The impact of using three-dimensional digital models of human embryos in the biomedical curriculum

Background: Knowledge of embryonic development is essential to understand the positioning of organs in the human body. Unfortunately, (bio)medical students have to struggle with textbooks that use static, two-dimensional (2D) schematics to grasp the intricate three-dimensional (3D) morphogenesis of the developing human body. To facilitate embryology education on an understandable and scientific level, a 3D Atlas of Human Embryology (3D Atlas) was created (Science, 2016), encompassing 14 interactive 3D-PDFs of various stages of human embryonic development (freely available from http://www.3datlasofhumanembryology.com). This study examined whether the use of the 3D atlas has added educational value and improves the students learning experience. Methods: The 3D atlas was introduced and integrated in lectures and practical classes of an existing embryology course at our university for first year biomedical students. By means of a questionnaire the use of the 3D atlas was evaluated. The outcomes in written examinations was compared between cohorts that followed the course before and after integration of the 3D atlas. Results: Our results showed that the 3D Atlas significantly improves students’ understanding of human embryology, reflected in significant higher test scores for new students. Furthermore, the 3D atlas also significantly improved repeaters’ test scores. Conclusions: The results indicate that the3D Atlas of Human Embryology facilitates students’ learning experience as a resource to support embryology lectures. Students appreciated the use of the 3D atlas in practical classes and liked its interactive aspect. Interestingly, the students also appreciated the physical hand-painted embryological models that were used in addition to the digital 3D atlas during practical classes. The 3D Atlas of Human Embryology has proven to be a valuable resource in addition to the existing resources to teach the intricate developmental processes of human embryology, especially in a blended learning curriculum

Bacterial meningitis presenting with a normal cerebrospinal fluid leukocyte count

Objectives: We describe clinical characteristics and outcome of adults with bacterial meningitis presenting with a normal CSF leukocyte count. Methods: We studied community-acquired bacterial meningitis with a normal CSF leukocyte count (≤ 5 per mm3) in adults from a prospective nationwide cohort study. Results: From 2006 through 2020, 39 of 2,357 (2%) episodes presented with a normal CSF leukocyte count. Immunocompromising conditions were present in 19 of 39 patients (49%), compared to 690 of 2303 (30%) in patients with elevated leukocytes (P = 0.02). The triad of fever, neck stiffness, and altered consciousness was present in 6 of 34 patients (18%). CSF protein was abnormal in 25 of 37 patients (68%). We identified 3 clinical subgroups: those with severe pneumococcal meningitis (20 patients [51%]), with mainly sepsis (8 [21%]), and a miscellaneous group (11 [28%]). All patients with severe pneumococcal meningitis presented with high CSF protein levels and 18 of 19 (95%) had bacteria in the CSF Gram stain. Outcome was unfavorable in 23 of 39 (59%) patients and 12 (31%) died. Conclusion: Patients with bacterial meningitis may present with normal CSF leukocyte counts. In these patients, CSF protein levels and Gram staining are important diagnostic parameters

Community-acquired Haemophilus influenzae meningitis in adults

Background: Haemophilus influenzae is an uncommon cause of meningitis in adults. Methods: We analyzed episodes of community-acquired H. influenzae meningitis in adults included in a prospective nationwide cohort study in the Netherlands. Results: From 2006 to July 2018, 82 of 2272 (4%) bacterial meningitis episodes were caused by H. influenzae (mean annual incidence 0.5 patients per 1,000,000). Median age was 61 years (IQR 46–68), and 48 episodes (59%) occurred in woman. Predisposing factors were otitis and/or sinusitis in 33 of 76 patients (49%), immunocompromising conditions in 19 of 75 patients (25%) and cerebrospinal fluid leak in 13 of 79 patients (17%). Serotyping showed 63 of 80 isolates (79%) were non-typeable (NTHi). Three patients (4%) died and 14 patients (17%) had an unfavorable outcome (Glasgow Outcome Scale score < 5 at discharge). Pneumonia (odds ratio [OR] 5.8, 95% confidence interval [95%CI] 1.1–30.8), presence of immunocompromising conditions (OR 6.0, 95%CI 1.5–24.4), and seizures on admission (OR 10.7, 95%CI 1.6–72.8) were associated with an unfavorable outcome, while NTHi was associated with a favorable outcome (OR 5.6, 95%CI 1.6–19.5). Conclusion: H. influenzae is an uncommon cause of adult bacterial meningitis patients mainly causing disease in those with predisposing factors, such as CSF leakage, ENT infections, and immunocompromised state. In adult patients the majority of H. influenzae meningitis is caused by non-typeable strains

Community-acquired bacterial meningitis in patients of 80 years and older

Background: Advanced age is a risk factor for unfavorable outcome in community-acquired bacterial meningitis, but clinical characteristics and outcome in meningitis patients of 80 years or older have not been defined. Methods: We compared clinical characteristics and outcome of community-acquired bacterial meningitis patients aged 80 years or older and adults under 80 years old within a prospective nationwide cohort study. Results: Out of 2140 episodes identified between March 2006 and July 2018, 149 occurred in patients aged 80 years or older (7%). Common predisposing factors other than age were diabetes mellitus (25 of 148 [17%]), otitis or sinusitis (30 of 136 [22%]), and pneumonia (23 of 141 [16%]). The triad of fever, neck stiffness and altered consciousness was present in 60 of 139 (43%). The most common causative pathogen was Streptococcus pneumoniae (99 of 149 [66%]). Atypical causative pathogens, such as Listeria monocytogenes, Staphylococcus aureus, and Escherichia coli, occurred more often compared to younger patients (49 of 149 [33%] vs 362 of 1991 [18%]; p < 0.001). Patients of 80 years and older had high case fatality rate (75 of 149 [50%]), but 45 of 149 (30%) had a favorable outcome. Characteristics associated with an unfavorable outcome were absence of otitis or sinusitis, presence of aphasia, mono- or hemiparesis, a lower score on the Glasgow Coma Scale, a higher heart rate, a higher blood C-reactive protein concentration and CSF leukocytes <100 per mm3. Conclusions: Bacterial meningitis in patients of 80 years of older is associated with high rates of unfavorable outcome and death. Atypical causative pathogens such as L. monocytogenes, S. aureus, and E. coli occur commonly and should be considered when starting empirical antimicrobial therapy in this age group

The antagonist SPECT tracer 123I-iododexetimide binds preferentially to the muscarinic M1 receptor in-vivo, but is it also a potential tool to assess the occupancy of muscarinic M1 receptors by agonists?

Cognitive deterioration in neuropsychiatric disorders is associated with high attrition rates giving an urgent need to develop better pharmaceutical therapies. The underlying mechanisms of cognitive impairments are unclear but research has shown that the muscarinic receptor subtype 1 (M1 receptor) plays a critical role. Blocking the M1 receptor gives rise to profound cognitive deficits, while the administration of M1 agonist drugs improves cognitive functioning. In this research highlight we will outline supporting data that the radiotracer 123I-iododexetimide preferentially binds to the M1 receptor in-vivo and can be used to assess changes in M1 receptor expression in-vivo associated with cognitive decline. These findings come from a previously published paper extensively examining binding characteristics of 123/127I-iododexetimide to muscarinic receptors. Results of biodistribution studies also has shown that acute administration of the M1/4 receptor agonist xanomeline could inhibit 127I-iododexetimide binding in M1-rich brain areas in rats, suggesting that 123I-iododexetimide may also be used to evaluate the occupancy of M1 receptors by M1 agonists in-vivo. This may be of clinical relevance considering the efficacy of M1 agonist drugs in the treatment of cognitive deficits. Here we show the results from new biodistribution experiments in rats conducted to test the hypothesis that 123I-iododexetimide may be a useful radiotracer to evaluate the M1 receptor occupancy by M1 agonists in-vivo. Contrary to our expectations, no significant change in 123I-iododexetimide ex-vivo binding was observed after acute administration of xanomeline in M1 receptor-rich brain areas, whereas significantly decreased 123I-iododexetimide binding was found after chronic treatment with xanomeline. 123I-iododexetimide single photon emission computed tomography (SPECT) may therefore be a useful imaging tool to further evaluate M1 receptor changes in neuropsychiatric disorders, as a potential stratifying biomarker, to assess the occupancy of M1 receptors after M1 antagonist treatment, or after chronic treatment with M1 agonists, although it may be less suited to evaluate the M1 receptor occupancy after acute treatment with M1 agonists. Future studies should concentrate efforts towards finding also an M1 agonist radiotracer for positron emission tomography (PET) or SPECT to assess the working mechanism of M1 agonists

Epidemiology, clinical features and outcome of adults with meningococcal meningitis: a 15-year prospective nationwide cohort study

Background: We describe the epidemiology, clinical features and outcome of adult meningococcal meningitis in the Netherlands over a 15-year period. Methods: We studied adults (age ≥ 16 years) who were listed by the Netherlands Reference Laboratory for Bacterial Meningitis and/or included in the prospective nationwide cohort study (MeninGene) between January 2006 and July 2021. Incidences were calculated per epidemiological year (July–June). Findings: We identified 442 episodes of adult meningococcal meningitis. The median patient age was 32 years (IQR 18–55) and 226 episodes (51%) occurred in female patients. The annual incidence per 100,000 adults fluctuated, from 0.33 in 2006–2007 to 0.05 in 2020–2021, with a temporal increase up to 0.30 from 2016 to 2018, driven by an outbreak of serogroup W (MenW). Of 442 episodes, 274 episodes (62%) in 273 patients were included in the clinical cohort study. The overall case fatality rate was 4% (10 of 274) and 16% (43 of 274) had an unfavourable outcome (Glasgow Outcome Scale score 1–4). Compared to other serogroups, MenW was associated with higher rates of unfavourable outcome (6 of 16 [38%] vs. 37 of 251 [15%], P = 0.03) and death (4 of 16 [25%] vs. 6 of 251 [2%], P = 0.001). Interpretation: The overall incidence of adult meningococcal meningitis in the Netherlands is low and outcome is generally favourable. An increase of MenW meningitis occurred from 2016 to 2018, which was associated with more unfavourable outcome and death. Funding: Netherlands Organisation for Health Research and Development, European Research Council, National Institute of Public Health and Environmental protection

CSF Neurofilament Light Chain Concentrations Predict Outcome in Bacterial Meningitis

BACKGROUND AND OBJECTIVES: Neurofilament light chain (NfL) is a biomarker for neuroaxonal damage and has been found to be elevated proportionally to the degree of neuronal damage in neurologic diseases. The objective of this study was to determine the prognostic accuracy of NfL concentrations on unfavorable outcome in adults with community-acquired bacterial meningitis. METHODS: We measured NfL concentration CSF samples from a prospective cohort study of adults with community-acquired bacterial meningitis in The Netherlands and determined associations between NfL CSF concentrations, clinical characteristics, and outcome in multivariate analyses. We identified independent predictors of an unfavorable outcome (Glasgow Outcome Scale scores 1-4) by logistic regression. RESULTS: CSF NfL concentrations were evaluated in 429 episodes of 425 patients with community-acquired bacterial meningitis. The median age of 429 episodes was 62 years (interquartile range, 50-69 years). Of note, 290 of 422 (68%) episodes presented with an altered mental status (Glasgow Coma Scale score < 14). Most common causative pathogens were Streptococcus pneumoniae (73%), Neisseria meningitidis (7%), and Listeria monocytogenes (5%). The overall case fatality rate was 62 of 429 (15%), and unfavorable outcome occurred in 57 (37%) of 429 episodes. In multivariate analysis, predictors of unfavorable outcome were older age (OR 1.03, 95% CI 1.01-1.05), cranial nerve palsy (OR 4, 95% CI 1.6-10.3), high serum C-reactive protein concentration (OR 1.3, 95% CI 1.01-1.05), and high CSF NfL concentration (OR 1.5, 95% CI 1.07-2.00). CSF NfL concentrations were higher in patients presenting with focal cerebral deficits (717 pg/mL [416-1,401] vs 412 pg/mL [278-731]; p < 0.001). The area under the curve (AUC) for predicting unfavorable outcome in bacterial meningitis of CSF NfL concentration was 0.69 (95% CI, 0.64-0.74). DISCUSSION: CSF NfL concentration is independently associated with unfavorable outcome in adults with community-acquired bacterial meningitis, suggesting that CSF NfL concentration may be a useful biomarker for prognostic assessment in bacterial meningitis. CLASSIFICATION OF EVIDENCE: Can the level of NfL in CSF (the index test) predict unfavorable outcome in patients with bacterial meningitis, in a cohort of bacterial meningitis patients with a favorable and unfavorable outcome? This study provides Class II evidence that NfL level in CSF is a moderate predictor, with the AUC for predicting unfavorable outcome in bacterial meningitis being 0.69 (95% CI, 0.64-0.74)

Characteristics and prognostic factors of bacterial meningitis in the intensive care unit: a prospective nationwide cohort study

Abstract Background Patients with bacterial meningitis can be severely ill necessitating intensive care unit (ICU) treatment. Here, we describe clinical features and prognostic factors of adults with bacterial meningitis admitted to the ICU in a nationwide prospective cohort study. Methods We prospectively assessed clinical features and outcome of adults (age > 16 years) with community-acquired bacterial meningitis included in the MeninGene study between March 1, 2006 and July 1, 2022, that were initially admitted to the ICU. We identified independent predictors for initial ICU admission and for unfavourable outcome (Glasgow Outcome Scale score between 1–4) by multivariable logistic regression. Results A total of 2709 episodes of bacterial meningitis were included, of which 1369 (51%) were initially admitted to the ICU. We observed a decrease in proportion of patients being admitted to the ICU during the Covid-19 pandemic in 2020 (decreased to 39%, p = 0.004). Median age of the 1369 patients initially admitted to the ICU was 61 years (IQR 49–69), and the rates of unfavourable outcome (47%) and mortality (22%) were high. During the Covid-19 pandemic, we observed a trend towards an increase in unfavourable outcome. Prognostic factors predictive for initial ICU admission were younger age, immunocompromised state, male sex, factors associated with pneumococcal meningitis, and those indicative of systemic compromise. Independent predictors for unfavourable outcome in the initial ICU cohort were advanced age, admittance to an academic hospital, cranial nerve palsies or seizures on admission, low leukocyte count in blood, high C-reactive protein in blood, low CSF: blood glucose ratio, listerial meningitis, need for mechanical ventilation, circulatory shock and persistent fever. 204 of 1340 episodes (15%) that were initially not admitted to the ICU were secondarily transferred to the ICU. The rates of unfavourable outcome (66%) and mortality (30%) in this group were high. Conclusions The majority of patients with community-acquired bacterial meningitis are admitted to the ICU, and the unfavourable outcome and mortality rates of these patients remain high. Patients that are initially admitted to non-ICU wards but secondarily transferred to the ICU also had very high rates of unfavourable outcome

A risk score for identifying patients at a low risk of bacterial meningitis amongst adults with cerebrospinal fluid leucocytosis and a negative gram stain result: a derivation and validation study

Objectives: We aimed to derive and validate a risk score to differentiate patients with bacterial meningitis from those with viral meningitis or encephalitis amongst patients presenting with cerebrospinal fluid (CSF) leucocytosis and a negative Gram staining result. Methods: We included adults with bacterial and viral meningitis or encephalitis presenting with CSF leukocyte counts of >10 per mm3 and a negative Gram staining result from cohorts in Houston, Texas (2004–2019), and the Netherlands (2012–2021). Derivation and the first validation were performed in the American patients and further validation in the Dutch patients. Results: Derivation was performed in 109 American patients with bacterial meningitis (median age, 56 years; interquartile range [IQR], 46–66 years; 46% women) and 194 with viral meningitis or encephalitis (median age, 46 years; IQR, 33–60 years; 53% women). Serum leukocyte counts of >10.0 × 109/L, CSF leukocyte counts of >2000 per mm3, granulocyte counts of >1180 per mm3, protein levels of >2.2 g/L, glucose levels of 0 present). The first validation showed a sensitivity of 100% (95% CI, 96.6–100) and specificity of 34.0% (95% CI, 27.4–41.2). Further validation in 262 Dutch patients with bacterial meningitis (median age, 57 years; IQR 44–70 years; 45% women) and 68 with viral meningitis (median age, 34 years; IQR, 28–45 years; 60% women) showed a sensitivity of 99.6% (95% CI, 97.9–100) and specificity of 41.2% (95% CI, 29.4–53.7). Conclusions: Our risk score may be able to rule out bacterial meningitis amongst patients presenting with CSF leucocytosis and a negative Gram staining result. However, it needs prospective testing prior to clinical implementation