Expanding the clinical spectrum of biglycan-related Meester-Loeys syndrome.

Pathogenic loss-of-function variants in BGN, an X-linked gene encoding biglycan, are associated with Meester-Loeys syndrome (MRLS), a thoracic aortic aneurysm/dissection syndrome. Since the initial publication of five probands in 2017, we have considerably expanded our MRLS cohort to a total of 18 probands (16 males and 2 females). Segregation analyses identified 36 additional BGN variant-harboring family members (9 males and 27 females). The identified BGN variants were shown to lead to loss-of-function by cDNA and Western Blot analyses of skin fibroblasts or were strongly predicted to lead to loss-of-function based on the nature of the variant. No (likely) pathogenic missense variants without additional (predicted) splice effects were identified. Interestingly, a male proband with a deletion spanning the coding sequence of BGN and the 5' untranslated region of the downstream gene (ATP2B3) presented with a more severe skeletal phenotype. This may possibly be explained by expressional activation of the downstream ATPase ATP2B3 (normally repressed in skin fibroblasts) driven by the remnant BGN promotor. This study highlights that aneurysms and dissections in MRLS extend beyond the thoracic aorta, affecting the entire arterial tree, and cardiovascular symptoms may coincide with non-specific connective tissue features. Furthermore, the clinical presentation is more severe and penetrant in males compared to females. Extensive analysis at RNA, cDNA, and/or protein level is recommended to prove a loss-of-function effect before determining the pathogenicity of identified BGN missense and non-canonical splice variants. In conclusion, distinct mechanisms may underlie the wide phenotypic spectrum of MRLS patients carrying loss-of-function variants in BGN.

Life-threatening gastrointestinal haemorrhage requiring surgical resection caused by SARS-CoV-2 induced ANCA associated vasculitis: A case report.

Introduction and importance: SARS-CoV-2 infection has been linked to the de novo diagnosis of various autoimmune conditions as well as flares in pre-existing disease. With such high prevalence of SARS-CoV-2 in the community, it is important to consider rare manifestations of autoimmune conditions when patients present with severe symptoms. Multi-specialty care is required to ensure optimal outcomes and prompt diagnosis. Case presentation: A 28-year-old male presented to our tertiary referral centre with progressive debilitating polyarthritis, a purpuric rash on both flanks and aphthous ulcers 6 weeks after infection with SARS-CoV-2. On the second day of admission, he developed severe gastrointestinal haemorrhage requiring multiple blood transfusions. Attempted angioembolisation failed to identify a site of active haemorrhage. On failing trial of conservative management, the decision was made to perform an exploratory laparotomy. The small bowel was found to have an extensive vasculitis requiring resection to control haemorrhage. Autoimmune serology revealed c-ANCA positivity with anti-PR3 antibodies. Clinical discussion: Patients presenting with acute vasculitic pathologies related to SARS-CoV-2 have the potential to rapidly progress to severe life-threatening gastrointestinal haemorrhage. Prompt surgical management is appropriate in selected cases. Conclusion: In the current era of COVID-19, the differential diagnosis of SARS-CoV-2 induced ANCA vasculitis must be considered for such cases with gastrointestinal haemorrhage. Compilation of similar cases and further studies are required to determine an optimal management pathway for these patients.

Initial assessment of the early arthritis for psoriatic patients diagnostic questionnaire in dermatology clinics in Australia, Korea and China.

OBJECTIVES: To conduct initial assessment of the early arthritis for psoriatic patients (EARP) questionnaire for Australian, Korean and Chinese populations using translated and linguistically validated versions. To measure the proportion of patients with psoriatic arthritis (PsA) among patients with psoriasis who attended dermatology clinics. METHODS: Questionnaires were translated and culturally validated into Australian English, Korean and Chinese. A multicenter, observational, descriptive estimate of the proportion of patients with PsA among patients with psoriasis attending dermatology clinics in Australia, Korea and China was conducted. Initial assessments included evaluations of floor and ceiling effects, internal consistency (using Cronbach's alpha), test-retest reliability (using intraclass coefficient), and correlations between EARP score and rheumatology findings. If the initial EARP score was ≥3, patients were assessed by a rheumatologist for PsA within 3 months of their retest questionnaire. RESULTS: Two hundred and fifty patients participated. Translated EARP questionnaires showed satisfactory internal consistency and test-retest reliability. A potential floor effect was observed for the Chinese and Korean versions. Cronbach's alpha was 0.885 (Australian), 0.776 (Korean) and 0.789 (Chinese), indicating acceptable internal consistency. Intraclass correlation coefficients were 0.89 (Australian), 0.86 (Korean) and 0.87 (Chinese), indicating acceptable test-retest reliability. EARP summary scores had weak to moderate linear correlation with the relevant PsA assessments. Overall, 32 (12.8%) patients were diagnosed with PsA based on Classification for Psoriatic Arthritis (CASPAR) score. CONCLUSION: The Australian, Korean, and Chinese versions of the EARP questionnaire are suitable for the early detection of PsA symptoms in patients with psoriasis by dermatologists working in specialist dermatology clinics. TRIAL REGISTRATION: NCT02470481.

Using lean thinking to improve hypertension in a community health centre: a quality improvement report.

Background: Achieving better care at lower cost in the US healthcare safety net will require federally qualified health centres (FQHC) to implement new models of team-based population healthcare. Lean thinking may offer a way to reduce the financial risk of practice transformation while increasing the likelihood of sustained improvement. Objective: To demonstrate system-level improvement in hypertension control in a large FQHC through the situational use of lean thinking and statistical process control. Setting: Lynn Community Health Center, the third largest FQHC in Massachusetts, USA. Participants: 4762 adult patients with a diagnosis of hypertension. Intervention: First, we created an organisation-wide focus on hypertension. Second, we implemented a multicomponent hypertension care pathway. The lean tools of strategy deployment, standardised work, job instruction, Plan-Do-Study-Adjust, 5S and visual control were used to overcome specific obstacles in the implementation. Measurements: The primary outcome was hypertension control, defined as last measured blood pressure <140/90. Statistical process control was used to establish baseline performance and assess special cause variation resulting from the two-step intervention. Results: Hypertension control improved by 11.6% from a baseline of 66.8% to a 6 month average of 78.2%. Limitations: Durability of system changes has not been demonstrated beyond the 14-month period of the intervention. The observed improvement may underestimate the effect size of the full hypertension care pathway, as two of the five steps have only been partially implemented. Conclusions: Success factors included experienced improvement leaders, a focus on engaging front-line staff, the situational use of lean principles to make the work easier, better, faster and cheaper (in that order of emphasis), and the use of statistical process control to learn from variation. The challenge of transforming care delivery in the safety net warrants a closer look at the principles, relevance and potential impact of lean thinking in FQHCs.

The effect of curing hepatitis C with direct-acting antiviral treatment on endothelial function.

BACKGROUND: Epidemiological data suggest that chronic HCV infection (CHC) is associated with increased cardiovascular risk, but it is unknown if it is associated with endothelial dysfunction. We aimed to assess the effect of antiviral treatment on endothelial function in non-cirrhotic adults with CHC. METHODS: Self-controlled before and after study. All patients had genotype-1 CHC and were treated with 12 weeks of paritaprevir/ritonavir, ombitasvir and dasabuvir (PrOD), with ribavirin added for those with genotype-1a infection. Endothelial function was assessed at three time points before antiviral treatment, at treatment weeks 1, 4, 8 and 12, and 12 weeks after the end of treatment. The main assessment tools were reactive hyperaemia peripheral arterial tonometry (RHPAT) and serum concentrations of angiopoietin-2 (Ang-2) and E-selectin. RESULTS: A total of 16 patients were enrolled. Mean (sd) age was 51.4 (6.9) years and 11 participants (69%) were male. All 16 patients achieved a sustained virological response. The mean (sd) baseline RHPAT index was 2.05 (0.48), and there was no significant change during treatment (mean within-patient change from baseline to end of treatment =-0.23 [0.45]; P= not significant). There was a significant improvement in both mean Ang-2 (baseline 2.44 [0.79] ng/ml, within-patient change -0.60 [0.44]; P<0.001) and E-selectin (baseline 48.7 [21.5] ng/ml, within-patient change -14.4 [13.0]; P<0.001). CONCLUSIONS: Removing HCV viraemia is associated with a significant improvement in endothelial function as measured by serum markers, but not in bedside microvascular reactivity. Chronic HCV viraemia may be associated with endothelial cell dysfunction and therefore long-term cardiovascular risk.

Paradoxical association of C-reactive protein with endothelial function in rheumatoid arthritis.

BACKGROUND: Within the general population, levels of C-reactive protein (CRP) are positively associated with atherosclerotic cardiovascular disease (CVD). Whether CRP is causally implicated in atherogenesis or is the results of atherosclerosis is disputed. A role of CRP to protect endothelium-derived nitric oxide (EDNO) has been suggested. We examined the association of CRP with EDNO-dependent vasomotor function and subclinical measures of atherosclerosis and arteriosclerosis in patients with raised CRP resulting from rheumatoid arthritis (RA). METHODOLOGY/PRINCIPAL FINDINGS: Patients with RA (n = 59) and healthy control subjects (n = 123), underwent measures of high sensitivity CRP, flow-mediated dilation (FMD, dependent on EDNO), intima-media thickness (IMT, a measure of subclinical atherosclerosis) and aortic pulse wave velocity (PWV, a measure of arteriosclerosis). IMT and PWV were elevated in patients with RA compared to controls but FMD was similar in the two groups. In patients with RA, IMT and PWV were not correlated with CRP but FMD was positively independently correlated with CRP (P<0.01). CONCLUSIONS/SIGNIFICANCE: These findings argue against a causal role of CRP in atherogenesis and are consistent with a protective effect of CRP on EDNO bioavailability.

Functional and work outcomes improve in patients with rheumatoid arthritis who receive targeted, comprehensive occupational therapy.

OBJECTIVE: Work disability is a serious consequence of rheumatoid arthritis (RA). We conducted a 6-month, prospective randomized controlled trial comparing assessments of function, work, coping, and disease activity in employed patients with RA receiving occupational therapy intervention versus usual care. METHODS: Employed patients with RA with increased perceived work disability risk were identified by the RA Work Instability Scale (WIS; score >or=10). Patients were stratified into medium- (score >or=10 and <17) and high-risk (>or=17) groups, then randomized into occupational therapy or usual care groups. Assessments were conducted at baseline and 6 months. The primary outcome was the Canadian Occupational Performance Measure (COPM), a standardized patient self-report of function. Other outcomes included the disability index (DI) of the Health Assessment Questionnaire (HAQ); Disease Activity Score in 28 joints (DAS28); RA WIS; EuroQol Index; visual analog scales (VAS) for pain, work satisfaction, and work performance; and days missed/month. Independent sample t-tests and Mann-Whitney U tests were used. RESULTS: We recruited 32 employed patients with RA. At baseline the groups were well matched. At 6 months the improvement in the occupational therapy group was significantly greater than that in the usual care group for all functional outcomes (COPM performance P < 0.001, COPM satisfaction P < 0.001, HAQ DI P = 0.02) and most work outcomes (RA WIS [P = 0.04], VAS work satisfaction [P < 0.001], VAS work performance [P = 0.01]). Additionally, Arthritis Helplessness Index (P = 0.02), Arthritis Impact Measurement Scales II pain subscale (P = 0.03), VAS pain (P = 0.007), EuroQol Index (P = 0.02), EuroQol global (P = 0.02), and DAS28 (P = 0.03) scores significantly improved. CONCLUSION: Targeted, comprehensive occupational therapy intervention improves functional and work-related outcomes in employed RA patients at risk of work disability.

An examination of work instability, functional impairment, and disease activity in employed patients with rheumatoid arthritis.

OBJECTIVE: To evaluate the relationship between the Disease Activity Score 28-joint count (DAS28), Health Assessment Questionnaire (HAQ), and Rheumatoid Arthritis-Work Instability Scale (RAWIS); and to define thresholds for clinical assessments associated with moderate to high RA-WIS. METHODS: Employed patients with RA were evaluated using DAS28, HAQ, and RA-WIS during routine clinics. Relationships between these assessments were evaluated by simple correlation. Multiple linear regression modeling was performed using RA-WIS as an outcome variable and HAQ, DAS28, age, sex, occupation, and disease duration as input variables. Receiver-operating characteristic curves were then formulated to determine optimal DAS28, and HAQ cutoff points for RA-WIS >or= 10, along with the odds ratio (OR). RESULTS: Ninety patients with RA completed the RA-WIS, which was moderately correlated with DAS28 (r =0.53) and HAQ (r = 0.66). Fifty-four percent of RA-WIS was explained by DAS28 (p = 0.002), HAQ (p = 0.001), and sex (p = 0.04). A DAS28 of 3.81 and HAQ of 0.55 were clinically important thresholds. High DAS28 and HAQ were associated with high RA-WIS (OR(DAS) 14.17, OR(HAQ) 25.13, OR(DAS+HAQ) 29.9). CONCLUSION: Functional impairment and disease activity significantly and independently contributed to patient-perceived work instability risk.

A critical appraisal of quantitative arthroscopy as an outcome measure in osteoarthritis of the knee.

BACKGROUND AND OBJECTIVES: To review the performance of arthroscopic assessment of articular cartilage damage in osteoarthritis. METHODS: The literature was reviewed for publications containing data regarding validity and reliability of arthroscopic systems of cartilage evaluation in knee osteoarthritis. RESULTS: Fifty-two distinct measurement systems were identified in 60 publications. There were 30 simple severity-scoring systems, 3 global visual analogue scale systems, and 19 composite systems. No systems consisted solely of measurements of lesion size or site, although 13 systems used either or both of these for the calculation of composite scores. Only 6 publications (10%) undertook any reliability evaluation and these generally used inappropriate methods of statistical analysis. Thirty-five publications (58%) evaluated validity. Construct validity was tested using several constructs (clinical in 2, magnetic resonance imaging in 10, radiographs in 10, or other arthroscopic assessments in 5 publications). Criterion validity was ascertained by using several methods including cartilage histology, histochemistry, or biomechanics in 10 publications. Responsiveness was determined in 1 publication. DISCUSSION: Many publications evaluated composite systems but only a few evaluated fundamental aspects of arthroscopic measurement. Conceptually, composite scoring systems have the best validity; however, at present, there is only enough evidence to support the use of simple chondropathy severity scores and there are little data on the responsiveness of these methods. A proposed program for comprehensive evaluation and development of valid and responsive arthroscopic assessments of articular cartilage is outlined.

Accuracy and reliability of arthroscopic estimates of cartilage lesion size in a plastic knee simulation model.

PURPOSE: The goal of the study was to determine the accuracy and reliability of arthroscopic percent area estimates in a plastic knee simulation model. A second goal was to determine the effect of lesion location within the knee and lesion size on accuracy and reliability. TYPE OF STUDY: Cross-sectional study of arthroscopic estimates of cartilage lesion size. METHODS: Three experienced arthroscopists performed 3 sets arthroscopic percent area estimates in 5 different plastic knees. Each knee had lesions drawn on 5 surfaces (patellar, medial and lateral femoral condyle, medial and lateral tibial plateaus). Accuracy and reliability were studied using Bland and Altman limits of agreement (LOA) and intraclass correlation coefficients. RESULTS: There was a strong tendency to overestimate lesion size by over 100% on the femoral and patellar surfaces. Intraobserver and interobserver reliabilities were generally poor. The range for the 95% LOA (+/- 1.96 standard deviation [SD] of the difference scores) between repeated measurements was almost 6 times the size of the lesion itself. Reliability of estimates was poorest for the largest lesions and worse at femoral, lateral tibial, and patellar sites. CONCLUSIONS: Assessments of arthroscopic measurements using LOA found that accuracy and reliability were generally poor, although results were better at the medial tibial plateau and for smaller lesions. In spite of these problems, arthroscopy remains a promising measurement tool because it permits physical assessment of cartilage integrity. This study sets the foundations for improvement in techniques of arthroscopic measurement of cartilage lesion size.