physiotherapist-led management.MethodsMulti-centre, pragmatic, two-arm superiority randomised controlled trial comparing physiotherapist-led management to hip arthroscopy for FAI. FAI participants were recruited from participating orthopaedic surgeons clinics, and randomly allocated to receive either physiotherapist-led conservative care or surgery. The surgical intervention was arthroscopic FAI surgery. The physiotherapist-led conservative management was an individualised physiotherapy program, named Personalised Hip Therapy (PHT). The primary outcome measure was change in dGEMRIC score between baseline and 12 months. Secondary outcomes included a range of patient-reported outcomes and structural measures relevant to FAI pathoanatomy and hip osteoarthritis development. Interventions were compared by intention-to-treat analysis.ResultsNinety-nine participants were recruited, of mean age 33 years and 58% male. Primary outcome data were available for 53 participants (27 in surgical group, 26 in PHT). The adjusted group difference in change at 12 months in dGEMRIC was -59 ms (95%CI − 137.9 to - 19.6) (p = 0.14) favouring PHT. Hip-related quality of life (iHOT-33) showed improvements in both groups with the adjusted between-group difference at 12 months showing a statistically and clinically important improvement in arthroscopy of 14 units (95% CI 5.6 to 23.9) (p = 0.003).ConclusionThe primary outcome of dGEMRIC showed no statistically significant difference between PHT and arthroscopic hip surgery at 12 months of follow-up. Patients treated with surgery reported greater benefits in symptoms at 12 months compared to PHT, but these benefits are not explained by better hip cartilage metabolism.Trial registration detailsAustralia New Zealand Clinical Trials Registry reference:ACTRN12615001177549. Trial registered 2/11/2015.

The study aimed to determine the associations between the morphological types of proximal tibiofibular joint (PTFJ) and the risk of total knee replacement (TKR) in a cohort of participants with progressive osteoarthritis. A nested case-control design was performed in Osteoarthritis Initiative study. The case knees were those with TKR at 24-60 months follow up (cases), and were 1:1 matched with control knees by age, sex, and Kellgren-Lawrence grade at baseline. The morphological type of each PTFJ was identified according to the coronal and sagittal MR images. Conditional logistic regression models were used to examine the association of the PTFJ types with the risk of TKR at baseline and the time point before TKR (T0 ). A total of 193 case knees at baseline and 148 case knees at T0 time point had matched controls between 12 and 60 M. Seven types of the PTFJ were identified and classified into three categories: plane, trochoid, and irregular types. The prevalence of the irregular type was higher in case knees than in controls both at baseline (cases vs. controls, 35.8% vs. 26.9%) and at T0 time point (cases vs. controls, 33.1% vs. 27.0%). The irregular type of the PTFJ at baseline (odds ratio: 1.62, 95% confidence interval: 1.01-2.59) rather than at T0 time point was significantly associated with increased odds of TKR. The irregular types of the PTFJ at baseline are associated with increased risk of TKR, suggesting PTFJ may play a role in knee osteoarthritis.

BACKGROUND: Osteoarthritis (OA) is one of the most common chronic joint diseases and a leading cause of pain and disability in Australia. A National Osteoarthritis Strategy (the Strategy) was developed to outline a national plan to achieve optimal health outcomes for people at risk of, or with, OA. OBJECTIVE: This article focuses on the theme of advanced care of patients with OA within the Strategy. DISCUSSION: The Strategy was developed in consultation with a leadership group, thematic working groups, an implementation advisory committee, multisectoral stakeholders and the public. This Strategy identified three priorities in advanced care for osteoarthritis. In brief, these include surgical decision making, referral for evidence-informed non-surgical alternatives and surgical services. A set of goals within these priority areas and strategies was also proposed by the working group in consultation with stakeholders nationwide. Peak arthritis bodies and major healthcare professional associations currently endorse the Strategy.

BACKGROUND: Osteoarthritis (OA) is one of the most common and debilitating chronic joint conditions in Australia. A National Osteoarthritis Strategy (the Strategy) was developed to outline a national plan to achieve optimal health outcomes for people at risk of, or with, OA. OBJECTIVE: This article focuses on the theme of prevention of OA within the Strategy. DISCUSSION: The Strategy was developed by a leadership group, three working groups, an implementation planning committee, multisectoral stakeholders and public consultation. The Strategy's 'Prevention Working Group' identified two priorities for action: 1) implement programs that target the prevention of obesity and increase physical activity, 2) adhere to joint injury prevention programs. The lack of implementable policies that promote OA prevention exposes Australians and the public health system to an enormous burden. A set of evidence-based strategies was proposed to assist implementation throughout Australia.

Background Conventional epidemiologic studies have evaluated associations between circulating lipid levels and breast cancer risk, but results have been inconsistent. As Mendelian randomization analyses may provide evidence for causal inference, we sought to evaluate potentially unbiased associations between breast cancer risk and four genetically predicted lipid traits. Methods Previous genome-wide association studies (GWAS) have identified 164 discrete variants associated with high density lipoprotein-cholesterol (HDL-C), low density lipoprotein-cholesterol (LDL-C), triglycerides and total cholesterol. We used 162 of these unique variants to construct weighted genetic scores (wGSs) for a total of 101 424 breast cancer cases and 80 253 controls of European ancestry from the Breast Cancer Association Consortium (BCAC). Unconditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) for associations between per standard deviation increase in genetically predicted lipid traits and breast cancer risk. Additional Mendelian randomization analysis approaches and sensitivity analyses were conducted to assess pleiotropy and instrument validity. Results Corresponding to approximately 15 mg/dL, one standard deviation increase in genetically predicted HDL-C was associated with a 12% increased breast cancer risk (OR: 1.12, 95% CI: 1.08–1.16). Findings were consistent after adjustment for breast cancer risk factors and were robust in several sensitivity analyses. Associations with genetically predicted triglycerides and total cholesterol were inconsistent, and no association for genetically predicted LDL-C was observed. Conclusions This study provides strong evidence that circulating HDL-C may be associated with an increased risk of breast cancer, whereas LDL-C may not be related to breast cancer risk.

Objective Diet and exercise (D+E) for knee osteoarthritis (OA) is effective and cost‐effective. However, cost‐effectiveness does not imply affordability; the impact of knee OA–specific D+E programs on insurer budgets is unknown. Methods We estimated changes in undiscounted medical expenditures (2016 US dollars) with and without a D+E program. We accounted for both additional program outlays and potential savings from reduced use of other knee OA treatments and from reduced incidence of comorbidities. We adopted the perspective of a representative commercial insurance plan covering 200 000 individuals aged 25 to 64 years and a representative Medicare Advantage plan covering 200 000 Medicare‐eligible individuals aged 65 years and older. We used the Osteoarthritis Policy Model, a validated microsimulation model of knee OA, to model D+E efficacy (measured by pain and weight reduction), adherence, and price based on the Intensive Diet and Exercise for Arthritis (IDEA) trial. In sensitivity analyses, we varied time horizon, D+E efficacy, and D+E price. Results Over 3 years, the D+E program increased spending by $752 200 ($0.10 per member per month [PMPM]) in the commercial plan and by $6.0 million ($0.84 PMPM) in the Medicare plan. Over 3 years, the D+E program reduced opioid use by 6% and 5% and reduced total knee replacements by 5% and 4% in the commercial and Medicare plans, respectively. Expenses were higher in the Medicare plan because it had more patients with knee OA than the commercial plan. Conclusion Although there is no established threshold to define affordability, a D+E program for knee OA would likely produce expenditures comparable with outlays for other health‐promotion interventions.

Fat necrosis is a common complication of autologous breast reconstruction; however, diagnostic criteria are yet to be standardized, making comparison of autologous breast reconstructive techniques challenging. A systematic review found six of 556 articles met inclusion criteria. These results were used to generate an algorithm for managing fat necrosis after autologous breast reconstruction.

Breast reconstruction surgery after mastectomy has demonstrated positive psychological benefits, and is reflected in the number of patients undergoing the procedure, rising from 26.94% of patients after mastectomy in 2005, to 43.30% in 2014. Most of this is attributable to implant and expander-based reconstruction, with the rate of free flaps only increasing from 1.25% to 3.96% in this time period. Increasingly, breast cancer patients have higher survival rates. There is now an emphasis on Value Based Health Care (VBHC), which focusses on outcomes, and that can be measured by Patient Reported Outcome Measures (PROMs). To date, there has been no systematic review to analyse PROMs between those undergoing autologous or alloplastic reconstruction, using validated measurement tools, to determine if there is a preferred technique from the patient's perspective. We performed a systematic search on EMBASE, and together with bibliographic linkage, identified 146 articles. After screening and assessment of articles through abstract, and full article appraisal, 13 were identified suitable for inclusion in this systematic review. Using BREAST-Q, satisfaction of breast and psychosocial well-being were rated highly by the autologous group when compared to implant-based reconstruction. Physical well-being was less significant, with the least significant difference noted for sexual well-being. EORTC-QLQ-BR23/C30 PROMs noted similar trends. SF-36 however, noted virtually no difference between the two methods of reconstruction regarding similar PROM quality of life (QoL) domains. From the patient perspective, autologous reconstruction is either equal to or superior to implant-based reconstruction, and should be offered to all patients.

ObjectivesThe recombinant zoster vaccine (RZV) containing a strong non-aluminium adjuvant is associated with increased risk of gout flares, presumably via NLRP3 inflammasome activation. We tested the possibility that other vaccines may also be associated with gout flares.MethodsWe conducted an online case-crossover study of patients with gout to examine the association between vaccination and gout flares. We collected information through the Internet on exposures to potential risk factors, including vaccinations, during 2-day hazard periods prior to gout flare and 2-day control periods without a flare. Conditional logistic regression was used to adjust for covariates.ResultsThere were 517 participants with gout (mean age 55 years, 79% male) who experienced gout flares during follow-up. There were 28 vaccinations during 990 hazard periods and 21 vaccinations during 1407 control periods. Vaccination was associated with twofold higher odds of gout flare (adjusted OR 1.99; 95% CI 1.01 to 3.89).ConclusionOur findings suggest vaccines other than RZV are associated with increased odds of gout flares, potentially through a shared pathogenetic mechanism like NLRP3 inflammasome. However, the absolute magnitude of increased odds of gout flares with vaccinations remains small and must be interpreted within the context of the overwhelming benefits of vaccinations.

OBJECTIVE To evaluate the association between hip injury/giving way and hip pain exacerbations in patients with symptomatic hip osteoarthritis (OA). METHODS We conducted an internet-based case-crossover study to assess hip injury and giving way for hip pain exacerbation. Eligible participants with symptomatic hip OA were followed up for 90 days and asked to complete online questionnaires at baseline and 10-day intervals (control periods). They also logged on to the study web site to complete questionnaires for an episode of a hip pain exacerbation (case periods) defined as an increase of 2 points in pain intensity compared with the baseline rating on a numeric rating scale (range 0-10). The relationship of hip injury and giving way to the risk of pain exacerbation was examined using conditional logistic regression. RESULTS Of 252 patients recruited into the study, we included 133 patients (53%) who provided data from both case and control periods. Hip injury during the last 7 days increased the risk of hip pain exacerbation (odds ratio [OR] 2.74 [95% confidence interval (95% CI) 1.62-4.62]). The hip giving way during the last 2 days was associated with an increased risk of hip pain exacerbation (OR 2.10 [95% CI 1.30-3.39]) and showed a significant relationship between the number of hip giving way events and the risk of hip pain exacerbations (P < 0.001). CONCLUSION Hip injury and episodes of the hip giving way were significantly related to pain exacerbation in patients with symptomatic hip OA. Methods to prevent exposure to injury may help to reduce the burden of pain in patients with hip OA.

Objective.To evaluate the association of sleep quality, sleep duration, and fatigue with hip pain exacerbations in persons with symptomatic hip osteoarthritis (OA).Methods.Participants (n = 252) were followed for 90 days and asked to complete online questionnaires at 10-day intervals (control periods). A hip pain exacerbation (case periods) was defined as an increase of 2 points in pain intensity compared with baseline on a numeric rating scale (0–10). Subjective sleep quality and sleep duration were assessed using the Pittsburgh Sleep Quality Index, and fatigue was measured by Multidimensional Assessment of Fatigue in both periods. Univariable and multivariable conditional logistic regressions were used to assess the association.Results.Of the 252 participants, 130 (52%) were included in the final analysis. Univariate association analysis showed that both poor sleep quality and greater fatigue were associated with increased odds of pain exacerbations (OR 1.72, 95% CI 1.04–2.86; OR 1.92, 95% CI 1.21–3.05, respectively). Short sleep duration was not associated with pain exacerbations. Poor sleep quality and greater fatigue remained associated with pain exacerbations after adjustment for physical activity and night pain levels in multivariable analysis. There was no significant interaction between sleep quality and fatigue (p = 0.21).Conclusion.Poor sleep quality and greater fatigue were related to pain exacerbation in persons with symptomatic hip OA. Sleep disorders and fatigue should be considered when dealing with pain exacerbations.

Necrotizing soft tissue infections are a group of conditions with a common pathophysiological basis, affecting any or all layers of the soft tissue compartment. They are rare, life-threatening diseases that require a high index of suspicion for early detection as well as urgent surgical debridement. Rarely, they can occur in more than one non-contiguous site of the body (‘multifocal’ disease), and this is associated with a much higher mortality than monofocal disease. Here, we present the case of a 46-year-old male with bilateral upper limb necrotizing soft tissue infection following an unclear history of trauma. The patient developed septic shock necessitating transfer to the intensive care unit following emergency surgery. Microbiological tests yielded Streptococcus pyogenes, Staphylococcus aureus and opportunistic Candida spp. and Actinomyces infections. A total of seven surgical debridements were performed; fortunately, the patient survived. We discuss the presentation, diagnosis and management of this case including primary reconstruction of the soft tissue defects, and review the literature on necrotizing soft tissue infections as a clinical entity, incorporating clinical updates from the latest guidelines worldwide. Level of Evidence: Level V, therapeutic study.