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The experience of our conscience belongs in the same category as feeling, thinking and wanting. However, it has a special aspect, namely the presence of other human beings as absolute entities. The process of experience is concerned with the way to best promote your own interests, with how far you will go in actualising your essential characteristics as an absolute entity. The discussion of our urge for survival shows that we can go quite far in that respect, and that to actualise that urge, there are in fact no boundaries; everything is permitted. The same can be said about actualising our other essential characteristics, but the difference is that our need to do so is perhaps less cogently present; it is not our life, or at least not our continued material existence, that is at stake. Nonetheless, we can and may even choose to go to extremes in this respect and thus to give ourselves priority over others. Respect for the interests of others is based on self-respect, which may lead you to decide to subject your dealings with other people to a set of standards for yourself. Here we enter the area of morals and ethics, to which we can attach a complete moral philosophy and on the basis of a belief, a moral theology. At the end of this road is total love of yourself and others, because you have come to realise that it is the only way that can lead to the fourth essential characteristic of human beings as, absolute entities, namely self-fulfilment. You will then have developed in a way that allows you to yourself and others the scope we need as absolute entities. (compassion, solidarity). Self-fulfilment is achieved through self-development, i.e. discovering and honing our gifts and talents and thus finding our own identity (development), a process by which the lives of human beings as absolute entities acquire purpose (the search for meaning). Self-fulfilment is self-actualisation, the that results from the realisation of the essential characteristics of human beings as absolute entities, and it leads to satisfaction derived from ourselves or our activities, a sense of being satisfied with what we have accomplished.

Abstract Parvovirus B19V (B19V) infection during pregnancy can be complicated by potentially life-threatening fetal hydrops, which can be managed by intrauterine transfusion (IUT). This study investigates the long-term temporal patterns in the epidemiology of B19V and evaluates the impact on fetal hydrops, by combining data on B19V infections from the Dutch Sentinel Surveillance system in the period 1990 to 2023, Dutch blood banking data and hospital data on fetal hydrops. Using wavelet analysis, we identified annual epidemic cycles in the Netherlands in the period 1990–2019 and we identified superimposed multiannual cycles in the period 1990–2009. After 2009, no multiannual cycle could be identified, although the incidence fluctuated and correlates with number of IUT performed. As of 2020, weekly reports of B19V infection demonstrated a historically low incidence and B19V-DNA positive blood donors were nearly absent. From May 2020 to May 2023, no IUT for B19V-related hydrops was performed. In the spring of 2023, B19V infections re-emerged, reaching pre-pandemic epidemic levels. Due to the changes in B19V epidemiology over the last 30 years and the near-absence of B19V during the COVID-19 pandemic, the resulting low immunity levels may lead to rebound outbreaks. Alertness to severe complications such as fetal hydrops is warranted.

Abstract Background and Aim This study investigates temporal trends in gastrointestinal cancer‐related mortality in the United States between 1999 and 2020, focusing on differences by sex, age, and race. Methods We investigated the Centers for Disease Control and Prevention Wide‐Ranging Online Data for Epidemiologic Research multiple causes of death database (Years 1999–2020) for gastrointestinal cancer‐related mortality with a focus on the underlying cause of death. Results A total of 3 115 243 gastrointestinal cancer‐related deaths occurred from 1999 to 2020. The overall age‐adjusted mortality rate decreased from 46.7 per 100 000 in 1999 to 38.4 per 100 000 in 2020. The average annual percent change (AAPC) for the study period was −0.9% (95% CI: −1.0%, −0.9%, P

Abstract. Introduction:. Lumbosacral radiculopathy (LR), also known as sciatica, is a common type of radiating neurologic pain involving burning, tingling, and numbness in the lower extremities. It has an estimated lifetime prevalence as high as 43%. Objectives:. The objective of this randomized controlled trial was to evaluate the impact of virtually delivered Mindfulness-Oriented Recovery Enhancement (MORE) on patients with LR during the COVID-19 pandemic. Methods:. Potentially eligible patients were identified using electronic health record queries and phone screenings. Participants were then randomized to MORE or treatment-as-usual (TAU) for 8 weeks, with pain intensity assessed daily. At baseline and follow-up visits, participants completed questionnaires assessing the primary outcome, disability, as well as quality of life, depression, mindful reinterpretation of pain, and trait mindfulness. Results:. In our study, patients undergoing virtual delivery of MORE had greater improvements in daily pain intensity (P = 0.002) but not in disability (P = 0.09), depression (P = 0.26), or quality of life (P = 0.99 and P = 0.89, SF-12 physical and mental component scores, respectively), relative to TAU patients. In addition, patients in MORE experienced significantly greater increases in mindful reinterpretation of pain (P = 0.029) and trait mindfulness (P = 0.035). Conclusion:. Among patients with lumbar radiculopathy, MORE significantly reduced daily pain intensity but did not decrease disability or depression symptoms. Given the long duration of symptoms in our sample, we hypothesize the discrepancy between changes in daily pain intensity and disability is due to fear avoidance behaviors common in patients with chronic pain. As the first trial of a mindfulness intervention in patients with LR, these findings should inform future integrative approaches to LR treatment, particularly when considering the increasing use of virtual interventions throughout the COVID-19 pandemic.

Background: Presumptive tuberculosis (TB) cases commonly had two to three sputum examinations in Taiwan. The incremental yield of serial sputum examinations has not been assessed before. Methods: In a pragmatic trial, presumptive TB patients with a frontline nucleic acid amplification test (NAAT) were classified as group A. Those without a frontline NAAT were randomized into group B frontline NAAT as intervention, and group C usual care. We investigated expected incremental yields and the number of examinations required for detection of one additional TB case from each serial sputum smear and culture. Results: Of 6835 presumptive TB cases, 395 (5.8%) were smear positive for acid-fast bacilli, and 195 (2.8%) culture positive for M tuberculosis. The expected incremental yield from a third smear was 3.5% and examination of 1712 (95% credibility interval 586–4706) third smears was required to detected one additional TB case. Sensitivity of one smear with an NAAT in group B was 46.8% (95% confidence interval 32.1%–61.9%), and that of two smears in Group C 40.0% (95% confidence interval 25.7%–55.7%). The expected incremental yield from a third culture was 8.4%, and the number of third cultures required to detect one additional TB case was 394 (95% credibility interval 231–670). Conclusions: The incremental yield of the third sputum smear was negligible. It may be reasonable to perform an NAAT, smear and culture on the first specimen and culture alone on the second. The utility of the third serial culture for the detection of additional TB case is debatable.

The role of the microbiota in health and disease is a research area receiving much attention in academia and industry. A person’s microbiota refers to a community of microorganisms found mainly in the gut. It is estimated that around 39 trillion bacteria can be found on and inside the human body and there is increasing evidence that they influence human health. Advances in sequencing techniques are revolutionizing characterization of the human microbiome. However, causality and underlying molecular mechanisms are still largely unknown due to the complexity of the human microbiome and its interaction with the host. Turning towards simpler host organisms and using well-defined microbiomes are two ways to strengthen studies of causality and mechanism. Here, we show that the nematode Caenorhabditis elegans can be used as host to study sub-microbiomes derived from human feces samples prepared for fecal microbiota transplantation following a simple feeding protocol. Approximately 200 amplicon sequence variants were identified in the worm gut following transplantation with human fecal microbiota samples. We find that the gut microbiome does not simply reflect the bacterial community initially fed to the worms. Hence, our experimental setup can be used to identify and characterize host genetic factors shaping the microbiota and improving our understanding of host–human microbiome interactions.

IntroductionSerological surveillance is useful for assessing SARS-CoV-2 immunity in populations. To effectively study the presence and persistence of antibodies, it is necessary to distinguish between persons with past infection, and persons who only received vaccination. Knowledge of the duration of antibody persistence is essential for correct interpretation of surveillance results.MethodsStarting in April 2020, waning of SARS-CoV-2 antibodies was studied in a longitudinal cohort study of 495 SARS-CoV-2 antibody-positive Dutch blood donors, not pre-selected by PCR testing or disease severity. Additionally, in May 2021, a sample of donors representative for the Dutch population was tested for antibodies against the SARS-CoV-2 spike (S) protein, using the Wantai Ab ELISA and the Elecsys® Anti-SARS-CoV-2 S assay; and for antibodies against the nucleocapsid protein, which indicate past infection, using the Elecsys® Anti-SARS-CoV-2 assay.ResultsThe anti-S response in donors that were infected in April or May 2020 remained positive in 100% of donors in the Elecsys® Anti-SARS-CoV-2 S assay one year after infection, after which follow up of waning was no longer possible because of large scale vaccination. The anti-nucleocapsid response results were still positive in approximately 80% of donors two years after infection. In May 2021, 51% of the donors showed anti-S reactivity and 16.8% tested positive for anti-nucleocapsid antibodies.ConclusionInfection with SARS-CoV-2 resulted in spike and nucleocapsid antibody levels still detectable in the majority of donors 1-2 years after infection. In May 2021, 51% of donors were vaccinated and 16.8% had had an infection. Thus, both Elecsys® SARS-CoV-2 antibody assays can be used to reliably assess the vaccination and infection status of individuals.

Introduction: In 2020, the first Dutch West Nile virus (WNV) infected birds were detected through risk-targeted surveillance of songbirds. Retrospective testing of patients with unexplained neurological disease revealed human WNV infections in July and August 2020. Bird ringers are highly exposed to mosquito bites and possibly avian excrements during ringing activities. This study therefore investigates whether bird ringers are at higher risk of exposure to WNV and Usutu virus (USUV). Methods: Dutch bird ringers were asked to provide a single serum sample (May – September 2021) and to fill out a survey. Sera were screened by protein microarray for presence of specific IgG against WNV and USUV non-structural protein 1 (NS1), followed by focus reduction virus neutralization tests (FRNT). Healthcare workers (2009–2010), the national immunity cohort (2016–2017) and blood donors (2021) were used as control groups without this occupational exposure. Results: The majority of the 157 participating bird ringers was male (132/157, 84%) and the median age was 62 years. Thirty-seven participants (37/157, 23.6%) showed WNV and USUV IgG microarray signals above background, compared to 6.4% (6/94) in the community cohort and 2.1% (2/96) in blood donors (p

Abstract Background A higher protein intake has been associated with a higher muscle mass and lower mortality rates in the general population, but data about protein intake and survival in patients with heart failure (HF) are lacking. Methods We studied the prevalence, predictors, and clinical outcome of estimated protein intake in 2516 patients from the BIOlogy Study to TAilored Treatment in Chronic Heart Failure (BIOSTAT‐CHF) index cohort. Protein intake was calculated in spot urine samples using a validated formula [13.9 + 0.907 * body mass index (BMI) (kg/m2) + 0.0305 * urinary urea nitrogen level (mg/dL)]. Association with mortality was assessed using multivariable Cox regression models. All findings were validated in an independent cohort. Results We included 2282 HF patients (mean age 68 ± 12 years and 27% female). Lower estimated protein intake in HF patients was associated with a lower BMI, but with more signs of congestion. Mortality rate in the lowest quartile was 32%, compared with 18% in the highest quartile (P

It is not exactly clear yet which type of immune response prevails to accomplish viral clearance in coronavirus disease 2019 (COVID-19). Studying a patient with chronic lymphocytic leukemia and hypogammaglobulinemia who suffered from COVID-19 provided insight in the immunological responses after treatment with COVID-19 convalescent plasma (CCP). Treatment consisted of oxygen, repeated glucocorticosteroids and multiple dosages of CCP guided by antibody levels. Retrospectively performed humoral and cellular immunity analysis made clear that not every serological test for COVID-19 is appropriate for follow-up of sufficient neutralizing antibodies after CCP. In retrospect, we think that CCP merely bought time for this patient to develop an adequate cellular immune response which led to viral clearance and ultimately clinical recovery.

Abstract Aims Parvovirus B19 (B19V) is often assumed to be a cause of dilated cardiomyopathy (DCM), based on the quantification of B19V DNA in endomyocardial biopsies (EMB). Whether the presence of B19V DNA correlates with active infection is still debated. Application of the enzyme endonuclease to blood samples results in degradation of B19V DNA remnants but leaves viral particles intact, which enables differentiation between active and past infection. In this study, the susceptibility to degradation by endonuclease of B19V DNA in blood was compared between DCM patients and a control group of recent B19V infections. Methods and results Twenty blood samples from 20 adult patients with DCM, who previously tested positive for B19V DNA in EMB and/or blood, were tested with B19V PCR before and after application of endonuclease to the samples. Six blood samples tested positive for B19V DNA with a mean viral load of 2.3 × 104 IU/mL. In five samples, B19V DNA became undetectable after endonuclease (100% load reduction); in one sample DNA load showed a 23% log load reduction (viral load before endonuclease: 9.1 × 104 IU/mL; after: 6.5 × 103 IU/mL). Presence of cardiac inflammation did not differ between patients with B19V DNAemia (1/4) and patients without B19V DNAemia (6/14) (P value = 1.0). In all 18 control samples of proven recent B19V infections, DNA remained detectable after application of endonuclease, showing only a mean log load reduction of 2.3% (mean viral load before endonuclease: 8.1 × 1011 IU/mL; after: 8.0 × 1011 IU/mL). Load reduction differed significantly between the DCM group and the control group; indicating the presence of intact viral particles in the control group with proven active infection and the presence of DNA remnants in the DCM group (P value = 0.000). Conclusion During recent B19V infection, viral DNA levels in blood were unaffected by endonuclease. In contrast, B19V DNA in blood in patients with DCM became undetectable or strongly reduced after application of endonuclease. Circulating viral DNA in this subset of patients with presumed parvovirus‐associated DCM does not consist of intact viral particles. Viral replicative activity cannot be assumed from demonstrating B19V DNA in cardiac tissue or in blood in DCM patients.

Introduction: Lumbosacral radiculopathy/radiculitis (LR) or “sciatica” is a commonly intractable sequelae of chronic low back pain (LBP), and challenges in the treatment of LR indicate that persistent pain may have both mechanical and neuropathic origins. Mindfulness-based interventions have been demonstrated to be effective tools in mitigating self-reported pain in LBP patients. This paper describes the protocol for a randomized controlled trial (RCT) evaluating the effects of the specific mindfulness-based intervention Mindfulness-Oriented Recovery Enhancement (MORE) on LR symptoms and sequelae, including mental health and physical function. Methods: Participants recruited from the Portland, OR area are screened before completing a baseline visit that includes a series of self-report questionnaires and surface electromyography (sEMG) of the lower extremity. Upon enrollment, participants are randomly assigned to the MORE (experimental) group or treatment as usual (control) group for 8 weeks. Self-reported assessments and sEMG studies are repeated after the intervention is complete for pre/post-intervention comparisons. The outcome measures evaluate self-reported pain, physical function, quality of life, depression symptoms, trait mindfulness, and reinterpretation of pain, with surface electromyography (sEMG) findings evaluating objective physical function in patients with LR. To our knowledge, this is the first trial to date using an objective measure, sEMG, to evaluate the effects of a mindfulness-based intervention on LR symptoms. Hypotheses: We hypothesize that MORE will be effective in improving self-reported pain, physical function, quality of life, depression symptoms, mindfulness, and reinterpretation of pain scores after 8 weeks of mindfulness training as compared to treatment as usual. Additionally, we hypothesize that individuals in the MORE group with abnormal sEMG findings at baseline will have improved sEMG findings at their 8-week follow-up visit.

Newborn hearing screening (NHS) was implemented in Albania in four maternity hospitals in 2018 and 2019. Implementation outcome, screening outcome, and screening quality measures were evaluated. Infants were first screened by midwives and nurses before discharge from the maternity hospital and returned for follow-up screening. Acceptability, appropriateness, feasibility, adoption, fidelity, coverage, attendance, and stepwise and final-referral rates were assessed by onsite observations, interviews, questionnaires, and a screening database. A post hoc analysis was performed to identify reasons for loss to follow up (LTFU) in a multivariate logistic regression. In total, 22,818 infants were born, of which 96.6% were screened. For the second screening step, 33.6% of infants were LTFU, 40.4% for the third, and 35.8% for diagnostic assessment. Twenty-two (0.1%) were diagnosed with hearing loss of ≥40 dB, six unilateral. NHS was appropriate and feasible: most infants are born in maternity hospitals, hence nurses and midwives could perform screening, and screening rooms and logistic support were supplied. Adoption among screeners was good. Referral rates decreased steadily, reflecting increasing skill. Occasionally, screening was repeated during a screening step, contrary to the protocol. NHS in Albania was implemented successfully, though LTFU was high. It is important to have effective data tracking and supervision throughout the screening.

Pulmonary arterial hypertension (PAH) is associated with increased right ventricular (RV) afterload, affecting RV remodeling and RV performance, a major determinant of outcome in PAH-patients. In children with PAH, treatment strategy is guided by risk stratification where noninvasive prognosticators are highly needed. The prognostic value of RV characteristics derived by cardiac magnetic resonance (CMR) has been scarcely studied in pediatric PAH. We aimed to identify CMR-derived morphometric and functional RV characteristics prognostic for outcome in children with PAH. From the Dutch National cohort, thirty-eight children with either idiopathic/heritable PAH (IPAH/HPAH) or PAH associated with congenital heart disease (PAH-CHD), who underwent CMR, were included (median (interquartile range) [IQR] age 13.0 years (10.8–15.0), 66% females). Patients had severe PAH, characterized by their World Health Organization Functional Class, increased N-terminal pro-B-type natriuretic peptide and high pulmonary arterial pressure and pulmonary vascular resistance index at time of CMR. RV-ejection fraction (RVEF), indexed RV-mass (RVMi), the ratio between RV and LV mass (RVM/LVM-ratio) and left ventricular eccentricity index (LVEI) all correlated with transplant-free survival from time of CMR. These correlations could not be confirmed in the PAH-CHD group. This study shows that CMR-derived measures reflecting RV function and remodeling (LVEI, RVMi, RVM/LVM-ratio, RVEF) predict transplant-free survival in children with IPAH/HPAH and may be included in risk stratification scores in pediatric PAH.

Abstract Background Prognostic models developed in general cohorts with a mixture of heart failure (HF) phenotypes, though more widely applicable, are also likely to yield larger prediction errors in settings where the HF phenotypes have substantially different baseline mortality rates or different predictor-outcome associations. This study sought to use individual participant data meta-analysis to develop an HF phenotype stratified model for predicting 1-year mortality in patients admitted with acute HF. Methods Four prospective European cohorts were used to develop an HF phenotype stratified model. Cox model with two rounds of backward elimination was used to derive the prognostic index. Weibull model was used to obtain the baseline hazard functions. The internal-external cross-validation (IECV) approach was used to evaluate the generalizability of the developed model in terms of discrimination and calibration. Results 3577 acute HF patients were included, of which 2368 were classified as having HF with reduced ejection fraction (EF) (HFrEF; EF

Large-scale experiments have been performed to investigate the possible consequences of realistic amounts of liquified hydrogen (LH2) encountering water. The experiments aimed at simulating an accidental release of LH2 onto water, for instance during the fuelling of a ship. For liquified natural gas (LNG), it has been demonstrated that physical explosions may occur when it is spilled onto water. These phenomena are referred as rapid phase transitions (RPTs). It cannot be excluded that RPTs are also possible in the case of LH2. The tests were performed at the Test Site Technical Safety of the Bundesanstalt für Materialforschung und –prüfung (BAM) in Horstwalde, Germany. The tests were performed in a 10 m x 10 x 1.5 m basin filled with water. LH2 releases of up to about 1 kg/s were established releasing directly from a trailer carrying LH2. The releases occurred from a height of 50 cm above the water surface pointing downwards, 30 cm under the water surface pointing downwards and 30 cm under the water surface pointed along the water surface. All release configurations resulted in a very chaotic LH2-water mixing zone, causing considerable evaporation and resulting in minor over pressures. No RPTs were observed. The main phenomenon to be observed is, however, an ignition of the released gas cloud resulting in significant blast wave overpressures and heat radiation to the surroundings. The ignition occurred in all under-water releases and in about 90 % of the releases above the water surface.

The Netherlands is a country highly affected by the COVID-19 pandemic. In this study, Slot, Hogema and colleagues report a low SARS-CoV-2 seroprevalence one month into the outbreak and provide insights into virus exposure by region and age group when widespread non-pharmaceutical interventions are in place.

Abstract Purpose To assess the differences in the frequency of clinical signs of temporomandibular disorder (TMD) pain and mandibular function impairment between mandibular advancement device (MAD) and nasal continuous positive airway pressure (nCPAP) therapies in obstructive sleep apnea (OSA) patients at baseline and after 6 month of treatment. Methods This study concerns a secondary analysis of a randomized placebo‐controlled trial in which different treatment effects of an objectively titrated MAD were compared with those of nCPAP and an intra‐oral placebo appliance in a parallel design. Sixty‐four mild to severe OSA patients (52.0 ± 9.6 years) were randomly assigned to these three groups. All patients underwent a shortened functional examination of their masticatory system at baseline and after 6 months to establish the presence of clinical signs of TMD pain. Mandibular function impairment was assessed with a questionnaire. Results Clinical signs of TMD pain were only rarely present at baseline and therapy evaluation. No significant differences were found between the three groups in the (low) frequency of clinical signs of TMD pain at both time points (p = .401–.176). In addition, the (low) scores of mandibular function impairment did not differ between the three groups either, neither at baseline (p = .744) nor after 6 months (p = .359). Conclusions A low frequency of clinical signs of TMD pain in mild to severe OSA patients was found after 6 months, regardless of treatment with MAD or nCPAP. In addition, no difference in mandibular function impairment was observed between the different treatment modalities.

In industrialized countries, the leading cause of bacterial gastroenteritis is Campylobacter jejuni. However, outbreaks are rarely reported, which may reflect limitations of surveillance, for which molecular typing is not routinely performed. To determine the frequency of genetic clusters among patients and to find links to concurrent isolates from poultry meat, broiler chickens, cattle, pigs, and dogs, we performed whole-genome sequencing on 1,509 C. jejuni isolates from 774 patients and 735 food or animal sources in Denmark during 2015–2017. We found numerous clusters; 366/774 (47.3%) clinical isolates formed 104 clusters of >2 isolates. A total of 41 patient clusters representing 199/366 (54%) patients matched a potential source, primarily domestic chickens/broilers. This study revealed serial outbreaks and numerous matches to concurrent food and animal isolates and highlighted the potential of whole-genome sequencing for improving routine surveillance of C. jejuni by enhancing outbreak detection, source tracing, and potentially prevention of human infections.

Background Frequent whole blood donors have an increased risk of developing iron deficiency. Iron deficiency can have detrimental health effects when left untreated. Donation intervals are commonly too short to replenish iron stores and extending these reduces donor availability. Oral iron supplementation is known to shorten iron store recovery time but may also induce gastrointestinal complaints. We aim to optimise the effectiveness of iron supplements while minimising the risks of side effects. Therefore, we will evaluate the impact of different iron supplementation protocols in terms of dosage and frequency on ferritin and haemoglobin levels, gastrointestinal side effects, iron deficiency-related symptoms and donor return compared with placebo supplementation.Methods Twelve hundred whole blood donors with ferritin levels ≤30 µg/L are included into a double-blind, randomised controlled trial. Participants are randomly allocated to one of six arms, administering capsules containing 0 mg, 30 mg or 60 mg of iron, either on alternate days or daily for 56 days. At baseline and 56, 122 and 182 days of follow-up, ferritin and haemoglobin levels are measured, and compliance, donor return, dietary iron intake, gastrointestinal, iron deficiency-related symptoms and general health are assessed by questionnaire.Ethics and dissemination This study will provide a comprehensive overview of the effects of different frequencies and dosages of administration of iron supplements on iron status and health effects, thereby considering individual differences in treatment adherence and lifestyle. The outcome will provide scientific evidence to guide the debate if and how oral iron supplements may support the recovery of whole blood donors with low ferritin levels.Trial registration number NL8590; The Dutch trial registry.

Summary: The Polyomaviridae is a family of ubiquitous dsDNA viruses that establish persistent infection early in life. Screening for human polyomaviruses (HPyVs), which comprise 14 diverse species, relies upon species-specific qPCRs whose validity may be challenged by accelerating genomic exploration of the virosphere. Using this reasoning, we tested 64 published HPyV qPCR assays in silico against the 1781 PyV genome sequences that were divided in targets and nontargets, based on anticipated species specificity of each qPCR. We identified several cases of problematic qPCR performance that were confirmed in vitro and corrected through using degenerate oligos. Furthermore, our study ranked 8 out of 52 tested BKPyV qPCRs as remaining of consistently high quality in the wake of recent PyV discoveries and showed how sensitivity of most other qPCRs could be rescued by annealing temperature adjustment. This study establishes an efficient framework for ensuring confidence in available HPyV qPCRs in the genomic era.

Background and aimsWe hypothesized that a drug's clinical signature (or phenotype) of liver injury can be assessed and used to quantitatively develop a computer-assisted DILI causality assessment-tool (DILI-CAT). Therefore, we evaluated drug-specific DILI-phenotypes for amoxicillin-clavulanate (AMX/CLA), cefazolin, cyproterone, and Polygonum multiflorum using data from published case series, to develop DILI-CAT scores for each drug.MethodsDrug specific phenotypes were made up of the following three clinical features: (1) latency, (2) R-value, and (3) AST/ALT ratio. A point allocation system was developed with points allocated depending on the variance from the norm (or "core") for the 3 variables in published datasets.ResultsThe four drugs had significantly different phenotypes based on latency, R-value, and AST/ALT ratio. The median cyproterone latency was 150 days versus < 43 days for the other three drugs (median: 26 for AMX/CLA, 20 for cefazolin, and 20 for Polygonum multiflorum; pConclusionsDILI-CAT is a data-driven, diagnostic tool built to define drug-specific phenotypes for DILI adjudication. The data provide proof of principle that a drug-specific, data-driven causality assessment tool can be developed for different drugs and raise the possibility that such a process could enhance causality assessment methods.

Introduction and Objectives: Covalently closed circular (ccc)DNA acts as a viral reservoir in the liver of patients with a chronic hepatitis B (CHB) infection and can only be quantified in liver biopsies. Hepatitis B core-related antigen (HBcrAg) levels in plasma/serum have been proposed to reflect intrahepatic cccDNA-levels and may therefore monitor treatment efficacy. This study aimed to validate the relationship between HBcrAg and other intrahepatic and circulating viral markers in CHB patients with high viral load, before and after combination treatment. Materials and methods: Plasma/serum levels of HBcrAg, HBsAg, HBV-DNA, and HBV pregenomic RNA (HBV-pgRNA), and intrahepatic cccDNA and HBV-DNA levels and fibrosis scores were measured in 89 CHB patients with HBV-DNA levels of >100,000 copies/mL (17,182 IU/mL). Measurements were done before and after a 48-week treatment with pegylated interferon alfa-2a and adefovir in a prospective study (ISRCTN77073364). Results: Baseline HBcrAg-values correlated strongly with intrahepatic cccDNA (ρ 0.77, p

An important property associated with turbulence in plasmas and fluids is anomalous transport. Plasma, being a good conductor, can in addition be affected by turbulence causing an anomalous resistivity that can significantly exceed its classical counterpart. While turbulent transport may be adequately described in configuration space, some aspects of the anomalous resistivity are best accounted for in phase space. Kinetic phenomena like electron and ion phase space vortices can thus act as obstacles for the free flow of slow charged particles. Plasma instabilities and large amplitude plasma waves are candidates for contributions to the anomalous resistivity by generating such structures. Langmuir waves can be relevant, but also others, such as upper- as well as lower-hybrid waves in magnetized plasmas. Often these anomalous resistivity effects can be small, but due to the large spatial and temporal scales involved in space plasmas, planetary ionosphere and magnetosphere in particular, even such moderate effects can be important. This mini-review is discussing elements of the description of plasma turbulence with particular attention to wave phenomena that contribute to anomalous resistivity and diffusion. Turbulence effects can have relevance for space weather phenomena as well, where ground based and airborne activities relying on for instance Global Positioning and Global Navigation Satellite Systems are influenced by plasma conditions in geospace.

We have read with great interest the article "Pediatric diseases with greater frequency in an international airport in Mexico" by Figueroa-Uribe A, et. al. where they show us the most registered diseases in medical attention in the emergency medical service of an international airport in Mexico. (1) When analyzing the data shown, we realize that it is possible to compare the results shown in their study in the Peruvian territory, since there is evidence from the Dirección de Epidemiología of the Dirección Regional de Salud (DIRESA) - Amazonas(2) which mentions a high prevalence of respiratory and digestive diseases, which are considered, as in the study conducted at the Mexican airport, to be more frequent.

Background: Treatment outcomes of the shorter regimen for rifampicin-resistant tuberculosis are not completely established. We report on these outcomes two years after treatment completion among patients enrolled in an observational cohort study in nine African countries. Methods: 1,006 patients treated with the nine-month regimen were followed every six months with sputum cultures up to 24 months after treatment completion. The risk of any unfavourable outcome, of failure and relapse, and of death during and after treatment was analysed according to patient's characteristics and initial drug susceptibility by Cox proportional hazard models. Findings: Respectively 67.8% and 57.2% patients had >=1 culture result six months and 12 months after treatment completion. Fourteen relapses were diagnosed. The probability of relapse-free success was 79.3% (95% confidence interval [CI] 76.6–82.0%) overall, 80.9% (95% CI 78.0–84.0%) among HIV-negative and 72.5% (95% CI 66.5–78.9%) among HIV-infected patients. Initial fluoroquinolone (adjusted hazard ratio [aHR] 6.7 [95% CI 3.4–13.1]) and isoniazid resistance (aHR 9.4 [95% CI 1.3–68.0]) were significantly associated with increased risk of failure/relapse and of any unfavourable outcome. Interpretation: The close to 80% relapse-free success indicates the good outcome of the regimen in low-and middle-income settings. Results confirm the lesser effectiveness of the regimen in patients with initial resistance to fluoroquinolones and support the use of high-dose isoniazid, but do not support exclusion of patients for resistance to drugs other than fluoroquinolones. Funding: Expertise-France and Agence Française de Développement. Keywords: Tuberculosis, Multidrug-resistance, Treatment outcome, Recurrence, Cohort studies, Proportional hazard models, Short regimen, Developing countries, Isoniazid, Fluoroquinolones

BACKGROUND:Meta-analyses on impact of isoniazid-resistant tuberculosis informed the World Health Organization recommendation of a levofloxacin-strengthened rifampicin-based regimen. We estimated the effect of initial rifampicin resistance (Rr) and/or isoniazid resistance (Hr) on treatment failure or relapse. We also determined the frequency of missed initial and acquired Rr to estimate the impact of true Hr. METHODS:Retrospective analysis of 7291 treatment episodes with known initial isoniazid and rifampicin status obtained from individual patient databases maintained by the Damien Foundation Bangladesh over 20 years. Drug susceptibility test results were confirmed by the programme's designated supra-national tuberculosis laboratory. To detect missed Rr among isolates routinely classified as Hr, rpoB gene sequencing was done randomly and on a sample selected for suspected missed Rr. RESULTS:Initial Hr caused a large recurrence excess after the 8-month regimen for new cases (rifampicin for two months), but had little impact on rifampicin-throughout regimens: (6 months, new cases; 3.8%; OR 0.8, 95%CI:0.3,2.8; 8 months, retreatment cases: 7.3%, OR 1.8; 95%CI:1.3,2.6). Rr was missed in 7.6% of randomly selected "Hr" strains. Acquired Rr was frequent among recurrences on rifampicin-throughout regimens, particularly after the retreatment regimen (31.9%). It was higher in mono-Hr (29.3%; aOR 3.5, 95%CI:1.5,8.5) and poly-Hr (53.3%; aOR 10.2, 95%CI 4.4,23.7) than in susceptible tuberculosis, but virtually absent after the 8-month new case regimen. Comparing Bangladesh (low Rr prevalence) with a high Rr prevalence setting,true Hr corrected for missed Rr caused only 2-3 treatment failures per 1000 TB cases (of whom 27% were retreatments) in both. CONCLUSIONS:Our analysis reveals a non-negligible extent of misclassifying as isoniazid resistance of what is actually missed multidrug-resistant tuberculosis. Recommending for such cases a "strengthened" regimen containing a fluoroquinolone provokes a direct route to extensive resistance while offering little benefit against the minor role of true Hr tuberculosis in rifampicin-throughout first-line regimen.

Abstract Background Current risk prediction models in heart failure (HF) including clinical characteristics and biomarkers only have moderate predictive value. The aim of this study was to use matrix assisted laser desorption ionisation mass spectrometry (MALDI-MS) profiling to determine if a combination of peptides identified with MALDI-MS will better predict clinical outcomes of patients with HF. Methods A cohort of 100 patients with HF were recruited in the biomarker discovery phase (50 patients who died or had a HF hospital admission vs. 50 patients who did not have an event). The peptide extraction from plasma samples was performed using reversed phase C18. Then samples were analysed using MALDI-MS. A multiple peptide biomarker model was discovered that was able to predict clinical outcomes for patients with HF. Finally, this model was validated in an independent cohort with 100 patients with HF. Results After normalisation and alignment of all the processed spectra, a total of 11,389 peptides (m/z) were detected using MALDI-MS. A multiple biomarker model was developed from 14 plasma peptides that was able to predict clinical outcomes in HF patients with an area under the receiver operating characteristic curve (AUC) of 1.000 (p = 0.0005). This model was validated in an independent cohort with 100 HF patients that yielded an AUC of 0.817 (p = 0.0005) in the biomarker validation phase. Addition of this model to the BIOSTAT risk prediction model increased the predictive probability for clinical outcomes of HF from an AUC value of 0.643 to an AUC of 0.823 (p = 0.0021). Moreover, using the prediction model of fourteen peptides and the composite model of the multiple biomarker of fourteen peptides with the BIOSTAT risk prediction model achieved a better predictive probability of time-to-event in prediction of clinical events in patients with HF (p = 0.0005). Conclusions The results obtained in this study suggest that a cluster of plasma peptides using MALDI-MS can reliably predict clinical outcomes in HF that may help enable precision medicine in HF.

The pathogenicity of Campylobacter concisus, increasingly found in the human gastrointestinal (GI) tract, is unclear. Some studies indicate that its role in GI conditions has been underestimated, whereas others suggest that the organism has a commensal-like phenotype. For the enteropathogen C. jejuni, the lipooligosaccharide (LOS) is a main driver of virulence. We investigated the LOS structure of four C. concisus clinical isolates and correlated the inflammatory potential of each isolate with bacterial virulence. Mass spectrometric analyses of lipid A revealed a novel hexa-acylated diglucosamine moiety with two or three phosphoryl substituents. Molecular and fragment ion analysis indicated that the oligosaccharide portion of the LOS had only a single phosphate and lacked phosphoethanolamine and sialic acid substitution, which are hallmarks of the C. jejuni LOS. Consistent with our structural findings, C. concisus LOS and live bacteria induced less TNF-α secretion in human monocytes than did C. jejuni. Furthermore, the C. concisus bacteria were less virulent than C. jejuni in a Galleria mellonella infection model. The correlation of the novel lipid A structure, decreased phosphorylation, and lack of sialylation along with reduced inflammatory potential and virulence support the significance of the LOS as a determinant in the relative pathogenicity of C. concisus.

The current state of research and development into the additive manufacturing of concrete is poised to become a disruptive technology in the construction industry. Although many academic and industrial institutions have successfully realised full-scale structures, the limitations in the current codes of practice to evaluate their structural integrity have resulted in most of these structures still not being certified as safe for public utilisation and thus deemed as test prototypes for display purpose only. To realise a 3D concrete printed (3DCP) structure which could be certified safe for public use, a bridge was realised using the print facility of the Eindhoven University of Technology (TU/e) based on the concept of ‘Design by Testing’. This paper holistically discusses the complications encountered while realising a reinforced 3DCP bridge in a public traffic network and decisions taken to find solutions for overcoming them.

Abstract Background A marked increase of hepatitis E cases has recently been observed in the Netherlands. Causes of the (re-)emergence of hepatitis E virus (HEV) and exact sources and routes of transmission of HEV infection are currently unknown. We aimed to identify risk factors for HEV seropositivity. Methods Using the Wantai EIA, 2100 plasma samples of blood donors from all over the Netherlands aged 18-70 years were tested for anti-HEV IgG antibodies. A questionnaire on socio-demographic characteristics, health, and potential risk factors for HEV exposure was sent to these participants. Results The overall IgG-seroprevalence was 31% (648/2100) and increased with age. Several food products were independently associated with IgG-seropositivity in a multivariate analysis adjusting for age and gender among 1562 participants who completed the questionnaire: traditional Dutch dry raw sausages called “cervelaat”, “fijnkost”, “salami” and “salametti” which are generally made from raw pork and beef (aOR 1.5; 95%CI 1.2-1.9), frequent consumption of bovine steak (aOR 1.3; 95%CI 1.0-1.7), and frequent consumption of smoked beef (aOR 1.3 95%CI 1.0-1.7). Although not frequently reported, contact with contaminated water was also a risk factor for seropositivity (aOR 2.5; 95%CI 1.5-4.4). Lower seroprevalence was associated with eating raspberries, going out for dinner, and contact with wild animals and dogs. Conclusion Several pork food products, mainly dry raw sausages, and contact with contaminated water were associated with past HEV infection in the Netherlands. Further investigation is needed into the prevalence and infectivity of HEV in these risk factor food products, as well as investigation of the production methods and possible origin of HEV-contamination within these sausages, e.g. very small amounts of pork liver, pig-derived blood products as food additive, or the pork muscle tissue.

Liquid hydrogen (LH2) spills share many of the characteristics of liquefied natural gas (LNG) spills. LNG spills on water sometimes result in localized vapor explosions known as rapid phase transitions (RPTs), and are a concern in the LNG industry. LH2 RPT is not well understood, and its relevance to hydrogen safety is to be determined. Based on established theory from LNG research, we present a theoretical assessment of an accidental spill of a cryogen on water, including models for pool spreading, RPT triggering, and consequence quantification. The triggering model is built upon film-boiling theory, and predicts that the mechanism for RPT is a collapse of the gas film separating the two liquids (cryogen and water). The consequence model is based on thermodynamical analysis of the physical processes following a film-boiling collapse, and is able to predict peak pressure and energy yield. The models are applied both to LNG and LH2, and the results reveal that (i) an LNG pool will be larger than an LH2 pool given similar sized constant rate spills, (ii) triggering of an LH2 RPT event as a consequence of a spill on water is very unlikely or even impossible, and (iii) the consequences of a hypothetical LH2 RPT are small compared to LNG RPT. Hence, we conclude that LH2 RPT seems to be an issue of only minor concern.

Pigs are suspected to be a major source of zoonotic hepatitis E virus (HEV) infection in industrialized countries, but the transmission route(s) from pigs to humans are ill-defined. Sequence comparison of HEV isolates from pigs with those from blood donors and patients in 372 samples collected in The Netherlands in 1998 and 1999 and between 2008 and 2015 showed that all sequences were genotype 3 except for six patients (with travel history). Subgenotype 3c (gt3c) was the most common subtype. While the proportion of gt3c increased significantly between 1998 and 2008, it remained constant between 2008 and 2015. Among the few circulating HEV subtypes, there was no difference observed between the human and the pig isolates. Hepatitis E viruses in humans are very likely to originate from pigs, but it is unclear why HEV gt3c has become the predominant subtype in The Netherlands.

The present studies address feeding of plankton in turbulent environments, discussed by a comparison of analytical results and field data. Various models for predator-prey encounters and capture probabilities are reviewed. Generalized forms for encounter rates and capture probabilities in turbulent environments are proposed. The analysis emphasizes ambush predators, exemplified by cod larvae Gadus morhua L. in the start-feeding phase (stage 7 larvae) collected in shallow waters near Lofoten, Norway. During this campaign, data were obtained at four sites with strongly turbulent conditions induced by tidal currents and long-wave swells, and one site where the turbulence had a lower level in comparison. The guts of the selected cod larvae were examined in order to determine the number of nauplii ingested. Analytically obtained probability densities for the gut content were compared with observations and the results used for estimating the rate of capture of the nauplii. This capture rate was then compared with analytical results using also data for the surroundings, such as measured prey densities and turbulence conditions, as quantified by the specific energy dissipation rate. Different from earlier studies, the presented data include conditions where the turbulence exceeds the level for optimal larval encounter-capture rates.

Forside, kolofon

The polyomavirus family currently includes thirteen human polyomavirus (HPyV) species. In immunocompromised and elderly persons HPyVs are known to cause disease, such as progressive multifocal leukoencephalopathy (JCPyV), haemorrhagic cystitis and nephropathy (BKPyV), Merkel cell carcinoma (MCPyV), and trichodysplasia spinulosa (TSPyV). Some recently discovered polyomaviruses are of still unknown prevalence and pathogenic potential. Because HPyVs infections persist and might be transferred by blood components to immunocompromised patients, we studied the seroprevalence of fourteen polyomaviruses in adult Dutch blood donors. For most polyomaviruses the observed seroprevalence was high (60-100%), sometimes slightly increasing or decreasing with age. Seroreactivity increased with age for JCPyV, HPyV6 and HPyV7 and decreased for BKPyV and TSPyV. The most recently identified polyomaviruses HPyV12, NJPyV and LIPyV showed low overall seroprevalence (~5%) and low seroreactivity, questioning their human tropism. Altogether, HPyV infections are common in Dutch blood donors, with an average of nine polyomaviruses per subject.

Elevated nonfasting TG-rich lipoprotein levels are a risk factor for CVD. To further evaluate the relevance of LDL-receptor (LDLr) pathway and heparan sulfate proteoglycans (HSPGs) in TG homeostasis, we analyzed fasting and postprandial TG levels in mice bearing combined heterozygous mutations in both Exostosin (Ext) 1 and Ldlr, in subjects with hereditary multiple exostosis (HME) due to a heterozygous loss-of-function mutation in EXT1 or EXT2 (N = 13), and in patients with heterozygous mutations in LDLR [familial hypercholesterolemia (FH)] and SNPs in major HSPG-related genes (n = 22). Mice bearing a homozygous mutation in hepatic Ext1 exhibited elevated plasma TGs similar to mice lacking other key enzymes involved in HSPG assembly. Compound heterozygous mice lacking Ldlr and Ext1 showed synergy on plasma TG accumulation and postprandial clearance. In human subjects, a trend was observed in HME patients toward reduced postprandial TG clearance with a concomitant reduction in chylomicron clearance [area under the curve (AUC)-retinyl ester (RE) HME, 844 ± 127 vs. controls, 646 ± 119 nM/h, P = 0.09]. Moreover, in FH subjects with a high HSPG gene score, retinyl palmitate excursions were higher (AUC-RE, 2,377 ± 293 vs. 1,565 ± 181 nM/h, P < 0.05). Incremental AUC-apoB48 was similar between the groups. In conclusion, the data are supportive for a minor yet additive role of HSPG in human postprandial TG clearance, and further studies are warranted.

To make blood components and blood products safe, many safety measures are applied to avoid transfusion-transmitted infections. Defining a balanced safety policy is not easy, we face several dilemmas: How safe should blood be? Should we opt for maximal or optimal safety? Are perceived threats real and relevant? Should blood be clean while food, air, or mosquitoes are not? Is vCJD still a threat? It seems wise to discuss these issues more in the open.