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Background Neisseria meningitidis (Nm) is a nasopharyngeal commensal carried by healthy individuals. However, invasive infections occurs in a minority of individuals, with devastating consequences. There is evidence that common polymorphisms are associated with invasive meningococcal disease (IMD), but the contributions of rare variants other than those in the complement system have not been determined. Methods We identified familial cases of IMD in the UK meningococcal disease study and the European Union Life-Threatening Infectious Disease Study. Candidate genetic variants were identified by whole-exome sequencing of 2 patients with familial IMD. Candidate variants were further validated by in vitro assays. Results Exomes of 2 siblings with IMD identified a novel heterozygous missense mutation in BPIFA1/SPLUNC1. Sequencing of 186 other nonfamilial cases identified another unrelated IMD patient with the same mutation. SPLUNC1 is an innate immune defense protein expressed in the nasopharyngeal epithelia; however, its role in invasive infections is unknown. In vitro assays demonstrated that recombinant SPLUNC1 protein inhibits biofilm formation by Nm, and impedes Nm adhesion and invasion of human airway cells. The dominant negative mutant recombinant SPLUNC1 (p.G22E) showed reduced antibiofilm activity, increased meningococcal adhesion, and increased invasion of cells, compared with wild-type SPLUNC1. Conclusions A mutation in SPLUNC1 affecting mucosal attachment, biofilm formation, and invasion of mucosal epithelial cells is a new genetic cause of meningococcal disease., Severe meningococcal disease may result from single-gene inborn errors of immunity, affecting bacterial colonization, biofilm formation, and invasion. Our findings demonstrate the host protective role SPLUNC1 plays in maintaining mucosal immunity in the upper respiratory tract, and preventing invasive disease.

Background Sepsis and severe focal infections represent a substantial disease burden in children admitted to hospital. We aimed to understand the burden of disease and outcomes in children with life-threatening bacterial infections in Europe. Methods The European Union Childhood Life-threatening Infectious Disease Study (EUCLIDS) was a prospective, multicentre, cohort study done in six countries in Europe. Patients aged 1 month to 18 years with sepsis (or suspected sepsis) or severe focal infections, admitted to 98 participating hospitals in the UK, Austria, Germany, Lithuania, Spain, and the Netherlands were prospectively recruited between July 1, 2012, and Dec 31, 2015. To assess disease burden and outcomes, we collected demographic and clinical data using a secured web-based platform and obtained microbiological data using locally available clinical diagnostic procedures. Findings 2844 patients were recruited and included in the analysis. 1512 (53·2%) of 2841 patients were male and median age was 39·1 months (IQR 12·4–93·9). 1229 (43·2%) patients had sepsis and 1615 (56·8%) had severe focal infections. Patients diagnosed with sepsis had a median age of 27·6 months (IQR 9·0–80·2), whereas those diagnosed with severe focal infections had a median age of 46·5 months (15·8–100·4; pInterpretation Mortality in children admitted to hospital for sepsis or severe focal infections is low in Europe. The disease burden is mainly in children younger than 5 years and is largely due to vaccine-preventable meningococcal and pneumococcal infections. Despite the availability and application of clinical procedures for microbiological diagnosis, the causative organism remained unidentified in approximately 50% of patients.

We investigated whether listener-assisted scanning, an alternative communication method for persons with severe motor and visual impairments but preserved cognitive skills, could be used for spelling with EEG. To that end spoken letters were presented sequentially, and the participants made selections by performing motor execution/imagery or a cognitive task. The motor task was a brisk dorsiflexion of both feet, and the cognitive task was related to working memory and perception of human voice. The motor imagery task yielded the most promising results with respect to letter selection accuracy, albeit with a large variation in individual performance. The cognitive task yielded significant ( $p = 0.05$ ) albeit moderate results. Closer inspection of grand average ERPs for the cognitive task revealed task-related modulation of a late negative component, which is novel in the auditory BCI literature. Guidelines for further development are presented.

One important feature of the baroreflex loop is its strong preference for oscillations around 0.1 Hz. In this study, we investigated heart rate intervals, arterial blood pressure (BP), and prefrontal oxyhemoglobin changes during 5 min rest and during brisk finger movements in 19 healthy subjects. We analyzed the phase coupling around 0.1 Hz between cardiovascular and (de)oxyhemoglobin oscillations, using the cross-spectral method. The analyses revealed phase shifts for slow oscillations in BP and heart rate intervals between -10° and -118° (BP always leading). These phase shifts increased significantly (p

The baroreflex is mainly involved in short-term blood pressure regulation and strongly influenced by activations of medullary circulation centres in the brain stem and higher brain centres. One important feature of the baroreflex is its strong preference for oscillations around 0.1Hz, which can be seen as resonance or "eigenfrequency" (EF) of the control loop (so-called Mayer waves). In the present study we investigated beat-to-beat heart rate intervals (RRI) and arterial blood pressure (BP) changes after brisk finger movement and their relationship to the "eigenfrequency" determined by cross spectral analysis between RRI and arterial blood pressure time series of 17 healthy subjects. The analyses revealed significant correlations between BP response magnitude (r=0.63, p0.01) respectively RRI response magnitude (r=0.59, p0.05) and EF. This can be interpreted in such a way that subjects with a "high" EF (0.10 Hz) elicit larger BP responses as well as larger RRI responses when compared to subjects with a "low" EF (0.10 Hz).

Measuring or calculating plasma osmolality is of interest in critical care medicine. Moreover, the osmolal gap (i.e. the difference between the measured and calculated osmolality) helps in the differentiation of metabolic acidosis. A variety of formulas for calculating osmolality have been published, most of them relying on sodium, urea and glucose. A novel formula developed by Zander has recently been published, which also takes into account the effects of potassium, chloride, lactate and bicarbonate on osmolality. We evaluate the previously published formulas including the novel formula by comparing calculated and measured osmolality.Arterial or venous blood samples from 41 outpatients and 195 acutely ill inpatients (total 236 subjects) were used to compare measured osmolality with calculated osmolality as obtained from 36 published formulas including the new formula. The performance of the formulas was statistically evaluated using the method of Bland and Altman.Mean differences up to 35 mosmol/kg H(2)O were observed between measured and calculated osmolality using the previously published formulas. In contrast, the novel formula had a negligible mean difference of 0.5 mosmol/kg H(2)O. The novel formula also had the closest 95 % limits of agreement ranging from -6.5 to 7.5 mosmol/kg H(2)O.Only 4 out of the 36 evaluated formulas gave mean differences between measured and calculated osmolality of less than 1 mosmol/kg H(2)O. Zander's novel formula showed excellent concordance with measured osmolality and facilitates a more precise diagnosis based on blood gas analysers. The new equation has the potential to replace separate measurements of osmolality in many cases.

We investigate whether an electroencephalography technique could be used for yes/no communication with auditory scanning. To be usable by the target group, i.e. minimally conscious individuals, such a brain-computer interface (BCI) has to be very simple and robust. This leads to the concept of a single-switch BCI (ssBCI). With an ssBCI it is possible to reliably detect one certain, individually trained, brain pattern of the individual, and use it to control all kinds of applications using yes/no responses. A total of 10 healthy volunteers (20–27 years) participated in an initial cue-based session with a motor imagery (MI) task after brisk passive feet/hand movement. Four of them reached MI classification accuracies above 70% and, thus, fulfilled the inclusion criterion for participation in the 2nd session. In the 2nd session, MI was used to communicate yes/no answers to a series of questions in an auditory scanning mode. Two of the three participants of the 2nd session were able to reliably communicate their intent with 90% or above correct and 0% false responses. This work showed, for the 1st time, the use of a ssBCI based on passive and imagined movements for communication in auditory scanning mode.