The cellular composition of chronic subdural hematoma.

INTRODUCTION: The pathophysiology of chronic subdural hematoma (CSDH) remains to be fully understood. Basic knowledge of the composition and features of cells in the CSDH fluid may contribute to the understanding of the seemingly complex processes involved in CSDH formation and recurrence. This study is the first to examine the composition of cells and of cellular features in both systemic blood and subdural fluid from CSDH patients. We hypothesized that the cellular composition and features in the hematoma fluid may be; 1) different from that in the systemic blood; 2) different between patients with and without recurrence; 3) and different between the first and second operation in patients with recurrent CSDH. METHODS: Systemic blood and subdural hematoma fluid were collected from CSDH patients with and without recurrent CSDH at the time of primary and secondary surgery. Analyses of cells and cellular features included total number of white blood cells, erythroblasts, reticulocytes, platelets, neutrophilocytes, lymphocytes, monocytes, eosinophils, basophils, reticulocytes, immature granulocytes, mean corpuscular cell volume (MCV), mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, hemoglobin and hematocrit. RESULTS: Of the 85 included patients, 20 patients were operated for a recurrent CSDH within 90 days follow-up. All cells found in the systemic blood were present in the CSDH fluid, but the composition was different (p < 0.0001). MCV was higher in the hematoma fluid from the primary operation of patients later developing a recurrent CSDH compared to patients not developing recurrence (p = 0.009). Also, the percentage distribution of inflammatory cells in hematoma fluid from patients with recurrent CSDH was different between the first and second operation (p = 0.0017). CONCLUSION: This study is the first to investigate the cellular composition of CSDH fluid. Compared to systemic blood and to a reference distribution, an increased number of immune cells were present in the hematoma fluid, supporting an inflammatory component of the CSDH pathophysiology. MCV was higher in the subdural fluid at time of the first operation of CSDH patients later developing recurrence. CLINICAL TRIAL REGISTRATION: The study was approved by the Scientific Ethical Committee of the Capital Region of Denmark (Journal no. H-20051073.

The OPI•AID Zone Tool as a composite outcome for postoperative pain management quality-A protocol for an observational pilot study.

BACKGROUND: Managing postoperative pain while minimizing opioid-related adverse drug events (ORADEs) remains a significant challenge. The OPI•AID Zone Tool is proposed as a novel clinical decision support tool that - both graphically and in a scoring-system - represents the relationship between pain management and the occurrence of ORADEs, aiming to enhance patient outcomes in postoperative care. The OPI•AID Zone Tool places pain score on the x-axis and an ORADE score on the y-axis, and stratifies patients into five zones to reflect the composite impact of pain severity and ORADEs on the quality of postoperative patient care. The study will have two key aims: (1) to explore whether the OPI•AID Zone Tool can function as a composite outcome measure for postoperative pain and ORADEs, and (2) to evaluate the use of the OPI•AID Zone Tool in visual presentations and for evaluation of patients' postoperative pain management quality. METHODS: This prospective observational cohort study will include 200 adults undergoing various surgical procedures in general anesthesia with a subsequent stay in the post-anesthesia care unit (PACU) at Bispebjerg Hospital, Denmark. Substudy 1 primary outcome: To assess whether a zone score in the OPI•AID Zone Tool is associated with patient-perceived health (EQ VAS), quality of recovery (QoR-PACU), and time to discharge readiness in PACU, and if the zone score has a stronger association than pain and ORADE score in themselves. Substudy 2 primary outcome: To assess how the use of intraoperative non-opioid analgesics impact where patients are placed in the OPI•AID Zone Tool's XY scatterplot right after surgery. To assess if patients who receive more comprehensive non-opioid analgesic basic regimens, generally fall into lower zones. CONCLUSION: The OPI•AID Zone Tool could potentially be a valuable clinical decision-making tool for optimizing postoperative care by simultaneously addressing pain management and the risk of ORADEs. By computing a composite measure of these two critical outcomes, the tool could guide more nuanced and patient-centered analgesic regimens, potentially improving patient satisfaction and operational efficiency in postoperative settings. The tool's applicability will be explored in this observational pilot and followed up in a planned series of studies (opiaid.dk).

Covert Consciousness in Acute Brain Injury Revealed by Automated Pupillometry and Cognitive Paradigms.

BACKGROUND: Identifying covert consciousness in intensive care unit (ICU) patients with coma and other disorders of consciousness (DoC) is crucial for treatment decisions, but sensitive low-cost bedside markers are missing. We investigated whether automated pupillometry combined with passive and active cognitive paradigms can detect residual consciousness in ICU patients with DoC. METHODS: We prospectively enrolled clinically low-response or unresponsive patients with traumatic or nontraumatic DoC from ICUs of a tertiary referral center. Age-matched and sex-matched healthy volunteers served as controls. Patients were categorized into clinically unresponsive (coma or unresponsive wakefulness syndrome) or clinically low-responsive (minimally conscious state or better). Using automated pupillometry, we recorded pupillary dilation to passive (visual and auditory stimuli) and active (mental arithmetic) cognitive paradigms, with task-specific success criteria (e.g., ≥ 3 of 5 pupillary dilations on five consecutive mental arithmetic tasks). RESULTS: We obtained 699 pupillometry recordings at 178 time points from 91 ICU patients with brain injury (mean age 60 ± 13.8 years, 31% women, and 49.5% nontraumatic brain injuries). Recordings were also obtained from 26 matched controls (59 ± 14.8 years, 38% women). Passive paradigms yielded limited distinctions between patients and controls. However, active paradigms enabled discrimination between different states of consciousness. With mental arithmetic of moderate complexity, ≥ 3 pupillary dilations were seen in 17.8% of clinically unresponsive patients and 50.0% of clinically low-responsive patients (odds ratio 4.56, 95% confidence interval 2.09-10.10; p < 0.001). In comparison, 76.9% healthy controls responded with ≥ 3 pupillary dilations (p = 0.028). Results remained consistent across sensitivity analyses using different thresholds for success. Spearman's rank analysis underscored the robust association between pupillary dilations during mental arithmetic and consciousness levels (rho = 1, p = 0.017). Notably, one behaviorally unresponsive patient demonstrated persistent command-following behavior 2 weeks before overt signs of awareness, suggesting prolonged cognitive motor dissociation. CONCLUSIONS: Automated pupillometry combined with mental arithmetic can identify cognitive efforts, and hence covert consciousness, in ICU patients with acute DoC.

Test-retest reliability of transfer function analysis metrics for assessing dynamic cerebral autoregulation to spontaneous blood pressure oscillations.

Transfer function analysis (TFA) is a widely used method for assessing dynamic cerebral autoregulation in humans. In the present study, we assessed the test-retest reliability of established TFA metrics derived from spontaneous blood pressure oscillations and based on 5 min recordings. The TFA-based gain, phase and coherence in the low-frequency range (0.07-0.20 Hz) from 19 healthy volunteers, 37 patients with subarachnoid haemorrhage and 19 patients with sepsis were included. Reliability assessments included the smallest real difference (SRD) and the coefficient of variance for comparing consecutive 5 min recordings, temporally separated 5 min recordings and consecutive recordings with a minimal length of 10 min. In healthy volunteers, temporally separating the 5 min recordings led to a 0.38 (0.01-0.79) cm s-1 mmHg-1 higher SRD for gain (P = 0.032), and extending the duration of recordings did not affect the reliability. In subarachnoid haemorrhage, temporal separation led to a 0.85 (-0.13 to 1.93) cm s-1 mmHg-1 higher SRD (P = 0.047) and a 20 (-2 to 41)% higher coefficient of variance (P = 0.038) for gain, but neither metric was affected by extending the recording duration. In sepsis, temporal separation increased the SRD for phase by 94 (23-160)° (P = 0.006) but was unaffected by extending the recording. A recording duration of 8 min was required to achieve stable gain and normalized gain measures in healthy individuals, and even longer recordings were required in patients. In conclusion, a recording duration of 5 min appears insufficient for obtaining stable and reliable TFA metrics when based on spontaneous blood pressure oscillations, particularly in critically ill patients with subarachnoid haemorrhage and sepsis.

Ventriculostomy-associated infection (VAI) in patients with acute brain injury-a retrospective study.

BACKGROUND: Ventriculostomy-associated infection (VAI) is common after external ventricular drains (EVD) insertion but is difficult to diagnose in patients with acute brain injury. Previously, we proposed a set of criteria for ruling out VAI in traumatic brain injury. This study aimed to validate these criteria. For exploratory purposes, we sought to develop and validate a score for VAI risk assessment in patients with different types of severe acute brain injury. METHODS: This retrospective cohort study included adults with acute brain injury who received an EVD and in whom CSF samples were taken over a period of 57 months. As standard non-coated bolt-connected EVDs were used. The predictive performance of biomarkers was analyzed as defined previously. A multivariable regression model was performed with five variables. RESULTS: A total of 683 patients with acute brain injury underwent EVD placement and had 1272 CSF samples; 92 (13.5%) patients were categorized as culture-positive VAI, 130 (19%) as culture-negative VAI, and 461 (67.5%) as no VAI. A low CSF WBC/RBC ratio (< 0.037), high CSF/plasma glucose ratio (> 0.6), and low CSF protein (< 0.5g/L) showed a positive predictive value of 0.09 (95%CI, 0.05-0.13). In the multivariable logistic regression model, days to sample (OR 1.09; 95%CI, 1.03-1.16) and CSF WBC/RBC ratio (OR 34.86; 95%CI, 3.94-683.15) were found to predict VAI. CONCLUSION: In patients with acute brain injury and an EVD, our proposed combined cut-off for ruling out VAI performed satisfactorily. Days to sample and CSF WBC/RBC ratio were found independent predictors for VAI in the multivariable logistic regression model.

Myths and methodologies: Assessment of dynamic cerebral autoregulation by the mean flow index.

The mean flow index-usually referred to as Mx-has been used for assessing dynamic cerebral autoregulation (dCA) for almost 30 years. However, concerns have arisen regarding methodological consistency, construct and criterion validity, and test-retest reliability. Methodological nuances, such as choice of input (cerebral perfusion pressure, invasive or non-invasive arterial pressure), pre-processing approach and artefact handling, significantly influence mean flow index values, and previous studies correlating mean flow index with other established dCA metrics are confounded by inherent methodological flaws like heteroscedasticity, while the mean flow index also fails to discriminate individuals with presumed intact versus impaired dCA (discriminatory validity), and its prognostic performance (predictive validity) across various conditions remains inconsistent. The test-retest reliability, both within and between days, is generally poor. At present, no single approach for data collection or pre-processing has proven superior for obtaining the mean flow index, and caution is advised in the further use of mean flow index-based measures for assessing dCA, as current evidence does not support their clinical application.

Predictors of shunt insertion in patients with aneurysmal subarachnoid haemorrhage-a single-centre retrospective analysis.

BACKGROUND: No standard has been established regarding timing and choice of strategy for discontinuation of external ventricular drainage (EVD) in patients with aneurysmal subarachnoid haemorrhage (aSAH), and little is known about the importance of clinical variables. A proportion of the patients who initially pass their discontinuation attempt return with delayed hydrocephalus and the need of a permanent shunt. Early differentiation between patients who need a shunt and those who do not would facilitate care. We conducted a retrospective analysis on patients with aSAH and an EVD to search significant differences in treatment and clinical variables between patients who received a permanent shunt during initial hospitalization or after readmission, and those who never received a shunt. METHODS: We included 183 patients with aSAH who received an EVD over a 4-year period between 2015 and 2018 and divided them into three groups: those who received a shunt during primary admission, those who were readmitted for delayed hydrocephalus and received a shunt, and those who never needed a shunt. Between these groups, we compared selected clinical variables as well as outcome at discharge and after 6 months. Additionally, we assessed the ability of a shunt dependency score (SDASH) to predict the need for permanent drainage in the patients. RESULTS: Of 183 included patients, 108 (59%) ultimately received a ventriculoperitoneal (VP) shunt. Of these, 89 (82%) failed discontinuation during the primary admission and received a permanent shunt before discharge from the neurosurgical department. The remaining 19 (18%) were discharged after successful discontinuation, but subsequently developed delayed hydrocephalus and were admitted for shunt placement a median of 39 (range: 18-235) days after ictus. Ninety-four patients were discharged after successful discontinuation of the EVD, consisting of those who never developed the need for a permanent shunt and the 19 who were readmitted with delayed hydrocephalus, corresponding to a 20% (19/94) readmittance rate. Clinical variables such as drainage volume or discontinuation strategy did not differ across the three groups of patients. The SDASH score failed to provide any clinically useful information regarding prediction of shunt placement. CONCLUSION: In this study, clinical variables including use of the predictive score SDASH predicted neither the overall need for nor the timing of shunt placement after aSAH. The homogeneous distribution of data between the three different groups renders strong independent clinical predictive factors unlikely. Thus, attempts to predict a permanent shunt requirement from these variables may be futile in these patients.

Cerebral fat emboli in a patient with paraplegia caused by bilateral femur fractures.

Cerebral fat embolism is a rare cause of stroke and therefore an overlooked diagnosis. Often it is seen as a consequence of major bone fractures or after arthroplasty, and can lead to respiratory or circulatory collapse. We present a case of a patient with a history of paraplegia after a thoracic spinal cord injury that developed cerebral fat embolism following a bilateral femur fracture. Since the patient was paraplegic and with an altered mental state upon admission, femoral bone fractures were not initially suspected. The case shows the difficulties in diagnosing this condition.

Urokinase Plasminogen Activator Receptor: An Important Focal Player in Chronic Subdural Hematoma?

Chronic subdural hematoma (CSDH) development involves inflammatory, angiogenetic, and fibrinolytic mechanisms, several components of which are now unraveled through intensive research. The urokinase plasminogen activator receptor (uPAR) is part of the plasminogen activator system and possesses inflammatory, angiogenetic, and fibrinolytic capabilities. As a first, this study aims to identify uPAR in the hematoma fluid, hematoma membrane, dura mater, and systemic blood from patients with CSDH and, if present, to investigate if the uPAR level at the time of surgery may be a predictor for later developing recurrent CSDH. uPAR expression in the hematoma membrane and dura mater was analyzed using immunohistochemistry and presented as the H-score of the positive immunostaining. The uPAR levels in the hematoma fluid and systemic blood were determined using a multiplex antibody bead kit (Luminex). Samples were collected at the time of the first CSDH surgery, and in the case of recurrent CSDH within 90 days, the samples were again collected at reoperation. A comparison of uPAR expression between the hematoma membrane and dura mater, as well as uPAR levels in systemic blood and hematoma fluid, was performed using the Wilcoxon rank sum test. We included 112 patients, 26 of whom had recurrent CSDH. The median hematoma uPAR level was 22,125 (14,845-33,237) and significantly higher than the median systemic blood level of 789 pg/L (465-2,088) (p < 0.001). Similarly, the uPAR level of the hematoma membrane was 14.3 (7.54-44.8) and significantly higher than the dural uPAR level of 0.81 (0.3-1.98) (p < 0.001). For the first time, we identified uPAR in the subdural fluid, hematoma membrane, dura mater, and systemic blood from patients with CSDH. The high expression of uPAR in the subdural fluid and hematoma membrane indicates that the mechanisms of CSDH are predominantly in the subdural fluid collection and surrounding hematoma membrane.

Near-infrared spectroscopy to measure brain oxygenation: A comparison of measurements on the skin, skull and dura mater.

BACKGROUND: The reliability of near-infrared spectroscopy (NIRS) for measuring cerebral oxygenation (ScO2 ) is controversial due to the possible contamination from extracranial tissues. We compared ScO2 measured with the NIRS optode on the forehead, the skull and the dura mater in anaesthetised patients undergoing craniotomy. We hypothesised that ScO2 measured directly on the skull and the dura mater would differ from ScO2 measured on the skin. METHODS: This prospective observational study included 17 adult patients scheduled for elective craniotomy. After induction of general anaesthesia, ScO2 was measured on the forehead skin, as well as on the skull and on the dura mater in the surgical field. The primary comparison was the difference in ScO2 measured on the dura mater and on ScO2 measured on the skin; secondary comparisons were the differences in ScO2 on the skull and ScO2 on the skin and the dura mater, respectively. Data were described with median (5%-95% range) and analysed with the Wilcoxon signed-rank test. RESULTS: ScO2 values on the dura mater were obtained in 11 patients, and median ScO2 (48%, 29%-95%) did not differ significantly from ScO2 on the skin (73%, 49%-92%; p = .052), median difference -25% (-35.6% to -1.2%). ScO2 on the skull (N = 16) was lower than that on the skin (63% [43%-79%] vs. 75% [61%-94%]; p = .0002), median difference -10% (-20.8 to -3.0). CONCLUSION: In adults undergoing craniotomy, NIRS-based ScO2 measured on the dura mater did not reach statistically significantly lower values than ScO2 measured on the skin, whereas values on the skull were lower than on the skin, indicating a contribution from scalp tissue to the signal.

(Re)animation of a stuffed plush bunny: A case report.

An expressed and constant wish of the first author's oldest daughter to enhance interaction with her favourite toy animal led to a (re)animation/resuscitation attempt of a 1½-year-old stuffed plush bunny. Initial physical examination found no vital signs. Based on the lack of identifiable airways, we hypothesised that tissue oxygenation might be caused by passive diffusion throughout the body. Hence, animation was attempted by mechanical chest compressions without including airway management or positive-pressure ventilation. Multimodal monitoring of arterial blood pressure (by proxy), intra-'cranial' pressure and oxygen tension, near-infrared spectroscopy of the head and laser-Doppler blood flow was successfully initiated, whereas an attempt at intracranial microdialysis was unsuccessful. Despite achieving measurable arterial blood pressure (by proxy) (12/3 mmHg) and an increase of cerebral perfusion by 30 points, spontaneous circulation or diffusion was not achieved apparently, and ultimately, animation attempts were ceased. Clinical experience, as well as common sense, forces us to conclude that our measurements were contaminated by the intervention, and that we must rethink the method for the animation of stuffed plush bunnies.

Mapping physical activity patterns in hospitalised patients with moderate to severe acquired brain injury - MAP-ABI: Protocol for an observational study.

Introduction: The physical activity level in patients hospitalised for rehabilitation across multiple diagnoses is low. Moderate to severe acquired brain injury further reduces activity levels as impaired physical and cognitive functioning affect mobility independence. Therefore, supervised out-of-bed mobilisation and physical activity training are essential rehabilitation strategies. Few studies have measured the physical activity patterns in the early phases of rehabilitation after moderate to severe brain injury. Objectives: To map and quantify physical activity patterns in patients admitted to brain injury rehabilitation. Further, to investigate which factors are associated with activity and if the early physical activity level is associated with functional outcome at discharge. Methods: This observational study includes patients admitted to rehabilitation after moderate to severe acquired brain injury. Mobility and physical activity patterns are measured continuously during rehabilitation at two separate seven-day periods using a wearable activity tracker. Activity will be categorised into four levels and presented descriptively. Linear and logistic regression models will analyse associations between descriptive variables and activity levels. Discussion: This protocol describes an observational study investigating patients' mobility and physical activity patterns with moderate to severe acquired brain injury during in-hospital rehabilitation. The ability to increase the amount of mobilisation and physical activity in subgroups may have profound consequences on the rehabilitation outcome. Furthermore, data from this study may be used to inform a large variety of trials investigating physical rehabilitation interventions. (NCT05571462).

Short-Term versus Long-Term Mentalization-Based Therapy for Borderline Personality Disorder: A Randomized Clinical Trial (MBT-RCT).

INTRODUCTION: Borderline personality disorder (BPD) is a severe and prevalent psychiatric disorder. Mentalization-based therapy (MBT) is an evidence-based intervention for BPD, and several countries offer treatment programs for BPD lasting for years, which is resource demanding. No previous trial has compared short-term with long-term MBT. OBJECTIVE: The aim of the study was to assess the efficacy and safety of short-term versus long-term MBT for outpatients with BPD. METHODS: Adult outpatients (≥18 years) with subthreshold or diagnosed BPD were randomly assigned (1:1) to short-term MBT (5 months) or long-term MBT (14 months). The primary outcome was BPD symptoms assessed with the Zanarini Rating Scale for Borderline Personality Disorder. Secondary outcomes were functional impairment, quality of life, global functioning, and severe self-harm. All outcomes were primarily assessed at 16 months after randomization. This trial was prospectively registered at ClinicalTrials.gov, NCT03677037. RESULTS: Between October 4, 2018, and December 3, 2020, we randomly assigned 166 participants to short-term MBT (n = 84) or long-term MBT (n = 82). Regression analyses showed no evidence of a difference when assessing BPD symptoms (MD 0.99; 95% CI: -1.06 to 3.03; p = 0.341), level of functioning (MD 1.44; 95% CI: -1.43 to 4.32; p = 0.321), quality of life (MD -0.91; 95% CI: -4.62 to 2.79; p = 0.626), global functioning (MD -2.25; 95% CI: -6.70 to 2.20; p = 0.318), or severe self-harm (RR 1.37; 95% CI: 0.70-2.84; p = 0.335). More participants in the long-term MBT group had a serious adverse event compared with short-term MBT (RR 1.63; 95% CI: 0.94-3.07; p = 0.088), primarily driven by a difference in psychiatric hospitalizations (RR 2.03; 95% CI: 0.99-5.09; p = 0.056). CONCLUSION: Long-term MBT did not lead to lower levels of BPD symptoms, nor did it influence any of the secondary outcomes compared with short-term MBT.

Detailed statistical analysis plan for a secondary Bayesian analysis of the SafeBoosC-III trial: a multinational, randomised clinical trial assessing treatment guided by cerebral oximetry monitoring versus usual care in extremely preterm infants.

BACKGROUND: Extremely preterm infants have a high mortality and morbidity. Here, we present a statistical analysis plan for secondary Bayesian analyses of the pragmatic, sufficiently powered multinational, trial-SafeBoosC III-evaluating the benefits and harms of cerebral oximetry monitoring plus a treatment guideline versus usual care for such infants. METHODS: The SafeBoosC-III trial is an investigator-initiated, open-label, randomised, multinational, pragmatic, phase III clinical trial with a parallel-group design. The trial randomised 1601 infants, and the frequentist analyses were published in April 2023. The primary outcome is a dichotomous composite outcome of death or severe brain injury. The exploratory outcomes are major neonatal morbidities associated with neurodevelopmental impairment later in life: (1) bronchopulmonary dysplasia; (2) retinopathy of prematurity; (3) late-onset sepsis; (4) necrotising enterocolitis; and (5) number of major neonatal morbidities (count of bronchopulmonary dysplasia, retinopathy of prematurity, and severe brain injury). The primary Bayesian analyses will use non-informed priors including all plausible effects. The models will use a Hamiltonian Monte Carlo sampler with 1 chain, a sampling of 10,000, and at least 25,000 iterations for the burn-in period. In Bayesian statistics, such analyses are referred to as 'posteriors' and will be presented as point estimates with 95% credibility intervals (CrIs), encompassing the most probable results based on the data, model, and priors selected. The results will be presented as probability of any benefit or any harm, Bayes factor, and the probability of clinical important benefit or harm. Two statisticians will analyse the blinded data independently following this protocol. DISCUSSION: This statistical analysis plan presents a secondary Bayesian analysis of the SafeBoosC-III trial. The analysis and the final manuscript will be carried out and written after we publicise the primary frequentist trial report. Thus, we can interpret the findings from both the frequentists and Bayesian perspective. This approach should provide a better foundation for interpreting of our findings. TRIAL REGISTRATION: ClinicalTrials.org, NCT03770741. Registered on 10 December 2018.

Ventricular CSF proteomic profiles and predictors of surgical treatment outcome in chronic hydrocephalus.

BACKGROUND: By applying an unbiased proteomic approach, we aimed to search for cerebrospinal fluid (CSF) protein biomarkers distinguishing between obstructive and communicating hydrocephalus in order to improve appropriate surgical selection for endoscopic third ventriculostomy vs. shunt implants. Our second study purpose was to look for potential CSF biomarkers distinguishing between patients with adult chronic hydrocephalus benefitting from surgery (responders) vs. those who did not (non-responders). METHODS: Ventricular CSF samples were collected from 62 patients with communicating hydrocephalus and 28 patients with obstructive hydrocephalus. CSF was collected in relation to the patients' surgical treatment. As a control group, CSF was collected from ten patients with unruptured aneurysm undergoing preventive surgery (vascular clipping). RESULTS: Mass spectrometry-based proteomic analysis of the samples identified 1251 unique proteins. No proteins differed significantly between the communicating hydrocephalus group and the obstructive hydrocephalus group. Four proteins were found to be significantly less abundant in CSF from communicating hydrocephalus patients compared to control subjects. A PCA plot revealed similar proteomic CSF profiles of obstructive and communicating hydrocephalus and control samples. For obstructive hydrocephalus, ten proteins were found to predict responders from non-responders. CONCLUSION: Here, we show that the proteomic profile of ventricular CSF from patients with hydrocephalus differs slightly from control subjects. Furthermore, we find ten predictors of response to surgical outcome (endoscopic third ventriculostomy or ventriculo-peritoneal shunt) in patients with obstructive hydrocephalus.

Distinct Cerebrospinal Fluid Lipid Signature in Patients with Subarachnoid Hemorrhage-Induced Hydrocephalus.

Patients with subarachnoid hemorrhage (SAH) may develop posthemorrhagic hydrocephalus (PHH), which is treated with surgical cerebrospinal fluid (CSF) diversion. This diversion is associated with risk of infection and shunt failure. Biomarkers for PHH etiology, CSF dynamics disturbances, and potentially subsequent shunt dependency are therefore in demand. With the recent demonstration of lipid-mediated CSF hypersecretion contributing to PHH, exploration of the CSF lipid signature in relation to brain pathology is of interest. Despite being a relatively new addition to the omic's landscape, lipidomics are increasingly recognized as a tool for biomarker identification, as they provide a comprehensive overview of lipid profiles in biological systems. We here employ an untargeted mass spectroscopy-based platform and reveal the complete lipid profile of cisternal CSF from healthy control subjects and demonstrate its bimodal fluctuation with age. Various classes of lipids, in addition to select individual lipids, were elevated in the ventricular CSF obtained from patients with SAH during placement of an external ventricular drain. The lipidomic signature of the CSF in the patients with SAH suggests dysregulation of the lipids in the CSF in this patient group. Our data thereby reveal possible biomarkers present in a brain pathology with a hemorrhagic event, some of which could be potential future biomarkers for hypersecretion contributing to ventriculomegaly and thus pharmacological targets for pathologies involving disturbed CSF dynamics.

Posthemorrhagic Hydrocephalus in Patients with Subarachnoid Hemorrhage Occurs Independently of CSF Osmolality.

The molecular mechanisms underlying the development of posthemorrhagic hydrocephalus (PHH) remain incompletely understood. As the disease pathogenesis often cannot be attributed to visible cerebrospinal fluid (CSF) drainage obstructions, we here aimed to elucidate whether elevated CSF osmolality following subarachnoid hemorrhage (SAH) could potentiate the formation of ventricular fluid, and thereby contribute to the pathological CSF accumulation observed in PHH. The CSF osmolality was determined in 32 patients with acute SAH after external ventricular drainage (EVD) placement and again upon EVD removal and compared with the CSF osmolality from 14 healthy control subjects undergoing vascular clipping of an unruptured aneurism. However, we found no evidence of elevated CSF osmolality or electrolyte concentration in patients with SAH when compared to that of healthy control subjects. We detected no difference in CSF osmolality and electrolyte content in patients with successful EVD weaning versus those that were shunted due to PHH. Taken together, elevated CSF osmolality does not appear to underlie the development of PHH following SAH. The pathological CSF accumulation observed in this patient group must thus instead be attributed to other pathological alterations associated with the abnormal presence of blood within the CSF compartments following SAH.

Adverse events in cognitive behavioral therapy and relaxation training for children and adolescents with obsessive-compulsive disorder: A mixed methods study and analysis plan for the TECTO trial.

Background: Knowledge on adverse events in psychotherapy for youth with OCD is sparse. No official guidelines exist for defining or monitoring adverse events in psychotherapy. Recent recommendations call for more qualitative and quantitative assessment of adverse events in psychotherapy trials. This mixed methods study aims to expand knowledge on adverse events in psychotherapy for youth with OCD. Methods: This is an analysis plan for a convergent mixed methods study within a randomized clinical trial (the TECTO trial). We include at least 128 youth aged 8-17 years with obsessive-compulsive disorder (OCD). Participants are randomized to either family-based cognitive behavioral therapy (FCBT) or family-based psychoeducation and relaxation training (FPRT). Adverse events are monitored quantitatively with the Negative Effects Questionnaire. Furthermore, we assess psychiatric symptoms, global functioning, quality of life, and family factors to investigate predictors for adverse events. We conduct semi-structured qualitative interviews with all youths and their parents on their experience of adverse events in FCBT or FPRT. For the mixed methods analysis, we will merge 1) a qualitative content analysis with descriptive statistics comparing the types, frequencies, and severity of adverse events; 2) a qualitative content analysis of the perceived causes for adverse events with prediction models for adverse events; and 3) a thematic analysis of the participants' treatment evaluation with a correlational analysis of adverse events and OCD severity. Discussion: The in-depth mixed methods analysis can inform 1) safer and more effective psychotherapy for OCD; 2) instruments and guidelines for monitoring adverse events; and 3) patient information on potential adverse events. The main limitation is risk of missing data. Trial registration: ClinicalTrials.gov identifier: NCT03595098. Registered on July 23, 2018.

Nocturnal increase in cerebrospinal fluid secretion as a circadian regulator of intracranial pressure.

BACKGROUND: It is crucial to maintain the intracranial pressure (ICP) within the physiological range to ensure proper brain function. The ICP may fluctuate during the light-dark phase cycle, complicating diagnosis and treatment choice in patients with pressure-related disorders. Such ICP fluctuations may originate in circadian or sleep-wake cycle-mediated modulation of cerebrospinal fluid (CSF) flow dynamics, which in addition could support diurnal regulation of brain waste clearance. METHODS: ICP was monitored continuously in patients who underwent placement of an external ventricular drain (EVD) and by telemetric monitoring in experimental rats. CSF was collected via the EVD in patients and the rodent CSF secretion rate determined by in vivo experimentation. Rodent choroid plexus transporter transcripts were quantified with RNAseq and transport activity with ex vivo isotope transport assays. RESULTS: We demonstrated that ICP increases by 30% in the dark phase in both species, independently of vascular parameters. This increase aligns with elevated CSF collection in patients (12%) and CSF production rate in rats (20%), the latter obtained with the ventriculo-cisternal perfusion assay. The dark-phase increase in CSF secretion in rats was, in part, assigned to increased transport activity of the choroid plexus Na+,K+,2Cl- cotransporter (NKCC1), which is implicated in CSF secretion by this tissue. CONCLUSION: CSF secretion, and thus ICP, increases in the dark phase in humans and rats, irrespective of their diurnal/nocturnal activity preference, in part due to altered choroid plexus transport activity in the rat. Our findings suggest that CSF dynamics are modulated by the circadian rhythm, rather than merely sleep itself.