Automated detection and classification of nuclei in immunohistochemical stainings for Fuchs' endothelial corneal dystrophy

Fuchs’ endothelial corneal dystrophy (FECD) is a degenerative disease that affects the elderly population, and which lacks a unifying pathogenic theory and tangible drug targets. Immunohistochemical stainings can be used to identify proteins involved in the pathogenesis of FECD. We introduce a method for the automatic quantification of the ratio of stained cells starting from full high-resolution cornea images. First, the endothelium is extracted using entropy information in a low-resolution resampling. Then, within the endothelium, we heuristically detect and classify nuclei based on their size, color, and the color of the surrounding cytoplasm. This method achieves comparable results to manual evaluation in a set of corneas of patients with and without FECD.status: publishe

Assessment of aberrant DNA methylation two years after paediatric critical illness:a pre-planned secondary analysis of the international PEPaNIC trial

Critically ill children requiring intensive care suffer from impaired physical/neurocognitive development 2 y later, partially preventable by omitting early use of parenteral nutrition (early-PN) in the paediatric intensive-care-unit (PICU). Altered methylation of DNA from peripheral blood during PICU-stay provided a molecular basis hereof. Whether DNA-methylation of former PICU patients, assessed 2 y after critical illness, is different from that of healthy children remained unknown. In a pre-planned secondary analysis of the PEPaNIC-RCT (clinicaltrials.gov-NCT01536275) 2-year follow-up, we assessed buccal-mucosal DNA-methylation (Infinium-HumanMethylation-EPIC-BeadChip) of former PICU-patients (N = 406 early-PN; N = 414 late-PN) and matched healthy children (N = 392). CpG-sites differentially methylated between groups were identified with multivariable linear regression and differentially methylated DNA-regions via clustering of differentially methylated CpG-sites using kernel-estimates. Analyses were adjusted for technical variation and baseline risk factors, and corrected for multiple testing (false-discovery-rate <0.05). Differentially methylated genes were functionally annotated (KEGG-pathway database), and allocated to three classes depending on involvement in physical/neurocognitive development, critical illness and intensive medical care, or pre-PICU-admission disorders. As compared with matched healthy children, former PICU-patients showed significantly different DNA-methylation at 4047 CpG-sites (2186 genes) and 494 DNA-regions (468 genes), with most CpG-sites being hypomethylated (90.3%) and with an average absolute 2% effect-size, irrespective of timing of PN initiation. Of the differentially methylated KEGG-pathways, 41.2% were related to physical/neurocognitive development, 32.8% to critical illness and intensive medical care and 26.0% to pre-PICU-admission disorders. Two years after critical illness in children, buccal-mucosal DNA showed abnormal methylation of CpG-sites and DNA-regions located in pathways known to be important for physical/neurocognitive development

Computerized prediction of intensive care unit discharge after cardiac surgery: development and validation of a Gaussian processes model

<p>Abstract</p> <p>Background</p> <p>The intensive care unit (ICU) length of stay (LOS) of patients undergoing cardiac surgery may vary considerably, and is often difficult to predict within the first hours after admission. The early clinical evolution of a cardiac surgery patient might be predictive for his LOS. The purpose of the present study was to develop a predictive model for ICU discharge after non-emergency cardiac surgery, by analyzing the first 4 hours of data in the computerized medical record of these patients with Gaussian processes (GP), a machine learning technique.</p> <p>Methods</p> <p>Non-interventional study. Predictive modeling, separate development (n = 461) and validation (n = 499) cohort. GP models were developed to predict the probability of ICU discharge the day after surgery (classification task), and to predict the day of ICU discharge as a discrete variable (regression task). GP predictions were compared with predictions by EuroSCORE, nurses and physicians. The classification task was evaluated using aROC for discrimination, and Brier Score, Brier Score Scaled, and Hosmer-Lemeshow test for calibration. The regression task was evaluated by comparing median actual and predicted discharge, loss penalty function (LPF) ((actual-predicted)/actual) and calculating root mean squared relative errors (RMSRE).</p> <p>Results</p> <p>Median (P25-P75) ICU length of stay was 3 (2-5) days. For classification, the GP model showed an aROC of 0.758 which was significantly higher than the predictions by nurses, but not better than EuroSCORE and physicians. The GP had the best calibration, with a Brier Score of 0.179 and Hosmer-Lemeshow p-value of 0.382. For regression, GP had the highest proportion of patients with a correctly predicted day of discharge (40%), which was significantly better than the EuroSCORE (p < 0.001) and nurses (p = 0.044) but equivalent to physicians. GP had the lowest RMSRE (0.408) of all predictive models.</p> <p>Conclusions</p> <p>A GP model that uses PDMS data of the first 4 hours after admission in the ICU of scheduled adult cardiac surgery patients was able to predict discharge from the ICU as a classification as well as a regression task. The GP model demonstrated a significantly better discriminative power than the EuroSCORE and the ICU nurses, and at least as good as predictions done by ICU physicians. The GP model was the only well calibrated model.</p

Health-related quality of life of children and their parents 2 years after critical illness

Background: Pediatric intensive care unit (PICU) survivors are at risk for prolonged morbidities interfering with daily life. The current study examined parent-reported health-related quality of life (HRQoL) in former critically ill children and parents themselves and aimed to determine whether withholding parenteral nutrition (PN) in the first week of critical illness affected children’s and parents’ HRQoL 2 years later. Methods: Children who participated in the pediatric early versus late parenteral nutrition in critical illness (PEPaNIC) trial and who were testable 2 years later (n = 1158) were included. Their HRQoL outcomes were compared with 405 matched healthy controls. At PICU admission, childre

The association of hypoglycemia with outcome of critically ill children in relation to nutritional and blood glucose control strategies

Abstract Background Withholding parenteral nutrition (PN) until one week after PICU admission facilitated recovery from critical illness and protected against emotional and behavioral problems 4 years later. However, the intervention increased the risk of hypoglycemia, which may have counteracted part of the benefit. Previously, hypoglycemia occurring under tight glucose control in critically ill children receiving early PN did not associate with long-term harm. We investigated whether hypoglycemia in PICU differentially associates with outcome in the context of withholding early PN, and whether any potential association with outcome may depend on the applied glucose control protocol. Methods In this secondary analysis of the multicenter PEPaNIC RCT, we studied whether hypoglycemia in PICU associated with mortality (N = 1440) and 4-years neurodevelopmental outcome (N = 674) through univariable comparison and multivariable regression analyses adjusting for potential confounders. In patients with available blood samples (N = 556), multivariable models were additionally adjusted for baseline serum NSE and S100B concentrations as biomarkers of neuronal, respectively, astrocytic damage. To study whether an association of hypoglycemia with outcome may be affected by the nutritional strategy or center-specific glucose control protocol, we further adjusted the models for the interaction between hypoglycemia and the randomized nutritional strategy, respectively, treatment center. In sensitivity analyses, we studied whether any association with outcome was different in patients with iatrogenic or spontaneous/recurrent hypoglycemia. Results Hypoglycemia univariably associated with higher mortality in PICU, at 90 days and 4 years after randomization, but not when adjusted for risk factors. After 4 years, critically ill children with hypoglycemia scored significantly worse for certain parent/caregiver-reported executive functions (working memory, planning and organization, metacognition) than patients without hypoglycemia, also when adjusted for risk factors including baseline NSE and S100B. Further adjustment for the interaction of hypoglycemia with the randomized intervention or treatment center revealed a potential interaction, whereby tight glucose control and withholding early PN may be protective. Impaired executive functions were most pronounced in patients with spontaneous or recurrent hypoglycemia. Conclusion Critically ill children exposed to hypoglycemia in PICU were at higher risk of impaired executive functions after 4 years, especially in cases of spontaneous/recurrent hypoglycemia

Impact of duration and magnitude of raised intracranial pressure on outcome after severe traumatic brain injury: A CENTER-TBI high-resolution group study.

Magnitude of intracranial pressure (ICP) elevations and their duration have been associated with worse outcomes in patients with traumatic brain injuries (TBI), however published thresholds for injury vary and uncertainty about these levels has received relatively little attention. In this study, we have analyzed high-resolution ICP monitoring data in 227 adult patients in the CENTER-TBI dataset. Our aim was to identify thresholds of ICP intensity and duration associated with worse outcome, and to evaluate the uncertainty in any such thresholds. We present ICP intensity and duration plots to visualize the relationship between ICP events and outcome. We also introduced a novel bootstrap technique to evaluate uncertainty of the equipoise line. We found that an intensity threshold of 18 ± 4 mmHg (2 standard deviations) was associated with worse outcomes in this cohort. In contrast, the uncertainty in what duration is associated with harm was larger, and safe durations were found to be population dependent. The pressure and time dose (PTD) was also calculated as area under the curve above thresholds of ICP. A relationship between PTD and mortality could be established, as well as for unfavourable outcome. This relationship remained valid for mortality but not unfavourable outcome after adjusting for IMPACT core variables and maximum therapy intensity level. Importantly, during periods of impaired autoregulation (defined as pressure reactivity index (PRx)>0.3) ICP events were associated with worse outcomes for nearly all durations and ICP levels in this cohort and there was a stronger relationship between outcome and PTD. Whilst caution should be exercised in ascribing causation in observational analyses, these results suggest intracranial hypertension is poorly tolerated in the presence of impaired autoregulation. ICP level guidelines may need to be revised in the future taking into account cerebrovascular autoregulation status considered jointly with ICP levels

Time course of altered DNA methylation evoked by critical illness and by early administration of parenteral nutrition in the paediatric ICU

Background: A genome-wide study identifed de novo DNA methylation alterations in leukocytes of children at paediatric intensive care unit (PICU) discharge, ofering a biological basis for their impaired long-term development. Early parenteral nutrition (early-PN) in PICU, compared with omitting PN in the frst week (late-PN), explained diferential methylation of 23% of the afected CpG-sites. We documented the time course of altered DNA methylation in PICU and the impact hereon of early nutritional management. Results: We selected 36 early-PN and 36 late-PN matched patients, and 42 matched healthy children. We quantifed DNA methylation on days 3, 5 and 7 for the 147 CpG-sites of which methylation was normal upon PICU admission in this subset and altered by critical illness at PICU discharge. Methylation in patients difered from healthy children for 64.6% of the 147 CpG-sites on day 3, for 72.8% on day 5 and for 90.5% on day 7 as revealed by ANOVA at each time point. Within-patients methylation time course analyses for each CpG-site identifed diferent patterns based on paired t test p value and direction of change. Rapid demethylation from admission to day 3 occurred for 76.2% of the CpG-sites, of which 67.9% remained equally demethylated or partially remethylated and 32.1% further demethylated beyond day 3. From admission to day 3, 19.7% of the CpG-sites became hypermethylated, of which, beyond day 3, 34.5% remained equally hypermethylated or partially demethylated again and 65.5% further hypermethylated. For 4.1% of the CpG-sites, changes only appeared beyond day 3. Finally, for the CpG-sites afected by early-PN on the last PICU day, earlier changes in DNA methylation were compared for early-PN and late-PN patients, revealing that 38.9% were already diferentially methylated by day 3, another 25.0% by day 5 and another 13.9% by day 7. Conclusions: Critical illness- and early-PN-induced changes in DNA methylation occurred mainly within 3 days. Most abnormalities were at least partially maintained or got worse with longer time in PICU. Interventions targeting aberrant DNA methylation changes should be initiated earl

Внешнеторговое сотрудничество Республики Корея со странами Северо-Восточной Азии

Вследствие быстрого развития и усложнения мирохозяйственных связей и торгово-экономического взаимодействия государств, тенденции развитие международного сотрудничества приобретают особую актуальность. Северо-Восточная Азия (СВА) – это регион, в котором очень тонко переплетаются исторические, идеологические, политические особенности и экономическая целесообразность торговли. Страновой состав региона Северо-Восточной Азии может рассматриваться с разных точек зрения, в рамках данного исследования под странами данного региона понимаются Республика Корея, Китай, Япония и вся Россия. Взаимодействие Республики Корея с каждым из трех государств имеет уникальную историю, достаточный потенциал для развития торговли, а также свои особенности формирования внешнеэкономических связей. Усиление роли Китая в качестве торгового партнера, снижение значимости Японии и сложная экономическая ситуация в России на текущий момент оказывают существенное влияние на развитие Республики Корея, опорой экономического роста которой традиционно являлась торговля. Эти три страны являются одними из важнейших партнеров для Республики Корея, поэтому изучение процессов формирования внешнеэкономических связей в рамках региона Северо-Восточной Азии необходимо для определения основных тенденций, качественных изменений и факторов, определяющих вектор торговых отношений. Цель исследования – выявить основные тенденции сотрудничества Республики Корея и стран Северо-Восточной Азии в сфере внешней торговли. Практическая значимость работы состоит в возможности получения всестороннего анализа внешнеторгового сотрудничества Республики Корея и стран Северо-Восточной Азии, глубоко раскрытия данной тематики, что может послужить основой для дальнейших исследований торговли Республики Корея со странами региона и определения будущих перспектив в сотрудничестве для формирования внешнеторговой политики страны.The final project is devoted to trade cooperation of the Republic of Korea and North-East Asian countries. This region is influenced by many factors and analyses of dynamics and structure of trade are extremely significant to reveal the reasons of current trends of international cooperation between countries

Impact of duration and magnitude of raised intracranial pressure on outcome after severe traumatic brain injury: A CENTER-TBI high-resolution group study

Magnitude of intracranial pressure (ICP) elevations and their duration have been associated with worse outcomes in patients with traumatic brain injuries (TBI), however published thresholds for injury vary and uncertainty about these levels has received relatively little attention. In this study, we have analyzed high-resolution ICP monitoring data in 227 adult patients in the CENTER-TBI dataset. Our aim was to identify thresholds of ICP intensity and duration associated with worse outcome, and to evaluate the uncertainty in any such thresholds. We present ICP intensity and duration plots to visualize the relationship between ICP events and outcome. We also introduced a novel bootstrap technique to evaluate uncertainty of the equipoise line. We found that an intensity threshold of 18 ± 4 mmHg (2 standard deviations) was associated with worse outcomes in this cohort. In contrast, the uncertainty in what duration is associated with harm was larger, and safe durations were found to be population dependent. The pressure and time dose (PTD) was also calculated as area under the curve above thresholds of ICP. A relationship between PTD and mortality could be established, as well as for unfavourable outcome. This relationship remained valid for mortality but not unfavourable outcome after adjusting for IMPACT core variables and maximum therapy intensity level. Importantly, during periods of impaired autoregulation (defined as pressure reactivity index (PRx)>0.3) ICP events were associated with worse outcomes for nearly all durations and ICP levels in this cohort and there was a stronger relationship between outcome and PTD. Whilst caution should be exercised in ascribing causation in observational analyses, these results suggest intracranial hypertension is poorly tolerated in the presence of impaired autoregulation. ICP level guidelines may need to be revised in the future taking into account cerebrovascular autoregulation status considered jointly with ICP levels

Impact of duration and magnitude of raised intracranial pressure on outcome after severe traumatic brain injury: A CENTER-TBI high-resolution group study

Magnitude of intracranial pressure (ICP) elevations and their duration have been associated with worse outcomes in patients with traumatic brain injuries (TBI), however published thresholds for injury vary and uncertainty about these levels has received relatively little attention. In this study, we have analyzed high-resolution ICP monitoring data in 227 adult patients in the CENTER-TBI dataset. Our aim was to identify thresholds of ICP intensity and duration associated with worse outcome, and to evaluate the uncertainty in any such thresholds. We present ICP intensity and duration plots to visualize the relationship between ICP events and outcome. We also introduced a novel bootstrap technique to evaluate uncertainty of the equipoise line. We found that an intensity threshold of 18 ± 4 mmHg (2 standard deviations) was associated with worse outcomes in this cohort. In contrast, the uncertainty in what duration is associated with harm was larger, and safe durations were found to be population dependent. The pressure and time dose (PTD) was also calculated as area under the curve above thresholds of ICP. A relationship between PTD and mortality could be established, as well as for unfavourable outcome. This relationship remained valid for mortality but not unfavourable outcome after adjusting for IMPACT core variables and maximum therapy intensity level. Importantly, during periods of impaired autoregulation (defined as pressure reactivity index (PRx)>0.3) ICP events were associated with worse outcomes for nearly all durations and ICP levels in this cohort and there was a stronger relationship between outcome and PTD. Whilst caution should be exercised in ascribing causation in observational analyses, these results suggest intracranial hypertension is poorly tolerated in the presence of impaired autoregulation. ICP level guidelines may need to be revised in the future taking into account cerebrovascular autoregulation status considered jointly with ICP levels