Ischaemic preconditioning of the liver before transplantation

Purpose: Assessment of the effect of a short ischaemic time prior to liver transplantation on the liver graft. Methods: White X Landrace pigs (N=10) were subjected to liver transplantation. Before being removed from the donor animal, the livers were randomised into two groups: group 1 - pre-procurement ischaemia (15 minutes' temporary arrest of portal venous and hepatic arterial inflow to the liver, followed by reperfusion of these vessels for a period of 15 minutes); group 2 - no prior inflow occlusion (control group). In group 1 a spleno-jugular bypass was established to prevent venous congestion, portal venous hypertension, intestinal oedema and bacterial translocation. The livers were perfused with Eurocollins solution (4oC), after which they were stored on ice for a period of 3 hours' cold ischaemic time. Hepatocellular injury was assessed according to liver cell function tests (aspartate aminotransferase, AST), biochemical indicators of reperfusion injury (malondialdehyde) and histopathology. Results: There was a significant rise of AST in both groups 1 hour after transplantation (from 51+27 IU/l to 357+152 IU/l in group 1 and from 29+10 IU/l to 359+198 IU/l in group 2). AST levels were marginally lower in group 1 at 2 and 4 hours after transplantation. There was also a rise in malondialdehyde levels in both groups at 5, 20, 40 and 60 minutes after transplantation. Levels of malondialdehyde were lower in the primed group at 5, 20 and 40 minutes, while the levels at 60 minutes after transplantation were comparable. Histological changes, as measured by vacuolisation, neutrophil infiltration and hepatic cell necrosis, were less in livers transplanted after ischaemic preconditioning, although the difference was not significant. Conclusions: Ischaemic preconditioning of the donor liver seems to decrease hepatocellular damage, reperfusion injury and histological changes in the liver after transplantation. Further studies with larger numbers are indicated

Adding four-dimensional data assimilation by analysis nudging to the Model for Prediction Across Scales – Atmosphere (version 4.0)

The Model for Prediction Across Scales – Atmosphere (MPAS-A) has been modified to allow four-dimensional data assimilation (FDDA) by the nudging of temperature, humidity, and wind toward target values predefined on the MPAS-A computational mesh. The addition of nudging allows MPAS-A to be used as a global-scale meteorological driver for retrospective air quality modeling. The technique of analysis nudging developed for the Penn State/National Center for Atmospheric Research (NCAR) Mesoscale Model, and later applied in the Weather Research and Forecasting model, is implemented in MPAS-A with adaptations for its polygonal Voronoi mesh. Reference fields generated from 1°&thinsp; × &thinsp;1° National Centers for Environmental Prediction (NCEP) FNL (Final) Operational Global Analysis data were used to constrain MPAS-A simulations on a 92–25&thinsp;km variable-resolution mesh with refinement centered over the contiguous United States. Test simulations were conducted for January and July 2013 with and without FDDA, and compared to reference fields and near-surface meteorological observations. The results demonstrate that MPAS-A with analysis nudging has high fidelity to the reference data while still maintaining conservation of mass as in the unmodified model. The results also show that application of FDDA constrains model errors relative to 2&thinsp;m temperature, 2&thinsp;m water vapor mixing ratio, and 10&thinsp;m wind speed such that they continue to be at or below the magnitudes found at the start of each test period.</p

Hierarchy of piecewise non-linear maps with non-ergodicity behavior

We study the dynamics of hierarchy of piecewise maps generated by one-parameter families of trigonometric chaotic maps and one-parameter families of elliptic chaotic maps of $\mathbf{cn}$ and $\mathbf{sn}$ types, in detail. We calculate the Lyapunov exponent and Kolmogorov-Sinai entropy of the these maps with respect to control parameter. Non-ergodicity of these piecewise maps is proven analytically and investigated numerically . The invariant measure of these maps which are not equal to one or zero, appears to be characteristic of non-ergodicity behavior. A quantity of interest is the Kolmogorov-Sinai entropy, where for these maps are smaller than the sum of positive Lyapunov exponents and it confirms the non-ergodicity of the maps.Comment: 18 pages, 8 figure

Prevalence of gastro-oesophageal reflux disease symptoms and reflux-associated respiratory symptoms in asthma

<p>Abstract</p> <p>Background</p> <p>Gastro-oesophageal reflux disease (GORD) symptoms are common in asthma and have been extensively studied, but less so in the Asian continent. Reflux-associated respiratory symptoms (RARS) have, in contrast, been little-studied globally. We report the prevalence of GORD symptoms and RARS in adult asthmatics, and their association with asthma severity and medication use.</p> <p>Methods</p> <p>A cross-sectional analytical study. A validated interviewer-administered GORD scale was used to assess frequency and severity of seven GORD symptoms. Subjects were consecutive asthmatics attending medical clinics. Controls were matched subjects without respiratory symptoms.</p> <p>Results</p> <p>The mean (SD) composite GORD symptom score of asthmatics was significantly higher than controls (21.8 (17.2) versus 12.0 (7.6); <it>P </it>< 0.001) as was frequency of each symptom and RARS. Prevalence of GORD symptoms in asthmatics was 59.4% (95% CI, 59.1%-59.6%) versus 28.5% in controls (95% CI, 29.0% - 29.4%). 36% of asthmatics experienced respiratory symptoms in association with both typical and atypical GORD symptoms, compared to 10% of controls (<it>P </it>< 0.001). An asthmatic had a 3.5 times higher risk of experiencing a GORD symptom after adjusting for confounders (OR 3.5; 95% CI 2.5-5.3). Severity of asthma had a strong dose-response relationship with GORD symptoms. Asthma medication use did not significantly influence the presence of GORD symptoms.</p> <p>Conclusions</p> <p>GORD symptoms and RARS were more prevalent in a cohort of Sri Lankan adult asthmatics compared to non-asthmatics. Increased prevalence of RARS is associated with both typical and atypical symptoms of GORD. Asthma disease and its severity, but not asthma medication, appear to influence presence of GORD symptoms.</p

Clinical Utility of a Unique Genome-Wide DNA Methylation Signature for KMT2A-Related Syndrome

Wiedemann\u2013Steiner syndrome (WDSTS) is a Mendelian syndromic intellectual disability (ID) condition associated with hypertrichosis cubiti, short stature, and characteristic facies caused by pathogenic variants in the KMT2A gene. Clinical features can be inconclusive in mild and unusual WDSTS presentations with variable ID (mild to severe), facies (typical or not) and other associated malformations (bone, cerebral, renal, cardiac and ophthalmological anomalies). Interpretation and classification of rare KMT2A variants can be challenging. A genome-wide DNA methylation episignature for KMT2A-related syndrome could allow functional classification of variants and provide insights into the pathophysiology of WDSTS. Therefore, we assessed genome-wide DNA methylation profiles in a cohort of 60 patients with clinical diagnosis for WDSTS or Kabuki and identified a unique highly sensitive and specific DNA methylation episignature as a molecular biomarker of WDSTS. WDSTS episignature enabled classification of variants of uncertain significance in the KMT2A gene as well as confirmation of diagnosis in patients with clinical presentation of WDSTS without known genetic variants. The changes in the methylation profile resulting from KMT2A mutations involve global reduction in methylation in various genes, including homeobox gene promoters. These findings provide novel insights into the molecular etiology of WDSTS and explain the broad phenotypic spectrum of the disease

Recognising Victimhood: Lessons from the International Criminal Court and Mass Claim Programmes for the Compensation Procedure Parallel to the Trial of International Crimes in the Netherlands

In the Netherlands, the Dutch criminal court in The Hague (hereinafter: ‘Netherlands International Crimes Court’ or ‘NIC court’) is assigned to try international crimes, and to provide compensation to victims of such crimes. Whereas it has specific criminal laws at its disposal to try international crimes, it applies ‘regular’ Dutch civil law to assess claims for compensation. Yet compensation for international crimes entails challenges that are quite different from domestic crimes: international crimes are normally committed against a large number of victims, and frequently result in bodily harm. This article argues that the NIC court will most likely rule a large number of claims for compensation inadmissible, as a consequence of which victims cannot benefit from the advantages inherent in the award of compensation within the criminal process. It then explores the adjudicative and reparatory standards that the International Criminal Court and mass claim programmes have applied to simplify both the adjudication of a large number of claims, and the calculation of a large number of instances of bodily damage. It is submitted that adoption by the NIC court of international reparatory standards could facilitate the assessment of a large number of civil claims within the criminal process, without prejudice to the legitimate interests of the defendant for an adequate procedure. However, these standards require the NIC court to strike a new balance between tailor-made compensation and symbolic compensation, and thereby between corrective justice and restorative justice

Novel diagnostic DNA methylation episignatures expand and refine the epigenetic landscapes of Mendelian disorders

Overlapping clinical phenotypes and an expanding breadth and complexity of genomic associations are a growing challenge in the diagnosis and clinical management of Mendelian disorders. The functional consequences and clinical impacts of genomic variation may involve unique, disorder-specific, genomic DNA methylation episignatures. In this study, we describe 19 novel episignature disorders and compare the findings alongside 38 previously established episignatures for a total of 57 episignatures associated with 65 genetic syndromes. We demonstrate increasing resolution and specificity ranging from protein complex, gene, sub-gene, protein domain, and even single nucleotide-level Mendelian episignatures. We show the power of multiclass modeling to develop highly accurate and disease-specific diagnostic classifiers. This study significantly expands the number and spectrum of disorders with detectable DNA methylation episignatures, improves the clinical diagnostic capabilities through the resolution of unsolved cases and the reclassification of variants of unknown clinical significance, and provides further insight into the molecular etiology of Mendelian conditions

Global, regional, and national sex-specific burden and control of the HIV epidemic, 1990–2019, for 204 countries and territories: the Global Burden of Diseases Study 2019

Background: The sustainable development goals (SDGs) aim to end HIV/AIDS as a public health threat by 2030. Understanding the current state of the HIV epidemic and its change over time is essential to this effort. This study assesses the current sex-specific HIV burden in 204 countries and territories and measures progress in the control of the epidemic. Methods: To estimate age-specific and sex-specific trends in 48 of 204 countries, we extended the Estimation and Projection Package Age-Sex Model to also implement the spectrum paediatric model. We used this model in cases where age and sex specific HIV-seroprevalence surveys and antenatal care-clinic sentinel surveillance data were available. For the remaining 156 of 204 locations, we developed a cohort-incidence bias adjustment to derive incidence as a function of cause-of-death data from vital registration systems. The incidence was input to a custom Spectrum model. To assess progress, we measured the percentage change in incident cases and deaths between 2010 and 2019 (threshold &gt;75% decline), the ratio of incident cases to number of people living with HIV (incidence-to-prevalence ratio threshold &lt;0·03), and the ratio of incident cases to deaths (incidence-to-mortality ratio threshold &lt;1·0). Findings: In 2019, there were 36·8 million (95% uncertainty interval [UI] 35·1–38·9) people living with HIV worldwide. There were 0·84 males (95% UI 0·78–0·91) per female living with HIV in 2019, 0·99 male infections (0·91–1·10) for every female infection, and 1·02 male deaths (0·95–1·10) per female death. Global progress in incident cases and deaths between 2010 and 2019 was driven by sub-Saharan Africa (with a 28·52% decrease in incident cases, 95% UI 19·58–35·43, and a 39·66% decrease in deaths, 36·49–42·36). Elsewhere, the incidence remained stable or increased, whereas deaths generally decreased. In 2019, the global incidence-to-prevalence ratio was 0·05 (95% UI 0·05–0·06) and the global incidence-to-mortality ratio was 1·94 (1·76–2·12). No regions met suggested thresholds for progress. Interpretation: Sub-Saharan Africa had both the highest HIV burden and the greatest progress between 1990 and 2019. The number of incident cases and deaths in males and females approached parity in 2019, although there remained more females with HIV than males with HIV. Globally, the HIV epidemic is far from the UNAIDS benchmarks on progress metrics. Funding: The Bill &amp; Melinda Gates Foundation, the National Institute of Mental Health of the US National Institutes of Health (NIH), and the National Institute on Aging of the NIH