Desflurane versus sevoflurane anesthesia and postoperative recovery in older adults undergoing minor- to moderate-risk noncardiac surgery - A prospective, randomized, observer-blinded, clinical trial.

STUDY OBJECTIVE: The effect of volatile anesthetics on postoperative recovery in older adults is still not entirely clear. Thus, we evaluated the effect of desflurane versus sevoflurane anesthesia on speed of postoperative recovery in older adults eligible for same-day discharge. We further evaluated the incidence of postoperative nausea and vomiting (PONV), bispectral index (BIS) values, and S100B concentrations. DESIGN: Single-center, prospective, observer-blinded, randomized clinical trial. SETTING: Operating room. PATIENTS: 190 patients ≥65 years of age and scheduled for minor- to moderate-risk noncardiac surgeries. INTERVENTIONS: Goal-directed administration of desflurane versus sevoflurane for maintenance of anesthesia with an intraoperative goal of BIS 50 ± 5. MEASUREMENTS: The primary outcome was the time to anesthesia recovery, which was defined as the time between arrival at the post-anesthesia care unit (PACU) and reaching criteria for discharge from PACU, based on modified Aldrete score ≥ 12 points. Modified Aldrete scores were assessed at PACU arrival and thereafter in five-minute intervals. PONV was evaluated during PACU stay and the first three postoperative days, BIS values were recorded during PACU stay, and S100B values were measured before and after surgery, and on the second postoperative day. MAIN RESULTS: 95 patients were randomized to receive desflurane, and 95 patients to receive sevoflurane. We did not observe a significant difference in median duration of postoperative recovery between the groups (desflurane: 0 min [0;0]; sevoflurane: 0 min [0;0]; p = 0.245). 77 patients (81.1%) in the desflurane group and 84 patients (88.4%) in the sevoflurane group already had Aldrete scores ≥12 points upon arrival at PACU (p = 0.277). There was also no significant difference in the incidences of PONV (p = 0.606), postoperative BIS values (p = 0.197), and postoperative maximum S100B concentrations (p = 0.821) between the groups. CONCLUSIONS: Despite previous reports, we did not observe significant faster recovery times after desflurane anesthesia. Both volatile anesthetics may be appropriate for same-day discharge in older adults.

Assessment Accuracy of 2D vs. 3D Imaging for Custom-Made Acetabular Implants in Revision Hip Arthroplasty.

Revision total hip arthroplasty (rTHA) presents significant challenges, particularly in patients with severe acetabular bone defects. Traditional treatment options often fall short, leading to the emergence of custom-made 3D-printed acetabular implants. Accurate assessment of implant positioning is crucial for ensuring optimal postoperative outcomes and for providing feedback to the surgical team. This single-center, retrospective cohort study evaluates the accuracy of standard 2D radiographs versus 3D CT scans in assessing the positioning of these implants, aiming to determine if 2D imaging could serve as a viable alternative for the postoperative evaluation. We analyzed the implant positions of seven rTHA patients with severe acetabular defects (Paprosky ≥ Type IIIA) using an alignment technique that integrates postoperative 2D radiographs with preoperative CT plans. Two independent investigators, one inexperienced and one experienced, measured the positioning accuracy with both imaging modalities. Measurements included translational shifts from the preoperatively templated implant position in the craniocaudal (CC), lateromedial (LM), and ventrodorsal (VD) directions, as well as rotational differences in anteversion (AV) and inclination (INCL). The study demonstrated that 2D radiographs, when aligned with preoperative CT data, could accurately assess implant positions with precision nearly comparable to that of 3D CT scans. Observed deviations were 1.4 mm and 2.7 mm in CC and LM directions, respectively, and 3.6° in AV and 0.7° in INCL using 2D imaging, all within clinically acceptable ranges. For 3D CT assessments, mean interobserver variability was up to 0.9 mm for translational shifts and 1.4° for rotation, while for 2D alignment, observer differences were 1.4 mm and 3.2° for translation and rotation, respectively. Comparative analysis of mean results from both investigators, across all dimensions (CC, LM, AV, and INCL) for 2D and 3D matching, showed no significant differences. In conclusion, conventional anteroposterior 2D radiographs of the pelvis can sufficiently determine the positioning of custom-made acetabular implants in rTHA. This suggests that 2D radiography is a viable alternative to 3D CT scans, potentially enhancing the implementation and quality control of advanced implant technologies.

Dexamethasone in adults with viral meningitis: an observational cohort study.

OBJECTIVES: To investigate whether there is a dose-dependent association between empiric dexamethasone and outcome in viral meningitis. METHODS: Observational cohort study of adults hospitalised for viral meningitis, both with and without a microbiologically confirmed diagnosis, in Denmark between 2015-2020. Dose-dependent associations between dexamethasone (one dose=10 mg) and an unfavourable outcome (Glasgow Outcome Scale score 1-4) at 30 days after discharge were assessed with weighted logistic regression. Entropy balancing was used to compute weights. RESULTS: Of 1,025 included patients, 658 (64%) did not receive dexamethasone, 115 (11%) received 1-2 doses, 131 (13%) received 3-4 doses, and 121 (12%) received ≥5 doses. Among patients treated with dexamethasone, the median number of doses was higher for those without an identified pathogen than for those with a microbiologically confirmed viral aetiology (5 [IQR 3-8] vs 3 [IQR 2-5]; p<0.001). Using no doses of dexamethasone as reference, the weighted odds ratios (OR) for an unfavourable outcome were 0.55 (95% CI 0.29-1.07) for 1-2 doses, 1.13 (95% CI 0.67-1.89) for 3-4 doses, and 1.43 (95% CI 0.77-2.64) for ≥5 doses. In the subgroup of enteroviral meningitis, the weighted OR was 3.08 (95% CI 1.36-6.94) for ≥5 doses but decreased to 2.35 (95% CI 0.65-8.40) when the reference group was restricted to patients treated with antibiotics for suspected bacterial meningitis. CONCLUSIONS: This study showed no dose-dependent association between dexamethasone and an unfavourable outcome in patients with viral meningitis. In enteroviral meningitis, ≥5 doses were associated with an increased risk of an unfavourable outcome. However, a sensitivity analysis indicated that the association was affected by unmeasured or residual confounding by severity.

Differences in metalloproteinases and their tissue inhibitors in the cerebrospinal fluid are associated with delirium.

BACKGROUND: The aetiology of delirium is not known, but pre-existing cognitive impairment is a predisposing factor. Here we explore the associations between delirium and cerebrospinal fluid (CSF) levels of matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs), proteins with important roles in both acute injury and chronic neurodegeneration. METHODS: Using a 13-plex Discovery Assay®, we quantified CSF levels of 9 MMPs and 4 TIMPs in 280 hip fracture patients (140 with delirium), 107 cognitively unimpaired individuals, and 111 patients with Alzheimer's disease dementia. The two delirium-free control groups without acute trauma were included to unravel the effects of acute trauma (hip fracture), dementia, and delirium. RESULTS: Here we show that delirium is associated with higher levels of MMP-2, MMP-3, MMP-10, TIMP-1, and TIMP-2; a trend suggests lower levels of TIMP-4 are also associated with delirium. Most delirium patients had pre-existing dementia and low TIMP-4 is the only marker associated with delirium in adjusted analyses. MMP-2, MMP-12, and TIMP-1 levels are clearly higher in the hip fracture patients than in both control groups and several other MMP/TIMPs are impacted by acute trauma or dementia status. CONCLUSIONS: Several CSF MMP/TIMPs are significantly associated with delirium in hip fracture patients, but alterations in most of these MMP/TIMPs could likely be explained by acute trauma and/or pre-fracture dementia. Low levels of TIMP-4 appear to be directly associated with delirium, and the role of this marker in delirium pathophysiology should be further explored.

Delirium is a syndrome in which there are substantial changes in a person's ability to focus, understand, or pay attention to events. Delirium often occurs in response to sudden trauma and is more common in persons with pre-existing cognitive impairment. What happens in the brain during delirium is not well understood. To learn more, we have studied whether markers in the cerebrospinal fluid were altered in people with delirium compared to people without delirium. To understand differences specifically caused by delirium, we included two control groups without acute trauma, one with cognitively healthy participants and one with dementia patients. We found several markers altered in people with delirium, with most of the markers similarly altered in people with cognitive impairment due to dementia. One marker was directly linked to delirium and could potentially shed light on the brain processes that cause the syndrome.

Peripheral apoptosis and limited clonal deletion during physiologic murine B lymphocyte development.

Self-reactive and polyreactive B cells generated during B cell development are silenced by either apoptosis, clonal deletion, receptor editing or anergy to avoid autoimmunity. The specific contribution of apoptosis to normal B cell development and self-tolerance is incompletely understood. Here, we quantify self-reactivity, polyreactivity and apoptosis during physiologic B lymphocyte development. Self-reactivity and polyreactivity are most abundant in early immature B cells and diminish significantly during maturation within the bone marrow. Minimal apoptosis still occurs at this site, however B cell receptors cloned from apoptotic B cells show comparable self-reactivity to that of viable cells. Apoptosis increases dramatically only following immature B cells leaving the bone marrow sinusoids, but above 90% of cloned apoptotic transitional B cells are not self-reactive/polyreactive. Our data suggests that an apoptosis-independent mechanism, such as receptor editing, removes most self-reactive B cells in the bone marrow. Mechanistically, lack of survival signaling rather than clonal deletion appears to be the underpinning cause of apoptosis in most transitional B cells in the periphery.

Tenascin-C in patients with central nervous system infections.

BACKGROUND: The extracellular matrix protein tenascin-C has been discovered to be an important regulator of the response to tissue injury and repair in cerebrovascular diseases. This study investigated if tenascin-C is released in response to infections in the central nervous system (CNS). METHODS: Tenascin-C concentration in the cerebrospinal fluid (CSF) was measured in patients, (>18 years) with and without CNS infections, admitted to a department of infectious diseases in Denmark. CSF tenascin-C was measured on the Meso-scale platform. RESULTS: 174 patients were included of which 140 were diagnosed with a CNS infection and 34 where this was ruled out (control group). Median CSF tenascin-C levels were significantly higher among patients with bacterial meningitis (147 pg/mL), viral meningitis (33 mg/mL), viral encephalitis (39 pg/mL) and Lyme neuroborreliosis (45 pg/mL) when compared to controls (21 pg/mL). Correlations between tenascin-C and CSF markers of inflammation and age were only moderate. CONCLUSION: Levels of CSF tenascin-C are higher among patients with bacterial and viral neuroinfections, already on admission, but exhibit only a modest correlation with baseline indices of neuroinflammation. CSF tenascin-C is highest among patients with bacterial meningitis compared to the other CNS infections. Patients with unfavorable outcomes presented with higher median CSF tenascin-C than their counterparts.

Resistance exercise snacks improve muscle mass in female university employees: a prospective, controlled, intervention pilot-study.

Background: Although resistance training (RT) is essential to preserve musculoskeletal fitness and maintain a healthy, independent life into old age, few women perform RT. We investigated whether resistance exercise snacking (RES) could be an efficient training approach for the workplace health promotion (WHP) to minimize barriers for participation and facilitate RT in women in order to improve musculoskeletal fitness. Methods: This pilot-study followed a prospective, controlled intervention design. Female employees with sedentary occupations doing RT on less than 2 days/week before study participation were included. Participants self-selected for either intervention (IG) or control group (CG). While the IG [N = 15, mean age 42.1 (SD = 11.1) years] did 10 min of RES on working days for 12 weeks, the CG [N = 15, mean age 49.9 (SD = 9.7) years] was instructed to maintain their habitual physical activity. Primary endpoint was change in muscle mass. Secondary endpoint was change in maximum isometric strength. Balance, cardiovascular fitness, perceived health, and general life satisfaction was assessed for exploratory purpose. Measurements were taken before and after the intervention. Results: 12 participants of IG and 14 of CG completed the study. Muscle mass improved significantly more in the IG [+0.42 (SD = 0.54) kg] compared to the CG [-0.16 (SD = 0.51) kg] (p = 0.01, ƞ2p = 0.24). Strength did not change significantly between groups. Nevertheless, there was a trend for greater improvements in the IG compared to the CG for trunk extension, trunk flexion, and upper body push but not upper body pull. Regarding exploratory endpoints, no significant between-group changes were found. Despite their poor fitness, both groups perceived their health as good and had high life satisfaction before and after the intervention. Conclusion: RES could be an effective approach for the WHP to promote RT in inactive women with sedentary occupations and improve their muscle mass.

Simulating photodynamic therapy for the treatment of glioblastoma using Monte Carlo radiative transport.

Significance: Glioblastoma (GBM) is a rare but deadly form of brain tumor with a low median survival rate of 14.6 months, due to its resistance to treatment. An independent simulation of the INtraoperative photoDYnamic therapy for GliOblastoma (INDYGO) trial, a clinical trial aiming to treat the GBM resection cavity with photodynamic therapy (PDT) via a laser coupled balloon device, is demonstrated. Aim: To develop a framework providing increased understanding for the PDT treatment, its parameters, and their impact on the clinical outcome. Approach: We use Monte Carlo radiative transport techniques within a computational brain model containing a GBM to simulate light path and PDT effects. Treatment parameters (laser power, photosensitizer concentration, and irradiation time) are considered, as well as PDT's impact on brain tissue temperature. Results: The simulation suggests that 39% of post-resection GBM cells are killed at the end of treatment when using the standard INDYGO trial protocol (light fluence = 200 J/cm2 at balloon wall) and assuming an initial photosensitizer concentration of 5 µM. Increases in treatment time and light power (light fluence = 400 J/cm2 at balloon wall) result in further cell kill but increase brain cell temperature, which potentially affects treatment safety. Increasing the p hotosensitizer concentration produces the most significant increase in cell kill, with 61% of GBM cells killed when doubling concentration to 10 µM and keeping the treatment time and power the same. According to these simulations, the standard trial protocol is reasonably well optimized with improvements in cell kill difficult to achieve without potentially dangerous increases in temperature. To improve treatment outcome, focus should be placed on improving the photosensitizer. Conclusions: With further development and optimization, the simulation could have potential clinical benefit and be used to help plan and optimize intraoperative PDT treatment for GBM.

Impaired glucose utilization in the brain of patients with delirium following hip fracture.

Alterations in brain energy metabolism have long been proposed as one of several neurobiological processes contributing to delirium. This is supported by previous findings of altered CSF lactate and neuron-specific enolase concentrations and decreased glucose uptake on brain-PET in patients with delirium. Despite this, there are limited data on metabolic alterations found in CSF samples, and targeted metabolic profiling of CSF metabolites involved in energy metabolism has not been performed. The aim of the study was to investigate whether metabolites related to energy metabolism in the serum and CSF of patients with hip fracture are associated with delirium. The study cohort included 406 patients with a mean age of 81 years (standard deviation 10 years), acutely admitted to hospital for surgical repair of a hip fracture. Delirium was assessed daily until the fifth postoperative day. CSF was collected from all 406 participants at the onset of spinal anaesthesia, and serum samples were drawn concurrently from 213 participants. Glucose and lactate in CSF were measured using amperometry, whereas plasma glucose was measured in the clinical laboratory using enzymatic photometry. Serum and CSF concentrations of the branched-chain amino acids, 3-hydroxyisobutyric acid, acetoacetate and ß-hydroxybutyrate were measured using gas chromatography-tandem mass spectrometry (GC-MS/MS). In total, 224 (55%) patients developed delirium pre- or postoperatively. Ketone body concentrations (acetoacetate, ß-hydroxybutyrate) and branched-chain amino acids were significantly elevated in the CSF but not in serum among patients with delirium, despite no group differences in glucose concentrations. The level of 3-hydroxyisobutyric acid was significantly elevated in both CSF and serum. An elevation of CSF lactate during delirium was explained by age and comorbidity. Our data suggest that altered glucose utilization and a shift to ketone body metabolism occurs in the brain during delirium.

Brain Abscess Caused by Oral Cavity Bacteria: A Nationwide, Population-based Cohort Study.

BACKGROUND: Oral cavity bacteria are the most frequent etiology of brain abscess. Yet, data on the clinical presentation and outcome are scarce. METHODS: We performed a nationwide, population-based study comprising all adults (aged ≥18 years) with brain abscess due to oral cavity bacteria in Denmark from 2007 through 2020. Prognostic factors for unfavorable outcome (Glasgow outcome scale, 1-4) were examined using modified Poisson regression to compute adjusted relative risks (RRs) with 95% confidence intervals (CIs). RESULTS: Among 287 identified patients, the median age was 58 years (interquartile range, 47-66), and 96 of 287 (33%) were female. Preexisting functional impairment was absent or mild in 253 of 280 (90%), and risk factors for brain abscess included immunocompromise in 95 of 287 (33%), dental infection in 68 of 287 (24%), and ear-nose-throat infection in 33 of 287 (12%). Overall, a neurological deficit was present in 246 of 276 (86%) and in combination with headache and fever in 64 of 287 (22%). Identified microorganisms were primarily the Streptococcus anginosus group, Fusobacterium, Actinomyces, and Aggregatibacter spp., and 117 of 287 (41%) were polymicrobial. Unfavorable outcome occurred in 92 of 246 (37%) at 6 months after discharge and was associated with antibiotics before neurosurgery (RR, 3.28; 95% CI, 1.53-7.04), rupture (RR, 1.89; 95% CI, 1.34-2.65), and immunocompromise (RR, 1.80; 95% CI, 1.29-2.51), but not with specific targeted antibiotic regimens. Identified dental infection was associated with favorable prognosis (RR, 0.58; 95% CI, .36-.93). CONCLUSIONS: Brain abscess due to oral cavity bacteria often occurred in previously healthy individuals without predisposing dental infections. Important risk factors for unfavorable outcome were rupture and immunocompromise. However, outcome was not associated with specific antibiotic regimens supporting carbapenem-sparing strategies.

Pulmonary arteriovenous malformations in patients with previous brain abscess: a cross-sectional population-based study.

BACKGROUND AND PURPOSE: Pulmonary arteriovenous malformations (PAVMs) may cause recurrent brain abscess. The primary aim was to determine the prevalence of PAVM amongst survivors of brain abscess. The proportion with cardiac right-to-left shunts was also assessed post hoc. METHODS: This was a cross-sectional population-based study of adult (≥18 years) survivors of cryptogenic bacterial brain abscess in Denmark from 2007 through 2016. Patients were invited for bubble-echocardiography to detect vascular right-to-left shunting and, if abnormal, subsequent computed tomography thorax for diagnosis of PAVM. Data are presented as n/N (%) or median with interquartile range (IQR). RESULTS: Study participation was accepted by 47/157 (30%) eligible patients amongst whom two did not appear for scheduled bubble-echocardiography. The median age of participants was 54 years (IQR 45-62) and 19/57 (33%) were females compared with 59 years (IQR 48-68, p = 0.05) and 41/85 females (48%, p = 0.22) in non-participants. Bubble-echocardiography was suggestive of shunt in 10/45 (22%) participants and PAVM was subsequently confirmed by computed tomography in one patient with grade 1 shunting. The corresponding prevalence of PAVM was 2% (95% confidence interval 0.06-11.8) amongst all examined participants. Another 9/45 (20%) were diagnosed with patent in persistent foramen ovale (n = 8) or atrial septum defect (n = 1), which is comparable with the overall prevalence of 25% amongst adults in the Danish background population. CONCLUSIONS: Undiagnosed PAVM amongst adult survivors of cryptogenic bacterial brain abscess is rare but may be considered in select patients. The prevalence of cardiac right-to-left shunts amongst brain abscess patients corresponds to the prevalence in the general population.

Patient-reported symptomatology and its course in spontaneous intracranial hypotension - Beware of a chameleon.

OBJECTIVE: Although orthostatic headache is the hallmark symptom of spontaneous intracranial hypotension (SIH), patients can present with a wide range of different complaints and thereby pose a diagnostic challenge for clinicians. Our aim was to describe and group the different symptoms associated with SIH and their course over time. METHODS: We retrospectively surveyed consecutive patients diagnosed and treated for SIH at our institution from January 2013 to May 2020 with a specifically designed questionnaire to find out about their symptomatology and its course. RESULTS: Of 112 eligible patients, 79 (70.5%) returned the questionnaire and were included in the analysis. Of those, 67 (84.8%) reported initial orthostatic headaches, whereas 12 (15.2%) denied having this initial symptom. All except one (98.7%) patients reported additional symptoms: most frequently cephalic pressure (69.6%), neck pain (68.4%), auditory disturbances (59.5%), nausea (57%), visual disturbances (40.5%), gait disturbance (20.3%), confusion (10.1%) or sensorimotor deficits (21.5%). Fifty-seven (72.2%) patients reported a development of the initial symptoms predominantly in the first three months after symptom onset. Age and sex were not associated with the symptomatology or its course (p > 0.1). CONCLUSION: Although characteristic of SIH, a relevant amount of patients present without orthostatic headaches. In addition, SIH can manifest with non-orthostatic headaches at disease onset or during the course of the disease. Most patients report a wide range of associated complaints. A high degree of suspicion is crucial for an early diagnosis and targeted treatment.

Benign recurrent lymphocytic meningitis (Mollaret's meningitis) in Denmark: a nationwide cohort study.

BACKGROUND AND PURPOSE: Data on clinical features and outcomes of benign recurrent lymphocytic meningitis (BRLM) are limited. METHODS: This was a nationwide population-based cohort study of all adults hospitalized for BRLM associated with herpes simplex virus type 2 (HSV-2) at the departments of infectious diseases in Denmark from 2015 to 2020. Patients with single-episode HSV-2 meningitis were included for comparison. RESULTS: Forty-seven patients with BRLM (mean annual incidence 1.2/1,000,000 adults) and 118 with single-episode HSV-2 meningitis were included. The progression risk from HSV-2 meningitis to BRLM was 22% (95% confidence interval [CI] 15%-30%). The proportion of patients with the triad of headache, neck stiffness and photophobia/hyperacusis was similar between BRLM and single-episode HSV-2 meningitis (16/43 [37%] vs. 46/103 [45%]; p = 0.41), whilst the median cerebrospinal fluid leukocyte count was lower in BRLM (221 cells vs. 398 cells; p = 0.02). Unfavourable functional outcomes (Glasgow Outcome Scale score of 1-4) were less frequent in BRLM at all post-discharge follow-up visits. During the study period, 10 (21%) patients with BRLM were hospitalized for an additional recurrence (annual rate 6%, 95% CI 3%-12%). The hazard ratio for an additional recurrence was 3.93 (95% CI 1.02-15.3) for patients with three or more previous episodes of meningitis. CONCLUSIONS: Clinical features of BRLM were similar to those of single-episode HSV-2 meningitis, whilst post-discharge outcomes were more favourable. Patients with three or more previous episodes of meningitis had higher risk of an additional recurrence.

Postoperative RNFL-Changes after Successful Trabeculectomy: 2-Year Outcomes. / Zwei-Jahres-Ergebnisse postoperativer RNFL-Entwicklung nach erfolgreicher Trabekulektomie.

BACKGROUND: The most important tool in glaucoma therapy is to lower the intraocular pressure to slow down the apoptosis of retinal ganglion cells. Trabeculectomy (TE) is considered the gold standard in glaucoma surgery. The aim of this study was to analyse the postoperative changes in retinal nerve fibre layer (RNFL) using optical coherence tomography (OCT) after TE. MATERIAL AND METHODS: We examined 40 patients naïve to prior glaucoma surgery retrospectively, who received a TE for medically uncontrolled primary open-angle glaucoma (POAG). Intraocular pressure (IOP), IOP-lowering medication, mean deviation of perimetry, visual acuity and peripapillary RNFL-thickness using OCT were evaluated during the first 24 month after TE. RESULTS: In total 40 eyes from 40 patients were treated with TE. Mean IOP decreased from 25.0 ± 0,9 to 13.9 ± 0.6 (p < 0.01), and the mean number of IOP-lowering eye drops from 3.3 ± 0.2 to 0.5 ± 0.2 (p < 0.01). Visual acuity and mean deviation in perimetry remained stable while mean global RNFL-thickness decreased from 67.8 ± 2.9 to 63.7 ± 2.9 (p < 0.01) and 63.4 ± 2.9 µm (p < 0.01) 12 and 24 months after TE. CONCLUSION: The TE is an effective method to reduce the IOD and the amount of IOP-lowering medication. Nevertheless, a significant further loss in RNFL thickness was observed in the first 12 months after TE. Thus, RNFL changes seem to stabilise only after a protracted period.

Viral lumbosacral radiculitis (Elsberg syndrome) in Denmark.

PURPOSE: To describe clinical features and outcomes of viral lumbosacral radiculitis (Elsberg syndrome). METHODS: Nationwide population-based cohort study of all adults hospitalised for viral lumbosacral radiculitis at departments of infectious diseases in Denmark from 2015 to 2020. RESULTS: Twenty-eight patients with viral lumbosacral radiculitis were included (mean annual incidence: 1.2/1,000,000 adults). The median age was 35 years (IQR 27-43), and 22/28 (79%) were female. All patients had urinary retention, with 17/28 (61%) needing a catheter. On admission, at least one sign or symptom of meningitis (headache, neck stiffness, photophobia/hyperacusis) was present in 18/22 (82%). Concurrent genital herpetic lesions were present in 11/24 (46%). The median cerebrospinal fluid leukocyte count was 153 cells/µL (IQR 31-514). Magnetic resonance imaging showed radiculitis/myelitis in 5/19 (26%). The microbiological diagnosis was herpes simplex virus type 2 in 19/28 (68%), varicella-zoster virus in 2/28 (7%), and unidentified in 7/28 (25%). Aciclovir/valaciclovir was administered in 27/28 (96%). At 30 days after discharge, 3/27 (11%) had persistent urinary retention with need of catheter. At 180 days after discharge, moderate disabilities (Glasgow Outcome Scale score of 4) were observed in 5/25 (20%). CONCLUSIONS: Urinary retention resolved within weeks in most patients with viral lumbosacral radiculitis, but moderate disabilities according to the Glasgow Outcome Scale were common at the end of follow-up.

Nucleolar Essential Protein 1 (Nep1): Elucidation of enzymatic catalysis mechanism by molecular dynamics simulation and quantum mechanics study.

The Nep1 protein is essential for the formation of eukaryotic and archaeal small ribosomal subunits, and it catalyzes the site-directed SAM-dependent methylation of pseudouridine (Ψ) during pre-rRNA processing. It possesses a non-trivial topology, namely, a 31 knot in the active site. Here, we address the issue of seemingly unfeasible deprotonation of Ψ in Nep1 active site by a distant aspartate residue (D101 in S. cerevisiae), using a combination of bioinformatics, computational, and experimental methods. We identified a conserved hydroxyl-containing amino acid (S233 in S. cerevisiae, T198 in A. fulgidus) that may act as a proton-transfer mediator. Molecular dynamics simulations, based on the crystal structure of S. cerevisiae, and on a complex generated by molecular docking in A. fulgidus, confirmed that this amino acid can shuttle protons, however, a water molecule in the active site may also serve this role. Quantum-chemical calculations based on density functional theory and the cluster approach showed that the water-mediated pathway is the most favorable for catalysis. Experimental kinetic and mutational studies reinforce the requirement for the aspartate D101, but not S233. These findings provide insight into the catalytic mechanisms underlying proton transfer over extended distances and comprehensively elucidate the mode of action of Nep1.

Peripheral death by neglect and limited clonal deletion during physiologic B lymphocyte development.

Autoreactive B cells generated during B cell development are inactivated by clonal deletion, receptor editing or anergy. Up to 97% of immature B cells appear to die before completing maturation, but the anatomic sites and reasons underlying this massive cell loss are not fully understood. Here, we directly quantitated apoptosis and clonal deletion during physiologic B lymphocyte development using Rosa26INDIA apoptosis indicator mice. Immature B cells displayed low levels of apoptosis in the bone marrow but started dying at high levels in the periphery upon release from bone marrow sinusoids into the blood circulation. Clonal deletion of self-reactive B cells was neither a major contributor to apoptosis in the bone marrow nor the periphery. Instead, most peripheral transitional 1 B cells did not encounter the signals required for positive selection into the mature B cell compartments. This study sheds new light on B cell development and suggests that receptor editing and/or anergy efficiently control most primary autoreactivity in mice.

Pentraxin 3 in the cerebrospinal fluid during central nervous system infections: A retrospective cohort study.

The present study describes diagnostic and prognostic abilities of Cerebrospinal fluid (CSF) Pentraxin 3 (PTX3) in central nervous system (CNS) infections. CSF PTX3 was measured retrospectively from 174 patients admitted under suspicion of CNS infection. Medians, ROC curves and Youdens index was calculated. CSF PTX3 was significantly higher among all CNS infections and undetectable in most of the patients in the control group, and significantly higher in bacterial infections compared to viral and Lyme infections. No association was found between CSF PTX3 and Glasgow Outcome Score. PTX3 in the CSF can distinguish bacterial infection from viral and Lyme infections and non-CNS infections. Highest levels were found in bacterial meningitis. No prognostic abilities were found.

Clinical features and prognostic factors in adults with viral meningitis.

Clinical features applicable to the entire spectrum of viral meningitis are limited, and prognostic factors for adverse outcomes are undetermined. This nationwide population-based prospective cohort study included all adults with presumed and microbiologically confirmed viral meningitis in Denmark from 2015 until 2020. Prognostic factors for an unfavourable outcome (Glasgow Outcome Scale score of 1-4) 30 days after discharge were examined by modified Poisson regression. In total, 1066 episodes of viral meningitis were included, yielding a mean annual incidence of 4.7 episodes per 100 000 persons. Pathogens were enteroviruses in 419/1066 (39%), herpes simplex virus type 2 in 171/1066 (16%), varicella-zoster virus in 162/1066 (15%), miscellaneous viruses in 31/1066 (3%) and remained unidentified in 283/1066 (27%). The median age was 33 years (IQR 27-44), and 576/1066 (54%) were females. In herpes simplex virus type 2 meningitis, 131/171 (77%) were females. Immunosuppression [32/162 (20%)] and shingles [90/149 (60%)] were frequent in varicella-zoster virus meningitis. The triad of headache, neck stiffness and hyperacusis or photophobia was present in 264/960 (28%). The median time until lumbar puncture was 3.0 h (IQR 1.3-7.1), and the median CSF leucocyte count was 160 cells/µl (IQR 60-358). The outcome was unfavourable in 216/1055 (20%) 30 days after discharge. Using unidentified pathogen as the reference, the adjusted relative risk of an unfavourable outcome was 1.34 (95% CI 0.95-1.88) for enteroviruses, 1.55 (95% CI 1.00-2.41) for herpes simplex virus type 2, 1.51 (95% CI 0.98-2.33) for varicella-zoster virus and 1.37 (95% CI 0.61-3.05) for miscellaneous viruses. The adjusted relative risk of an unfavourable outcome was 1.34 (95% CI 1.03-1.75) for females. Timing of acyclovir or valacyclovir was not associated with the outcome in meningitis caused by herpes simplex virus type 2 or varicella-zoster virus. In summary, the outcome of viral meningitis was similar among patients with different aetiologies, including those with presumed viral meningitis but without an identified pathogen. Females had an increased risk of an unfavourable outcome. Early antiviral treatment was not associated with an improved outcome in meningitis caused by herpes simplex virus type 2 or varicella-zoster virus.