Heterogeneity after harmonisation: A retrospective cohort study of bleeding and stroke risk after the introduction of direct oral anticoagulants in four Western European countries.

PURPOSE: Database heterogeneity can impact effect estimates. Harmonisation provided by common protocols and common data models (CDMs) can increase the validity of pharmacoepidemiologic research. In a case study measuring the changes in the safety and effectiveness of stroke prevention therapy after the introduction of direct oral anticoagulants (DOACs), we performed an international comparison. METHODS: Using data from Stockholm, Denmark, Scotland and Norway, harmonised with a common protocol and CDM, two calendar-based cohorts were created: 2012 and 2017. Patients with a diagnosis code of atrial fibrillation 5 years preceding the 1-year cohort window were included. DOAC, vitamin K antagonist and aspirin treatment were assessed in the 6 months prior to the start of each year while strokes and bleeds were assessed during the year. A Poisson regression generated incidence rate ratios (IRRs) to compare outcomes from 2017 to 2012 adjusted for changes in individual-level baseline characteristics. RESULTS: In 280 359 patients in the 2012 cohort and 356 779 in the 2017 cohort, treatment with OACs increased on average from 45% to 65%, while treatment with aspirin decreased from 30% to 10%. In all countries except Scotland, there were decreases in the risk of stroke and no changes in bleeding risk, after adjustment for changes in baseline characteristics. In Scotland, major bleeding (IRR 1.09, 95% confidence interval [CI] [1.00; 1.18]) and intracranial haemorrhage (IRR 1.31, 95% CI [1.13; 1.52]) increased from 2012 to 2017. CONCLUSIONS: Stroke prevention therapy improved from 2012 to 2017 with a corresponding reduction in stroke risk without increasing the risk of bleeding in all countries, except Scotland. The heterogeneity that remains after methodological harmonisation can be informative of the underlying population and database.

Correcting for missing and irregular data in home-range estimation.

Home-range estimation is an important application of animal tracking data that is frequently complicated by autocorrelation, sampling irregularity, and small effective sample sizes. We introduce a novel, optimal weighting method that accounts for temporal sampling bias in autocorrelated tracking data. This method corrects for irregular and missing data, such that oversampled times are downweighted and undersampled times are upweighted to minimize error in the home-range estimate. We also introduce computationally efficient algorithms that make this method feasible with large data sets. Generally speaking, there are three situations where weight optimization improves the accuracy of home-range estimates: with marine data, where the sampling schedule is highly irregular, with duty cycled data, where the sampling schedule changes during the observation period, and when a small number of home-range crossings are observed, making the beginning and end times more independent and informative than the intermediate times. Using both simulated data and empirical examples including reef manta ray, Mongolian gazelle, and African buffalo, optimal weighting is shown to reduce the error and increase the spatial resolution of home-range estimates. With a conveniently packaged and computationally efficient software implementation, this method broadens the array of data sets with which accurate space-use assessments can be made.

Albedo and atmospheric constraints of dwarf planet Makemake from a stellar occultation.

Pluto and Eris are icy dwarf planets with nearly identical sizes, comparable densities and similar surface compositions as revealed by spectroscopic studies. Pluto possesses an atmosphere whereas Eris does not; the difference probably arises from their differing distances from the Sun, and explains their different albedos. Makemake is another icy dwarf planet with a spectrum similar to Eris and Pluto, and is currently at a distance to the Sun intermediate between the two. Although Makemake's size (1,420 ± 60 km) and albedo are roughly known, there has been no constraint on its density and there were expectations that it could have a Pluto-like atmosphere. Here we report the results from a stellar occultation by Makemake on 2011 April 23. Our preferred solution that fits the occultation chords corresponds to a body with projected axes of 1,430 ± 9 km (1σ) and 1,502 ± 45 km, implying a V-band geometric albedo p(V) = 0.77 ± 0.03. This albedo is larger than that of Pluto, but smaller than that of Eris. The disappearances and reappearances of the star were abrupt, showing that Makemake has no global Pluto-like atmosphere at an upper limit of 4-12 nanobar (1σ) for the surface pressure, although a localized atmosphere is possible. A density of 1.7 ± 0.3 g cm(-3) is inferred from the data.

Systems Biology in Kidney Transplantation: The Application of Multi-Omics to a Complex Model.

In spite of reduction of rejection rates and improvement in short-term survival post-kidney transplantation, modest progress has occurred in long-term graft attrition over the years. Timely identification of molecular events that precede clinical and histopathological changes might help in early intervention and thereby increase the graft half-life. Evolution of "omics" tools has enabled systemic investigation of the influence of the whole genome, epigenome, transcriptome, proteome and microbiome on transplant function and survival. In this omics era, systemic approaches, in-depth clinical phenotyping and use of strict validation methods are the key for further understanding the complex mechanisms associated with graft function. Systems biology is an interdisciplinary holistic approach that focuses on complex and dynamic interactions within biological systems. The complexity of the human kidney transplant is unlikely to be captured by a reductionist approach. It appears essential to integrate multi-omics data that can elucidate the multidimensional and multilayered regulation of the underlying heterogeneous and complex kidney transplant model. Herein, we discuss studies that focus on genetic biomarkers, emerging technologies and systems biology approaches, which should increase the ability to discover biomarkers, understand mechanisms and stratify patients and responses post-kidney transplantation.

Effects of DNA Methylation on Progression to Interstitial Fibrosis and Tubular Atrophy in Renal Allograft Biopsies: A Multi-Omics Approach.

Progressive fibrosis of the interstitium is the dominant final pathway in renal destruction in native and transplanted kidneys. Over time, the continuum of molecular events following immunological and nonimmunological insults lead to interstitial fibrosis and tubular atrophy and culminate in kidney failure. We hypothesize that these insults trigger changes in DNA methylation (DNAm) patterns, which in turn could exacerbate injury and slow down the regeneration processes, leading to fibrosis development and graft dysfunction. Herein, we analyzed biopsy samples from kidney allografts collected 24 months posttransplantation and used an integrative multi-omics approach to understand the underlying molecular mechanisms. The role of DNAm and microRNAs on the graft gene expression was evaluated. Enrichment analyses of differentially methylated CpG sites were performed using GenomeRunner. CpGs were strongly enriched in regions that were variably methylated among tissues, implying high tissue specificity in their regulatory impact. Corresponding to this methylation pattern, gene expression data were related to immune response (activated state) and nephrogenesis (inhibited state). Preimplantation biopsies showed similar DNAm patterns to normal allograft biopsies at 2 years posttransplantation. Our findings demonstrate for the first time a relationship among epigenetic modifications and development of interstitial fibrosis, graft function, and inter-individual variation on long-term outcomes.

BK Polyomavirus-Specific 9mer CD8 T Cell Responses Correlate With Clearance of BK Viremia in Kidney Transplant Recipients: First Report From the Swiss Transplant Cohort Study.

BK polyomavirus (BKPyV) causes premature kidney transplant (KT) failure in 1-15% of patients. Because antivirals are lacking, most programs screen for BKPyV-viremia and, if positive, reduce immunosuppression. To evaluate the relationship of viremia and BKPyV-specific immunity, we examined prospectively cryopreserved plasma and peripheral blood mononuclear cells at the time of transplantation (T0) and at 6 mo (T6) and 12 mo (T12) after transplant from 28 viremic KT patients and 68 nonviremic controls matched for the transplantation period. BKPyV IgG seroprevalence was comparable between cases (89.3%) and controls (91.2%; p = 0.8635), but cases had lower antibody levels (p = 0.022) at T0. Antibody levels increased at T6 and T12 but were not correlated with viremia clearance. BKPyV-specific T cell responses to pools of overlapping 15mers (15mer peptide pool [15mP]) or immunodominant CD8 9mers (9mer peptide pool [9mP]) from the early viral gene region were not different between cases and controls at T0; however, clearance of viremia was associated with stronger 9mP responses at T6 (p = 0.042) and T12 (p = 0.048), whereas 15mP responses were not informative (T6 p = 0.359; T12 p = 0.856). BKPyV-specific T cells could be expanded in vitro from all patients after transplant, permitting identification of 78 immunodominant 9mer epitopes including 50 new ones across different HLA class I. Thus, 9mP-responses may be a novel marker of reconstituting CD8 T cell function that warrants further study as a complement of plasma BKPyV loads for guiding immunosuppression reduction.

Complexity of Host Micro-RNA Response to Cytomegalovirus Reactivation After Organ Transplantation.

Human (Homo sapiens) micro-RNAs (hsa-miRNAs) regulate virus and host-gene translation, but the biological impact in patients with human cytomegalovirus (hCMV) infection is not well defined in a clinically relevant model. First, we compared hsa-miRNA expression profiles in peripheral blood mononuclear cells from 35 transplant recipients with and without CMV viremia by using a microarray chip covering 847 hsa-miRNAs. This approach demonstrated a set of 142 differentially expressed hsa-miRNAs. Next, we examined the effect of each of these miRNAs on viral growth by using human fibroblasts (human foreskin fibroblast-1) infected with the hCMV Towne strain, identifying a subset of proviral and antiviral hsa-miRNAs. miRNA-target prediction software indicated potential binding sites within the hCMV genome (e.g., hCMV-UL52 and -UL100 [UL = unique long]) and host-genes (e.g., interleukin-1 receptor, IRF1). Luciferase-expressing plasmid constructs and immunoblotting confirmed several predicted miRNA targets. Finally, we determined the expression of selected proviral and antiviral hsa-miRNAs in 242 transplant recipients with hCMV-viremia. We measured hsa-miRNAs before and after antiviral therapy and correlated hsa-miRNA expression levels to hCMV-replication dynamics. One of six antiviral hsa-miRNAs showed a significant increase during treatment, concurrent with viral decline. In contrast, six of eight proviral hsa-miRNAs showed a decrease during viral decline. Our results indicate that a complex and multitargeted hsa-miRNA response occurs during CMV replication in immunosuppressed patients. This study provides mechanistic insight and potential novel biomarkers for CMV replication.

Effect of Twice-Yearly Denosumab on Prevention of Bone Mineral Density Loss in De Novo Kidney Transplant Recipients: A Randomized Controlled Trial.

We conducted an open-label, prospective, randomized trial to assess the efficacy and safety of RANKL inhibition with denosumab to prevent the loss of bone mineral density (BMD) in the first year after kidney transplantation. Ninety kidney transplant recipients were randomized 1:1 2 weeks after surgery to receive denosumab (60 mg at baseline and 6 months) or no treatment. After 12 months, total lumbar spine areal BMD (aBMD) increased by 4.6% (95% confidence interval [CI] 3.3-5.9%) in 46 patients in the denosumab group and decreased by -0.5% (95% CI -1.8% to 0.9%) in 44 patients in the control group (between-group difference 5.1% [95% CI 3.1-7.0%], p < 0.0001). Denosumab also increased aBMD at the total hip by 1.9% (95% CI, 0.1-3.7%; p = 0.035) over that in the control group at 12 months. High-resolution peripheral quantitative computed tomography in a subgroup of 24 patients showed that denosumab increased volumetric BMD at the distal tibia and radius (all p < 0.05). Biomarkers of bone turnover (C-terminal telopeptide of type I collagen, procollagen type I N-terminal propeptide) markedly decreased with denosumab (all p < 0.0001). Episodes of cystitis and asymptomatic hypocalcemia occurred more often with denosumab, whereas graft function, rate of rejections, and incidence of opportunistic infections were similar. In conclusion, denosumab increased BMD in the first year after kidney transplantation but was associated with more frequent episodes of urinary tract infection.

A bird pollinator shows positive frequency dependence and constancy of species choice in natural plant communities.

Animal pollinators mediate reproduction of many plant species. Foraging theory suggests that animal pollinators exhibit preferences for common plant species in natural communities (positive frequency-dependent foraging) and temporary single-species specialization (flower constancy) during foraging bouts. Positive frequency dependence may favor common plant species; flower constancy may enhance conspecific pollen transfer particularly in rare plant species. Previous experimental studies suggest that avian pollinators are unlikely to exhibit these behaviors. We studied foraging behavior of Cape Sugarbirds (Promerops cafer), the main avian pollinator of many Protea species, using focal-plant and focal-bird sampling, assisted by high-resolution maps of the spatiotemporal distribution of Protea individuals and their flowering status. We found that Sugarbird's visitation preference increased with species' relative floral abundance, and that individual Sugarbirds tended to visit single species in sequence. Flower constancy during foraging bouts was significantly higher than expected from random plant-animal encounters at the scale of pollinator movements. Positive frequency dependence may favor the reproduction of abundant plant species while flower constancy may be particularly important for rare plant species. This first simultaneous study of both behaviors in a natural plant-pollinator system shows that bird pollinators exhibit both types of behavior and, in this way, possibly influence plant community structure.

Estimating where and how animals travel: an optimal framework for path reconstruction from autocorrelated tracking data.

An animal's trajectory is a fundamental object of interest in movement ecology, as it directly informs a range of topics from resource selection to energy expenditure and behavioral states. Optimally inferring the mostly unobserved movement path and its dynamics from a limited sample of telemetry observations is a key unsolved problem, however. The field of geostatistics has focused significant attention on a mathematically analogous problem that has a statistically optimal solution coined after its inventor, Krige. Kriging revolutionized geostatistics and is now the gold standard for interpolating between a limited number of autocorrelated spatial point observations. Here we translate Kriging for use with animal movement data. Our Kriging formalism encompasses previous methods to estimate animal's trajectories--the Brownian bridge and continuous-time correlated random walk library--as special cases, informs users as to when these previous methods are appropriate, and provides a more general method when they are not. We demonstrate the capabilities of Kriging on a case study with Mongolian gazelles where, compared to the Brownian bridge, Kriging with a more optimal model was 10% more precise in interpolating locations and 500% more precise in estimating occurrence areas.

Intestinal infection at onset of mycophenolic acid-associated chronic diarrhea in kidney transplant recipients.

BACKGROUND: Chronic diarrhea after kidney transplantation is often attributed to mycophenolic acid (MPA) toxicity. We hypothesize that intestinal infections contribute to the pathogenesis of chronic MPA-associated diarrhea. METHODS: In this retrospective study, all patients (n = 726) receiving a kidney transplant between 2000 and 2010 at the University Hospital Zurich were followed until July 2014 for occurrence of chronic diarrhea (≥4 weeks). Infectious triggers at diarrhea onset were assessed by reviewing medical history, stool microbiology, and histology of colon biopsies. RESULTS: In 46 patients (6.3% of the cohort), a total of 51 episodes of chronic diarrhea during MPA treatment were documented. The diarrhea episodes were often severe, as confirmed by significant weight loss. The cumulative incidence of chronic diarrhea was uniformly distributed throughout the post-transplant period, with 2.0%, 5.1%, and 9.6% at 1, 5, and 10 years, respectively. Evidence was found for intestinal infection at diarrhea onset in 38 episodes (74.5%). Occurrence of diarrhea onset showed a seasonal distribution with peaks in April and October/November. Specific antimicrobial treatment alone was associated with a 19% resolution rate only, whereas combination with dose reduction of MPA or switch from mycophenolate mofetil to enteric-coated mycophenolate sodium resulted in a 22.7% and 76.5% resolution rate, respectively. Change to an MPA-free regimen was associated with a 100% resolution rate. CONCLUSION: These results provide first evidence for a contribution of intestinal infections in chronic post-transplant diarrhea associated with MPA treatment.

Decreased Urinary Sodium-to-urinary Creatinine Ratio Identifies Sodium Depletion in Pediatric Acute Gastroenteritis.

UNLABELLED: In acute gastroenteritis (AG) fecal losses may cause depletion of sodium (NaD) which may not be recognized because of normal plasma Na (pNa) concentrations. We studied the incidence of this state of normonatremic sodium depletion (NNaD) and the suitability of the urinary Na/urinary creatinine ratio (uNa/uCr) for diagnosing NNaD. PATIENTS: 16 AG- and 16 healthy control children aged 0.8-15.0 years. METHODS: Prospective cross sectional pilot study. Measurements of Na, K and creatinine in plasma (p) and urine (u). Calculation of uNa/uCr Ratio, fractional excretion of Na (FENa) and uNa/uK ratio as the hitherto best known parameters of prerenal Na depletion, respectively. RESULTS: pNa concentrations were normal in 15/16 AG patients (93.8%) with only one subnormal value of 133 mmol/L, and a mean value of 137.9±2.3 mmol/L not different from the normal control group (139.4±2.2 mmol/L). Also, mean uNa concentrations and uNa/uK ratios did not differ between both groups. However, uNa/uCr ratios were below normal in 13/16 AG children (81.3%) but normal in all healthy controls with a significantly lower mean value in the AG group (12.6±8.8 vs. 31.2±8.3 mmol/mmol; p<0.0001). Similarly, 14/16 AG patients (87.5%) had a decreased FENa<0.5% with a mean FENa value significantly lower than in controls (0.36±0.28% vs. 0.95±0.26%, p<0.0001). The good agreement between FENa and uNa/uCr results was also reflected by a high correlation coefficient of r=0.9333. CONCLUSIONS: The majority of AG patients was found to have NNaD as determined by uNa/uCr and FENa. Calculation of uNa/uCr may be useful for diagnosing NNaD in AG.

What's hot, what's new at WTC--clinical science.

More than 3000 abstracts of innovative and exciting findings, covering the whole field of organ transplantation, were presented at the World Transplant Congress 2014. Key areas of presentations across all organs and tissues included HLA antibodies, antibody-mediated rejection, living donation, immunosuppression, organ perfusion and surgical procedures. In addition, cutting edge science and future perspectives were presented in state-of-the-art lectures. This review will present highlights of this meeting and demonstrate strength and success of clinical sciences in transplantation.

Rigorous home range estimation with movement data: a new autocorrelated kernel density estimator.

Quantifying animals' home ranges is a key problem in ecology and has important conservation and wildlife management applications. Kernel density estimation (KDE) is a workhorse technique for range delineation problems that is both statistically efficient and nonparametric. KDE assumes that the data are independent and identically distributed (IID). However, animal tracking data, which are routinely used as inputs to KDEs, are inherently autocorrelated and violate this key assumption. As we demonstrate, using realistically autocorrelated data in conventional KDEs results in grossly underestimated home ranges. We further show that the performance of conventional KDEs actually degrades as data quality improves, because autocorrelation strength increases as movement paths become more finely resolved. To remedy these flaws with the traditional KDE method, we derive an autocorrelated KDE (AKDE) from first principles to use autocorrelated data, making it perfectly suited for movement data sets. We illustrate the vastly improved performance of AKDE using analytical arguments, relocation data from Mongolian gazelles, and simulations based upon the gazelle's observed movement process. By yielding better minimum area estimates for threatened wildlife populations, we believe that future widespread use of AKDE will have significant impact on ecology and conservation biology.

Prothrombin G20210A mutation and lower extremity peripheral arterial disease: a systematic review and meta-analysis.

OBJECTIVE/BACKGROUND: Despite being an important risk factor for venous thromboembolism, the role of the prothrombin G20210A mutation in patients with arterial disease remains unclear. The aim of this review was to evaluate the association of prothrombin G20210A and lower extremity peripheral arterial disease (PAD). METHODS: This was a systematic review and meta-analysis of case-control studies. A systematic review of electronic databases, including MEDLINE and Embase, was conducted to assess the prevalence of prothrombin G20210A in patients with lower extremity PAD. The main outcome was the prevalence of prothrombin G20210A in patients with lower extremity PAD. The random effects model odds ratio (OR) was used as the primary outcome measure. RESULTS: The initial electronic search identified 168 relevant abstracts of which five studies evaluating 1,524 cases of PAD and 1,553 controls were included. Prothrombin G20210A was found in 70 of 1,524 patients with lower extremity PAD and 44 of 1,553 of the controls (random effects OR 1.68, 95% confidence interval [CI] 0.8-3.2). In those with critical limb ischemia (CLI), the prevalence of prothrombin G20210A was 23 of 302 compared with 31 of 1,253 of the controls (OR 3.2, 95% CI 1.6-6.1). CONCLUSION: Despite finding no significant association between lower extremity PAD and prothrombin G20210A, the meta-analysis suggests that the prevalence of prothrombin G20210A is significantly elevated in those with atherosclerotic occlusive disease of the lower extremities presenting with CLI. Well-designed prospective cohort studies evaluating the role of prothrombin G20210A as a predictor of disease progression or adverse vascular events are highly needed.

Active control of the nucleation temperature enhances freezing survival of multipotent mesenchymal stromal cells.

Cryopreservation is a technique that has been extensively used for storage of multipotent mesenchymal stromal cells (MSCs) in regenerative medicine. Therefore, improving current cryopreservation procedures in terms of increasing cell viability and functionality is important. In this study, we optimized the cryopreservation protocol of MSCs derived from the common marmoset Callithrix jacchus (cj), which can be used as a non-human primate model in various pathological and transplantation studies and have a great potential for regenerative medicine. We have investigated the effect of the active control of the nucleation temperature using induced nucleation at a broad range of temperatures and two different dimethylsulfoxide concentrations (Me2SO, 5% (v/v) and 10%, (v/v)) to evaluate the overall effect on the viability, metabolic activity and recovery of cells after thawing. Survival rate and metabolic activity displayed an optimum when ice formation was induced at -10 °C. Cryomicroscopy studies indicated differences in ice crystal morphologies as well as differences in intracellular ice formation with different nucleation temperatures. High subzero nucleation temperatures resulted in larger extracellular ice crystals and cellular dehydration, whereas low subzero nucleation temperatures resulted in smaller ice crystals and intracellular ice formation.

Body mass index stratification enables cytokine-based prediction of ACPA status and Power-Doppler disease activity in rheumatoid arthritis.

OBJECTIVE: Rheumatoid arthritis can be classified according to ACPA and RF status. ACPA status may be associated with other pathophysiological differences, e.g., the cytokines driving inflammation. Obesity influences the course of RA, likely involving leptin; the exact mechanisms are not completely understood. This study investigates BMI influence on RA cytokine profiles and the possibility of predicting ACPA status and disease activity measured by Power-Doppler sonography (PDS). METHODS: Patients were examined using a multi-biomarker disease assay and PDS examination of wrists and MCP and PIP joints and stratified according to ACPA status and BMI, using prediction precision to determine BMI cutoff. Analysis was performed using elastic net regularization of logistic and multiple regression. We then attempted to predict ACPA status/PDS activity based on a bootstrap approach. RESULTS: A total of 120 measurements from 95 patients were performed. ACPA status prediction peaked at BMI 26 kg/m2, with AUC 0.82. PDS activity prediction had a mean average error of < 1.6 PDS points for all groups. In obese patients, cytokine profiles appear to align in ACPA-positive and -negative patients, with leptin playing a greater role in predicting PDS activity, but with some remaining differences. CONCLUSION: When stratified according to BMI, cytokine patterns can predict ACPA status and PDS activity in RA with a high degree of precision. This indicates that studies into the pathophysiology of RA should take BMI into account, to differentiate between disease- and obesity-associated phenomena. The underlying pathological processes of ACPA-negative and -positive RA appear different. Multi-cytokine evaluations may provide a deeper understanding of disease processes. Key Points • A multi-cytokine approach combined with ultrasonography and modern mathematical methods can contribute to a deeper understanding of the relationship between systemic and joint inflammation. • BMI influences cytokine profiles in rheumatoid arthritis and appears to "override" disease-specific processes. • Using cytokines only, and adjusting for BMI, it is possible to predict the ACPA status and joint inflammation with considerable precision.

CCR5-Δ32 genotype does not improve predictive value of IL28B polymorphisms for treatment response in chronic HCV infection.

IL28B polymorphisms strongly predict spontaneous and treatment-induced clearance of hepatitis C virus (HCV) infection. A recent study proposed a 32-base pair deletion in the CC-chemokine receptor 5 (CCR5) gene (CCR5-Δ32) interacting with the IL28B polymorphisms to influence spontaneous HCV clearance. The aim of this study was to clarify the role of CCR5-Δ32 in treatment-induced clearance of chronic hepatitis C (CHC). A cross-sectional cohort of 813 Caucasian patients with CHC genotype 1 (365 responders and 448 non-responders) who had received standard of care dual therapy with interferon (IFN)-α and ribavirin (RBV) was genotyped for the CCR5-Δ32 and IL28B polymorphisms to examine their interaction with respect to treatment response. CCR5-Δ32 did not influence treatment-induced recovery to IFN-α/RBV in CHC, and did not improve prediction of sustained virological response in the context of the IL28B polymorphisms in a multivariate model. CCR5-Δ32 homozygotes were significantly more frequent in those with CHC than healthy controls in the European cohorts (2.9% vs 0.4%, P<0.0001), but not in Australians of European ancestry. In conclusion, CCR5-Δ32 does not influence treatment response in the context of IL28B polymorphisms. Although CCR5-Δ32 may affect viral clearance within closely controlled geographical and genetic environments, we found no effect in larger cohorts treated with dual therapy.

Oxazolone and ethanol induce colitis in non-obese diabetic-severe combined immunodeficiency interleukin-2Rγ(null) mice engrafted with human peripheral blood mononuclear cells.

Oxazolone-induced colitis in mice has become a recognized model to study the efficacy of therapeutics targeting the immunological response underlying the development of inflammatory bowel disease. However, this model cannot be used when therapeutics designed to address human targets do not interact with the respective murine counterpart. In this study, we examined the induction of oxazolone mediated colitis in non-obese diabetic-severe combined immunodeficiency interleukin-2Rγ(null) (NOD-SCID IL2Rγ(null)) mice engrafted with human peripheral blood mononuclear cells (hPBMC) derived from patients suffering from ulcerative colitis (UC), atopic dermatitis (AD) and healthy volunteers. NOD-SCID IL2Rγ (null) mice were engrafted with hPBMC followed by challenge with oxazolone or ethanol vehicle. Mice developed the same symptoms as observed previously in immunocompetent mice. The clinical activity score increased and the colon architecture was characterized by the development of oedema, fibrosis, crypt loss and dense infiltration of predominantly T cells into the lamina propria. Fluorescence activated cell sorter (FACS) analysis of lymphocytes in the colon identified natural killer (NK) T cells as a major constituent. In contrast to studies with immunocompetent mice, we observed the same phenotype in the group challenged with ethanol vehicle. The phenotype was most pronounced in mice engrafted with PBMC derived from a patient suffering from UC, suggesting that the immunological history of the donors predisposes the engrafted mice to react to ethanol. The model described here has the potential to study the efficacy of therapeutics targeting human lymphocytes in a model which is more reflective of the human disease. In addition, it might be developed to elucidate molecular mechanisms underlying the disease.

Pandemic and post-pandemic influenza A (H1N1) seasons in a tertiary care university hospital-high rate of complications compared to previous influenza seasons.

INTRODUCTION: The aim was to study the characteristics and case severity of patients hospitalized for influenza with a pandemic strain at a German tertiary care university hospital in 2009/10 and 2010/11 and to compare them to two previous influenza seasons. METHODS: An observational study of all patients hospitalized for laboratory-confirmed influenza during the last four influenza seasons at Regensburg University Hospital was undertaken. RESULTS: During the last four seasons, a rising number of patients were admitted due to influenza (4 in 2007/8, 16 in 2008/9, 27 in 2009/10, and 55 in 2010/11). Patients seen in the last two seasons were younger (median age 63 years in 2007/8, 52 years in 2008/9, 42 years in 2009/10, and 48 years in 2010/11) (p = 0.046) and presented with a lower rate of major comorbidities (75 % in 2007/8, 62.5 % in 2008/9, 37 % in 2009/10, and 47.3 % in 2010/11). The pandemic and post-pandemic seasons were characterized by a high rate of seriously ill patients with longer hospitalizations (11 days in 2007/8, 7 days in 2008/9, 22 days in 2009/10 and 2010/11) (p = 0.004) and higher rates of intensive care unit (ICU) admission (25 % in 2007/8, 18.8 % in 2008/9, 66.7 % in 2009/10, and 52.7 % in 2010/11) (p = 0.003) and mechanical ventilation (25 % in 2007/8, 6.3 % in 2008/9, 63 % in 2009/10, and 49.1 % in 2010/11) (p < 0.001). Extracorporeal membrane oxygenation (ECMO) was necessary in 33.3 % of patients in 2009/10 and 25.5 % in 2010/11. We had six fatalities in both pandemic and post-pandemic seasons. CONCLUSION: Compared to seasonal influenza, we observed even more so in the post-pandemic than the pandemic season a higher number of younger patients, with less serious comorbidities often showing a very severe course.