Beneficial and harmful effects of physical activity on care-seeking for low back pain: the AUTBACK study.

PURPOSE: People who seek more care for low back pain (LBP) tend to experience poorer recovery (e.g. higher pain and disability levels). Understanding the factors associated with care-seeking for LBP might improve patient outcomes and potentially alleviate the burden of LBP on global health systems. This study aimed to investigate the relationship between different intensities, volumes, and domains of physical activity and care-seeking behaviours, in people with a history of LBP. METHODS: Longitudinal data from adult twins were drawn from the AUstralian Twin BACK study. The primary outcome was the total self-reported frequency (counts) of overall utilisation of care for LBP, over 1 year. Secondary outcomes were the utilisation of health services, and the utilisation of self-management strategies, for LBP (assessed as total frequency over 1 year). Explanatory variables were device-based measures of sedentary behaviour and moderate-to-vigorous intensity physical activity, and self-reported physical workload, and work, transport, household, and leisure domain physical activity, at baseline. RESULTS: Data from 340 individuals were included. Median age was 56.4 years (IQR 44.9-62.3 years) and 73% of participants were female. Medium-to-high baseline volumes of sedentary behaviour were significantly associated with greater counts of overall care utilisation (IRR 1.60, 95%CI 1.04-2.44) and utilisation of self-management strategies (IRR 1.60, 95%CI 1.02-2.50) for LBP, over 1 year. Medium-to-high baseline volumes of household domain physical activity were significantly associated with greater counts of utilising self-management strategies for LBP over 1 year (IRR 1.62, 95%CI 1.04-2.53). No explanatory variables were associated with the utilisation of health services for LBP. CONCLUSION: People who engage in higher baseline volumes of sedentary behaviour or physical activity in the household setting (e.g. housework, gardening, yard work, general household maintenance) utilise 1.6 times more care for LBP over 1 year. Findings suggest that higher volumes of these behaviours may be harmful for LBP. No intensities, volumes, or domains of physical activity demonstrated clear benefits for LBP. Where feasible, patients and clinicians should collaborate to screen and develop strategies to reduce engagement in sedentary behaviour or physical activity in the household setting. Contextual factors (e.g. patient symptom severity, sociocultural roles, occupational demands) should be considered when devising appropriate behaviour change strategies.

Urinary metabolite quantitative trait loci in children and their interaction with dietary factors.

Human metabolism is influenced by genetic and environmental factors. Previous studies have identified over 23 loci associated with more than 26 urine metabolites levels in adults, which are known as urinary metabolite quantitative trait loci (metabQTLs). The aim of the present study is the identification for the first time of urinary metabQTLs in children and their interaction with dietary patterns. Association between genome-wide genotyping data and 44 urine metabolite levels measured by proton nuclear magnetic resonance spectroscopy was tested in 996 children from the Human Early Life Exposome project. Twelve statistically significant urine metabQTLs were identified, involving 11 unique loci and 10 different metabolites. Comparison with previous findings in adults revealed that six metabQTLs were already known, and one had been described in serum and three were involved the same locus as other reported metabQTLs but had different urinary metabolites. The remaining two metabQTLs represent novel urine metabolite-locus associations, which are reported for the first time in this study [single nucleotide polymorphism (SNP) rs12575496 for taurine, and the missense SNP rs2274870 for 3-hydroxyisobutyrate]. Moreover, it was found that urinary taurine levels were affected by the combined action of genetic variation and dietary patterns of meat intake as well as by the interaction of this SNP with beverage intake dietary patterns. Overall, we identified 12 urinary metabQTLs in children, including two novel associations. While a substantial part of the identified loci affected urinary metabolite levels both in children and in adults, the metabQTL for taurine seemed to be specific to children and interacted with dietary patterns.

Automated Annotation of Untargeted All-Ion Fragmentation LC-MS Metabolomics Data with MetaboAnnotatoR.

Untargeted metabolomics and lipidomics LC-MS experiments produce complex datasets, usually containing tens of thousands of features from thousands of metabolites whose annotation requires additional MS/MS experiments and expert knowledge. All-ion fragmentation (AIF) LC-MS/MS acquisition provides fragmentation data at no additional experimental time cost. However, analysis of such datasets requires reconstruction of parent-fragment relationships and annotation of the resulting pseudo-MS/MS spectra. Here, we propose a novel approach for automated annotation of isotopologues, adducts, and in-source fragments from AIF LC-MS datasets by combining correlation-based parent-fragment linking with molecular fragment matching. Our workflow focuses on a subset of features rather than trying to annotate the full dataset, saving time and simplifying the process. We demonstrate the workflow in three human serum datasets containing 599 features manually annotated by experts. Precision and recall values of 82-92% and 82-85%, respectively, were obtained for features found in the highest-rank scores (1-5). These results equal or outperform those obtained using MS-DIAL software, the current state of the art for AIF data annotation. Further validation for other biological matrices and different instrument types showed variable precision (60-89%) and recall (10-88%) particularly for datasets dominated by nonlipid metabolites. The workflow is freely available as an open-source R package, MetaboAnnotatoR, together with the fragment libraries from Github (https://github.com/gggraca/MetaboAnnotatoR).

High-flow nasal cannula versus non-invasive ventilation for acute hypercapnic respiratory failure in adults: a systematic review and meta-analysis of randomized trials.

BACKGROUND: Non-invasive ventilation (NIV) with bi-level positive pressure ventilation is a first-line intervention for selected patients with acute hypercapnic respiratory failure. Compared to conventional oxygen therapy, NIV may reduce endotracheal intubation, death, and intensive care unit length of stay (LOS), but its use is often limited by patient tolerance and treatment failure. High-flow nasal cannula (HFNC) is a potential alternative treatment in this patient population and may be better tolerated. RESEARCH QUESTION: For patients presenting with acute hypercapnic respiratory failure, is HFNC an effective alternative to NIV in reducing the need for intubation? METHODS: We searched EMBASE, MEDLINE, and the Cochrane library from database inception through to October 2021 for randomized clinical trials (RCT) of adults with acute hypercapnic respiratory failure assigned to receive HFNC or NIV. The Cochrane risk-of-bias tool for randomized trials was used to assess risk of bias. We calculated pooled relative risks (RR) for dichotomous outcomes and mean differences (MD) for continuous outcomes, with corresponding 95% confidence intervals (CI) using a random-effects model. RESULTS: We included eight RCTs (n = 528) in the final analysis. The use of HFNC compared to NIV did not reduce the risk of our primary outcome of mortality (RR 0.86, 95% CI 0.48-1.56, low certainty), or our secondary outcomes including endotracheal intubation (RR 0.80, 95% CI 0.46-1.39, low certainty), or hospital LOS (MD - 0.82 days, 95% CI - 1.83-0.20, high certainty). There was no difference in change in partial pressure of carbon dioxide between groups (MD - 1.87 mmHg, 95% CI - 5.34-1.60, moderate certainty). INTERPRETATION: The current body of evidence is limited in determining whether HFNC may be either superior, inferior, or equivalent to NIV for patients with acute hypercapnic respiratory failure given imprecision and study heterogeneity. Further studies are needed to better understand the effect of HFNC on this population.

DNA methylation age as a biomarker for cancer.

Cancer is well established as an age-associated disease, and there is substantial overlap in the molecular, cellular and physiological changes observed with both ageing and the progression of cancer. Age-specific declines in resilience mechanisms such as DNA repair or epigenetic maintenance may contribute to the development of cancer. These declines may be assessed through biomarkers that measure biological age and through the related concept of "age acceleration". Epigenetic clocks, assessed through DNA methylation levels, are among the most widely used biological age markers in cancer studies. In this review, we discuss the use of DNA methylation ageing measures to predict population cancer incidence, mortality and survival. Blood-based DNA methylation age estimators appear to be promising measures of increased cancer risk and mortality, although their reported effects are generally weak, thus its clinical relevance remains to be validated in large case-cohort and longitudinal studies. Future development of epigenetic and other biological age biomarkers will likely further elucidate the links between ageing and cancer.

Variability of multi-omics profiles in a population-based child cohort.

BACKGROUND: Multiple omics technologies are increasingly applied to detect early, subtle molecular responses to environmental stressors for future disease risk prevention. However, there is an urgent need for further evaluation of stability and variability of omics profiles in healthy individuals, especially during childhood. METHODS: We aimed to estimate intra-, inter-individual and cohort variability of multi-omics profiles (blood DNA methylation, gene expression, miRNA, proteins and serum and urine metabolites) measured 6 months apart in 156 healthy children from five European countries. We further performed a multi-omics network analysis to establish clusters of co-varying omics features and assessed the contribution of key variables (including biological traits and sample collection parameters) to omics variability. RESULTS: All omics displayed a large range of intra- and inter-individual variability depending on each omics feature, although all presented a highest median intra-individual variability. DNA methylation was the most stable profile (median 37.6% inter-individual variability) while gene expression was the least stable (6.6%). Among the least stable features, we identified 1% cross-omics co-variation between CpGs and metabolites (e.g. glucose and CpGs related to obesity and type 2 diabetes). Explanatory variables, including age and body mass index (BMI), explained up to 9% of serum metabolite variability. CONCLUSIONS: Methylation and targeted serum metabolomics are the most reliable omics to implement in single time-point measurements in large cross-sectional studies. In the case of metabolomics, sample collection and individual traits (e.g. BMI) are important parameters to control for improved comparability, at the study design or analysis stage. This study will be valuable for the design and interpretation of epidemiological studies that aim to link omics signatures to disease, environmental exposures, or both.

Optimal method for metabolic tumour volume assessment of cervical cancers with inter-observer agreement on [18F]-fluoro-deoxy-glucose positron emission tomography with computed tomography.

PURPOSE: Cervical cancer metabolic tumour volume (MTV) derived from [18F]-FDG PET/CT has a role in prognostication and therapy planning. There is no standard method of outlining MTV on [18F]-FDG PET/CT. The aim of this study was to assess the optimal method to outline primary cervical tumours on [18F]-FDG PET/CT using MRI-derived tumour volumes as the reference standard. METHODS: 81 consecutive cervical cancer patients with pre-treatment staging MRI and [18F]-FDG PET/CT imaging were included. MRI volumes were compared with different PET segmentation methods. Method 1 measured MTVs at different SUVmax thresholds ranging from 20 to 60% (MTV20-MTV60) with bladder masking and manual adjustment when required. Method 2 created an isocontour around the tumour prior to different SUVmax thresholds being applied. Method 3 used an automated gradient method. Inter-observer agreement of MTV, following manual adjustment when required, was recorded. RESULTS: For method 1, the MTV25 and MTV30 were closest to the MRI volumes for both readers (mean percentage change from MRI volume of 2.9% and 13.4% for MTV25 and - 13.1% and - 2.0% for MTV30 for readers 1 and 2). 70% of lesions required manual adjustment at MTV25 compared with 45% at MTV30. There was excellent inter-observer agreement between MTV30 to MTV60 (ICC ranged from 0.898-0.976 with narrow 95% confidence intervals (CIs)) and moderate agreement at lower thresholds (ICC estimates of 0.534 and 0.617, respectively for the MTV20 and MTV25 with wide 95% CIs). Bladder masking was performed in 86% of cases overall. For method 2, excellent correlation was demonstrated at MTV25 and MTV30 (mean % change from MRI volume of -3.9% and - 8.6% for MTV25 and - 16.9% and 19% for MTV30 for readers 1 and 2, respectively). This method also demonstrated excellent ICC across all thresholds with no manual adjustment. Method 3 demonstrated excellent ICC of 0.96 (95% CI 0.94-0.97) but had a mean percentage difference from the MRI volume of - 19.1 and - 18.2% for readers 1 and 2, respectively. 21% required manual adjustment for both readers. CONCLUSION: MTV30 provides the optimal correlation with MRI volume taking into consideration the excellent inter-reader agreement and less requirement for manual adjustment.

Early COVID-19 pandemic modeling: Three compartmental model case studies from Texas, USA.

The novel coronavirus (SARS-CoV-2) emerged in late 2019 and spread globally in early 2020. Initial reports suggested the associated disease, COVID-19, produced rapid epidemic growth and caused high mortality. As the virus sparked local epidemics in new communities, health systems and policy makers were forced to make decisions with limited information about the spread of the disease. We developed a compartmental model to project COVID-19 healthcare demands that combined information regarding SARS-CoV-2 transmission dynamics from international reports with local COVID-19 hospital census data to support response efforts in three Metropolitan Statistical Areas (MSAs) in Texas, USA: Austin-Round Rock, Houston-The Woodlands-Sugar Land, and Beaumont-Port Arthur. Our model projects that strict stay-home orders and other social distancing measures could suppress the spread of the pandemic. Our capacity to provide rapid decision-support in response to emerging threats depends on access to data, validated modeling approaches, careful uncertainty quantification, and adequate computational resources.

In utero and childhood exposure to tobacco smoke and multi-layer molecular signatures in children.

BACKGROUND: The adverse health effects of early life exposure to tobacco smoking have been widely reported. In spite of this, the underlying molecular mechanisms of in utero and postnatal exposure to tobacco smoke are only partially understood. Here, we aimed to identify multi-layer molecular signatures associated with exposure to tobacco smoke in these two exposure windows. METHODS: We investigated the associations of maternal smoking during pregnancy and childhood secondhand smoke (SHS) exposure with molecular features measured in 1203 European children (mean age 8.1 years) from the Human Early Life Exposome (HELIX) project. Molecular features, covering 4 layers, included blood DNA methylation and gene and miRNA transcription, plasma proteins, and sera and urinary metabolites. RESULTS: Maternal smoking during pregnancy was associated with DNA methylation changes at 18 loci in child blood. DNA methylation at 5 of these loci was related to expression of the nearby genes. However, the expression of these genes themselves was only weakly associated with maternal smoking. Conversely, childhood SHS was not associated with blood DNA methylation or transcription patterns, but with reduced levels of several serum metabolites and with increased plasma PAI1 (plasminogen activator inhibitor-1), a protein that inhibits fibrinolysis. Some of the in utero and childhood smoking-related molecular marks showed dose-response trends, with stronger effects with higher dose or longer duration of the exposure. CONCLUSION: In this first study covering multi-layer molecular features, pregnancy and childhood exposure to tobacco smoke were associated with distinct molecular phenotypes in children. The persistent and dose-dependent changes in the methylome make CpGs good candidates to develop biomarkers of past exposure. Moreover, compared to methylation, the weak association of maternal smoking in pregnancy with gene expression suggests different reversal rates and a methylation-based memory to past exposures. Finally, certain metabolites and protein markers evidenced potential early biological effects of postnatal SHS, such as fibrinolysis.

Exploring Cancer Metabolism: Applications of Metabolomics and Metabolic Phenotyping in Cancer Research and Diagnostics.

Altered metabolism is one of the key hallmarks of cancer. The development of sensitive, reproducible and robust bioanalytical tools such as Nuclear Magnetic Resonance Spectroscopy and Mass Spectrometry techniques offers numerous opportunities for cancer metabolism research, and provides additional and exciting avenues in cancer diagnosis, prognosis and for the development of more effective and personalized treatments. In this chapter, we introduce the current state of the art of metabolomics and metabolic phenotyping approaches in cancer research and clinical diagnostics.

Determinants of the urinary and serum metabolome in children from six European populations.

BACKGROUND: Environment and diet in early life can affect development and health throughout the life course. Metabolic phenotyping of urine and serum represents a complementary systems-wide approach to elucidate environment-health interactions. However, large-scale metabolome studies in children combining analyses of these biological fluids are lacking. Here, we sought to characterise the major determinants of the child metabolome and to define metabolite associations with age, sex, BMI and dietary habits in European children, by exploiting a unique biobank established as part of the Human Early-Life Exposome project ( http://www.projecthelix.eu ). METHODS: Metabolic phenotypes of matched urine and serum samples from 1192 children (aged 6-11) recruited from birth cohorts in six European countries were measured using high-throughput 1H nuclear magnetic resonance (NMR) spectroscopy and a targeted LC-MS/MS metabolomic assay (Biocrates AbsoluteIDQ p180 kit). RESULTS: We identified both urinary and serum creatinine to be positively associated with age. Metabolic associations to BMI z-score included a novel association with urinary 4-deoxyerythreonic acid in addition to valine, serum carnitine, short-chain acylcarnitines (C3, C5), glutamate, BCAAs, lysophosphatidylcholines (lysoPC a C14:0, lysoPC a C16:1, lysoPC a C18:1, lysoPC a C18:2) and sphingolipids (SM C16:0, SM C16:1, SM C18:1). Dietary-metabolite associations included urinary creatine and serum phosphatidylcholines (4) with meat intake, serum phosphatidylcholines (12) with fish, urinary hippurate with vegetables, and urinary proline betaine and hippurate with fruit intake. Population-specific variance (age, sex, BMI, ethnicity, dietary and country of origin) was better captured in the serum than in the urine profile; these factors explained a median of 9.0% variance amongst serum metabolites versus a median of 5.1% amongst urinary metabolites. Metabolic pathway correlations were identified, and concentrations of corresponding metabolites were significantly correlated (r > 0.18) between urine and serum. CONCLUSIONS: We have established a pan-European reference metabolome for urine and serum of healthy children and gathered critical resources not previously available for future investigations into the influence of the metabolome on child health. The six European cohort populations studied share common metabolic associations with age, sex, BMI z-score and main dietary habits. Furthermore, we have identified a novel metabolic association between threonine catabolism and BMI of children.

USA300, A strain of community-associated methicillin-resistant Staphylococcus aureus, crossing Belgium's borders: outbreak of skin and soft tissue infections in a hospital in Belgium.

OBJECTIVE: to investigate an outbreak of community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) USA300 in a hospital setting, and the effect of infection control measures. DESIGN: outbreak investigation and retrospective chart review. SETTING: local inpatient and outpatient clinic. PATIENTS: all patients with a history of skin and soft tissue infections with culture-confirmed methicillin-resistant Staphylococcus aureus USA 300 infection from September, 2014, through June, 2015. INTERVENTIONS: an outbreak investigation with a "search and destroy" policy was carried out. A review of infection control practices was conducted. Chart reviews were conducted to study the management and outcomes of the patients. Infection control measures included education and cultures of skin colonization sites (anterior nares, pharynx, perineum). Specific decontamination schemes for uncomplicated and complicated carriers were enforced. Separate decontamination schemes for neonates and children under 5 years of age were implemented. RESULTS: between September 2014 and June 2015, 12 clinical cases and six carriers were identified. Of the twelve clinical presentations with positive cultures, eight were children. Of the four patients who had a relapse, three were children (75%). After outbreak investigation and infection control measures have been implemented, three persistent carriers remained. A policy of periodic screening, consultation, and watchful waiting for skin infections was instituted for these patients. No new cases linked to the CA-MRSA outbreak have since been reported. CONCLUSION: we report the first Belgian outbreak of CA-MRSA USA300 in this article. A strict search and destroy strategy and continued surveillance are required in the management of CA-MRSA USA300.

Interaction between synaptic inhibition and glial-potassium dynamics leads to diverse seizure transition modes in biophysical models of human focal seizures.

How focal seizures initiate and evolve in human neocortex remains a fundamental problem in neuroscience. Here, we use biophysical neuronal network models of neocortical patches to study how the interaction between inhibition and extracellular potassium ([K (+)] o ) dynamics may contribute to different types of focal seizures. Three main types of propagated focal seizures observed in recent intracortical microelectrode recordings in humans were modelled: seizures characterized by sustained (∼30-60 Hz) gamma local field potential (LFP) oscillations; seizures where the onset in the propagated site consisted of LFP spikes that later evolved into rhythmic (∼2-3 Hz) spike-wave complexes (SWCs); and seizures where a brief stage of low-amplitude fast-oscillation (∼10-20 Hz) LFPs preceded the SWC activity. Our findings are fourfold: (1) The interaction between elevated [K (+)] o (due to abnormal potassium buffering by glial cells) and the strength of synaptic inhibition plays a predominant role in shaping these three types of seizures. (2) Strengthening of inhibition leads to the onset of sustained narrowband gamma seizures. (3) Transition into SWC seizures is obtained either by the weakening of inhibitory synapses, or by a transient strengthening followed by an inhibitory breakdown (e.g. GABA depletion). This reduction or breakdown of inhibition among fast-spiking (FS) inhibitory interneurons increases their spiking activity and leads them eventually into depolarization block. Ictal spike-wave discharges in the model are then sustained solely by pyramidal neurons. (4) FS cell dynamics are also critical for seizures where the evolution into SWC activity is preceded by low-amplitude fast oscillations. Different levels of elevated [K (+)] o were important for transitions into and maintenance of sustained gamma oscillations and SWC discharges. Overall, our modelling study predicts that the interaction between inhibitory interneurons and [K (+)] o glial buffering under abnormal conditions may explain different types of ictal transitions and dynamics during propagated seizures in human focal epilepsy.

Yunis-varon syndrome: further delineation of cardiovascular and endocrine outcome.

Yunis-Varon syndrome is a rare autosomal recessive condition initially characterized by specific skeletal and ectodermal abnormalities, and a poor prognosis, due to neurological and cardiovascular involvement. We describe the cardiovascular and endocrine complications in a 26-year-old man who had been reported previously, adding dilated cardiomyopathy to the clinical features consistent with Yunis-Varon syndrome. Short stature, successfully treated with growth hormone, and hypertension secondary to bilateral renal artery stenosis expand the phenotype.

Predicting Brain Amyloid Status Using the National Institute of Health Toolbox (NIHTB) for Assessment of Neurological and Behavioral Function.

BACKGROUND: Amyloid-beta (Aß) plaque is a neuropathological hallmark of Alzheimer's disease (AD). As anti-amyloid monoclonal antibodies enter the market, predicting brain amyloid status is critical to determine treatment eligibility. OBJECTIVE: To predict brain amyloid status utilizing machine learning approaches in the Advancing Reliable Measurement in Alzheimer's Disease and Cognitive Aging (ARMADA) study. DESIGN: ARMADA is a multisite study that implemented the National Institute of Health Toolbox for Assessment of Neurological and Behavioral Function (NIHTB) in older adults with different cognitive ability levels (normal, mild cognitive impairment, early-stage dementia of the AD type). SETTING: Participants across various sites were involved in the ARMADA study for validating the NIHTB. PARTICIPANTS: 199 ARMADA participants had either PET or CSF information (mean age 76.3 ± 7.7, 51.3% women, 42.3% some or complete college education, 50.3% graduate education, 88.9% White, 33.2% with positive AD biomarkers). MEASUREMENTS: We used cognition, emotion, motor, sensation scores from NIHTB, and demographics to predict amyloid status measured by PET or CSF. We applied LASSO and random forest models and used the area under the receiver operating curve (AUROC) to evaluate the ability to identify amyloid positivity. RESULTS: The random forest model reached AUROC of 0.74 with higher specificity than sensitivity (AUROC 95% CI:0.73 - 0.76, Sensitivity 0.50, Specificity 0.88) on the held-out test set; higher than the LASSO model (0.68 (95% CI:0.68 - 0.69)). The 10 features with the highest importance from the random forest model are: picture sequence memory, cognition total composite, cognition fluid composite, list sorting working memory, words-in-noise test (hearing), pattern comparison processing speed, odor identification, 2-minutes-walk endurance, 4-meter walk gait speed, and picture vocabulary. Overall, our model revealed the validity of measurements in cognition, motor, and sensation domains, in associating with AD biomarkers. CONCLUSION: Our results support the utilization of the NIH toolbox as an efficient and standardizable AD biomarker measurement that is better at identifying amyloid negative (i.e., high specificity) than positive cases (i.e., low sensitivity).

NMR metabolomic modeling of age and lifespan: A multicohort analysis.

Metabolomic age models have been proposed for the study of biological aging, however, they have not been widely validated. We aimed to assess the performance of newly developed and existing nuclear magnetic resonance spectroscopy (NMR) metabolomic age models for prediction of chronological age (CA), mortality, and age-related disease. Ninety-eight metabolic variables were measured in blood from nine UK and Finnish cohort studies (N ≈31,000 individuals, age range 24-86 years). We used nonlinear and penalized regression to model CA and time to all-cause mortality. We examined associations of four new and two previously published metabolomic age models, with aging risk factors and phenotypes. Within the UK Biobank (N ≈102,000), we tested prediction of CA, incident disease (cardiovascular disease (CVD), type-2 diabetes mellitus, cancer, dementia, and chronic obstructive pulmonary disease), and all-cause mortality. Seven-fold cross-validated Pearson's r between metabolomic age models and CA ranged between 0.47 and 0.65 in the training cohort set (mean absolute error: 8-9 years). Metabolomic age models, adjusted for CA, were associated with C-reactive protein, and inversely associated with glomerular filtration rate. Positively associated risk factors included obesity, diabetes, smoking, and physical inactivity. In UK Biobank, correlations of metabolomic age with CA were modest (r = 0.29-0.33), yet all metabolomic model scores predicted mortality (hazard ratios of 1.01 to 1.06/metabolomic age year) and CVD, after adjustment for CA. While metabolomic age models were only moderately associated with CA in an independent population, they provided additional prediction of morbidity and mortality over CA itself, suggesting their wider applicability.

Coinfection of hepatitis B and hepatitis delta virus in Belgium: a multicenter BASL study. Prospective epidemiology and comparison with HBV mono-infection.

Epidemiological data on hepatitis delta virus (HDV) infection in Belgium are lacking. A multicenter questionnaire-based registry on HDV infection was collated between March 1, 2008 and February 28, 2009. It consisted of patients coinfected with hepatitis B virus (HBV) and HDV. The data samples were compared to those of a concurrent registry on HBV infection. Prospective data of patients with HBV-HDV coinfection were collected. Active HBV replication is defined as HBeAg positivity or HBV DNA > 2,000 IU/ml. Forty-four patients from 15 centers were registered. A comparison of 29 patients infected with HDV (registered in the concurrent HBV registry) was made against 785 HBV mono-infected patients. The seroprevalence of patients coinfected with HBV and HDV in Belgium is reported to be 3.7% (29/785), consisting solely of the HBV-HDV coinfected patients in the HBV registry. This rises to 5.5% (44/800) if all patients infected with HDV from the two registries combined are included. The patients coinfected with HBV and HDV had higher (P < 0.05) ALT values and more advanced liver disease (Metavir score ≥F2), but had less active HBV replication and lower HBV DNA titers when compared with the patients infected only with HBV. Additionally, the majority of HBV-HDV coinfected patient was male, and 13.6% (6/44) of the patients that were coinfected HBV and HDV were also infected with HCV. In conclusion, this study provided much needed epidemiological data on the current state of HDV infection in Belgium.

von Willebrand factor contributes to longer half-life of PEGylated factor VIII in vivo.

PEGylation of B-domain deleted factor VIII (PEG-FVIII-BDD) prolongs the half-life of the molecule by approximately twofold in animals (Mei et al., Blood 2010; 116: 270). To investigate the role of von Willebrand factor (vWF) in the catabolism of PEG-FVIII-BDD in vivo, a FVIII-BDD mutant (F8V), which is incapable of binding vWF, was generated by deleting the vWF-binding region in the a3 domain of FVIIII-BDD. F8V was expressed, purified and PEGylated by site-specific conjugation. The biochemical and biological properties of F8V and PEGylated F8V (PEG-F8V) were evaluated in vitro and in vivo. The specific activity of purified F8V by a chromogenic assay was similar to FVIII-BDD and PEGylation had minimal impact on the specific activity of F8V in this assay. Analysis by Biacore indicated that both F8V and PEG-F8V display greatly reduced vWF binding in vitro. Pharmacokinetic studies in FVIII knockout (HaemA) mice showed that the terminal half-life (T1/2 ) of F8V was dramatically reduced relative to FVIII-BDD (0.6 h vs. 6.03 h). PEGylation of F8V promoted a significant increase in T1/2 , although PEGylation did not fully compensate for the loss in vWF binding. PEG-F8V showed a shorter T1/2 than PEG-FVIII-BDD both in HaemA mice (7.7 h vs. 14.3 h) and in Sprague-Dawley male rats (2.0 ± 0.3 h vs. 6.0 ± 0.5 h). These data demonstrated that vWF contributes to the longer T1/2 of PEG-FVIII-BDD. Furthermore, this suggests that the clearance of the FVIII:vWF complex, through vWF receptors, is not the sole factor which places an upper limit on the duration of PEG-FVIII circulation in plasma.

Pseudoaneurysms around the foot and ankle: case report and literature review.

Pseudoaneurysms developing around the foot and ankle are known to be an uncommon complication following surgery. We present a case of a pseudoaneurysm following ankle surgery for a tibial plafond fracture and comprehensively review the literature with emphasis on their anatomic location, aetiology and treatment options.