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BackgroundCanada's approach to refugee resettlement includes government sponsorship, a pioneering private sponsorship model and a third blended approach. Refugees are selected and supported differently in each approach including healthcare navigation. Little is known about how well private sponsors facilitate primary care navigation and whether this changed during the large-scale 2015 Syrian resettlement initiative characterized by civic and healthcare systems engagement.Methods and findingsPopulation-based cohort study of resettled refugees arriving in Ontario between April 1, 2008 and March 31, 2017, with one-year follow-up, using linked health and demographic administrative databases. We evaluated associations of resettlement model (GARs, Privately Sponsored Refugees [PSRs], and Blended-Visa Office Referred [BVORs]) by era of arrival (pre-Syrian and Syrian era) and by country cohort, on measures of primary care (PC) navigation using adjusted Cox proportional hazards and logistic regression. There were 34,591 (pre-Syrian) and 24,757 (Syrian era) resettled refugees, approximately half of whom were GARs. Compared with the reference group pre-Syrian era PSRs, Syrian PSRs had slightly earlier PC visits (mean = 116 days [SD = 90]) (adjusted hazard ratios [aHR] = 1.19, 95% CI 1.14-1.23). Syrian GARs (mean = 72 days [SD = 65]) and BVORs (mean = 73 days [SD = 76]) had their first PC visit sooner than pre-Syrian era PSRs (mean = 149 days [SD = 86]), with respective aHRs 2.27, 95% CI 2.19-2.35 and 1.89, 95% CI 1.79-1.99. Compared to pre-Syrian PSRs, Syrian GARs and BVORs had much greater odds of a CHC visit (adjusted odds ratios 14.69, 95% CI 12.98-16.63 and 14.08, 95% 12.05-16.44 respectively) and Syrian PSRs had twice the odds of a CHC visit.ConclusionsLess timely primary care and lower odds of a CHC visit among PSRs in the first year may be attributed to selection factors and gaps in sponsors' knowledge of healthcare navigation. Improved primary care navigation outcomes in the Syrian era suggests successful health systems engagement.

Background and objective Hyponatremia and the syndrome of inappropriate antidiuretic hormone secretion (SIADH) are associated with and can be caused by tuberculosis (TB) through meningitis by locally invading the hypothalamus, adrenal, or pituitary glands or possibly through ectopic ADH production. This study assessed the association of TB mortality with hyponatremia and SIADH in a large cohort of a university hospital in Austria. Methods This retrospective study enrolled patients with hyponatremia and patients diagnosed with TB from 01/2001-11/2019 to assess the prevalence of TB in hyponatremia and TB morbidity and mortality in patients with and without hyponatremia. Sex, age, microbiological results, laboratory tests and comorbidities were analysed and used to calculate survival rates. Results Of 107.532 patients with hyponatremia (0.07%) and 186 patients with TB (43%), 80 patients were diagnosed with both—hyponatremia and TB. Only three TB patients had SIADH, precluding further SIADH analysis. In hyponatremia, young age and high CRP levels showed significant associations with TB diagnosis (pConclusion In this study of a large cohort from a tertiary care hospital in a non-endemic area of TB, 0.07% of patients presenting with hyponatremia, but especially younger patients and patients with high CRP values, were diagnosed with TB. Crucially, patients with moderate to profound hyponatremia had a significantly higher mortality rate and thus required increased medical care.

Intestinal cells control delivery of lipids to the body by adsorption, storage and secretion. Copper (Cu) is an important trace element and has been shown to modulate lipid metabolism. Mutation of the liver Cu exporter ATP7B is the cause of Wilson disease and is associated with Cu accumulation in different tissues. To determine the relationship of Cu and lipid homeostasis in intestinal cells, a CRISPR/Cas9 knockout of ATP7B (KO) was introduced in Caco-2 cells. KO cells showed increased sensitivity to Cu, elevated intracellular Cu storage, and induction of genes regulating oxidative stress. Chylomicron structural protein ApoB48 was significantly downregulated in KO cells by Cu. Apolipoproteins ApoA1, ApoC3 and ApoE were constitutively induced by loss of ATP7B. Formation of small sized lipid droplets (LDs) was enhanced by Cu, whereas large sized LDs were reduced. Cu reduced triglyceride (TG) storage and secretion. Exposure of KO cells to oleic acid (OA) resulted in enhanced TG storage. The findings suggest that Cu represses intestinal TG lipogenesis, while loss of ATP7B results in OA-induced TG storage.

Positive affect is associated with alleviating mental and physiological stress responses. As laughter is a common physiological operationalization of positive affect, we investigated whether the effects of experiencing a stressful event on stress symptoms is lessened by frequency and intensity of daily laughter. Using an intensive longitudinal design, we ambulatory assessed the self-reported experience of stressful events, stress symptoms and the frequency as well as the intensity of laughter in university students' daily lives. Our hierarchical ecological momentary assessment data were analyzed with multilevel models. The results support the stress-buffering model of positive affect: We found that the frequency of laughter attenuated the association between stressful events and subsequent stress symptoms. The level of intensity of laughter, however, was found to have no significant effect. Future studies should use additional psychophysiological indicators of stress and straighten out the differential contributions of frequency and intensity of daily laughter.

Wilson's disease (WD) is a monogenetic liver disease that is based on a mutation of the ATP7B gene and leads to a functional deterioration in copper (Cu) excretion in the liver. The excess Cu accumulates in various organs such as the liver and brain. WD patients show clinical heterogeneity, which can range from acute or chronic liver failure to neurological symptoms. The course of the disease can be improved by a life-long treatment with zinc or chelators such as D-penicillamine in a majority of patients, but serious side effects have been observed in a significant portion of patients, e.g. neurological deterioration and nephrotoxicity, so that a liver transplant would be inevitable. An alternative therapy option would be the genetic correction of the ATP7B gene. The novel gene therapy method CRISPR/Cas9, which has recently been used in the clinic, may represent a suitable therapeutic opportunity. In this study, we first initiated an artificial ATP7B point mutation in a human cell line using CRISPR/Cas9 gene editing, and corrected this mutation by the additional use of single-stranded oligo DNA nucleotides (ssODNs), simulating a gene correction of a WD point mutation in vitro. By the addition of 0.5 mM of Cu three days after lipofection, a high yield of CRISPR/Cas9-mediated ATP7B repaired cell clones was achieved (60%). Moreover, the repair efficiency was enhanced using ssODNs that incorporated three blocking mutations. The repaired cell clones showed a high resistance to Cu after exposure to increasing Cu concentrations. Our findings indicate that CRISPR/Cas9-mediated correction of ATP7B point mutations is feasible and may have the potential to be transferred to the clinic.

Many insect species rely on the polarization properties of object-reflected light for vital tasks like water or host detection. Unfortunately, typical glass-encapsulated photovoltaic modules, which are expected to cover increasingly large surfaces in the coming years, inadvertently attract various species of water-seeking aquatic insects by the horizontally polarized light they reflect. Such polarized light pollution can be extremely harmful to the entomofauna if polarotactic aquatic insects are trapped by this attractive light signal and perish before reproduction, or if they lay their eggs in unsuitable locations. Textured photovoltaic cover layers are usually engineered to maximize sunlight-harvesting, without taking into consideration their impact on polarized light pollution. The goal of the present study is therefore to experimentally and computationally assess the influence of the cover layer topography on polarized light pollution. By conducting field experiments with polarotactic horseflies (Diptera: Tabanidae) and a mayfly species (Ephemeroptera: Ephemera danica), we demonstrate that bioreplicated cover layers (here obtained by directly copying the surface microtexture of rose petals) were almost unattractive to these species, which is indicative of reduced polarized light pollution. Relative to a planar cover layer, we find that, for the examined aquatic species, the bioreplicated texture can greatly reduce the numbers of landings. This observation is further analyzed and explained by means of imaging polarimetry and ray-tracing simulations. The results pave the way to novel photovoltaic cover layers, the interface of which can be designed to improve sunlight conversion efficiency while minimizing their detrimental influence on the ecology and conservation of polarotactic aquatic insects.

To evaluate unmet clinical need in unselected hypertrophic cardiomyopathy (HCM) patients to determine the risk of a wide range of subsequent cardiovascular disease endpoints and safety endpoints relevant for trial design.Population based cohort (CALIBER, linked primary care, hospital and mortality records in England, period 1997-2010), all people diagnosed with HCM were identified and matched by age, sex and general practice with ten randomly selected people without HCM. Random-effects Poisson models were used to assess the associations between HCM and cardiovascular diseases and bleeding.Among 3,290,455 eligible people a diagnosis of hypertrophic cardiomyopathy was found in 4 per 10,000. Forty-one percent of the 1,160 individuals with hypertrophic cardiomyopathy were women and the median age was 57 years. The median follow-up was 4.0 years. Compared to general population controls, people with HCM had higher risk of ventricular arrhythmia (incidence rate ratio = 23.53, [95% confidence interval 12.67-43.72]), cardiac arrest or sudden cardiac death (6.33 [3.69-10.85]), heart failure (4.31, [3.30-5.62]), and atrial fibrillation (3.80 [3.04-4.75]). HCM was also associated with a higher incidence of myocardial infarction ([MI] 1.90 [1.27-2.84]) and coronary revascularisation (2.32 [1.46-3.69]).The absolute Kaplan-Meier risks at 3 years were 8.8% for the composite endpoint of cardiovascular death or heart failure, 8.4% for the composite of cardiovascular death, stroke or myocardial infarction, and 1.5% for major bleeding.Our study identified major unmet need in HCM and highlighted the importance of implementing improved cardiovascular prevention strategies to increase life-expectancy of the contemporary HCM population. They also show that national electronic health records provide an effective method for identifying outcomes and clinically relevant estimates of composite efficacy and safety endpoints essential for trial design in rare diseases.

Mobility impairment in older persons is associated with brain white matter hyperintensities (WMH), a common finding in magnetic resonance images and one established imaging biomarker of small vessel disease. The contribution of possible microstructural abnormalities within normal-appearing white matter (NAWM) to mobility, however, remains unclear. We used diffusion tensor imaging (DTI) measures, i.e. fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), radial diffusivity (RD), to assess microstructural changes within supratentorial NAWM and WMH sub-compartments, and to investigate their association with changes in mobility performance, i.e. Tinetti assessment and the 2.5-meters walk time test. We analyzed baseline (N = 86, age ≥75 years) and 4-year (N = 41) follow-up data. Results from cross-sectional analysis on baseline data showed significant correlation between WMH volume and NAWM-FA (r = -0.33, p = 0.002), NAWM-AD (r = 0.32, p = 0.003) and NAWM-RD (r = 0.39, p = 0.0002). Our longitudinal analysis showed that after 4-years, FA and AD decreased and RD increased within NAWM. In regional tract-based analysis decrease in NAWM-FA and increase in NAWM-RD within the genu of the corpus callosum correlated with slower walk time independent of age, gender and WMH burden. In conclusion, global DTI indices of microstructural integrity indicate that significant changes occur in the supratentorial NAWM over four years. The observed changes likely reflect white matter deterioration resulting from aging as well as accrual of cerebrovascular injury associated with small vessel disease. The observed association between mobility scores and regional measures of NAWM microstructural integrity within the corpus callosum suggests that subtle changes within this structure may contribute to mobility impairment.

In August 2011, Ontario, Canada introduced a rotavirus immunization program using Rotarix™ vaccine. No assessments of rotavirus vaccine coverage have been previously conducted in Ontario.We assessed vaccine coverage (series initiation and completion) and factors associated with uptake using the Electronic Medical Record Administrative data Linked Database (EMRALD), a collection of family physician electronic medical records (EMR) linked to health administrative data. Series initiation (1 dose) and series completion (2 doses) before and after the program's introduction were calculated. To identify factors associated with series initiation and completion, adjusted odds ratios (aOR) and 95% confidence intervals (95%CI) were calculated using logistic regression.A total of 12,525 children were included. Series completion increased each year of the program (73%, 79% and 84%, respectively). Factors associated with series initiation included high continuity of care (aOR = 2.15; 95%CI, 1.61-2.87), maternal influenza vaccination (aOR = 1.55; 95%CI,1.24-1.93), maternal immmigration to Canada in the last five years (aOR = 1.47; 95% CI, 1.05-2.04), and having no siblings (aOR = 1.62; 95%CI,1.30-2.03). Relative to the first program year, infants were more likely to initiate the series in the second year (aOR = 1.71; 95% CI 1.39-2.10) and third year (aOR = 2.02; 95% CI 1.56-2.61) of the program. Infants receiving care from physicians with large practices were less likely to initiate the series (aOR 0.91; 95%CI, 0.88-0.94, per 100 patients rostered) and less likely to complete the series (aOR 0.94; 95%CI, 0.91-0.97, per 100 patients rostered). Additional associations were identified for series completion.Family physician delivery achieved moderately high coverage in the program's first three years. This assessment demonstrates the usefulness of EMR data for evaluating vaccine coverage. Important insights into factors associated with initiation or completion (i.e. high continuity of care, smaller roster sizes, rural practice location) suggest areas for research and potential program supports.

OBJECTIVE:To explore the value of machine learning methods for predicting multiple sclerosis disease course. METHODS:1693 CLIMB study patients were classified as increased EDSS≥1.5 (worsening) or not (non-worsening) at up to five years after baseline visit. Support vector machines (SVM) were used to build the classifier, and compared to logistic regression (LR) using demographic, clinical and MRI data obtained at years one and two to predict EDSS at five years follow-up. RESULTS:Baseline data alone provided little predictive value. Clinical observation for one year improved overall SVM sensitivity to 62% and specificity to 65% in predicting worsening cases. The addition of one year MRI data improved sensitivity to 71% and specificity to 68%. Use of non-uniform misclassification costs in the SVM model, weighting towards increased sensitivity, improved predictions (up to 86%). Sensitivity, specificity, and overall accuracy improved minimally with additional follow-up data. Predictions improved within specific groups defined by baseline EDSS. LR performed more poorly than SVM in most cases. Race, family history of MS, and brain parenchymal fraction, ranked highly as predictors of the non-worsening group. Brain T2 lesion volume ranked highly as predictive of the worsening group. INTERPRETATION:SVM incorporating short-term clinical and brain MRI data, class imbalance corrective measures, and classification costs may be a promising means to predict MS disease course, and for selection of patients suitable for more aggressive treatment regimens.

Structural analysis of biological membranes is important for understanding cell and sub-cellular organelle function as well as their interaction with the surrounding environment. Imaging of whole cells in three dimension at high spatial resolution remains a significant challenge, particularly for thick cells. Cryo-transmission soft X-ray microscopy (cryo-TXM) has recently gained popularity to image, in 3D, intact thick cells (∼10μm) with details of sub-cellular architecture and organization in near-native state. This paper reports a new tool to segment and quantify structural changes of biological membranes in 3D from cryo-TXM images by tracking an initial 2D contour along the third axis of the microscope, through a multi-scale ridge detection followed by an active contours-based model, with a subsequent refinement along the other two axes. A quantitative metric that assesses the grayscale profiles perpendicular to the membrane surfaces is introduced and shown to be linearly related to the membrane thickness. Our methodology has been validated on synthetic phantoms using realistic microscope properties and structure dimensions, as well as on real cryo-TXM data. Results demonstrate the validity of our algorithms for cryo-TXM data analysis.

Diffusion tensor imaging (DTI) is a sensitive tool for the assessment of microstructural alterations in brain white matter (WM). We propose a new processing technique to detect, local and global longitudinal changes of diffusivity metrics, in homologous regions along WM fiber-bundles. To this end, a reliable and automatic processing pipeline was developed in three steps: 1) co-registration and diffusion metrics computation, 2) tractography, bundle extraction and processing, and 3) longitudinal fiber-bundle analysis. The last step was based on an original Gaussian mixture model providing a fine analysis of fiber-bundle cross-sections, and allowing a sensitive detection of longitudinal changes along fibers. This method was tested on simulated and clinical data. High levels of F-Measure were obtained on simulated data. Experiments on cortico-spinal tract and inferior fronto-occipital fasciculi of five patients with Multiple Sclerosis (MS) included in a weekly follow-up protocol highlighted the greater sensitivity of this fiber scale approach to detect small longitudinal alterations.

Familial amyloid polyneuropathy (FAP) is caused by mutations of the transthyretin (TTR) gene, predominantly expressed in the liver. Two compounds that knockdown TTR, comprising a small interfering RNA (siRNA; ALN-TTR-02) and an antisense oligonucleotide (ASO; IONIS-TTRRx), are currently being evaluated in clinical trials. Since primary hepatocytes from FAP patients are rarely available for molecular analysis and commercial tissue culture cells or animal models lack the patient-specific genetic background, this study uses primary cells derived from urine of FAP patients. Urine-derived cells were reprogrammed to induced pluripotent stem cells (iPSCs) with high efficiency. Hepatocyte-like cells (HLCs) showing typical hepatic marker expression were obtained from iPSCs of the FAP patients. TTR mRNA expression of FAP HLCs almost reached levels measured in human hepatocytes. To assess TTR knockdown, siTTR1 and TTR-ASO were introduced to HLCs. A significant downregulation (>80%) of TTR mRNA was induced in the HLCs by both oligonucleotides. TTR protein present in the cell culture supernatant of HLCs was similarly downregulated. Gene expression of other hepatic markers was not affected by the therapeutic oligonucleotides. Our data indicate that urine cells (UCs) after reprogramming and hepatic differentiation represent excellent primary human target cells to assess the efficacy and specificity of novel compounds.

There is a high and rising rate of immune-mediated diseases in the Western world. Immigrants from South Asia have been reported to be at higher risk upon arrival to the West. We determined the risk of immune-mediated diseases in South Asian and other immigrants to Ontario, Canada, and their Ontario-born children.Population-based cohorts of patients with asthma, type 1 diabetes (T1DM), type 2 diabetes (T2DM), and inflammatory bowel disease (IBD) were derived from health administrative data. We determined the standardized incidence, and the adjusted risk of these diseases in immigrants from South Asia, immigrants from other regions, compared with non-immigrant residents of Ontario. The risk of these diseases in the Ontario-born children of immigrants were compared to the children of non-immigrants.Compared to non-immigrants, adults from South Asia had higher risk of asthma (IRR 1.56, 95%CI 1.51-1.61) and T2DM (IRR 2.59, 95%CI 2.53-2.65). Adults from South Asia had lower incidence of IBD than non-immigrants (IRR 0.32, 95%CI 0.22-0.49), as did immigrants from other regions (IRR 0.29, 95%CI 0.20-0.42). Compared to non-immigrant children, the incidence of asthma (IRR 0.66, 95%CI 0.62-0.71) and IBD (IRR 0.47, 95%CI 0.33-0.67) was low amongst immigrant children from South Asia. However, the risk in Ontario-born children of South Asian immigrants relative to the children of non-immigrants was higher for asthma (IRR 1.75, 95%CI 1.69-1.81) and less attenuated for IBD (IRR 0.90, 95%CI 0.65-1.22).Early-life environmental exposures may trigger a genetic predisposition to the development of asthma and IBD in South Asian immigrants and their Canada-born children.

OBJECTIVE:Routinely collected health data, collected for administrative and clinical purposes, without specific a priori research questions, are increasingly used for observational, comparative effectiveness, health services research, and clinical trials. The rapid evolution and availability of routinely collected data for research has brought to light specific issues not addressed by existing reporting guidelines. The aim of the present project was to determine the priorities of stakeholders in order to guide the development of the REporting of studies Conducted using Observational Routinely-collected health Data (RECORD) statement. METHODS:Two modified electronic Delphi surveys were sent to stakeholders. The first determined themes deemed important to include in the RECORD statement, and was analyzed using qualitative methods. The second determined quantitative prioritization of the themes based on categorization of manuscript headings. The surveys were followed by a meeting of RECORD working committee, and re-engagement with stakeholders via an online commentary period. RESULTS:The qualitative survey (76 responses of 123 surveys sent) generated 10 overarching themes and 13 themes derived from existing STROBE categories. Highest-rated overall items for inclusion were: Disease/exposure identification algorithms; Characteristics of the population included in databases; and Characteristics of the data. In the quantitative survey (71 responses of 135 sent), the importance assigned to each of the compiled themes varied depending on the manuscript section to which they were assigned. Following the working committee meeting, online ranking by stakeholders provided feedback and resulted in revision of the final checklist. CONCLUSIONS:The RECORD statement incorporated the suggestions provided by a large, diverse group of stakeholders to create a reporting checklist specific to observational research using routinely collected health data. Our findings point to unique aspects of studies conducted with routinely collected health data and the perceived need for better reporting of methodological issues.

To describe barriers to physical activity (PA) in type 2 diabetes patients and their general practitioners (GPs), looking for practitioner's influence on PA practice of their patients.We conducted a cross-sectional study on GPs (n = 48) and their type 2 diabetes patients (n = 369) measuring respectively barriers to prescribe and practice PA using a self-assessment questionnaire: barriers to physical activity in diabetes (BAPAD). Statistical analysis was performed accounting hierarchical data structure. Similar practitioner's patients were considered a cluster sharing common patterns.The higher the patient's BAPAD score, the higher the barriers to PA, the higher the risk to declare practicing no PA (p

In cluster detection of disease, the use of local cluster detection tests (CDTs) is current. These methods aim both at locating likely clusters and testing for their statistical significance. New or improved CDTs are regularly proposed to epidemiologists and must be subjected to performance assessment. Because location accuracy has to be considered, performance assessment goes beyond the raw estimation of type I or II errors. As no consensus exists for performance evaluations, heterogeneous methods are used, and therefore studies are rarely comparable. A global indicator of performance, which assesses both spatial accuracy and usual power, would facilitate the exploration of CDTs behaviour and help between-studies comparisons. The Tanimoto coefficient (TC) is a well-known measure of similarity that can assess location accuracy but only for one detected cluster. In a simulation study, performance is measured for many tests. From the TC, we here propose two statistics, the averaged TC and the cumulated TC, as indicators able to provide a global overview of CDTs performance for both usual power and location accuracy. We evidence the properties of these two indicators and the superiority of the cumulated TC to assess performance. We tested these indicators to conduct a systematic spatial assessment displayed through performance maps.

Grey matter (GM) damage is a clinically relevant feature of multiple sclerosis (MS) that has been previously assessed with diffusion tensor imaging (DTI). Fractional anisotropy (FA) of the basal ganglia and thalamus might be increased in MS patients, and correlates with disability scores. Despite the established role of the striatum and thalamus in motor control, mood and cognition, the impact of DTI changes within these structures on motor and neuropsychological performance has not yet been specifically addressed in MS. We investigated DTI metrics of deep GM nuclei and their potential association with mobility and neuropsychological function. DTI metrics from 3T MRI were assessed in the caudate, putamen, and thalamus of 30 MS patients and 10 controls. Sixteen of the patients underwent neuropsychological testing. FA of the caudate and putamen was higher in MS patients compared to controls. Caudate FA correlated with Expanded Disability Status Scale score, Ambulation Index, and severity of depressive symptomatology. Putamen and thalamus FA correlated with deficits in memory tests. In contrast, cerebral white matter (WM) lesion burden showed no significant correlation with any of the disability, mobility and psychometric parameters. Our findings support evidence of FA changes in the basal ganglia in MS patients, as well as deep GM involvement in disabling features of MS, including mobility and cognitive impairment. Deep GM FA appears to be a more sensitive correlate of disability than WM lesion burden.

BACKGROUND: While low socioeconomic status (SES) has been associated with inferior cancer outcome among adults, its impact in pediatric oncology is unclear. Our objective was therefore to conduct a systematic review to determine the impact of SES upon outcome in children with cancer. METHODS: We searched Ovid Medline, EMBASE and CINAHL from inception to December 2012. Studies for which survival-related outcomes were reported by socioeconomic subgroups were eligible for inclusion. Two reviewers independently assessed articles and extracted data. Given anticipated heterogeneity, no quantitative meta-analyses were planned a priori. RESULTS: Of 7,737 publications, 527 in ten languages met criteria for full review; 36 studies met final inclusion criteria. In low- and middle-income countries (LMIC), lower SES was uniformly associated with inferior survival, regardless of the measure chosen. The majority of associations were statistically significant. Of 52 associations between socioeconomic variables and outcome among high-income country (HIC) children, 38 (73.1%) found low SES to be associated with worse survival, 15 of which were statistically significant. Of the remaining 14 (no association or high SES associated with worse survival), only one was statistically significant. Both HIC studies examining the effect of insurance found uninsured status to be statistically associated with inferior survival. CONCLUSIONS: Socioeconomic gradients in which low SES is associated with inferior childhood cancer survival are ubiquitous in LMIC and common in HIC. Future studies should elucidate mechanisms underlying these gradients, allowing the design of interventions mediating socioeconomic effects. Targeting the effect of low SES will allow for further improvements in childhood cancer survival.

Cerebral palsy (CP) has a multifactorial etiology, and placental vascular disease may be one major risk factor. The risk of placental vascular disease may be lower among some immigrant groups. We studied the association between immigrant status and the risk of CP.We conducted a population-based retrospective cohort study of all singleton and twin livebirths in Ontario between 2002-2008, and who survived ≥28 days after birth. Each child was assessed for CP up to age 4 years, based on either a single inpatient or ≥2 outpatient pediatric diagnoses of CP. Relative to non-immigrants (n = 566,668), the risk of CP was assessed for all immigrants (n = 177,390), and further evaluated by World region of origin. Cox proportional hazard ratios (aHR) were adjusted for maternal age, income, diabetes mellitus, obesity, tobacco use, Caesarean delivery, year of delivery, physician visits, twin pregnancy, preterm delivery, as well as small- and large-for-gestational age birthweight.There were 1346 cases of CP, with a lower rate among immigrants (1.45 per 1000) than non-immigrants (1.92 per 1000) (aHR 0.77, 95% confidence interval [CI] 0.67 to 0.88). Mothers from East Asia and the Pacific (aHR 0.54, 95% CI 0.39 to 0.77) and the Caribbean (aHR 0.58, 95% CI 0.37 to 0.93) were at a significantly lower risk of having a child with CP. Whether further adjusting for preeclampsia, gestational hypertension, placental abruption or placental infraction, or upon using a competing risk analysis that further accounted for stillbirth and neonatal death, these results did not change.Immigration and ethnicity appear to attenuate the risk of CP, and this effect is not fully explained by known risk factors.

Successful socialization requires the ability of understanding of others' mental states. This ability called as mentalization (Theory of Mind) may become deficient and contribute to everyday life difficulties in multiple sclerosis. We aimed to explore the impact of brain pathology on mentalization performance in multiple sclerosis. Mentalization performance of 49 patients with multiple sclerosis was compared to 24 age- and gender matched healthy controls. T1- and T2-weighted three-dimensional brain MRI images were acquired at 3Tesla from patients with multiple sclerosis and 18 gender- and age matched healthy controls. We assessed overall brain cortical thickness in patients with multiple sclerosis and the scanned healthy controls, and measured the total and regional T1 and T2 white matter lesion volumes in patients with multiple sclerosis. Performances in tests of recognition of mental states and emotions from facial expressions and eye gazes correlated with both total T1-lesion load and regional T1-lesion load of association fiber tracts interconnecting cortical regions related to visual and emotion processing (genu and splenium of corpus callosum, right inferior longitudinal fasciculus, right inferior fronto-occipital fasciculus, uncinate fasciculus). Both of these tests showed correlations with specific cortical areas involved in emotion recognition from facial expressions (right and left fusiform face area, frontal eye filed), processing of emotions (right entorhinal cortex) and socially relevant information (left temporal pole). Thus, both disconnection mechanism due to white matter lesions and cortical thinning of specific brain areas may result in cognitive deficit in multiple sclerosis affecting emotion and mental state processing from facial expressions and contributing to everyday and social life difficulties of these patients.

The complex architecture of their structural elements and compartments is a hallmark of eukaryotic cells. The creation of high resolution models of whole cells has been limited by the relatively low resolution of conventional light microscopes and the requirement for ultrathin sections in transmission electron microscopy. We used soft x-ray tomography to study the 3D ultrastructural organization of whole cells of the unicellular green alga Chlamydomonas reinhardtii at unprecedented spatial resolution. Intact frozen hydrated cells were imaged using the natural x-ray absorption contrast of the sample without any staining. We applied different fiducial-based and fiducial-less alignment procedures for the 3D reconstructions. The reconstructed 3D volumes of the cells show features down to 30 nm in size. The whole cell tomograms reveal ultrastructural details such as nuclear envelope membranes, thylakoids, basal apparatus, and flagellar microtubule doublets. In addition, the x-ray tomograms provide quantitative data from the cell architecture. Therefore, nanoscale soft x-ray tomography is a new valuable tool for numerous qualitative and quantitative applications in plant cell biology.

Brain atrophy and cognitive dysfunction are neurodegenerative features of Multiple Sclerosis (MS). We used a candidate gene approach to address whether genetic variants implicated in susceptibility to late onset Alzheimer's Disease (AD) influence brain volume and cognition in MS patients.MS subjects were genotyped for five single nucleotide polymorphisms (snps) associated with susceptibility to AD: PICALM, CR1, CLU, PCK1, and ZNF224. We assessed brain volume using Brain Parenchymal Fraction (BPF) measurements obtained from Magnetic Resonance Imaging (MRI) data and cognitive function using the Symbol Digit Modalities Test (SDMT). Genotypes were correlated with cross-sectional BPF and SDMT scores using linear regression after adjusting for sex, age at symptom onset, and disease duration. 722 MS patients with a mean (±SD) age at enrollment of 41 (±10) years were followed for 44 (±28) months. The AD risk-associated allele of a non-synonymous SNP in the PCK1 locus (rs8192708G) is associated with a smaller average brain volume (P=0.0047) at the baseline MRI, but it does not impact our baseline estimate of cognition. PCK1 is additionally associated with higher baseline T2-hyperintense lesion volume (P=0.0088). Finally, we provide technical validation of our observation in a subset of 641 subjects that have more than one MRI study, demonstrating the same association between PCK1 and smaller average brain volume (P=0.0089) at the last MRI visit.Our study provides suggestive evidence for greater brain atrophy in MS patients bearing the PCK1 allele associated with AD-susceptibility, yielding new insights into potentially shared neurodegenerative process between MS and late onset AD.

Structural analysis of biological membranes is important for understanding cell and sub-cellular organelle function as well as their interaction with the surrounding environment. Imaging of whole cells in three dimension at high spatial resolution remains a significant challenge, particularly for thick cells. Cryo-transmission soft X-ray microscopy (cryo-TXM) has recently gained popularity to image, in 3D, intact thick cells (∼10μm) with details of sub-cellular architecture and organization in near-native state. This paper reports a new tool to segment and quantify structural changes of biological membranes in 3D from cryo-TXM images by tracking an initial 2D contour along the third axis of the microscope, through a multi-scale ridge detection followed by an active contours-based model, with a subsequent refinement along the other two axes. A quantitative metric that assesses the grayscale profiles perpendicular to the membrane surfaces is introduced and shown to be linearly related to the membrane thickness. Our methodology has been validated on synthetic phantoms using realistic microscope properties and structure dimensions, as well as on real cryo-TXM data. Results demonstrate the validity of our algorithms for cryo-TXM data analysis.

The complex architecture of their structural elements and compartments is a hallmark of eukaryotic cells. The creation of high resolution models of whole cells has been limited by the relatively low resolution of conventional light microscopes and the requirement for ultrathin sections in transmission electron microscopy. We used soft x-ray tomography to study the 3D ultrastructural organization of whole cells of the unicellular green alga Chlamydomonas reinhardtii at unprecedented spatial resolution. Intact frozen hydrated cells were imaged using the natural x-ray absorption contrast of the sample without any staining. We applied different fiducial-based and fiducial-less alignment procedures for the 3D reconstructions. The reconstructed 3D volumes of the cells show features down to 30 nm in size. The whole cell tomograms reveal ultrastructural details such as nuclear envelope membranes, thylakoids, basal apparatus, and flagellar microtubule doublets. In addition, the x-ray tomograms provide quantitative data from the cell architecture. Therefore, nanoscale soft x-ray tomography is a new valuable tool for numerous qualitative and quantitative applications in plant cell biology.