Faculty Bibliography

Background: Optical coherence tomography (OCT) derived measures of retinal layer thicknesses have been shown to correlate with visual function, grey matter volume and Expanded Disability Status Scale (EDSS) scores in multiple sclerosis (MS). However, the prognostic value of retinal measurements for predicting long term disability in MS patients is still being evaluated. Goal: To determine whether retinal thicknesses as assessed by OCT predict disability in MS 10 years later. Methods: A total of 89 MS patients who were scanned on Stratus OCT between 2006 and 2007 underwent formal, blinded EDSS determination during 2015-2016. Average peripapillary retinal nerve fibre layer (RNFL) thickness and total macular volume (TMV) were assessed by calculating the mean value of these measures for both eyes in each subject. Patients were categorised by baseline diagnosis as relapsing remitting (RRMS), secondary progressive (SPMS), or primary progressive MS (PPMS). Mixed effects linear regression models were used to investigate whether average TMV and RNFL thicknesses at baseline predict EDSS scores after 10 years. Results: The final analysis included 75 RRMS, 9 SPMS, and 5 PPMS patients. 14 of the 75 patients with a baseline diagnosis of RRMS transitioned to SPMS during follow-up period. Baseline analyses revealed that the RRMS cohort was significantly younger than the SPMS and PPMS cohorts (mean differences= 21.5 years and 11.7 years respectively; p< 0.001 for both) and that SPMS patients had a longer disease duration than RRMS and PPMS patients (mean differences=14.2 years and 13.2 years respectively; p< 0.001 for both). A history of optic neuritis (ON) was observed in the RRMS and SPMS cohorts (41% and 44%, respectively), but not in the PPMS cohorts (0%; p=0.253). Adjusting for age, sex, and a history of ON, the mean TMV values at baseline predicted EDSS scores after a median follow-up of 9.3 years. On average, a 1mm3 lower TMV value at baseline predicts a mean decrease of 2 in EDSS at follow-up (adjusted R²=0.20; p=0.012). Mean baseline RNFL values did not significantly predict EDSS scores (adjusted R²=0.18; p=0.069). Conclusions: As has been previously shown with brain atrophy and lesion volume, retinal measures can have predictive value for medium-term disability in MS. Our preliminary findings support the utility of OCT as a tool to predict neurodegeneration and disease progression over time in MS patients

AKI, a frequently transient condition, is not accepted by the US Food and Drug Association as an end point for drug registration trials. We assessed whether an intermediate-term change in eGFR after AKI has a sufficiently strong relationship with subsequent ESRD to serve as an alternative end point in trials of AKI prevention and/or treatment. Among 161,185 United States veterans undergoing major surgery between 2004 and 2011, we characterized in-hospital AKI by Kidney Disease Improving Global Outcomes creatinine criteria and decline in eGFR from prehospitalization to postdischarge time points and quantified associations of these values with ESRD and mortality over a median of 3.8 years. An eGFR decline of ≥30% at 30, 60, and 90 days after discharge occurred in 3.1%, 2.5%, and 2.6%, of survivors without AKI and 15.9%, 12.2%, and 11.7%, of survivors with AKI. For patients with in-hospital AKI compared with those with no AKI and stable eGFR, a 30% decline in eGFR at 30, 60, and 90 days after discharge demonstrated adjusted hazard ratios (95% confidence intervals) of ESRD of 5.60 (4.06 to 7.71), 6.42 (4.76 to 8.65), and 7.27 (5.14 to 10.27), with corresponding estimates for 40% decline in eGFR of 6.98 (5.21 to 9.35), 8.03 (6.11 to 10.56), and 10.95 (8.10 to 14.82). Risks for mortality were smaller but consistent in direction. A 30%-40% decline in eGFR after AKI could be a surrogate end point for ESRD in trials of AKI prevention and/or treatment, but additional trial evidence is needed.

Surgical sterilization is the primary method of contraception among low-income women in India. This article, using qualitative analysis of key informant, in-depth interviews, and quantitative analyses, examines the antecedents, process, and outcomes of sterilization for women in a low-income area in Mumbai, India. Family planning policies, socioeconomic factors, and gender roles constrain women's reproductive choices. Procedures for sterilization rarely follow protocol, particularly during pre-procedure counseling and consent. Women who choose sterilization often marry early, begin conceiving soon after marriage, and reach or exceed ideal family size early due to problems in accessing reversible contraceptives. Despite these constraints, this study indicates that from the perspective of women, the decision to undergo sterilization is empowering, as they have fulfilled their reproductive duties and can effectively exercise control over their fertility and sexuality. This empowerment results in little post-sterilization regret, improved emotional health, and improved sexual relationships following sterilization.

PURPOSE OF THE STUDY: Cognitive impairment (CI) is one of several factors known to influence hospitalization, hospital length of stay, and rehospitalization among older adults. Redesigning care delivery systems sensitive to the influence of CI may reduce acute care utilization while improving care quality. To develop a foundation of fundamental needs for health care redesign, we conducted focus groups with inpatient and outpatient providers to identify barriers, facilitators, and suggestions for improvements in care delivery for patients with CI. DESIGN AND METHODS: Focus group sessions were conducted with providers to identify their approach to caring for cognitively impaired hospitalized adults; obstacles and facilitators to providing this care; and suggestions for improving the care process. Using a thematic analysis, two reviewers analyzed these transcripts to develop codes and themes. RESULTS: Seven themes emerged from the focus group transcripts. These were: (1) reflections on serving the cognitively impaired population; (2) descriptions of perceived barriers to care; (3) strategies that improve or facilitate caring for hospitalized older adults; (4) the importance of fostering a hospital friendly to the needs of older adults; (5) the need for educating staff, patients, and caregivers; (6) the central role of good communication; and (7) steps needed to provide more effective care. IMPLICATIONS: Providing effective acute care services to older adults with CI is an important challenge in health care reform. An understanding derived from the perspective of multiple professional disciplines is an important first step. Future research will build on this preliminary study in developing new acute care models for patients with CI.

The APOL1 high-risk genotype, present in approximately 13% of blacks in the United States, is a risk factor for kidney function decline in populations with CKD. It is unknown whether genetic screening is indicated in the general population. We evaluated the prognosis of APOL1 high-risk status in participants in the population-based Atherosclerosis Risk in Communities (ARIC) study, including associations with eGFR decline, variability in eGFR decline, and related adverse health events (AKI, ESRD, hypertension, diabetes, cardiovascular disease, pre-ESRD and total hospitalization rate, and mortality). Among 15,140 ARIC participants followed from 1987-1989 (baseline) to 2011-2013, 75.3% were white, 21.5% were black/APOL1 low-risk, and 3.2% were black/APOL1 high-risk. In a demographic-adjusted analysis, blacks had a higher risk for all assessed adverse health events; however, in analyses adjusted for comorbid conditions and socioeconomic status, blacks had a higher risk for hypertension, diabetes, and ESRD only. Among blacks, the APOL1 high-risk genotype associated only with higher risk of ESRD in a fully adjusted analysis. Black race and APOL1 high-risk status were associated with faster eGFR decline (P<0.001 for each). However, we detected substantial overlap among the groups: median (10th-90th percentile) unadjusted eGFR decline was 1.5 (1.0-2.2) ml/min per 1.73 m(2) per year for whites, 2.1 (1.4-3.1) ml/min per 1.73 m(2) per year for blacks with APOL1 low-risk status, and 2.3 (1.5-3.5) ml/min per 1.73 m(2) per year for blacks with APOL1 high-risk status. The high variability in eGFR decline among blacks with and without the APOL1 high-risk genotype suggests that population-based screening is not yet justified.

BACKGROUND:The primary biomarkers used to define CKD are serum creatinine and albuminuria. These biomarkers have directed focus on the filtration and barrier functions of the kidney glomerulus even though albuminuria results from tubule dysfunction as well. Given that proximal tubules make up ∼90% of kidney cortical mass, we evaluated whether a sensitive and specific marker of proximal tubule injury, urinary kidney injury molecule-1 (KIM-1), is elevated in individuals with CKD or with risk factors for CKD. METHODS:We measured urinary KIM-1 in participants of five cohort studies from the USA and Sweden. Participants had a wide range of kidney function and were racially and ethnically diverse. Multivariable linear regression models were used to test the association of urinary KIM-1 with demographic, clinical and laboratory values. RESULTS:In pooled, multivariable-adjusted analyses, log-transformed, creatinine-normalized urinary KIM-1 levels were higher in those with lower eGFR {β = -0.03 per 10 mL/min/1.73 m(2) [95% confidence interval (CI) -0.05 to -0.02]} and greater albuminuria [β = 0.16 per unit of log albumin:creatinine ratio (95% CI 0.15-0.17)]. Urinary KIM-1 levels were higher in current smokers, lower in blacks than nonblacks and lower in users versus nonusers of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers. CONCLUSION:Proximal tubule injury appears to be an integral and measurable element of multiple stages of CKD.

AIMS:To develop a prediction equation for 10-year risk of a combined endpoint (incident coronary heart disease, stroke, heart failure, chronic kidney disease, lower extremity hospitalizations) in people with diabetes, using demographic and clinical information, and a panel of traditional and non-traditional biomarkers. METHODS:We included in the study 654 participants in the Atherosclerosis Risk in Communities (ARIC) study, a prospective cohort study, with diagnosed diabetes (visit 2; 1990-1992). Models included self-reported variables (Model 1), clinical measurements (Model 2), and glycated haemoglobin (Model 3). Model 4 tested the addition of 12 blood-based biomarkers. We compared models using prediction and discrimination statistics. RESULTS:Successive stages of model development improved risk prediction. The C-statistics (95% confidence intervals) of models 1, 2, and 3 were 0.667 (0.64, 0.70), 0.683 (0.65, 0.71), and 0.694 (0.66, 0.72), respectively (p < 0.05 for differences). The addition of three traditional and non-traditional biomarkers [β-2 microglobulin, creatinine-based estimated glomerular filtration rate (eGFR), and cystatin C-based eGFR] to Model 3 significantly improved discrimination (C-statistic = 0.716; p = 0.003) and accuracy of 10-year risk prediction for major complications in people with diabetes (midpoint percentiles of lowest and highest deciles of predicted risk changed from 18-68% to 12-87%). CONCLUSIONS:These biomarkers, particularly those of kidney filtration, may help distinguish between people at low versus high risk of long-term major complications.

Expression of plasminogen activator inhibitor (PAI)-1, the major physiological inhibitor of fibrinolysis, is increased in the lung following inhalation of ozone (O3), a gaseous air pollutant. PAI-1 regulates expression of interleukin (IL)-6, keratinocyte chemoattractant (KC), and macrophage inflammatory protein (MIP)-2, which are cytokines that promote lung injury, pulmonary inflammation, and/or airway hyperresponsiveness following acute exposure to O3 Given these observations, we hypothesized that PAI-1 contributes to the severity of the aforementioned sequelae by regulating expression of IL-6, KC, and MIP-2 following acute exposure to O3 To test our hypothesis, wild-type mice and mice genetically deficient in PAI-1 (PAI-1-deficient mice) were acutely exposed to either filtered room air or O3 (2 ppm) for 3 h. Four and/or twenty-four hours following cessation of exposure, indices of lung injury [bronchoalveolar lavage fluid (BALF) protein and epithelial cells], pulmonary inflammation (BALF IL-6, KC, MIP-2, macrophages, and neutrophils), and airway responsiveness to aerosolized acetyl-beta-methylcholine chloride (respiratory system resistance) were measured in wild-type and PAI-1-deficient mice. O3 significantly increased indices of lung injury, pulmonary inflammation, and airway responsiveness in wild-type and PAI-1-deficient mice. With the exception of MIP-2, which was significantly lower in PAI-1-deficient as compared to wild-type mice 24 h following cessation of exposure to O3, no other genotype-related differences occurred subsequent to O3 exposure. Thus, following acute exposure to O3, PAI-1 neither regulates pulmonary expression of IL-6 and KC nor functionally contributes to any of the pulmonary pathological sequelae that arise from the noxious effects of inhaled O3.

PURPOSE:The development of a sustainable pediatric diabetes surveillance system for the United States requires a better understanding of issues related to case ascertainment. METHODS:Using the SEARCH for Diabetes in Youth registry, we examined whether time from diabetes diagnosis to case registration differed by diabetes type, patient demographics, and the type of provider reporting the case to the study. Plots for time from diagnosis to registration were developed, and differences by key variables were examined using the log-rank test. RESULTS:Compared with time to registration for type 1 cases, it took 2.6 (95% confidence interval [CI], 2.5-2.6) times longer to register 50% of type 2 diabetes cases, and 2.3 (95% CI, 2.0-2.5) times longer to register 90% of type 2 cases. For type 1 diabetes cases, a longer time to registration was associated with older age, minority race/ethnicity, and cases, where the referring provider was not an endocrinologist. For type 2 diabetes cases, older age, non-Hispanic white race/ethnicity, and cases reported by providers other than an endocrinologist took longer to identify and register. CONCLUSIONS:These findings highlight the need for continued childhood diabetes surveillance to identify future trends and influences on changes in prevalence and incidence.

AIMS: To identify population characteristics associated with local variation in the prevalence of diabetic complications and compare the geographic distribution of different types of complications in New York City. METHODS: Using an all-payer database of emergency visits, we identified the proportion of unique adults with diabetes who also had cardiac, neurologic, renal and lower extremity complications. We performed multivariable regression to identify associations of demographic and socioeconomic factors, and diabetes-specific emergency department use with the prevalence of diabetic complications by Census tract. We also used geospatial analysis to compare local hotspots of diabetic complications. RESULTS: We identified 4.6million unique New York City adults, of which 10.5% had diabetes. Adjusting for demographic and socioeconomic factors, diabetes-specific emergency department use was associated with severe microvascular renal and lower extremity complications (p-values<0.001), but not with severe macrovascular cardiac or neurologic complications (p-values of 0.39 and 0.29). Our hotspot analysis demonstrated significant geographic heterogeneity in the prevalence of diabetic complications depending on the type of complication. Notably, the geographic distribution of hotspots of myocardial infarction were inversely correlated with hotspots of end-stage renal disease and lower extremity amputations (coefficients: -0.28 and -0.28). CONCLUSIONS: We found differences in the local geographic distribution of diabetic complications, which highlight the contrasting risk factors for developing macrovascular versus microvascular diabetic complications. Based on our analysis, we also found that high diabetes-specific emergency department use was correlated with poor diabetic outcomes. Emergency department utilization data can help identify the location of specific populations with poor glycemic control.