Individual responsiveness of macrophage migration inhibitory factor predicts long-term cognitive impairment after bacterial meningitis.

BACKGROUND: Patients with pneumococcal meningitis are at risk for death and neurological sequelae including cognitive impairment. Functional genetic polymorphisms of macrophage migration inhibitory factor (MIF) alleles have shown to predict mortality of pneumococcal meningitis. METHODS: We investigated whether MIF concentrations during the acute phase of disease were predictive for death in a nationwide prospective cohort study. Subsequently, we studied whether individual ex vivo MIF response years after meningitis was associated with the development of cognitive impairment. RESULTS: We found that in the acute illness of pneumococcal meningitis, higher plasma MIF concentrations were predictive for mortality (p = 0.009). Cognitive impairment, examined 1-5 years after meningitis, was present in 11 of 79 patients after pneumococcal meningitis (14%), as compared to 1 of 63 (2%) in controls, and was consistently associated with individual variability in MIF production by peripheral blood mononuclear cells after ex vivo stimulation with various infectious stimuli. CONCLUSIONS: Our study confirms the role of MIF in poor disease outcome of pneumococcal meningitis. Inter-individual differences in MIF production were associated with long-term cognitive impairment years after pneumococcal meningitis. The present study provides evidence that MIF mediates long-term cognitive impairment in bacterial meningitis survivors and suggests a potential role for MIF as a target of immune-modulating adjunctive therapy.

[A drug induced deviation of the eyes: the oculogyric crisis]. / De oculogyre crisis.

An oculogyric crisis is a tonic conjugated deviation of the eyes, usually upward. We present two cases with a drug induced oculogyric crisis. The differential diagnoses should include epilepsy, a functional neurological movement disorder, ocular tics, ocular dyskinesia or ocular bobbing. Typically, in an oculogyric crisis the patient's awareness is intact; accompanied signs can be blepharospasm, neck flexion, jaw opening with or without tongue protrusion and autonomic symptoms. The underlying pathophysiology seems an imbalance between cholinergic and dopaminergic pathways. Most frequently an oculogyric crisis is caused by antidopaminergic medications, for example neuroleptics and metoclopramide. Treatment of medication-induced oculogyric crisis with parenteral anticholinergics typically leads to a fast remission of symptoms. Consider tocontinue anticholinergic therapy orally for a few days.

Complement C5 Contributes to Brain Injury After Subarachnoid Hemorrhage.

Previous studies showed that complement activation is associated with poor functional outcome after aneurysmal subarachnoid hemorrhage (SAH). We investigated whether complement activation is underlying brain injury after aneurysmal SAH (n = 7) and if it is an appropriate treatment target. We investigated complement expression in brain tissue of aneurysmal SAH patients (n = 930) and studied the role of common genetic variants in C3 and C5 genes in outcome. We analyzed plasma levels (n = 229) to identify the functionality of a single nucleotide polymorphism (SNP) associated with outcome. The time course of C5a levels was measured in plasma (n = 31) and CSF (n = 10). In an SAH mouse model, we studied the extent of microglia activation and cell death in wild-type mice, mice lacking the C5a receptor, and in mice treated with C5-specific antibodies (n = 15 per group). Brain sections from aneurysmal SAH patients showed increased presence of complement components C1q and C3/C3b/iC3B compared to controls. The complement component 5 (C5) SNP correlated with C5a plasma levels and poor disease outcome. Serial measurements in CSF revealed that C5a was > 1400-fold increased 1 day after aneurysmal SAH and then gradually decreased. C5a in plasma was 2-fold increased at days 3-10 after aneurysmal SAH. In the SAH mouse model, we observed a ≈ 40% reduction in both microglia activation and cell death in mice lacking the C5a receptor, and in mice treated with C5-specific antibodies. These data show that C5 contributes to brain injury after experimental SAH, and support further study of C5-specific antibodies as novel treatment option to reduce brain injury and improve prognosis after aneurysmal SAH.

Host genetic variability and pneumococcal disease: a systematic review and meta-analysis.

BACKGROUND: Pneumonia, sepsis, meningitis, and empyema due to Streptococcus pneumoniae is a major cause of morbidity and mortality. We provide a systemic overview of genetic variants associated with susceptibility, phenotype and outcome of community acquired pneumococcal pneumonia (CAP) and invasive pneumococcal disease (IPD). METHODS: We searched PubMed for studies on the influence of host genetics on susceptibility, phenotype, and outcome of CAP and IPD between Jan 1, 1983 and Jul 4, 2018. We listed methodological characteristics and when genetic data was available we calculated effect sizes. We used fixed or random effect models to calculate pooled effect sizes in the meta-analysis. RESULTS: We identified 1219 studies of which 60 studies involving 15,358 patients were included. Twenty-five studies (42%) focused on susceptibility, 8 (13%) on outcome, 1 (2%) on disease phenotype, and 26 (43%) on multiple categories. We identified five studies with a hypothesis free approach of which one resulted in one genome wide significant association in a gene coding for lincRNA with pneumococcal disease susceptibility. We performed 17 meta-analyses of which two susceptibility polymorphisms had a significant overall effect size: variant alleles of MBL2 (odds ratio [OR] 1·67, 95% confidence interval [CI] 1·04-2·69) and a variant in CD14 (OR 1·77, 95% CI 1·18-2·66) and none of the outcome polymorphisms. CONCLUSIONS: Studies have identified several host genetics factors influencing risk of pneumococcal disease, but many result in non-reproducible findings due to methodological limitations. Uniform case definitions and pooling of data is necessary to obtain more robust findings.

How a teaching rotation in medical school affects graduates' subsequent careers.

INTRODUCTION: Teaching opportunities and teacher courses for medical students are increasingly offered by medical schools but little has been investigated about their long-term effect. The aim of our study was to investigate the long-term career effect of an intensive elective teaching experience for final year medical students. METHODS: We approached UMC Utrecht medical graduates who had taken a final year, 6­week full time student teaching rotation (STR) elective, 6 to 9 years after graduation, with an online survey to ask about their educational activities and obtained teaching certificates, their current roles related to education, and their appreciation of the rotation, even if this was a long time ago. In addition, we surveyed control groups of students who had not taken the STR, divided into those who had expressed interest in the STR but had not been placed and those who had not expressed such interest. RESULTS: We received responses from 50 STR graduates and 88 non-STR graduates (11 with interest and 77 without interest in the STR). STR graduates were more educationally active, had obtained more university teaching certificates and were more enthusiastic teachers. However, we could not exclude confounding, caused by a general interest in education even before the STR. CONCLUSIONS: Our findings indicate a high appreciation of the student teaching rotation and a likely but not proven long-term association between STR participation and building an educational career.

Exome Array Analysis of Susceptibility to Pneumococcal Meningitis.

Host genetic variability may contribute to susceptibility of bacterial meningitis, but which genes contribute to the susceptibility to this complex disease remains undefined. We performed a genetic association study in 469 community-acquired pneumococcal meningitis cases and 2072 population-based controls from the Utrecht Health Project in order to find genetic variants associated with pneumococcal meningitis susceptibility. A HumanExome BeadChip was used to genotype 102,097 SNPs in the collected DNA samples. Associations were tested with the Fisher exact test. None of the genetic variants tested reached Bonferroni corrected significance (p-value <5 × 10(-7)). Our strongest signals associated with susceptibility to pneumococcal meningitis were rs139064549 on chromosome 1 in the COL11A1 gene (p = 1.51 × 10(-6); G allele OR 3.21 [95% CI 2.05-5.02]) and rs9309464 in the EXOC6B gene on chromosome 2 (p = 6.01 × 10(-5); G allele OR 0.66 [95% CI 0.54-0.81]). The sequence kernel association test (SKAT) tests for associations between multiple variants in a gene region and pneumococcal meningitis susceptibility yielded one significant associated gene namely COL11A1 (p = 1.03 × 10(-7)). Replication studies are needed to validate these results. If replicated, the functionality of these genetic variations should be further studied to identify by which means they influence the pathophysiology of pneumococcal meningitis.

Community-acquired bacterial meningitis in adults in the Netherlands, 2006-14: a prospective cohort study.

BACKGROUND: We studied causative pathogens, clinical characteristics, and outcome of adult community-acquired bacterial meningitis after the introduction of adjunctive dexamethasone treatment and nationwide implementation of paediatric conjugate vaccines. METHODS: In this cohort study, we prospectively assessed adults (age >16 years) with community-acquired bacterial meningitis in the Netherlands, identified through the National Reference Laboratory for Bacterial Meningitis or individual physicians between Jan 1, 2006, and July 1, 2014. We identified independent predictors of an unfavourable outcome (Glasgow Outcome Scale score 1-4) by logistic regression. FINDINGS: We assessed 1412 episodes of community-acquired bacterial meningitis. Incidence declined from 1·72 cases per 100,000 adults per year in 2007-08, to 0·94 per 100,000 per year in 2013-14. Streptococcus pneumoniae caused 1017 (72%) of 1412 episodes. Rates of adult bacterial meningitis decreased most sharply among pneumococcal serotypes included in paediatric conjugate vaccine, and in meningococcal meningitis. We found no evidence of serotype or serogroup replacement. The overall case fatality rate was 244 (17%) of 1412 episodes and unfavourable outcome occurred in 531 (38%) of 1412 episodes. Predictors of unfavourable outcome were advanced age, absence of otitis or sinusitis, alcoholism, tachycardia, lower score on the Glasgow Coma Scale, cranial nerve palsy, a cerebrospinal fluid white-cell count lower than 1000 cells per µL, a positive blood culture, and a high serum C-reactive protein concentration. Adjunctive dexamethasone was administered for 1234 (89%) of 1384 assessed episodes. The multivariable adjusted odds ratio of dexamethasone treatment for unfavourable outcome was 0·54 (95% CI 0·39-0·73). INTERPRETATION: The incidence of adult bacterial meningitis has decreased substantially, which is partly explained by herd protection by paediatric conjugate vaccines. Adjunctive dexamethasone treatment was associated with substantially improved outcome. FUNDING: European Research Council, National Institute of Public Health and the Environment, European Union, Academic Medical Center, and Netherlands Organization for Health Research and Development.

The desirability of education in didactic skills according to medical interns.

Since all doctors at some point in their career will be faced with their role as a teacher, it appears desirable that future doctors are educated in didactic skills. At present, however, there are no formal opportunities for developing didactic skills at the majority of Dutch medical faculties. The main question of this study is: How do medical interns perceive the quality and quantity of their education in didactic skills? The Dutch Association for Medical Interns (LOCA) ran a national survey among 1,008 medical interns that measured the interns' self-assessed needs for training in didactic skills during medical school. Almost 80 % of the respondents argue that the mastery of didactic skills composes an essential competency for doctors, with the skill of providing adequate feedback considered to be the most important didactic quality for doctors. Of the respondents, 41 % wish to be educated in didactic skills, both during their medical undergraduate degree and during their subsequent training to become a resident. Teaching while being observed and receiving feedback in this setting is regarded as a particularly valuable didactic method by 74 % of the medical interns. Of the respondents, 82 % would invest time to follow training for the development of didactic skills if it was offered. Medical interns stress the importance of doctors' didactic skills during their clinical internships. Compared with current levels, most interns desire increased attention to the formal development of didactic skills during medical school. Considering the importance of didactic skills and the need for more extensive training, the LOCA advises medical faculties to include more formal didactic training in the medical curriculum.