Increased frequency of hepatic steatosis and fibrosis in patients with gout detected by transient elastography.

OBJECTIVES: It has been suggested that gout is associated with non-alcoholic fatty liver disease (NAFLD). Our aim was to assess NAFLD in gout patients using the validated non-invasive imaging technique, transient elastography (FibroScan). METHODS: FibroScans in consecutive gout patients in a single centre from 11/1/2016 to 11/1/2021 and reviewed retrospectively. FibroScan results include the E- score (kPA), measuring liver stiffness, and controlled attenuation parameter (CAP) score (dB/m), assessing steatosis. In addition, a FIB-4 fibrosis score was calculated. RESULTS: 47 gout patients (7 females, 14.9%; 40 males, 85.1%) underwent FibroScans. The mean age was 59.8 years, the mean body mass index (BMI) was 30.95 kg/m2, and gout duration 0-49 years. Tophi were present in 11 (26.2%). Comorbidities included dyslipidaemia (86.7%), diabetes mellitus (31.1%), known liver disease (33.3%), current alcohol consumption (46.8%), ALT or AST elevations (54.4%), and hyperuricaemia (53.7%). FibroScan results revealed hepatic steatosis (CAP >238 dB/m) in 40 (85.1%) and were significantly associated with BMI (r=0.53, p=0.0001) but not age, serum urate (SU), glucose, triglycerides, ALT, AST. FibroScan also revealed fibrosis (E score >7) in 9 (19.1%); severe fibrosis (cirrhosis) in 8. Fibrosis was significantly associated with age (p=0.03) and known liver disease (p=0.003) but not BMI, SU, or comorbidities. The FIB-4 score was significantly associated with the fibrosis score (r2=0.24, p=0.0009) but not with CAP, ALT, or AST. CONCLUSIONS: Despite not being associated with common gout comorbidities, fatty liver and liver fibrosis were common in this gout cohort, suggesting FibroScan screening in gout patients to assess NAFLD, irrespective of serum transaminase levels.

Improvement in hepatic fibrosis estimated by Fibrosis-4 index in pegloticase treated chronic refractory gout patients.

OBJECTIVES: To determine whether lowering serum urate (SU) affects the course of non-alcoholic fatty liver disease (NAFLD). METHODS: Retrospective data analysis from chronic refractory gout patients who participated in two 6-month pegloticase randomised clinical trials compared patients who received pegloticase biweekly to those who received placebo. Patients with persistent urate-lowering to <1 mg/dL in response to biweekly pegloticase (responders, n=36) were compared to those who received placebo (n=43). NAFLD was assessed using the Fibrosis-4 (Fib-4) index. Comparisons between groups were carried out using 2 sample Wilcoxon tests or regression analysis. RESULTS: At baseline the mean (standard deviation [SD]) Fib-4 values were 1.40 (0.86) in pegloticase responders, and 1.04 (0.53) in patients receiving placebo. Patients receiving placebo exhibited a change of 0.26 (0.41) in Fib-4 score over 6 months vs 0.13 (0.62) for pegloticase responders (p=0.048). When only patients with a Fib-4 value >1.3 were considered (n=27), a significant difference in the change in the Fib-4 values between pegloticase responders vs. placebo was observed (-0.15 [0.67] vs. 0.7 [0.42], p=0.04). The correlation between the SU area under the curve (AUC) over the 6-month trial period and the change in Fib-4 value was R=0.33 (p=0.0004). Multivariable analysis indicated SU AUC was the only significant contributor to the change in Fib-4 values (p=0.018). CONCLUSIONS: Persistent lowering of SU significantly reduced Fib-4 scores, implying a possible effect on NAFLD progression. These results support the consideration of a complete analysis of the impact of profound urate-lowering on NAFLD as measured by the Fib-4 index.

Pegloticase causes prolonged improvement in multiple disease parameters in patients with chronic refractory gout who maintain low serum urate levels.

OBJECTIVES: To assess the benefit of long-term urate-lowering with pegloticase. METHODS: The results from two, 6-month, randomised controlled trials (RCTs) and their 30-month open-label extension (OLE) were analysed. Efficacy was assessed in urate responders (patients with plasma urate <6.0 mg/dL for ≥80% of assessments around the 3- and 6-month time periods) to the approved regimen (8 mg every 2 weeks [q2w]) and responders to q4w treatment. Assessments included serum urate (sU), Patient Global Assessment (PtGA), tender and swollen joints (TJC and SJC), pain, Health Assessment Questionnaire Disability Index, bodily pain, the Arthritis-Specific Health Index, and reduction of target tophi. RESULTS: 34 responders to pegloticase in the RCTs were followed throughout the 2.5 years of the OLE. Of these, 20 received 8 mg pegloticase q2w and 14 q4w. The results for patients who received pegloticase q2w indicated significant improvements between RCT baseline and the final OLE evaluation for sU (p<0.0001), PtGA (p<0.0001), TJC (p=0.0001), and SJC (p=0.0014); 61.5%, had complete target tophus resolution. The results for patients treated monthly indicated significant improvements between RCT baseline and the final OLE evaluation for sU (p<0.001), PGA (p=0.0003), TJC (p=0.008), and SJC (p<0.0001);100% had complete target tophus resolution. CONCLUSIONS: There were significant sustained clinical benefits with long-term pegloticase treatment in patients with chronic refractory gout achieving a urate-lowering effect during the first 6 months of therapy and followed for up to 30 additional months.

Post-hoc analysis of pegloticase pivotal trials in chronic refractory gout: relationship between fluctuations in plasma urate levels and acute flares.

OBJECTIVES: To determine factors associated with gout flares in subjects treated with pegloticase. METHODS: Gout flares from two randomised controlled trials comparing pegloticase (8 mg every 2 weeks [q2] or monthly [q4]) versus placebo were analysed. Responders had persistent urate lowering (<6mg/dL) whereas, non-responders had transient urate lowering during the 6-month RCTs. Gout flares (self-reported) were defined as acute joint pain and swelling requiring treatment. Gout flare prophylaxis (colchicine, 0.6 mg once or twice daily, or a non-steroidal anti-inflammatory drug) was initiated 1 week before the first infusion and continued throughout the study. Plasma urate at the time of flare and the change in urate preceding a flare were analysed. RESULTS: Mean flare rates increased with pegloticase versus placebo during the first 3 months followed by marked reductions during months 4-6. The increase in flares with pegloticase during the first 3 months was most evident (p=0.0006) and the decrease during the second 3 months was least marked (p=0.0006) in subjects receiving monthly pegloticase. Fluctuation in urate levels was highest in monthly responders (p=0.002) and was associated with flare occurrence. Multivariate linear regression analysis indicated the only variables significantly associated with flares were treatment group and absolute change in plasma urate before flares. CONCLUSIONS: Pegloticase treatment increased flares during the first 3 months of treatment in all groups when plasma urate was significantly lowered and was followed by a decline in months 4-6 in patients maintaining a low plasma urate. Flares associated with pegloticase treatment were associated with decreases and fluctuations in plasma urate levels.

Patient ancestry significantly contributes to molecular heterogeneity of systemic lupus erythematosus.

Gene expression signatures can stratify patients with heterogeneous diseases, such as systemic lupus erythematosus (SLE), yet understanding the contributions of ancestral background to this heterogeneity is not well understood. We hypothesized that ancestry would significantly influence gene expression signatures and measured 34 gene modules in 1566 SLE patients of African ancestry (AA), European ancestry (EA), or Native American ancestry (NAA). Healthy subject ancestry-specific gene expression provided the transcriptomic background upon which the SLE patient signatures were built. Although standard therapy affected every gene signature and significantly increased myeloid cell signatures, logistic regression analysis determined that ancestral background significantly changed 23 of 34 gene signatures. Additionally, the strongest association to gene expression changes was found with autoantibodies, and this also had etiology in ancestry: the AA predisposition to have both RNP and dsDNA autoantibodies compared with EA predisposition to have only anti-dsDNA. A machine learning approach was used to determine a gene signature characteristic to distinguish AA SLE and was most influenced by genes characteristic of the perturbed B cell axis in AA SLE patients.

Development of a multivariable improvement measure for gout.

BACKGROUND: Gout is a heterogeneous inflammatory disease with numerous clinical manifestations. A composite means to assess the impact of therapy on numerous aspects of gout could be useful. METHODS: Results from patients treated with pegloticase or placebo in two randomized clinical trials and their open-label extension were assessed using a novel evidence-based Gout Multivariable Improvement Measure (GMIM) derived from previously reported criteria for remission and complete response. Improvement was defined as serum urate (sU) < 6 mg/dL and absence of flares during the preceding 3 months plus 20, 50, and 70% improvement in tophus size, patient global assessment, pain, and swollen and tender joints. RESULTS: Patients treated with pegloticase manifested a significantly greater GMIM20, 50, and 70 response vs those treated with placebo (GMIM20 at 6 months 37.1% vs 0%, respectively). Higher response rates were significantly more frequent in subjects with persistent urate lowering (GMIM 58.1% at 6 months) in response to pegloticase versus those with only transient urate lowering (GMIM 7.1% at 6 months). However, when the requirement for a decrease in sU to < 6 mg/dL was omitted, a substantial percentage of subjects with transient urate lowering met the GMIM clinical criteria. A sensitivity analysis indicated that gout flares contributed minimally to the model. The response measured by GMIM persisted into the open-level extension for as long as 2 years. Finally, subjects who received placebo in the randomized control trials, but pegloticase in the open-label extension, manifested GMIM responses comparable to that noted with pegloticase-treated subjects in the randomized controlled trials. CONCLUSIONS: GMIM captures changes in disease activity in response to treatment with pegloticase and may serve as an evidence-based tool for assessment of responses to other urate-lowering therapies in gout patients.

Dissociation Between Clinical Benefit and Persistent Urate Lowering in Patients with Chronic Refractory Gout Treated with Pegloticase.

OBJECTIVE: To assess clinical benefit in patients with chronic refractory gout who did not meet the protocol-defined criteria of responders to pegloticase. METHODS: This analysis used results from 2 randomized controlled trials (ClinicalTrials.gov: NCT00325195, NCT01356498) to assess the clinical efficacy in responders and nonresponders to treatment (8 mg of pegloticase every 2 weeks). Serum urate was measured before each infusion and the following were recorded: assessment of gout flares, tophus reduction, patient's global assessment (PtGA), tender and swollen joints (TJC and SJC), pain using a 100-mm visual analog scale, and a variety of patient-reported outcomes [Medical Outcomes Study Short Form-36 questionnaire physical component summary score and arthritis-specific health index (ASHI) score]. RESULTS: The analysis included 36 persistent urate responders, 49 nonresponders, and 43 patients who received placebo. Results for both responders and nonresponders indicated significant reduction in tophi and improvements from baseline in PtGA, TJC, SJC, pain, and ASHI. No significant improvements were observed in the patients who received placebo. CONCLUSION: Chronic refractory gout patients not achieving protocol-defined persistent urate lowering still achieve significant clinical benefits with pegloticase treatment, suggesting that transient reduction in serum urate may result in sustained clinical benefit.

Evaluation of Proposed Criteria for Remission and Evidence-Based Development of Criteria for Complete Response in Patients With Chronic Refractory Gout.

OBJECTIVE: The objective of this study is to assess criteria for gout remission and to use the results to inform criteria for a complete response (CR). METHODS: A post hoc analysis of two clinical trials was undertaken to determine the frequency with which subjects with chronic refractory gout who were treated with pegloticase met remission criteria. Mixed modeling was then employed to identify the components that best correlated with time to maximum benefit. RESULTS: Of the 56 subjects treated with biweekly pegloticase for whom adequate data were collected, 48.2% met the remission criteria. When subjects with persistent lowering of urate levels were examined separately, 27 of 32 (84.4%) met the criteria for remission. In contrast, even when the requirement for lowering of serum urate levels was waived, only 2 of 24 (8.3%) subjects without persistent lowering of urate levels and 0 of 43 subjects receiving placebo met criteria. Mixed modeling indicated that in addition to urate levels, assessment of tophi, swollen joints, and tender joints and patient global assessment best correlated with time to maximum benefit. Using these criteria of CR, 23 of the responders (71.9%) met the criteria. All patients who achieved a CR maintained it for a mean duration of 507.4 days. Finally, 64% of persistent responders to monthly pegloticase also met criteria for CR. CONCLUSION: These results have validated the proposed remission criteria for gout and have helped define criteria for CR in individuals with chronic gout treated with pegloticase. This composite CR index can serve as an evidence-based target to inform the design and end points of future clinical trials.

Pegloticase Treatment Significantly Decreases Blood Pressure in Patients With Chronic Gout.

Serum urate is correlated with blood pressure (BP), and lowering urate may decrease BP, but a consistent effect has not been observed. Here, we evaluated whether pegloticase, a recombinant uricase conjugated to polyethylene glycol, which can lead to persistently low serum urate levels (<1 mg/dL), can modulate BP in subjects with chronic refractory gout. This post hoc analysis used results from two 6-month randomized clinical trials in which subjects were treated with 8 mg pegloticase every 2 or 4 weeks (q2w or q4w) or placebo. Responders in this study were defined as those individuals in whom a persistently low urate level (<6 mg/dL and usually <1 mg/dL) was maintained. Serial sitting BP was measured in 173 subjects, and estimated glomerular filtration rate was determined at baseline and after 3 and 6 months. Significant reductions in mean arterial pressure (MAP) from baseline to 6 months were noted in q2w responders ( P=0.0028), whereas reductions in MAP in other groups were not significant. Significant decreases in both systolic and diastolic BP paralleled the change in MAP. Of the 62% of q2w responders exhibiting persistent decreases in MAP, there were no significant differences in baseline age, sex, race, weight, body mass index, history of hypertension, hyperlipidemia, history of coronary artery disease, gout duration, MAP, serum urate, estimated glomerular filtration rate or urinary uric acid/creatinine ratio compared with those who did not lower MAP. No significant changes in estimated glomerular filtration rate occurred in any of the groups during the study. Responders to biweekly pegloticase who maintained a persistently lower serum urate level throughout the trial experienced significant reductions in both systolic and diastolic BP that were independent of changes in renal function. Clinical Trial Registration- URL: http://www.clinicaltrials.gov . Unique identifier: NCT00325195.

Characterization of patients with chronic refractory gout who do and do not have clinically apparent tophi and their response to pegloticase.

OBJECTIVES: To determine the characteristics and response to pegloticase of patients with chronic refractory gout with and without clinically apparent tophi. METHODS: Results from two randomized controlled trials of pegloticase in patients with chronic refractory gout with clinically apparent tophi or without tophi were used to assess baseline and on-treatment between-group differences. RESULTS: Patients with tophi were significantly older than those without tophi, had a significantly longer duration of disease, higher numbers of tender and swollen joints, higher Patient Global Assessment scores and Health Assessment Questionnaire-Disability Index scores, and lower Arthritis-Specific Health Index scores. Patients with tophaceous gout also had significantly lower scores for physical functioning, role physical, social functioning, and the physical component summary scores of the Short Form 36 vs patients without tophi. In addition, subjects with clinically apparent tophi had a significantly lower mean estimated glomerular filtration rate. Pegloticase treatment of tophaceous patients caused significant reductions in serum urate, flares, Patient Global Assessment, tender joints, swollen joints, Health Assessment Questionnaire-Disability Index, visual analogue scale pain and Short Form 36 Bodily Pain, whereas patients without tophi had significant improvement in serum urate, flares, Patient Global Assessment, tender joints, and Short Form 36 Bodily Pain, but not swollen joints, Health Assessment Questionnaire-Disability Index functional score or pain visual analogue scale. Treatment with pegloticase had no effect on estimated glomerular filtration rate despite significant lowering of the urinary uric acid: creatinine ratio. CONCLUSION: Patients with chronic refractory gout and clinically apparent tophi have more severe disease as well as reduced renal function. Both groups experienced significant clinical benefit with pegloticase treatment, although no change in renal function was noted.

Tophus resolution in patients with chronic refractory gout who have persistent urate-lowering responses to pegloticase.

BACKGROUND: Pegloticase is a recombinant mammalian uricase conjugated to polyethylene glycol approved in the United States for treatment of chronic refractory gout. It can profoundly decrease serum urate to < 1 mg/dl. In patients receiving pegloticase who did not generate high-titer antidrug antibodies (responders), the serum urate remained low for the duration of therapy, 6 months in the phase III clinical trials plus the open-label extension. The objective of this study was to assess the velocity of tophus resolution in subjects treated with pegloticase. METHODS: Data from two randomized controlled trials of pegloticase in chronic refractory gout were analyzed. Tophi were assessed by computer-assisted measurements of standardized digital photographs. Subjects were designated as responders and nonresponders based on maintenance of serum urate < 6 mg/dl at months 3 and 6 of treatment. The projected time of complete resolution of all tophi was determined by linear regression analysis. RESULTS: The mean total tophus area at baseline was 585.8 mm2 for responders, 661.5 mm2 for nonresponders, and 674.4 mm2 for placebo-treated patients. Complete resolution at 6 months of at least one tophus was achieved by 69.6% of 23 responders, 27.9% of 43 nonresponders, and 14.3% of 21 patients who received placebo. Complete resolution of all photographed tophi was achieved by 34.8% of biochemical responders, 11.6% of nonresponders, and 0% of placebo-treated patients. The mean velocity of resolution of all tophi was 60.1 mm2/month in responders with a mean projected time of complete resolution of 9.9 months (4.6-32.6 months). There was a significant inverse correlation between serum urate AUC and tophus resolution velocity (r = - 0.40, P = 0.0002), although considerable heterogeneity in the velocity of resolution was noted. The only patient characteristic that correlated with the velocity of tophus resolution was the baseline tophus area. CONCLUSIONS: Pegloticase treatment caused a rapid resolution of tophi in responders that correlated with the serum urate lowering associated with this therapy.

Frequency, distribution and immunologic nature of infusion reactions in subjects receiving pegloticase for chronic refractory gout.

BACKGROUND: To assess frequency and distribution of infusion reactions (IRs) in responders and nonresponders in randomized clinical trials (RCTs) of intravenous pegloticase and the utility of the National Institute of Allergy and Infectious Disease/Food and Allergy and Anaphylaxis Network (NIAID/FAAN) criteria for identifying anaphylaxis in subjects experiencing IRs. METHODS: IRs from two RCTs of pegloticase were evaluated and categorized as anaphylaxis, hypersensitivity, or other. Serum levels of tryptase and total hemolytic complement (CH50) were evaluated at the time of all IRs. Frequency of IRs by each category was evaluated in all subjects, responders or nonresponders to pegloticase. RESULTS: There were 113 IRs in 1695 infusions. Of the 113 IRs, 6 met criteria for anaphylaxis, 53 had one feature of anaphylaxis and were designated as "hypersensitivity", and 54 had no features and were designated "other". In subjects receiving pegloticase every 2 weeks (Q2w), a total of 852 infusions were administered and the IR frequency was 0.5% in responders and 9.7% in nonresponders. In subjects receiving pegloticase every 4 weeks (Q4w), a total of 846 infusions were given and the IR frequency was 2.6% in responders and 12.2% in nonresponders. There were no differences among the three categories of IRs with regard to clinical course or biochemical evidence of immune activation determined by CH50 or tryptase levels. CONCLUSION: IRs mostly occurred in nonresponders. NIAID/FAAN criteria for anaphylaxis did not identify pegloticase-related IRs as having a higher frequency of immune activation or a more severe course. The results are consistent with the conclusion that discontinuance of pegloticase if uric acid rises to >6 mg/dL will decrease the frequency of IRs.

The Burden of Hepatitis C Infection-Related Liver Fibrosis in the United States.

BACKGROUND: Knowledge of the estimated proportion of hepatitis C virus (HCV)-infected persons with advanced fibrosis or cirrhosis is critical to estimating healthcare needs. METHODS: We analyzed HCV-related testing conducted by Quest Diagnostics from January 2010 through December 2013. Tests included hepatitis C antibody, HCV RNA, HCV genotype (nucleic acid tests [NAT]), liver function tests, and platelet counts; patient age was also determined. Aspartate aminotransferase (AST)-to-platelet ratio (APRI) was calculated as = 100*(aspartate aminotransferase [AST]/upper limit of AST)/platelet. Fibrosis-4 (FIB-4) was calculated as (age × AST)/(platelet ×√ alanine aminotransferase [ALT]). Persons were "currently infected" if they had ≥1 positive HCV NAT; "in care" if a positive RNA test was followed <6 months by ≥1 additional NAT(s), or ALT, AST, and platelets <90 days, or any test ordered by an infectious diseases or gastroenterology specialist; and "evaluated for treatment" if they had a genotype test. RESULTS: Approximately 10 million HCV test results were analyzed, representing 5.6 million unique patients. Of the 2.6 million patients with data to estimate liver disease, 5% were currently infected. Among those currently infected, APRI and FIB-4 scores indicated that 23% overall-and 27% among the cohort born during 1945-1965-had advanced fibrosis or cirrhosis at first diagnosis. A total of 54% of infected were in care and 51% of infected with advanced fibrosis or cirrhosis were evaluated for treatment. CONCLUSIONS: Testing from a large US commercial laboratory indicates that about 1 in 4 HCV-infected persons have levels of liver disease put them at highest risk for complications and could benefit from immediate antiviral therapy.

Application of dsRNA in cancer immunotherapy: current status and future trends.

Cancer cells create a microenvironment that prevents tumor rejection by the host's immune system. The activation of pattern recognition receptors (PRRs) can elicit an innate immune response and guide the adaptive immune response to overcome this. dsRNA analogs can trigger TLR3, RIG-I, MDA5, NLRP3 and several other PRRs to induce not only robust immune response against cancer but also programmed cell death. This review focuses on the signal pathways activated by dsRNA and examines examples of their clinical application in cancer treatment.

The six-minute walk test is an excellent predictor of functional ambulation after total knee arthroplasty.

BACKGROUND: The Six-minute walk (6 MW) and Timed-Up-and-Go (TUG) are short walk tests commonly used to evaluate functional recovery after total knee arthroplasty (TKA). However, little is known about walking capacity of TKA recipients over extended periods typical of everyday living and whether these short walk tests actually predict longer, more functional distances. Further, short walk tests only correlate moderately with patient-reported outcomes. The overarching aims of this study were to compare the performance of TKA recipients in an extended walk test to healthy age-matched controls and to determine the utility of this extended walk test as a research tool to evaluate longer term functional mobility in TKA recipients. METHODS: The mobility of 32 TKA recipients one year post-surgery and 43 healthy age-matched controls were assessed using the TUG, 6 MW and 30-minute walk (30 MW) tests. The latter test was repeated one week later. Self-reported function was measured using the WOMAC Index and a physical activity questionnaire. RESULTS: 30 MW distance was significantly shorter amongst TKA recipients (mean 2108 m [95% CI 1837 to 2381 m]; Controls 3086 m [2981 to 3191 m], P < 0.001). Test-retest repeatability was high (ICC = 0.97, TKA; 0.96, Controls). Amongst TKA recipients, the 30 MW distance correlated strongly with the shorter tests (6 MW, r = 0.97, P < 0.001; TUG, r = -0.82, P < 0.001). Multiple regression modeling found 6 MW distance to be the only significant predictor (P < 0.001) of 30 MW distance, explaining 96% of the variability. The TUG test models were moderate predictors of WOMAC function (55%) and physical activity (36%) and were stronger predictors than 6 MW and 30 MW tests. CONCLUSIONS: Though TKA recipients are able to walk for 30 minutes one year post-surgery, their performance falls significantly short of age-matched norms. The 30 MW test is strongly predicted by 6 MW test performance, thus providing strong construct validity for the use of the 6 MW test in the TKA population. Neither a short nor long walk test is a strong predictor of patient-reported function after TKA.

The effects of TLR activation on T-cell development and differentiation.

Invading pathogens have unique molecular signatures that are recognized by Toll-like receptors (TLRs) resulting in either activation of antigen-presenting cells (APCs) and/or costimulation of T cells inducing both innate and adaptive immunity. TLRs are also involved in T-cell development and can reprogram Treg cells to become helper cells. T cells consist of various subsets, that is, Th1, Th2, Th17, T follicular helper (Tfh), cytotoxic T lymphocytes (CTLs), regulatory T cells (Treg) and these originate from thymic progenitor thymocytes. T-cell receptor (TCR) activation in distinct T-cell subsets with different TLRs results in differing outcomes, for example, activation of TLR4 expressed in T cells promotes suppressive function of regulatory T cells (Treg), while activation of TLR6 expressed in T cells abrogates Treg function. The current state of knowledge of regarding TLR-mediated T-cell development and differentiation is reviewed.

Changes in left atrial volume in diabetes mellitus: more than diastolic dysfunction?

AIM: To evaluate left atrial (LA) volume and function as assessed by strain and strain rate derived from 2D speckle tracking and their association with diastolic dysfunction (DD) in patients with diabetes mellitus (DM). METHODS AND RESULTS: Seventy three patients with DM were compared with age- and gender-matched normal controls; 30 patients with DM alone were compared to those with hypertension (HT) alone. The maximum LA volume, traditional measures of atrial function, 2D strain and strain rate were analysed. The LA indexed volume (LAVI) was larger in DM group than that in normal controls (38.2 ± 9.9 vs. 20.5 ± 4.8 ml/m(2), P< 0.0001), as well as in DM alone compared with hypertensive patients (33.9 ± 10 vs. 25.7 ± 8 ml/m(2), P< 0.0001). Global strain was significantly reduced in the DM group compared with that in normal controls (22.5 ± 8.67 vs. 30.6 ± 8.27%; P< 0.0001) but was similar with HT. There was a weak correlation between LAVI and global strain with increasing grades of DD (r= 0.439, P< 0.0001 and r= - 0.316, P< 0.0001, respectively) in the diabetic group. However, there was no significant difference in LAVI between these groups. A logistic regression analysis for predictors of LAVI demonstrated that only diabetes was a determinant of LAVI. Patients with diabetes showed a significant reduction in global strain compared with normal controls but no difference with increasing grades of diastolic function. CONCLUSIONS: LA enlargement in DM is independent of associated HT and diastolic function. LA enlargement is associated with LA dysfunction as evaluated by 2D strain. It is likely that a combination of DD and a diabetic atrial myopathy contribute to LA enlargement in patients with DM.

Improvements in knee range and symptomatic and functional behavior after knee arthroplasty based on preoperative restriction in range.

Recovery of knee range and Oxford Knee Score post knee arthroplasty based on preoperative knee range is described. A total of 191 patients recruited across 5 hospitals were assessed preoperatively, at 8 weeks postoperatively and 1 year. Preoperative knee range was categorized into "low" (≤ 109), "moderate" (> 109 to ≤ 120), and "high" (> 120°) flexion and "normal" (± -5) and "restricted" (> +5°) terminal extension. Recovery was analyzed using MIXED modeling procedures. The low-flexion group gained flexion across time. The moderate-flexion and high-flexion groups lost flexion initially then recovered, but 1-year flexion remained lower than preoperative values. The restricted terminal extension group gained extension across time. The normal terminal extension group lost extension initially then recovered to preoperative values at 1 year. Recovery in Oxford score was independent of preoperative knee range limitation. Improvement in knee range postoperatively, but not self-reported behavior, is highly dependent on the initial restriction in range.