Trends in the Care of Diabetic Macular Edema: Analysis of a National Cohort

Purpose

To evaluate how the monitoring and treatment for diabetic macular edema (DME) has changed in a national sample.

Design

Retrospective cohort study.

Methods

Setting: Administrative medical claims data from a large, national U.S. insurer. Study population: Beneficiaries of a U.S. insurance company. Observation procedures: All incident cases of DME were found. Those in years 2002/3, 2006 and 2010 were followed for a 2-year observation period and those from 2009, 2010 and 2011 for a 1-year observation period. Main Outcome Measures: Types and frequencies of treatment were tallied and compared over each of the cohorts.

Results

Two-year cohorts had 233, 251 and 756 patients in 2002/3, 2006 and 2010 respectively. One-year cohorts had 1002, 1119 and 1382 patients in 2009, 2010 and 2011, respectively. Both percentage of patients receiving therapy and number of treatments given increased across the 2-year cohorts for both focal laser and anti-vascular endothelial growth factor (anti-VEGF) (p<0.001). The highest use of anti-VEGF agents in any of the cohorts was in the 2011 1-year group that only averaged 3.78 injections. Focal laser was used 2.5x as frequently as anti-VEGF injections in the most recent cohorts with only a high of 14.0% of DME patients receiving anti-VEGF therapy in any of the cohorts.

Conclusion

Regardless of treatment modality (laser or injection) DME patients received vastly fewer treatments than patients in randomized control trials. Despite the proven superior visual outcomes of anti-VEGF agents over focal laser in DME, focal laser was still used more frequently.     

Effects of Acute Supramaximal Cycle Exercise on Plasma FFA Concentration in Obese Adolescent Boys

Aims

The aims of the present study are 1) to evaluate the free fatty acid (FFA) profile and 2) to determine the relative anaerobic and aerobic contributions to total energy consumption during repeated supramaximal cycling bouts (SCE) in adolescent boys with different body weight statuses.

Materials and Methods

Normal-weight (NW), overweight (OW), and obese (OB) adolescent boys (n =15 per group) completed a SCE sessions consisted of 6 x 6s maximal sprints with 2 min of passive rest between each repetition. Plasma FFA levels were determined at rest, immediately after a 10 min warm-up, and immediately at the end of SCE. The anaerobic and aerobic contributions (%) were measured via repeated SCE bouts. Insulin resistance was calculated using the homoeostatic model assessment (HOMA-IR) index.

Results

The FFA concentrations measured immediately after SCE were higher in the OB group than in the OW and NW (p<0.01 and p<0.01, respectively) groups. Moreover, the anaerobic contributions to SCE were significantly lower in obese adolescents (p<0.01) and decreased significantly during the 2^nd, 3^rd and 4^th repetitions. The FFA levels were significantly associated with the HOMA-IR index and aerobic contribution among adolescent boys (r=0.83 and r=0.91, respectively, p<0.01).

Conclusion

In contrast to the NW and OW groups, there is an increase in lipid mobilization and sift to aerobic energy metabolism during SCE in the OB group.     

Care Needs and Clinical Outcomes of Older People with Dementia: A Population-Based Propensity Score-Matched Cohort Study

Objective

To explore the healthcare resource utilization, psychotropic drug use and mortality of older people with dementia.

Design

A nationwide propensity score-matched cohort study.

Setting

National Health Insurance Research database.

Participants

A total of 32,649 elderly people with dementia and their propensity-score matched controls (n=32,649).

Measurements

Outpatient visits, inpatient care, psychotropic drug use, in-hospital mortality and all-cause mortality at 90 and 365 days.

Results

Compared to the non-dementia group, a higher proportion of patients with dementia used inpatient services (1 year after index date: 20.91% vs. 9.55%), and the dementia group had more outpatient visits (median [standard deviation]: 7.00 [8.87] vs. 3.00 [8.30]). Furthermore, dementia cases with acute admission had the highest psychotropic drug utilization both at baseline and at the post-index dates (difference-in-differences: all <0.001). Dementia was associated with an increased risk of all-cause mortality (90 days, Odds ratio (OR)=1.85 [95%CI 1.67-2.05], p<0.001; 365 days, OR=1.59 [1.50-1.69], p<0.001) and in-hospital mortality (90 days, OR=1.97 [1.71-2.27], p<0.001; 365 days, OR=1.82 [1.61-2.05], p<0.001) compared to matched controls.

Conclusions

When older people with dementia are admitted for acute illnesses, they may increase their use of psychotropic agents and their risk of death, particularly in-hospital mortality.     

Accuracy of [18F]FDG PET/MRI for the Detection of Liver Metastases

Background

The aim of this study was to compare the diagnostic accuracy of [¹⁸F]FDG-PET/MRI with PET/CT for the detection of liver metastases.

Methods

32 patients with solid malignancies underwent [¹⁸F]FDG-PET/CT and subsequent PET/MRI of the liver. Two readers assessed both datasets regarding lesion characterization (benign, indeterminate, malignant), conspicuity and diagnostic confidence. An imaging follow-up (mean interval: 185±92 days) and/-or histopathological specimen served as standards of reference. Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were calculated for both modalities. Accuracy was determined by calculating the area under the receiver operating characteristic (ROC) curve. Values of conspicuity and diagnostic confidence were compared using Wilcoxon-signed-rank test.

Results

The standard of reference revealed 113 liver lesions in 26 patients (malignant: n = 45; benign: n = 68). For PET/MRI a higher accuracy (PET/CT: 82.4%; PET/MRI: 96.1%; p<0.001) as well as sensitivity (67.8% vs. 92.2%, p<0.01) and NPV (82.0% vs. 95.1%, p<0.05) were observed. PET/MRI offered higher lesion conspicuity (PET/CT: 2.0±1.1 [median: 2; range 0–3]; PET/MRI: 2.8±0.5 [median: 3; range 0–3]; p<0.001) and diagnostic confidence (PET/CT: 2.0±0.8 [median: 2; range: 1–3]; PET/MRI 2.6±0.6 [median: 3; range: 1–3]; p<0.001). Furthermore, PET/MRI enabled the detection of additional PET-negative metastases (reader 1: 10; reader 2: 12).

Conclusions

PET/MRI offers higher diagnostic accuracy compared to PET/CT for the detection of liver metastases.     

Anterior and Posterior Ocular Biometry in Healthy Chinese Subjects: Data Based on AS-OCT and SS-OCT

Background

To measure the anterior and posterior ocular biometric characteristics concurrently and to determine the relationship between the iris and choroid in healthy Chinese subjects.

Methods

A total of 148 subjects (270 eyes) were enrolled in this cross-section study. The anterior and posterior ocular biometric characteristics were measured simultaneously by anterior segment optical coherence tomography (AS-OCT) and swept-source optical coherence tomography (SS-OCT).

Results

Compared with male eyes, female eyes had narrower anterior biometric parameters that presented with smaller anterior segment parameters [including anterior chamber depth (ACD), width (ACW), area (ACA), and volume (ACV); (all p<0.001)], narrower anterior chamber angle parameters [including angle opening distance (AOD750), trabecular–iris space area (TISA750), and angle recess area (ARA); (all p<0.001)], higher iris curvature (ICURV) (p = 0.003), and larger lens vaults (LV) (p = 0.019). These anterior ocular biometric parameters were correlated with increasing age (p<0.01). Iris thickness (IT750) and iris area (IAREA) were associated with age, ACW, and pupil diameter (all p<0.05), while choroidal thickness (CT) was associated with age, gender, and axial length (all p<0.05). Univariate regression analysis showed that greater CT was significantly associated with smaller IAREA (p = 0.026).

Conclusion

Compared with male eyes, female eyes had narrower anterior biometric parameters that correlated with increasing age, which would be helpful in explaining the higher prevalence of angle closure rates in the female gender and in aging people. Increased CT might be associated with smaller iris area; however, this possibility needs to be investigated in future studies before this conclusion is made.     

The Sex and Race Specific Relationship between Anthropometry and Body Fat Composition Determined from Computed Tomography: Evidence from the Multi-Ethnic Study of Atherosclerosis

Background

Few studies have investigated the relationship of anthropometric measurements with computed tomography (CT) body fat composition, and even fewer determined if these relationships differ by sex and race.

Methods

CT scans from 1,851 participants in the population based Multi-Ethnic Study of Atherosclerosis were assessed for visceral and subcutaneous fat areas by semi-automated segmentation of body compartments. Regression models were used to investigate relationships for anthropometry with visceral and subcutaneous fat separately by sex and race/ethnicity.

Results

Participants were 50% female, 41% Caucasian, 13% Asian, 21% African American, and 25% Hispanic. For visceral fat, the positive relationship with weight (p = 0.028), waist circumference (p<0.001), waist to hip ratio (p<0.001), and waist to height ratio (p = 0.05) differed by sex, with a steeper slope for men. That is, across the range of these anthropometric measures the rise in visceral fat is faster for men than for women. Additionally, there were differences by race/ethnicity in the relationship with height (p<0.001), weight (p<0.001), waist circumference (p<0.001), hip circumference (p = 0.006), and waist to hip ratio (p = 0.001) with the Hispanic group having shallower slopes. For subcutaneous fat, interaction by sex was found for all anthropometric indices at p<0.05, but not for race/ethnicity.

Conclusion

The relationship between anthropometry and underlying adiposity differs by sex and race/ethnicity. When anthropometry is used as a proxy for visceral fat in research, sex-specific models should be used.     

The Economic Crisis and Acute Myocardial Infarction: New Evidence Using Hospital-Level Data

Objective

This research sought to assess whether and to what extent the ongoing economic crisis in Italy impacted hospitalizations, in-hospital mortality and expenditures associated with acute myocardial infarction (AMI).

Methods

The data were obtained from the hospital discharge database of the Italian Health Ministry and aggregated at the hospital level. Each hospital (n = 549) was observed for 4 years and was geographically located within a “Sistema Locale del Lavoro” (SLL, i.e., clusters of neighboring towns with a common economic structure). For each SLL, the intensity of the crisis was determined, defined as the 2012–2008 increase in the area-specific unemployment rate. A difference-in-differences (DiD) approach was employed to compare the increases in AMI-related outcomes across different quintiles of crisis intensity.

Results

Hospitals located in areas with the highest intensity of crisis (in the fifth quintile) had an increase of approximately 30 AMI cases annually (approximately 13%) compared with hospitals in area with lower crisis intensities (p<0.001). A significant increase in total hospital days was observed (13%, p<0.001) in addition to in-hospital mortality (17%, p<0.001). As a consequence, an increase of around €350.000 was incurred in annual hospital expenditures for AMI (approximately 36%, p<0.001).

Conclusions

More attention should be given to the increase in health needs associated with the financial crisis. Policies aimed to contrast unemployment in the community by keeping and reintegrating workers in jobs could also have positive impacts on adverse health outcomes, especially in areas of high crisis intensity.     

A Comparison of Radiologic Tumor Volume and Pathologic Tumor Volume in Renal Cell Carcinoma (RCC)

Objective

To investigate the difference between preoperative radiologic tumor volume (RTV) and postoperative pathologic tumor volume (PTV) in patients who received nephrectomy for renal cell carcinoma (RCC).

Materials and Methods

We reviewed 482 patients who underwent preoperative computed tomography (CT) within 4 weeks before radical or partial nephrectomy for renal cell carcinoma. RTV measured by a three dimensional rendering program was compared with PTV (π/6ⅹheightⅹlengthⅹwidth) measured in surgical specimen according to pathologic tumor size and histologic subtype. Correlation of the inter-quartile range (IQR) of the RTV and Fuhrman nuclear grade was also investigated.

Results

There was a significant positive linear correlation between RTV and PTV (p<0.001, r = 0.911), and the mean RTV and mean PTV were not significantly different (79.0 vs 76.9cm³, p = 0.393). For pathologic tumor size (PTS) <4cm, the mean RTV was larger than the mean PTV (10.9 vs 7.1cm³, p<0.001). For a PTS of 4-7cm, the mean RTV was larger than the mean PTV (56.0 vs 44.7cm³, p<0.001). However, for a PTS ≥7cm, there was no statistical difference between RTV and PTV (p>0.05). Among patients with clear cell RCC, the mean RTV was significantly larger than the mean PTV (p = 0.042), not for non-clear cell group (p = 0.055). As the quartile of the RTV increased, the Fuhrman grade also increased (p<0.001).

Conclusions

RTV was correlated with PTV and pathologic grade. RTV was larger than the PTV for a tumor size 7 cm or less or in clear cell RCC. RTV may be useful to measure tumor burden preoperatively.     

Systemic Inflammation Predicts All-Cause Mortality: A Glasgow Inflammation Outcome Study

Introduction

Markers of the systemic inflammatory response, including C-reactive protein and albumin (combined to form the modified Glasgow Prognostic Score), as well as neutrophil, lymphocyte and platelet counts have been shown to be prognostic of survival in patients with cancer. The aim of the present study was to examine the prognostic relationship between these markers of the systemic inflammatory response and all-cause, cancer, cardiovascular and cerebrovascular mortality in a large incidentally sampled cohort.

Methods

Patients (n = 160 481) who had an incidental blood sample taken between 2000 and 2008 were studied for the prognostic value of C-reactive protein (>10mg/l, albumin (>35mg/l), neutrophil (>7.5×10⁹/l) lymphocyte and platelet counts. Also, patients (n = 52 091) sampled following the introduction of high sensitivity C-reactive protein (>3mg/l) measurements were studied. A combination of these markers, to make cumulative inflammation-based scores, were investigated.

Results

In all patients (n = 160 481) C-reactive protein (>10mg/l) (HR 2.71, p<0.001), albumin (>35mg/l) (HR 3.68, p<0.001) and neutrophil counts (HR 2.18, p<0.001) were independently predictive of all-cause mortality. These associations were also observed in cancer, cardiovascular and cerebrovascular mortality before and after the introduction of high sensitivity C-reactive protein measurements (>3mg/l) (n = 52 091). A combination of high sensitivity C-reactive protein (>3mg/l), albumin and neutrophil count predicted all-cause (HR 7.37, p<0.001, AUC 0.723), cancer (HR 9.32, p<0.001, AUC 0.731), cardiovascular (HR 4.03, p<0.001, AUC 0.650) and cerebrovascular (HR 3.10, p<0.001, AUC 0.623) mortality.

Conclusion

The results of the present study showed that an inflammation-based prognostic score, combining high sensitivity C-reactive protein, albumin and neutrophil count is prognostic of all-cause mortality.     

Validation of Smartphone Based Retinal Photography for Diabetic Retinopathy Screening

Aim

To evaluate the sensitivity and specificity of “fundus on phone’ (FOP) camera, a smartphone based retinal imaging system, as a screening tool for diabetic retinopathy (DR) detection and DR severity in comparison with 7-standard field digital retinal photography.

Design

Single-site, prospective, comparative, instrument validation study.

Methods

301 patients (602 eyes) with type 2 diabetes underwent standard seven-field digital fundus photography with both Carl Zeiss fundus camera and indigenous FOP at a tertiary care diabetes centre in South India. Grading of DR was performed by two independent retina specialists using modified Early Treatment of Diabetic Retinopathy Study grading system. Sight threatening DR (STDR) was defined by the presence of proliferative DR(PDR) or diabetic macular edema. The sensitivity, specificity and image quality were assessed.

Results

The mean age of the participants was 53.5 ±9.6 years and mean duration of diabetes 12.5±7.3 years. The Zeiss camera showed that 43.9% had non-proliferative DR(NPDR) and 15.3% had PDR while the FOP camera showed that 40.2% had NPDR and 15.3% had PDR. The sensitivity and specificity for detecting any DR by FOP was 92.7% (95%CI 87.8–96.1) and 98.4% (95%CI 94.3–99.8) respectively and the kappa (ĸ) agreement was 0.90 (95%CI-0.85–0.95 p<0.001) while for STDR, the sensitivity was 87.9% (95%CI 83.2–92.9), specificity 94.9% (95%CI 89.7–98.2) and ĸ agreement was 0.80 (95%CI 0.71–0.89 p<0.001), compared to conventional photography.

Conclusion

Retinal photography using FOP camera is effective for screening and diagnosis of DR and STDR with high sensitivity and specificity and has substantial agreement with conventional retinal photography.     

Clinical and Angioarchitectural Risk Factors Associated with Intracranial Hemorrhage in Dural Arteriovenous Fistulas: A Single-Center Retrospective Study

Purpose

To investigate which clinical and angioarchitectural features were associated with the occurrence of intracranial hemorrhage in patients with intracranial dural arteriovenous fistulas (DAVFs).

Materials and Methods

We retrospectively reviewed the clinical and angioarchitectural features of 236 consecutive patients diagnosed with DAVF in our department from April 2009 to November 2013. Two groups of patients, with or without intracranial hemorrhage as clinical presentation at the initial diagnosis, were analysed to identify the differences in clinical and angioarchitectural features in univariate analysis. A multivariate logistic regression model was also developed to assess the independent contribution of the potential risk factors. Associations were considered significant for p<0.05.

Results

Fifty-six patients (23.7%) presented with intracranial hemorrhage at the initial diagnosis of DAVF. In univariate analysis, male patients (p = 0.002), patients with medical history of smoking (p<0.001) or alcohol consumption (p = 0.022), and DAVFs located at the tentorium (p = 0.010), frontalbasal (p = 0.007), foramen magnum (p = 0.043) or cerebral convexity (p<0.001) were associated with an increased risk of intracranial hemorrhage. A higher risk of hemorrhagic occurrence was also observed in DAVFs with superficial cortical venous drainage (p<0.001), deep venous drainage (p = 0.003), occluded venous sinus (p<0.032), or higher Borden type (p<0.001). A multivariate logistic regression model showed that intracranial hemorrhage in patients with DAVFs was correlated with higher Borden classification (OR 5.880; 95% CI, 3.370–10.257; p<0.001).

Conclusion

Venous drainage pattern was the only independent risk factor of intracranial hemorrhage in our patients with intracranial DAVF. The other potential risk factors may be confounding factors in predicting intracranial hemorrhage.     

Expression of Cytokines,Chmokines and Growth Factors in Patients Undergoing Cataract Surgery with Femtosecond Laser Pretreatment

Purpose

To describe cytokines, chemokines and growth factors profiles in patients undergoing cataract surgery with femtosecond laser pretreatment and investigate their relationships with the postoperative in vivo inflammation index.

Methods

Aqueous humor was collected from 22 eyes after femtosecond laser pretreatment and from 22 eyes at the beginning of routine cataract surgery. The levels of 45 inflammation-related mediators were measured using multiplex fluorescent bead-based immunoassays. Laser flare photometry was measured preoperatively and at 1 day, 7 days and 30 days postoperatively.

Results

Compared with the control group, the femtosecond laser treatment group showed significantly higher aqueous humor levels of fibroblast growth factor (FGF-2), tumor necrosis factor (TNF)-α, leukemia inhibitor factor (LIF), interleukin (IL)-1ra and IL-18, and significantly lower aqueous humor levels of IL-9, platelet-derived growth factor (PDGF)-BB, eotaxin and TNF-β. Postoperative aqueous flare was significantly greater in the manual cataract surgery group at 1 day (p<0.001), 7days (p<0.001) and 30 days (p = 0.002).No correlation was found between the analyzed mediators and the aqueous flare values.

Conclusions

The expression profiles of cytokines, chemokines and growth factors and the correlations of these profiles with the in vivo inflammatory indexes for patients undergoing cataract surgery with femtosecond laser pretreatment were identified. Our data indicate a disturbance of postoperative inflammation response after femtosecond laser treatment.     

Effects of a 12-Week Hatha Yoga Intervention on Metabolic Risk and Quality of Life in Hong Kong Chinese Adults with and without Metabolic Syndrome

Objective

To determine the efficacy of a 12-week Hatha yoga intervention to improve metabolic risk profiles and health-related quality of life (HRQoL) in Chinese adults with and without metabolic syndrome (MetS).

Methods

We conducted a controlled trial within an university-affiliated hospital. 173 Chinese men and women aged 18 or above were assigned to either the yoga intervention group (n = 87) or the control group (n = 86). Primary outcomes included 12-week change in metabolic risk factors and MetS z score. Secondary outcome was HRQoL (Medical Outcomes Short Form Survey at 12 weeks).

Results

The mean age of participants was 52.0 (SD 7.4, range 31-71) years. Analysis involving the entire study population revealed that the yoga group achieved greater decline in waist circumference (p<0.001), fasting glucose (p<0.01), triglycerides (p<0.05), and MetS z score (p<0.01). Yoga training also improved general health perceptions (p<0.01), physical component score (p<0.01), and social functioning (p<0.01) domains score of HRQoL. However, no significant differences between groups were observed in the mean change of systolic/diastolic blood pressures or high-density lipid protein cholesterol (all p>0.05). There were no significant differences in the intervention effects on waist circumference and MetS z score between the MetS subgroups (both p>0.05).

Conclusion

A 12-week Hatha yoga intervention improves metabolic risk profiles and HRQoL in Chinese adults with and without MetS.

Trial Registration

Australian New Zealand Clinical Trials Registry ACTRN12613000816752     

Suppression and regression of choroidal neovascularization in mice by a novel CCR2 antagonist, INCB3344

Purpose

To investigate the effect of an intravitreally administered CCR2 antagonist, INCB3344, on a mouse model of choroidal neovascularization (CNV).

Methods

CNV was induced by laser photocoagulation on Day 0 in wild type mice. INCB3344 or vehicle was administered intravitreally immediately after laser application. On Day 14, CNV areas were measured on retinal pigment epithelium (RPE)-choroid flat mounts and histopathologic examination was performed on 7 µm-thick sections. Macrophage infiltration was evaluated by immunohistochemistry on RPE-choroid flat mounts and quantified by flow cytometry on Day 3. Expression of vascular endothelial growth factor (VEGF) protein in RPE-choroid tissue was examined by immunohistochemistry and ELISA, VEGF mRNA in sorted macrophages in RPE-choroid tissue was examine by real-time PCR and expression of phosphorylated extracellular signal-regulated kinase (p-ERK 1/2) in RPE-choroid tissue was measured by Western blot analysis on Day 3. We also evaluated the efficacy of intravitreal INCB3344 to spontaneous CNV detected in Cu, Zn-superoxide dismutase (SOD1) deficient mice. Changes in CNV size were assessed between pre- and 1week post-INCB3344 or vehicle administration in fundus photography and fluorescence angiography (FA).

Results

The mean CNV area in INCB3344-treated mice decreased by 42.4% compared with the vehicle-treated control mice (p<0.001). INCB3344 treatment significantly inhibited macrophage infiltration into the laser-irradiated area (p<0.001), and suppressed the expression of VEGF protein (p = 0.012), VEGF mRNA in infiltrating macrophages (p<0.001) and the phosphorylation of ERK1/2 (p<0.001). The area of spontaneous CNV in Sod1 ^−/− mice regressed by 70.35% in INCB3344-treated animals while no change was detected in vehicle-treated control mice (p<0.001).

Conclusions

INCB3344 both inhibits newly forming CNV and regresses established CNV. Controlling inflammation by suppressing macrophage infiltration and angiogenic ability via the CCR-2/MCP-1 signal may be a useful therapeutic strategy for treating CNV associated with age-related macular degeneration.     

Serum Trimethylamine-N-Oxide Is Strongly Related to Renal Function and Predicts Outcome in Chronic Kidney Disease

Background

The microbial metabolite Trimethylamine-N-oxide (TMAO) has been linked to adverse cardiovascular outcome and mortality in the general population.

Objective

To assess the contribution of TMAO to inflammation and mortality in chronic kidney disease (CKD) patients ranging from mild-moderate to end-stage disease and 1) associations with glomerular filtration rate (GFR) 2) effect of dialysis and renal transplantation (Rtx) 3) association with inflammatory biomarkers and 4) its predictive value for all-cause mortality.

Methods

Levels of metabolites were quantified by a novel liquid chromatography/tandem mass spectrometry-based method in fasting plasma samples from 80 controls and 179 CKD 3–5 patients. Comorbidities, nutritional status, biomarkers of inflammation and GFR were assessed.

Results

GFR was the dominant variable affecting TMAO (β = -0.41; p<0.001), choline (β = -0.38; p<0.001), and betaine (β = 0.45; p<0.001) levels. A longitudinal study of 74 CKD 5 patients starting renal replacement therapy demonstrated that whereas dialysis treatment did not affect TMAO, Rtx reduced levels of TMAO to that of controls (p<0.001). Following Rtx choline and betaine levels continued to increase. In CKD 3–5, TMAO levels were associated with IL-6 (Rho = 0.42; p<0.0001), fibrinogen (Rho = 0.43; p<0.0001) and hsCRP (Rho = 0.17; p = 0.022). Higher TMAO levels were associated with an increased risk for all-cause mortality that remained significant after multivariate adjustment (HR 4.32, 95% CI 1.32–14.2; p = 0.016).

Conclusion

Elevated TMAO levels are strongly associated with degree of renal function in CKD and normalize after renal transplantation. TMAO levels correlates with increased systemic inflammation and is an independent predictor of mortality in CKD 3–5 patients.     

Lesion Load May Predict Long-Term Cognitive Dysfunction in Multiple Sclerosis Patients

Background

Magnetic Resonance Imaging (MRI) techniques provided evidences into the understanding of cognitive impairment (CIm) in Multiple Sclerosis (MS).

Objectives

To investigate the role of white matter (WM) and gray matter (GM) in predicting long-term CIm in a cohort of MS patients.

Methods

303 out of 597 patients participating in a previous multicenter clinical-MRI study were enrolled (49.4% were lost at follow-up). The following MRI parameters, expressed as fraction (f) of intracranial volume, were evaluated: cerebrospinal fluid (CSF-f), WM-f, GM-f and abnormal WM (AWM-f), a measure of lesion load. Nine years later, cognitive status was assessed in 241 patients using the Symbol Digit Modalities Test (SDMT), the Semantically Related Word List Test (SRWL), the Modified Card Sorting Test (MCST), and the Paced Auditory Serial Addition Test (PASAT). In particular, being SRWL a memory test, both immediate recall and delayed recall were evaluated. MCST scoring was calculated based on the number of categories, number of perseverative and non-perseverative errors.

Results

AWM-f was predictive of an impaired performance 9 years ahead in SDMT (OR 1.49, CI 1.12–1.97 p = 0.006), PASAT (OR 1.43, CI 1.14–1.80 p = 0.002), SRWL-immediate recall (OR 1.72 CI 1.35–2.20 p<0.001), SRWL-delayed recall (OR 1.61 CI 1.28–2.03 p<0.001), MCST-category (OR 1.52, CI 1.2–1.9 p<0.001), MCST-perseverative error(OR 1.51 CI 1.2–1.9 p = 0.001), MCST-non perseverative error (OR 1.26 CI 1.02–1.55 p = 0.032).

Conclusion

In our large MS cohort, focal WM damage appeared to be the most relevant predictor of the long-term cognitive outcome.     

Intravascular Ultrasound Observation of the Mechanism of No-Reflow Phenomenon in Acute Myocardial Infarction

Objective

To study the mechanism of the no-reflow phenomenon using coronary angiography (CAG) and intravascular ultrasound (IVUS).

Methods

A total of 120 patients with acute myocardial infarction (AMI) who successfully underwent indwelling intracoronary stent placement by percutaneous coronary intervention (PCI). All patients underwent pre- and post-PCI CAG and pre-IVUS. No-reflow was defined as post-PCI thrombolysis in myocardial infarction (TIMI) grade 0, 1, or 2 flow in the absence of mechanical obstruction. Normal reflow was defined as TIMI grade 3 flow. The pre-operation reference vascular area, minimal luminal cross-sectional area, plaque cross-sectional area, lesion length, plaque volume and plaque traits were measured by IVUS.

Results

The no-reflow group was observed in 14 cases (11.6%) and normal blood-flow group in 106 cases (89.4%) based on CAG results. There was no statistically significant difference in the patients’ medical history, reference vascular area (no-flow vs. normal-flow; 15.5 ± 3.2 vs. 16.2 ± 3.3, p> 0.05) and lesion length (21.9 ± 5.1 vs. 19.5 ± 4.8, p> 0.05) between the two groups. No-reflow patients had a longer symptom onset to reperfusion time compared to normal blood-flow group [(6.6 ± 3.1) h vs (4.3 ± 2.7) h; p< 0.05] and higher incidence of TIMI flow grade< 3 (71.4% vs 49.0%, p< 0.05). By IVUS examination, the no-reflow group had a significantly increased coronary plaque area and plaque volume compared to normal blood-flow group [(13.7 ± 3.0) mm² vs (10.2 ± 2.9) mm²; (285.4 ± 99.8) mm³ vs (189.7 ± 86.4) mm³; p< 0.01]. The presence of IVUS-detected soft plaque (57.1% vs. 24.0%, p< 0.01), eccentric plaque (64.2% vs. 33.7%, p< 0.05), plaque rupture (50.0% vs. 21.2%, p< 0.01), and thrombosis (42.8% vs. 15.3%) were significantly more common in no-reflow group.

Conclusion

There was no obvious relationship between the coronary risk factors and no-reflow phenomenon. The symptom onset to reperfusion time, TIMI flow grade before stent deployment, plaque area, soft plaques, eccentric plaques, plaque rupture and thrombosis may be risk factors for the no-reflow phenomenon after PCI.     

Free Fatty Acid Effects on the Atrial Myocardium: Membrane Ionic Currents Are Remodeled by the Disruption of T-Tubular Architecture

Background

Epicardial adiposity and plasma levels of free fatty acids (FFAs) are elevated in atrial fibrillation, heart failure and obesity, with potentially detrimental effects on myocardial function. As major components of epicardial fat, FFAs may be abnormally regulated, with a potential to detrimentally modulate electro-mechanical function. The cellular mechanisms underlying such effects of FFAs are unknown.

Objective

To determine the mechanisms underlying electrophysiological effects of palmitic (PA), stearic (SA) and oleic (OA) FFAs on sheep atrial myocytes.

Methods

We used electrophysiological techniques, numerical simulations, biochemistry and optical imaging to examine the effects of acutely (≤ 15 min), short-term (4–6 hour) or 24-hour application of individual FFAs (10 μM) on isolated ovine left atrial myocytes (LAMs).

Results

Acute and short-term incubation in FFAs resulted in no differences in passive or active properties of isolated left atrial myocytes (LAMs). 24-hour application had differential effects depending on the FFA. PA did not affect cellular passive properties but shortened (p<0.05) action potential duration at 30% repolarization (APD₃₀). APD₅₀ and APD₈₀ were unchanged. SA had no effect on resting membrane potential but reduced membrane capacitance by 15% (p<0.05), and abbreviated APD at all values measured (p≤0.001). OA did not significantly affect passive or active properties of LAMs. Measurement of the major voltage-gated ion channels in SA treated LAMs showed a ~60% reduction (p<0.01) of the L-type calcium current (I_Ca-L) and ~30% reduction (p<0.05) in the transient outward potassium current (I_TO). A human atrial cell model recapitulated SA effects on APD. Optical imaging showed that SA incubated for 24 hours altered t-tubular structure in isolated cells (p<0.0001).

Conclusions

SA disrupts t-tubular architecture and remodels properties of membrane ionic currents in sheep atrial myocytes, with potential implications in arrhythmogenesis.     

Treatment of Osteoarthritis of the Knee with a Combination of Autologous Conditioned Serum and Physiotherapy: A Two-Year Observational Study

Background

Autologous conditioned serum (ACS) is an autologous blood product that has shown efficacy against knee osteoarthritis (OA) in randomized controlled trials. However, there are few reports of its effectiveness in everyday practice. Here, we report clinical efficacy results from a two-year prospective observational study of patients with highly symptomatic knee OA who received ACS in conjunction with physiotherapy.

Methods

118 patients with unilateral knee OA (Kellgren-Lawrence grades I–IV), who were candidates for surgery but instead chose conservative treatment, were treated with a combination of four intra-articular injections of ACS (2 mL each) once weekly over four weeks and subsequent physiotherapy applied 4 weeks after ACS injection. Main endpoints of the study were pain (Numeric Rating Scale [NRS]) assessed at 0, 3, 6, 12 and 24 months, and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) global score, assessed at 0 and 24 months. The effect size (Cohen’s d) was calculated for pain and WOMAC outcomes, with effect sizes >0.8 considered large.

Results

By 3 months, there were significant improvements in pain (NRS) from baseline (-63.0%, p<0.001), which were maintained over 24 months. Mean WOMAC global score was reduced at 24 months compared to baseline (-56.9%, p<0.001), as were WOMAC subscores of pain (-86.0%, p<0.001) and function (-51.3%, p<0.001). Effect sizes for pain (>5) and WOMAC improvement (8.0–13.6) were very large. Only one patient received total knee joint replacement during the study. Clinical improvement did not correlate with gender, age, Kellgren-Lawrence grade, or body mass index.

Conclusions

Treatment with ACS and physiotherapy produced a rapid decline in pain, which was sustained for the entire two years of the study. This was accompanied by a large improvement in WOMAC scores at two years. These results confirm that ACS combined with physiotherapy is an effective treatment for OA of the knee.     

Corneal Confocal Microscopy Detects Neuropathy in Patients with Type 1 Diabetes without Retinopathy or Microalbuminuria

Objective

Corneal innervation is increasingly used as a surrogate marker of human diabetic peripheral neuropathy (DPN) however its temporal relationship with the other microvascular complications of diabetes is not fully established. In this cross-sectional, observational study we aimed to assess whether neuropathy occurred in patients with type 1 diabetes, without retinopathy or microalbuminuria.

Materials and Methods

All participants underwent detailed assessment of peripheral neuropathy [neuropathy disability score (NDS), vibration perception threshold (VPT), peroneal motor nerve conduction velocity (PMNCV), sural sensory nerve conduction velocity (SSNCV) and in vivo corneal confocal microscopy (IVCCM)], retinopathy (digital fundus photography) and albuminuria status [albumin: creatinine ratio (ACR)].

Results

53 patients with Type 1 diabetes with (n=37) and without retinopathy (n=16) were compared to control subjects (n=27). SSNCV, corneal nerve fibre (CNFD) and branch (CNBD) density and length (CNFL) were reduced significantly (p<0.001) in diabetic patients without retinopathy compared to control subjects. Furthermore, CNFD, CNBD and CNFL were also significantly (p<0.001) reduced in diabetic patients without microalbuminuria (n=39), compared to control subjects. Greater neuropathic severity was associated with established retinopathy and microalbuminuria.

Conclusions

IVCCM detects early small fibre damage in the absence of retinopathy or microalbuminuria in patients with Type 1 diabetes.