Arm recovery varies greatly among stroke survivors. Wearable surface electromyography (sEMG) sensors have been used to track recovery in research; however, sEMG is rarely used within acute and subacute clinical settings. The purpose of this case study was to describe the use of wireless sEMG sensors to examine changes in muscle activity during acute and subacute phases of stroke recovery, and understand the participant’s perceptions of sEMG monitoring. Beginning three days post-stroke, one stroke survivor wore five wireless sEMG sensors on his involved arm for three to four hours, every one to three days. Muscle activity was tracked during routine care in the acute setting through discharge from inpatient rehabilitation. Three- and eight-month follow-up sessions were completed in the community. Activity logs were completed each session, and a semi-structured interview occurred at the final session. The longitudinal monitoring of muscle and movement recovery in the clinic and community was feasible using sEMG sensors. The participant and medical team felt monitoring was unobtrusive, interesting, and motivating for recovery, but desired greater in-session feedback to inform rehabilitation. While barriers in equipment and signal quality still exist, capitalizing on wearable sensing technology in the clinic holds promise for enabling personalized stroke recovery. AboutAnother key wearable technology is surface electromyography (sEMG). Surface EMG sensors detect and record electrical impulses from muscle tissue that reflect the activation of the corticospinal tract, reflexes, and other neural pathways . Scienti2.2.1.The participant, Jack (a pseudonym), was a previously healthy 56-year-old Caucasian, right-handed male with a right caudate body and lentiform nucleus ischemic stroke, likely of small vessel disease etiology. He was not a candidate for tissue plasminogen activator or thrombectomy. His exam was notable for left hemiparesis, left facial droop, and dysarthria. His total NIH Stroke Scale score was 10, with scores of 4 for both the left upper and lower extremities. Further clinical assessment revealed intact sensation to light touch in all extremities, right gaze preference, and a Modified Ashworth Scale score of 1 for left elbow flexion and extension and left wrist extension, suggesting a slight increase in muscle tone. However, no spasms or hypertonicity were documented thereafter. Rehabilitation services were initiated on hospital day zero and continued throughout his acute care stay and subsequent transfer to inpatient rehabilitation. Motor function was evaluated with manual muscle testing (MMT) throughout the 4-day acute hospital course, in which Jack exhibited motor recovery of his left leg, but little improvement of his left arm. On average, Jack participated in occupational and/or physical therapies two to four times per week during his acute course.Subsequently, Jack was transferred to the inpatient rehabilitation unit of an affiliated hospital with left hemiparesis, impaired coordination, impaired balance, and dysarthria. He was fitted with a GiveMohr® sling  for mild shoulder subluxation and pain. On average, Jack spent about 90 min in occupational therapy (OT) and 150 min in physical therapy (PT) per day, five to seven days per week. Over the 16-day course of inpatient rehabilitation, he had significant motor recovery in his left upper extremity and improvement in fine motor coordination and initiation of motor movements, as documented by traditional clinical measurements and medical records . At his As Jack remained within the same hospital system for acute and inpatient recovery, he was the only participant who took place in this research group’s hospital-based sEMG study as well as a community-based qualitative study with stroke survivors following his discharge, and was the only participant in either study to have experience with sEMG monitoring in both settings. Thus, the study team capitalized on the ability to synthesize both sEMG outcomes and qualitative responses for this single participant.2.2.3 in a housing made of a flexible, low-durometer silicone. These sensors were selected from many research lab-owned systems due to their low profile, flexibility, remote monitoring capabilities, and ability to sanitize in-hospital environments [All study procedures were conducted with approval by the authors’ institutional review board and with informed consent from the participant. A standard protocol was used for all study procedures to ensure repeatability across this study as well as in future work. A set of five wireless, water-resistant sEMG sensors  were placed on the participant’s left upper extremity. Each sensor was 6.6 × 3.4 × 0.3 cmronments ,29. Prioronments . Bony anMuscle signal data were collected for three to four hour sessions every one to three days, beginning on post-stroke day three through discharge from inpatient rehabilitation. Session length was limited by the local memory storage allowance (32 MB) of each sensor. During each session, a researcher documented activity at 30-min intervals, but did not remain in the room throughout data collection, so as not to interfere with regularly scheduled activities or rest . Two addEMG data were recorded at 1000 Hz with a resolution of 0.0006 mV, range of ±200 mV, and no hardware signal processing. Data processing and analysis were performed in MATLAB® . Missing or faulty data were removed by comparing signal data to the data collection log . Data were bandpass filtered (20–400 Hz), conditioned with a Teager–Kaiser energy operator, rectified, and low-pass filtered  ,32. SignDuring the 8-month follow up in the community, a semi-structured, in-depth interview was also conducted to understand Jack’s perceptions of recovery, rehabilitation, and benefits and drawbacks of his experience with sEMG. The interview was audio recorded, transcribed verbatim, and coded by the research team until 100% agreement was reached for emergent themes. .3.Ten data recordings were captured from late January through late September of 2018. Two sessions occurred in the acute hospital setting, six during inpatient rehabilitation, and two in the community at three and eight months post-stroke, consecutively, for a total of 34 h and 17 min of data recordings. The quantitative and qualitative results that follow are presented chronologically, describing (1) acute recovery, (2) inpatient rehabilitation, (3) recovery at home, and (4) perceptions of sEMG use.3.1.Jack’s description of his mobility during the early days following stroke correlate with his MMT scores , Quote 13.2.Although Jack continued to experience significant functional limitations at the end of inpatient rehabilitation, improvements were noted in strength and his ability to complete tasks , Quote 23.3.Jack continued with outpatient physical and occupational therapy after discharge, noting continued progress in his everyday functional abilities , Quote 33.4.Both the participant and the medical staff engaged in his care were interested in detecting muscle signals in the involved upper extremity over time and appreciated real-time muscle signal and acceleration graphs on the Biostamp RC® tablet. The participant would have preferred if the tablet remained in proximity, alerted him when a new threshold was reached, or better described what the graphs represented in terms of his recovering muscle activity, especially in noting subtle changes between sessions , Quote 54.Though the scope is limited, this case study is among the first to describe both the proof-of-concept of the preliminary implementation of commercial sEMG sensors directly in clinical and community settings to monitor upper extremity muscle activity in the acute and subacute phases of rehabilitation, and report the participant’s experiences of recovery and perceptions of such sEMG monitoring after stroke. This study presented a unique opportunity to describe sEMG monitoring results together with qualitative participant perceptions of recovery and monitoring in a single individual who took place in two sets of study procedures. Although previous work has examined the return of finger extension mobility beginning at 14 days post-stroke, or in subacute populations, most frequently studies incorporating sEMG examine upper extremity recovery of nonhospitalized chronic stroke survivors ,34-36. TJack’s clinical assessments showed linear improvement, but the metrics from sEMG were highly variable. This may indicate that compensation was responsible for some of the improved functional scores during hospitalization . While iIt was feasible to set up and run three- to four-hour recording sessions during the participant’s routine clinical care in both acute and inpatient environments with minimal to no interference in routine care. A structured inpatient rehabilitation schedule made it easier to apply the sensors and capture therapeutic activities, compared to acute care scheduling that often varied based on therapist availability and medical procedures. The variability in schedule and different therapeutic activities may have impacted sEMG outcomes. However, it is advantageous to use sEMG to record and track this variability as it may more accurately reflect typical trajectories of arm use and motor control during recovery . What isThere were several limitations to this study. First, there was a lack of consistent quantitative data in Jack’s electronic medical record that described functional recovery. The available data were reported and compared with sEMG output. Despite purposefully selecting the Biostamp sensors for their technical features among many other systems previously researched by this study team, there were also limitations in the sEMG sensors themselves, pointing to important needs for future development and research ,29. WhilFuture research must broaden the context of this case study to track sEMG data and qualitative responses on recovery and muscle monitoring over time in a larger and more diverse sample of participants. Additionally, repeated-measure monitoring at multiple points in the same day could be useful to allow the direct comparison of muscle activity and sensor reliability. As stroke recovery is a highly complex process, equally complex analyses should also be implemented in future work that explore the role of sEMG in monitoring recovery. For example, coherence analysis, which has been used to investigate neural mechanisms of muscle activity through linear correlation, has been examined in sEMG-intramuscular EMG and sEMG and electroencephalogram pairings, or in sEMG rectification processes ,47. This5.This study demonstrates that using sEMG sensors to clinically monitor upper extremity muscle activity during acute and subacute stroke recovery is feasible, and preliminary outcomes suggest that changes in muscle activity are observed that track quantitative and qualitative changes in function. Wireless sEMG sensors have the potential to significantly improve tracking and training activities in neurorehabilitation following stroke and may be able to aid in long-term prognostication or improve targeted interventions to promote functional outcomes. Surface EMG technology may also offer hope and motivation to stroke survivors during their early recovery, provided they have access to a simple, intuitive user interface as well as appropriate feedback and education on the signals measured and how they correlate to function. However, current limitations in technology, processing time and procedures, and the user interface must be addressed to provide more useful and valuable information to both clinicians and users. Future studies should examine qualitative and quantitative outcomes in greater numbers of participants with diverse post-stroke presentations, and the further trial of other types of wearable sEMG sensor technologies should be undertaken in healthcare and community settings. Further research should also consider which sEMG metrics most accurately reflect recovery.


The current antimicrobial therapy of bacterial infections of the central nervous system (CNS) in adults and pediatric patients is faced with many pitfalls as the drugs have to reach necessary levels in serum and cross the blood-brain barrier. Furthermore, several studies report that different factors such as the structure of the antimicrobial agent, the severity of disease, or the degree of inflammation play a significant role. Despite the available attempts to establish pharmacokinetic (PK) modeling to improve the required dosing regimen for adults and pediatric patients, conclusive recommendations for the best therapeutic strategies are still lacking. For instance, bacterial meningitis, the most common CNS infections, and ventriculitis, a severe complication of meningitis, are still associated with 10% and 30% mortality, respectively. Several studies report on the use of vancomycin and meropenem to manage meningitis and ventriculitis; therefore, this review aims to shed light on the current knowledge about their use in adults and pediatric patients. Consequently, studies published from 2015 until mid-July 2021 are included, and data about the study population, levels of drugs in serum and cerebrospinal fluid (CSF), and measured PK data in serum and CSF are provided. The overall aim is to provide the readers a recent reference that summarizes the pitfalls and success of the current therapy and emphasizes the importance of performing more studies to improve the clinical outcome of the current therapeutical approach. Bacterial infections of the central nervous system (CNS) are a significant health concern affecting adults and pediatric patients ,2. BacteAntibiotics used to treat CNS infections are given intravenously as a commonly used practice ,15. HoweTo overcome the problems associated with the penetration of antibiotics through the BBB and the resulting variations in the antibiotics’ concentrations in the CSF, alternatives to intravenous administration such as intrathecal  and intraventricular  administration of antibiotics can be used ,25,26,27An additional complication for CNS infection is adjusting the dosing regimens of drugs in children. Extrapolating the approved doses for adults to the lower body weight of children is not sufficient to ensure safe and effective use ,29, and A helpful tool is PK modeling, which creates a mathematical model that can predict the drug’s PK behavior . PK modewww.idsociety.org (accessed on 20 December 2021)) and the European Society of Clinical Microbiology and Infectious Diseases ) while meropenem or other β-lactams are used as alternative or in combination therapy, based on local in vitro susceptibility pattern. Therefore, this review aims to highlight the current knowledge about the PK of meropenem and vancomycin in pediatric and adult patients suffering from meningitis and ventriculitis.Vancomycin is recommended for empiric treatment of bacterial meningitis by the Infectious Diseases Society of America  infections and also against other Gram-positive β-lactam-resistant bacteria [Vancomycin, a glycopeptide antibiotic, has a broad application area and is effective against most Gram-positive cocci and bacilli. It is predominantly used in methicillin-resistant bacteria ,39. In cbacteria . Due to bacteria ,40. Compbacteria , which mbacteria . For vanbacteria .In the following, the main findings on the currently published studies on vancomycin use alone or in combination with meropenem in adults and pediatrics suffering from meningitis and ventriculitis are presented. In the last six years, only three presented studies are reported on the use of vancomycin in pediatric patients , all of coagulase-negative Staphylococci of this center (1 mg/L). CSF drainage ranged from 5 to 10 mL/kg/day in all infants. The data demonstrated that larger intraventricular doses led to higher vancomycin concentrations in CSF that were maintained at sufficient levels for a longer period. At a dose of 3 mg, CSF levels were maintained above 20 mg/L for 18–24 h and declined under 10 mg/L at around 48 h after administration. There were also cases where CSF concentration declined faster, which is why the authors emphasize an individualized dosing regimen and recommend daily monitoring of CSF vancomycin levels. The authors did not observe adverse events that connect to the intraventricular administration route, and resolution of ventriculitis was accomplished in all patients in a median of 5.5 days (2–31 days) [Since only limited data are available on the use of intraventricular vancomycin in preterm infants, Parasuraman et al. conducted a retrospective study on the use of different doses ranging from 3 to 15 mg in ventriculitis affected infants born at less than 28 weeks gestation. The degree of ventricular dilatation was used as clinical guidance for the initial dosing. Intravenous vancomycin was used additionally at 15 mg/kg in the majority of the cases, and vancomycin was re-administered when CSF concentration was below 10 mg/L, which corresponds to 10 times the MIC levels for 31 days) . Consequ31 days) .Staphylococcus aureus and Staphylococcus epidermidis infections. None of the treatment concentrations affected the auditory brain response. Nevertheless, two cases, treated with 10 and 20 mg vancomycin, relapsed. Interestingly, the study of Matsunaga et al. showed that also 5 mg vancomycin leads to a sufficiently maintained CSF concentration, reducing the risk of overdosing. Therefore, monitoring CSF concentrations should determine appropriate administration intervals [Matsunaga et al. aimed to determine optimal intraventricular administration of vancomycin for ventriculitis shunt infections in newborns. In this study, newborns were treated with the recommended doses for infants (10 or 20 mg vancomycin) and a lower dose of only 5 mg. In most cases, intravenous administration of 40.5 (±9.2) mg/kg/day was used concomitantly. Treatment with 20 and 10 mg led to CSF concentrations of over 20 mg/L after 78 h, which is above the recommended trough level of 5–10 mg/L in CSF for ntervals .coagulase-negative Staphylococci (CoNS). Recommended serum trough concentrations of vancomycin in adults for this type of infection are 15–20 mg/L. Gibson et al. aimed to analyze whether this range of concentrations is also suitable for pediatric patients’ treatment success. Patients were treated with 15 mg/kg every 6 h. In 26.7% of patients, the antibiotic rifampin was used additionally. The median vancomycin trough level was 8.8 (5.4–27.7) mg/L, and in only 2 of 11 patients, the trough concentration was ≥15 mg/L. However, this did not negatively affect the treatment outcome. Since no recurrent infections occurred, Gibson et al. question the advantages of targeting vancomycin serum trough concentrations of 15–20 mg/L in children with CoNS shunt ventriculitis [In the retrospective study of Gibson et al., vancomycin serum trough levels were measured in patients with ventriculitis shunt infections caused by iculitis .Collectively, it is evident that the current therapy of pediatric patients is not yet optimal, and (TDM) monitoring is needed to ensure achieving the required levels to eradicate the infection.0–24 in serum and CSF of 455.09 mg∙h/L and 14.10 mg∙h/L, respectively. Very low vancomycin concentrations were found in 34% of CSF samples. After 30 days, no deaths were reported. A three-compartment linear population PK model suggested that the penetration of vancomycin into the CSF was even slower than the CSF clearance. Moreover, there was no correlation between vancomycin AUC in plasma and CSF. No covariates, such as CSF protein or CSF drain, influenced CSF penetration. Simulation of different dosing regimens showed that in cases of severe infections, for example, MRSA or methicillin-resistant Staphylococcus epidermidis (MRSE), where MIC ≥ 1 mg/L, a standard dosing regimen of 2000 mg every 12 h as a prolonged infusion most likely does not lead to sufficient CSF concentrations [In all studies on the use of vancomycin in ventriculitis in adult patients , patienttrations . Howevertrations ; Consequtrations .In the study of Jalusic et al., patients received a total daily dose of 2000–4000 mg vancomycin, depending on creatinine clearance, either as a continuous infusion or as an intermittent infusion every 6 h. Patients were treated additionally with ceftazidime. Targeted serum trough concentrations were 15–20 mg/L for bolus infusions and 20–25 mg/L for continuous infusion, aiming to achieve CSF trough levels of >1 mg/L. Median CSF penetration was higher in patients treated with bolus injections than in patients treated with continuous infusion. Interestingly, in both groups, the CSF penetration significantly correlated with markers of cerebral inflammation such as CSF lactate. In this patient population, median CSF lactate was 3.3 mmol/L, higher than the concentrations in healthy adults. Simulations of different dosing regimens revealed that dosing of 1350 mg/L every 8 h achieved target CSF concentrations above 1 mg/mL at a lactate concentration of 3.3 mmol/L, and 4000 mg every 24 h was recommended for continuous infusion. A linear three-compartmental model demonstrated that total vancomycin plasma clearance (Cl) depends on creatinine clearance and that CSF lactate concentration correlates with the clearance between the central and the CSF department. Therefore, Jalusic et al. recommend the application of TDM and consider the degree of inflammation, measured by CSF lactate, and renal function for vancomycin dosing [Staphylococcus aureus isolates. Out of all samples, 33% were below the target concentration. The targeted CSF concentration was 2 mg/L, which set to the breakpoint for susceptible Staphylococcus aureus isolates. With this regimen, the CSF penetration varied enormously between patients, ranging from 3% to 48%, and resulted in exceeding the targeted CSF concentration in only 70% of the cases. Death occurred in 32% of patients [In the study of Mader et al., patients received vancomycin and/or meropenem via continuous infusion. Patients were treated with an initial bolus of 30 mg/kg of vancomycin and subsequently received 30 mg/kg/day. The targeted serum concentration for vancomycin was 20–30 mg/L, which was set to attain a PD target of AUC/MIC above 400 for susceptible patients .S. epidermidis healthcare-associated meningitis. Patients were treated via continuous infusion with a bolus infusion of 15 mg/kg followed by 60 mg/kg/day. Patients of this study showed a low inflammatory status, which was shown by low CSF protein and low serum C-reactive protein. Even though sufficient vancomycin serum concentrations were achieved, concentrations of vancomycin in CSF were not sufficient for an effective treatment. Therefore, the administration of vancomycin was replaced by other antibiotics, predominantly linezolid. Overall, Mounier et al. point out the high risk of treatment failure in patients without strong meningeal inflammation and suggest reassessing the use of vancomycin as a first-line treatment in this patient group [In all studies on the use of vancomycin in meningitis , patientnt group .In the study of Ishikawa et al., patients were treated with intermittent vancomycin infusions two to four times a day. Doses were adjusted using TDM to achieve serum trough concentrations of 15–20 mg/L. Two out of seven patients received CSF drainage of 200–300 mL per day. In two patients (with and without drainage), vancomycin treatment was ineffective. Ishikawa et al. found no significant correlation between serum and CSF concentration, and CSF/serum ratio was not significantly correlated with cell count or glucose levels in CSF. However, they found that the protein concentration in CSF/serum albumin ratio showed a strong positive correlation with the vancomycin CSF/serum ratio. Therefore, CSF/serum albumin ratio could help estimate CSF penetration in meningitis patients .min over 15 mg/L (achieved in 9 of 22 patients) and under 15 mg/L. In addition, only CSF Cmin was correlated with a positive clinical response, namely the decline of the number of white blood cells in the CSF. However, neither serum Cmin nor CSF Cmin or CSF penetration was associated with clinical response [In the prospective study on patients with proven or highly suspected post-neurosurgical meningitis of Wang et al., patients received 500 mg vancomycin every 6 h. In patients with a negative culture of CSF, vancomycin was used in combination with ceftriaxone. A total of 54.5% of patients were categorized as cured, and the condition of the remaining 45.5% did improve after 3–5 days of treatment. Wang et al. investigated the connection between vancomycin CSF penetration and clinical outcome. In contrast to the previously described study, Wang et al. found a significant correlation of the vancomycin concentration in serum and CSF. Interestingly, no significant differences in clinical response were seen in patients with serum Cresponse .Taheri et al. conducted a randomized clinical trial with post-neurosurgical meningitis patients and compared intermittent and continuous infusion of vancomycin. All patients received an initial dose of 25 mg/kg over two hours followed by an infusion of 25 mg/kg every 12 h in the intermittent infusion group or by a continuous infusion of 50 mg/kg/day. In addition, patients of both groups were treated with meropenem. Dexamethasone was administered in the first two days. In both groups, serum and CSF vancomycin concentration were positively correlated. In the continuous infusion group, the mean CSF concentration was significantly higher than in patients who received intermittent infusion. CSF penetration, on the other hand, was not significantly different between the groups. Therapy was well-tolerated under both dosing regimens, and all patients recovered [In another study, Cai et al. compared vancomycin penetration into CSF in community-acquired meningitis patients and postoperative intracranial infection patients. All patients received 1000 mg vancomycin every 12 h. Following the same initial vancomycin schedule, patients were given various antibiotics. CSF drainage was performed in all intracranial infection patients but in none of the meningitis patients. In patients with postoperative intracranial infections, vancomycin concentrations and CSF penetration were similar to meningitis patients. In addition, the average serum vancomycin was lower than the recommended concentrations (15–20 mg/L). Serum concentration was correlated to bodyweight but not age and serum creatinine. Serum and CSF concentrations were weakly correlated. In postoperative intracranial infection patients, CSF/serum ratio was correlated to white blood cell count in CSF, but this was not the case in meningitis patients. Furthermore, CSF protein and glucose level were not correlated with CSF/serum ratio in both patient groups .Staphylococcus epidermidis meningitis in a neutropenic patient that was unrelated to a neurosurgical device. As an empiric treatment, intravenous vancomycin and meropenem were administered. The central venous catheter was suspected to be the source of the patients’ bacteremia and was removed. After identification of Staphylococcus epidermidis, intravenous vancomycin treatment was continued with 1 g every 12 h, and rifampin was added orally. Noguchi et al. present this case as the first successfully treated patient with this specific disease condition [Noguchi et al. presented the administration of intravenous vancomycin in a rare case of ondition .In summary, the currently available data show the large variability of treatment outcomes of patients treated with vancomycin and that in many cases, the standard recommended dosing regimen might not be effective.Meropenem is a broad-spectrum carbapenem antibiotic that is used in a broad range of serious infections, including CNS infections. It has activity against Gram-positive and Gram-negative pathogens and is especially important as empirical treatment of serious bacterial infections in hospitalized patients . MeropenRecent studies reported on the use of intravenous meropenem in children  includedOhata et al. used data from pediatric patients with bacterial meningitis and other infections for creating a three-compartment population PK model for meropenem infusion. The majority of included patients received 40 mg/kg meropenem every 8 h. All children with bacterial meningitis received dexamethasone concomitantly for the first 4 days of therapy. The overall mortality rate was low with this therapeutic approach, with 3 deaths reported out of 117 meningitis patients. For creating the PK model of meropenem in CSF, samples from five adults with bacterial meningitis, who received 2 g meropenem every 8 h, were also included. Simulations of different meropenem dosages  and infusion durations  demonstrated that an increase in dosing leads to a distinct increase in target attainment rates (50%T > MIC in CSF) but that increased infusion duration is advantageous only for target attainment in plasma and not in CSF. Thirty-six pediatric patients, for which pathogen-specific MICs were available, had a satisfactory clinical response and showed at least 75.3%T > MIC in CSF. CSF penetration of meropenem (population mean CSF/plasma AUC ratio) was estimated as 0.146. In patients with bacterial meningitis younger than 6 months, meropenem AUC in CSF and the CSF/plasma AUC ratio were higher than in older pediatric patients. In addition, patients with glucose ratios under the threshold for bacterial meningitis (<0.4) had a significantly greater CSF/plasma AUC ratio. Based on their results, Ohata et al. suggest a dosing regimen of 40 mg/kg every 8 h for pediatric patients with bacterial meningitis. However, it was estimated that with pathogens with MIC > 1 mg/L, sufficient meropenem concentrations could only be achieved in less than half of this patient population .serum ratios [Verscheijden et al. developed a physiologically based PK model (PBPK) for pediatric patients that can be used for meropenem in bacterial meningitis patients. Simulated AUC CSF/AUC plasma ratios ranged from 0.09 to 0.12. Overall, in comparison to relatively healthy individuals, patients with sepsis or meningitis had higher AUC CSF/AUCm ratios .Serratia marcescens ventriculitis, in which changing the antibacterial treatment from intermittent to continuous intravenous infusion of meropenem led to a successful clinical outcome. After unsuccessful treatment with cefotaxime, meropenem was administered at a 40 mg/kg dosing regimen every 6 h, and amikacin was used additionally. Due to remaining positive CSF cultures, treatment was changed to continuous 200 mg/kg/day infusion. With the PD target set to ≥40% free time above MIC (≥40% fT > MIC), the continuous infusion of meropenem led to a probability of target attainment of 100% in serum and CSF. The patient had a computed meropenem clearance from the serum of 10.2 mL/kg/min, which is significantly higher than the population PK estimates generated from both healthy volunteers and other pediatric ICU patients. Cies et al. highlight the importance of TDM in serum and CSF to ensure sufficient drug exposure [Cies et al. reported the case of a 2-year-old patient diagnosed with exposure .Only two studies, which use an intermittent and continuous dosing approach, are published on intravenous meropenem treatment in ventriculitis .0–24 in serum and CSF were 350.22 mg∙h/L and 26.56 mg∙h/L, respectively. No deaths were reported after 30 days. A three-compartment linear population PK model was developed, which identified no covariates. Simulation of different dosing regimens  showed that CSF trough concentration of 2 mg/L could only be exceeded in 53.8% of simulated patients when treated with 2000 mg meropenem every 8 h but exceeded 95.1% in simulated patients that received 5000 mg every 6 h. Due to the high interindividual variability in reported concentrations and CSF/serum ratios, Blassmann et al. recommend TDM in serum and CSF [Blassmann et al. reported a prospective observational study in which meropenem was given as a prolonged 4 h infusion at a dose of 1000 mg every 8 h for patients with adverse drug effects or renal impairment and at a dose of 2000 mg every 8 h for the remaining patients. In addition to meropenem, all patients received vancomycin, which was replaced by linezolid in one patient. Some patients concomitantly received dexamethasone or fosfomycin. The median AUCPseudomonas aeruginosa, and CSF concentrations were kept above 2 mg/L. The mean penetration of meropenem showed high interindividual differences  and Acinetobacter baumannii (MIC = 2 mg/L) caused meningitis. Overall, the results indicated that higher dose and shorter dosing intervals (2 g every 8 h and 1 g every 6 h) are more efficient for the treatment of this patient population [Only two studies are reported in the use of meropenem in adults affected with meningitis. In the first study, Zhang et al. conducted a prospective open-label study to examine the PK of meropenem in patients with post-neurosurgical meningitis . Patientpulation .Lu et al. developed a two-compartment model with an additional CSF compartment for intravenous meropenem in patients with bacterial meningitis after neurosurgery and especially paid attention to the influence of CSF drainage volume. The model identified no significant covariate. Monte Carlo simulation was performed, and PD targets were chosen as 40%T > MIC in plasma and 50% and 100% T > MIC in CSF. Simulations showed a higher probability of target attainment with prolonged infusions and that increased CSF drainage results in a lower probability of target attainment in CSF. Based on their results, Lu et al. recommend a meropenem dosing regimen of 2 g every 8 h as a 4 h infusion and a CSF drainage rate of fewer than 150 mL/day for the highest probability of target attainment. With this dosing regimen, there was a >80% probability of attaining T > MIC in CSF of 50% and 100% for MICs ≤1 and ≤0.5 mg/L, respectively .Based on the aforementioned data, both vancomycin and meropenem were administered as an intermittent or continuous infusion, irrespective of the type of infection. However, based on the reviewed papers, which dosing regimen resulted in a better clinical outcome cannot be clearly stated. For instance, for meropenem, a simulation of intermittent and continuous infusion showed that the latter one leads to lower %T > MIC in CSF in infants; however, the switch from intermittent to continuous infusion enabled successful treatment in a pediatric patient. Interestingly, conflicting data exist for vancomycin, whereby direct comparison of continuous and intermittent administration in a study with meningitis patients showed higher CSF concentrations under continuous infusion but no difference in CSF penetration. In contrast, in another study on ventriculitis patients, CSF penetration was slightly higher with intermittent vancomycin infusion.Interestingly, in 3 out of 10 papers, the authors report that intravenous administration of vancomycin was ineffective for at least part of the patients. However, it is not possible to rate the overall success of the intravenous vancomycin treatment since it was administered in combination with other antibiotics in many of the discussed cases. It is worth mentioning that intraventricular administration of antibiotics, which was only used in the case of vancomycin in infants with ventriculitis, is not connected to adverse events, and higher CSF concentrations can be achieved. Therefore, the intraventricular administration could be beneficial for treating pathogens with high MICs; yet, it needs to be further elucidated, in which patient groups intraventricular administration of vancomycin is more beneficial or necessary to improve treatment outcomes.Finally, when comparing the PK parameters and available treatment outcomes of all reviewed studies, no superior dosing regimen for vancomycin or meropenem could be identified, neither for meningitis nor ventriculitis.This review presents PK data on the use of meropenem and vancomycin in pediatric and adult patients with ventriculitis and meningitis. Intraventricular administration of vancomycin was only practiced in two studies, both of them in infant ventriculitis, while in the vast majority of studies, meropenem and vancomycin were administered intravenously as an intermittent or continuous infusion in adult meningitis and ventriculitis patients. Interestingly, the dosing regimens varied between studies despite treating patients with the same type of infection (meningitis or ventriculitis). In many of the included studies, concentrations of vancomycin and meropenem in serum and CSF showed high interindividual variability, which also applied to the penetration of both antibiotics into the CSF. Eight out of the 18 evaluated publications contained a PK model. For vancomycin, all PK models were regarding its use in ventriculitis. According to the simulations of different treatment regimens, one study recommended the adaption of dosing to the degree of inflammation and renal function, while another study recommends further investigation of continuous infusion for reduction in renal toxicity. For treatment of bacterial meningitis, CSF/serum albumin ratio was identified as a potential predictor of CSF penetration of vancomycin, while a continuous infusion of vancomycin showed no impact on CSF penetration in this patient population. Five out of the eight publications on meropenem included a PK model. Overall, six studies specifically recommend therapeutic drug monitoring of serum and CSF to ensure efficient concentrations. Due to high variability in the dosing regimen and high inter- and intra-individual variability outcome of treating meningitis and ventriculitis, larger studies are necessary to identify the optimal dosing regimens that are well-suited not only for the type of infection but also for the individual patient. In pediatric patients, four out of the seven available studies on the use of meropenem and vancomycin contain a PK model. The obtained data demonstrate that PK modeling in this patient population is equally, if not more substantial, than in adults. Overall, parameters that could potentially impact the PK properties of vancomycin and meropenem in ventriculitis and meningitis patients are still controversial. Finally, further characterization could help achieve better target attainment and treatment outcomes.


Alzheimer’s disease (AD), dementia with Lewy bodies (DLB) and frontotemporal dementia (FTD) represent the three major neurodegenerative dementias characterized by abnormal brain protein accumulation. In this study, we investigated extracellular vesicles (EVs) and neurotrophic factors in the cerebrospinal fluid (CSF) of 120 subjects: 36 with AD, 30 with DLB, 34 with FTD and 20 controls. Specifically, CSF EVs were analyzed by Nanoparticle Tracking Analysis and neurotrophic factors were measured with ELISA. We found higher EV concentration and lower EV size in AD and DLB groups compared to the controls. Classification tree analysis demonstrated EV size as the best parameter able to discriminate the patients from the controls . The diagnostic performance of the EV concentration/size ratio resulted in a fair discrimination level with an area under the curve of 0.74. Moreover, the EV concentration/size ratio was associated with the p-Tau181/Aβ42 ratio in AD patients. In addition, we described altered levels of cystatin C and progranulin in the DLB and AD groups. We did not find any correlation between neurotrophic factors and EV parameters. In conclusion, the results of this study suggest a common involvement of the endosomal pathway in neurodegenerative dementias, giving important insight into the molecular mechanisms underlying these pathologies. Major neurodegenerative dementias are multifactorial conditions that share key underlying pathophysiological processes. A variety of triggers encompassing genetic, environmental, vascular, metabolic and inflammatory factors converge to activate common neurodegenerative mechanisms that take place in the brain of individuals affected by major neurodegenerative dementias and can partially explain their overlap . AbnormaAlzheimer’s disease (AD) represents the most common form of dementia in the elderly and is characterized by intra- and extra-cellular amyloid-β (Aβ) peptide aggregates forming the amyloid plaques and by phosphorylated tau protein accumulation in neurofibrillary tangles, pathognomonic of the disease ,5. TheseIn recent years, extracellular vesicles (EVs) have been reported as a new concept in the biomarker field. Serving as transfer vehicles between cells of molecules, they represent a promising source of biomarkers for a number of diseases, including neurodegenerative disorders ,13. EVs In this current study, we extended our investigation to the cerebrospinal fluid (CSF) compartment with the aim of investigating in more depth the role of EVs and neurotrophic factors in the three most common form of dementia.n = 36 AD, n = 30 DLB, n = 34 sporadic FTD patients and n = 20 samples from subjects with subjective memory complaints and a MMSE score >26, as control group (CTRL), were included in this retrospective study. All participants underwent CSF drawn by lumbar puncture and CSF samples were collected and stored at −80 °C following standard procedures. Patients were enrolled at the MAC Memory Clinic of the IRCCS Fatebenefratelli, Brescia, and at the Neurology 5/Neuropathology Unit, IRCCS Besta, Milan. Clinical diagnosis for probable AD, DLB and FTD was made according to international guidelines [Human CSF samples from idelines ,36,37. PTM, Waltham, MA, USA) after optimization according to the manufacturer’s protocol. Briefly, 125 µL of CSF added with 75 µL of 0.2 µm filtered 1× phosphate-buffered saline (PBS) were centrifugated at 2000× g for 30 min at +4 °C, and subsequently 10,000× g at +4 °C for 30 min, and then transferred into new tubes, mixed with 200 µL of Exosome Precipitation Reagent  and incubated for 1 h at +2–8 °C. After incubation, samples were centrifugated at 10,000× g for 1 h at +4 °C. EV pellets were resuspended in 100 µL of 0.2 µm filtered 1× PBS and stored at +4 °C until nanoparticle tracking analysis (NTA) was performed. As the negative control, an aliquot of 100 µL of 1× PBS was processed as described above. For EV characterization, a representative CSF EV pellet was lysed with 30 µL of ice-cold Exosome Resuspension Buffer  and stored at −20 °C. Alix and Calnexin expression were analyzed in EVs by Western blotting analysis according to standard protocols. Briefly, lysed EVs (40 µg) were separated using BoltTM 4–12% Bis-Tris Plus Gels  with MOPS SDS running buffer . Samples were electro-transferred onto nitrocellulose membranes  for 90 min at 90 V, the membranes were immunoblotted with primary antibodies overnight at +4 °C  or for 2 h at +37 °C  and then incubated with horseradish peroxidase-conjugated secondary antibodies  for 1 h at +37 °C. Immuno-positive bands were detected by ultra-sensitive enhanced chemiluminescence  according to the manufacturer’s instructions.EV isolation was performed with the Total Exosome Isolation Kit (from other body fluids) . To gain an optimal reading range from 20–150 particles/frame, EV suspensions were diluted with 0.2 µm filtered 1X PBS. For each sample, 5 videos of 60 s were recorded, and the relative data were analyzed using NanoSight NTA Software 3.2 . The instrument settings were optimized and kept constant between samples. Data collected consisted of particle concentration (particles/mL), average size (nm) and particle size distribution . Finally, raw concentration data (particles/mL) obtained from the instrument were normalized to calculate the EV concentration in CSF samples.® ELISA kit  according to standard protocols; samples were diluted at 1:80. The mean intra-assay coefficient of variation (%CV) was <5% and the mean inter-assay CV% was <4%. BDNF and GDNF CSF concentrations were measured with Human Premixed Multiplex-Magnetic Luminex® Assays  following the manufacturer’s protocol; samples were diluted at 1:1. PGRN CSF concentration was measured with the Progranulin (human) ELISA kit  following the manufacturer’s protocol; samples were diluted at 1:10. The mean intra-assay %CV was <3% and the mean inter-assay CV% was <5%. Aβ 40, Aβ 42, p-Tau 181 and Tau CSF concentrations were measured using Innotest ELISA kits  following the manufacturer’s protocol. All samples were analyzed in duplicate.Cystatin C CSF concentration was measured using the Human Cystatin C QuantikineNormality assumption of continuous variables was evaluated with graphical inspection and the Kolmogorov–Smirnov test. The linear model or generalized linear model  adjusted for age were used for the comparison across the four subject groups. Bonferroni post-hoc tests were applied. The chi-square test was used to assess the association between the demographic characteristics  of the subjects within the four groups. A classification tree (CT)  was applp = 0.002) despite not reaching the significance level in the FTD group . EV size had an opposite trend, being lower in PTS than in CTRL (p < 0.001) even though not significant in the FTD group . EV concentration and size distribution are depicted in the p < 0.001, r = −0.39). EV concentration/size ratio (p < 0.001), specifically in AD and DLB .Clinical and demographic variables of the participants under study are shown in TD group a . Progranulin concentration was increased in AD samples compared to DLB samples . BDNF and GDNF were not detectable in any CSF samples.Cystatin C concentration was decreased in DLB samples compared to all other groups a  or collapsed in PTS. The best CT  was obtained with PTS and CTRL groups revealing EV parameters as the best predictors: EV size smaller than 114.9 nm was able to classify the patients from the controls (96.7% vs. 3.3%) . To esti for FTD .p = 0.031). In the stratified analysis, the AD group resulted in being the only group with EV concentration/size and p-Tau 181/Aβ 42 ratios significantly correlated . CysC and PGRN were not correlated with EV parameters.To evaluate the interaction of the biological variables under study and the diagnostic groups, partial correlation analyses were performed among the CSF EV concentration/size ratio, CysC and PGRN (neurotrophic factor), Aβ 40, Aβ 42, p-Tau 181, Tau, Aβ 42/Aβ 40 and p-Tau 181/Aβ 42 (core biomarkers for AD). The analyses were carried out for the entire study group as well as in PTS, in each diagnostic group  and in CTRL. A positive correlation was found in PTS between EV concentration/size and p-Tau 181/Aβ 42 ratios  and in AD, compared to the controls. Moreover, EVs were associated with CSF biomarkers of AD; specifically, a negative correlation between EV concentration and CSF Aβ1-42 levels was found in the MCI group, while CSF Tau levels (t-Tau and p-Tau) were positively correlated with EV concentration both in MCI and AD ,44. MoreWe then investigated whether an alteration of neurotrophic factors in CSF might also be detected in AD, DLB and FTD, and if their levels could be related to EV release. We observed a decrease in CysC in dementia patients and more specifically in DLB patients; in line with our results, lower CysC CSF levels have been previously shown to be associated with DLB ,52. RegaIn conclusion, we confirmed a common involvement of the endosomal pathway in neurodegenerative dementias, as suggested by the alterations of CSF EVs in AD and DLB. However, the role of the EVs has to be understood in more depth since the literature is still contradictory about their protective/pathogenic function in neurodegeneration. Since we described blood EVs (EV concentration/size) as a cross-disease biomarker with high diagnostic performance, more studies are needed in order to clarify the molecular mechanism underlying the observed effect at the peripheral level and the relationship with the inverse alteration observed at central level in CSF. Thus, although CSF EV variables show a fair diagnostic performance, plasma EVs could represent a better biomarker due the more feasible access for sampling and the better diagnostic accuracy. However, the results of this study indicate CSF EVs as a promising source for further investigation into the interaction of EVs and aggregation-prone proteins to give insight into the molecular mechanisms underlying the pathology.


In contrast, the negative εHf(t) and high δ18O values of the post-Archaean inherited zircons indicate that their parental magma contained recycled older crust due to the enhanced crust-mantle interactions during the evolution of the early continental crust. Therefore, the inherited zircons in the back-arc volcanic rocks not only reflect the evolution of the local magmatism, but they also contain a record of the Archaean crustal fragment and of several global continental amalgamation events.Magmatism has profoundly influenced the evolution of the geosphere, hydrosphere, atmosphere, and biosphere in back-arc basins. However, the timing of the magmatism in the Okinawa Trough (OT) is not well constrained by the age spectra of zircons. Here, for the first time, we carry out an integrated study combining in situ analysis of zircon U–Th–Pb and Hf–O isotopes, and trace element compositions of zircons from the volcanic rocks from the southernmost part of the OT. We found that the young (< 100 ka) zircons in these volcanic rocks have old (108 Ma to 2.7 Ga) inherited cores, which were captured as the magma ascended through the rifting continental crust. In particular, the inherited Archean zircons strongly suggest that remnants of the old East Asian continental blocks underlie the embryonic crustal rifting zone. Moreover, the ages of most of the inherited zircons correspond to five supercontinent amalgamation events. Specifically, the Archaean inherited zircons, which have positive εHf However, the nature of the basement is a controversial issue. Conventional wisdom suggests that the OT basement may be an offshore part of the continental lithosphere of the South China Block, which was related to the northwestward subduction of the Philippine Sea Plate beneath the Eurasian Plate2; In contrast, an allochthonous origin for the OT basement has been proposed by Niu et al.3, that is, it was originally a thinned continental block within the palaeo-Pacific Plate and moved westward with the palaeo-Pacific Plate. However, the lack of basement rock samples has limited our understanding for these issues. The crustal thickness decreases from > 25 km in the northern OT to ~ 10 km on the axis of the SOT graben2. The southernmost part of the OT (SPOT) is considered to be an embryonic crustal rifting zone4, in which the crust (25–30 km) has not experienced significant thinning5 and is characterized by a cluster of active volcanoes dominated by dacites and rhyolites7. These < 0.2 Ma silicic magmas evolved via mixing of a mantle-derived basaltic magma and a crustal felsic magma, followed by extensive fractional crystallization6. Mg element diffusion chronology of the plagioclase in the dacites suggests that relatively long-lived magma storage (at least 600 yrs) occurred in the shallow silicic magma reservoir5. However, the duration of the submarine volcanism in the OT is still poorly constrained. At present, no studies have reported the timing of the magmatism based on age spectra of zircons from the OT volcanic eruptions.The OT, which is located on the western Pacific active continental margin Fig. , is a ba11. Furthermore, inherited zircons in volcanic rocks can provide samples of deeper crustal levels, which makes them a powerful tool for unlocking the mysteries of the Earth’s deep crust15. In this study, we used Quaternary magmatic zircons from the SPOT volcanic rocks and old inherited zircon cores captured from the deep crust during mantle-derived magma ascent through the rifting upper crust to analyze the era of magmatic activity and reveal the nature of the basement rocks in this region, as well as the record of supercontinent amalgamation events.Zircon, which is a common accessory mineral, is a powerful tool for understanding magmatic systems because it often records the protracted history prior to eruptionZircons were separated from the three submarine volcanic rock samples collected at the three stations  ranges  values of − 54.5 to − 6.8, which correspond to εHf(t) values of − 15.7 to + 4.9 and two-stage crustal Hf model ages (TDM2) of 1419–2837 Ma  values of the ~ 2.7 Ga Archaean dark-CL domains are positive  values   Fig. . We inte6  during magma ascent15. Experimental results have demonstrated that the retention times of O isotopes in 20–120 μm zircons at a temperature of 900 °C are between 160 and 5700 years23. For hotter mantle magmas, the time required for the δ18O to reach diffusive equilibrium with the homogeneous mantle value is much shorter than 5.7 ka24. The Zr-undersaturation level of mafic melts causes the fast dissolution of pre-existing zircons under normal conditions25. Thus, it would not be possible for continent-derived zircon crystals that have been recycled back into the mantle by subduction to preserve highly variable O isotope signatures at mantle temperatures24. Therefore, the dark-CL domains with highly variable δ18O values  They lack significant Eu anomalies, exhibit relatively flat HREE patterns  They have oxygen isotope compositions  values  values within the lower crustal range29  They exhibit clear, bright, and broad oscillatory zoning in the CL images and euhedral to subhedral rather than oval shapes Fig. A, indica16.  They lacrns Fig. , suggest16.  They lac16.  They lac16.  They lac30. Similarly, the Archaean inherited zircons (2.7–2.5 Ga) in the studied volcanic rocks suggest the presence of unexposed Archaean lower crust beneath the SPOT  has a very low εHf(t) value (− 15.7) and an Hf model age (TDM2) of 2.6 Ga  and three Mesozoic inherited zircons (150.9–237.5 Ma) exhibit slightly negative εHf(t) values (− 3.3 to − 5.7) and Proterozoic Hf model ages  values and low oxygen isotope values (5.74–5.85‰) , 1.3–0.95 Ga (Rodinia), 0.7–0.5 Ga (Gondwana), and 0.35–0.18 Ga (Pangea)  values of these inherited zircons indicate that their parent magmas contained recycled older crust27. Moreover, the variations in the negative εHf(t) and heterogeneous high oxygen isotope values  Fig. , are uniThe zircon U–Th–Pb ages, trace element compositions, and Hf–O isotopes support the following model for the two silicic magma eruptions in the southwest OT. (1) There were long-lived (at least 100 ka) magma reservoirs beneath the submarine volcanos, indicating that the time of OT rifting is at least 100 ka . (2) The zircon xenocrysts were acquired during the ascent of mantle-derived magma through the overlying crust rather than from recycled subducted sediments. (3) The occurrence of these Archean zircons suggests the presence of unexposed Archean materials in the crust of the southern OT, which have experienced complex modifications related to the addition of juvenile material and the reworking from the Neoarchean onward. (4) The inherited zircons record five supercontinent amalgamation events.The zircons were separated from the three volcanic rock samples Fig. . Represe238U–230Th disequilibrium ages and trace element compositions were obtained using the CAMECA IMS 1270 SIMS at the University of California Los Angeles (UCLA) following the analytical protocols described by Schmitt et al.39 and Bell and Harrison40. Zircon U–Pb and O analyses were performed using the CAMECA IMS 1280 at the Institute of Geology and Geophysics, Chinese Academy of Sciences (IGGCAS) following the analytical procedures described by Li et al.41 and Tang et al.42. Finally, Hf isotope analysis was carried out on the zircons using the LA-MC-ICP-MS at Nanjing University, China. The details of the analytical methods and zircon U–Th–Pb–O–Hf isotopic and trace element data are presented in the Supplementary Information.The zircons Supplementary Information.


Soluble triggering receptor expressed on myeloid cells 2 (sTREM2) in cerebrospinal fluid (CSF) has been described as a biomarker for microglial activation, which were observed increased in a variety of neurological disorders.Our objective was to explore whether genetically determined CSF sTREM2 levels are causally associated with different neurological diseases by conducting a two-sample Mendelian randomization (MR) study.Single nucleotide polymorphisms significantly associated with CSF sTREM2 levels were selected as instrumental variables to estimate the causal effects on clinically common neurological diseases, including stroke, Alzheimer’s diseases, Parkinson’s diseases, amyotrophic lateral sclerosis, multiple sclerosis, and epilepsy and their subtypes. Summary-level statistics of both exposure and outcomes were applied in an MR framework.p = 0.002). Null association was found in risk of other included neurological disorders.Genetically predicted per 1 pg/dL increase of CSF sTREM2 levels was associated with higher risk of multiple sclerosis (OR = 1.038, 95%CI = 1.014–1.064, These findings provide support for a potential causal relationship between elevated CSF sTREM2 levels and higher risk of multiple sclerosis.The online version contains supplementary material available at 10.1186/s12974-022-02443-9. In the management of neurological diseases, numerous biomarkers have been identified to improve the accuracy of differential diagnosis and of prognostic assessment. Triggering receptor expressed on myeloid cells 2 (TREM2), which is mainly expressed by microglia, the resident immunocytes in central nervous system (CNS), have been extensively studied and found associated with microglia functions . EvidencMendelian randomization (MR) appears great superiority in investigating causality between traits and diseases, utilizing genetic variants as instrumental variables, which could mimic the coin toss in the randomized trail , 15. ConThis genetic association study used only published summary data from studies involving human participants, and approved by the Ethics Committee of Tongji Hospital. Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guidelines were followed. The full period of data collection was June 1, 2021, to July 1, 2021.An overview of the study design and used data sources are displayed in Fig. p < 5e−8). Second, a reference panel of 503 Europeans from phase III (version 5) of the 1000 Genomes Project was used for linkage disequilibrium (LD) clumping (r2 < 0.001) [r2 ≥ 0.8) based on the European ancestry would take place of the certain SNP which was not available in the summary statistics of the outcome. Fourth, F-statistics for each SNP were calculated to quantify the strength of the instruments and weak ones would be excluded (F-statistics < 10) [The following procedures were taken to select appropriate genetic variants that preferably satisfy three instrument assumptions of the MR analysis . First, < 0.001) . Third, cs < 10) . A flow The publicly available GWAS summary statistics for different neurological diseases and subtypes were extracted from corresponding authoritative consortium or cohort study. An overview of the used data sources is displayed in Additional file n = 4373), small vessel (n = 5386), and cardioembolic (n = 7193) stroke [https://finngen.gitbook.io/documentation/).Summary-level data for ischemic stroke and subtypes were obtained from the MEGASTROKE consortium encompassing 29 genome-wide association studies (GWASs) with a final sample of 440,328 individuals , subtyped according to the Trial of Org 10,172 in Acute Stroke Treatment criteria  into lar) stroke  includinFrom the International Genomics of Alzheimer's Project (IGAP), we derived GWAS summary statistics for Alzheimer's disease  . The metThe publicly available GWAS summary statistics for Parkinson's disease included up to 9581 cases and 33,245 controls of European ancestry, which was accessible on the PDGene database [Amyotrophic lateral sclerosis summary statistics utilized in this study were collected from a cohort of 20,806 cases and 59,804 controls of European ancestry .Genetic associations with multiple sclerosis were obtained from the data of GWAS on individuals of European ancestry contributed by the International Multiple Sclerosis Genetics Consortium (IMSGC), which included 14,802 cases and 26,703 controls [We further extracted summary estimates of the identified genetic variants from the International League Against Epilepsy (ILAE) Consortium cohort . 44,889 Q statistic and leave-one-SNP-out analysis were conducted to examine the heterogeneity among estimates between each SNP. In addition, simple mode and weighted mode methods were also conducted to assess the robustness of the significant results. All analyses were performed using the TwoSampleMR [https://www.R-project.org).The inverse variance weighted (IVW) method was performed as the major analysis, which provides an estimate with the highest power but is not sensitive to horizontal pleiotropy of instruments. Therefore, the weighted median method and MR-Egger regression were used as secondary methods to correct for pleiotropy. Odd ratios (ORs) and corresponding 95% confidence intervals (95% CI) for outcomes were scaled to 1 pg/dL increase in levels of CSF sTREM2. Cochran’s SampleMR  and MRPRSampleMR  in R SofThe data sets analyzed in this study are publicly available summary statistics. Data used can be obtained through cited papers and websites.p = 0.002), using the inverse-variance weighted method , as well as rs11686262 mapped at ARHGAP25 and rs7232 mapped at MS4A6A. These three enrolled SNPs could explain 11.2% variance in CSF sTREM2 levels. In addition, results of sensitive analysis indicated no horizontal pleiotropy  or heterogeneity  existing among the selected instruments  were positively associated with higher odds for multiple sclerosis  had a similar relation to the risk for multiple sclerosis as the supposedly causal exposure [Triggering receptor expressed on myeloid cells 2 (TREM2) is a kind of cell surface transmembrane glycoprotein composed of 230 amino acids . Studiesexposure .Multiple sclerosis (MS) is the most common chronic central nervous system (CNS) disorder among young adults, which may lead to severe physical disability in working-age adults. The pathologic characteristics of MS are inflammation, demyelination, glial hyperplasia, and axonal damage in the lesion area . The corNull causal relationship was estimated between CSF sTREM2 levels and applied diseases except for MS. However, interpretation of negative results must be treated with caution for the reason that they may simply be due to poor statistical power in addition to biological causes.p-tau, and t-tau in CSF are well performed as disease progression markers [p-tau, and t-tau [Numerous studies reported increased CSF sTREM2 levels in Alzheimer's disease, which is a progressive, clinically heterogeneous, and particularly complex neurodegenerative disease characterized by cognitive decline , 46, 47. markers , 50, whind t-tau , 16, andnd t-tau . Taking nd t-tau –53, actiThe most important strengths of our study are its relatively large sample size and the idea of the application of a two-sample MR approach which minimizes the risk of bias from confounding and allowed us to leverage large-scale genetic data on different neurological diseases.Meanwhile, there are several limitations in this study as well. First, although the largest scale GWAS for CSF sTREM2 levels to date has been included, only 1001 individuals were enrolled due to difficulty of CSF sample collection. In addition, using an AD cohort to estimate the correlation between genetic variants and CSF sTREM2 levels in MS might decrease the validity of instrumental variables considering the potential bias caused from disease type, disease state, age, sex, and etc. Future updated MR analysis using the summary statistics of larger genetic study is warranted to confirm the results of our MR study. Another important limitation of our current study is that we could not directly assess associations of individual genetic variants with potential confounders of association between CSF sTREM2 levels and neurological diseases due to the lack of knowledge of potential confounders and the unavailability of individual-level data. Indeed, potential confounding variables, such as innate immune activation pathways, glial biology, etc., may interfere the results of the feasible causality. Deeper investigation on the functions of selected instrumental variables and more precise algorithm in the MR framework may help eliminate or minimize influences of confounding factors. Third, the CSF sTREM2 level that was measured at a specific timepoint may be affected by many temporary factors, such as age and inflammation, which may not reflect the lifelong CSF sTREM2 level determined by the encoding gene. Fourth, current public database does not contain the summary-level statistics of MS subcategories, making it not possible to further examine the potential relationship between CSF sTREM2 level and risk for subtypes of MS. Fifth, the GWAS data included mainly samples of European, which may limit the generalizability of our findings to other racial/ethnic populations. Finally, although this study suggests that CSF sTREM2 level is causally associated with multiple sclerosis, Mendelian randomization analysis is only a prediction result without verification. Therefore, this kind of causal relationship as well as the underlying pathological mechanism need to be further explored and verified in animal or human experiments.A Mendelian randomization study has been conducted to suggest that genetic predisposition to higher CSF sTREM2 levels is associated with higher risk of multiple sclerosis. More attention may need to be paid to explore the potential mechanism of CSF sTrem2 in the pathogenesis of MS, so as to provide a theoretical basis for the proposal of emerging and meaningful therapeutic strategies.Additional file 1: Table S1. Detailed information on used studies. Table S2. Detailed information on used studies from FinnGen consortium. Table S3. Associations of CSF sTREM2 with neurological diseases and subtypes in inverse-variance weighted method, as well as weighted median method and MR-Egger method. Table S4. Effects of genetic liability to MS on CSF sTREM2 levels in reverse Mendelian randomization analysis. Figure S1. Leave-one-SNP-out sensitivity analyze for CSF sTREM2 levels on MS.


The immunologic effects of anti-B7H3 therapy are not fully elucidated. A 6-year-old male was diagnosed with metastates of neuroblastoma to the received intraventricular 131I-omburtamab on an IRB-approved protocol. A treatment cycle consisted of a 2 mCi dosimetry dose and a 50 mCi treatment dose. Dosimetry by serial imaging, pharmacokinetics and safety were investigated. Clinical status, magnetic resonance imaging, CSF cell count and cytology were evaluated pre- and post-131I-omburtamab at 5 and 26 weeks. The patient did well with cycle 1. Three hours after the dosimetry dose of cycle 2, he developed a fever (39 °C), chills and headache. Blood and CSF samples were sent for culture. CSF was notable for nucleated cell pleocytosis with profound mast cell proliferation consistent with chemical meningitis. He was treated with supportive care; symptoms resolved over 48 h. Further therapy with 131I-omburtamab was electively discontinued. CSF cell count 5 weeks later demonstrated resolution of CSF pleocytosis. Local–regional administration of intraventricular 131I-omburtamab targeting B7H3 can result in a profound nucleated CSF pleocytosis with mastocytosis consistent with an acute allergic reaction.Omburtamab is a B7H3-specific murine monoclonal antibody. B7H3 (CD 276) is a member of the B7 family of immune checkpoint co-inhibitory receptors overexpressed on many human malignancies. Radioimmunotherapy with  B7H3 functions beyond immune costimulation have been identified, with recent work indicating a crucial role for B7H3 in promoting carcinogenesis and metastases. (1) Overexpression of B7H3 protein has been demonstrated in many human malignancies (2) and is generally considered to be a negative prognostic marker. (3–5) Omburtamab (8H9) is a murine monoclonal antibody specific for B7H3. (2) Anti-B7H3 tumor-targeted radioimmunotherapy has been studied using A 4-year-old male was diagnosed with stage 4 neuroblastoma involving a right adrenal mass, bones and bone marrow. Tumor biopsy showed amplification of the MYCN gene with unfavorable histology. He achieved a complete remission following standard multiagent chemotherapy, tandem high-dose myeloablative therapy with stem cell rescue and immunotherapy with anti-GD2 antibodies, GM-CSF and IL-2. Two years after initial diagnosis, a routine surveillance scan demonstrated a left temporal lobe brain tumor with subacute hemorrhage. Surgical resection confirmed an isolated central nervous system progression of neuroblastoma.131I-omburtamab on a phase 2 IRB-approved protocol (NCT00089245) [131I-omburtamab at 5 and 26 weeks.The patient underwent treatment according to Memorial Sloan Kettering Cancer Center salvage regimen consisting of craniospinal radiation therapy, chemotherapy and intraventricular 131I-omburtamab, the patient was in a radiographic and cytologic remission. CSF was unremarkable for the presence of nucleated or extrinsic cells); total protein and glucose were within normal parameters. The patient did well with the first cycle consisting of the dosimetry and therapy dose. Five weeks after the completion of cycle 1, CSF on routine examination was notable for cell differential showing 66% lymphocytes, 33% monocytes and 1% eosinophils. Serum complete blood count was also unremarkable, total WBC 2.3 K/mcL, differential 67% neutrophils, 12.3% monocytes, 4.8% eosinophils and 14.9% lymphocytes. One week later, the patient proceeded to cycle 2. Three hours following the dosimetry dose of the second cycle (2 mCi 131I-omburtamab), the patient developed a high fever (39 °C) with chills and headache, approximately 3 h after administration. Blood and CSF samples were sent for culture. Serum complete blood count was unremarkable . CSF was notable for nucleated cell pleocytosis (26 uL) initially interpreted as polymorphic white blood cells with abundant intracellular and extracellular bacteria. Further evaluation showed these cells were mast cells with basophilic granules consistent with mastocytosis  [B7H3 CD 276) is a member of the B7 family of immune checkpoint co-inhibitory receptors playing a role in local T cell regulation. B7H3 functions beyond immune costimulation have been identified, with recent work indicating a crucial role for B7H3 in promoting carcinogenesis and metastases 76 is a m–6. Omburid (CSF) . The imm131I-omburtamab, atypical chemical meningitis as an adverse event has been noted rarely (< 10%) but that such reactions are typically associated with atypical lymphocytosis or macrophage proliferation. As a murine antibody, omburtamab might be expected to elicit an allergic reaction; however, this is the first instance whereby anti-B7H3 therapy resulted in a mastocytosis. Mast cells mediate inflammatory responses such as hypersensitivity and allergic reactions and as such are not routinely detected in the CSF. In our patient, the acute onset of fever and chills accompanied by headache appears to have been due to the chemical mediators in the mast cell degranulation process, producing the responses typical of an allergic reaction. For a minority of individuals predisposed to an allergic reaction, the previous exposure to murine anti-B7H3 therapy in cycle 1 may “prime” or sensitize them by stimulating the production of IgE antibodies, which attach to mast cells and basophils resulting in an allergic reaction. Future patients may benefit from serum or CSF IgE levels if the setting of mastocytosis. While this patient did not receive further therapy for concern of another drug-related adverse event, further analysis to learn more about mast cell recruitment in the CSF may be undertaken if a similar adverse event is observed in future patients.As a co-stimulatory molecule of the cell surface B7 protein superfamily, B7H3 is a potentially powerful therapeutic target, whose overexpression on many human solid tumors has been demonstrated. Intraventricular administration of anti-B7H3-targeted therapy has been a therapeutic modality for many years, often resulting in a CSF pleocytosis with monocytes and lymphocytes. We note that among > 200 patients treated with nearly 600 injections of intraventricular Although B7H3-targeted therapy is designed to stimulate immune response against tumor cells, therapies that recruit inhibitory molecules like Fas ligand (Fas-L), transforming growth factor beta (TGF-β) and prostaglandin E2 (PGE2) may decrease the cytotoxicity by altering the immunosuppressive tumor microenvironment . It is u131I-omburtamab targeting B7-H3 can result in a profound nucleated CSF pleocytosis with mastocytosis consistent with an acute allergic reaction.We now add the recruitment of mast cells into the CSF compartment to the immune phenomena exhibited when targeting B7H3. While targeting tumor-associated B7H3 as the next generation of immune checkpoint therapy is actively investigated in the form of monoclonal antibodies, small molecules and chimeric antigen receptor T cells, it is important to recognize the potential for occurrence of this phenomena. Local–regional administration of intraventricular Data for this case report are presented below. No additional data will be provided for this report.


We report the case of a 9-months-old boy that has presented a steroid-dependent post-pneumococcal chronic aseptic meningitis was associated with persistence of pneumococcal cell wall components in cerebrospinal fluid during more than 20 months. Suggesting that this antigenic persistence could be involved in post-infectious manifestations through innate immunity response. Pneumococcal meningitis is a potentially life-threatening infection which often cause sequelae despite antimicrobial chemotherapy. Corticosteroids are indicated to reduce sequelae . In thisHaemophilus influenzae type b) and two injections of 13-valent pneumococcal conjugated vaccine.A previously healthy 9-months-old boy was admitted on December 2017 to the pediatric intensive care unit of Arnaud de Villeneuve Hospital  for febrile meningeal syndrome. In his history, he received two doses of combined vaccine , 1.65 g of protein/L, and <0.1 mmol of glucose/L. Gram staining revealed gram-positive diplococci. Empirical therapy consisting of intravenous cefotaxime (300 mg/kg/day) and dexamethasone (0.15 mg/kg/6h) was started. CSF and blood culture were positive to Streptococcus pneumoniae (SP) serotype 24F.At hospital admission, the CRP level was 543 mg/liter. Cerebrospinal fluid (CSF) samples contained 28WBC/mmAt day one a status epilepticus occurred, rapidly stopped with antiepileptic therapy. Cerebral Magnetic Resonance Imaging (MRI) showed osteitis foci in both mastoids without empyema vasculitis or ischemia. Apyrexia was quickly obtained, and dexamethasone stopped after 4 days.On the fifth day, meningeal syndrome reappeared. CRP rebounded (347 mg/liter), CSF culture was sterile. Brain MRI revealed a lepto-pachymeningitis. Dexamethasone was reintroduced with a progressive decrease.On the tenth day, antibiotic therapy was switched for amoxicillin and rifamicin for a total duration of 21 days. On the fourteenth day, with dexamethasone 0.15 mg/kg/day, fever reappeared. CSF culture was sterile. Symptomatology regressed with dexamethasone increase. Dexamethasone was switched for prednisolone 3 mg/kg/day, on the twenty-second day.Thereafter despite a very gradual decrease, aseptic meningitis (AM) reappeared six times daily dose of prednisolone was reduced under 10 mg . Every time, CRP risen again over 60 mg/L, CSF showed an increase of WBC (predominance of granulocytes), moderate elevation of CSF protein concentration, whereas CSF tested negative for SP by PCR and microbiological culture. The Sofia SP fluorescence immunoassay  (SPFI) revealed persistent positive SP soluble antigens in CSF. Viral searches were negative, excepted at 19-month-old where enterovirus was weakly positive. Every time the symptomatology was quickly normalized increasing prednisolone. Away from an AM episode, CSF was normal except persistence of SP antigen .When he was 31-months-old, during a common fever without meningitis manifestation, SP antigen in CSF was negative. Prednisolone therapy was definitively stopped at 33-months-old. Brain MRI control was normal. Signs of meningeal irritation did not reoccur during 8 months of follow-up. At a distance neurodevelopment was perfect.Immunological explorations were performed: Howell-Jolly bodies were absent. Immunoglobulin levels, post-vaccinal antibody titers , complement's fractions, lymphocyte subpopulations and extended lymphocyte phenotyping were normal. Deep exploration of the complement was normal . To avoid an auto-immune disease we have check for antinuclear antibodies and anti-neutrophil cytoplasmic antibody that were absent. HIV serology and search of chronic septic granulomatosis were negative. Trio whole exome sequencing was performed for the proband and his unaffected parents to explore all known genes involved in immunodeficiencies and auto-inflammatory syndromes, none pathologic mutation was observed in these genes . CerebroDosage of cytokines in CSF were performed during the AM of the 19th-month and away from any AM: IL1 was stable while IL6 and IL8 clearly increased in AM CSF.In order to evaluate specific immunological response, we perform antibodies dosage against pneumococcal capsular polysaccharides. Regarding the serotype 24F, specific ELISA and opsophagocytic assay revealed the production of specific antibodies but non-functional . WrittenBrouwer et al.  reportedStreptococcus pneumoniae serotypes. It should be noted that Streptococcus mitis and Streptococcus oralis are also known to harbor pneumococal C polysaccharide like antigens, however they are uncommun cause of bacterial meningitis.Pneumococci have a unique structure that includes a capsule, a polysaccharide cell wall and a cell membrane. C polysaccharide cell wall antigen is common to all Although the pathophysiological phenomenon remained unknown, the authors hypothesized the presence of inflammatory phenomena in response to the persistence of pneumococcal cell wall components in CSF. In addition, in the two reported cases, patients had responded to an anti-inflammatory treatment .In our patient, we relate the occurrence of repeated AM episodes with corticosteroid dependence in the aftermath of SP meningitis. This strongly suggests a chronic meningeal inflammation contained by corticosteroid therapy.Using the SPFI we observed the antigenic persistence of CPA in CSF during more than 20 months. To our knowledge it is the longest duration of detection of pneumococcal soluble antigen  .In our observation, relapsing meningitis episodes have stopped after negativisation of SPFI suggesting the persistence of CPA could participate in the pathophysiology of aseptic meningitis. A variety of pneumococcal cell wall compounds are known to be proinflammatory. This was showed after experimental approach as intracisternal inoculation of heat-killed unencapsulated pneumococci, purified pneumococcal cell wall, cell wall lipoteichoic acid, or cell wall peptidoglycan . A cliniIn our case, antibiotics have killed the germs but the elimination of bacterial compounds from the CSF seems to have been faulty. We then hypothesized that in the sanctuary space of CSF, recognition of different bacterial pathogen-associated molecular patterns (PAMPs) by antigen presenting cell (APCs) has activated an immune reaction. Thus, as mechanisms leading to aseptic meningitis, we can properly suspect a persistent inflammatory response of the host, triggered by a direct interaction of the pneumococcal cell wall components with host's TLRs, which maintain the production of pro-inflammatory cytokines related to innate immunity.By performing cytokine assays in the CSF away and during a meningeal episode, we logically observed an increase in the level of IL6 and IL8 that are pro-inflammatory cytokines, involved particularly in innate immunity and auto-inflammatory pathways. Unfortunately, cytokine assays during meningeal inflammation were carried out on the 19th month episode (CSF weakly positive for enterovirus). Thus, we cannot distinguish phenomena related to the lifting of immunosuppression and what could be due to the potential immune stimulation induced by enterovirus (this episode occurred concomitantly with a corticosteroid therapy decrease). In fact, the meningeal syndrome resolved immediately after increasing prednisolone therapy.Experimental animal models have shown that prognostic of bacterial meningitis is related to the severity of inflammation in the subarachnoid space and that the outcome can be improved by modulation of the inflammatory response with dexamethasone. In central nervous system corticosteroid therapy decreases proinflammatory cytokine production  and increases the production of anti-inflammatory cytokines .Since glucocorticoids act on multiple molecules of the TLR downstream signaling cascade, we could imagine the use of a specific therapy targeting TLRs  or their pathway  would be effective to control AM.Mechanisms of non-clearance of pneumococcal components within CSF over the time remain unclear. Pneumococci are extracellular pathogens that need to be phagocytosed to be eliminated. Their polysaccharide capsule protects them against phagocytosis, complement-mediated lysis and from T-cell and natural killer cell immunity. T-independent B lymphocytes that produce anti-polysaccharide antibodies are therefore the most important form of acquired immunity against these organisms. Antibodies interact with capsular polysaccharides and surface proteins and permit opsonisation with the help of activated complement. Thereafter phagocytose of pneumococci is favored. To explore the implication of a polysaccharide antibodies failure as a result of CPA persistence in CSF, we have conducted opsophagocytosis tests  with specific antibodies against 24F polysaccharide in serum, as these tests are not validated in CSF, we consider that these tests reflect a systemic response effective in central nervous system. This test shows that these specific antibodies were present but not functional. Moreover, regarding the post-vaccine antibodies we also showed that they are present but ineffective. In 2013, Oishi et al. suggest that low opsonic activities may be explained by the lowed avidity of serotype specific IgG .This lack of polysaccharide response could be explained in part by the physiological immaturity of T independent humoral response, in toddlers. A control after 5 years old will be proceed to eliminate an anti-polysaccharide immunodeficiency.Nevertheless, we could hypothesize to explain chronic post-SP meningitis that adaptative immunity failure was “balanced” by an innate immunity response directed against a lifeless antigen. That is responsive of a chronic inflammatory response based on autoinflammatory pathway.Further studies are needed to precise these potential interactions between innate and acquired immunity.The original contributions presented in the study are included in the article/Written informed consent was obtained from the legal guardian for the publication of any potentially identifiable images or data included in this article.EJ: concept and design. ML, YD, KB, AB, and GB: aquisition of data. YD, FB, AB, KB, GB, ET, and SG: data analysis and interpretation. ML, EJ, and GS: drafting of manuscript and critical revision. All authors contributed to the article and approved the submitted manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Fighting against coronavirus disease-2019 (COVID-19) goes hand in hand with the provision of proper water, sanitation, and hygiene (WASH) services. In this case, proper handwashing with soap and water plays a major role in the prevention of COVID-19, since it helps to deactivate and remove virus particles from the hands. This letter points out the drivers for the improvement of functional handwashing facilities during the COVID-19 pandemic in Tanzania, whereby three out of every 20 non-functional handwashing facilities were improved to make them functional. The letter also provides several recommendations to maintain momentum for improving functional handwashing facilities. To the Editor:Severe acute respiratory syndrome corona virus 2 (SARS-CoV-2) has been identified as the causative agent for the COVID-19 outbreak. It is believed that SARS-CoV-2 has a zoonotic origin and transmission to humans was either from bats or through an unknown intermediate host , 4. As oTanzania is among the countries that took initiatives to prevent the spread of COVID-19 by adhering to WHO recommendations. Prior to the outbreak, 59% of Tanzanian households had handwashing facilities that included soap and water; however, only 22.83% of these facilities were functional [According to data from the Ministry of Health, Community Development, Gender, Elderly and Children, which can be accessed through the Tanzania WASH portal, the coverage of the functional handwashing facilities has always been low, but it is also characterized by a gradual increase over time. As the above initiatives were implemented during the onset of COVID-19 in Tanzania, however, there was a rise in the trajectory of functional handwashing facilities, in terms of percentage increase. This is because the implemented measures resulted in a 14.81% increase in the number of households with functional handwashing facilities, from 22.83% in September 2019 to 37.64% by June 2020 [It can be concluded that, for every 20 non-functional handwashing facilities in the country, three were made functional through the various measures discussed above. This is a good start that should be improved upon and maintained, because it will help in the fight against COVID-19 and other infectious diseases. We must insist on the provision of adequate handwashing facilities, an enabling environment, and the promotion of proper hand hygiene, to ensure that Tanzanians achieve sustainable handwashing behaviors throughout the country.We recommend the following to maintain this momentum. There should be a show of political will and good leadership. This was observed during the onset of COVID-19, when many political leaders, including the president, participated in initiatives to raise awareness of the importance of hand hygiene. The involvement of these key figures made the campaign a success. The government should increase the amount of resources allocated to hygiene issues (of which handwashing is part and parcel) and water supply, to make proper handwashing practices possible.Quick and concerted actions should be taken all over the country to make sure awareness is raised to the level that allows the country to attain 100% coverage as far as handwashing facilities are concerned, since this is the first line of defense in the prevention of infectious diseases.Handwashing facilities should be easily accessible to all, so as to convince more people to acquire and use them. It is important to ensure that handwashing facilities are available in all public areas, such as markets, stadium, bus terminals, and in all schools and colleges. The provision of handwashing facilities at entry points should be mandatory in all health care facilities.The focus should not only be on improving WASH infrastructures, but also on behavioral change. Proper handwashing behaviors should be encouraged even after the COVID-19 pandemic, because it will be useful for controlling other infectious diseases. The country’s health policy should also be revised to include a WASH component in times of pandemics. This component should include a plan to ensure the availability, accessibility, and sustainability of WASH services in health care facilities, schools, households, and all public places.