Modulation of endogenous antioxidant defense and the progression of kidney disease in multi-heritage groups of patients with type 2 diabetes: PRospective EValuation of Early Nephropathy and its Treatment (PREVENT).

BACKGROUND: Diabetes is the western world's leading cause of end-stage renal disease. Glucose-dependent, oxidative stress is linked to the development of renal inflammation and sclerosis, which, in animal models of diabetes, can be prevented by anti-oxidative treatment. Patients of non-Caucasian heritage have low activity of the selenoprotein, antioxidant enzyme, glutathione peroxidase (GPx) and its co-factor vitamin E, which may be linked to their increased propensity to developing end-stage renal disease. RESEARCH DESIGN AND METHODS: We have designed a double-blind, randomized, placebo controlled study with selenium and/or vitamin E versus placebo as the interventions for patients with type 2 diabetes and chronic kidney disease (CKD) stages 1-3. A 2 × 2 factorial design will allow a balanced representation of the heritage groups exposed to each intervention. The primary biochemical outcome is change in GPx activity, and clinical outcome measure is the actual, rate of-and/or percentage change in estimated glomerular filtration rate (eGFR) from baseline. Analysis will be with a marginal model for longitudinal data using Generalized Estimating Equations corrected for measures of baseline serum antioxidant enzyme activities (GPx, superoxide dismutase and catalase), micronutrient levels (vitamins E and C), measures of inflammation (interleukin 6, c-reactive protein and monocyte chemoattractant protein-1) and markers of oxidative damage (plasma 8-isoprostaglandin F2α and urinary 8-hydroxydeoxyguanosine). EXPECTED RESULTS: The study will assess the relationship between GPx activity, oxidative stress, inflammation and eGFR. It will test the null hypothesis that antioxidant therapy does not influence the activity of GPx or other antioxidant enzymes and/or alter the rate of change in eGFR in these patient groups. CONCLUSIONS: Outcome data on the effect of antioxidants in human diabetic renal disease is limited. Previous post hoc analyses have not shown a beneficial effect of vitamin E on renal function. A recent trial of a pharmaceutical antioxidant agent, improved eGFR, but in patients with advanced diabetes-related chronic kidney disease its use was associated with an increased incidence of cardiovascular events. We will explore whether the nutritional antioxidants, vitamin E and selenium alone, or in combination in patients at high risk of renal disease progression, forestalls a reduction in eGFR. The study will describe whether endogenous antioxidant enzyme defenses can be safely modified by this intervention and how this is associated with changes in markers of oxidative stress. Trial registration ISRCTN 97358113. Registered 21st September 2009.

INTRAVENOUS PAMIDRONATE IS ASSOCIATED WITH REDUCED MORTALITY IN PATIENTS WITH CHRONIC CRITICAL ILLNESS.

OBJECTIVE: Chronic critical illness (CCI), characterized by prolonged mechanical ventilation and tracheostomy, commonly manifests with elevated bone resorption, which has previously been shown to abate after treatment with intravenous (IV) bisphosphonates. Our study assessed the impact of pamidronate administration on clinical outcomes in a CCI cohort. METHODS: A retrospective case series was performed on 148 patients admitted to The Mount Sinai Hospital Respiratory Care Unit (RCU) from 2009-2010. We identified patients with CCI who did (n = 30) or did not (n = 118) receive IV pamidronate (30 to 90 mg). Both groups included patients with normal and abnormal renal function. Pamidronate was administered for elevated urine or serum N-telopeptide, hypercalciuria, or hypercalcemia. RESULTS: RCU and 1-year mortality were significantly lower in the pamidronate group (0 and 20%, respectively) compared to nonreceivers (19 and 56%, respectively) (P = .0077 and P = .0004, respectively). After adjusting for differences in baseline creatinine, estimated glomerular filtration rate, and serum calcium, the association with reduced mortality remained significant at 1 year (P = .0132) and with borderline significance for RCU mortality (P = .0911). Creatinine was significantly lower 7 days following pamidronate administration (P = .0025), with no significant difference at 14 days compared to baseline. Pamidronate receivers showed a greater increase in albumin during the RCU stay (2.49 to 3.23 g/dL), compared to nonreceivers (2.43 to 2.64 g/dL) (P = .0007). Pamidronate administration was associated with a significantly reduced rate of hypoglycemia compared to RCU patients not receiving pamidronate (0.09 versus 0.12; P = .0071). CONCLUSION: Pamidronate use in a CCI population is associated with reduced mortality, lower hypoglycemia rates, improved albumin, and stable renal function. ABBREVIATIONS: BMI = body mass index CCI = chronic critical illness CI = confidence interval CKD = chronic kidney disease CTx = C-telopeptide eGFR = estimated glomerular filtration rate ICU = intensive care unit IV = intravenous NTx = N-telopeptide PMV = prolonged mechanical ventilation RCU = respiratory care unit.

Statin Use is Associated with Better Cognitive Function in Elderly with Type 2 Diabetes.

The pleiotropic contribution of statins on cognition is uncertain. From 840 patients in the cohort from the Israel Diabetes and Cognitive Decline Study, we identified 61 non-statin users and compared them with 45 patients who had used statins at least 90% of the time. Analysis of covariance was performed to compare mean cognitive z-scores between statin users and non-users while adjusting for socio-demographic, diabetes-related, and cardiovascular covariates which included change in cholesterol by year. Overall cognition, memory, and executive function was found to be significantly better in statin users (p <  0.0008). This suggests a positive effect of statins on cognitive function of type 2 diabetes patients that is independent of cholesterol levels.

Ultrasound accurately identifies soft tissue foreign bodies in a live anesthetized porcine model.

BACKGROUND: Some subcutaneous foreign bodies (FBs) are not easily visualized during physical examination and may not be detected on radiographic evaluation. Ultrasound (US) is capable of visualizing FBs of varying compositions. Previous studies have examined the use of US to detect FBs in deceased animal or human tissue. This study used live anesthetized porcine tissue to more closely model clinical conditions. OBJECTIVES: The objectives were to examine the test characteristics of US in the evaluation of FBs in living tissue and to evaluate if secondary findings such as surrounding edema and hematoma improve diagnostic accuracy. METHODS: Institutional Animal Care and Use Committee (IACUC) approval was obtained. FBs 1 cm in length and 1 to 3 mm in width were created from toothpicks (wood), 21-gauge needles (metal), and a broken ampule (glass) and inserted subcutaneously into an anesthetized 20-kg Yorkshire swine. There were 72 sites implanted with equal proportions of each FB type and null sites. Half of the FBs were inserted at time 0 and half were inserted after 2 hours. Immediately after placement, four blinded physicians performed US evaluations of the first 36 sites. At 2 hours after placement, they evaluated each of the original 36 sites and the 36 new sites. They documented the presence or absence of FBs and surrounding edema. RESULTS: After initial FB placement, 122 of the 144 interpretations (85%) were correct, with a sensitivity of 85% (95% confidence interval [CI] = 79% to 92%) and a specificity of 86% (95% CI = 76% to 98%). No sites demonstrated surrounding edema. At 2 hours after placement, 127 of 144 interpretations (88%) for these same sites were correct, with a sensitivity of 87% (95% CI = 82% to 93%) and a specificity of 89% (95% CI = 81% to 97%). Of the 108 observations (27 sites that contained FBs), eight of the 108 (7%) observations had surrounding edema (four glass, three wood, one metal). For the 36 new sites with FBs placed 2 hours later, 126 of the 144 interpretations (83%) were correct, with a sensitivity of 88% (95% CI = 82% to 94%) and a specificity of 83% (95% CI = 73% to 95%). No sites had surrounding edema present. CONCLUSIONS: Ultrasound was sensitive, specific, and accurate in identifying FBs in live anesthetized porcine tissue. Surrounding edema or hematoma 2 hours after placement was so infrequently observed that it was not possible to determine its influence on the test characteristics.

Safety, clinical, and immunologic efficacy of a Chinese herbal medicine (Food Allergy Herbal Formula-2) for food allergy.

BACKGROUND: Food Allergy Herbal Formula-2 (FAHF-2) is a 9-herb formula based on traditional Chinese medicine that blocks peanut-induced anaphylaxis in a murine model. In phase I studies FAHF-2 was found to be safe and well tolerated. OBJECTIVE: We sought to evaluate the safety and effectiveness of FAHF-2 as a treatment for food allergy. METHODS: In this double-blind, randomized, placebo-controlled study 68 subjects aged 12 to 45 years with allergies to peanut, tree nut, sesame, fish, and/or shellfish, which were confirmed by baseline double-blind, placebo-controlled oral food challenges (DBPCFCs), received FAHF-2 (n = 46) or placebo (n = 22). After 6 months of therapy, subjects underwent DBPCFCs. For those who demonstrated increases in the eliciting dose, a repeat DBPCFC was performed 3 months after stopping therapy. RESULTS: Treatment was well tolerated, with no serious adverse events. By using intent-to-treat analysis, the placebo group had a higher eliciting dose and cumulative dose (P = .05) at the end-of-treatment DBPCFC. There was no difference in the requirement for epinephrine to treat reactions (P = .55). There were no significant differences in allergen-specific IgE and IgG4 levels, cytokine production by PBMCs, or basophil activation between the active and placebo groups. In vitro immunologic studies performed on subjects' baseline PBMCs incubated with FAHF-2 and food allergen produced significantly less IL-5, greater IL-10 levels, and increased numbers of regulatory T cells than untreated cells. Notably, 44% of subjects had poor drug adherence for at least one third of the study period. CONCLUSION: FAHF-2 is a safe herbal medication for subjects with food allergy and shows favorable in vitro immunomodulatory effects; however, efficacy for improving tolerance to food allergens is not demonstrated at the dose and duration used.

Low-Cost High-Resolution Microendoscopy for the Detection of Esophageal Squamous Cell Neoplasia: An International Trial.

BACKGROUND & AIMS: Esophageal squamous cell neoplasia has a high mortality rate as a result of late detection. In high-risk regions such as China, screening is performed by Lugol's chromoendoscopy (LCE). LCE has low specificity, resulting in unnecessary tissue biopsy with a subsequent increase in procedure cost and risk. The purpose of this study was to evaluate the accuracy of a novel, low-cost, high-resolution microendoscope (HRME) as an adjunct to LCE. METHODS: In this prospective trial, 147 consecutive high-risk patients were enrolled from 2 US and 2 Chinese tertiary centers. Three expert and 4 novice endoscopists performed white-light endoscopy followed by LCE and HRME. All optical images were compared with the gold standard of histopathology. RESULTS: By using a per-biopsy analysis, the sensitivity of LCE vs LCE + HRME was 96% vs 91% (P = .0832), specificity was 48% vs 88% (P < .001), positive predictive value was 22% vs 45% (P < .0001), negative predictive value was 98% vs 98% (P = .3551), and overall accuracy was 57% vs 90% (P < .001), respectively. By using a per-patient analysis, the sensitivity of LCE vs LCE + HRME was 100% vs 95% (P = .16), specificity was 29% vs 79% (P < .001), positive predictive value was 32% vs 60%, 100% vs 98%, and accuracy was 47% vs 83% (P < .001). With the use of HRME, 136 biopsies (60%; 95% confidence interval, 53%-66%) could have been spared, and 55 patients (48%; 95% confidence interval, 38%-57%) could have been spared any biopsy. CONCLUSIONS: In this trial, HRME improved the accuracy of LCE for esophageal squamous cell neoplasia screening and surveillance. HRME may be a cost-effective optical biopsy adjunct to LCE, potentially reducing unnecessary biopsies and facilitating real-time decision making in globally underserved regions. ClinicalTrials.gov, NCT 01384708.

In vivo classification of colorectal neoplasia using high-resolution microendoscopy: Improvement with experience.

BACKGROUND AND AIMS: High-resolution microendoscopy (HRME) is a novel, low-cost "optical biopsy" technology that allows for subcellular imaging. The study aim was to evaluate the learning curve of HRME for the differentiation of neoplastic from non-neoplastic colorectal polyps. METHODS: In a prospective cohort fashion, a total of 162 polyps from 97 patients at a single tertiary care center were imaged by HRME and classified in real time as neoplastic (adenomatous, cancer) or non-neoplastic (normal, hyperplastic, inflammatory). Histopathology was the gold standard for comparison. Diagnostic accuracy was examined at three intervals over time throughout the study; the initial interval included the first 40 polyps, the middle interval included the next 40 polyps examined, and the final interval included the last 82 polyps examined. RESULTS: Sensitivity increased significantly from the initial interval (50%) to the middle interval (94%, P = 0.02) and the last interval (97%, P = 0.01). Similarly, specificity was 69% for the initial interval but increased to 92% (P = 0.07) in the middle interval and 96% (P = 0.02) in the last interval. Overall accuracy was 63% for the initial interval and then improved to 93% (P = 0.003) in the middle interval and 96% (P = 0.0007) in the last interval. CONCLUSIONS: In conclusion, this in vivo study demonstrates that an endoscopist without prior colon HRME experience can achieve greater than 90% accuracy for identifying neoplastic colorectal polyps after 40 polyps imaged. HRME is a promising modality to complement white light endoscopy in differentiating neoplastic from non-neoplastic colorectal polyps.

SHOX gene variants: growth hormone/insulin-like growth factor-1 status and response to growth hormone treatment.

CONTEXT: Short stature homeobox-containing gene (SHOX) variants of unknown clinical significance occur frequently among children with short stature, yet their growth hormone (GH)/insulin-like growth factor-1 (IGF-1) status and response to GH have not been studied. OBJECTIVE: To define GH and IGF-1 status in children with SHOX variants and assess their response to GH. PATIENTS AND METHODS: This is a retrospective review of children with short stature. Children with SHOX variants were compared to those with no variants. Height standard deviation scores (SDS) and IGF-1 SDS at baseline and during GH treatment at 6, 12, and 24 months were analyzed. Growth velocity (GV), maximum GH dose, IGF-BP3, and changes in height SDS, IGF-1 SDS, and GV were compared. RESULTS: Among 355 children, 83 (23%) had SHOX variants. Nineteen different SHOX variants were detected. There was no difference in age, height SDS, IGF-1 SDS, or IGF-BP3 between children with SHOX variants and those with normal SHOX. Height SDS, IGF-1 SDS, IGF-BP3, GV, and GH dose were not different between patients with SHOX variants and those without. CONCLUSIONS: The GH and IGF-1 characteristics of children with short stature were not different between children with SHOX+ variants and children with no variants. Although these findings suggest that SHOX variants are polymorphisms, studies prospectively comparing individual SHOX variants are needed.

Is prostate cancer changing?: evolving patterns of metastatic castration-resistant prostate cancer.

BACKGROUND: Metastatic castration-resistant prostate cancer (mCRPC) most commonly metastasizes to the bone, and less commonly to nonosseous sites (eg, lymph nodes, liver, lung). With new therapies extending survival in mCRPC, it was hypothesized that the pattern of metastases is changing over time. The pattern of metastatic disease was evaluated in men with mCRPC, as reported in baseline characteristics of prospective clinical trials over 2 decades. METHODS: This study identified all phase 2 and 3 therapeutic studies in men with mCRPC in PubMed and American Society of Clinical Oncology abstracts from 1990 to 2012. Studies were excluded if they did not report demographic data and sites of metastasis, or excluded patients with a specific site of metastatic disease (except brain). For each type of metastasis, weighted least squares linear regression models were used to evaluate temporal trends. RESULTS: A total of 290 eligible studies (270 phase 2 studies and 20 phase 3 studies) involving 19,110 patients were identified. Between 1990 and 2012, the rate of nonosseous metastasis increased significantly at 1.6% per year (P < .0001), whereas the rate of osseous metastasis decreased at 0.5% per year (P < .0001). The rate of lymph node metastasis increased at 1.4% per year (P < .0001), but the rate of liver and lung metastasis remained relatively stable. CONCLUSIONS: A notable change was found in the pattern of metastasis in patients with mCRPC. Because these evolving patterns may have important implications in treatment selection and prognosis, it is crucial that future clinical trials of patients with mCRPC define patients with a uniform reporting of nonosseous metastasis.

Success with single-agent immunosuppression for multifocal choroidopathies.

PURPOSE: To evaluate the success of single-agent immunosuppression for patients with the posterior uveitides, birdshot chorioretinitis, multifocal choroiditis with panuveitis, and punctate inner choroiditis. DESIGN: Retrospective case series. METHODS: setting: Tertiary care uveitis practices. population: Patients initiated on immunomodulatory therapy. intervention: Patients were treated with prednisone 1 mg/kg and mycophenolate 2 g daily. Prednisone was tapered after 1 month. Immunosuppression was escalated to mycophenolate 3 g daily, with addition of a second agent, as needed, to achieve treatment success. outcome measure: Treatment success, defined as no disease activity with prednisone dose ≤10 mg daily, at 6, 12, and 24 months. RESULTS: Twenty-seven patients were followed. Mean presentation and 2-year follow-up acuities were 20/41 and 20/42, respectively. For birdshot chorioretinitis, mean (±standard deviation) quantitative Goldmann visual field scores improved from 761 ± 69 degrees (IV/4 isopter) and 496 ± 115 degrees (I/4 isopter) at presentation to 784 ± 57 degrees and 564 ± 125 degrees, respectively. Prednisone was successfully tapered in 95% of patients; mean prednisone doses at 1 and 2 years were 5.3 ± 4.1 and 5.7 ± 4.8 mg/day, respectively. At 2 years, prednisone was discontinued in 11% of patients. Treatment success was achieved in 74% of patients on 1 immunosuppressant, and in an additional 21% of patients on 2 agents, for an overall 95% success rate at 2 years. CONCLUSIONS: Posterior uveitides can be treated with 1 agent in most patients, but the data suggest a need to escalate therapy to higher mycophenolate doses, and in one fifth of cases to add a second agent to maintain disease suppression with acceptably low prednisone doses.

The S curve: a novel morphological finding in the internal carotid artery in patients with fibromuscular dysplasia.

Fibromuscular dysplasia (FMD) is a non-atherosclerotic vascular disease commonly affecting the renal and internal carotid arteries (ICAs). A previously unrecognized finding is a redundancy of the mid-distal ICA in FMD patients causing an 'S'-shaped curve. Carotid artery duplex ultrasounds were reviewed in 116 FMD patients to determine S-curve prevalence. FMD patients with an S curve were matched to four control patients divided equally into two groups: (1) age and sex-matched and (2) age ≥70 and sex-matched. S curves were present in 37 (32%) FMD patients. Of these, nine (24%) had angiographic evidence of FMD in their ICA only, 13 (35%) had renal artery FMD only, and 15 (41%) had both ICA and renal FMD. Two patients in the age and sex-matched group had S curves (odds ratio 16.86, 95% CI 3.92-72.48; p<0.0001) while 12 (16.2%) patients in the age ≥70 and sex-matched group had S curves (odds ratio 2.42, 95% CI 1.16-5.03; p=0.016). In conclusion, the S curve is a novel morphological pattern of the mid-distal ICA. While the S curve may not be specific, its presence in individuals <70 years old should alert the clinician to the possibility that FMD is present.

The Israel Diabetes and Cognitive Decline (IDCD) study: Design and baseline characteristics.

BACKGROUND: Type 2 diabetes (T2D) is associated with increased risk of dementia. The prospective longitudinal Israel Diabetes and Cognitive Decline study aims at identifying T2D-related characteristics associated with cognitive decline. METHODS: Subjects are population-based T2D 65+, initially cognitively intact. Medical conditions, blood examinations, and medication use data are since 1998; cognitive, functional, demographic, psychiatric, DNA, and inflammatory marker study assessments were conducted every 18 months. Because the duration of T2D reflects its chronicity and implications, we compared short (0-4.99 years), moderate (5-9.99), and long (10+) duration for the first 897 subjects. RESULTS: The long duration group used more T2D medications, had higher glucose, lower glomerular filtration rate, slower walking speed, and poorer cognitive functioning. Duration was not associated with most medical, blood, urine, and vital characteristics. CONCLUSIONS: Tracking cognition, with face-to-face evaluations, exploiting 15 years of historical detailed computerized, easily accessible, and validated T2D-related characteristics may provide novel insights into T2D-related dementia.

Dietary advanced glycation end products are associated with decline in memory in young elderly.

We recently reported that serum methylglyoxal (sMG) is associated with a faster rate of decline in a global measure of cognition in the very elderly. We here provide for the first time evidence in which high levels of dietary AGE (dAGE) are associated with faster rate of decline in memory in 49 initially non-demented young elderly (p=0.012 in mixed regression models adjusting for sociodemographic and cardiovascular factors). Since modifying the levels of AGEs in the diet may be relatively easy, these preliminary results suggest a simple strategy to diminish cognitive compromise in the elderly and warrant further investigation.

Phase Ib/II trial of gemcitabine, cisplatin, and lenalidomide as first-line therapy in patients with metastatic urothelial carcinoma.

BACKGROUND: Outcomes with current chemotherapy in metastatic urothelial carcinoma (MUC) remain poor. Lenalidomide, an antiangiogenic and immunomodulatory agent, enhances the effects of chemotherapy in preclinical studies. In this phase Ib/II study, we sought to determine a tolerable dose of lenalidomide in combination with gemcitabine and cisplatin (GCL) in patients with MUC and to explore the safety and activity of this regimen. METHODS: Patients with chemotherapy-naïve MUC received gemcitabine 1,000 mg/m(2) on days 1 and 8 and cisplatin 70 mg/m(2) on day 1 every 21 days. In phase Ib, there were four planned escalating dose levels of lenalidomide (10, 15, 20, and 25 mg) daily on days 1-14. RESULTS: Seven patients received GCL in phase Ib. The dose of lenalidomide was not escalated beyond 10 mg because of cytopenias requiring repeated dose delays and reductions. Two additional patients were enrolled in phase II, but the study was ultimately terminated due to poor tolerability and slow accrual. The most frequent grade ≥ 3 adverse events were cytopenias and diarrhea. Three of the nine patients experienced an objective response (one complete response, two partial responses). CONCLUSION: Chronic administration of the GCL regimen was poorly tolerated because of additive and cumulative myelosuppression.

Phase Ib study of dovitinib in combination with gemcitabine plus cisplatin or gemcitabine plus carboplatin in patients with advanced solid tumors.

PURPOSE: Dovitinib is a small molecule kinase inhibitor with activity against the fibroblast growth factor and vascular endothelial growth factor receptor families. The purpose of this phase Ib study was to define the recommended phase 2 dose of the combinations of gemcitabine and cisplatin or gemcitabine and carboplatin plus dovitinib. METHODS: Patients with advanced solid tumors were enrolled in two parallel dose escalation arms (cisplatin- or carboplatin-based regimens). Treatment was administered with gemcitabine (1,000 mg/m(2) on days 1 and 8), cisplatin (70 mg/m(2)), or carboplatin (AUC 5) on day 1, and dovitinib (orally on days 1-5, 8-12, and 15-19), every 21 days. The starting dose of dovitinib was 300 mg and was dose escalated in successive cohorts using 3 + 3 dose escalation rules. RESULTS: Fourteen patients with advanced solid tumors were enrolled, five to the cisplatin arm and nine to the carboplatin arm. Patients enrolled in the cisplatin arm received a median of two cycles of treatment (range 1-5), and patients enrolled in the carboplatin arm received a median of one cycle of treatment (range 1-4). There were no protocol-defined dose-limiting toxicities in the cisplatin arm. However, the cohort was closed due to the need for frequent dose delays and/or reductions and two patients experiencing severe thromboembolic events. There were two dose-limiting toxicities in the carboplatin arm at the starting dose level of dovitinib (both prolonged neutropenia), and the dose of dovitinib was de-escalated to 200 mg. Two additional dose-limiting toxicities (prolonged neutropenia and febrile neutropenia) occurred in the lower dose cohort, and the study was closed. No patients achieved an objective response to treatment. CONCLUSIONS: Dovitinib in combination with gemcitabine plus cisplatin or gemcitabine plus carboplatin was poorly tolerated due to myelosuppression.

Trajectories in glycemic control over time are associated with cognitive performance in elderly subjects with type 2 diabetes.

OBJECTIVE: To study the relationships of long-term trajectories of glycemic control with cognitive performance in cognitively normal elderly with type 2 diabetes (T2D). METHODS: Subjects (n = 835) pertain to a diabetes registry (DR) established in 1998 with an average of 18 HbA1c measurements per subject, permitting identification of distinctive trajectory groups of HbA1c and examining their association with cognitive function in five domains: episodic memory, semantic categorization, attention/working memory, executive function, and overall cognition. Analyses of covariance compared cognitive function among the trajectory groups adjusting for sociodemographic, cardiovascular, diabetes-related covariates and depression. RESULTS: Subjects averaged 72.8 years of age. Six trajectories of HbA1c were identified, characterized by HbA1c level at entry into the DR (Higher/Lower), and trend over time (Stable/Decreasing/Increasing). Both groups with a trajectory of decreasing HbA1c levels had high HbA1c levels at entry into the DR (9.2%, 10.7%), and high, though decreasing, HbA1c levels over time. They had the worst cognitive performance, particularly in overall cognition (p<0.02) and semantic categorization (p<0.01), followed by that of subjects whose HbA1c at entry into the DR was relatively high (7.2%, 7.8%) and increased over time. Subjects with stable HbA1c over time had the lowest HbA1c levels at entry (6.0%, 6.8%) and performed best in cognitive tests. CONCLUSION: Glycemic control trajectories, which better reflect chronicity of T2D than a single HbA1c measurement, predict cognitive performance. A trajectory of stable HbA1c levels over time is associated with better cognitive function.

The effects of PM2.5 and its components from indoor and outdoor sources on cough and wheeze symptoms in asthmatic children.

Particulate matter with aerodynamic diameter <2.5 µm (PM2.5) is associated with asthma exacerbation. In the Children's Air Pollution Asthma Study, we investigated the longitudinal association of PM2.5 and its components from indoor and outdoor sources with cough and wheeze symptoms in 36 asthmatic children. The sulfur tracer method was used to estimate infiltration factors. Mixed proportional odds models for an ordinal response were used to relate daily cough and wheeze scores to PM2.5 exposures. The odds ratio associated with being above a given symptom score for a SD increase in PM2.5 from indoor sources (PMIS) was 1.24 (95% confidence interval: 0.92-1.68) for cough and 1.63 (1.11-2.39) for wheeze. Ozone was associated with wheeze (1.82, 1.19-2.80), and cough was associated with indoor PM2.5 components from outdoor sources (denoted with subscript "OS") bromine (BrOS: 1.32, 1.05-1.67), chlorine (ClOS: 1.27, 1.02-1.59) and pyrolyzed organic carbon (OPOS: 1.49, 1.12-1.99). The highest effects were seen in the winter for cough with sulfur (SOS: 2.28, 1.01-5.16) and wheeze with organic carbon fraction 2 (OC2OS: 7.46, 1.19-46.60). Our results indicate that exposure to components originating from outdoor sources of photochemistry, diesel and fuel oil combustion is associated with symptom's exacerbation, especially in the winter. PM2.5 mass of indoor origin was more strongly associated with wheeze than with cough.

Association of glycemic control parameters with clinical outcomes in chronic critical illness.

OBJECTIVE: Chronic critical illness (CCI) is a term used to designate patients requiring prolonged mechanical ventilation and tracheostomy with associated poor outcomes. The present study assessed the impact of glycemic parameters on outcomes in a CCI population. METHODS: A retrospective case series was performed including 148 patients in The Mount Sinai Hospital Respiratory Care Unit (2009-2010). Utilizing a semi-parametric mixture model, trajectories for the daily mean blood glucose (BG), BG range, and hypoglycemia rate over time identified low- (n = 87) and high-risk (n = 61) hyperglycemia groups and low- (n = 90) and high-risk (n = 58) hypoglycemia groups. The cohort was also classified into diabetes (DM, n = 48), stress hyperglycemia (SH, n = 85), and normal glucose (n = 15) groups. RESULTS: Hospital- (28% vs. 13%, P = .0199) and 1-year mortality (66% vs. 46%, P = .0185) rates were significantly greater in the high- versus low-risk hyperglycemia groups, respectively. The hypoglycemia rate (<70 mg/dL) was lower among ventilator-liberated patients compared to those who failed to liberate (0.092 vs. 0.130, P<.0001). In the SH group, both hospital mortality (high-risk hyperglycemia 48% and low-risk hyperglycemia 15%, P = .0013) and 1-year mortality (high-risk 74% and low-risk 50%, P = .0482) remained significantly different, while no significant difference in the diabetes group was observed. There were lower hypoglycemia rates with SH compared to diabetes (<70 mg/dL: 0.086 vs. 0.182, P<.0001; <40 mg/dL: 0.012 vs. 0.022, P = .0118, respectively). CONCLUSION: Tighter glycemic control was associated with improved outcomes in CCI patients with SH but not in CCI patients with diabetes. Confirmation of these findings may lead to stratified glycemic control protocols in CCI patients based on the presence or absence of diabetes.

Epiretinal membranes in uveitic macular edema: effect on vision and response to therapy.

PURPOSE: To evaluate the effects of epiretinal membranes on the response of uveitic macular edema to therapy and on visual acuity outcomes. DESIGN: Retrospective case series. METHODS: One hundred four eyes of 77 patients with uveitic macular edema were identified at a tertiary care center. Epiretinal membranes were diagnosed when identified by 2 investigators' grading of spectral-domain optical coherence tomography and scored for the presence or absence of surface wrinkling. Outcomes included best-corrected visual acuity, central subfield thickness, and rates of macular edema improvement (>20% reduction in central subfield thickness) and resolution (reduction of central subfield thickness to <315 µm) at 3 and 6 months follow-up. RESULTS: Seventy-two eyes of 59 patients had an epiretinal membrane on presentation. Eyes without epiretinal membranes and with epiretinal membranes without surface wrinkling were not significantly different at presentation or at 3 and 6 months follow-up. Conversely, eyes with an epiretinal membrane with retinal surface wrinkling had a greater proportion of eyes with 20/200 or worse visual acuity at presentation, and had worse mean acuities at 3 months (20/94 vs 20/35 for eyes without an epiretinal membrane, P = .002) and at 6 months follow-up (20/110 vs 20/36 for eyes without an epiretinal membrane, P = .02). At 6 months of follow-up the mean central subfield thicknesses were: eyes without an epiretinal membrane, 338 ± 23 µm; and eyes with an epiretinal membrane and surface wrinkling, 405 ± 22 µm (P = .05). CONCLUSIONS: In eyes with epiretinal membranes and retinal surface wrinkling, uveitic macular edema had a poorer visual acuity response to medical therapy and thicker maculae at 6 months.

Visual-spatial working memory performance and temporal gray matter volume predict schizotypal personality disorder group membership.

BACKGROUND: Prior work shows individuals with schizotypal personality disorder (SPD) evince temporal lobe volume abnormalities similar to schizophrenia but sparing of prefrontal cortex, which may mitigate psychosis and the severe neurocognitive impairments observed in schizophrenia. This study examined the extent to which frontal-temporal gray matter volume and neurocognitive performance predict: (1) SPD group membership in a demographically-balanced sample of 51 patients and 37 healthy controls; and (2) symptom severity in SPD. METHODS: Dimensional gray-matter volume (left frontal-temporal regions (Brodmann area (BA) 10, 21, 22)) and neurocognitive performance on key memory tasks (California Verbal Learning Test (CVLT), Dot Test, Paced Auditory Serial Addition Test (PASAT)), all salient to schizophrenia-spectrum disorders were examined in a multi-variable model. RESULTS: Middle temporal gyrus (BA21) volume and spatial-working memory (Dot Test) performance were significant predictors of SPD group membership likelihood, with poorer working-memory performance indicating increased probability of SPD membership. Combining across regional volumes or cognitive measures resulted in fair-to-good discrimination of group membership, but including neurocognitive and non-collinear regional volume measures together resulted in a receiver-operating-characteristic (ROC) curve with improved diagnostic discrimination. Larger BA10 volume in dorsolateral prefrontal cortex (DLPFC) significantly predicted less symptom severity in SPD. CONCLUSIONS: These findings suggest that temporal lobe volume and spatial-working memory performance are promising biological/phenotype markers for likelihood of SPD classification, while greater DLPFC volume may serve as a protective factor.