Panretinal Photocoagulation vs Intravitreous Ranibizumab for Proliferative Diabetic Retinopathy: A Randomized Clinical Trial.

IMPORTANCE: Panretinal photocoagulation (PRP) is the standard treatment for reducing severe visual loss from proliferative diabetic retinopathy. However, PRP can damage the retina, resulting in peripheral vision loss or worsening diabetic macular edema (DME). OBJECTIVE: To evaluate the noninferiority of intravitreous ranibizumab compared with PRP for visual acuity outcomes in patients with proliferative diabetic retinopathy. DESIGN, SETTING, AND PARTICIPANTS: Randomized clinical trial conducted at 55 US sites among 305 adults with proliferative diabetic retinopathy enrolled between February and December 2012 (mean age, 52 years; 44% female; 52% white). Both eyes were enrolled for 89 participants (1 eye to each study group), with a total of 394 study eyes. The final 2-year visit was completed in January 2015. INTERVENTIONS: Individual eyes were randomly assigned to receive PRP treatment, completed in 1 to 3 visits (n = 203 eyes), or ranibizumab, 0.5 mg, by intravitreous injection at baseline and as frequently as every 4 weeks based on a structured re-treatment protocol (n = 191 eyes). Eyes in both treatment groups could receive ranibizumab for DME. MAIN OUTCOMES AND MEASURES: The primary outcome was mean visual acuity change at 2 years (5-letter noninferiority margin; intention-to-treat analysis). Secondary outcomes included visual acuity area under the curve, peripheral visual field loss, vitrectomy, DME development, and retinal neovascularization. RESULTS: Mean visual acuity letter improvement at 2 years was +2.8 in the ranibizumab group vs +0.2 in the PRP group (difference, +2.2; 95% CI, -0.5 to +5.0; P < .001 for noninferiority). The mean treatment group difference in visual acuity area under the curve over 2 years was +4.2 (95% CI, +3.0 to +5.4; P < .001). Mean peripheral visual field sensitivity loss was worse (-23 dB vs -422 dB; difference, 372 dB; 95% CI, 213-531 dB; P < .001), vitrectomy was more frequent (15% vs 4%; difference, 9%; 95% CI, 4%-15%; P < .001), and DME development was more frequent (28% vs 9%; difference, 19%; 95% CI, 10%-28%; P < .001) in the PRP group vs the ranibizumab group, respectively. Eyes without active or regressed neovascularization at 2 years were not significantly different (35% in the ranibizumab group vs 30% in the PRP group; difference, 3%; 95% CI, -7% to 12%; P = .58). One eye in the ranibizumab group developed endophthalmitis. No significant differences between groups in rates of major cardiovascular events were identified. CONCLUSIONS AND RELEVANCE: Among eyes with proliferative diabetic retinopathy, treatment with ranibizumab resulted in visual acuity that was noninferior to (not worse than) PRP treatment at 2 years. Although longer-term follow-up is needed, ranibizumab may be a reasonable treatment alternative, at least through 2 years, for patients with proliferative diabetic retinopathy. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01489189.

Analysis of Interview Breakoff in the Behavioral Risk Factor Surveillance System, 2018 and 2019.

Introduction: Survey breakoff is an important source of total survey error. Most studies of breakoff have been of web surveys-less is known about telephone surveys. In the past decade, the breakoff rate has increased in the Behavioral Risk Factor Surveillance System, the world's largest annual telephone survey. Analysis of breakoff in Behavioral Risk Factor Surveillance System can improve the quality of Behavioral Risk Factor Surveillance System. It will also provide evidence in research of total survey error on telephone surveys. Methods: We used data recorded as breakoff in the 2018 and 2019 Behavioral Risk Factor Surveillance System. We converted questions and modules to a time variable and applied Kaplan-Meier method and a proportional hazard model to estimate the conditional and cumulative probabilities of breakoff and study the potential risk factors associated with breakoff. Results: Cumulative probability of breakoffs up to the end of the core questionnaire was 7.03% in 2018 and 9.56% in 2019. The highest conditional probability of breakoffs in the core was 2.85% for the physical activity section. Cumulative probability of breakoffs up to the end of the core was higher among those states that inserted their own questions or optional modules than among those that did not in both years. The median risk ratio of breakoff among all states was 5.70 in 2018 and 3.01 in 2019. Survey breakoff was associated with the length of the questionnaire, the extent of expected recollection, and the location of questions. Conclusions: Breakoff is not an ignorable component of total survey error and should be considered in Behavioral Risk Factor Surveillance System data analyses when variables have higher breakoff rates.

Estimated Uncovered Costs For HIV Preexposure Prophylaxis In The US, 2018.

The cost of HIV preexposure prophylaxis (PrEP) medication and care is a key barrier to PrEP use. Using population-based surveys and published information, we estimated the number of people with uncovered costs for PrEP care among US adults with PrEP indications, stratified by HIV transmission risk group, insurance status, and income. Accounting for existing PrEP payer mechanisms, we estimated annual uncovered costs for PrEP medication, clinical visits, and laboratory testing based on the 2021 PrEP clinical practice guideline. Of 1.2 million US adults with PrEP indications in 2018, we estimated that 49,860 (4 percent) of them had PrEP-related uncovered costs, including 32,350 men who have sex with men, 7,600 heterosexual women, 5,070 heterosexual men, and 4,840 people who inject drugs. Of those 49,860 people with uncovered costs, 3,160 (6 percent) incurred $18.9 million in uncovered costs for PrEP medication, clinical visits, and lab testing, and 46,700 (94 percent) incurred $83.5 million in uncovered costs for only clinical visits and lab testing. The total annual uncovered costs for adults with PrEP indications were $102.4 million in 2018. The proportion of people with uncovered costs for PrEP is less than 5 percent among adults with PrEP indications, but the magnitude of costs is significant.

Assessing changes in relapse rates in multiple sclerosis.

Multiple Sclerosis (MS) annualized relapse rates (ARRs) in trials may be declining due to changes in diagnostic criteria, MS etiology, study criteria, and selection biases. This review examines if there is a trend in the ARR for relapsing-remitting MS patients (RRMS) over time and if so, why. A comprehensive literature search was performed using PubMed, Web of Science(®), and the Cochrane Library using electronic searches, screen scraping for abstracts, and hand searching of references for randomized trials conducted between 1960 and 2008. Out of 72 randomized trials, 56 (77.8%) defined relapse. This study uses 32 placebo relapsing-remitting studies out of the 37 (66.1%) with RRMS. The mean ARR for the treatment arms was 0.68 and the one for the placebo groups was 1.002. The year of publication was negatively associated with the ARR (p = 0.0001). The annual reduction amounts to 0.36 relapses over a 10-year period. Age and duration of symptoms were negatively associated with the ARR. Year of publication was significantly negatively associated with ARR after controlling for covariates. ARRs have fallen with relapse definition, entrance criteria remain important, but time exceeds all these variables and reflects two likely sources, selection of patients for trials by clinicians and rescue of patients truncating the number of multiple relapses. The impact of truncating the number of relapses on the falling rates is important, not only on the ARRs, but also on the impact of informative censoring in drop-outs.

Mitral valve prolapse with a late-systolic regurgitant murmur may be associated with significant hemodynamic consequences.

The late-systolic murmur of mitral regurgitation (MR) in degenerative mitral valve disease is widely believed to represent regurgitation of a degree that is not associated with hemodynamic significance. However, the extent of left ventricular (LV) remodeling associated with the late-systolic murmur has not been systematically assessed. Accordingly, we studied 82 patients sent for evaluation of at least moderate isolated MR by echocardiography/Doppler examination. All patients had a physical examination and cardiac magnetic resonance imaging to measure LV volumes by summation of serial short-axis slices. Forty-five patients had a pan-systolic murmur and 37 had a late-systolic murmur on auscultation that was verified by timing of onset of regurgitant turbulence by cine magnetic resonance imaging. Systolic blood pressures (124 +/- 3 versus 124 +/- 3 mm Hg) and LV ejection fraction (61 +/- 1% versus 61 +/- 1%) did not differ significantly between pan-systolic and late-systolic murmur groups. Although LV end-diastolic volume index was greater in the pan-systolic versus late-systolic murmur (108 +/- 4 versus 95 +/- 4 mL/m2, P = 0.007), both groups were significantly greater than normals (68 +/- 2 mL/m2, P < 0.0001). However, LV end-systolic volume index (42 +/- 2 versus 38 +/- 2 mL/m2) and LV end-systolic dimension (38 +/- 1 versus 37 +/- 1 mm), critical markers of adverse LV remodeling in isolated MR, did not differ significantly between pan-systolic and late-systolic murmur groups. In conclusion, the late systolic isolated MR murmur may be associated with significant adverse LV remodeling, and should not be considered evidence of hemodynamically unimportant MR.

Distinct B-cell and T-cell lymphoproliferative disease prevalence among dog breeds indicates heritable risk.

Immunophenotypes in lymphoproliferative diseases (LPD) are prognostically significant, yet causative factors for these conditions, and specifically those associated with heritable risk, remain elusive. The full spectrum of LPD seen in humans occurs in dogs, but the incidence and lifetime risk of naturally occurring LPD differs among dog breeds. Taking advantage of the limited genetic heterogeneity that exists within dog breeds, we tested the hypothesis that the prevalence of LPD immunophenotypes would differ among different breeds. The sample population included 1,263 dogs representing 87 breeds. Immunophenotype was determined by the presence of clonal rearrangements of immunoglobulin heavy chain or T-cell receptor gamma chain. The probability of observing the number of B-cell or T-cell tumors in a particular breed or breed group was compared with three reference populations. Significance was computed using chi2 test, and logistic regression was used to confirm binomial predictions. The data show that, among 87 breeds tested, 15 showed significant differences from the prevalence of LPD immunophenotypes seen across the dog population as a whole. More significantly, elevated risk for T-cell LPD seems to have arisen ancestrally and is retained in related breed groups, whereas increased risk for B-cell disease may stem from different risk factors, or combinations of risk factors, arising during the process of breed derivation and selection. The data show that domestic dogs provide a unique and valuable resource to define factors that mediate risk as well as genes involved in the initiation of B-cell and T-cell LPD.

Obesity is Associated With Poor Surgical Outcome in Crohn's Disease.

BACKGROUND: Published data suggest a link between obesity and adverse outcomes in Crohn's disease (CD). We aimed to test the hypothesis that obese CD patients would be more likely than non-obese CD patients to have poor surgical outcome when undergoing surgery for a complication of CD. METHODS: We designed a retrospective cohort study to test our hypothesis. The population comprised of adult CD patients who underwent CD related surgery at a tertiary referral center. The exposed and unexposed cohorts were represented by patients who were obese vs. non-obese at the pre-op visit respectively. Outcome was represented by successful vs. unsuccessful surgical outcome as deemed by the treating clinician. RESULTS: Ninety CD patients were eligible for inclusion into this cohort study of which 36 were obese (exposed cohort) and 54 were non-obese (unexposed cohort). Among obese CD patients, 64% had an unsuccessful surgical outcome vs. 41% with unsuccessful surgical outcome among the non-obese. Based on unadjusted bivariate analysis, potential confounders identified included age and type of surgery. Gender distribution, disease duration, ethnicity, tobacco use, steroid use, traditional and biological immune modulator use and clinical disease activity were similar between the two groups. Logistic regression adjusted for age and type of surgery revealed that obese CD patients were approximately 2.5 times more likely to have a poor surgical outcome than patients with CD who were not obese (P = 0.05 OR 2.53 95% CI 0.99 - 6.52). BMI as a continuous variable (adjusted for age and type of surgery) appeared to be associated with poor surgical outcome (P = 0.06 OR 1.07 95% CI 0.99 - 1.15). CONCLUSIONS: Obesity may be associated with poor surgical outcome in CD patients.

Relation of torsion and myocardial strains to LV ejection fraction in hypertension.

OBJECTIVES: The goal of this study was to define the mechanism of preserved ejection fraction (EF) despite depressed myocardial strains in hypertension (HTN). BACKGROUND: Concentric left ventricular (LV) remodeling in HTN may have normal or supranormal EF despite depressed myocardial strains. The reason for such discordance is not clear. The aim of this study was to comprehensively evaluate the LV mechanics in a well-defined HTN population to define underlying reasons for such a paradox. METHODS: Sixty-seven patients with resistant HTN and 45 healthy control subjects were studied by cardiac magnetic resonance imaging and tissue tagging with 3-dimensional analysis. Amplitude and directional vector of longitudinal (Ell), circumferential (Ecc), and principal strain for maximal shortening (E3) were computed at basal, mid, and distal LV levels, respectively. LV torsion, defined as the rotation angle of apex relative to base, and LV twist, which accounts for the effects of differential LV remodeling on torsion for comparison among the 2 groups, were also calculated. RESULTS: LV mass index and LV mass/LV end-diastolic volume ratio were significantly higher in the HTN group compared with controls, consistent with concentric LV remodeling. Ell and Ecc were significantly decreased in amplitude with altered directional vector in HTN compared with controls. However, the amplitude of E3 was similar in the 2 groups. Torsion and twist were significantly higher in HTN, which was mainly due to increase in apical rotation. The HTN group demonstrated significantly increased LV wall thickening compared with controls that resulted in greater LVEF in the HTN group compared with controls (70% vs. 65%, p < 0.001, respectively). CONCLUSIONS: In compensated LV remodeling secondary to HTN, there is increased LV wall thickening with preserved E3 and increased torsion compared with normal controls. This, therefore, contributes to supranormal LVEF in HTN despite depressed longitudinal and circumferential strains.

A randomized controlled phase IIb trial of beta(1)-receptor blockade for chronic degenerative mitral regurgitation.

OBJECTIVES: The purpose of the study was to evaluate the effect of long-term ß(1)-aderergic receptor (AR) blockade on left ventricular (LV) remodeling and function in patients with chronic, isolated, degenerative mitral regurgitation (MR). BACKGROUND: Isolated MR currently has no proven therapy that attenuates LV remodeling or preserves systolic function. METHODS: Thirty-eight asymptomatic subjects with moderate to severe, isolated MR were randomized either to placebo or ß(1)-AR blockade (Toprol-XL, AstraZeneca, London, United Kingdom) for 2 years. Magnetic resonance imaging with tissue tagging and 3-dimensional analysis was performed at baseline and at 6-month intervals for 2 years. Rate of progression analysis was performed for endpoint variables for primary outcomes: LV end-diastolic volume/body surface area, LV ejection fraction, LV end-diastolic (ED) mass/ED volume ratio, LV ED 3-dimensional radius/wall thickness; LV end-systolic volume/body surface area, LV longitudinal strain rate, and LV early diastolic filling rate. RESULTS: Baseline LV magnetic resonance imaging or demographic variables did not differ between the 2 groups. Significant treatment effects were found on LV ejection fraction (p = 0.006) and LV early diastolic filling rate (p = 0.001), which decreased over time in untreated patients on an intention-to-treat analysis and remained significant after sensitivity analysis. There were no significant treatment effects found on LV ED or LV end-systolic volumes, LV ED mass/LV ED volume or LV ED 3-dimensional radius/wall thickness, or LV longitudinal strain rate. Over 2 years, 6 patients treated in the placebo group and 2 patients in the ß(1)-AR blockade group required mitral valve surgery (p = 0.23). CONCLUSIONS: ß(1)-AR blockade improves LV function over a 2-year follow-up in isolated MR and provides the impetus for a large-scale clinical trial with clinical outcomes. (Molecular Mechanisms of Volume Overload-Aim 1 [SCCOR in Cardiac Dysfunction and Disease]; NCT01052428).

Increased oxidative stress and cardiomyocyte myofibrillar degeneration in patients with chronic isolated mitral regurgitation and ejection fraction >60%.

OBJECTIVES: This study assessed myocardial damage in patients with chronic isolated mitral regurgitation (MR) and left ventricular ejection fraction (LVEF) >60%. BACKGROUND: Typically, MR patients have decreased LVEF after mitral valve (MV) repair despite normal pre-operative LVEF. METHODS: Twenty-seven patients with isolated MR had left ventricular (LV) biopsies taken at time of MV repair. Magnetic resonance imaging with tissue tagging was performed in 40 normal subjects and in MR patients before and 6 months after MV repair. RESULTS: LVEF (66 +/- 5% to 54 +/- 9%, p < 0.0001) and LV end-diastolic volume index (108 +/- 28 ml/m(2) to 78 +/- 24 ml/m(2), p < 0.0001) decreased, whereas left ventricular end-systolic (LVES) volume index was 60% above normal pre- and post-MV repair (p < 0.05). The LV circumferential and longitudinal strain rates decreased below normal following MV repair (6.38 +/- 1.38 vs. 5.11 +/- 1.28, p = 0.0009, and 7.51 +/- 2.58 vs. 5.31 +/- 1.61, percentage of R to R interval, p < 0.0001), as LVES stress/LVES volume index ratio was depressed at baseline and following MV repair versus normal subjects (0.25 +/- 0.10 and 0.28 +/- 0.05 vs. 0.33 +/- 0.12, p < 0.01). LV biopsies demonstrated cardiomyocyte myofibrillar degeneration versus normal subjects (p = 0.035). Immunostaining and immunoblotting demonstrated increased xanthine oxidase in MR versus normal subjects (p < 0.05). Lipofuscin deposition was increased in cardiomyocytes of MR versus normal subjects (0.62 +/- 0.20 vs. 0.33 +/- 0.11, percentage of area: p < 0.01). CONCLUSIONS: Decreased LV strain rates and LVES wall stress/LVES volume index following MV repair indicate contractile dysfunction, despite pre-surgical LVEF >60%. Increased oxidative stress could cause myofibrillar degeneration and lipofuscin accumulation resulting in LV contractile dysfunction in MR.

Rapid reversal of left ventricular hypertrophy and intracardiac volume overload in patients with resistant hypertension and hyperaldosteronism: a prospective clinical study.

We have shown previously that patients with resistant hypertension and hyperaldosteronism have increased brain natriuretic peptide suggestive of increased intravascular volume. In the present study, we tested the hypothesis that hyperaldosteronism contributes to cardiac volume overload. Thirty-seven resistant hypertensive patients with hyperaldosteronism (urinary aldosterone > or = 12 microg/24 hours and plasma renin activity < or = 1.0 ng/mL per hour) and 71 patients with normal aldosterone status were studied. Both groups had similar blood pressure and left ventricular mass, whereas left and right ventricular end-diastolic volumes measured by cardiac MRI were greater in high versus normal aldosterone subjects (P<0.05). Spironolactone treatment (19 patients in the high aldosterone group and 15 patients from the normal aldosterone group participated in the follow-up) resulted in a significant decrease in clinic systolic blood pressure, right and left ventricular end diastolic volumes, left atrial volume, left ventricular mass, and brain natriuretic peptide at 3 and 6 months of follow-up in patients with high aldosterone, whereas in those with normal aldosterone status, spironolactone decreased blood pressure and left ventricular mass without changes in ventricular or atrial volumes or plasma brain natriuretic peptide. Hyperaldosteronism causes intracardiac volume overload in patients with resistant hypertension in spite of conventional thiazide diuretic use. Mineralocorticoid receptor blockade induces rapid regression of left ventricular hypertrophy irrespective of aldosterone status. In subjects with high aldosterone, mineralocorticoid receptor blockade induces a prominent diuretic effect compared with a greater vasodilatory effect in subjects with normal aldosterone status.