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Cerebrospinal fluid (CSF) galactomannan is an adjunctive test for central nervous system (CNS) aspergillosis diagnosis with unclear diagnostic test characteristics. To evaluate the diagnostic test characteristics of CSF galactomannan in CNS aspergillosis. Systematic review and meta-analysis. MEDLINE, Embase, Web of Science, and Scopus, from inception to 24 February 2023. Prospective and retrospective studies with 1-group and 2-group designs using any galactomannan assay on CSF to diagnose CNS aspergillosis. Adult and/or paediatric patients with CNS aspergillosis. Galactomannan testing on CSF specimens. European Organization for Research and Treatment of Cancer and the Mycoses Study Group Education and Research Consortium (EORTC/MSGERC) diagnostic criteria, or equivalent. QUADAS-2 assessment in duplicate. Bivariate restricted maximum likelihood estimation random-effects meta-analysis, summarized using forest and summary receiver operating characteristic plots; bivariate meta-regression models to investigate heterogeneity; and subgroup and sensitivity analyses to explore subgroup effects and methodologic choices (PROSPERO registration: CRD42022296331; funding: none). We included eight studies (n = 342 participants). The summary estimates of CSF galactomannan sensitivity and specificity were 69.0% (95% CI, 57.2–78.7%) and 94.4% (95% CI, 82.8–98.3%), respectively. Using meta-regression, galactomannan cut-off (p = 0.38), EORTC/MSGERC criteria version (p = 0.48), or whether the reference standard was defined as both proven and probable or only proven aspergillosis (p = 0.48) did not explain observed heterogeneity. No subgroup effects were demonstrated by analysing the EORTC/MSGERC criteria reference standard used (e.g. 2002 vs. 2008 definitions) or whether paediatric patients were included. Diagnostic sensitivity was improved using a galactomannan cut-off of 1.0, and by excluding high risk of bias and 1-group design studies. CSF galactomannan is a highly specific but insensitive test for use as a component of CNS aspergillosis diagnosis. Few included studies, no prospective studies, and a high risk of bias are study limitations. [ABSTRACT FROM AUTHOR]

Bacterial meningitis is a serious central nervous system (CNS) infection, claiming millions of human lives annually around the globe. The deadly infection involves severe inflammation of the protective sheath of the brain, i.e., meninges, and sometimes also consists of the brain tissue, called meningoencephalitis. Several inflammatory pathways involved in the pathogenesis of meningitis caused by Streptococcus pneumoniae, Neisseria meningitidis, Escherichia coli, Haemophilus influenzae, Mycobacterium tuberculosis, Streptococcus suis , etc. are mentioned in the scientific literature. Many in-vitro and in-vivo analyses have shown that after the disruption of the blood-brain barrier (BBB), these pathogens trigger several inflammatory pathways including Toll-Like Receptor (TLR) signaling in response to Pathogen-Associated Molecular Patterns (PAMPs), Nucleotide oligomerization domain (NOD)-like receptor-mediated signaling, pneumolysin related signaling, NF-κB signaling and many other pathways that lead to pro-inflammatory cascade and subsequent cytokine release including interleukine (IL)-1β, tumor necrosis factor(TNF)-α, IL-6, IL-8, chemokine (C-X-C motif) ligand 1 (CXCL1) along with other mediators, leading to neuroinflammation. The activation of another protein complex, nucleotide-binding domain, leucine-rich–containing family, pyrin domain–containing-3 (NLRP3) inflammasome, also takes place resulting in the maturation and release of IL-1β and IL-18, hence potentiating neuroinflammation. This review aims to outline the inflammatory signaling pathways associated with the pathogenesis of bacterial meningitis leading to extensive pathological changes in neurons, astrocytes, oligodendrocytes, and other central nervous system cells. • Bacterial meningitis is a serious central nervous system infection, claiming millions of human lives annually around the globe. • The deadly infection involves severe inflammation of the protective sheath of the brain, i.e., meninges, and sometimes also consists of the brain tissue, called meningoencephalitis. • Several inflammatory pathways involved in the pathogenesis of meningitis caused by Streptococcus pneumoniae, Neisseria meningitidis, Escherichia coli, Haemophilus influenzae, Mycobacterium tuberculosis, Streptococcus suis , etc. are mentioned in the scientific literature. • Many in-vitro and in-vivo analyses have shown that after the disruption of the blood-brain barrier (BBB), these pathogens trigger several inflammatory pathways. • Toll-Like Receptor (TLR) signaling in response to Pathogen-Associated Molecular Patterns (PAMPs), Nucleotide oligomerization domain (NOD)-like receptor-mediated signaling, pneumolysin related signaling, NF-κB signaling and many other pathways that lead to pro-inflammatory cascade, and subsequent cytokine release including interleukine (IL)-1β, tumor necrosis factor(TNF)-α, IL-6, IL-8, chemokine (C-X-C motif) ligand 1 (CXCL1), nucleotide-binding domain, leucine-rich–containing family, pyrin domain–containing-3 (NLRP3) inflammasome, along with other mediators, leading to neuroinflammation. [ABSTRACT FROM AUTHOR]

Isolated tumefactive demyelinating lesions (≥2 cm) may be difficult to distinguish from contrast-enhancing brain tumors, central nervous system infections, and (rarely) tissue dysgenesis, which may all occur with increased signal on T2-weighted images. Establishing an accurate diagnosis is essential for management, and we delineate our single-center experience. We performed a retrospective review of medical records, imaging, and biopsy specimens for patients under 18 years presenting with isolated tumefactive demyelination over a 10-year period. Ten children (eight female) met inclusion criteria, with a median age of 14.1 years. Lesions were most likely to involve the thalamus (six of 10), brainstem (five of 10), basal ganglia (four of 10), or corpus callosum (four of 10). Eighty percent had perilesional edema at presentation, and 60% had midline shift. Biopsies demonstrated demyelination with perivascular lymphocytic infiltration and axonal damage ranging from mild to severe. All patients were initially treated with high-dose corticosteroids, and eight of 10 required additional medical therapies such as intravenous immunoglobulin, plasmapheresis, cyclophosphamide, or rituximab. Increased intracranial pressure was managed aggressively with two of 10 patients requiring decompressive craniectomies. Clinical outcomes varied. Solitary tumefactive demyelinating lesions are rare, and aggressive management of inflammation and increased intracranial pressure is essential. Biopsy is helpful to evaluate for other diagnoses on the differential and maximize therapies. Treatment beyond initial therapy with corticosteroids is often required. Isolated tumefactive demyelinating lesions are uncommon; multicenter natural history studies are needed to better delineate differential diagnoses and optimal therapies. [ABSTRACT FROM AUTHOR]

Viral encephalitis is an infectious disease severely affecting human health. It is caused by a wide variety of viral pathogens, including herpes viruses, flaviviruses, enteroviruses, and other viruses. The laboratory diagnosis of viral encephalitis is a worldwide challenge. Recently, high-throughput sequencing technology has provided new tools for diagnosing central nervous system infections. Thus, In this study, we established a multipathogen detection platform for viral encephalitis based on amplicon sequencing. We designed nine pairs of specific polymerase chain reaction (PCR) primers for the 12 viruses by reviewing the relevant literature. The detection ability of the primers was verified by software simulation and the detection of known positive samples. Amplicon sequencing was used to validate the samples, and consistency was compared with Sanger sequencing. The results showed that the target sequences of various pathogens were obtained at a coverage depth level greater than 20×, and the sequence lengths were consistent with the sizes of the predicted amplicons. The sequences were verified using the National Center for Biotechnology Information BLAST, and all results were consistent with the results of Sanger sequencing. Amplicon-based high-throughput sequencing technology is feasible as a supplementary method for the pathogenic detection of viral encephalitis. It is also a useful tool for the high-volume screening of clinical samples. [ABSTRACT FROM AUTHOR]

Watertight closure of dura mater after intracranial surgery can avoid cerebrospinal fluid leakage and central nervous system infection and herniation. When primary closure is not possible, the pericranium is the preferential choice. When it is not available, a dural substitute becomes necessary. Bovine pericardium treated with polyethylene glycol and ethanol is herein tested as a dural substitute. A pilot study comparing bovine pericardium with pericranium in supratentorial neurosurgery was performed. Twenty patients were initially allocated into a bovine pericardium group (group 1) or a pericranium group (group 2). Three patients from group 1 and 2 from group 2 had a loss of follow-up, being excluded. In the remaining 15 patients, epidemiological analysis demonstrated a male:female ratio of 3:4 and 4:4 for groups 1 and 2. Ages varied from 28 to 68 (Mean = 49.6) in group 1 and 40–80 (Mean = 61.2) in group 2, with a mean difference of 11.68 years (P = 0.09). Two cases of surgical site infection and 1 of hydrocephalus were observed. Although the calculated relative risk for complications was higher in group 1 (Relative Risk = 1.08), Fisher exact test demonstrated no statistically significant difference between groups (P = 1.00). Procedure mean time was 23 minutes and 11 seconds in group 1 versus 27 minutes and 55 seconds in group 2 (P = 0.47). Mean graft area was 13.17 and 6.23 cm2 in groups 1 and 2 (P = 0.02). Bovine pericardium treated with polyethylene glycol and ethanol was comparable to pericranium as a dural substitute. More studies are encouraged to certify our findings. [ABSTRACT FROM AUTHOR]

This study aims to identify risk factors for central nervous system (CNS) infection in elderly patients hospitalized with traumatic brain injury (TBI) and to develop a reliable predictive tool for assessing the likelihood of CNS infection in this population. We conducted a retrospective study on 742 elderly TBI patients treated at Tangdu Hospital, China. Clinical data was randomly split into training and validation sets (7:3 ratio). By conducting univariate and multivariate logistic regression analysis in the training set, we identified a list of variables to develop a nomogram for predicting the risk of CNS infection. We evaluated the performance of the predictive model in both cohorts respectively, using receiver operating characteristics curves, calibration curves, and decision curve analysis. Results of the logistic analysis in the training set indicated that surgical intervention (P = 0.007), red blood cell count (P = 0.019), C-reactive protein concentration (P < 0.001), and cerebrospinal fluid leakage (P < 0.001) significantly predicted the occurrence of CNS infection in elderly TBI patients. The model constructed based on these variables had high predictive capability (area under the curve-training = 0.832; area under the curve-validation = 0.824) as well as clinical utility. A nomogram constructed based on several key predictors reasonably predicts the risk of CNS infection in elderly TBI patients upon hospital admission. The model of the nanogram may contribute to timely interventions and improve health outcomes among affected individuals. [ABSTRACT FROM AUTHOR]

We compared characteristics and outcomes of individuals who in the cerebrospinal fluid (CSF) were positive for herpes simplex virus (HSV) or varicella-zoster virus (VZV)-intrathecal antibody index test ([AI]-positive) vs. individuals who were PCR-positive for HSV type 1 (HSV1), type 2 (HSV2), and for VZV. Nationwide cohort study of all Danish residents with positive CSF-AI or -PCR for HSV or VZV (1995–2021). We calculated short- and long-term risks as age-, sex-, and comorbidity-adjusted odds ratios (aOR), adjusted hazard ratios (aHR), and absolute risk differences with 95% CIs. Compared with individuals with positive PCR for HSV1 (n = 321), HSV2 (n = 497), and VZV (n = 1054), individuals with a positive AI for HSV (n = 177) and VZV (n = 219) had CSF pleocytosis less frequently (leucocyte count >10/μL: HSV-AI: 39%, VZV-AI: 52%, HSV1-PCR: 81%, HSV2-PCR: 92%, VZV-PCR: 83%), and were less frequently diagnosed with central nervous system infection ([aOR {95%CI}]: HSV-AI vs. HSV1-PCR: [0.1 {0.1, 0.2}], HSV-AI vs. HSV2-PCR: [0.1 {0.0, 0.1}], VZV-AI vs. VZV-PCR: [0.2 {0.2, 0.3}]). Individuals with a positive HSV-AI or VZV-AI had increased risk of demyelinating disease ([aOR {95%CI}; aHR {95%CI}]: HSV-AI vs. HSV1-PCR: [4.6 {0.9, 24.5}; aHR not applicable], HSV-AI vs. HSV2-PCR: [10.4 {2.3, 45.9}; 12.4 {2.3, 66.0}], VZV-AI vs. VZV-PCR: [aOR not applicable; 10.3 {1.8, 58.8}]). Disability pension was less frequent among HSV-AI than HSV1-PCR cohort members (5-year risk difference: −23.6%, 95%CI: −35.2, −11.8), and more frequent among VZV-AI than VZV-PCR cohort members (5-year risk difference: 16.8%, 95%CI: 5.0, 28.7). AI-positive individuals differ from PCR-positive individuals in several aspects. AI appears unspecific for current central nervous system infections. [ABSTRACT FROM AUTHOR]

An important factor for the prognosis of spinal surgery is the perioperative use of opioids. However, the relationship is not clear. The purpose of this study was to evaluate the effect of perioperative opioid use on the prognosis of patients following spinal surgery. Systematic review and meta-analysis. A meta-analysis was conducted using the random-effects method to calculate pooled odds ratios (ORs) with 95% confidence intervals (CIs). The PubMed, Embase, and Cochrane Library databases were systematically searched to find relevant articles that were published until September 2, 2022. The primary outcome was prolonged postoperative opioid use, and secondary outcomes included the length of stay (LOS), reoperation, the time to return to work (RTW), postoperative complications, gastrointestinal complications, new permanent disability, central nervous system events and infection. In addition, subgroup analysis of the primary outcome was conducted to explore the main sources of heterogeneity, and sensitivity analysis of all outcomes was performed to evaluate the stability of the results. A total of 60 cohort studies involving 13,219,228 individuals met the inclusion criteria. Meta-analysis showed that perioperative opioid use was specifically related to prolonged postoperative opioid use (OR 6.91, 95% CI 6.09 to 7.84, p<.01). Furthermore, the results also showed that perioperative opioid use was significantly associated with prolonged LOS (OR 1.74, 95% CI 1.39 to 2.18, p<.01), postoperative complications (OR 1.72, 95% CI 1.26 to 2.36, p<.01), reoperation (OR 2.38, 95% CI 1.85 to 3.07, p<.01), the time to RTW (OR 0.45, 95% CI 0.39 to 0.52, p<.01), gastrointestinal complications (OR 1.39, 95% CI 1.30 to 1.48, p<.01), central nervous system events (OR 1.99, 95% CI 1.21 to 3.27, p=.07) and infection (OR 1.22, 95% CI 1.09 to 1.36, p=.01). These results were corroborated by the trim-and-fill procedure and leave-one-out sensitivity analyses. Based on the current evidence, patients with perioperative opioid use, in comparison to controls, appear to have prolonged postoperative opioid use, which may increase the risk of poor outcomes including prolonged LOS, complications, reoperation, RTW and so on. However, these results must be carefully interpreted as the number of studies included was small and the studies were statistically heterogeneous. These findings may help clinicians to realize the harmfulness of perioperative use of opioids, reduce the use of prescription opioids, necessarily withdraw before operation or significantly wean to the lowest tolerable preoperative amount, and provide some inspiration for standardizing the use of opioids in the future. [ABSTRACT FROM AUTHOR]

Early switch to oral antimicrobials has been suggested as a treatment strategy in patients with brain abscess, but the practice is controversial. This review aimed to summarize the background, current evidence, and future perspectives for early transition to oral antimicrobials in patients with brain abscess. The review was based upon a previous systematic review carried out during the development of the ESCMID guidelines on diagnosis and treatment of brain abscess. The search used 'brain abscess' or 'cerebral abscess' as text or MESH terms in PubMed, EMBASE, and the Cochrane Library. Studies included in the review were required to be published in the English language within the last 25 years and to have a study population of ≥10 patients. Other studies known by the authors were also included. In this review, the background for some experts to suggest early transition to oral antimicrobials in patients with mild and uncomplicated brain abscess was clarified. Next, results from observational studies were summarized and limitations discussed. Indirect support for early oral treatment of brain abscess was described with reference to other serious central nervous system infections and general pharmacological considerations. Finally, variations within and between countries in the use of early transition to oral antimicrobials in patients with brain abscess were highlighted. Early transition to oral antimicrobials in patients with uncomplicated brain abscess may be of benefit for patients due to convenience of treatment and potential decreased risks associated with prolonged hospitalization and intravenous lines. The strategy may also confer a more rational allocation of healthcare resources and decrease expenses. However, the benefit/risk ratio for this strategy remains unresolved at present. [ABSTRACT FROM AUTHOR]

The primary objective of this systematic review is to evaluate the effectiveness of intraoperative ultrasound (IOUS) in improving outcomes in patients undergoing pituitary surgery. A systematic review was performed by searching MEDLINE (PubMed), Web of Science, Scopus, and Embase electronic bibliographic databases from conception to 2022. The included studies yielded a total of 660 patients, with 488 patients undergoing IOUS. Outcome were available for 341 patients treated with IOUS and 157 patients who were treated without the IOUS application, and the remission rates following surgery were 76% and 59%, respectively. Only 2 studies reported remission rates for both groups, and meta-analysis for these studies showed significant superiority of intraoperative ultrasonography (Random effect, odds ratio 4.99, P < 0.01). Regarding extent of resection, IOUS resulted in 71% gross total resection, while absence of IOUS yielded a gross total resection rate of 44%. Among studies with available follow-up on IOUS, the recurrence rate was 3%. Pituitary dysfunction (34%), cerebrospinal fluid leak (31%), and central nervous system infection (8%) were the most common complications in the IOUS group. The mean follow-up was 19.97 months in studies reporting follow-up time. The application of the IOUS is both safe and effective and could improve the outcome of pituitary surgeries. IOUS can assist surgeons in the identification of pituitary tumors and their surrounding anatomy and can help minimize the risk of complications associated with this complex surgical procedure. [ABSTRACT FROM AUTHOR]

Consensus guidelines for antibiotic prophylaxis in endoscopic endonasal surgery (EES) have not been developed. The study objective was to define the microbiologic and clinical characteristics of post-EES central nervous system (CNS) infections. This was a single-center retrospective study of patients >18 years of age who underwent EES between January 2010 and July 2021 at a high-volume skull base center. Patients with confirmed CNS infection within 30 days of EES were included. During the study period, the standard prophylaxis regimen was ceftriaxone 2 g every 12 hours for 48 hours. For patients with a documented penicillin allergy, vancomycin plus aztreonam was recommended. In total, 2440 EES procedures were performed on 2005 patients; the CNS infection rate was 1.8% (37/2005). CNS infections were more common among patients with a history of previous EES (6.5%; 20/307) compared with those who did not (1%; 17/1698; P < 0.001). The median time from EES to CNS infection was 12 (6–19) days. Thirty-two percent (12/37) of CNS infections were polymicrobic, which was more common among patients without previous EES (52.9%; 9/17) compared with those with previous EES (15%; 3/20; P = 0.03). Across all cases, Staphylococcus aureus (n = 10) and Pseudomonas aeruginosa (n = 8) were commonly isolated pathogens. Among those with confirmed methicillin-resistant Staphylococcus aureus (MRSA) nares colonization before EES, 75% (3/4) developed MRSA CNS infections compared with 6.1% (2/33) of noncolonized patients (P = 0.005). CNS infection after EES is rare and causative pathogens vary. Further studies are needed to identify the impact of MRSA nares screening on antimicrobial prophylaxis before EES. [ABSTRACT FROM AUTHOR]

Listeria monocytogenes sometimes causes central nervous system infections. However, rhombencephalitis is a rare form of L. monocytogenes infection. Its clinical symptoms and magnetic resonance imaging (MRI) findings are often similar to those of vertebrobasilar stroke. We present the case of a 79-year-old woman with Listeria rhombencephalitis presenting with rhinorrhea and productive cough. She had giant cell arteritis (GCA) treated with prednisolone and methotrexate. She was admitted for loss of appetite, rhinorrhea, and productive cough. These symptoms were alleviated without specific treatment; however, she suddenly developed multiple cranial nerve palsies, and MRI showed hyperintense signals on diffusion-weighted imaging and hypointense signals on apparent diffusion coefficient in the brainstem. Ischemic stroke due to exacerbation of GCA was suspected, and treatment with intravenous methylprednisolone was initiated; however, seizures occurred, and a lumbar puncture was performed. Cerebrospinal fluid and blood cultures revealed L. monocytogenes , and she was diagnosed with Listeria rhombencephalitis. Although antibiotic treatment was continued, the patient died. Thus, when patients with rhinorrhea or productive cough develop sudden cranial nerve palsy, Listeria rhombencephalitis should be considered as a differential diagnosis, and lumbar puncture should be performed. [ABSTRACT FROM AUTHOR]

The blood brain barrier (BBB) controls the passage of molecules between the circulatory system and the central nervous system. Despite this, some fungi find ways to bypass the BBB, resulting in infections of the central nervous system (CNS) including meningitis, meningoencephalitis, and abscesses. While these infections are rare, the resultant mortality rates range from 30 to 99%, in part due to the poor penetration of most commercially available antifungals. Additionally, laboratory diagnostics can lack sensitivity and/or specificity and may require specialized diagnostic testing facilities, also contributing to the high mortality rate seen in CNS mycoses. Despite the high risk of mortality, detailed understanding of how these infections occur is limited to only a few of the most common fungi, and there is a dearth of research examining novel therapies to aid in the treatment of these infections. [ABSTRACT FROM AUTHOR]

Central nervous system (CNS) infection is one of the most serious complications after neurosurgery. This study aimed to analyze the effect of penicillin allergy (PA) and alternative prophylactic antibiotics on risk of postoperative CNS infection in patients undergoing neurosurgery. Data of patients who underwent neurosurgical procedures from January 2015 to December 2021 were analyzed retrospectively. Patients with PA were compared with patients without PA in a 1:1 ratio. A multivariate logistic regression model was used to examine whether PA was a risk factor for postoperative CNS infection. Overall, 15,049 eligible neurosurgical records were reviewed, from which 578 surgical records of 556 patients with PA were matched to 578 records of 570 patients without PA. Patients with PA showed significantly lower probability to receive prophylactic cephalosporins (55.9% vs. 98.8%, P < 0.01), but significantly higher probability to receive clindamycin (41.86% vs. 1.03%, P < 0.01), than patients without PA. Multivariate analysis revealed that patients with PA were more likely to experience postoperative CNS infection than patients without PA (odds ratio = 2.03; 95% confidence interval, 1.15–3.56; P = 0.014). The incidence of postoperative CNS infection returned to a level comparable to that in general population when patients with suspected PA received prophylactic cephalosporins. PA is associated with higher risk of postoperative CNS infection in patients undergoing neurosurgery. This may be attributed to the use of alternative prophylactic antibiotics other than cephalosporins, especially clindamycin. [ABSTRACT FROM AUTHOR]

Linezolid is a valuable therapeutic option for infections of the central nervous system caused by multi-drug resistant Gram-positive pathogens. Data regarding linezolid pharmacokinetics in cerebrospinal fluid from post-operative neurosurgical patients have revealed wide inter-individual variability. The objectives of this study were to establish a population pharmacokinetic model for linezolid in plasma and cerebrospinal fluid, as well as to optimize dosing strategies in this susceptible population. This was a prospective pharmacokinetic study in post-operative neurosurgical patients receiving intravenous linezolid. Parallel blood and cerebrospinal fluid samples were collected and analyzed. The population pharmacokinetic modelling and Monte Carlo simulations were performed using the Phoenix NLME software. A two-compartment model (central plasma and cerebrospinal fluid compartments) fit the linezolid data well, with creatinine clearance and serum procalcitonin as significant variables. Linezolid demonstrated highly variable penetration into cerebrospinal fluid, with a mean cerebrospinal fluid/plasma ratio of 0.53. A strong correlation was found between plasma trough concentration and cerebrospinal fluid exposure of linezolid. Based on simulation results, optimal dosage regimens stratified by various renal functions and inflammatory status were proposed. A modeling and simulating strategy was employed in dose individualization to improve the efficacy and safety of linezolid treatment. [ABSTRACT FROM AUTHOR]

Children hospitalized with infectious diseases may develop severe, life-threatening conditions, often requiring admission to pediatric intensive care unit (PICU). The objectives of this study were to identify independent risk factors for PICU hospitalization with an infectious disease in children <5 years of age. In southern Israel, two populations live side by side: the middle–high income Jewish population and the low-income Bedouin population, both receiving equal and free medical care at the only tertiary medical center in the area. The study population included all children born in southern Israel and hospitalized at PICU with an infectious disease during 1991–2012. Risk factors for PICU hospitalizations were retrospectively studied by Kaplan–Meier and Cox proportional hazard survival analyses. 9951 Jewish children and 18,002 Bedouin children were enrolled; overall, 1135 episodes of PICU hospitalizations with an infectious disease were recorded (879, 77.4% Bedouin and 256, 22.6% Jewish patients). Bedouin children had a higher risk for PICU hospitalization with an infectious disease compared with Jewish children (adjusted Hazard Ratio [adj. HR] 1.7, 95% CI 1.5–2.0); maternal multiparity and low-birth weight (<2500 g) were additional risk factors for PICU hospitalization with an infectious disease compared to firstborns (adj. HR = 1.2, 95% CI 1.0–1.5) or to children with a birth weight ≥2500 g (adj. HR = 1.5, 95% 1.2–1.9). Older age was a protective factor for PICU hospitalization (adj. HR = 0.98, 95% CI 0.97–0.99). Children hospitalized with a central nervous system infection had the highest risk of PICU hospitalization (adj. HR 6.8, 95% CI 5.5–8.4), followed by those with urinary tract infections (UTI, adj. HR 3.1, 95% CI 2.5–3.8) and those with lower respiratory tract infections (LRTI, adj. HR 2.9, 95% CI 2.4–3.4). Bedouin ethnicity, low birth weight, maternal multiparity and younger age were significant risk factors for PICU hospitalizations with an infectious disease. Among the infectious diseases analyzed, CNS infection had the highest risk for PICU hospitalization, followed by UTI and LRTI. [ABSTRACT FROM AUTHOR]

To investigate the risk factor associated with central nervous system infection, a rare and dire complication after spinal surgery. Univariate and multivariate logistic regression analyses were performed to screen for the independent risk factors. According to the different administration methods of antibiotics, patients were divided into intravenous and intrathecal groups. The differences in time needed for body temperature, white blood cells (WBC), and C-reactive protein (CRP) to return to normal and the time of antibiotic application were compared between the 2 groups. In addition, the differences in WBC, neutrophil ratio, CRP, procalcitonin in blood, and WBC in cerebrospinal fluid were compared before intrathecal injection, after the first one, and the last one. The incidence of complications in the 2 groups was observed. Dural tears, laminectomy, and operation time >3 hours were identified as independent risk factors. The time needed for body temperature, WBC, and CRP to return to normal and the antibiotic application time were significantly different between the 2 groups (all P < 0.05). Before and after the first intrathecal injection and after the last intrathecal injection, the differences in WBCs, neutrophil ratios, CRP, procalcitonin in blood, and cerebrospinal fluid-WBC were statistically significant in overall and pairwise comparisons (P < 0.05). Complications occurred in 2 and 14 cases, respectively. The independent risk factors for central nervous system infection after spinal surgery were a dural tear, laminectomy, and operation time > 3 hours. Combined intravenous and intrathecal injections of antibiotics led to a better effect than intravenous injection alone; however, this approach was associated with more complications. [ABSTRACT FROM AUTHOR]

• The first case of meningoencephalitis-associated Penicillium spp. • Case report of brain injury caused by Penicillium chrysogenum in a patient who is immunocompetent. • The need for studies to determine treatment for severe forms of invasive infections. Fungal infections of the central nervous system present a variety of clinical syndromes, such as meningitis, encephalitis, raised intracranial pressure with a nonspecific presentation, and, in the last two decades, have increased the incidence of these fungal infections. Fungal meningoencephalitis is frequently associated with Cryptococcus , but this report stands out for presenting one species of Penicillium genus. Here, we present the first case of meningoencephalitis associated with brain injury caused by Penicillium chrysogenum , in a patient who is immunocompetent and was admitted to Hospital Naval Marcílio Dias, Rio de Janeiro, Brazil. To identify the fungal species, we performed phenotypic and genotypic methodologies, from the culture to the sequencing of internal transcribed spacer region, and β-tubulin gene, a rare fungus in cerebrospinal fluid cultures, belonging to the genus Penicillium , was identified. We highlight the importance of the first report of meningoencephalitis caused by P. chrysogenum in a patient who is immunocompetent, registered in Brazil. We also emphasize the need for further studies to determine an effective treatment with the least possible side effects for patients infected by fungi that are rarely related to the most severe forms of invasive infections. [Display omitted] [ABSTRACT FROM AUTHOR]

Rapid and accurate diagnosis of herpes simplex virus (HSV)-1 and -2 (HSV1/2) in cerebrospinal fluid (CSF) is important for patient management. Summarize the diagnostic accuracy of commercial rapid sample-to-answer PCR assays (results in <90 minutes, without a separate nucleic acid extraction step) for HSV1/2 detection in CSF. Four databases (MEDLINE, EMBASE, Scopus, and CENTRAL) and five conference abstract datasets from January 2012 to March 2022. Eligible diagnostic accuracy studies provided sufficient data for the construction of a standard diagnostic accuracy two-by-two table. Patients with suspected meningitis and/or encephalitis. FilmArray Meningitis-Encephalitis Panel and Simplexa HSV 1&2 Direct Kit PCR. Real-time PCR assay. Two investigators independently extracted data, rated risk of bias, and assessed quality using QUADAS-2. Accuracy estimates were pooled using Bayesian random effects models. Thirty-one studies were included (27 FilmArray; 4 Simplexa), comprising 9924 samples, with 95 HSV-1 and 247 HSV-2 infections. Pooled FilmArray sensitivities were 84.3% (95% credible interval, 72.3–93.0) and 92.9% (95% credible interval (CrI), 82.0–98.5) for HSV-1 and HSV-2, respectively; specificities were 99.8% (95% CrI, 99.6–99.9) and 99.9% (95% CrI, 99.9–100). Pooled Simplexa sensitivities were 97.1% (95% CrI, 88.1–99.6) and 97.9% (95% CrI, 89.6–99.9), respectively; specificities were 98.9% (95% CrI, 96.8–99.7) and 98.9% (95% CrI, 97.1–99.7). Pooled FilmArray sensitivities favoured industry-sponsored studies by 10.0 and 13.0 percentage points for HSV-1 and HSV-2, respectively. Incomplete reporting frequently led to unclear risk of bias. Several FilmArray studies did not fully report true negative data leading to their exclusion. Our results suggest Simplexa is accurate for HSV1/2 detection in CSF. Moderate FilmArray sensitivity for HSV-1 suggests additional testing and/or repeat CSF sampling is required for suspected HSV encephalitis when the HSV-1 result is negative. Low prevalence of HSV-1 infections limited summary estimates' precision. Underreporting of covariates limited exploration of heterogeneity. [ABSTRACT FROM AUTHOR]

[Display omitted] • Dual-targeted strategy (AFAA-lipo) is proposed for central nervous system infection. • AFAA-lipo achieves inflammatory regulation and prognosis improvement. • AFAA-lipo enables disease process monitoring through in vivo NIR-II imaging. Precise antibacterial activity and effective inflammatory response reduction are critical for successful treatment of Intracranial infection after craniocerebral surgery, which remains an unmet clinical challenge. Herein, an intracranial drug delivery liposome (AFAA-lipo) that possesses dual active&passive targeting capability, direct antibacterial ability, favorable inflammation regulation, and excellent biocompatibility is developed as an antibiotics-free and hardly bacterial-resistance-induced platform for the management of intracranial infection. The surface-anchored specific peptide sequence HRERMS (the oligopeptide designed sourced from β-amyloid precursor protein) makes AFAA-lipo actively penetrate the blood–brain barrier and then perforated and lysed under the stimulation of α-toxin secreted by methicillin-resistant Staphylococcus aureus (MRSA, a severe and widespread intracranial infection type) in the infected site. Our results demonstrate that the AFAA-lipo can eliminate bacteria and biofilms, and reduce inflammatory response through mitochondrial function protection, DNA preservation from damage, TNFR1/NF-κB signaling pathway inhibition, and promotion of microglial polarization towards the anti-inflammatory subtype, ultimately improving post-infection prognosis and survival rate. More interestingly, the pre-intake of AFAA-lipo is capable to reduce MRSA infection risk and alleviate inflammatory response. Furthermore, the near-infrared (NIR) II region imaging fluorescence signal intensity variations of AFAA-lipo is proved the validation to monitor the course of the disease. [ABSTRACT FROM AUTHOR]

• Central nervous system infections by Burkholderia cepacia complex are rare. • We report the first case of choroid plexitis caused by B. cepacia complex after severe COVID-19. • The patient recovered after long-term therapy with multiple antibiotics. Burkholderia cepacia complex (BCC) encompasses opportunistic pathogen with various clinical manifestations ranging from no symptoms to severe respiratory infections and septicemia. Central nervous system infections caused by BCC are rare. To the best of our knowledge, we present the first reported case of choroid plexitis caused by BCC after severe COVID-19. A 67-year-old woman who had been previously diagnosed with COVID-19 presented with a mild fever and headache. Gadolinium-enhanced T1-weighted brain magnetic resonance imaging showed contrast effects in the right choroid plexus and encapsulated abscess. Gram staining of cerebrospinal fluid revealed the presence of gram-negative rods. Broad-range polymerase chain reaction amplification of 16S ribosomal RNA from the cerebrospinal fluid, followed by sequence analysis, identified BCC; thus, choroid plexitis caused by BCC was diagnosed. After prolonged antimicrobial treatment with a multiantibiotic regimen, the patient recovered completely. This case highlights the importance of long-term therapy with a carefully selected multiantibiotic regimen to achieve complete recovery after BCC infection. [ABSTRACT FROM AUTHOR]

• For the first time, a successful establishment and verification of a mathematical model that directly predicts the concentration of voriconazole in cerebrospinal fluid has been achieved. • The proposed model incorporates the influence of genetic variations in the CYP2C19 gene and the mechanism of time-dependent inhibition of CYP3A4. • The study successfully obtained the distribution of voriconazole concentration in both the central nervous system and plasma. Additionally, it offered a reference for the concentration of voriconazole under various prescription regimens. Voriconazole is a classical antifungal drug that is often used to treat CNS fungal infections due to its permeability through the BBB. However, its clinical use remains challenging because of its narrow therapeutic window and wide inter-individual variability. In this study, we proposed an optimised and validated PBPK model by integrating in vitro, in vivo and clinical data to simulate the distribution and PK process of voriconazole in the CNS, providing guidance for clinical individualised treatment. The model structure was optimised and tissue-to-plasma partition coefficients were obtained through animal experiments. Using the allometric relationships, the distribution of voriconazole in the human CNS was predicted. The model integrated factors affecting inter-individual variation and drug interactions of voriconazole—polymorphisms in the CYP2C19 gene and auto-inhibition and then was validated using real clinical data. The overall AFE value showing model predicted differences was 1.1420 in the healthy population; and in the first prediction of plasma and CSF in actual clinical patients, 89.5% of the values were within the 2-fold error interval, indicating good predictive performance of the model. The bioavailability of voriconazole varied at different doses (39%-86%), and the optimised model conformed to this pattern (46%–83%). Combined with the relevant pharmacodynamic indexes, the PBPK model provides a feasible way for precise medication in patients with CNS infection and improve the treatment effect and prognosis. A combination of "bottom-up" and "top-down" approach was used to build a PBPK model for voriconazole in human CNS. The PBPK model was optimised and validated by integrating in vitro, in vivo and clinical data successfully, providing a feasible way for precise medication in patients with CNS infection and improve the treatment effect and prognosis. [Display omitted] [ABSTRACT FROM AUTHOR]

[Display omitted] • Potentiostatic electrodeposition formed Au-Bi NPs on CPE to detect cefotaxime. • SEM revealed the successful integration of gold nanoparticle clusters into the bismuth layer on the CPE surface. • CV and EIS experiments showed the sensor's lower charge transfer resistance and better electron transfer. • Deposition durations, voltage, solution pH, and metal precursor concentration ratio affect AuBiNPs senstivity. • The electrochemical oxidation mechanism of cefotaxime on the fabricated electrode was elucidated via CV and CA. Antibiotics are crucial due to their widespread use in human and veterinary medicine. Cefotaxime, a third-generation cephalosporin, prevents bacterial production and treats central nervous system infections like meningitis and septicemia. This study developed a novel electrochemical sensor for detecting Cefotaxime (CFTX) by electrodepositing gold-bismuth nanoparticles (Au-Bi NPs) on a carbon paste electrode (CPE). The electrochemical parameters were optimized for the successful deposition of Au-BiNPs. Morphological and X-ray diffraction (XRD) analyses revealed nanoparticle clusters of cubic Au and stacked monoclinic BiNPs on the CPE surface, with crystallite sizes of 7.5 and 6.3 nm, respectively. Cyclic voltammetry (CV) showed that the sensor had superior electrochemical activity for CFTX oxidation compared to bare CPE, BiNPs/CPE, and AuNPs/CPE, mainly due to the synergetic effect of Au-Bi nanoparticles. Electrochemical impedance spectroscopy (EIS) indicated minimal resistance to electron transfer at Au-BiNPs/CPE. Voltammetric investigations revealed a diffusion-controlled electrooxidation process involving two protons and two electrons, influenced by solution pH and scan rate. The sensor displayed excellent analytical parameters for CFTX detection, including a wide linear range (0.5 μM to 20 μM), high sensitivity (4.55 μAμM−1 cm−2), and a low detection limit (0.094 μM). Density Functional Theory (DFT) calculations provided theoretical insights into the sensor's performance. The sensor also showed excellent reproducibility, repeatability (RSD values of 3.74 % and 1.71 %, respectively), and long-term stability of about one month, offering a new method for accurate and sensitive CFTX detection. [ABSTRACT FROM AUTHOR]

Human Immunodeficiency virus (HIV) is effectively suppressed in the blood by the Antiretroviral Therapy in people living with HIV, but in rare cases can be present in some tissues and body fluids. In recent years, integrated systems were validated for detecting HIV-1 in plasma or serum. but not in cerebrospinal fluid (CSF). We evaluated the performance of ELITE InGenius® in comparison with the cobas® in this area. To test the diagnostic accuracy of the HIV-1 ELITe MGB® kit on CSF samples, we tested CSF samples previously characterised with the cobras® HIV1 test. Archived CSF samples were also spiked with serial dilutions of the 4th WHO International Standard for HIV-1 NAT and assays and tested to assess the repeatability and reproducibility of the ELITechGroup assay. The HIV-1 ELITe MGB® Kit confirmed all the HIV-1 negative CSF samples from patients HIV positive in plasma and from non-HIV1 patients. All the CSF samples that were HIV-1 positive by the cobas®, were confirmed positive by the ELITe InGenius®. Concordance across the methods was also observed when processing the CSF dilutions spiked at medium-low titre, mimicking HIV-1 low-load infections. The two systems were equivalent in the detection and quantification of HIV-1 RNA in CSF samples. • HIV infection in the Central nervous system, represents a major cause of morbidity and mortality for PLWH. • HIV viral load (VL) is accepted as a key biomarker in HIV transmission and pathogenesis. • Diagnosis of HIV-1 encephalitis requested performance with high sensitivity, specificity and accuracy. [ABSTRACT FROM AUTHOR]

During the past decades, studies on patients with severe viral infections have revealed rare inborn errors of immunity (IEIs) underlying these diseases. This has led to important new insights into the molecular genetics and immunological mechanisms governing susceptibility to viral infection in humans. Herein, the current knowledge on major IEIs predisposing to severe or chronic viral infections are described and discussed, and the clinical implications of these findings for individualized prophylaxis and treatment are outlined. The review is based on a broad literature search, including relevant studies primarily based on patients, supported by experimental molecular models in vitro or in mice, to characterize the pathophysiological mechanism governing these disease conditions. Current concepts and principles of genetic predisposition to viral infections in humans are described with a major focus on defects related to innate immune responses and new concepts of constitutive immune mechanisms. The topic therefore spans from seminal studies on the human genetics of herpesvirus infections in the central nervous system, severe influenza, and disease after vaccination with live attenuated viral vaccines, to genetic resistance to viral infection. Past and present studies of patients with IEIs conferring vulnerability to viral infections have taught us important lessons on protective innate and adaptive antiviral immunity in humans. Such knowledge also has important clinical implications, allowing development of prophylactic and therapeutic solutions to prevent or dampen the clinical consequences of insufficient or dysregulated antiviral immunity in patients. Collectively, such measures are likely to improve patient management at an individualized level and help societies reduce the disease burden from viral infections. [ABSTRACT FROM AUTHOR]

Objectives: In Europe, a definite diagnosis of Lyme neuroborreliosis (LNB) requires intrathecally produced Borrelia-specific antibodies. We aimed to examine if the time from symptom debut to lumbar puncture (LP) correlated with findings of intrathecal production of Borrelia-specific IgM and/or IgG antibodies in LNB METHODS: A retrospective study of 544 patients with a positive Borrelia burgdorferi antibody index (Bb-AI) analysed at the Department of Clinical Microbiology, Odense University Hospital, Denmark, between 01.01.1995 and 31.12.2020 RESULTS: The delay from symptom onset to LP for patients with positive Bb-AI IgM was 30 days (IQR 14-95 days), IgG 24 days (IQR 11-62), IgM+IgG 24 days (IQR 14-48), P = 0.098. Ninety-three patients had a second LP after median 125 days (IQR 28-432) and 25 had a third LP after median 282 days (IQR 64-539). Most patients (66.7%) did not convert from their initial intrathecal antibody finding. The prevalence of different clinical manifestations differed significantly between the three Bb-AI groups.Conclusions: Intrathecal Borrelia-specific antibody production did not follow the typical immune response of initial IgM production followed by IgG production. Diagnosis of LNB stage should not be based on the type of antibodies found in the cerebrospinal fluid. [ABSTRACT FROM AUTHOR]

While neurosurgeons are experienced in treating penetrating brain injuries (PBIs) in civilian settings, much less is known about management and outcomes of PBIs in military settings. A systematic review was performed according to Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines. Data extracted included surgical management, age, gender, location/type of injury, initial Glasgow Coma Scale (GCS) score, and outcomes. The primary outcomes were last reported Glasgow Outcome Score (GOS) and mortality. The secondary outcomes included central nervous system infections, seizures, and cerebrospinal fluid leak/fistula. Odds ratios (ORs) with corresponding 95% confidence intervals (CIs) were used for outcome analysis. Twelve studies with 1738 patients treated for PBIs in military settings were included. The weighted mean age was 27.8 years, 86.7% were male, and 64.3% underwent neurosurgical intervention. Most patients (64.3%) presented with a GCS score >8, while 31.0% presented in a coma (GCS score <8). Over a median last follow-up time of 9 months, 68.6% achieved a favorable (GOS = 4–5) outcome and 34.2% achieved a poor (GCS score = 1–3) outcome. The overall mortality was 18.0%. A meta-analysis was performed using 5 of 12 studies to evaluate the effect of the presenting GCS score on primary outcomes. Patients with an initial GCS score <8 had statistically significant lower odds of a favorable (GOS = 4–5) outcome (OR: 0.03; 95% CI: 0.00–0.19; P : 0.000) and higher odds of mortality (OR: 28.46; 95% CI: 8.62–94; P : 0.000) than patients with an initial GCS score >8. The pooled rates of central nervous system infection, seizures, and cerebrospinal fluid leak/fistula were 13.8%, 13.2%, and 5.4%, respectively. In this first systematic review and meta-analysis of outcomes following combat-related PBIs, a GCS score >8 at presentation was found to be an important predictor of a favorable GOS and decreased mortality. [ABSTRACT FROM AUTHOR]

Few Japanese hospitals can perform in-house cerebrospinal fluid (CSF) polymerase chain reaction (PCR) to screen for herpes simplex virus, leading to patients being administered acyclovir (ACV) for several days. The FilmArray Meningitis/Encephalitis Panel (ME Panel) is a multiplex PCR test that can identify 14 major pathogens within 1 h. We aimed to investigate the efficacy of the ME Panel in children admitted with central nervous system infections in Japan. We conducted a single-center, quasi-experimental study. The ME panel was introduced in April 2020. We outsourced the CSF samples to a laboratory during the pre-intervention period (April 2016 to March 2020) and performed the ME panel at our hospital during the post-intervention period (April 2020 to December 2021). Duration and dose of ACV and antibiotic use, length of stay (LOS) in the pediatric intensive care unit (PICU), and total LOS after testing were compared using the Mann-Whitney U test. The number of cases in the pre- and post-intervention periods was 67 and 22 cases, respectively. The median duration of ACV decreased significantly from 6 days to 0 day (p < 0.001), and the median dose of ACV use decreased significantly from 14 vials to 0 vial (p < 0.001). No significant differences were noted in the total duration and dose of antibiotic use, LOS in PICU, and the total LOS after testing. The introduction of ME panel may contribute to appropriate ACV use; however, there was no significant change in the duration and dose of antibiotic use or LOS. [ABSTRACT FROM AUTHOR]

To investigate the efficacy of surgical intervention with antibiotic treatment for congenital dermal sinus (CDS) with central nervous system infection. Clinical data of 20 patients with CDS and central nervous system infection were retrospectively analyzed. All patients received early surgical treatment combined with postoperative antibiotic therapy after the diagnosis was confirmed. The infection control effect was evaluated according to the clinical symptoms, laboratory examination results, and improvement of neurological function. All 20 patients were treated with complete resection of the CDS and postoperative antibiotic therapy. No severe surgical complications occurred. Patients were followed for 3–81 months with a median follow-up time of 37.5 months. Postoperative infection was effectively controlled with no recurrence. Neurological dysfunction and related symptoms improved to varying extents after treatment, and the Spina Bifida Neurological Scale score at the final follow-up significantly increased. Patients with CDS and central nervous system infection should receive surgical management at an early stage with antibiotic treatment. This treatment algorithm was effective for control infection and protection of neurological function. [ABSTRACT FROM AUTHOR]

• Therapeutic drug monitoring (TDM) was done in children prescribed with meropenem. • Drug dosing was 20 mg/kg IV bolus (IB) or 40 mg/kg extended infusion (EI) q 8 hours. • Meropenem should not be initiated with a 20 mg/kg by IB in critically ill children. • Greater drug exposure was observed by using meropenem 40 mg/kg with EI. • TDM of meropenem should be implemented in children to improve dose optimization. To compare the unbound plasma meropenem concentrations at mid-dosing intervals (C mid , 50%fT), end-dosing intervals (C trough , 100%fT), and proportions of patients achieving 50%fT and 100%fT above minimum inhibitory concentration (MIC) (50%fT >MIC and 100%fT >MIC) between extended infusion (EI) and intermittent bolus (IB) administration in a therapeutic drug monitoring (TDM) program in children. A prospective observational study was conducted in children aged 1 month to 18 years receiving meropenem every 8 hours by either EI or IB. Meropenem C mid , C trough , and proportions of patients achieving 50%fT >MIC and 100%fT >MIC were compared. TDM data from 72 patients with a median age (interquartile range [IQR]) of 12 months (3−37) were used. Meropenem dose was 120 and 60 mg/kg/day in EI and IB groups, respectively. Geometric mean (95% confidence interval [CI]) C mid of EI versus IB was 17.3 mg/L (13.7−21.8) versus 3.4 mg/L (1.7–6.7) (P <0.001). Geometric mean (95% CI) C trough of EI versus IB was 2.3 mg/L (1.6−3.4) versus 0.8 mg/L (0.4−1.5) (P =0.005). Greater proportions of patients achieving 50%fT >MIC and 100%fT >MIC were observed in the EI group. A meropenem dose of 20 mg/kg/dose given by IB should not be used in critically ill children, even if they are not suspected of having a central nervous system infection. A dose of 40 mg/kg/dose given by EI resulted in higher C mid , C trough , and proportions of patients achieving 50%fT >MIC and 100%fT >MIC. [ABSTRACT FROM AUTHOR]

Objectives: To describe the epidemiology and clinical presentation of central nervous system (CNS) infections in solid organ transplant (SOT) recipients in the current era of transplantation.Methods: Patients from the Swiss Transplant Cohort Study (STCS) transplanted between 2008 and 2018 were included with a median follow-up of 3.8 years. Epidemiological, microbiological, and clinical data were extracted from the STCS database and patients' medical records. We calculated incidence rates and 90-day survival of transplant recipients with CNS infection.Results: Among 4762 patients, 42 episodes of CNS infection in 41 (0.8%) SOT recipients were identified, with an overall incidence rate of 2.06 per 1000 patient-years. Incidence of CNS infections was similar across all types of transplantations. Time to CNS infection onset ranged from 0.6 to 97 months after transplant. There were 22/42 (52.4%) cases of viral infections, 11/42 (26.2%) of fungal infections, 5/42 (11.9%) of bacterial infections and 4/42 (9.5%) of probable viral/bacterial etiology. Clinical presentation was meningitis/encephalitis in 25 cases (59.5%) and brain-space occupying lesions in 17 cases (40.5%). Twenty-three cases (60.5%) were considered opportunistic infections. Diagnosis were achieved mainly by brain biopsy/necropsy (15/42, 36%) or by cerebrospinal fluid analysis (20/42, 48%). Up to 40% of cases (17/42) had concurrent extra-neurological disease localizations. Overall, 90-day mortality rate was 29.0% (73.0% for fungal, 14.0% for viral and 11.0% for bacterial and probable infections, p<0.0001).Conclusions: CNS infections were rare in the STCS, with viral meningoencephalitis being the most common disease. Fungal infections were associated with a high mortality. [ABSTRACT FROM AUTHOR]

The blood–brain barrier (BBB) efficiently protects the central nervous system (CNS) from infectious insults. Yet, the apicomplexan parasite Toxoplasma gondii has a remarkable capability to establish latent cerebral infection in humans and other vertebrates. In addition to the proposed mechanisms for access to the brain parenchyma, recent findings highlight a paramount role played by the BBB in restricting parasite passage and minimizing parasite loads in the brain. Consistent with clinically asymptomatic primary infections in humans, mounting evidence indicates that the original colonization of the brain by T. gondii encompasses previously unappreciated, nondisruptive translocation processes that precede the onset of parasite-limiting immune responses. Within the extensive cerebral vascular network, passage of Toxoplasma gondii to the brain parenchyma takes place principally across cortical capillaries. Early passage of T. gondii occurs in the absence of a generalized increase in BBB permeability, perivascular leukocyte cuffs or hemorrhage, albeit with focal BBB permeability elevations. Inflammatory responses and transient dysregulation of the BBB during T. gondii infection facilitate parasite translocation to the brain parenchyma. Mechanisms proposed for T. gondii passage to the brain parenchyma include growth across endothelium (transcellular traversal), direct transmigration (paracellular traversal), and trafficking within parasitized leukocytes (Trojan horse). [ABSTRACT FROM AUTHOR]

Morus alba L. are widely used as ethnomedicine and functional food in China, Japan, Korea and other Asian countries. Morus alba L. have a variety of pharmacological activity such as antiviral, antioxidation, anti-cholesterol, anticancer, hypoglycemia, and neuroprotection. Morus alba L. has demonstrated antiviral efficacy against influenza viruses, SARS-CoV-2 and so on, but its potential activity against pseudorabies virus (PRV) remains uncertain. This study endeavors to delve into the anti-pseudorabies virus (PRV) potential of the ethanol extract of Morus alba L. leaves (MLE), while simultaneously elucidating its underlying mechanism of action. The anti-PRV activities of Morus alba L. extracts at different concentrations were evaluated by qPCR and immunoblotting. The inhibitory effects of MLE on PRV replication in three distinct treatment modes (pretreatment, co-treatment, and post-treatment) were detected by qPCR and indirect immunofluorescence assays. qPCR was used to investigate the effects of MLE on PRV attachment, entrance, and cytokine expression in PRV-infected cells. The chemical components in MLE were analyzed by UPLC-MS/MS. MLE significantly inhibits PRV replication and protein expression in a dose-dependent manner. MLE displays inhibitory effects against PRV at three different modes of treatment. The most significant inhibitory effect of MLE was observed when used in co-treatment mode, resulting in an inhibition rate of 99.42%. MLE inhibits PRV infection in the early stage. MLE inhibits PRV infection by affecting viral attachment and viral entry. Furthermore, MLE exerts its inhibition on PRV replication by mitigating the heightened expression of cytokines (TNF-α and IFN-α) triggered by PRV. Analysis of its chemical composition highlights phenolic acids and flavonoids as the principal constituents of MLE. The results illustrate that MLE effectively impedes PRV infection by suppressing viral adsorption and entry, while also curbing the expression of antiviral cytokines. Therefore, MLE may be a potential resource for creating new medications to treat human and animal PRV infections. [Display omitted] • Ethanol extract of Morus alba leaves (MLE) significantly inhibits PRV replication in a dose-dependent manner. • MLE displays a significant inhibitory effect against PRV when added before, simultaneously with, or after virus infection. • MLE inhibits PRV replication during the period of viral attachment and entry to host cells. • MLE suppresses the gene expression of PRV-activated cytokines (TNF-α and IFN-α). • LC-MS analysis characterizes MLE, with flavonoids as the predominant molecules, followed by phenolic acids. [ABSTRACT FROM AUTHOR]

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). 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. 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. 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. • CSF concentrations of tenascin-c are increased during neuroinfections. • Bacterial meningitis increases CSF tenascin-c more than other neuroinfections. • High CSF tenascin-c is associated with unfavorable outcomes. [ABSTRACT FROM AUTHOR]

• Coxsackieviruses are one of the most common enterovirus types that cause human infections. • Coxsackieviruses have been associated with a broad spectrum of clinical presentations. • Coxsackieviruses are widely associated with central nervous system infection. • Coxsackieviruses CNS infections in young infants can induce a neurodevelopmental delay. Coxsackieviruses-induced infections, particularly in infants and young children, are one of the most important public health issues in low- and middle-income countries, where the surveillance system varies substantially, and these manifestations have been disregarded. They are widespread throughout the world and are responsible for a broad spectrum of human diseases, from mildly symptomatic conditions to severe acute and chronic disorders. Coxsackieviruses (CV) have been found to have 27 identified genotypes, with overlaps in clinical phenotypes between genotypes. In this review, we present a concise overview of the most recent studies and findings of coxsackieviruses-associated disorders, along with epidemiological data that provides comprehensive details on the distribution, variability, and clinical manifestations of different CV types. We also highlight the significant roles that CV infections play in the emergence of neurodegenerative illnesses and their effects on neurocognition. The current role of CVs in oncolytic virotherapy is also mentioned. This review provides readers with a better understanding of coxsackieviruses-associated disorders and pointing the impact that CV infections can have on different organs with variable pathogenicity. A deeper knowledge of these infections could have implications in designing current surveillance and prevention strategies related to severe CVs-caused infections, as well as encourage studies to identify the emergence of more pathogenic types and the etiology of the most common and most severe disorders associated with coxsackievirus infection. [ABSTRACT FROM AUTHOR]

Central nervous system infection after neurosurgical procedures is a severe complication with high morbidity rates and sometimes mortality. Our experimental study aimed to investigate the biochemical and histopathologic effects of vancomycin on neural tissues when applied to the cisterna magna. Wistar albino rats were randomly divided into 4 groups: Control (Group 1) and different vancomycin dose groups (Groups 2, 3, and 4). In Group 1, 0.1 mL cerebrospinal fluid was drained from the cisterna magna and 0.1 mL 0.9% NaCI (normal saline) was administered into the subarachnoid space. In the study groups, 0.1 mL cerebrospinal fluid was drained from the cisterna magna and 0.1 mg/200g rat per day (Group 2), 0.2 mg/200g rat per day (Group 3), and 0.4 mg/200g rat per day (Group 4) vancomycin were administered into the subarachnoid space for 7 days. All rats were sacrificed on the eighth day. Serum superoxide dismutase and catalase levels were measured. Histopathologic and immunohistochemical analyses were conducted. The findings showed that the administration of 0.2 and 0.4 mg/kg doses had significant differences in superoxide dismutase and catalase activity compared with the controls (P < 0.05). These vancomycin doses also induced the apoptotic process, and the enzyme activity results correlated with immunohistochemical results. Dose-related neurotoxicity of intrathecal vancomycin was shown at the cellular level. The importance of dose regulation of intrathecal vancomycin has come into view. To our knowledge, this is the first study in the literature that has investigated the neurotoxic effects of vancomycin. [ABSTRACT FROM AUTHOR]

Children with acute neurologic illness are at high risk of mortality and long-term neurologic disability. Severe traumatic brain injury, cardiac arrest, stroke, and central nervous system infection are often complicated by cerebral hypoxia, hypoperfusion, and edema, leading to secondary neurologic injury and worse outcome. Owing to the paucity of targeted neuroprotective therapies for these conditions, management emphasizes close physiologic monitoring and supportive care. In this review, we will discuss advanced neurologic monitoring strategies in pediatric acute neurologic illness, emphasizing the physiologic concepts underlying each tool. We will also highlight recent innovations including novel monitoring modalities, and the application of neurologic monitoring in critically ill patients at risk of developing neurologic sequelae. [ABSTRACT FROM AUTHOR]

• Phase IV, single-site, participant-blinded, randomized, placebo-controlled trial. • No effect of rabies vaccination on the incidence of self-reported illness episodes. • Little evidence that sex modifies the effect of vaccine on evaluated outcomes. Vaccines may affect recipients' immune systems in ways that change morbidity or mortality rates to unrelated infections in vaccinated populations. It has been proposed that these non-specific effects differ by type of vaccine and by sex, with non-live vaccines enhancing susceptibility of females to unrelated infections, and live vaccines enhancing resistance in both sexes. Rabies vaccine–a non-live vaccine–has been associated with protection against unrelated central nervous system infections. Data from randomized controlled trials are needed to assess this effect against other illnesses. This phase IV, single-site, participant-blinded, randomized, placebo-controlled trial in a population of veterinary students on the rabies-free island of St. Kitts assessed the effect of a primary course of rabies vaccine on the incidence rate of weekly self-reported new episodes of common infectious disease (CID) syndromes, defined as a new episode of any one of the following syndromes in a particular week: upper respiratory illness (URI), influenza-like illness (ILI), diarrheal illness (DIA) or undifferentiated febrile illness (UFI). As a secondary objective, we tested for modification of the effect of rabies vaccine on study outcomes by sex. 546 participants were randomized (274 to rabies vaccine and 272 to placebo). No statistically significant differences between groups were observed for any study outcomes: CID incidence rate ratio (IRR) 0.95 (95% CI 0.77–1.18); URI IRR 1.15 (95% CI 0.86–1.54); ILI IRR 0.83 (95% CI 0.54–1.27); DIA IRR 0.93 (95% CI 0.70–1.24) and UFI IRR 1.09 (95% CI 0.48–2.44). In a secondary analysis, there was little evidence that sex modified the effect of vaccination on any of the evaluated outcomes, although the power to detect this was low. In conclusion, rabies vaccine did not provide protection against mild self-reported illness among a young and healthy group of adults attending veterinary school. Clinical trial registration. ClinicalTrials.gov: NCT03656198. [ABSTRACT FROM AUTHOR]

We aimed to describe the clinical presentation, risk of bleeding and recurrent thrombosis, and perioperative anticoagulant management of children with cerebral venous thrombosis (CVT) and an associated head or neck infection. In this subgroup analysis of the EINSTEIN-Jr study, we included children with CVT and an associated head or neck infection who received therapeutic anticoagulants with either low-molecular-weight heparin (with or without subsequent vitamin K antagonists) or rivaroxaban for a period of 3 months. Analyses are descriptive. Of 74 included children, 59 (80%) had otomastoiditis, 21 (28%) a central nervous system infection, 18 (24%) sinusitis, and 9 (12%) another upper respiratory tract infection; 29 (39%) had infection of multiple regions of the head or neck. All 74 children received antibiotics and therapeutic anticoagulants; 41 (55%) underwent surgery, of whom 34 were diagnosed with CVT preoperatively. Anticoagulation was started before surgery in 12 children and interrupted 0-1 days prior to surgery. Anticoagulation was (re)started in all 34 children at a median of 1 day (interquartile range: 0-1) postoperatively, in therapeutic doses in 94%. Overall, one child (1%, 95% confidence interval: 0-7) had recurrent thrombosis, and one (1%, 95% confidence interval: 0-7) had major bleeding; neither was associated with surgery. At 3 months, no children had died, 3 (4%) had persistent focal neurologic deficits, and 2 (3%) had impaired vision. Children with CVT and an associated head or neck infection administered therapeutic anticoagulants generally had low risks of bleeding and thrombotic complications, including those who had surgical interventions with delay or interruption of anticoagulation. [ABSTRACT FROM AUTHOR]

There is a gap of knowledge regarding cerebrospinal fluid (CSF) ion concentrations in normal and pathological states, particularly during the neonatal period. We aim to compare CSF ion concentrations in newborns with different causes of neonatal-onset epilepsy (NOE) and acute symptomatic seizures (ASS) and controls, to examine their usefulness for diagnostic purposes. A descriptive retrospective study was conducted from January 2019 to June 2020 in a tertiary hospital. We analyzed CSF K+, Na+, Cl−, and Ca2+ concentrations in frozen samples from patients with neonatal seizures (NS) secondary to NOE and ASS (neonatal arterial ischemic stroke [NAIS] and hypoxic-ischemic encephalopathy). As the control group, we selected CSF samples from newborns who had undergone CSF analysis as part of the diagnostic workup and in whom central nervous system infections had been ruled out, without signs of dehydration, gastroenteritis, or history of seizures. Sixty-eight newborns were included, 16 with NOE, 13 with ASS, and 39 without NS (control group). In comparison with the control group, [K+] CSF was lower in patients with KCNQ2-related epilepsy (P = 0.007), other causes of NOE (P = 0.010), and NAIS (P = 0.002). Changes in [Na+] CSF , [Cl−] CSF , and [Ca2+] CSF were less consistent among subgroups. Here we report for the first time ionic imbalances in the CSF of neonates with NOE and NAIS. No differences were observed between newborns with different causes of NS. Further studies should be undertaken to investigate the physiopathology behind these changes and their impact on biological function. [ABSTRACT FROM AUTHOR]

Microglia, the resident immune cells of the central nervous system (CNS), are poised to respond to neuropathology. Microglia play multiple roles in maintaining homeostasis and promoting inflammation in numerous disease states. The study of microglial innate immune programs has largely focused on exploring neurodegenerative disease states with the use of genetic targeting approaches. Our understanding of how microglia participate in immune responses against pathogens is just beginning to take shape. Here, we review existing animal models of CNS infection, with a focus on how microglial physiology and inflammatory processes control protozoan and viral infections of the brain. We further discuss how microglial participation in over-exuberant immune responses can drive immunopathology that is detrimental to CNS health and homeostasis. Microglia, the primary immune cell population in the brain, play distinct roles in development and homeostasis. To study them during neuroinflammatory states, researchers use experimental paradigms such as an inducible-cre system and pharmacological antagonism of the colony stimulating factor 1 receptor (CSF1R) with its antagonist PLX5622. Microglia are poised to respond to key signals for inflammation, damage, and infection in the central nervous system (CNS). They are able to promote inflammation via the release of proinflammatory cytokines and potentially serve as functional antigen-presenting cells (APCs) during infection. Understanding the specific roles of microglia in experimental infection models will allow us to gain a deeper knowledge on how important microglia-induced inflammation is for combatting neurotropic pathogens, while also recognizing that this inflammation may cause significant damage to other cell types in the CNS. [ABSTRACT FROM AUTHOR]

Congenital cytomegalovirus (cCMV) infection can result in considerable morbidity and mortality. However, the impact of cCMV on health system utilisation beyond infancy is poorly defined. Here we sought to describe the burden of cCMV health service use and mortality using linked population-based datasets. The design was a matched cohort study using record-linked administrative datasets. Participants included all children aged 0–15 years identified through the New South Wales (NSW), Australia, Admitted Patient Data Collection who were hospitalised with an admission code for cCMV infection between 2001 and 2011. Participants were then matched by age, sex and birth postcode quintile using Socio-Economic Indexes for Area, to children randomly selected from the NSW Perinatal Data Collection, excluding those with central nervous system infections or cerebral palsy. We calculated rate ratios (RR) for hospital admissions adjusted for preterm birth, the median length of stay, cost weights of admission and odds ratio (OR) for deaths. There were 130 children with cCMV matched to 2672 children. Neonates (aged <1 month) with cCMV had twice the rate of admissions (RR 2.4 95%CI 2.0, 2.8) and children aged ≥ 5yr to < 15yrs with cCMV almost eight times the rate of admissions (RR 7.8 95%CI 5.1, 11.5). Children with cCMV had significantly higher cost weights of admissions and an increased risk of mortality (OR 18.4 95%CI 7.8, 43.6). Throughout childhood, children with cCMV had higher rates of hospital admissions, higher admission cost weights and an increased risk of mortality compared with matched peers without cCMV. • Children with congenital cytomegalovirus have higher rates of admission and more costly hospital stays. • The neurodevelopmental sequelae of congenital cytomegalovirus have an on-going impact on hospital utilisation throughout childhood. • Congenital cytomegalovirus increases the risk of mortality amongst children <5 years of age. [ABSTRACT FROM AUTHOR]

Intracranial Arachnoid cysts (AC) are stable cerebral spinal fluid (CSF)-filled sacs that can rarely undergo progressive shrinkage or disappearance throughout life. In this manuscript, we present a case of post-traumatic complete resolution of an AC, review the possible triggers of this phenomenon, and discuss the pathophysiological mechanisms behind them. After presenting our case, we performed a literature review using the PubMed Database of all the reported cases of AC reduction or resolution (last updated in February 2021). Spontaneous cases were excluded. An analysis of the remaining cases (1985–2021) according to their inciting event, demographical, and clinical characteristics was then presented. 58 patients were identified, 33 of which spontaneously resolved. The remaining 25 were included in the survey in addition to the case we presented. The mean age was 20.2 years, average time to resolution was 25.3 months, with only two third of the cases showing complete disappearance of the AC. A central nervous system infection was the inciting cause of resolution in one infant (4%), a history of head trauma in 16 (62%) patients and an intracranial procedure in 9 (35%) patients. AC disappearance is a rare phenomenon that can occur spontaneously or after an inciting event. The cyst wall rupture and CSF flow perturbation theories seem to be the most applicable pathophysiological mechanisms in triggered AC resolution. • Intracranial arachnoid cysts disappearance is rare and incompletely understood. • Possible reduction triggers include head trauma, a procedure, or an infection. • Induced cyst wall rupture or CSF flow perturbation are the main involved theories. [ABSTRACT FROM AUTHOR]

Evaluation of the incidence of infectious diseases after natural disasters can help develop healthcare policies. This study provides a global review of the most prevalent infectious diseases observed after earthquakes. A systematic review and meta-analysis were performed. A systematic review was performed on electronic databases, including PubMed, Scopus and Web of Science, up to March 2020 (with no time limitations). Studies addressing earthquakes and infectious diseases were collected based on specified inclusion and exclusion criteria. Subsequently, the quality of the studies was assessed by the Newcastle-Ottawa scale (NOS). Data analyses were carried out on six subgroups under five different disease categories using comprehensive meta-analysis software. In total, 24 studies qualified for the systematic review and 18 were included in the meta-analysis. The incidences of gastrointestinal infections, dermal infections, respiratory infections, central nervous system infections and other infectious diseases were as follows: odds ratio (OR) 163.4 (95% confidence interval [CI]: 31.0–858.1), OR 84.5 (95% CI: 27.1–262.8), OR 9.9 (95% CI: 3.5–27.7), OR 0.5 (95% CI: 0.2–1.1) and OR 4.4 (95% CI: 1.9–9.9) cases per 100,000 people, respectively. The association between the incidences of infectious diseases before and after earthquakes was significant, namely, 1.561 (95% CI: 1.244–1.957) with a P -value <0.001. The results show an increase in the prevalence of infectious diseases after earthquakes. Governments should take essential measures to be better prepared for such unpredictable catastrophes. [ABSTRACT FROM AUTHOR]

In central nervous system infections, early and correct management is of utmost importance. Rapid syndromic panel testing can potentially provide valuable guidance. The FilmArray meningitis/encephalitis (ME) panel detects 14 pathogens through multiplex PCR. Our study objectives were to assess its performance compared with established diagnostic procedures, especially real-time quantitative PCR for detection of viruses, and to determine the diagnostic and clinical significance of discrepant results. All cerebrospinal fluid samples sent for viral diagnostics to our microbiological laboratory over 34 months were analysed with the ME panel and in-house real-time PCR for herpes simplex virus type 1 (HSV-1), HSV-2, varicella zoster virus and enteroviruses. Other pathogens detected by the panel were confirmed by routine diagnostic procedures. Discrepant results were analysed through interpretation of biological and clinical data, and performance data were calculated for individual pathogens. Altogether, 315 pathogens were detected by the ME panel in 4199 cerebrospinal fluid samples (7.5%) and an additional 21 viral targets were identified using real-time PCR. Thirty-four ME panel detections were not confirmed, totalling 55 discrepant results. After discrepancy analysis, 20 false-positive and 21 false-negative ME panel results remained. Performance varied between pathogens. Sensitivity for HSV-1 was calculated at 82.4% (59.0%–93.8%) with three false-negative results. Also noteworthy were 13 false-negative enterovirus and eight false-positive Streptococcus pneumoniae results. Our analysis shows good performance for the ME panel in diagnosing central nervous system infection. The risk of false-negative HSV-1 results, however, warrants additional testing when encephalitis is suspected. Uncertainties in interpretation of enterovirus and S. pneumoniae results represent other limitations. [ABSTRACT FROM AUTHOR]

[Display omitted] Viral infections in the central nervous system (CNS) can lead to severe disease manifestations often mediated by a combination of viral cytopathic effects and immunopathology. Moreover, neuronal tissue and brain activities are highly sensitive to excessive inflammation that disturb homeostasis. Immune responses to virus infections in the CNS should therefore be tightly balanced and limited in magnitude and duration to avoid immunopathology and tissue damage. Recent data from genetic studies of patients with viral infections in the CNS as well as experimental cell and animal models have provided evidence of non-redundant roles for constitutive and latent immune mechanisms, which mediate a first line of antiviral control without significantly triggering inflammatory activities. Collectively, accumulating data suggest the existence of a layer of immune mechanisms in the CNS exerting immediate control of infection, hence buffering the need for activation of more potent immune reactions with inherent potential to induce immunopathology and disease. [ABSTRACT FROM AUTHOR]

Central nervous system (CNS) infection due to Exophiala dermatitidis is rare and fatal, and primarily reported in immunocompromised patients or those with caspase recruitment domain-containing protein 9 deficiency. Herein, we describe a case of an otherwise healthy person (without underlying disease or gene deficiency) diagnosed with Exophiala dermatitidis meningoencephalitis. The patient achieved clinical remission under high-dose antifungal therapy in the first 14 months but died after 2 years of the therapy. A 15-year-old student with headache and fever was admitted to our department. Lumbar puncture showed increased cerebrospinal fluid (CSF) pressure, moderately high CSF protein levels and cell counts, and a remarkable decrease in CSF glucose and chloride. Magnetic resonance imaging of the brain revealed multiple lesions and cerebral pia mater enhancement. CSF culture confirmed E. dermatitidis infection. We administered 4-week antifungal therapy of amphotericin B, but his CSF culture remained positive. After receiving the 12-week standard dose of voriconazole (200 mg q12h), the patient's CSF culture became negative, but his condition deteriorated with intracranial lesion enlargement. We administered a high-dose voriconazole therapy (600–800 mg per day) for 12 months, which led to clinical remission. The voriconazole dose was reduced due to adverse effects including hepatic dysfunction and hypokalemia, and the disease progressed with high intracranial pressure and epileptic seizures. CNS infection caused by E. dermatitidis is fatal and the most serious form of fungal infection. Initially, high-dose and long-term antifungal therapy could be effective. Gene defect and related antifungal immunodeficiency may be the most important pathogenic and lethal factor. [ABSTRACT FROM AUTHOR]

P-Glycoprotein serves as a gatekeeper in the blood-brain-barrier wherein, it shows a vital part in the elimination of xenobiotics, drugs, foreign molecules etc. and guards the central nervous system from infections and external toxic molecules by functioning as an efflux transporter. It plays an essential role in various brain-related conditions like Parkinsonism, Alzheimer's disease, depression, cancer, etc. and terminates the entry of therapeutic agents across blood-brain-barrier which remains a significant challenge serving as major hindrance in pharmacotherapy of disease. The physiological structure and topology of P-glycoprotein and its relation with blood-brain-barrier and central nervous system gives an idea for targeting nanocarriers across the barrier into brain. This review article provides an overview of current understanding of the nanoformulations-based P-gp trafficking strategies like nanocarriers, stem cell therapy, drugs, substrates, polymeric materials, chemical compounds as well as naturally occurring active constituents for improving drug transport in brain across blood-brain-barrier and contributing in effective nanotherapeutic development for treatment of CNS disorders. P-Glycoprotein modulation using nanocarriers, natural substances, chemical compounds and stem cells for enhancing the drug delivery across BBB. [Display omitted] • Role of P-gp transporter in protecting brain from foreign matter. • Structure of P-gp and relation with various CNS-conditions. • Applications of nanoformulation for modulating P-gp activity. [ABSTRACT FROM AUTHOR]

External ventricular drain (EVD) placement is a common neurosurgical procedure, and EVD-related infection is a significant complication. We examined the effect of infection control protocol changes on EVD-related infection incidence. Changes in EVD placement protocol and incidence density of infections after implementation of protocol changes in the neurocritical care unit were tracked from 2007 to 2019. EVD infections were defined using a modified U.S. Centers for Disease Control and Prevention National Healthcare Safety Network surveillance definition of meningitis/ventriculitis for patients with EVDs in situ for at least 2 days confirmed by positive culture. Contribution of protocol changes to EVD infection risk was assessed via multivariate regression. Fifteen major changes in EVD protocol were associated with a reduction in infections from 6.7 to 2.0 per 1000 EVD days (95% confidence interval [CI], 4.1–5.3; P < 0.001). Gram-positive bacterial infection incidence decreased from 4.8 to 1.7 per 1000 EVD days (95% CI, 2.3–3.9; P = 0.00882) and gram-negative infection incidence decreased from 1.9 to 0.5 per 1000 EVD days (95% CI, 0.6–2.3; P = 0.0303). Of all protocol changes since 2007, the largest reduction in incidence was 3.9 infections per 1000 days (95% CI, 0.50–7.30; P = 0.011), associated with combined standardization of reduced EVD sampling frequency, cutaneous antisepsis with alcoholic chlorhexidine before EVD placement, and use of a subcutaneous tunneling technique during EVD insertion. The most significant reduction in EVD infections may be achieved through the combination of reducing EVD sampling frequency and standardizing alcoholic chlorhexidine cutaneous antisepsis and subcutaneous tunneling of the EVD catheter. [ABSTRACT FROM AUTHOR]