High-resolution spatial and spatiotemporal modelling of air pollution using fixed site and mobile monitoring in a Canadian city.

The development of high-resolution spatial and spatiotemporal models of air pollutants is essential for exposure science and epidemiological applications. While fixed-site sampling has conventionally provided input data for statistical predictive models, the evolving mobile monitoring method offers improved spatial resolution, ideal for measuring pollutants with high spatial variability such as ultrafine particles (UFP). The Quebec Air Pollution Exposure and Epidemiology (QAPEE) study measured and modelled the spatial and spatiotemporal distributions of understudied pollutants, such as UFPs, black carbon (BC), and brown carbon (BrC), along with fine particulate matter (PM2.5), nitrogen dioxide (NO2), and ozone (O3) in Quebec City, Canada. We conducted a combined fixed-site (NO2 and O3) and mobile monitoring (PM2.5, BC, BrC, and UFPs) campaign over 10-months. Mobile monitoring routes were monitored on a weekly basis between 8am-10am and designed using location/allocation modelling. Seasonal fixed-site sampling campaigns captured continuous 24-h measurements over two-week periods. Generalized Additive Models (GAMs), which combined data on pollution concentrations with spatial, temporal, and spatiotemporal predictor variables were used to model and predict concentration surfaces. Annual models for PM2.5, NO2, O3 as well as seven of the smallest size fractions in the UFP range, had high out of sample predictive accuracy (range r2: 0.54-0.86). Varying spatial patterns were observed across UFP size ranges measured as Particle Number Counts (PNC). The monthly spatiotemporal models for PM2.5 (r2 = 0.49), BC (r2 = 0.27), BrC (r2 = 0.29), and PNC (r2 = 0.49) had moderate or moderate-low out of sample predictive accuracy. We conducted a sensitivity analysis and found that the minimum number of 'n visits' (mobile monitoring sessions) required to model annually representative air pollution concentrations was between 24 and 32 visits dependent on the pollutant. This study provides a single source of exposure models for a comprehensive set of air pollutants in Quebec City, Canada. These exposure models will feed into epidemiological research on the health impacts of ambient UFPs and other pollutants.

Molecular Efficacy of Gnetin C as Dual-Targeted Therapy for Castrate-Resistant Prostate Cancer.

SCOPE: Resistance of castrate-resistant prostate cancer (CRPC) to enzalutamide (Enz) involves the expression of constitutively active androgen receptor splice variant (AR-V7). In addition to altered AR pathways, CRPC is characterized by "non-AR-driven" signaling, which includes an overexpression of metastasis-associated protein 1 (MTA1). Combining natural compounds with anticancer drugs may enhance drug effectiveness while reducing adverse effects. In this study, the in vitro and in vivo anticancer effects of Gnetin C (GnC) alone and in combination with Enz against CRPC are examined. METHODS AND RESULTS: The effects of GnC alone and in combination with Enz are assessed by cell viability, clonogenic survival, cell migration, and AR and MTA1 expression using 22Rv1 cells. The tumor growth in vivo is assessed by bioluminescent imaging, western blots, RT-PCR, and IHC. GnC alone and in combined treatment inhibit cell viability, clonogenic survival and migration, and AR and MTA1 expression in 22Rv1 cells. The underlying AR- and MTA1-targeted anticancer mechanisms of treatments in vivo involve inhibition of proliferation and angiogenesis, and induction of apoptosis. CONCLUSION: The findings demonstrate that GnC alone and GnC combined with Enz effectively inhibits AR- and MTA1-promoted tumor-progression in advanced CRPC, which indicates its potential as a novel therapeutic approach for CRPC.

Evaluating the effectiveness of low-sulphur marine fuel regulations at improving urban ambient PM2.5 air quality: Source apportionment of PM2.5 at Canadian Atlantic and Pacific coast cities with implementation of the North American Emissions Control Area.

Ambient fine size fraction particulate matter (PM2.5) sources were resolved by positive matrix factorization at two Canadian cities on the Atlantic and Pacific coast over the 2010-2016 period, corresponding to implementation of the North American Emissions Control Area (NA ECA) low-sulphur marine fuel regulations. Source types contributing to local PM2.5 concentrations were: ECA regulation-related (residual oil, anthropogenic sulphate), urban transportation and residential (gasoline, diesel, secondary nitrate, biomass burning, road dust/soil), industry (refinery, Pb-enriched), and largely natural (biogenic sulphate, sea salt). Anthropogenic sources accounted for approximately 80 % of PM2.5 mass over 2010-2016. Anthropogenic and biogenic sources of PM2.5-sulphate were separated and apportioned. Anthropogenic PM2.5-sulphate was approximately 2-3 times higher than biogenic PM2.5-sulphate prior to implementation of the NA ECA low-S marine fuel regulations, decreasing to 1-2 times higher after regulation implementation. Non-marine anthropogenic sources (gasoline, road dust, local industry factors) were shown to together contribute 38 % - 45 % of urban PM2.5. At both coastal cities, the residual oil and anthropogenic sulphate factors clearly reflected the effects of the low-S fuel regulations at reducing primary and secondary sulphur-related PM2.5 emissions. Comparing a pre-regulation and post-regulation period, residual oil combustion PM2.5 decreased by 0.24-0.25 µg/m3 (94%-95 % decrease) in both cities and anthropogenic sulphate PM2.5 decreased by 0.78 µg/m3 in Halifax (47 % decrease) and 0.71 µg/m3 in Burnaby (58 % decrease). Regulation-related PM2.5 across these factors decreased by approximately 1 µg/m3 after regulation implementation, providing a quantified lower estimate of the beneficial influence of the regulations on urban ambient PM2.5 concentrations. Further reductions in coastal city ambient PM2.5 may best consider air quality strategies that include multiple sources, including marine shipping and non-marine anthropogenic source types given this analysis found that marine vessel emissions remain an important source of urban ambient PM2.5.

Expression of two major isoforms of MYO7A in the retina: Considerations for gene therapy of Usher syndrome type 1B.

Usher syndrome type 1B (USH1B) is a deaf-blindness disorder, caused by mutations in the MYO7A gene, which encodes the heavy chain of an unconventional actin-based motor protein. Here, we examined the two retinal isoforms of MYO7A, IF1 and IF2. We compared 3D models of the two isoforms and noted that the 38-amino acid region that is present in IF1 but absent from IF2 affects the C lobe of the FERM1 domain and the opening of a cleft in this potentially important protein binding domain. Expression of each of the two isoforms of human MYO7A and pig and mouse Myo7a was detected in the RPE and neural retina. Quantification by qPCR showed that the expression of IF2 was typically âˆ¼ 7-fold greater than that of IF1. We discuss the implications of these findings for any USH1B gene therapy strategy. Given the current incomplete knowledge of the functions of each isoform, both isoforms should be considered for targeting both the RPE and the neural retina in gene augmentation therapies.

Association between panic disorder and childhood adversities: a systematic review and meta-analysis.

BACKGROUND: Adverse childhood experiences (ACEs) increase the risk of mental health difficulties in general, but the link to panic disorder (PD) has received comparatively little attention. There are no data for the magnitudes between ACEs and PD. This systematic review and meta-analysis estimated the overall, as well as the subgroups, odds ratio of having PD in adults who report ACEs, compared to adults who do not. METHODS: The study was pre-registered on PROSPERO [CRD42018111506] and the database was searched in June 2021. In order to overcome the violation of independent assumptions due to multiple estimations from the same samples, we utilized a robust variance estimation model that supports meta-analysis for clustered estimations. Accordingly, an advanced method relaxing the distributional and asymptotic assumptions was used to assess publication bias and sensitivity. RESULTS: The literature search and screening returned 34 final studies, comprising 192,182 participants. Ninety-six estimations of 20 types of ACEs were extracted. Pooled ORs are: overall 2.2, CI (1.82-2.58), sexual abuse 1.92, CI (1.37-2.46), physical abuse 1.71, CI (1.37-2.05), emotional abuse 1.61, CI (0.868-2.35), emotional neglect 1.53, CI (0.756-2.31), parental alcoholism 1.83, CI (1.24-2.43), and parental separation/loss 1.82, CI (1.14-2.50). No between-group difference was identified by either sociolegal classification (abuse, neglect, household dysfunction) or threat-deprivation dimensions (high on threat, high on deprivation and mixed). CONCLUSIONS: There are links of mild to medium strength between overall ACEs and PD as well as individual ACEs. The homogeneous effect sizes across ACEs either suggest the effects of ACEs on PD are comparable, or raised the question whether the categorical or dimensional approaches to classifying ACEs are the definitive ways to conceptualize the impact of ACEs on later mental health.

Acute stress and PTSD among trauma-exposed children and adolescents: Computational prediction and interpretation.

BACKGROUND: Youth receiving medical care for injury are at risk of PTSD. Therefore, accurate prediction of chronic PTSD at an early stage is needed. Machine learning (ML) offers a promising approach to precise prediction and interpretation. AIMS: The study proposes a clinically useful predictive model for PTSD 6-12 months after injury, analyzing the relationship among predictors, and between predictors and outcomes. METHODS: A ML approach was utilized to train models based on 1167 children and adolescents of nine perspective studies. Demographics, trauma characteristics and acute traumatic stress (ASD) symptoms were used as initial predictors. PTSD diagnosis at six months was derived using DSM-IV PTSD diagnostic criteria. Models were validated on external datasets. Shapley value and partial dependency plot (PDP) were applied to interpret the final model. RESULTS: A random forest model with 13 predictors (age, ethnicity, trauma type, intrusive memories, nightmares, reliving, distress, dissociation, cognitive avoidance, sleep, irritability, hypervigilance and startle) yielded F-scores of.973,0.902 and.961 with training and two external datasets. Shapley values were calculated for individual and grouped predictors. A cumulative effect for intrusion symptoms was observed. PDP showed a non-linear relationship between age and PTSD, and between ASD symptom severity and PTSD. A 43 % difference in the risk between non-minority and minority ethnic groups was detected. CONCLUSIONS: A ML model demonstrated excellent classification performance and good potential for clinical utility, using a few easily obtainable variables. Model interpretation gave a comprehensive quantitative analysis on the operations among predictors, in particular ASD symptoms.

Trajectory of post-traumatic stress and depression among children and adolescents following single-incident trauma.

OBJECTIVE: Post-traumatic stress disorder and depression have high comorbidity. Understanding their relationship is of clinical and theoretical importance. A comprehensive way to understand post-trauma psychopathology is through symptom trajectories. This study aims to look at the developmental courses of PTSD and depression symptoms and their interrelationship in the initial months post-trauma in children and adolescents. METHODS: Two-hundred-and-seventeen children and adolescents aged between eight and 17 exposed to single-event trauma were included in the study. Post-traumatic stress symptoms (PTSS) and depression symptoms were measured at 2 weeks, 2 months and 9 months, with further psychological variables measured at the 2-week assessment. Group-based trajectory modelling (GBTM) was applied to estimate the latent developmental clusters of the two outcomes. Logistic regression was used to identify predictors associated with high symptom groups. RESULTS: The GBTM yielded a three-group model for PTSS and a three-group model for depression. PTSS trajectories showed symptoms reduced to a non-clinical level by 9 months for all participants (if they were not already in the non-clinical range): participants were observed to be resilient (42.4%) or recovered within 2 months (35.6%), while 21.9% experienced high level PTSS but recovered by 9 months post-trauma. The depression symptom trajectories predicted a chronic non-recovery group (20.1%) and two mild symptom groups (45.9%, 34.0%). Further analysis showed high synchronicity between PTSS and depression groups. Peri-event panic, negative appraisals, rumination and thought suppression at 2 weeks predicted slow recovery from PTSS. Pre-trauma wellbeing, post-trauma anxiety and negative appraisals predicted chronic depression. CONCLUSIONS: Post-trauma depression was more persistent than PTSS at 9 months in the sampled population. Cognitive appraisal was the shared risk factor to high symptom groups of both PTSS and depression.

Objetivo: El trastorno de estrés postraumático y la depresión tienen una alta comorbilidad. Comprender su relación es de importancia clínica y teórica. Una forma integral de comprender la psicopatología postraumática es a través de las trayectorias de los síntomas. Este estudio tiene como objetivo observar los cursos de desarrollo del TEPT y los síntomas de depresión y su interrelación en los primeros meses posteriores al trauma en niños/ñas y adolescentes.Métodos: Se incluyeron en el estudio 217 niños/ñas y adolescentes de ocho a diecisiete años expuestos a un evento traumático único. Los síntomas de estrés postraumático (SEPT) y los síntomas de depresión se midieron a las 2 semanas, 2 meses y 9 meses, con otras variables psicológicas medidas en la evaluación de 2 semanas. Se aplicó un modelo de trayectoria basado en grupos (MTBG) para estimar los grupos de desarrollo latentes de los dos resultados. Se utilizó la regresión logística para identificar predictores asociados con grupos de síntomas elevados.Resultados: El MTBG arrojó un modelo de tres grupos para SEPT y un modelo de tres grupos para depresión. Las trayectorias de SEPT mostraron síntomas reducidos a un nivel no clínico en 9 meses para todos los participantes (si ellos aún no estaban en el rango no clínico): se observó que los participantes eran resilientes (42,4%) o se recuperaron en 2 meses (35,6%), mientras que el 21,9% experimentó un SEPT de alto nivel pero se recuperó a los 9 meses después del trauma. Las trayectorias de los síntomas de depresión predijeron un grupo crónico de no-recuperación (20,1%) y dos grupos de síntomas leves (45,9%, 34,0%). Un análisis posterior mostró una alta sincronicidad entre los grupos de SEPT y depresión. El pánico peri-evento, las evaluaciones negativas, la rumiación y la supresión del pensamiento a las 2 semanas predijeron una recuperación lenta del SEPT. El bienestar pre-traumático, la ansiedad post-traumática y las valoraciones negativas predijeron la depresión crónica.Conclusiones: La depresión post-traumática fue más persistente que el SEPT a los 9 meses en la población muestreada. La evaluación cognitiva fue el factor de riesgo compartido para los grupos de síntomas altos tanto de SEPT como de depresión.

Predicting intraurban airborne PM1.0-trace elements in a port city: Land use regression by ordinary least squares and a machine learning algorithm.

Airborne particulate matter (PM) has been associated with cardiovascular and respiratory morbidity and mortality, and there is some evidence that spatially varying metals found in PM may contribute to adverse health effects. We developed spatially refined models for PM trace elements using ordinary least squares land use regression (OLS-LUR) and machine leaning random forest land-use regression (RF-LUR). Two-week integrated measurements of PM1.0 (median aerodiameter < 1.0 µm) were collected at 50 sampling sites during fall (2010), winter (2011), and summer (2011) in the Halifax Regional Municipality, Nova Scotia, Canada. PM1.0 filters were analyzed for metals and trace elements using inductively coupled plasma-mass spectrometry. OLS- and RF-LUR models were developed for approximately 30 PM1.0 trace elements in each season. Model predictors included industrial, commercial, and institutional/ government/ military land use, roadways, shipping, other transportation sources, and wind rose information. RF generated more accurate models than OLS for most trace elements based on 5-fold cross validation. On average, summer models had the highest cross validation R2 (OLS-LUR = 0.40, RF-LUR = 0.46), while fall had the lowest (OLS-LUR = 0.27, RF-LUR = 0.31). Many OLS-LUR models displayed overprediction in the final exposure surface. In contrast, RF-LUR models did not exhibit overpredictions. Taking overpredictions and cross validation performances into account, OLS-LUR performed better than RF-LUR in roughly 20% of the seasonal trace element models. RF-LUR models provided more interpretable predictors in most cases. Seasonal predictors varied, likely due to differences in seasonal distribution of trace elements related to source activity, and meteorology.

Proteomic analysis reveals the direct recruitment of intrinsically disordered regions to stress granules in S. cerevisiae.

Stress granules (SGs) are stress-induced membraneless condensates that store non-translating mRNA and stalled translation initiation complexes. Although metazoan SGs are dynamic compartments where proteins can rapidly exchange with their surroundings, yeast SGs seem largely static. To gain a better understanding of yeast SGs, we identified proteins that sediment after heat shock using mass spectrometry. Proteins that sediment upon heat shock are biased toward a subset of abundant proteins that are significantly enriched in intrinsically disordered regions (IDRs). Heat-induced SG localization of over 80 proteins were confirmed using microscopy, including 32 proteins not previously known to localize to SGs. We found that several IDRs were sufficient to mediate SG recruitment. Moreover, the dynamic exchange of IDRs can be observed using fluorescence recovery after photobleaching, whereas other components remain immobile. Lastly, we showed that the IDR of the Ubp3 deubiquitinase was critical for yeast SG formation. This work shows that IDRs can be sufficient for SG incorporation, can remain dynamic in vitrified SGs, and can play an important role in cellular compartmentalization upon stress.This article has an associated First Person interview with the first author of the paper.

Disparities in Receipt of Bariatric Surgery in Canada: An Analysis of Data From an Ontario Bariatric Surgery Referral Center.

BACKGROUND: Patients with lower socioeconomic status (SES) in the United States have reduced access to many health services including bariatric surgery. It is unclear whether disparities in bariatric surgery exist in countries with government-sponsored universal health benefits. The authors used data from a large regional Canadian bariatric surgery referral center to examine the relationship between SES and receipt of bariatric surgery. METHODS: The Toronto Western Hospital bariatric surgery registry was used to identify all adults referred for bariatric surgery assessment from 2010 to 2017. The authors compared demographics, SES measures, and clinical measures among patients who did not and did undergo bariatric surgery (Roux-en-Y or sleeve gastrectomy). Multiple logistic regression was used to examine differences in receipt of bariatric surgery according to patient demographic characteristics and SES factors. RESULTS: Among 2417 patients included in the study, 646 (26.7%) did not receive surgery and 1771 patients (73.2%) did. Patients who did not undergo surgery were more likely to be male individual (29.1% vs. 19.3%; P<0.001), black (12.1% vs. 8.3%; P=0.005), South Asian/Middle Eastern (8.2% vs. 4.5%; P<0.001), and less likely to be white (68.9% vs. 76.7%; P<0.001). In multiple logistic regression, factors associated with not receiving surgery were male sex, Black and South Asian/Middle Eastern ethnicity, being single, lack of employment, and history of psychiatric illness. CONCLUSIONS: Among patients referred for bariatric surgery, those who were male individuals, nonwhite, single, and unemployed were less likely to undergo surgery. Our results suggest that even with equal insurance, there are disparities in receipt of bariatric surgery.

Opposite Molecular Signatures of Depression in Men and Women.

BACKGROUND: Major depressive disorder (MDD) affects women approximately twice as often as men. Women are three times as likely to have atypical depression, with hypersomnia and weight gain. This suggests that the molecular mechanisms of MDD may differ by sex. METHODS: To test this hypothesis, we performed a large-scale gene expression meta-analysis across three corticolimbic brain regions: the dorsolateral prefrontal cortex, subgenual anterior cingulate cortex, and basolateral amygdala (26 men, 24 women with MDD and sex-matched control subjects). Results were further analyzed using a threshold-free approach, Gene Ontology, and cell type-specific analyses. A separate dataset was used for independent validation (13 MDD subjects/sex and 22 control subjects [13 men, 9 women]). RESULTS: Of the 706 genes differentially expressed in men with MDD and 882 genes differentially expressed in women with MDD, only 21 were changed in the same direction in both sexes. Notably, 52 genes displayed expression changes in opposite directions between men and women with MDD. Similar results were obtained using a threshold-free approach, in which the overall transcriptional profile of MDD was opposite in men and women. Gene Ontology indicated that men with MDD had decreases in synapse-related genes, whereas women with MDD exhibited transcriptional increases in this pathway. Cell type-specific analysis indicated that men with MDD exhibited increases in oligodendrocyte- and microglia-related genes, while women with MDD had decreases in markers of these cell types. CONCLUSIONS: The brain transcriptional profile of MDD differs greatly by sex, with multiple transcriptional changes in opposite directions between men and women with MDD.

Can Patient Selection Explain the Obesity Paradox in Orthopaedic Hip Surgery? An Analysis of the ACS-NSQIP Registry.

BACKGROUND: The "obesity paradox" is a phenomenon described in prior research in which patients who are obese have been shown to have lower postoperative mortality and morbidity compared with normal-weight individuals. The paradox is that clinical experience suggests that obesity is a risk factor for difficult wound healing and adverse cardiovascular outcomes. We suspect that the obesity paradox may reflect selection bias in which only the healthiest patients who are obese are offered surgery, whereas nonobese surgical patients are comprised of both healthy and unhealthy individuals. We questioned whether the obesity paradox (decreased mortality for patients who are obese) would be present in nonurgent hip surgery in which patients can be carefully selected for surgery but absent in urgent hip surgery where patient selection is minimized. QUESTIONS/PURPOSES: (1) What is the association between obesity and postoperative mortality in urgent and nonurgent hip surgery? (2) How is obesity associated with individual postoperative complications in urgent and nonurgent hip surgery? (3) How is underweight status associated with postoperative mortality and complications in urgent and nonurgent hip surgery? METHODS: We used 2011 to 2014 data from the American College of Surgeons National Surgical Quality Improvement Project (ACS-NSQIP) to identify all adults who underwent nonurgent hip surgery (n = 63,148) and urgent hip surgery (n = 29,047). We used logistic regression models, controlling for covariants including age, sex, anesthesia risk, and comorbidities, to examine the relationship between body mass _index (BMI) category (classified as underweight < 18.5 kg/m, normal 18.5-24.9 kg/m, overweight 25-29.9 kg/m, obese 30-39.9 kg/m, and morbidly obese > 40 kg/m) and adverse outcomes including 30-day mortality and surgical complications including wound complications and cardiovascular events. RESULTS: For patients undergoing nonurgent hip surgery, regression models demonstrate that patients who are morbidly obese were less likely to die within 30 days after surgery (odds ratio [OR], 0.12; 95% confidence interval [CI], 0.01-0.57; p = 0.038) compared with patients with normal BMI, consistent with the obesity paradox. For patients undergoing urgent hip surgery, patients who are morbidly obese had similar odds of death within 30 days compared with patients with normal BMI (OR, 1.18; 95% CI, 0.76-1.76; p = 0.54). Patients who are morbidly obese had higher odds of wound complications in both nonurgent (OR, 4.93; 95% CI, 3.68-6.65; p < 0.001) and urgent cohorts (OR, 4.85; 95% CI, 3.27-7.01; p < 0.001) compared with normal-weight patients. Underweight patients were more likely to die within 30 days in both nonurgent (OR, 3.79; 95% CI, 1.10-9.97; p = 0.015) and urgent cohorts (OR, 1.47; 95% CI, 1.23-1.75; p < 0.001) compared with normal-weight patients. CONCLUSIONS: Patients who are morbidly obese appear to have a reduced risk of death in 30 days after nonurgent hip surgery, but not for urgent hip surgery. Our results suggest that the obesity paradox may be an artifact of selection bias introduced by careful selection of the healthiest patients who are obese for elective hip surgery. Surgeons should continue to consider obesity a risk factor for postoperative mortality and complications such as wound infections for both urgent and nonurgent surgery. LEVEL OF EVIDENCE: Level III, therapeutic study.

High Glucose Induces Mitochondrial Dysfunction in Retinal Müller Cells: Implications for Diabetic Retinopathy.

Purpose: To investigate whether high glucose (HG) induces mitochondrial dysfunction and promotes apoptosis in retinal Müller cells. Methods: Rat retinal Müller cells (rMC-1) grown in normal (N) or HG (30 mM glucose) medium for 7 days were subjected to MitoTracker Red staining to identify the mitochondrial network. Digital images of mitochondria were captured in live cells under confocal microscopy and analyzed for mitochondrial morphology changes based on form factor (FF) and aspect ratio (AR) values. Mitochondrial metabolic function was assessed by measuring oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) using a bioenergetic analyzer. Cells undergoing apoptosis were identified by differential dye staining and TUNEL assay, and cytochrome c levels were assessed by Western blot analysis. Results: Cells grown in HG exhibited significantly increased mitochondrial fragmentation compared to those grown in N medium (FF = 1.7 ± 0.1 vs. 2.3 ± 0.1; AR = 2.1 ± 0.1 vs. 2.5 ± 0.2; P < 0.01). OCR and ECAR were significantly reduced in cells grown in HG medium compared to those grown in N medium (steady state: 75% ± 20% of control, P < 0.02; 64% ± 22% of control, P < 0.02, respectively). These cells also exhibited a significant increase (∼2-fold) in the number of apoptotic cells compared to those grown in N medium (P < 0.01), with a concomitant increase in cytochrome c levels (247% ± 94% of control, P < 0.05). Conclusions: Findings indicate that HG-induced mitochondrial morphology changes and subsequent mitochondrial dysfunction may contribute to retinal Müller cell loss associated with diabetic retinopathy.

Complications of the Arteriovenous Fistula: A Systematic Review.

The implementation of patient-centered care requires an individualized approach to hemodialysis vascular access, on the basis of each patient's unique balance of risks and benefits. This systematic review aimed to summarize current literature on fistula risks, including rates of complications, to assist with patient-centered decision making. We searched Medline from 2000 to 2014 for English-language studies with prospectively captured data on ≥100 fistulas. We assessed study quality and extracted data on study design, patient characteristics, and outcomes. After screening 2292 citations, 43 articles met our inclusion criteria (61 unique cohorts; n>11,374 fistulas). Median complication rates per 1000 patient days were as follows: 0.04 aneurysms (14 unique cohorts; n=1827 fistulas), 0.11 infections (16 cohorts; n>6439 fistulas), 0.05 steal events (15 cohorts; n>2543 fistulas), 0.24 thrombotic events (26 cohorts; n=4232 fistulas), and 0.03 venous hypertensive events (1 cohort; n=350 fistulas). Risk of bias was high in many studies and event rates were variable, thus we could not present pooled results. Studies generally did not report variables associated with fistula complications, patient comorbidities, vessel characteristics, surgeon experience, or nursing cannulation skill. Overall, we found marked variability in complication rates, partly due to poor quality studies, significant heterogeneity of study populations, and inconsistent definitions. There is an urgent need to standardize reporting of methods and definitions of vascular access complications in future clinical studies to better inform patient and provider decision making.

Association of reduced Connexin 43 expression with retinal vascular lesions in human diabetic retinopathy.

Connexin 43 (Cx43) downregulation promotes apoptosis in retinal vascular cells of diabetic animal models; however, its relevance to human diabetic retinopathy has not been established. In this study, we investigated whether diabetes alters Cx43 expression and promotes retinal vascular lesions in human retinas. Diabetic human eyes (aged 64-94 years) and non-diabetic human eyes (aged 61-90 years) were analyzed in this study. Retinal protein samples and retinal capillary networks were assessed for Cx43 level by Western blot (WB) analysis and immunostaining. In parallel, retinal capillary networks were stained with hematoxylin and periodic acid Schiff to determine the extent of pericyte loss (PL) and acellular capillaries (AC) in these retinas. Cx43 protein expression was significantly reduced in the diabetic retinas compared to non-diabetic retinas as indicated by WB analysis (81 ± 11% of control). Additionally, a significant decrease in the number of Cx43 plaques per unit length of vessel was observed in the diabetic retinas compared to those of non-diabetic retinas (62 ± 10% of control; p < 0.005). Importantly, a strong inverse relationship was noted between Cx43 expression and the relative number of AC (r = -0.89; p < 0.0005), and between Cx43 expression and number of pericyte loss (r = -0.88; p < 0.0005). Overall, these results show that Cx43 expression is reduced in the human diabetic retinas and Cx43 reduction is associated with increased vascular cell death. These findings suggest that diabetes decreases retinal Cx43 expression and that the development of PL and AC is associated with reduced Cx43 expression in human diabetic retinopathy.