Markers of endothelial dysfunction and inflammation predict progression of diabetic nephropathy in African Americans with type 1 diabetes.

African Americans with early-onset type 1 diabetes mellitus are at a high risk for severe diabetic nephropathy and end-stage renal disease. In order to determine whether baseline plasma levels of inflammatory markers predict incidence of overt proteinuria or renal failure in African Americans with type 1 diabetes mellitus, we re-examined data of 356 participants in our observational follow-up study of 725 New Jersey African Americans with type 1 diabetes. At baseline and 6-year follow-up, a detailed structured clinical interview was conducted to document medical history including kidney dialysis or transplant, other diabetic complications, and renal-specific mortality. Plasma levels of 28 inflammatory biomarkers were measured using a multiplex bead analysis system. After adjusting for baseline age, glycohemoglobin, and other confounders, the baseline plasma levels of soluble intercellular adhesion molecule-1 (sICAM-1) in the upper two quartiles were, respectively, associated with a three- to fivefold increase in the risk of progression from no albuminuria or microalbuminuria to overt proteinuria. Baseline plasma levels of the chemokine eotaxin in the upper quartile were significantly associated with a sevenfold increase in risk of incident renal failure. These associations were independent of traditional risk factors for progression of diabetic nephropathy. Thus, in type 1 diabetic African Americans, sICAM-1 predicted progression to overt proteinuria and eotaxin-predicted progression to renal failure.

Aerosol delivery and humidification with the Boussignac continuous positive airway pressure device.

BACKGROUND: A simple method for effective bronchodilator aerosol delivery while administering continuing continuous positive airway pressure (CPAP) would be useful in patients with severe bronchial obstruction. OBJECTIVE: To assess the effectiveness of bronchodilator aerosol delivery during CPAP generated by the Boussignac CPAP system and its optimal humidification system. METHODS: First we assessed the relationship between flow and pressure generated in the mask with the Boussignac CPAP system. Next we measured the inspired-gas humidity during CPAP, with several humidification strategies, in 9 healthy volunteers. We then measured the bronchodilator aerosol particle size during CPAP, with and without heat-and-moisture exchanger, in a bench study. Finally, in 7 patients with acute respiratory failure and airway obstruction, we measured work of breathing and gas exchange after a ß(2)-agonist bronchodilator aerosol (terbutaline) delivered during CPAP or via standard nebulization. RESULTS: Optimal humidity was obtained only with the heat-and-moisture exchanger or heated humidifier. The heat-and-moisture exchanger had no influence on bronchodilator aerosol particle size. Work of breathing decreased similarly after bronchodilator via either standard nebulization or CPAP, but P(aO(2)) increased significantly only after CPAP aerosol delivery. CONCLUSIONS: CPAP bronchodilator delivery decreases the work of breathing as effectively as does standard nebulization, but produces a greater oxygenation improvement in patients with airway obstruction. To optimize airway humidification, a heat-and-moisture exchanger could be used with the Boussignac CPAP system, without modifying aerosol delivery.

Childhood trauma and prevalence of cardiovascular disease in patients with type 1 diabetes.

OBJECTIVE: To examine the relationship between childhood trauma and prevalence of cardiovascular disease (CVD) (either coronary disease or stroke) in Type 1 diabetes (DM). METHODS: From an original cohort of 725 African Americana with Type 1 DM, 444 (61.2%) were reexamined as part of a 6-year follow-up. In both examinations, patients underwent a structured clinical interview to determine their medical history and a detailed ocular examination. At follow-up, patients completed the Childhood Trauma Questionnaire, Hostility and Direction of Hostility Questionnaire, and Beck Depression Inventory. Diabetic patients who had CVD and those had not developed CVD at the 6-year follow-up were compared for their experience of childhood trauma at the same time controlling for the presence of known risk factors for CVD. RESULTS: Of the 393 patients at risk, 60 (15.3%) had developed any CVD, 52 (12.9%) had coronary disease, and 16 (3.8%) had a stroke at the 6-year follow-up. On univariate analysis, childhood trauma was significantly associated with 6-year incidence of any CVD (p < .01), coronary disease (p < .05), and stroke (p < .01). Childhood trauma scores were also significantly associated with depression (p < .001) and hostility (p < .001) scores, age (p < .05), and renal disease (p < .05). In primary multivariate analyses, childhood trauma predicted CVD independent of age, body mass index, blood pressure, and proteinuria. Secondary analyses suggested that association between the 6-year incidence of CVD and childhood trauma was also independent of depression ratings. CONCLUSION: Childhood seems to be an independent risk factor for the incidence of CVD in Type 1 DM.

Suicide attempts and ideation in African-American type 1 diabetic patients.

In order to examine suicidality and its correlates in type 1 diabetics 412 African-American type 1 diabetics and 404 African-American controls underwent a semi-structured interview that asked if they had ever attempted suicide. Patients completed the Childhood Trauma Questionnaire (CTQ), Hostility and Direction of Hostility Questionnaire (HDHQ), and Beck Depression Inventory (BDI). Diabetics and controls were compared for their rate of suicide attempt. Diabetic patients who had or had never attempted suicide were compared on socio-demographic and clinical data. It was found that diabetics were 3 to 4 times more likely to attempt suicide than controls (13.3% vs 3.5%, respectively, P<0.001). Diabetic attempters were significantly more likely to be female, depressed and hostile, and to report a history of childhood trauma, smoking, alcohol abuse, and drug abuse than diabetic non-attempters. Multivariate analyses showed that female sex, severity of childhood abuse, history of alcohol abuse, and depression were significantly and independently associated with having attempted suicide. These results suggest that African-Americans with type 1 diabetes have a raised risk of attempting suicide. Suicide risk in diabetics appears to be multifactorial and includes gender, developmental, personality, psychiatric, and substance abuse determinants.

Depression is a risk factor for poor glycemic control and retinopathy in African-Americans with type 1 diabetes.

OBJECTIVE: To examine longitudinal data about depression in relationship to glycemic control and as a risk factor for diabetic retinopathy (DR). Depression is a common psychiatric disorder among diabetic persons and has been shown in cross-sectional studies to be associated with the vascular complications of diabetes. METHODS: A total of 483 African-American patients with Type 1 diabetes had a baseline examination and 6-year follow-up examination. Evaluations at both visits included administering the Beck Depression Inventory (BDI), a detailed ophthalmologic examination, retinal photographs, and measurement of glycosylated hemoglobin as an index of glycemic control. Six-year progression of DR between baseline and follow-up visits was evaluated from the change in retinopathy severity using the Early Treatment of Diabetic Retinopathy Study grading scale. RESULTS: Patients with high BDI scores at both baseline and 6-year follow-up visits had significantly higher baseline glycosylated hemoglobin values (p = .01), and were more likely to show progression of DR (odds ratio (OR) = 2.44; 95% confidence interval (CI): 1.01-5.88; p = .049) and progression to proliferative diabetic retinopathy (PDR) (OR = 3.19; 95% CI: 1.30-7.87; p = .01) than patients with low BDI scores at both visits. This was independent of baseline medical risk factors for DR. CONCLUSION: Six-year longitudinal data indicate that depression is significantly associated with both poor glycemic control and higher 6-year progression to PDR in African-Americans with Type 1 diabetes.

Six-year incidence of visual loss in african americans with type 1 diabetes mellitus: the New Jersey 725.

OBJECTIVE: To report the 6-year incidence of visual loss and associated risk factors in African Americans with type 1 diabetes mellitus. METHODS: African Americans with type 1 diabetes (n=483) who participated in the New Jersey 725 study were reexamined as part of a 6-year follow-up. Best-corrected visual acuity, a structured clinical interview, fundus photographs, and blood pressure measurements were obtained. The biological evaluation included blood and urine assays. Any visual loss was defined as a visual acuity of 20/40 or worse in the better eye, blindness as a visual acuity of 20/200 or worse in the better eye, and doubling of the visual angle (DVA) as the loss of 15 or more letters between the first and second visits. RESULTS: Over 6 years, 19 of 440 patients (4.3%) developed visual loss in the better eye, 3 of 472 patients (0.6%) became blind, 47 of 481 patients (9.8%) developed DVA in the better eye, and 65 of 481 (13.5%) developed DVA in either eye. Baseline older age, high glycosylated hemoglobin level, retinopathy severity, and proteinuria were characteristics significantly (P<.001 for all) and independently associated with DVA in either eye at follow-up. CONCLUSIONS: The 6-year incidence of DVA in either eye (13.5%) is high in African Americans with type 1 diabetes. Baseline poor glycemic control, diabetic retinopathy severity, proteinuria, and older age are predictors of visual loss in this population.

Six-year progression of retinopathy and associated risk factors in African American patients with type 1 diabetes mellitus: the New Jersey 725.

OBJECTIVE: To report the 6-year progression of diabetic retinopathy (DR) and associated risk factors among African American patients with type 1 (insulin-dependent) diabetes mellitus. METHODS: Participants from the New Jersey 725 included 483 African American patients with type 1 diabetes who underwent reexamination as part of a 6-year follow-up. Evaluations included a structured clinical interview, ocular examination, 7 stereoscopic fundus photographs, and blood pressure measurements. Severity of DR was determined via masked grading of fundus photographs. Biological evaluation included blood and urine assays. RESULTS: During the 6-year period, 56.1% of patients at risk showed progression of DR; 15.0% showed progression to proliferative DR; and 15.9% developed macular edema. A baseline high glycosylated hemoglobin level and systemic hypertension were significant risk factors for progression of DR, progression to proliferative DR, and incidence of macular edema. Progression to proliferative DR was significantly associated with baseline older age, renal disease, and severity of DR. The incidence of macular edema was significantly associated with baseline older age, low socioeconomic status, severity of DR, and total serum cholesterol level. CONCLUSIONS: Six-year progression of DR is high in African American patients with type 1 diabetes. Improving glycemic and blood pressure control may reduce the ocular morbidity of diabetes in African Americans.

No relationship between serum cholesterol and suicidal ideation and depression in African-American diabetics.

Low serum cholesterol has been associated with suicidal behavior. Depression has been postulated to be a mediating factor between low serum cholesterol and suicidal behavior. Therefore, this possibility was examined in a large group of 459 diabetic patients that had blood drawn for serum cholesterol levels on the same day that they completed the Beck Depression Inventory. The results failed to show any significant relationship between serum cholesterol levels and either total Beck Depression Inventory (BDI) scores or BDI scores on the item measuring current suicidal ideation. The limitations of the study are discussed.

Plasma markers of inflammation and prediction of cardiovascular disease and mortality in African Americans with type 1 diabetes.

BACKGROUND: To determine whether plasma levels of markers of inflammation are predictive of the incidence of cardiovascular disease (CVD), hypertension, or mortality in African Americans with type 1 diabetes mellitus. METHODS: A total of 484 African Americans with type 1 diabetes were included. At baseline and 6-year follow-up, a clinical interview and examination were conducted to document CVD and systemic hypertension. Venous blood for glycated hemoglobin and cholesterol was obtained and albumin excretion rate measured. Mortality was assessed annually between baseline and 6-year follow-up by review of the social security death index. Baseline plasma levels of 28 inflammatory biomarkers were measured using multiplex bead analysis system. RESULTS: After adjusting for baseline age and other confounders, African Americans with type 1 diabetes in the highest quartile of plasma interferon-inducible protein 10 (IP-10) were three times more likely to develop CVD than those in the lowest quartile. African Americans with type 1 diabetes in the lowest quartiles of plasma stromal derived factor-1 (SDF-1) had a 75% higher risk of death than patients in the highest quartile, independently of age, low density lipoprotein cholesterol, body mass index, hypertension, and albuminuria. CONCLUSION: In African Americans with type 1 diabetes, high plasma IP-10 is an independent predictor for incident CVD and low SDF-1 an independent predictor for mortality.

Management of pseudophakic cystoid macular edema.

Pseudophakic cystoid macular edema (PCME) is a common complication following cataract surgery. Acute PCME may resolve spontaneously, but some patients will develop chronic macular edema that affects vision and is difficult to treat. This disease was described more than 50 years ago, and there are multiple options for clinical management. We discuss mechanisms, clinical efficacy, and adverse effects of these treatment modalities. Topical non-steroidal anti-inflammatory agents and corticosteroids are widely used and, when combined, may have a synergistic effect. Intravitreal corticosteroids and anti-vascular endothelial growth factor (anti-VEGF) agents have shown promise when topical medications either fail or have had limited effects. Randomized clinical studies evaluating anti-VEGF agents are needed to fully evaluate benefits and risks. When PCME is either refractory to medical therapy or is associated with significant vitreous involvement, pars plana vitrectomy has been shown to improve outcomes, though it is associated with additional risks.

The prevalence of diabetic retinopathy among adult type 1 diabetic persons in the United States.

OBJECTIVE: To estimate the US prevalence of diabetic retinopathy (DR) among persons with type 1 diabetes mellitus (DM). METHODS: Prevalence data from the New Jersey 725 and Wisconsin Epidemiologic Study of Diabetic Retinopathy were used to estimate the prevalence of DR by age, gender, and race among persons 18 years and older having type 1 DM diagnosed before age 30 years. Severity of DR was determined via masked grading of 7-field stereoscopic fundus photographs. Any DR was defined as retinopathy severity level of 14 or more; and vision-threatening retinopathy, as retinopathy severity level of 50 or more, the presence of clinically significant macular edema, or both. The estimates of the prevalence of DR among persons with type 1 DM were applied to the estimated number of persons with type 1 DM diagnosed before age 30 years in the 2000 US population to obtain prevalence estimates of DR due to type 1 DM in the general population. RESULTS: Among 209 million Americans 18 years and older, an estimated 889 000 have type 1 DM diagnosed before age 30 years. Among persons with type 1 DM, the crude prevalences of DR of any level (74.9% vs 82.3% in black and white persons, respectively) and of vision-threatening retinopathy (30.0% vs 32.2%, respectively) are high. The prevalence of DR due to type 1 DM diagnosed before age 30 years in the general population 18 years and older is estimated at 767 000 persons having DR of any level (0.37%), and 376 000 persons having vision-threatening retinopathy (0.18%). CONCLUSION: Retinopathy due to type 1 DM is an important public health problem in the United States, affecting 1 per 300 persons 18 years and older, and 1 per 600 persons with advanced, vision-threatening retinopathy.

Proteinuria in African Americans with type 1 diabetes.

AIMS: African Americans with type 1 diabetes are at a high risk for end-stage renal disease (ESRD). Factors associated with the presence of (any) proteinuria were examined in this ethnic group. METHODS: Proteinuria and creatinuria were measured in both first-voided and 4-h timed urine specimens in African Americans with type 1 diabetes (N=717). Other evaluations included clinical interview, ocular examination, fundus photography, blood pressure, and glycosylated hemoglobin measurements. RESULTS: Of the 717 patients, 357 (49.8%) had any proteinuria. Frequency of any proteinuria increased significantly with (a). age, from 34.2% of patients 20-30 years of age to 84.7% in those >or=45 years of age, and (b). duration of diabetes from 24.1% in those with 0-4 years of diabetes to 77.5% in those with >or=25 years of diabetes. Multivariate logistic regression showed that any proteinuria was significantly and independently associated with male sex, systemic hypertension, poor glycemic control, and longer duration of diabetes. CONCLUSION: Proteinuria is common in African Americans with type 1 diabetes. Risk factors include male sex, systemic hypertension, poor glycemic control, and longer duration of diabetes. Whether early protection of renal function, in addition to glycemic control, may prevent such morbidity in this ethnic group requires study.

Cerebrospinal fluid monoamine metabolites in cocaine patients: no relationship to cue-induced craving.

We aimed to examine the relationship between central monoamine metabolites and craving cocaine in cocaine-dependent patients. Cerebrospinal fluid (CSF) monoamine metabolite concentrations were determined in 20 withdrawn cocaine-dependent patients. Patients also participated in a cue-elicited cocaine craving procedure. There were no significant relationships between cocaine craving scores and CSF concentrations of the dopamine metabolite, homovanillic acid, the serotonin metabolite, 5-hydroxyindoleacetic acid, or the norepinephrine metabolite, 3-methoxy-4-hydroxyphenylethylglycol. CSF monoamine metabolite concentrations were not related to cocaine craving in withdrawn cocaine-dependent patients.

Blue cone electroretinogram amplitudes are related to dopamine function in cocaine-dependent patients.

The objective of the study was to examine the relationship between an index of central dopamine function and electroretinographic (ERG) blue cone amplitudes in cocaine-dependent patients. Thus, 17 recently abstinent cocaine-dependent patients had an ERG performed. They also had a lumbar puncture for determination of cerebrospinal (CSF) concentrations of the dopamine metabolite homovanillic acid (HVA). It was found that patients who had reduced ERG blue cone b-wave amplitudes (<0.5 microV) had significantly lower concentrations of CSF HVA than patients who had ERG blue cone b-wave amplitudes greater than 0.5 microV. There was also a significant positive correlation between ERG blue cone amplitudes and CSF HVA concentrations. These results suggest the possibility that ERG blue cone amplitudes may be a neurobiologic marker related to central dopamine function in cocaine-dependent patients.

Inflammatory biomarkers and progression of diabetic retinopathy in African Americans with type 1 diabetes.

PURPOSE: We examined whether baseline plasma levels of markers of inflammation and endothelial dysfunction are associated with the incidence of diabetic retinopathy (DR) in African Americans with type 1 insulin-dependent diabetes mellitus (T1DM). METHODS: At baseline and follow-up examinations, detailed ocular examination, structured clinical interview, venous blood specimens, and masked grading of seven standard field retinal photographs were obtained. Baseline plasma levels of 28 inflammatory biomarkers, measured using multiplex bead analysis system, were measured in the participants. RESULTS: After adjusting for age, glycemic control, and other potential confounders, baseline plasma levels of E-selectin were associated significantly with progression of DR, E-selectin and tumor necrosis factor-α (TNF-α) levels with incidence of proliferative DR (PDR), and soluble intercellular adhesion molecule-1 (sICAM-1) and TNF-α levels with incidence of macular edema (ME). CONCLUSIONS: In African Americans with T1DM, inflammation and endothelial dysfunction precede the development of DR, thus supporting the notion that inflammation may influence progression/incidence of disease.

Relationship of retinal vessel caliber to cardiovascular disease and mortality in African Americans with type 1 diabetes mellitus.

OBJECTIVE: To examine the relationship between retinal arteriolar and venular diameter and the 6-year incidence of cardiovascular disease and mortality among African Americans with type 1 diabetes mellitus. METHODS: Included were 468 African Americans with type 1 diabetes mellitus who participated in the New Jersey 725 and who had undergone a 6-year follow-up examination. At both baseline and 6-year follow-up, hypertension and presence of heart disease, stroke, or lower extremity arterial disease (LEAD) were documented and confirmed by review of hospital admission and medical records. Computer-assisted grading from digitized images of retinal photographs was accomplished to determine the average diameter of retinal arterioles (central retinal arteriolar equivalent) and venules (central retinal venular equivalent). Retinal vessel diameter size was examined in relation to the 6-year incidence of hypertension, any cardiovascular disease (heart disease, stroke, or LEAD), heart disease or stroke, LEAD, and mortality. RESULTS: Narrower central retinal arteriolar equivalent at baseline significantly and independently predicted 6-year incidence of any cardiovascular disease and LEAD, whereas larger retinal venular diameter at baseline significantly and independently predicted 6-year incidence of hypertension. Proteinuria and retinopathy severity at baseline were stronger predictors of mortality than retinal vascular diameter. CONCLUSION: In African Americans with type 1 diabetes mellitus, baseline retinal vessel caliber is an independent predictor of incident hypertension and LEAD.

Global prevalence and major risk factors of diabetic retinopathy.

OBJECTIVE: To examine the global prevalence and major risk factors for diabetic retinopathy (DR) and vision-threatening diabetic retinopathy (VTDR) among people with diabetes. RESEARCH DESIGN AND METHODS: A pooled analysis using individual participant data from population-based studies around the world was performed. A systematic literature review was conducted to identify all population-based studies in general populations or individuals with diabetes who had ascertained DR from retinal photographs. Studies provided data for DR end points, including any DR, proliferative DR, diabetic macular edema, and VTDR, and also major systemic risk factors. Pooled prevalence estimates were directly age-standardized to the 2010 World Diabetes Population aged 20-79 years. RESULTS: A total of 35 studies (1980-2008) provided data from 22,896 individuals with diabetes. The overall prevalence was 34.6% (95% CI 34.5-34.8) for any DR, 6.96% (6.87-7.04) for proliferative DR, 6.81% (6.74-6.89) for diabetic macular edema, and 10.2% (10.1-10.3) for VTDR. All DR prevalence end points increased with diabetes duration, hemoglobin A(1c), and blood pressure levels and were higher in people with type 1 compared with type 2 diabetes. CONCLUSIONS: There are approximately 93 million people with DR, 17 million with proliferative DR, 21 million with diabetic macular edema, and 28 million with VTDR worldwide. Longer diabetes duration and poorer glycemic and blood pressure control are strongly associated with DR. These data highlight the substantial worldwide public health burden of DR and the importance of modifiable risk factors in its occurrence. This study is limited by data pooled from studies at different time points, with different methodologies and population characteristics.

Childhood trauma and depressive symptoms in type 1 diabetes.

BACKGROUND: To examine the relationship of childhood trauma to depressive symptoms in type 1 diabetes, a chronic disease in which the frequency of depression is increased. METHOD: One hundred fifty African American patients with type 1 diabetes seen between August 1993 and January 1998 completed the Beck Depression Inventory and Childhood Trauma Questionnaire. They were also genotyped for a functional serotonin transporter promoter polymorphism (5-HTTLPR) that modulates resiliency. Patients who had Beck Depression Inventory scores above and below 14 were compared. RESULTS: Diabetic patients who had Beck Depression Inventory scores ≥ 14 had experienced significantly more different types of childhood trauma than those with Beck Depression Inventory scores < 14 (P < .001), independent of potential interaction with 5-HTTLPR genotype. CONCLUSIONS: Childhood trauma appears to be a determinant of depressive symptoms in type 1 diabetes, independently of genotype of a functional locus modulating resiliency.

Retinal venular diameter as an early indicator of progression to proliferative diabetic retinopathy with and without high-risk characteristics in African Americans with type 1 diabetes mellitus.

OBJECTIVE: To examine the relationship between retinal arteriolar and venular diameter and the 6-year progression of diabetic retinopathy (DR) in African Americans with type 1 insulin-dependent diabetes mellitus. METHODS: Included were 468 African Americans with type 1 diabetes mellitus who participated in the New Jersey 725 and who had undergone a 6-year follow-up examination. Seven standard field retinal photographs were obtained at both examinations. Computer-assisted grading, from digitized images of field 1 of baseline retinal photographs, was accomplished to determine the average diameter of retinal arterioles (central retinal arteriolar equivalent [CRAE]) and venules (central retinal venular equivalent [CRVE]). Retinal vessel diameter was examined in relation to the 6-year incidence and/or progression of DR. RESULTS: For right and left eyes, mean (SD) CRAE was 168.8 (16.0) µm and mean CRVE was 254.2 (25.2) µm. Both CRAE and CRVE were correlated between eyes (P < .001). Multivariate analysis with generalized estimating equations showed that larger CRVE in either the right or left eye was significantly associated with 6-year progression to either proliferative DR (PDR) or PDR with high-risk characteristics after adjusting for baseline clinical risk factors. Notably, a significant association between baseline CRVE and progression to PDR was present for eyes with no to moderate nonproliferative DR and also between baseline CRVE and progression to PDR with high-risk characteristics for eyes with no or nonproliferative DR. CONCLUSION: Larger retinal venular diameter is an independent and early indicator of progression to either PDR or PDR with high-risk characteristics in African Americans with type 1 diabetes mellitus.

Medical and psychological risk factors for incident hypertension in type 1 diabetic african-americans.

Objective. To determine risk factors for the development of hypertension among African-Americans living with type 1 diabetes. Methods. African-Americans with type 1 diabetes (n = 483) participated in a 6-year followup. At both baseline and followup blood pressure was measured twice in both sitting and standing positions using a standard protocol. Patients had a structured clinical interview, ocular examination, retinal photographs, and blood and urine assays and completed the Hostility and Direction of Hostility Questionnaire (HDHQ) and the Beck Depression Inventory (BDI). Results. Of the 280 diabetic patients with no hypertension at baseline, 82 (29.3%) subsequently developed hypertension over the 6-year followup. Baseline older age, longer duration of diabetes, family history of hypertension, greater mean arterial blood pressure, overt proteinuria, increasing retinopathy severity, peripheral neuropathy, smoking, and higher hostility scores were significantly associated with the development of hypertension. Multivariate analyses showed that higher hostility scores and overt proteinuria were significantly and independently associated with the development of hypertension in this population. Conclusions. The development of hypertension in African-Americans living with type 1 diabetes appears to be multifactorial and includes both medical (overt proteinuria) as well as psychological (high hostility) risk factors.