Common variable immunodeficiency disorder-related liver disease is common and results in portal hypertension and an increased risk of death.

BACKGROUND: Common variable immunodeficiency disorder (CVID) manifests with recurrent infections and inflammatory complications, including liver disease. We report the clinical features, natural history, and outcomes of patients with CVID-related liver disease (CVID-rLD) from a tertiary immunology and hepatology center. METHODS: Two hundred eighteen patients were identified; CVID-rLD was defined by persistently abnormal liver function tests or evidence of chronic liver disease (CLD) or portal hypertension (PHTN) by radiological or endoscopic investigation, after exclusion of other causes. Patients with CVID-rLD were investigated and managed following a joint pathway between immunology and hepatology services. Data, including clinical parameters, investigations, and outcomes, were retrospectively collected. RESULTS: A total of 91/218 (42%) patients had evidence of CVID-rLD, and 40/91 (44%) had PHTN. Patients with CVID-rLD were more likely to have other noninfectious complications of CVID (85/91, 93.4% vs. 75/127, 59.1%, p<0.001) including interstitial lung disease, gut disease, and autoimmune cytopenias. Nodular regenerative hyperplasia (NRH) was identified in 63.8% of liver biopsies, and fibrosis in 95.3%. Liver stiffness measurements (LSMs) were frequently elevated (median 9.95 kPa), and elevated LSM was associated with PHTN. All-cause mortality was higher in those with CVID-rLD (24/91, 26.4% vs. 14/127, 11%, p=0.003), which was the only organ complication associated with mortality (HR 2.24, 1.06-4.74, p=0.04). Factors predicting mortality in CVID-rLD included PHTN, increasing fibrosis, and LSM. CONCLUSIONS: Liver disease is a common complication of CVID as part of complex, multi-organ involvement and is associated with high rates of PHTN and an increased hazard of mortality.

Common variable immunodeficiency disorder (CVID)-related liver disease: assessment of the main histological aspects using novel semiquantitative scoring systems, image analysis and correlation with clinical parameters of liver stiffness and portal hypertension.

AIMS: We aimed to investigate the relationship between T-cell-mediated sinusoidal injury, nodular regenerative hyperplasia like changes (NRH-LC) and fibrosis, clinical measures of fibrosis and portal hypertension, and progression rate in common variable immunodeficiency disorder (CVID)-related liver disease. METHODS: This is a retrospective single-centre study. Liver biopsies from CVID patients with liver disease were reviewed to assess for NRH-LC, fibrosis and elastosis, including collagen and elastin proportionate areas. CD3 positive T-cells infiltration and sinusoidal endothelial changes by CD34 expression were quantified by image analysis and a semiquantitative method, respectively. These findings were correlated with liver stiffness measurements (LSM) and hepatic venous pressure gradient (HVPG). RESULTS: NRH-LC and pericellular elastosis were present in most biopsies (32/40 and 38/40, respectively). All biopsies showed fibrosis, which was limited to pericellular in 21/40 (52.5%) and included bridging fibrous septa in 19/40 (47.5%). 28/40 liver biopsies showed enhanced sinusoidal expression of CD34. There were more CD3 positive cells in biopsies with NRH-LC compared with those without. There was no significant correlation between LSM, HVPG and fibrosis/elastosis scores. Five of seven patients with at least two biopsies showed progression in fibrosis stage. CONCLUSIONS: NRH-LC and fibrosis in CVID patients often coexist along with the presence of sinusoidal endothelial changes and sinusoidal lymphocytic infiltration. Fibrosis progresses over time, and significant fibrosis can be observed in young patients (<30 years old), potentially reflecting a more aggressive form of CVID-related liver disease. Further studies are necessary to investigate the relationship between histological findings, clinical measures of fibrosis and portal hypertension and outcome.

Laser Scribing Fabrication of Graphitic Carbon Biosensors for Label-Free Detection of Interleukin-6.

Interleukin-6 (IL-6) is an important immuno-modulating cytokine playing a pivotal role in inflammatory processes in disease induction and progression. As IL-6 serves as an important indicator of disease state, it is of paramount importance to develop low cost, fast and sensitive improved methods of detection. Here we present an electrochemical immunosensor platform based on the use of highly porous graphitic carbon electrodes fabricated by direct laser writing of commercial polyimide tapes and chemically modified with capture IL-6 antibodies. The unique porous and 3D morphology, as well as the high density of edge planes of the graphitic carbon electrodes, resulted in a fast heterogeneous electron transfer (HET) rate, k0 = 0.13 cm/s. The resulting immunosensor showed a linear response to log of concentration in the working range of 10 to 500 pg/mL, and low limit of detection (LOD) of 5.1 pg/mL IL-6 in phosphate buffer saline. The total test time was approximately 90 min, faster than the time required for ELISA testing. Moreover, the assay did not require additional sample pre-concentration or labelling steps. The immunosensor shelf-life was long, with stable results obtained after 6 weeks of storage at 4 °C, and the selectivity was high, as no response was obtained in the presence of another inflammatory cytokine, Interlukin-4. These results show that laser-fabricated graphitic carbon electrodes can be used as selective and sensitive electrochemical immunosensors and offer a viable option for rapid and low-cost biomarker detection for point-of-care analysis.

ICD-10-AM codes for cirrhosis and related complications: key performance considerations for population and healthcare studies.

OBJECTIVE: The utility of International Classification of Diseases (ICD) codes relies on the accuracy of clinical reporting and administrative coding, which may be influenced by country-specific codes and coding rules. This study explores the accuracy and limitations of the Australian Modification of the 10th revision of ICD (ICD-10-AM) to detect the presence of cirrhosis and a subset of key complications for the purpose of future large-scale epidemiological research and healthcare studies. DESIGN/METHOD: ICD-10-AM codes in a random sample of 540 admitted patient encounters at a major Australian tertiary hospital were compared with data abstracted from patients' medical records by four blinded clinicians. Accuracy of individual codes and grouped combinations was determined by calculating sensitivity, positive predictive value (PPV), negative predictive value and Cohen's kappa coefficient (κ). RESULTS: The PPVs for 'grouped cirrhosis' codes (0.96), hepatocellular carcinoma (0.97) ascites (0.97) and 'grouped varices' (0.95) were good (κ all >0.60). However, codes under-detected the prevalence of cirrhosis, ascites and varices (sensitivity 81.4%, 61.9% and 61.3%, respectively). Overall accuracy was lower for spontaneous bacterial peritonitis ('grouped' PPV 0.75; κ 0.73) and the poorest for encephalopathy ('grouped' PPV 0.55; κ 0.21). To optimise detection of cirrhosis-related encounters, an ICD-10-AM code algorithm was constructed and validated in an independent cohort of 116 patients with known cirrhosis. CONCLUSION: Multiple ICD-10-AM codes should be considered when using administrative databases to study the burden of cirrhosis and its complications in Australia, to avoid underestimation of the prevalence, morbidity, mortality and related resource utilisation from this burgeoning chronic disease.

Delivery of the UN Convention on the Rights of the Child in an acute paediatric setting: an audit of information available and service gap analysis.

BACKGROUND: The United Nations Convention on Children's Rights stresses the importance of providing children with information relating to their health and well-being, yet reports suggest children are offered insufficient support in healthcare environments. We audited the information provided to children and families requiring planned surgical admission in comparison to those admitted acutely to medical paediatrics. Additionally, we identified examples of child-specific information resources in national and international hospitals. METHODS: Three approaches were taken to gain insight into practice locally, nationally and internationally.(1) Information resources provided to paediatric inpatients admitted to the acute receiving unit were audited in comparison to information given to children with planned admissions via process observations.(2) Qualitative feedback was gained from play specialists (n=2), families (n=30) and children (n=9; aged 3-15 years) via interviews.(3) A review, including UK, Australian and US hospitals, was conducted to assess child-specific information resources (n=36 hospitals) and to systematically compare the information available on websites (n=9 hospitals). RESULTS: At the study site, no child-specific information resources were available for acute admissions, whereas planned admissions were offered significant information face-to-face with supplemental resources. Child, parent and play specialist interviews highlighted gaps in information provision regarding hospital practicalities and processes. Twelve external child-specific resources were identified, for 4-14 year olds, explaining key care information: medical procedures, equipment and staff. These resources could positively respond to the topics cited as lacking by the interviewed patients and families at the study site. International hospital websites provided considerably more in-depth information compared with UK hospitals. CONCLUSIONS: The hospital experience of children and families can be improved by ensuring they are provided with adequate information relating to their hospital stay. It is essential that suitable high-quality resources are consistently available and that feedback from children informs the process of resource development.

Remote ischaemic conditioning reduces infarct size in animal in vivo models of ischaemia-reperfusion injury: a systematic review and meta-analysis.

Aims: The potential of remote ischaemic conditioning (RIC) to ameliorate myocardial ischaemia-reperfusion injury (IRI) remains controversial. We aimed to analyse the pre-clinical evidence base to ascertain the overall effect and variability of RIC in animal in vivo models of myocardial IRI. Furthermore, we aimed to investigate the impact of different study protocols on the protective utility of RIC in animal models and identify gaps in our understanding of this promising therapeutic strategy. Methods and results: Our primary outcome measure was the difference in mean infarct size between RIC and control groups in in vivo models of myocardial IRI. A systematic review returned 31 reports, from which we made 22 controlled comparisons of remote ischaemic preconditioning (RIPreC) and 21 of remote ischaemic perconditioning and postconditioning (RIPerC/RIPostC) in a pooled random-effects meta-analysis. In total, our analysis includes data from 280 control animals and 373 animals subject to RIC. Overall, RIPreC reduced infarct size as a percentage of area at risk by 22.8% (95% CI 18.8-26.9%), when compared with untreated controls (P < 0.001). Similarly, RIPerC/RIPostC reduced infarct size by 22.2% (95% CI 17.1-25.3%; P < 0.001). Interestingly, we observed significant heterogeneity in effect size (T2 = 92.9% and I2 = 99.4%; P < 0.001) that could not be explained by any of the experimental variables analysed by meta-regression. However, few reports have systematically characterized RIC protocols, and few of the included in vivo studies satisfactorily met study quality requirements, particularly with respect to blinding and randomization. Conclusions: RIC significantly reduces infarct size in in vivo models of myocardial IRI. Heterogeneity between studies could not be explained by the experimental variables tested, but studies are limited in number and lack consistency in quality and study design. There is therefore a clear need for more well-performed in vivo studies with particular emphasis on detailed characterization of RIC protocols and investigating the potential impact of gender. Finally, more studies investigating the potential benefit of RIC in larger species are required before translation to humans.

Exogenous Administration of Recombinant MIF at Physiological Concentrations Failed to Attenuate Infarct Size in a Langendorff Perfused Isolated Mouse Heart Model.

PURPOSE: Evidence suggests a two-pronged role of endogenous macrophage migration inhibitory factor (MIF) release in ischemia/reperfusion injury. We aimed to assess whether its exogenous administration confers cardioprotection. METHODS: Male C57/BL6 mice were randomly allocated to receive recombinant mouse MIF (rMIF) at physiological (ng/mL) concentrations in a dose-response fashion before or after a protocol of 35 min of ischemia and 2 h of reperfusion in an isolated Langendorff-perfused model with infarct size as endpoint. Isolated primary cardiomyocytes were also used for cell survival studies using rMIF at a supra-physiological concentration of 1 µg/mL. Pro-survival kinase activation was also studied using Western blot analyses. RESULTS: Exogenous MIF did not elicit a cardioprotective effect either when administered before the ischemic insult or when applied at reperfusion. rMIF did not confer protection when it was applied immediately before or after a hypoxia/reoxygenation insult in primary isolated cardiomyocytes. Consistently, hearts treated with MIF did not show a significant increase in phosphorylated Akt and ERK1/2. CONCLUSION: The exogenous administration of rMIF in a physiological concentration range both before ischemia and at reperfusion did not show cardioprotective effects. Although these results do not address the role of endogenous MIF after an ischemic insult followed by reperfusion, they may limit the potential translational value of rMIF.

These Shoes Are Made for Walking: Sensitivity Performance Evaluation of Commercial Activity Monitors under the Expected Conditions and Circumstances Required to Achieve the International Daily Step Goal of 10,000 Steps.

INTRODUCTION: Physical activity is a vitally important part of a healthy lifestyle, and is of major benefit to both physical and mental health. A daily step count of 10,000 steps is recommended globally to achieve an appropriate level of physical activity. Accurate quantification of physical activity during conditions reflecting those needed to achieve the recommended daily step count of 10,000 steps is essential. As such, we aimed to assess four commercial activity monitors for their sensitivity/accuracy in a prescribed walking route that reflects a range of surfaces that would typically be used to achieve the recommended daily step count, in two types of footwear expected to be used throughout the day when aiming to achieve the recommended daily step count, and in a timeframe required to do so. METHODS: Four commercial activity monitors were worn simultaneously by participants (n = 15) during a prescribed walking route reflective of surfaces typically encountered while achieving the daily recommended 10,000 steps. Activity monitors tested were the Garmin Vivofit ™, New Lifestyles' NL-2000 ™ pedometer, Withings Smart Activity Monitor Tracker (Pulse O2) ™, and Fitbit One ™. RESULTS: All activity monitors tested were accurate in their step detection over the variety of different surfaces tested (natural lawn grass, gravel, ceramic tile, tarmacadam/asphalt, linoleum), when wearing both running shoes and hard-soled dress shoes. CONCLUSION: All activity monitors tested were accurate in their step detection sensitivity and are valid monitors for physical activity quantification over the variety of different surfaces tested, when wearing both running shoes and hard-soled dress shoes, and over a timeframe necessary for accumulating the recommended daily step count of 10,000 steps. However, it is important to consider the accuracy of activity monitors, particularly when physical activity in the form of stepping activities is prescribed as an intervention in the treatment or prevention of a disease state.

OPA1 in Cardiovascular Health and Disease.

Mitochondria are known to play crucial roles in normal cellular physiology and in more recent years they have been implicated in a wide range of pathologies. Central to both these roles is their ability to alter their shape interchangeably between two different morphologies: an elongated interconnected network and a fragmented discrete phenotype - processes which are under the regulation of the mitochondrial fusion and fission proteins, respectively. In this review article, we focus on the mitochondrial fusion protein optic atrophy protein 1 (OPA1) in cardiovascular health and disease and we explore its role as a potential therapeutic target for treating cardiovascular and metabolic disease.

Targeting mitochondria for cardioprotection: examining the benefit for patients.

Mitochondria are critical for sustaining life, not only as the essential powerhouses of cells but as critical mediators of cell survival and death. Mitochondrial dysfunction has been identified as a key perturbation underlying numerous pathologies including myocardial ischemia-reperfusion injury and the subsequent development of impaired left ventricular systolic function and compensatory cardiac hypertrophy. This article outlines the role of mitochondrial dysfunction in these important cardiac pathologies and highlights current cardioprotective strategies and their clinical efficacy in acute myocardial infarction and heart failure patients. Finally, we explore novel mitochondrial targets and evaluate their potential future translation for clinical cardioprotection.

Loss of PINK1 increases the heart's vulnerability to ischemia-reperfusion injury.

OBJECTIVES: Mutations in PTEN inducible kinase-1 (PINK1) induce mitochondrial dysfunction in dopaminergic neurons resulting in an inherited form of Parkinson's disease. Although PINK1 is present in the heart its exact role there is unclear. We hypothesized that PINK1 protects the heart against acute ischemia reperfusion injury (IRI) by preventing mitochondrial dysfunction. METHODS AND RESULTS: Over-expressing PINK1 in HL-1 cardiac cells reduced cell death following simulated IRI (29.2±5.2% PINK1 versus 49.0±2.4% control; N = 320 cells/group P<0.05), and delayed the onset of mitochondrial permeability transition pore (MPTP) opening (by 1.3 fold; P<0.05). Hearts excised from PINK1+/+, PINK1+/- and PINK1-/- mice were subjected to 35 minutes regional ischemia followed by 30 minutes reperfusion. Interestingly, myocardial infarct size was increased in PINK1-/- hearts compared to PINK1+/+ hearts with an intermediate infarct size in PINK1+/- hearts (25.1±2.0% PINK1+/+, 38.9±3.4% PINK1+/- versus 51.5±4.3% PINK1-/- hearts; N>5 animals/group; P<0.05). Cardiomyocytes isolated from PINK1-/- hearts had a lower resting mitochondrial membrane potential, had inhibited mitochondrial respiration, generated more oxidative stress during simulated IRI, and underwent rigor contracture more rapidly in response to an uncoupler when compared to PINK1+/+ cells suggesting mitochondrial dysfunction in hearts deficient in PINK1. CONCLUSIONS: We show that the loss of PINK1 increases the heart's vulnerability to ischemia-reperfusion injury. This may be due, in part, to increased mitochondrial dysfunction. These findings implicate PINK1 as a novel target for cardioprotection.

Physiological and metabolic diversity in the yeast Kluyveromyces marxianus.

Kluyveromyces marxianus is homothallic hemiascomycete yeast frequently isolated from dairy environments. It possesses phenotypic traits such as enhanced thermotolerance, inulinase production, and rapid growth rate that distinguish it from its closest relative Kluyveromyces lactis. Certain of these traits, notably fermentation of lactose and inulin to ethanol, make this yeast attractive for industrial production of ethanol from inexpensive substrates. There is relatively little known, however, about the diversity in this species, at the genetic, metabolic or physiological levels. This study compared phenotypic traits of 13 K. marxianus strains sourced from two European Culture Collections. A wide variety of responses to thermo, osmotic, and cell wall stress were observed, with some strains showing multi-stress resistance. These traits generally appeared unlinked indicating that, as with other yeasts, multiple resistance/adaptation pathways are present in K. marxianus. The data indicate that it should be possible to identify the molecular basis of traits to facilitate selection or engineering of strains adapted for industrial environments. The loci responsible for mating were also identified by genome sequencing and PCR analysis. It was found that K. marxianus can exist as stable haploid or diploid cells, opening up additional prospects for future strain engineering.