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Streptococcus suis is an opportunistic bacterial porcine pathogen that can cause severe disease in humans, most commonly meningitis and sepsis (1). Human S. suis infections occur both through direct contact [...]

Streptococcus suis, a zoonotic bacterial pathogen circulated through swine, can cause severe infections in humans. Because human S. suis infections are not notifiable in most countries, incidence is underestimated. We aimed to increase insight into the molecular epidemiology of human S. suis infections in Europe. To procure data, we surveyed 7 reference laboratories and performed a systematic review of the scientific literature. We identified 236 cases of human S. suis infection from those sources and an additional 87 by scanning gray literature. We performed whole-genome sequencing to type 46 zoonotic S. suis isolates and combined them with 28 publicly available genomes in a core-genome phylogeny. Clonal complex (CC) 1 isolates accounted for 87% of typed human infections; CC20, CC25, CC87, and CC94 also caused infections. Emergence of diverse zoonotic clades and notable severity of illness in humans support classifying S. suis infection as a notifiable condition.

Currently, two-level Mokken scale analysis for clustered test data is being developed. This paper contributes to this development by providing model-fit procedures for two-level Mokken scale analysis. New theoretical insights suggested that the existing model-fit procedure from traditional (one-level) Mokken scale analyses can be used for investigating model fit at both level 1 (respondent level) and level 2 (cluster level) of two-level Mokken scale analysis. However, the traditional model-fit procedure requires some modifications before it can be used at level 2. In this paper, we made these modifications and investigated the resulting model-fit procedure. For two model assumptions, monotonicity and invariant item ordering, we investigated the false-positive count and the sensitivity count of the level 2 model-fit procedure, with respect to the number of model violations detected, and the number of detected model violations deemed statistically significant. For monotonicity, the detection of model violations was satisfactory, but the significance test lacked power. For invariant item ordering, both aspects were satisfactory.

Abstract Intrinsic or added immune activating molecules are key for most vaccines to provide desired immunity profiles but may increase systemic reactogenicity. Regulatory agencies require rabbit pyrogen testing (RPT) for demonstration of vaccine reactogenicity. Recently, the monocyte activation test (MAT) gained popularity as in vitro alternative, yet this assay was primarily designed to test pyrogen-free products. The aim was to adjust the MAT to enable testing of pyrogen containing vaccines in an early stage of development where no reference batch is yet available. The MAT and RPT were compared for assessing unknown safety profiles of pertussis outer membrane vesicle (OMV) vaccine candidates to those of Bexsero as surrogate reference vaccine. Pertussis OMVs with wild-type LPS predominantly activated TLR2 and TLR4 and were more reactogenic than Bexsero. However, this reactogenicity profile for pertussis OMVs could be equalized or drastically reduced compared to Bexsero or a whole-cell pertussis vaccine, respectively by dose changing, modifying the LPS, intranasal administration, or a combination of these. Importantly, except for LPS modified products, reactogenicity profiles obtained with the RPT and MAT were comparable. Overall, we demonstrated that this pertussis OMV vaccine candidate has an acceptable safety profile. Furthermore, the MAT proved its applicability to assess reactogenicity levels of pyrogen containing vaccines at multiple stages of vaccine development and could eventually replace rabbit pyrogen testing.

Abstract JNJ-54175446 is a selective purine P2X7 receptor (P2X7R) antagonist that attenuates microglial IL-1β/IL-18 release. In healthy volunteers, JNJ-54175446 suppressed peripheral interleukin (IL)-1β release, and attenuated dexamphetamine-induced improvements of mood and (visuo)motor performance in a human dexamphetamine-challenge paradigm. In depression, P2X7R inhibition may dampen immune-related dysregulation of mood. These results suggest that the impact of P2X7R inhibition is most prominent in situations where mood regulation is disrupted. Total sleep deprivation (TSD) results in an acute emotional perturbation, which yields a transient antidepressant effect. In the current study, TSD was applied as a behavioral challenge to investigate whether such effects could be modulated by JNJ-54175446. This was a double-blind, placebo-controlled, randomized study to assess the safety and pharmacokinetics of JNJ-54175446 and explore its effects in patients with single episode and recurrent major depressive disorder (MDD) (N = 69) and baseline total Inventory of Depressive Symptomatology Clinician Rated (IDS-C) > 30. Patients were randomized to receive JNJ-54175446 throughout the 10-day treatment period, placebo for days 1–3 followed by JNJ-54175446 or placebo throughout. All patients underwent 36 h of TSD starting on day three until the evening of day four. The early start group was hypothesized to experience a reduced effect from TSD whilst the late starting group was hypothesized to experience prolonged effects from the TSD. JNJ-54175446 was well-tolerated and adverse events were mild to moderate. JNJ-54175446 reduced IL-1β release by LPS-stimulated peripheral white blood cells in the presence of the P2X receptor agonist benzyl adenosine triphosphate (BzATP). JNJ-54175446 did not have a significant effect on mood as assessed using the Hamilton Depression Rating Scale, 17 items (HDRS17) and the Self-rated Quick Inventory of Depressive Symptoms (QIDS-SR). However, JNJ-54175446 blunted an acute reduction of anhedonia that occurred as a result of TSD, assessed by the Snaith-Hamilton Pleasure Scale (SHAPS) and the Probabilistic Instrumental Learning Task (PILT).

Summary: Streptococcus suis is a zoonotic pathogen that can cause meningitis and septicaemia. The consumption of undercooked pig products is an important risk factor for zoonotic infections, suggesting an oral route of infection. In a human enteroid model, we show that the zoonotic CC1 genotype has a 40% higher translocation frequency than the non-zoonotic CC16 genotype. Translocation occurred without increasing the permeability or disrupting the adherens junctions and tight junctions of the epithelial monolayer. The translocation of zoonotic S. suis was correlated with the presence of Gb3-positive cells, a human glycolipid receptor found on Paneth cells and targeted by multiple enteric pathogens. The virulence factors Streptococcal adhesin Protein and suilysin, known to interact with Gb3, were not essential for translocation in our epithelial model. Thus, the ability to translocate across an enteroid monolayer correlates with S. suis core genome composition and the presence of Gb3-positive cells in the intestinal epithelium.

ABSTRACTPhase-variable type I restriction modification (RM) systems are epigenetic regulatory systems that have been identified in numerous human bacterial pathogens. We previously showed that an emerging zoonotic lineage of Streptococcus suis acquired a phase-variable type I RM system, named SsuCC20p. The SsuCC20p locus was identified in the genome of multiple streptococcal species, indicating that it is not restricted to S. suis and can be acquired through horizontal gene transfer. We demonstrate that SsuCC20p phase variability relies on a recombinase present within the locus. SsuCC20p is the single RM system responsible for the genome methylation profiles that were detected in the representative zoonotic S. suis isolate 861160 in vitro. In addition, we show that, contrary to previous observations, hsdS genes located downstream of hsdM and the recombinase gene contribute to the SsuCC20p genome methylation profile. SsuCC20p locked mutants expressing a single hsdS each show a unique genome methylation profile and, when grown in human serum, have distinct transcriptomes. In a zebrafish larvae infection model, we observed significant differences in virulence between the locked mutants and a corresponding shift in hsdS allele distribution in the wild type. These data indicate that the streptococcal phase-variable type I RM system SsuCC20p can impact bacterial fitness via epigenetic regulation of gene expression, which impacts the virulence of S. suis in the zebrafish larvae infection model.IMPORTANCEPhase variation allows a single strain to produce phenotypic diverse subpopulations. Phase-variable restriction modification (RM) systems are systems that allow for such phase variation via epigenetic regulation of gene expression levels. The phase-variable RM system SsuCC20p was found in multiple streptococcal species and was acquired by an emerging zoonotic lineage of Streptococcus suis. We show that the phase variability of SsuCC20p is dependent on a recombinase encoded within the SsuCC20p locus. We characterized the genome methylation profiles of the different phases of SsuCC20p and demonstrated the consequential impact on the transcriptome and virulence in a zebrafish infection model. Acquiring mobile genetic elements containing epigenetic regulatory systems, like phase-variable RM systems, enables bacterial pathogens to produce diverse phenotypic subpopulations that are better adapted to specific (host) environments encountered during infection.

JNJ-42165279 is a selective inhibitor of fatty acid amide hydrolase (FAAH), the enzyme responsible for the degradation of fatty acid amides (FAA) including anandamide (AEA), palmitoylethanolamide (PEA), and N-oleoylethanolamide (OEA). We assessed the efficacy, safety, tolerability, pharmacokinetics, and pharmacodynamics of treatment with JNJ-42165279 in subjects with social anxiety disorder (SAD). This was a multicenter, double-blind, placebo-controlled study randomizing subjects to 12 weeks of treatment with either JNJ-42165279 (25 mg daily) or placebo (PBO). The primary endpoint was the change in the Liebowitz Social Anxiety Scale (LSAS) total score from baseline to end of study. Secondary endpoints included the Hamilton Anxiety Scale (HAM-A), Hamilton Depression Rating Scale (HDRS17), and the Clinical Global Impression-Improvement (CGI-I). Samples were collected for plasma concentration of AEA, PEA, OEA, and JNJ-42165279. A total of 149 subjects were enrolled with a mean baseline LSAS total score of 102.6 (SD 16.84). The mean change from baseline (SD) in LSAS total score at week 12 was numerically greater for JNJ-42165279: -29.4 (27.47) compared to PBO: -22.4 (23.57) but not significant. The percentage of subjects with ≥30% improvement from baseline in the LSAS total score was significantly higher for JNJ-42165279 (42.4%) compared to PBO (23.6%) (p value = 0.04). The percentage of subjects with a CGI-I score of much or very much improved was also significantly higher for JNJ-42165279 (44.1%) than for PBO (23.6%) (p value = 0.02). The drug was well tolerated. JNJ-42165279 appears to elicit an anxiolytic effect in subjects with SAD although trough concentrations with 25 mg once daily appeared to be insufficient to completely inhibit FAAH activity which may have led to suboptimal efficacy. ClinicalTrials.gov Identifier: NCT02432703.

Several intraclass correlation coefficients (ICCs) are available to assess the interrater reliability (IRR) of observational measurements. Selecting an ICC is complicated, and existing guidelines have three major limitations. First, they do not discuss incomplete designs, in which raters partially vary across subjects. Second, they provide no coherent perspective on the error variance in an ICC, clouding the choice between the available coefficients. Third, the distinction between fixed or random raters is often misunderstood. Based on generalizability theory (GT), we provide updated guidelines on selecting an ICC for IRR, which are applicable to both complete and incomplete observational designs. We challenge conventional wisdom about ICCs for IRR by claiming that raters should seldom (if ever) be considered fixed. Also, we clarify how to interpret ICCs in the case of unbalanced and incomplete designs. We explain four choices a researcher needs to make when selecting an ICC for IRR, and guide researchers through these choices by means of a flowchart, which we apply to three empirical examples from clinical and developmental domains. In the Discussion, we provide guidance in reporting, interpreting, and estimating ICCs, and propose future directions for research into the ICCs for IRR. [ABSTRACT FROM AUTHOR]

Streptococcus suis is an emerging zoonotic pathogen. Over 100 putative virulence factors have been described, but it is unclear to what extent these virulence factors could contribute to zoonotic potential of S. suis. We identified all S. suis virulence factors studied in experimental models of human origin in a systematic review and assessed their contribution to zoonotic potential in a subsequent genomic meta-analysis. PubMed and Scopus were searched for English-language articles that studied S. suis virulence published until 31 March 2021. Articles that analyzed a virulence factor by knockout mutation, purified protein, and/or recombinant protein in a model of human origin, were included. Data on virulence factor, strain characteristics, used human models and experimental outcomes were extracted. All publicly available S. suis genomes with available metadata on host, disease status and country of origin, were included in a genomic meta-analysis. We calculated the ratio of the prevalence of each virulence factor in human and pig isolates. We included 130 articles and 1703 S. suis genomes in the analysis. We identified 53 putative virulence factors that were encoded by genes which are part of the S. suis core genome and 26 factors that were at least twice as prevalent in human isolates as in pig isolates. Hhly3 and NisK/R were particularly enriched in human isolates, after stratification by genetic lineage and country of isolation. This systematic review and genomic meta-analysis have identified virulence factors that are likely to contribute to the zoonotic potential of S. suis.

Abstract Background In the Netherlands, healthcare professionals attending patients in the last phase of life, can consult an expert palliative care team (PCT) in case of complex problems. There are two types of PCTs: regional PCTs, which are mainly consulted by general practitioners, and hospital PCTs, which are mainly consulted by healthcare professionals in the hospital. Integration of these PCTs is expected to facilitate continuity of care for patients receiving care in different settings. We studied facilitators and barriers in the process of developing and implementing an integrated transmural palliative care consultation service. Methods A multiple case study was performed in four palliative care networks in the southwest Netherlands. We aimed to develop an integrated transmural palliative care consultation service. Researchers were closely observing the process and participated in project team meetings. A within-case analysis was conducted for each network, using the Consolidated Framework for Implementation Research (CFIR). Subsequently, all findings were pooled. Results In each network, project team members thought that the core goal of a transmural consultation service is improvement of continuity of palliative care for patients throughout their illness trajectory. It was nevertheless a challenge for hospital and non-hospital healthcare professionals to arrive at a shared view on goals, activities and working procedures of the transmural consultation service. All project teams experienced the lack of evidence-based guidance on how to organise the service as a barrier. The role of the management of the involved care organisations was sometimes perceived as unsupportive, and different financial reimbursement systems for hospital and out-of-hospital care made implementation of a transmural consultation service complex. Three networks managed to develop and implement a transmural service at some level, one network did not manage to do so. Conclusions Healthcare professionals are motivated to collaborate in a transmural palliative care consultation service, because they believe it can contribute to high-quality palliative care. However, they need more shared views on goals and activities of a transmural consultation service, more guidance on organisational issues and appropriate financing. Further research is needed to provide evidence on benefits and costs of different models of integrated transmural palliative care consultation services.

Abstract Background One of the strategies to promote the quality of palliative care in non-specialised settings is the appointment of palliative care nurse champions. It is unclear what the most effective model to implement the concept of nurse champions is and little is known about palliative care nurse champions’ own views on their role and responsibilities. This paper aims to describe views of palliative care nurse champions in hospitals and home care on their role, responsibilities and added value. Methods In 2018, a qualitative interview study was conducted with 16 palliative care nurse champions in two hospitals and four home care organisations in the southwest of the Netherlands. The framework approach was used to analyse the data. Results Most palliative care nurse champions described their role by explaining concrete tasks or activities. Most nurse champions perceive their main task as disseminating information about palliative care to colleagues. A few nurses mentioned activities aimed at raising awareness of palliative care among colleagues. Most nurses were to a limited extent involved in collaboration with the palliative care expert team. Hospital nurse champions suggested that more support from the palliative care expert team would be helpful. Most nurse champions feel little responsibility for organisational tasks and inter-organisational collaboration. Especially hospital nurses found it difficult to describe their role. Conclusion The role of palliative care nurse champions in hospital and home care varies a lot and nurses have diverging views on palliative care in these settings. Comprehensively fulfilling the role of palliative care nurse champion is a challenge. Careful selection, training, support and task descriptions for nurse champions are needed to make the concept of nurse champions work in palliative care.

Respiratory infections caused by Bordetella pertussis are reemerging despite high pertussis vaccination coverage. Since the introduction of the acellular pertussis vaccine in the late twentieth century, circulating B. pertussis strains increasingly lack expression of the vaccine component pertactin (Prn). In some countries, up to 90% of the circulating B. pertussis strains are deficient in Prn. To better understand the resurgence of pertussis, we investigated the response of human monocyte-derived dendritic cells (moDCs) to naturally circulating Prn-expressing (Prn-Pos) and Prn-deficient (Prn-Neg) B. pertussis strains from 2016 in the Netherlands. Transcriptome analysis of moDC showed enriched IFNα response-associated gene expression after exposure to Prn-Pos B. pertussis strains, whereas the Prn-Neg strains induced enriched expression of interleukin- and TNF-signaling genes, as well as other genes involved in immune activation. Multiplex immune assays confirmed enhanced proinflammatory cytokine secretion by Prn-Neg stimulated moDC. Comparison of the proteomes from the Prn-Pos and Prn-Neg strains revealed, next to the difference in Prn, differential expression of a number of other proteins including several proteins involved in metabolic processes. Our findings indicate that Prn-deficient B. pertussis strains induce a distinct and stronger immune activation of moDCs than the Prn-Pos strains. These findings highlight the role of pathogen adaptation in the resurgence of pertussis as well as the effects that vaccine pressure can have on a bacterial population.

Reliability is usually estimated for a total score, but it can also be estimated for item scores. Item-score reliability can be useful to assess the repeatability of an individual item score in a group. Three methods to estimate item-score reliability are discussed, known as method MS, method [lambda][subscript 6], and method CA. The item-score reliability methods are compared with four well-known and widely accepted item indices, which are the item-rest correlation, the item-factor loading, the item scalability, and the item discrimination. Realistic values for item-score reliability in empirical-data sets are monitored to obtain an impression of the values to be expected in other empirical-data sets. The relation between the three item-score reliability methods and the four well-known item indices are investigated. Tentatively, a minimum value for the item-score reliability methods to be used in item analysis is recommended.

We propose a general cognitive diagnosis model framework to diagnose mental disorders using item scores obtained from clinical measurement instruments. This framework can be used to validate the extent to which the items measure the specific disorders. The method is illustrated using data obtained with the Dutch version of Millon Clinical Multiaxial Inventory-III.

Background: Advance care planning (ACP) can help to enhance the care of patients with limited life expectancy. Despite physicians’ key role in ACP, the ways in which physicians estimate and communicate prognosis can be improved. Aim: To determine how physicians in different care settings self-assess their performance in estimating and communicating prognosis to patients in palliative care, and how they perceive their communication with other physicians about patients’ poor prognosis. Design & setting: A survey study was performed among a random sample of GPs, hospital physicians (HPs), and nursing home physicians (NHPs) in the southwest of the Netherlands (n = 2212). Method: A questionnaire was developed that had three versions for GPs, HPs, and NHPs. Each specialism filled in an appropriate version. Results: A total of 547 physicians participated: 259 GPs, 205 HPs, and 83 NHPs. In the study, 61.1% of physicians indicated being able to adequately estimate whether a patient will die within 1 year, which was associated with use of the Surprise Question (odds ratio [OR] = 1.65, P = 0.042). In the case of a prognosis of

Gut organoids are stem cell derived 3D models of the intestinal epithelium that are useful for studying interactions between enteric pathogens and their host. While the organoid model has been used for both bacterial and viral infections, this is a closed system with the luminal side being inaccessible without microinjection or disruption of the organoid polarization. In order to overcome this and simplify their applicability for transepithelial studies, permeable membrane based monolayer approaches are needed. In this paper, we demonstrate a method for generating a monolayer model of the human fetal intestinal polarized epithelium that is fully characterized and validated. Proximal and distal small intestinal organoids were used to generate 2D monolayer cultures, which were characterized with respect to epithelial cell types, polarization, barrier function, and gene expression. In addition, viral replication and bacterial translocation after apical infection with enteric pathogens Enterovirus A71 and Listeria monocytogenes were evaluated, with subsequent monitoring of the pro-inflammatory host response. This human 2D fetal intestinal monolayer model will be a valuable tool to study host-pathogen interactions and potentially reduce the use of animals in research.