Progress Towards Elimination of Trachoma in Kenya 2017-2020.

PURPOSE: Trachoma is endemic in Kenya. Since baseline trachoma surveys in 2004, a concerted programme has been undertaken to reduce the prevalence of disease. Here, we report on trachoma prevalence surveys carried out between 2017 and 2020 after interventions were implemented in some areas for trachoma elimination purposes. METHODS: A total of 48 cross-sectional population-based trachoma prevalence surveys were conducted in 39 evaluation units (EUs; covering 45 subcounties) of Kenya between 2017 and 2020. Thirty EUs were surveyed once and nine EUs were surveyed twice over this period. Individuals ≥ 1 year old were assessed for trachomatous inflammation-follicular (TF), trachomatous inflammation-intense (TI) and trichiasis. Data were collected on household access to water, sanitation and hygiene (WASH). RESULTS: A total of 147,573 people were examined. At the end of 2020, in the 39 EUs surveyed, the prevalence of TF in 1-9-year-olds was ≥5% in 11 EUs and the prevalence of trichiasis unknown to the health system in individuals aged ≥15 years was ≥0.2% in 25 EUs. A small minority of households (median <50% for all indicators) had access to improved WASH facilities. CONCLUSION: Kenya has made excellent progress towards elimination of trachoma as a public health problem. However, there is more work to do. Between one and three rounds of antibiotic mass drug administration are required in 11 EUs. Sustained investment in surgical provision, continued TT case-finding, promotion of facial cleanliness and environmental improvement are required throughout the surveyed area.

Factor XI Inhibition With Heparin Reduces Clot Formation in Simulated Pediatric Extracorporeal Membrane Oxygenation.

Extracorporeal membrane oxygenation (ECMO) supplies circulatory support and gas exchange to critically ill patients. Despite the use of systemic anticoagulation, blood exposure to ECMO surfaces causes thromboembolism complications. Inhibition of biomaterial surface-mediated activation of coagulation factor XI (FXI) may prevent device-associated thrombosis. Blood was collected from healthy volunteers (n = 13) following the U.S. Army Institute of Surgical Research standard operating procedure for testing in an ex vivo ECMO circuit. A roller-pump circuit circulated either 0.5 U/ml of unfractionated heparin alone or in combination with the anti-FXI immunoglobulin G (IgG) (AB023) for 6 hours or until clot formation caused device failure. Coagulation factor activity, platelet counts, time to thrombin generation, peak thrombin, and endogenous thrombin potential were quantified. AB023 in addition to heparin sustained circuit patency in all tested circuits (5/5) after 6 hours, while 60% of circuits treated with heparin alone occluded (3/8), log-rank p < 0.03. AB023 significantly prolonged the time to clot formation as compared to heparin alone (15.5 vs . 3.3 minutes; p < 0.01) at the 3-hour time point. AB023 plus heparin significantly reduced peak thrombin compared to heparin alone (123 vs . 217 nM; p < 0.01). Inhibition of contact pathway activation of FXI may be an effective adjunct to anticoagulation in extracorporeal life support.

Comparison of the diagnostic value of a small, single channel, electrocardiogram monitoring patch with a standard 3-lead Holter system over 24 hours in dogs.

INTRODUCTION/OBJECTIVES: The aim of this study was to compare a novel small event recorder device, the Carnation Ambulatory Monitor (CAM), with a standard Holter. ANIMALS: Nineteen adult dogs. MATERIAL AND METHODS: Comparative and explorative study. The two devices were simultaneously applied for approximately 24 h. RESULTS: Analysis time (P=0.013) and percentage of artefacts (P<0.001) were greater for the CAM (110 min [40-264]; and 9% [0-34], respectively) compared to a standard Holter (30 min [18-270]; and 0.3% [0-9], respectively). The total number of beats (P=0.017) and maximum (P=0.02) and mean (P=0.037) heart rates were lower for the CAM (113,806 ± 23,619 beats; 227 ± 35 bpm; and 88 ± 22 bpm, respectively) compared to the standard Holter (131,640 ± 40,037 beats; 260 ± 64 bpm; and 92 ± 26 bpm, respectively). The minimal heart rate (P=0.725), number of pauses (P=0.078), duration of the longest pause (P=0.087), number of ventricular ectopic complexes (P=0.55), ventricular couplets (P=0.186), ventricular triplets (P=0.203), ventricular tachycardia (P=0.05), Lown grade (P=0.233), presence or absence of ventricular bigeminy, trigeminy, supraventricular tachycardia, and atrial fibrillation (P=0.98) did not differ. The CAM missed some relevant events, like complex ventricular arrhythmias, and the Lown grade did not match in 5/19 dogs when comparing the devices. CONCLUSIONS: Cardiac Ambulatory Monitor can be used to record ECG traces in dogs over a prolonged period, allowing to detect arrhythmias. Due to some clinically relevant limitations, including a higher percentage of artefacts, a longer reading time (which precludes quantitative counts of >300ventricular premature complexes), and underestimation of complex ventricular arrhythmias, the CAM appears not suitable for quantitative arrhythmia analysis in dogs.

Prevalence of Trachomatous Trichiasis in Ten Evaluation Units of Embu and Kitui Counties, Kenya.

BACKGROUND: Late-stage blinding sequalae of trachoma such as trachomatous trichiasis (TT) typically take decades to develop and often do so in the absence of ongoing ocular Chlamydia trachomatis infection. This suggests that most TT risk accumulates in early life; as a result, population-level TT incidence and prevalence can remain high years after C. trachomatis transmission among children has decreased. In Embu and Kitui counties, Kenya, the prevalence of trachomatous inflammation - follicular is low in children. In this survey, we set out to determine the prevalence of TT in ten evaluation units (EUs) in these counties. METHODS: We undertook ten cross-sectional prevalence surveys for TT. In each EU, people aged ≥15 years were selected by a two-stage cluster sampling method and examined for TT. Those with TT were asked questions on whether they had been offered management for it. Prevalence was adjusted to the underlying age and gender structure of the population. RESULTS: A total of 18,987 people aged ≥15 years were examined. Per EU, the median number of examined participants was 1,656 (range: 1,451 - 3,016) and median response rate was 86% (range: 81 - 95%). The prevalence of TT unknown to the health system in people aged ≥15 years was above the threshold for elimination (≥0.2%) in all ten EUs studied (range: 0.2-0.7%). TT was significantly more common in older than younger individuals and in women than in men. DISCUSSION: Provision of surgical services should be strengthened in Embu and Kitui counties of Kenya to achieve the World Health Organization threshold for eliminating TT as a public health problem.

Usefulness of cardiac biomarker screening to detect dilated cardiomyopathy in Dobermanns.

OBJECTIVES: To assess the diagnostic accuracy of two cardiac biomarker assays (N-terminal pro-BNP , Troponin I) in detecting dilated cardiomyopathy in Dobermanns. MATERIALS AND METHODS: Dobermanns undergoing cardiac biomarker testing were screened by echocardiography and Holter monitoring, then assigned to a group: normal, equivocal, arrhythmia form of dilated cardiomyopathy, echocardiographic form of dilated cardiomyopathy or both. Some were reassessed to identify final status. Initial cardiac biomarker results were compared to final status. Receiver operating characteristic curves were used to identify area under the curve and corresponding sensitivity (Se), specificity (Sp) for different cut-offs (CO) for each cardiac biomarker. RESULTS: A total of 118 Dobermanns with cardiac biomarker data had echocardiography/Holter assessment. Repeat assessment was carried out in 47 Dobermanns after 394.5 ±151.0 days. Seventeen dogs changed group between initial and final status. The final status of 59 was normal, nine were equivocal and 50 had dilated cardiomyopathy (prevalence 42.4%). Of the dilated cardiomyopathy group, 25 had dilated cardiomyopathy-both, 13 dilated cardiomyopathy-echocardiography and 12 dilated cardiomyopathy-Holter. Receiver operating characteristic area under the curve=0.807 for N-terminal proBNP (Se 0.69 and Sp 0.81) and 0.873 for high-sensitivity cardiac Troponin I (Se 0.77 and Sp 0.86). When both Se and Sp were optimised for all forms of dilated cardiomyopathy, N-terminal proBNP cut-off was 626 pmol/L (Se and Sp 0.79) and high-sensitivity cardiac Troponin I cut-off was 0.056 ng/mL (Se and Sp 0.84). Receiver operating characteristic area under the curve was higher for dilated cardiomyopathy-echocardiography (NT-proBNP 0.883; high-sensitivity cardiac Troponin I 0.907) than dilated cardiomyopathy-Holter. CLINICAL SIGNIFICANCE: Cardiac biomarker screening may be useful to select Dobermanns which would benefit from further assessment by echocardiography and Holter.

Holter monitoring in dogs: 24 h vs. 48 h.

Holter monitoring has an important role in the diagnosis of cardiac arrhythmias in dogs with underlying heart disease or clinical signs such as intermittent weakness/ collapse or exercise intolerance, and in the assessment of antiarrhythmic treatment efficacy. A typical recording lasts for 24 h, although 48 h or any number of days up to 7 are possible, especially when investigating clinical signs that may not happen during the first 24 h. The objective of this study was to review retrospectively a large number of 48 h Holter recordings obtained from dogs to assess the possible incremental diagnostic yield of the second 24 h period in comparison to the first 24 h. Three hundred and fifty four 48 h Holter recordings were included in the study for analysis. A 48 h Holter recording contributed to a 14.5% increase in the likelihood of documenting the cardiac rhythm during an event of interest; a 24 h recording increased the diagnostic yield from 32.2% to 46.7%. When the recordings were grouped according to the most important rhythm abnormalities (supraventricular arrhythmias group, ventricular arrhythmias group, bradyarrhythmias group, no arrhythmias group), the 48 h Holter monitor contributed to a 5% increase in the likelihood of identifying a relevant cardiac rhythm abnormality, increasing the diagnostic yield from 58% to 63%. This benefit occurred mostly in dogs with iterative or paroxysmal supraventricular arrhythmias. In dogs with bradyarrhythmias or ventricular arrhythmias, an additional 24 h of analysis was useful in only a limited number of cases.

Heart rhythm during episodes of collapse in boxers with frequent or complex ventricular ectopy.

OBJECTIVES: To describe heart rhythm during collapse events in boxer dogs using ambulatory electrocardiogram and determine the predictive value of frequent or complex ventricular ectopy for collapse associated with ventricular tachycardia. MATERIALS AND METHODS: A total of 659 ambulatory electrocardiogram recordings from 429 boxer dogs were identified from a database in the UK. Summary statistics described the frequency and complexity of ventricular ectopy during all recordings, recordings in which collapse occurred and associated boxer demographics. Positive predictive values were calculated to investigate whether frequent ventricular ectopy was useful to predict heart rhythm during episodes of collapse. RESULTS: Of the 659 ambulatory electrocardiogram recordings, 250 recordings showed <50 single ventricular beats (Group 1), and frequent (≥50) or complex ventricular ectopy were observed in 409 recordings (Group 2). A total of 90 collapse events were observed in 72 ambulatory electrocardiograms from 68 dogs, comprising 30 dogs in Group 1 and 38 dogs in Group 2. In both groups, sinus rhythm was the most frequent collapse rhythm, followed by neurally mediated collapse and then ventricular tachycardia. The proportion of dogs that displayed ventricular tachycardia-associated episodic collapse given that they had frequent (≥50) or complex ventricular ectopy in the study population was 0.11 [95% confidence interval = 0.01 to 0.21]. CLINICAL SIGNIFICANCE: These results challenge the preconception that UK boxer dogs with collapse will have ventricular tachycardia and, consequently, the authors recommend definitive diagnosis of the cause of episodic collapse to guide selection of therapeutic drugs.

Factors associated with first thrombosis in patients presenting with obstetric antiphospholipid syndrome (APS) in the APS Alliance for Clinical Trials and International Networking Clinical Database and Repository: a retrospective study.

OBJECTIVE: To evaluate the subsequent rate of thrombosis among women with obstetric antiphospholipid syndrome (Ob-APS) in a multicentre database of antiphospholipid antibody (aPL)-positive patients, and the clinical utility of the adjusted Global Antiphospholipid Syndrome Score (aGAPSS), a validated tool to assess the likelihood of developing new thrombosis, in this group of patients. DESIGN: Retrospective study. SETTING: The Antiphospholipid Syndrome Alliance for Clinical Trials and International Networking Clinical Database and Repository. POPULATION: Women with Ob-APS. METHODS: Comparison of clinical and laboratory characteristics and measurement of aGAPSS in women with Ob-APS, with or without thrombosis, after initial pregnancy morbidity (PM). MAIN OUTCOME MEASURES: Risk factors for thrombosis and aGAPSS. RESULTS: Of 550 patients, 126 had Ob-APS; 74/126 (59%) presented with thrombosis, and 47 (63%) of these women developed thrombosis after initial PM, in a mean time of 7.6 ± 8.2 years (4.9/100 patient years). Younger age at diagnosis of Ob-APS, additional cardiovascular risk factors, superficial vein thrombosis, heart valve disease, and multiple aPL positivity increased the risk of first thrombosis after PM. Women with thrombosis after PM had a higher aGAPSS compared with women with Ob-APS alone [median 11.5 (4-16) versus 9 (4-13); P = 0.0089]. CONCLUSION: Based on a retrospective analysis of our multicentre aPL database, 63% of women with Ob-APS developed thrombosis after initial obstetric morbidity; additional thrombosis risk factors, selected clinical manifestations, and high-risk aPL profile increased the risk. Women with subsequent thrombosis after Ob-APS had a higher aGAPSS at entry to the registry. We believe that aGAPSS is a valid tool to improve risk stratification in aPL-positive women. TWEETABLE ABSTRACT: More than 60% of women with obstetric antiphospholipid syndrome had thrombosis after initial pregnancy morbidity.

Pneumococcal disease burden, clinical presentations and vaccine coverage in the Jamaican population.

BACKGROUND: Pneumococcal serotypes circulating in any population vary over time and between countries and impacts the effectiveness of pneumococcal vaccination. OBJECTIVE: This study investigated the epidemiology of pneumococcal disease in Jamaica. METHODS: Streptococcus pneumoniae isolates (n= 349) along with demographic and clinical information were collected from patients presenting at the 4 major hospitals in Jamaica over a 2-year period. Serotyping was done using latex agglutination tests and the Quellung reaction assay. RESULTS: Invasive pneumococcal disease (IPD) incidence was 45.4/100,000 in children under 5 yrs and 16.3/100,000 in adults over 65 yrs. Thirteen serogroups were identified among the 120 isolates subjected to grouping; the most common being serogroups: 19 (22/120,18.3%), 6 (20/120,16.7%), 14 (20/120,16.7%), 23 (18/120,15.0%), 3 (11/120,9.2%) and nontypeable (8/120,2.3%). The estimated vaccine coverage rates for the PCV7 and PCV13 vaccines in children less than 5 yrs were 82.5% and 88.7% respectively. The 23-valent PPV23 provided 100% coverage rate in adults over 65 yrs and 82.9% coverage rate for the entire population. CONCLUSIONS: Pneumococcal vaccine coverage rates in Jamaica are comparable to those reported in certain developed countries and higher than in other developing countries. The high incidence of IPD in the paediatric population indicates that routine vaccination would be beneficial.

Hydroxychloroquine in the primary thrombosis prophylaxis of antiphospholipid antibody positive patients without systemic autoimmune disease.

Objective The objective of this study was to determine the efficacy of hydroxychloroquine (HCQ) in the primary thrombosis prevention of antiphospholipid antibody (aPL)-positive patients with no other systemic autoimmune diseases. Methods Under the auspices of Antiphospholipid Syndrome Alliance for Clinical Trials and International Networking, a multicenter, international, randomized controlled trial (RCT) was initiated, in which persistently aPL-positive but thrombosis-free patients without systemic autoimmune diseases were randomized to receive HCQ or no treatment in addition to their standard regimen. The primary objective was the efficacy of HCQ in preventing the first thrombosis. The secondary objectives were the thrombosis incidence rate, and the effects of HCQ on aPL profile and mortality rate. Patients were risk-stratified based on antiplatelet agent use. The goal was to follow patients every 6 months for 5 years. Results We recruited 20 persistently aPL-positive patients (female: 19, mean age: 46.6 ± 9.9 years, and baseline antiplatelet medication: 14); 9/20 were randomized to HCQ. During the mean follow-up of 1.7 years, no patients developed thrombosis or a serious adverse event. The study was terminated early due to the low recruitment rate, exacerbated by the prolonged manufacturing shortage and significant price increase of HCQ in the United States. Conclusion Given that a small number of patients with a relatively short follow-up were enrolled in our RCT, and no patients developed thrombosis, we cannot accurately assess the effectiveness of HCQ for primary thrombosis prevention in persistently aPL-positive patients with no other systemic autoimmune diseases. Our experience suggests that conducting an international RCT, especially without pharmaceutical support, is an extremely challenging undertaking.

Clinical associations of proinflammatory cytokines, oxidative biomarkers and vitamin D levels in systemic lupus erythematosus.

Background The abnormal biological activity of cytokines plays an important role in the pathophysiology of both systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS). Several studies have highlighted the association of vitamin D and certain pro-inflammatory cytokines with disease activity in SLE. However, there are limited data on the association of vitamin D and antiphospholipid antibodies (aPL) with various proinflammatory biomarkers in these patients and their relative impact on clinical outcomes. Methods The serum levels of several aPL, 25-hydroxy-vitamin D, pro-inflammatory cytokines including IFNα, IL-1ß, IL-6, IL-8, IP10, sCD40L, TNFα and VEGF were measured in 312 SLE patients from the Jamaican ( n = 45) and Hopkins ( n = 267) lupus cohorts using commercial Milliplex and ELISA assays. Oxidized LDL/ß2glycoprotein antigenic complexes (oxLß2Ag) and their associated antibodies were also measured in the Jamaican cohort. Healthy controls for oxidative marker and cytokine testing were used. Results Abnormally low vitamin D levels were present in 61.4% and 73.3% of Hopkins and Jamaican SLE patients, respectively. Median concentrations of IP10, TNFα, sCD40L and VEGF were elevated in both cohorts, oxLß2Ag and IL-6 were elevated in the Jamaican cohort, and IFNα, IL-1ß and IL-8 were the same or lower in both cohorts compared to controls. IP10 and VEGF were independent predictors of disease activity, aPL, IP10 and IL-6 were independent predictors of thrombosis and IL-8, and low vitamin D were independent predictors of pregnancy morbidity despite there being no association of vitamin D with pro-inflammatory cytokines. Conclusions Our results indicate that aPL-mediated pro-inflammatory cytokine production is likely a major mechanism of thrombus development in SLE patients. We provide presumptive evidence of the role IL-8 and hypovitaminosis D play in obstetric pathology in SLE but further studies are required to characterize the subtle complexities of vitamin D's relationship with cytokine production and disease activity in these patients.

A unique antiphospholipid assay recognizing phospholipid mixture compared with criteria antiphospholipid immunoassays in lupus patients.

Background While essential for the classification of antiphospholipid syndrome (APS), anticardiolipin (aCL) assays lack specificity and anti-ß2glycoproteinI (anti-ß2GPI) assays lack sensitivity in this regard. Our aim was to perform a comparative analysis of the APhL ELISA assay (IgG/IgM) and criteria antiphospholipid (aPL) immunoassays in identifying APS-related clinical manifestations in a large group of patients with systemic lupus erythematosus (SLE). Methods Serum samples from 1178 patients from the Hopkins ( n = 543), LUMINA ( n = 588) and Jamaican SLE cohorts ( n = 47) were examined for IgG/IgM positivity in aCL (in-house), anti-ß2GPI (two commercial kits) and APhL (Louisville APL) ELISA assays. Correlation of assay positivity with clinical manifestations and sensitivity, specificity, positive and negative predictive values and likelihood ratios were evaluated. A case series analysis was also performed in patients for whom there was isolated positivity in the specific aPL assays. Results The prevalence of aCL positivity was 34.9%, anti-ß2GPI kit A was 22.6%, APhL was 11.5% and anti-ß2GPI kit B was 7.6% in the study population. Anti-ß2GPI kit B, aCL and APhL assays were correlated with venous thrombosis, while only APhL was significantly correlated with arterial thrombosis and consistently correlated with pregnancy-related morbidity. No significant correlations were noted for anti-ß2GPI kit A. Sensitivity was greatest for aCL assays followed by anti-ß2GPI kit A, APhL and anti-ß2GPI kit B, while specificity was greatest and equal for anti-ß2GPI kit B and APhL assays. Conclusions Overall, APhL antibodies, especially IgG, represent a promising biomarker for the classification of APS patients in the context of autoimmunity and in risk assessment with regards to pregnancy morbidity and thrombotic manifestations.

International standards for IgG and IgM anti-ß2glycoprotein antibody measurement.

International standards for anti-beta2 glycoprotein I (anti-ß2GPI) testing are needed. We evaluated the suitability of polyclonal/monoclonal candidate reference materials (RM) for the assay. IgG/IgM anti-ß2GPI were affinity-purified (AP) from high-positive antiphospholipid syndrome sera and IgG from HCAL clone supernatant. Igs were tested for purity by SDS-PAGE, pooled, concentrated, sterile-filtered and the protein concentration determined. One unit was defined as the binding activity of 1 µg/ml of AP anti-ß2GPI Ig. IgG/IgM RM were each assigned a unit value using the respective AP material as a calibrator. Polyclonal/monoclonal RM and 30 samples were evaluated for linearity, unit equivalency and commutability. Polyclonal AP material was assigned a value of 100 U IgG and 15 U IgM anti-ß2GPI, respectively. IgG-RM had a value of 270 IgG and the IgM-RM of 220.3 IgM anti-ß2GPI U. The linearity (R (2)) of each RM curve for the various assays ranged from 0.96 to 0.99. Commutability samples fit very well within 95% prediction intervals and had excellent correlation when comparing assays. IgG and IgM polyclonal and IgG monoclonal RM displayed excellent linearity and commutability, being good candidates for better standardization of anti-ß2GPI immunoassays.

Complement C5-inhibitor rEV576 (coversin) ameliorates in-vivo effects of antiphospholipid antibodies.

Activation of the complement cascade is an important mechanism for antiphospholipid antibody-mediated thrombosis. We examined the effects of rEV576 (coversin), a recombinant protein inhibitor of complement factor 5 activation, on antiphospholipid antibody-mediated tissue factor up-regulation and thrombosis. Groups of C57BL/6J mice (n=5) received either IgG from a patient with antiphospholipid syndrome (APS) or control IgG from normal human serum (NHS). Each of these groups of mice had IgG administration preceded by either rEV576, or phosphate buffer control. For each of the four treatment groups, the size of induced thrombus, tissue factor activity in carotid homogenates, anticardiolipin and anti-ß2glycoprotein I (anti-ß2GPI) levels were measured 72 h after the first injection. Mice treated with IgG-APS had significantly higher titers of anticardiolipin antibodies and anti-ß2GPI at thrombus induction compared with those treated with IgG-NHS. The IgG-APS/phosphate buffer treatment induced significantly larger thrombi and tissue factor activity compared with other groups. Mice treated with IgG-APS/rEV576 had significantly smaller thrombi and reduced tissue factor activity than those treated with IgG-APS/phosphate buffer. The data confirm involvement of complement activation in antiphospholipid antibody-mediated thrombogenesis and suggest that complement inhibition might ameliorate this effect.

Effects of statins on proinflammatory/prothrombotic biomarkers and on disease activity scores in SLE patients: data from LUMINA (LXXVI), a multi-ethnic US cohort.

OBJECTIVES: We sought to determine the effect of statin therapy on the levels of proinflammatory/prothrombotic markers and disease activity scores in patients with SLE in a multi-ethnic, multi-centre cohort (LUMINA). METHODS: Plasma/serum samples from SLE patients placed on statins (n=21) therapy taken before and after at least 6 months of treatment were tested. Disease activity was assessed using SLAM-R scores. Interleukin (IL)-1ß, IL-6, IL-8, tumour necrosis factor (TNF)-α, vascular endothelial growth factor (VEGF) and soluble CD40 ligand (sCD40L) levels were determined by a multiplex immunoassay. Soluble intercellular cell adhesion molecule (ICAM)-1, vascular cell adhesion molecule (VCAM)-1 and anticardiolipin (aCL) antibodies were evaluated using ELISA assays while high sensitivity C-reactive protein (hsCRP) was assessed by nephelometry. Plasma/serum samples from frequency- matched healthy donors were used as controls. RESULTS: Levels of IL-6, VEGF, sCD40L and TNF-α were significantly elevated in SLE patients versus controls. Statin therapy resulted in a significant decrease in SLAM-R scores (p=0.0199) but no significant changes in biomarker levels were observed. There was no significant association of biomarkers with SLAM-R scores. CONCLUSIONS: Statin therapy resulted in significant clinical improvement in SLE patients, underscoring the use of statins in the treatment of SLE.

The Otto Aufranc Award. On the etiology of the cam deformity: a cross-sectional pediatric MRI study.

BACKGROUND: Femoroacetabular impingement (FAI) has been recognized as a common cause of hip pain as well as a cause of hip arthritis, yet despite this, little is known about the etiology of the cam morphology or possible risk factors associated with its development. QUESTIONS/PURPOSES: The purposes of our study were to determine when the cam morphology associated with FAI developed in a cross-sectional cohort study of pediatric patients pre- and postphyseal closure using MRI and whether increased activity level during the period of physeal closure is associated with an increased likelihood that the cam deformity will develop. METHODS: Alpha angles were measured at the 3 o'clock (anterior head-neck junction) and 1:30 (anterosuperior head-neck junction) positions in both hips with a cam deformity defined as an alpha angle ≥ 50.5° at the 3 o'clock position. Forty-four volunteers (88 hips) were studied: 23 with open physes (12 females, mean age 9.7 years; 11 males, age 11.7 years) and 21 with closed physes (five females, age 15.2 years; 16 males, age 16.2 years). Daily activity level using the validated Habitual Activity Estimation Scale was compared for patients in whom cam morphology did and did not develop. RESULTS: None of the 23 (0%) patients prephyseal closure had cam morphology, whereas three of 21 (14%, p = 0.02; all males) postclosure had at least one hip with cam morphology. Daily activity level was higher (p = 0.02) for patients with the cam morphology (7.1 hours versus 2.9 hours). Mean alpha angles at the 3 o'clock head-neck position were 38° (95% confidence interval [CI], 37.2°-39.1°) in the open physes group and 42° (95% CI, 40.16°-43.90°) in the closed physes group; at the 1:30 head-neck position, they were 45° (95% CI, 44.0°-46.4°) in the open physes group and 50° (47.9°-52.3°) in the closed physes group. CONCLUSIONS: The fact that cam morphology was present exclusively in the closed physeal group strongly supports its development during the period of physeal closure with increased activity level as a possible risk factor.

Longitudinal analysis of quality of life, clinical, radiographic, echocardiographic, and laboratory variables in dogs with myxomatous mitral valve disease receiving pimobendan or benazepril: the QUEST study.

BACKGROUND: Myxomatous mitral valve disease (MMVD) is an important cause of morbidity and mortality in dogs. OBJECTIVES: To compare, throughout the period of follow-up of dogs that had not yet reached the primary endpoint, the longitudinal effects of pimobendan versus benazepril hydrochloride treatment on quality-of-life (QoL) variables, concomitant congestive heart failure (CHF) treatment, and other outcome variables in dogs suffering from CHF secondary to MMVD. ANIMALS: A total of 260 dogs in CHF because of MMVD. METHODS: A prospective single-blinded study with dogs randomized to receive pimobendan (0.4-0.6 mg/kg/day) or benazepril hydrochloride (0.25-1.0 mg/kg/day). Differences in outcome variables and time to intensification of CHF treatment were compared. RESULTS: A total of 124 dogs were randomized to pimobendan and 128 to benazepril. No difference was found between groups in QoL variables during the trial. Time from inclusion to 1st intensification of CHF treatment was longer in the pimobendan group (pimobendan 98 days, IQR 30-276 days versus benazepril 59 days, IQR 11-121 days; P = .0005). Postinclusion, dogs in the pimobendan group had smaller heart size based on VHS score (P = .013) and left ventricular diastolic (P = .035) and systolic (P = .0044) dimensions, higher body temperature (P = .030), serum sodium (P = .0027), and total protein (P = .0003) concentrations, and packed cell volume (P = .030). Incidence of arrhythmias was similar in treatment groups. CONCLUSIONS AND CLINICAL IMPORTANCE: Pimobendan versus benazepril resulted in similar QoL during the study, but conferred increased time before intensification of CHF treatment. Pimobendan treatment resulted in smaller heart size, higher body temperature, and less retention of free water.

Efficacy of pimobendan in the prevention of congestive heart failure or sudden death in Doberman Pinschers with preclinical dilated cardiomyopathy (the PROTECT Study).

BACKGROUND: The benefit of pimobendan in delaying the progression of preclinical dilated cardiomyopathy (DCM) in Dobermans is not reported. HYPOTHESIS: That chronic oral administration of pimobendan to Dobermans with preclinical DCM will delay the onset of CHF or sudden death and improve survival. ANIMALS: Seventy-six client-owned Dobermans recruited at 10 centers in the UK and North America. METHODS: The trial was a randomized, blinded, placebo-controlled, parallel group multicenter study. Dogs were allocated in a 1:1 ratio to receive pimobendan (Vetmedin capsules) or visually identical placebo. The composite primary endpoint was prospectively defined as either onset of CHF or sudden death. Time to death from all causes was a secondary endpoint. RESULTS: The proportion of dogs reaching the primary endpoint was not significantly different between groups (P = .1). The median time to the primary endpoint (onset of CHF or sudden death) was significantly longer in the pimobendan (718 days, IQR 441-1152 days) versus the placebo group (441 days, IQR 151-641 days) (log-rank P = 0.0088). The median survival time was significantly longer in the pimobendan (623 days, IQR 491-1531 days) versus the placebo group (466 days, IQR 236-710 days) (log-rank P = .034). CONCLUSION AND CLINICAL IMPORTANCE: The administration of pimobendan to Dobermans with preclinical DCM prolongs the time to the onset of clinical signs and extends survival. Treatment of dogs in the preclinical phase of this common cardiovascular disorder with pimobendan can lead to improved outcome.

Safety and pharmacokinetics of aciclovir in women following release from a silicone elastomer vaginal ring.

OBJECTIVES: Systemic aciclovir and its prodrug valaciclovir are effective in treating and reducing recurrences of genital herpes simplex virus (HSV) and reducing transmission. Local aciclovir delivery, if it can achieve and maintain comparable intracellular genital tract levels, may be equally effective in the treatment and suppression of genital HSV. Intravaginal ring (IVR) delivery of aciclovir may provide pre-exposure prophylaxis against HSV acquisition. METHODS: Tolerability and pharmacokinetics were evaluated in six HIV-negative women with recurrent genital HSV who switched their daily oral valaciclovir suppression to an aciclovir IVR for 7 days (n = 3) or 14 days (n = 3). Blood and cervicovaginal lavage (CVL) were collected after oral and IVR dosing to measure aciclovir concentrations and genital swabs were obtained to quantify HSV shedding by PCR. RESULTS: The rings were well tolerated. Median plasma aciclovir concentrations were 110.2 ng/mL (IQR, 85.9-233.5) 12-18 h after oral valaciclovir. Little or no drug was detected in plasma following IVR dosing. Median (IQR) CVL aciclovir levels were 127.3 ng/mL (21-660.8) 2 h after oral valaciclovir, 154.4 ng/mL (60.7-327.5) 12-18 h after oral valaciclovir and 438 ng/mL (178.5-618.5) after 7 days and 393 ng/mL (31.6-1615) after 14 days of aciclovir ring use. Median CVL aciclovir levels 2 h after oral dosing were similar to levels observed 7 (P = 0.99) and 14 (P = 0.75) days after ring use. HSV DNA was not detected in genital swabs and there was no significant change in inflammatory mediators. CONCLUSIONS: This first-in-human study demonstrated that an IVR could safely deliver mucosal levels of aciclovir similar to oral valaciclovir without systemic absorption. More intensive site-specific pharmacokinetic studies are needed to determine whether higher local concentrations are needed to achieve optimal drug distribution within the genital tract.