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Objectives While the gastrointestinal symptom cluster (GISC) is common in patients receiving chemotherapy, limited information is available on its underlying mechanism(s). Emerging evidence suggests a role for inflammatory processes through the actions of the nuclear factor kappa B (NF-κB) signaling pathway. This study evaluated for associations between a GISC and levels of DNA methylation for genes within this pathway. Methods Prior to their second or third cycle of chemotherapy, 1071 outpatients reported symptom occurrence using the Memorial Symptom Assessment Scale. A GISC was identified using exploratory factor analysis. Differential methylation analyses were performed in two independent samples using EPIC ( n = 925) and 450K ( n = 146) microarrays. Trans expression-associated CpG (eCpG) loci for 56 NF-κB signaling pathway genes were evaluated. Loci significance were assessed using an exploratory false discovery rate (FDR) of 25% for the EPIC sample. For the validation assessment using the 450K sample, significance was assessed at an unadjusted p-value of 0.05. Results For the EPIC sample, the GISC was associated with increased expression of lymphotoxin beta ( LTB) at one differentially methylated trans eCpG locus (cg03171795; FDR = 0.168). This association was not validated in the 450K sample. Conclusions This study is the first to identify an association between a GISC and epigenetic regulation of a gene that is involved in the initiation of gastrointestinal immune responses. Findings suggest that increased LTB expression by hypermethylation of a trans eCpG locus is involved in the occurrence of this cluster in patients receiving chemotherapy. LTB may be a potential therapeutic target for this common cluster.

Context Cutpoints can be used as a threshold for screening symptom(s) that warrant intervention(s) and for monitoring patients’ responses to these interventions. Objectives In a sample of oncology patients undergoing chemotherapy, study purposes were to determine the optimal cutpoints for low, moderate, and high symptom burden and determine if these cutpoints distinguished among the symptom groups in any demographic, clinical, and stress characteristics, as well as QOL outcomes. Methods Total of 1329 patients completed a modified version of the Memorial Symptom Assessment Scale (38 symptoms). Using the methodology of Serlin and colleagues, cutpoints were created using symptom occurrence rates and cancer-specific quality of life (QOL) scores. Cutpoints were validated using measures of stress and resilience and a generic measure of QOL (i.e., Medical Outcomes Study Short Form 12 (SF-12)). Results Of the 25 possible cutpoints evaluated, the optimal cutpoint, with the largest between category F statistic, was CP8,15 (Low = 0–8, Moderate = 9–15, High = 16–38 symptoms). Percentage of patients in the Low, Moderate, and High cutpoint groups were 25.3%, 36.3%, and 38.4%, respectively. Significant differences were found among the symptom burden groups in global, cancer-specific, and cumulative life stress (i.e., Low Moderate > High) scores. Conclusion Our findings provide evidence for clinically meaningful cutpoints that can be used to guide symptom assessment and management. These cutpoints may be used to establish alert thresholds for electronic monitoring of symptoms in oncology patients.

IntroductionDespite the prevalence of shunt failure in the treatment of hydrocephalus and the near-constant need for shunt revisions, there are a limited number of methods that yield quick, quantifiable measures of catheter obstruction. We developed and assessed a gravity-driven device that measures flow through ventricular catheters. The model provides neurosurgeons with a quick, simple device that can send useful data to researchers. It can also be used by researchers to quantitatively compare catheter obstruction between different models of catheters. The model was used in this study to quantitatively analyze unused ventricular catheters used in the treatment of hydrocephalus; failed hydrocephalus catheters from our catheter biorepository were also quantitatively analyzed using the same device. The mechanisms of catheter obstruction are still poorly understood, but the literature suggests that resistance to fluid flow plays a significant role.MethodsCatheters of three manufacturing companies were inserted into the benchtop model, which records time, flow rate, and pressure data using sensors. The relative resistances of catheters across six design models were evaluated. Experiments were performed to evaluate changes in the relative resistance of a catheter when the catheter’s holes were progressively closed. Relative resistance of explanted catheters from our catheter biorepository was also measured.ResultsExperimental results showed significant differences (P < 0.05) between the relative resistances of different catheter models just after being removed from their packaging. Furthermore, a trend of increasing resistance was observed in the experiments on catheters with manually plugged ventricular catheter holes. Data from five individual benchtop models were compared, and the differences in measured data between the models were found to be negligible. A significant increase (P < 0.05) in relative resistance was observed in explanted catheters.ConclusionThe current study is meant both to validate the proposed model and to examine data on differences in relative resistance among catheter models. From these experiments, we can rapidly correlate clinical patient cohorts to identify mechanisms of luminal shunt obstruction. Collecting data for predictive analyses of potential patient outcomes is an area of potential future work, assuming sufficient sample size.

OBJECTIVEThis investigation is aimed at gaining a better understanding of the factors that lead to mechanical failure of shunts used for the treatment of hydrocephalus, including shunt catheter-valve disconnection and shunt catheter fracture.METHODSTo determine the root cause of mechanical failure, the authors created a benchtop mechanical model to mimic mechanical stressors on a shunt system. To test shunt fracture, cyclical loading on the catheter-valve connection site was tested with the shunt catheter held perpendicular to the valve. Standard methods were used to secure the catheter and valves with Nurolon. These commercial systems were compared to integrated catheters and valves (manufactured as one unit). To test complete separation/disconnection of the shunt catheter and valve, a parallel displacement test was conducted using both Nurolon and silk sutures. Finally, the stiffness of the catheters was assessed. All mechanical investigations were conducted on shunts from two major shunt companies, assigned as either company A or company B.RESULTSCyclical loading experiments found that shunts from company B fractured after a mean of 4936 ± 1725 cycles (95% CI 2990–6890 cycles), while those of company A had not failed after 8000 cycles. The study of parallel displacement indicated complete disconnection of company B’s shunt catheter-valve combination using Nurolon sutures after being stretched an average 32 ± 5.68 mm (95% CI 25.6–38.4 mm), whereas company A’s did not separate using either silk or Nurolon sutures. During the stiffness experiments, the catheters of company B had statistically significantly higher stiffness of 13.23 ± 0.15 N compared to those of company A, with 6.16 ± 0.29 N (p < 0.001).CONCLUSIONSMechanical shunt failure from shunt catheter-valve disconnection or fracture is a significant cause of shunt failure. This study demonstrates, for the first time, a correlation between shunt catheters that are less mechanically stiff and those that are less likely to disconnect from the valve when outstretched and are also less likely to tear when held at an angle from the valve outlet. The authors propose an intervention to the standard of care wherein less stiff catheters are trialed to reduce disconnection.

ObjectivesImproved understanding of the stability and consistency of symptom clusters across time, symptom dimensions and cancer diagnoses will lead to refinements in symptom assessments and management, and provide direction for mechanistic studies. Study purposes were to describe the occurrence, severity and distress of 38 symptoms; evaluate the stability and consistency of symptom clusters across a cycle of chemotherapy, three symptom dimensions and four distinct cancer types; and identify common and distinct symptom clusters.MethodsOncology outpatients (n=1329) completed the Memorial Symptom Assessment Scale prior to their next cycle of chemotherapy (T1), 1 week after chemotherapy (T2) and 2 weeks after chemotherapy (T3). Symptom clusters were identified using exploratory factor analysis using unweighted least squares. GEOMIN rotated factor loadings with absolute values ≥0.40 were considered meaningful. Clusters were stable if they were identified across each time point and/or dimension. Clusters were consistent if the same two or three symptoms with the highest factor loadings were identified across each time point and/or dimension.ResultsPatients reported 13.9 (±7.2) symptoms at T1, 14.0 (±7.0) at T2 and 12.2 (±6.8) at T3. Psychological, weight gain, gastrointestinal and respiratory clusters were stable across time and dimensions. Only the psychological, weight gain and respiratory clusters were consistent across time and dimensions.ConclusionGiven the stability of the psychological, weight gain and gastrointestinal clusters across cancer diagnoses, symptoms within these clusters need to be routinely assessed. However, respiratory and hormonal clusters are unique to specific cancer types and the symptoms within these clusters are variable.

The breakdown of the ventricular zone (VZ) with the presence of blood in cerebrospinal fluid (CSF) has been shown to increase shunt catheter obstruction in the treatment of hydrocephalus, but the mechanisms by which this occurs are generally unknown. Using a custom-built incubation chamber, we immunofluorescently assayed cell attachment and morphology on shunt catheters with and without blood after 14 days. Samples exposed to blood showed significantly increased cell attachment (average total cell count 392.0±317.1 versus control of 94.7±44.5, P

Background Pediatric hydrocephalus is a devastating and costly disease. The mainstay of treatment is still surgical shunting of cerebrospinal fluid (CSF). These shunts fail at a high rate and impose a significant burden on patients, their families and society. The relationship between clinical decision making and shunt failure is poorly understood and multifaceted, but catheter occlusion remains the most frequent cause of shunt complications. In order to investigate factors that affect shunt failure, we have established the Wayne State University (WSU) shunt biobank. Methods To date, four hospital centers have contributed various components of failed shunts and CSF from patients diagnosed with hydrocephalus before adulthood. The hardware samples are transported in paraformaldehyde and transferred to phosphate-buffered saline with sodium azide upon deposit into the biobank. Once in the bank, they are then available for study. Informed consent is obtained by the local center before corresponding clinical data are entered into a REDCap database. Data such as hydrocephalus etiology and details of shunt revision history. All data are entered under a coded identifier. Results 293 shunt samples were collected from 228 pediatric patients starting from May 2015 to September 2019. We saw a significant difference in the number of revisions per patient between centers (Kruskal–Wallis H test, p value Conclusion The retrospective analysis identified that differences exist between currently enrolled centers, although further work is needed before clinically actionable recommendations can be made. Moreover, the variables collected from this chart review explain a meaningful amount of variance in the number of revision surgeries. Future work will expand on the contribution of different site-specific and patient-specific factors to identify potential cause and effect relationships.

Bioreactors have become a critical step for the testing of new biomaterials and pharmaceuticals. They need to be controllable, ideally high-throughput, and produce a biologically relevant environment. For example, in the brain, it is essential to recreate multiple flow–pressure profiles daily and mimic brain fluid movement for a bioreactor to be more physiologic. In this study, we demonstrate a scalable system that regulates flow rate, pressure, and pulsation amplitude. We also show that with new microcontroller technology, up to 15 chambers running in parallel is theoretically possible. Our system, the Flow Limiting Operator (FLO), achieves these goals by multiplexing a series of valves and pumps to control pressure and volumetric flow rate instead of relying on head gas pressure. With the ability to control multiple parameters and its ease of use, both scientists and clinicians can use FLO to study the effects of pulsation amplitude of the fluid flow, flow rate, and pressure on intercellular interactions for both biomaterials and pharmaceuticals.

Background The flow of physiologic fluids through organs and organs systems is an integral component of their function. The complex fluid dynamics in many organ systems are still not completely understood, and in-vivo measurements of flow rates and pressure provide a testament to the complexity of each flow system. Variability in in-vivo measurements and the lack of control over flow characteristics leave a lot to be desired for testing and evaluation of current modes of treatments as well as future innovations. In-vitro models are particularly ideal for studying neurological conditions such as hydrocephalus due to their complex pathophysiology and interactions with therapeutic measures. The following aims to present the reciprocating positive displacement pump, capable of inducing pulsating flow of a defined volume at a controlled beat rate and amplitude. While the other fluidic applications of the pump are currently under investigation, this study was focused on simulating the pulsating cerebrospinal fluid production across profiles with varying parameters. Methods Pumps were manufactured using 3D printed and injection molded parts. The pumps were powered by an Arduino-based board and proprietary software that controls the linear motion of the pumps to achieve the specified output rate at the desired pulsation rate and amplitude. A range of 0.01 mlmin to 0.7 mlmin was tested to evaluate the versatility of the pumps. The accuracy and precision of the pumps’ output were evaluated by obtaining a total of 150 one-minute weight measurements of degassed deionized water per output rate across 15 pump channels. In addition, nine experiments were performed to evaluate the pumps’ control over pulsation rate and amplitude. Results Volumetric analysis of a total of 1200 readings determined that the pumps achieved the target output volume rate with a mean absolute error of -0.001034283 mlmin across the specified domain. It was also determined that the pumps can maintain pulsatile flow at a user-specified beat rate and amplitude. Conclusion The validation of this reciprocating positive displacement pump system allows for the future validation of novel designs to components used to treat hydrocephalus and other physiologic models involving pulsatile flow. Based on the promising results of these experiments at simulating pulsatile CSF flow, a benchtop model of human CSF production and distribution could be achieved through the incorporation of a chamber system and a compliance component.

Understanding the composition characteristics of the glial scar contributing to the high failure rate of neuroprosthetic devices implanted in the brain has been limited, to date, with the evaluation of cells, tissue, and biomarkers obstructing the implant. However, there remains a critical knowledge gap in gene expression profiles of the obstructing cells. This first-time study investigates the phenotypic expression specific to astrocyte scarring from those cells on hydrocephalus shunt surfaces at the time of failure, aimed at the development of therapeutic approaches to target reactive astrocytes for improved functional outcome. Recent evidence has indicated that the tissue obstructing shunts is over 80% inflammatory, with a more exaggerated astrocytic response. To understand how to mitigate the astrocyte immune response to shunts, we performed gene expression profiling of the C3 and EMP1 genes to quantify if astrocytes were classically activated and pro-inflammatory (A1) or alternatively activated and anti-inflammatory (A2), respectively. Shunt catheters were removed from patients at the time of failure and categorized by obstructed vs non-obstructed shunts. RNAscope fluorescent in situ hybridization and quantitative PCR analysis of the C3 and EMP1 expressed genes revealed that a heterogeneous mixed population of both the A1 and A2 reactive phenotype exist on the shunt surface. However, the number of A2 reactive astrocytes are significantly higher on obstructed shunts compared to A1 reactive astrocytes. ELISA data also confirmed higher levels of IL-6 for obstructed shunts involved in A2 reactive astrocyte proliferation and glial scar formation on the shunt surface. Since TNF-α and IL-1β propel resting astrocytes into an A2 reactive state, by simply blocking the secretion or action of these cytokines, astrocyte activation and attachment on obstructing shunts could be inhibited.

Background Many animal models have been used to study the pathophysiology of hydrocephalus; most of these have been rodent models whose lissencephalic cerebral cortex may not respond to ventriculomegaly in the same way as gyrencephalic species and whose size is not amenable to evaluation of clinically relevant neurosurgical treatments. Fewer models of hydrocephalus in gyrencephalic species have been used; thus, we have expanded upon a porcine model of hydrocephalus in juvenile pigs and used it to explore surgical treatment methods. Methods Acquired hydrocephalus was induced in 33–41-day old pigs by percutaneous intracisternal injections of kaolin (n = 17). Controls consisted of sham saline-injected (n = 6) and intact (n = 4) animals. Magnetic resonance imaging (MRI) was employed to evaluate ventriculomegaly at 11–42 days post-kaolin and to plan the surgical implantation of ventriculoperitoneal shunts at 14–38-days post-kaolin. Behavioral and neurological status were assessed. Results Bilateral ventriculomegaly occurred post-induction in all regions of the cerebral ventricles, with prominent CSF flow voids in the third ventricle, foramina of Monro, and cerebral aqueduct. Kaolin deposits formed a solid cast in the basal cisterns but the cisterna magna was patent. In 17 untreated hydrocephalic animals. Mean total ventricular volume was 8898 ± 5917 SD mm3 at 11–43 days of age, which was significantly larger than the baseline values of 2251 ± 194 SD mm3 for 6 sham controls aged 45–55 days, (p Conclusions Kaolin induction of acquired hydrocephalus in juvenile pigs produced an in vivo model that is highly translational, allowing systematic studies of the pathophysiology and clinical treatment of hydrocephalus.

The breakdown of the ventricular zone (VZ) with the presence of blood in cerebrospinal fluid (CSF) has been shown to increase shunt catheter obstruction in the treatment of hydrocephalus, but the mechanisms by which this occurs are generally unknown. Using a custom-built incubation chamber, we immunofluorescently assayed cell attachment and morphology on shunt catheters with and without blood after 14 days. Samples exposed to blood showed significantly increased cell attachment (average total cell count 392.0±317.1 versus control of 94.7±44.5, P

Background and purposeSince 2001, symptom cluster research has grown considerably. However, because multiple methodological considerations remain, ongoing synthesis of the literature is needed to identify gaps in this area of symptom science. This systematic review evaluated the progress in symptom clusters research in adults receiving primary or adjuvant chemotherapy since 2016.MethodsEligible studies were published in English between 1 January 2017 and 17 May 2021; evaluated for and identified symptom clusters ‘de novo;’ and included only adults being treated with primary or adjuvant chemotherapy. Studies were excluded if patients had advanced cancer or were receiving palliative chemotherapy; symptoms were measured after treatment; symptom clusters were pre-specified or a patient-centred analytic approach was used. For each study, symptom instrument(s); statistical methods and symptom dimension(s) used to create the clusters; whether symptoms were allowed to load on more than one factor; method used to assess for stability of symptom clusters and associations with secondary outcomes and biomarkers were extracted.ResultsTwenty-three studies were included. Memorial Symptom Assessment Scale was the most common instrument and exploratory factor analysis was the most common statistical method used to identify symptom clusters. Psychological, gastrointestinal, and nutritional clusters were the most commonly identified clusters. Only the psychological cluster remained relatively stable over time. Only five studies evaluated for secondary outcomes.DiscussionWhile symptom cluster research has evolved, clear criteria to evaluate the stability of symptom clusters and standardised nomenclature for naming clusters are needed. Additional research is needed to evaluate the biological mechanism(s) for symptom clusters.PROSPERO registration numberCRD42021240216.

Purpose In a sample of oncology patients, identify subgroups of patients with distinct depressive symptom profiles and evaluate for differences in demographic and clinical characteristics, levels of stress and resilience, and the severity of common co-occurring symptoms. Methods Patients (n=1327) had a diagnosis of breast, gastrointestinal, gynecological, or lung cancer; had received chemotherapy within the preceding four weeks; and were scheduled to receive at least two additional cycles of chemotherapy. Demographic and clinical characteristics, stress, resilience, and co-occurring symptoms were evaluated at enrollment. Depressive symptoms were evaluated using the Center for Epidemiological Studies-Depression (CES-D) scale a total of six times over two cycles of chemotherapy. Latent profile analysis (LPA) was used to identify subgroups of patients (i.e., latent classes) with distinct depressive symptom profiles using the six CES-D scores. Results Based on the findings from the LPA, 47.3% of the patients were classified as “None”; 33.6% as “Subsyndromal”; 13.8% as “Moderate”; and 5.3% as “High”. Compared to None class, patients in the Subsyndromal, Moderate, and High classes had a lower functional status, a higher comorbidity burden, and a self-reported diagnosis of depression or back pain. Those patients with higher levels of depressive symptoms reported higher levels of stress, lower levels of resilience, and increased severity of co-occurring symptoms. Conclusions Inter-individual variability in depressive symptoms was associated with demographic and clinical characteristics, multiple types of stress and levels of resilience, as well as with the increased severity of multiple co-occurring symptoms. The risk factors associated with worse depressive symptom profiles can assist clinicians to identify high risk patients and initiate more timely supportive care interventions.

The purposes of this study, in a sample of oncology patients (n = 1326) receiving chemotherapy, were to identify subgroups of patients with distinct anxiety profiles and evaluate for differences in demographic and clinical characteristics, stress and resilience measures, and severity of co-occurring symptoms (i.e., depression, sleep disturbance, attentional function, fatigue, pain).Patients completed self-report questionnaires a total of six times over two cycles of chemotherapy. Severity of state anxiety was evaluated using the Spielberger State Anxiety Inventory and resilience was assessed using the Connor-Davidson Resilience Scale. Symptoms were assessed using the Center for Epidemiologic Studies Depression Scale, General Sleep Disturbance Scale, Lee Fatigue Scale, Attentional Function Index and Brief Pain Inventory.Based on the findings from the latent profile analysis that utilized the six assessments of state anxiety, 47.7% of the patients were classified as "Low," 28.3% as "Moderate," 19.5% as "High," and 4.5.% as "Very High." Anxiety levels remained relatively stable across the six timepoints. Compared to the Low class, membership in the Moderate, High, and Very High classes was associated with a number of characteristics (e.g., younger age, female gender, lower functional status, more comorbidities). Those patients with higher levels of anxiety reported higher levels of stress, lower levels of resilience, and increased severity of co-occurring symptoms.Our findings suggest that a substantial number of oncology patients may warrant referral to psychological services. Clinicians need to perform systematic assessments of anxiety, stress, and common symptoms and initiate appropriate interventions to enhance resilience and coping.

Little is known about the associations between pain, stress, and co-occurring symptoms in oncology patients. Purpose was to identify subgroups of patients with distinct worst pain profiles and evaluate for differences among the subgroups in demographic and clinical characteristics, as well as stress and symptom scores. Oncology outpatients (n = 1305) completed questionnaires prior to their second or third chemotherapy cycle. Worst pain intensity was assessed 6 times over 2 chemotherapy cycles using a 0 to 10 numeric rating scale. The 371 patients (28.4%) who had ≤1 occurrence of pain over the 6 assessments were classified as the None class. For the remaining 934 patients whose data were entered into the latent profile analysis, 3 distinct worst pain profiles were identified (ie Mild [12.5%], Moderate [28.6%], Severe [30.5%]). Compared to None class, Severe class had fewer years of education and a lower annual income; were less likely to be employed and married; less likely to exercise on a regular basis, had a higher comorbidity burden, and a worse functional status. Compared to None class, Severe class reported higher levels of general, disease-specific, and cumulative life stress and lower levels of resilience, as well as higher levels of depressive symptoms, anxiety, fatigue, sleep disturbance, and cognitive dysfunction. This study is the first to identify distinct worst pain profiles in a large sample of oncology patients receiving chemotherapy and associated risk factors. Perspective Unrelieved pain remains a significant problem for oncology patients receiving chemotherapy. High levels of stress and co-occurring symptoms contribute to a more severe pain profile in these patients.

Background Implantation of ventricular catheters (VCs) to drain cerebrospinal fluid (CSF) is a standard approach to treat hydrocephalus. VCs fail frequently due to tissue obstructing the lumen via the drainage holes. Mechanisms driving obstruction are poorly understood. This study aimed to characterize the histological features of VC obstructions and identify links to clinical factors. Methods 343 VCs with relevant clinical data were collected from five centers. Each hole on the VCs was classified by degree of tissue obstruction after macroscopic analysis. A subgroup of 54 samples was analyzed using immunofluorescent labelling, histology and immunohistochemistry. Results 61.5% of the 343 VCs analyzed had tissue aggregates occluding at least one hole (n = 211) however the vast majority of the holes (70%) showed no tissue aggregates. Mean age at which patients with occluded VCs had their first surgeries (3.25 yrs) was lower than in patients with non-occluded VCs (5.29 yrs, p Conclusion Our data show that age of the first surgery and length of time a VC is implanted are factors that influence the degree of VC obstruction. The tissue aggregates obstructing VCs are composed predominantly of astrocytes and macrophages; microglia have a relatively small presence.

The incorporation of omics approaches into symptom science research can provide researchers with information about the molecular mechanisms that underlie symptoms. Most of the omics analyses in symptom science have used a single omics approach. Therefore, these analyses are limited by the information contained within a specific omics domain (e.g., genomics and inherited variations, transcriptomics and gene function). A multi-staged data-integrated multi-omics (MS-DIMO) analysis integrates multiple types of omics data in a single study. With this integration, a MS-DIMO analysis can provide a more comprehensive picture of the complex biological mechanisms that underlie symptoms. The results of a MS-DIMO analysis can be used to refine mechanistic hypotheses and/or discover therapeutic targets for specific symptoms. The purposes of this paper are to: (1) describe a MS-DIMO analysis using “Symptom X” as an example; (2) discuss a number of challenges associated with specific omics analyses and how a MS-DIMO analysis can address them; (3) describe the various orders of omics data that can be used in a MS-DIMO analysis; (4) describe omics analysis tools; and (5) review case exemplars of MS-DIMO analyses in symptom science. This paper provides information on how a MS-DIMO analysis can strengthen symptom science research through the prioritization of functional genes and biological processes associated with a specific symptom.

A major cause of hydrocephalus shunt failure is cell adhesion and obstruction of shunt catheter holes. An estimated 50% of pediatric shunts fail in the first 2 years of insertion, decreasing cell attachment and catheter obstruction can prolong the lifetime and effectiveness of the device. From previous studies, it was shown that treatment of the polydimethylsiloxane (PDMS) surface of a standard catheter with an N-acetyl-cysteine (NAC/1-ethyl-3-(3-dimethylanimopropyl)carbodiimide hydrochloride/N-hydroxysuccinimide) layer increases the wettability of the surface and has been shown to decrease cell adhesion. Other studies indicate that NAC's antioxidant behavior induces glutathione and in turn modulates cell inflammatory pathways. The current study explores the longevity of the NAC coating from the surface of the catheter over time and shows its effect on valve function. Using SEM imaging, contact angle testing, and nanodrop spectrophotometry, this release was quantified for shunt samples incubated for 0, 10, 30, 60, and 90 days. Contact angle showed a significant increase in wettability of the surface when shunts were treated with NAC, confirming successful surface modification. Pressure assays determined that if the coating is release it had no detrimental downstream effects, such as on the shunt valve mechanism. SEM imaging revealed slight deformations in surface coating indicative of salt deposition on the modified shunt samples, while nanodrop spectrophotometry and contact angle data trends suggested some discharge of the NAC coating from the catheter surfaces. The effects of NAC on cell activity may transform the way hydrocephalus is treated in the future by increasing the longevity of the shunt to protect from obstruction.

To test which intracerebral hemorrhage (ICH) characteristics impact incidence of hydrocephalus and characterize subsequent impact on outcomes.A search of the electronic medical record of Sinai Grace Hospital between January 2009 and April 2018 using International Classification of Diseases, Ninth Revision and Tenth Revision codes for ICH identified 847 patients. After excluding patients with hemorrhagic conversion of stroke, subarachnoid hemorrhage, and traumatic hemorrhage, 560 patients remained for analysis. Generalized linear modeling was used to assess variance in modified Rankin Scale (mRS) score and length of stay.Incidence of hydrocephalus on arrival varied with ICH volume (P0.001), intraventricular hemorrhage (IVH) status (P0.001), bleed location (P0.001), and external ventricular drain (EVD) status (P0.001). An EVD was inserted in 47% of patients presenting with IVH (n = 102/217), while 4% of patients without IVH received an EVD (n = 14/343) (P0.001). Hemorrhage locations had different rates of EVD placement: thalamic 43%, basal ganglia 22%, cerebellar 28%, brainstem 21%, lobar 7% (P0.001). Shunt dependency did not vary between bleed locations (P = 0.072). Variance in mRS score was explained by IVH, bleed location, hydrocephalus on arrival, and ICH volumes. In particular, cerebellar hemorrhage location was associated with better outcomes (mean discharge mRS score of 3.3 vs. 3.9, P0.001).Bleed characteristics affect incidence of hydrocephalus on admission, rates of long-term shunt dependency, and outcomes. Hemorrhage location did not predict shunt dependency; however, it did predict outcomes. Specifically, cerebellar ICH was associated with a better discharge mRS score.

COVID-19 is an acute respiratory tract infection caused by a coronavirus known as SARS-CoV-2. The common signs of infection include respiratory symptoms such as shortness of breath, breathing difficulties, dry cough, fever, and in some patients, severe acute respiratory syndrome, kidney failure, and death. 312,009 deaths from COVID-19 has been reported as of today. While respiratory symptoms are commonly caused by the infection, the use of mechanical ventilation is required for some patients. The following is intended to review the development and testing of a 3D printed and open-source mechanical ventilation device that is capable of adjusting breathing rate, volume, and pressure simultaneously and was designed according to the latest clinical observations of the current pandemic. The intuitive design of this device along with the use of primarily 3D printed or readily available components allow the rapid manufacturing and transportation of this ventilation device to the impacted regions.

Background Pediatric hydrocephalus is a devastating and costly disease. The mainstay of treatment is still surgical shunting of cerebrospinal fluid (CSF). These shunts fail at a high rate and impose a significant burden on patients, their families and society. The relationship between clinical decision making and shunt failure is poorly understood and multifaceted, but catheter occlusion remains the most frequent cause of shunt complications. In order to investigate factors that affect shunt failure, we have established the Wayne State University (WSU) shunt biobank.Methods To date, six hospital centers have contributed various components of failed shunts and CSF from patients diagnosed with hydrocephalus at a young age. The hardware samples are transported in paraformaldehyde and transferred to phosphate-buffered saline with sodium azide upon deposit into the biobank. Once in the bank, they are then available for study. Informed consent is obtained by the local center before corresponding clinical data are entered into a REDCap database. All data are entered under a coded identifier. Collaborators may then correlate biologic findings against the clinical database.Results 295 shunt samples were collected from 228 patients starting from May 2015 to September 2019. Patients with multiple samples in the bank provide a unique opportunity to study longitudinal changes in disease. With the clinical data alone, we saw a significant difference in the number of revisions per patient between centers (Kruskal-Wallis H test, p-value= 0.000022). There was no significant difference between the distributions of hydrocephalus etiologies between centers, and the leading etiology at all centers was post-hemorrhagic hydrocephalus.Conclusion Hospital center and patient recruitment for the biobank is ongoing. The biobank will yield insights for future collaborators, allow centers to benchmark their performance, and offer a unique-longitudinal perspective on the pathology of this lifelong condition. Future work will expand on the contribution of different site-specific and patient-specific factors to identify potential cause and effect relationships.

OBJECTIVEHydrocephalus affects approximately 1 in 500 people in the US, yet ventricular shunting, the gold standard of treatment, has a nearly 85% failure rate. Endoscopic third ventriculostomy (ETV) is an alternative surgical approach for a specific subset of hydrocephalic patients, but can be limited by the inability of neurosurgical residents to practice prior to patient contact. The goal of this study was to create an affordable ETV model and endoscope for resident training.METHODSOpen-source software was used to isolate the skull and brain from the CT and MR images of a 2-year-old boy with hydrocephalus. A 3D printer created the skull and a 3D mold of the brain. A mixture of silicone and silicone tactile mutator was used to cast the brain mold prior to subsequent compression and shearing modulus testing. A mimetic endoscope was then created from basic supplies and a 3D printed frame. A small cohort of neurosurgical residents and attending physicians evaluated the ETV simulator with mimetic endoscope.RESULTSThe authors successfully created a mimetic endoscope and ETV simulator. After compression and shearing modulus testing, a silicone/Slacker ratio between 10:6 and 10:7 was found to be similar to that of human brain parenchyma. Eighty-seven percent of participants strongly agreed that the simulator was useful for resident training, and 93% strongly agreed that the simulator helped them understand how to orient themselves with the endoscope.CONCLUSIONSThe authors created an affordable (US$123, excluding 3D printer), easy-to-use ETV simulator with endoscope. Previous models have required expensive software and costly operative endoscopes that may not be available to most residents. Instead, this attempt takes advantage of open-source software for the manipulation and fabrication of a patient-specific mold. This model can assist with resident development, allowing them to safely practice use of the endoscope in ETV.

Cancer-related cognitive impairment (CRCI) is a significant problem for patients receiving chemotherapy. While a growing amount of pre-clinical and clinical evidence suggests that inflammatory mechanisms underlie CRCI, no clinical studies have evaluated for associations between CRCI and changes in gene expression. Therefore, the purpose of this study was to evaluate for differentially expressed genes and perturbed inflammatory pathways across two independent samples of patients with cancer who did and did not report CRCI. The Attentional Function Index (AFI) was the self-report measure used to assess CRCI. AFI scores of5 and of7.5 indicate low versus high levels of cognitive function, respectively. Of the 185 patients in Sample 1, 49.2% had an AFI score of5 and 50.8% had an AFI score of7.5. Of the 158 patients in Sample 2, 50.6% had an AFI score of5 and 49.4% had an AFI score of7.5. Data from 182 patients in Sample 1 were analyzed using RNA-seq. Data from 158 patients in Sample 2 were analyzed using microarray. Twelve KEGG signaling pathways were significantly perturbed between the AFI groups, five of which were signaling pathways related to inflammatory mechanisms (e.g., cytokine-cytokine receptor interaction, tumor necrosis factor signaling). This study is the first to describe perturbations in inflammatory pathways associated with CRCI. Findings highlight the role of cytokines both in terms of cytokine-specific pathways, as well as pathways involved in cytokine production and cytokine activation. These findings have the potential to identify new targets for therapeutics and lead to the development of interventions to improve cognition in patients with cancer.

Highlights • Recognize patients with previous surgeries, especially those involving subcutaneous implants. • Distal shunt catheters must be passed around potential spaces to avoid coiling leading to shunt malfunction. • Note that if a peritoneal catheter does not pass easily a different approach should be considered., Introduction Hydrocephalus is one of the most common disorders of neurosurgery and ventricular shunting, the primary surgical intervention, malfunctions in 85% of patients by 10 years. Presentation of case Here we present a case of a 12-year-old girl with history of a vagal nerve stimulator (VNS) and ventricular shunt, most recently revised from ventriculoatrial (VA) to ventriculoperitoneal (VP) shunt at an outside hospital. The patient presented with a new left chest bulge, nausea, emesis, and seizures. Imaging revealed the patient’s distal shunt catheter to have completely migrated and coiled into the VNS subcutaneous pocket. Subsequently, the patient’s distal shunt catheter was externalized, and later internalized back to a VA shunt. Discussion Potential spaces from previous surgeries such as VNS can lead to coiling of distal shunt catheters. In this case, the coiled distal shunt catheter led to hydrocephalus and the patient’s presenting symptoms. Conclusion It is imperative to recognize patients with previous surgeries, especially those involving subcutaneous implants and to avoid passing of distal shunt catheters through these potential spaces.

Although cerebrospinal fluid (CSF) shunt placement is the most common procedure performed by pediatric neurosurgeons, shunts remain among the most failure-prone life-sustaining medical devices implanted in modern medical practice. This article provides an overview of the mechanisms of CSF shunt failure for the 3 most commonly employed definitive CSF shunts in the practice of pediatric neurosurgery: ventriculoperitoneal, ventriculopleural, and ventriculoatrial. The text has been partitioned into the broad modes of shunt failure: obstruction, infection, mechanical shunt failure, overdrainage, and distal catheter site-specific failures. Clinical management strategies for the various modes of shunt failure are discussed as are research efforts directed towards reducing shunt complication rates. As it is unlikely that CSF shunting will become an obsolete procedure in the foreseeable future, it is incumbent on the pediatric neurosurgery community to maintain focused efforts to improve our understanding of and management strategies for shunt failure and shunt-related morbidity.

Grand Duke Michael (Mikhail) Aleksandrovich, the youngest brother of Tsar Nicholas II, usually receives a passing mention in histories of the Russian Revolutions of 1917. When Nicholas II abdicated...

Idiopathic normal pressure hydrocephalus (iNPH) is a subtype of hydrocephalus that occurs more often in the elderly population. It is usually characterized by gait disturbance, dementia and urinary incontinence. Epidemiological studies indicate that 15.7–17.8% of iNPH patients present with type-2 diabetes mellitus (DM). A review of the primary literature shows that these occurrence rates are higher than age- and cohort-matched non-iNPH controls. This suggests that this already vulnerable patient group has an increased risk for presenting with DM compared to their non-iNPH counterparts. Postoperative outcome when treating iNPH patients is inversely related to the number of patient comorbidities and a lower comorbidity status is correlated with better outcomes. This review highlights the need for further research into the relationship between iNPH and DM and speculates on a possible mechanism for an association between the development of ventriculomegaly and the development of DM and iNPH.

Review of Richard Meyer Forsting, Raising Heirs to the Throne in Nineteenth Century Spain: The Education of the Constitutional Monarch (Cham: Palgrave Macmillan, 2018).

OBJECTIVE Shunt obstruction by cells and/or tissue is the most common cause of shunt failure. Ventricular catheter obstruction alone accounts for more than 50% of shunt failures in pediatric patients. The authors sought to systematically collect explanted ventricular catheters from the Seattle Children's Hospital with a focus on elucidating the cellular mechanisms underlying obstruction. METHODS In the operating room, explanted hardware was placed in 4% paraformaldehyde. Weekly, samples were transferred to buffer solution and stored at 4°C. After consent was obtained for their use, catheters were labeled using cell-specific markers for astrocytes (glial fibrillary acidic protein), microglia (ionized calcium-binding adapter molecule 1), and choroid plexus (transthyretin) in conjunction with a nuclear stain (Hoechst). Catheters were mounted in custom polycarbonate imaging chambers. Three-dimensional, multispectral, spinning-disk confocal microscopy was used to image catheter cerebrospinal fluid–intake holes (10× objective, 499.2-μm-thick z-stack, 2.4-μm step size, Olympus IX81 inverted microscope with motorized stage and charge-coupled device camera). Values are reported as the mean ± standard error of the mean and were compared using a 2-tailed Mann-Whitney U-test. Significance was defined at p < 0.05. RESULTS Thirty-six ventricular catheters have been imaged to date, resulting in the following observations: 1) Astrocytes and microglia are the dominant cell types bound directly to catheter surfaces; 2) cellular binding to catheters is ubiquitous even if no grossly visible tissue is apparent; and 3) immunohistochemical techniques are of limited utility when a catheter has been exposed to Bugbee wire electrocautery. Statistical analysis of 24 catheters was performed, after excluding 7 catheters exposed to Bugbee wire cautery, 3 that were poorly fixed, and 2 that demonstrated pronounced autofluorescence. This analysis revealed that catheters with a microglia-dominant cellular response tended to be implanted for shorter durations (24.7 ± 6.7 days) than those with an astrocyte-dominant response (1183 ± 642 days; p = 0.027). CONCLUSIONS Ventricular catheter occlusion remains a significant source of shunt morbidity in the pediatric population, and given their ability to intimately associate with catheter surfaces, astrocytes and microglia appear to be critical to this pathophysiology. Microglia tend to be the dominant cell type on catheters implanted for less than 2 months, while astrocytes tend to be the most prevalent cell type on catheters implanted for longer time courses and are noted to serve as an interface for the secondary attachment of ependymal cells and choroid plexus.

CONTEXT: By occluding the fourth ventricle simultaneously obtaining telemetric data on intracranial pressure (ICP) and cerebrospinal fluid (CSF) production, the authors of this study investigate a variety of physiologic parameters in cases of experimental hydrocephalus. AIMS: The aim of this study is to provide a new context on the disrupted homeostasis in hydrocephalus and guide toward improved treatment based on multiple physiological parameters. MATERIALS AND METHODS: Hydrocephalus was induced in ten 21-day-old Sprague–Dawley rats by blocking the flow of CSF to the fourth ventricle with kaolin. Ten days post induction, when physical signs of ventriculomegaly reached Evan's ratio (ER) of ≥0.46, CSF flow and ICP were measured while manipulating body position (0°, 45°, 90°) and heart rate. RESULTS: In hydrocephalic animals (ER ≥0.46), we found a near-steady average acute ICP (13.638 ± 2.331) compared to age-matched controls (ER

Perhaps one of the most intriguing events in neurosurgical history is the invention and use of the shunt system to treat hydrocephalus, despite the shunt’s high failure rates. The shunt system, classically composed of a proximal catheter, valve, and distal catheter, was developed in the 1950s. The system was envisioned by John Holter, a toolmaker, whose son, Casey, had hydrocephalus. The concept, modeled after the nipple of a baby bottle, allowed for one-way flow through a pressure-regulated valve. The shunt system could take advantage of surgical aseptic technique (1860s), and followed historical predecessors: the external ventricular drain (1881), and ventricular-subdural shunts made of glass wool, gold tubes, bundled catgut (1890s), rubber (1903), glass, silver, and linen threads (1908–1926). Catheters from the ventricles to the cisterna magna and Nulsen-Spitz’s ventriculo-jugular shunt were revolutionary precursors made of rubber or polyethylene (1940–1950) [1]. The Spitz–Holter valve is the result of these efforts and that of John Holter. The modern-day shunt remains similar now as when it was created (1955, implanted in 1957/58): slight modifications to the catheter, major iterations to the shunt valve, and the addition of compensators for gravity and siphoning are key components to treatment.

Topic Significance & Study Purpose/Background/Rationale An inpatient hematology unit at a NCCN designated cancer center experienced a dramatic increase in patients receiving a chimeric antigen receptor (CAR) T-cell therapy in 2018. Neurologic toxicity at any grade is observed in most patients receiving a CAR T-cell therapy, with more than 58% of patients who received Kymriah™ (1) and 87% of patients who received Yescarta® (2). Although nursing staff was completing a neurologic assessment each shift to identify neurologic toxicity, the assessment and documentation by each nurse varied considerably. Nurses were also having difficulty identifying clear and concrete assessment changes to report to physicians. As the neurologic changes observed in this population can initially be subtle, a tool to accurately and consistently identify changes is vital. A request was made by nursing leadership in May 2018 to create a standardized neurological assessment for patients receiving a CAR T-cell therapy. Methods, Intervention, & Analysis Unit leadership and the unit based practice council collaborated to create a standardized CAR T-cell neurotoxicity assessment tool for nurses. A review of the literature was completed, and the CAR T-cell therapy associated TOXicity (CARTOX) 10-point neurological assessment tool was reviewed. An adapted version of the CARTOX-10 was agreed upon by unit staff, nursing leadership and the CAR T-cell working group. The final version consists of a verbal and writing assessment. The UBPC is presently in the process of educating all nursing staff on how to complete this tool and notify physicians when changes are assessed. Staff are educated during staff huddles, shift handoff, staff meetings, and can view literature on a unit education board. Findings & Interpretation While the implementation of this new tool is currently ongoing, the feedback from nursing staff has been positive and the reception from patients and caregivers has been enthusiastic. Discussion & Implications Implementing a practice change must be interdisciplinary and requires close collaboration amongst frontline nurses, nursing leadership, and physicians. As nursing practice becomes standardized with the development and implementation of this neurotoxicity assessment, we will assess nurse's perception of its feasibility in practice. An accurate neurologic assessment in CAR T-cell recipients is vital and we will validate its effectiveness in identifying neurologic conditions that warrant intervention. 1. Novartis Pharmaceuticals Corporation. (2018). Kymriah™ (tisagenlecleucel) [Package Insert]. East Hanover, NJ: Author. 2. Kite Pharma Inc. (2017). Yescarta® (axicabtagene ciloleucel) [Package Insert]. Santa Monica, CA: Author.

Motivation: The arbor morphologies of brain microglia are important indicators of cell activation. This article fills the need for accurate, robust, adaptive and scalable methods for reconstructing 3-D microglial arbors and quantitatively mapping microglia activation states over extended brain tissue regions. Results: Thick rat brain sections (100–300 µm) were multiplex immunolabeled for IBA1 and Hoechst, and imaged by step-and-image confocal microscopy with automated 3-D image mosaicing, producing seamless images of extended brain regions (e.g. 5903 × 9874 × 229 voxels). An over-complete dictionary-based model was learned for the image-specific local structure of microglial processes. The microglial arbors were reconstructed seamlessly using an automated and scalable algorithm that exploits microglia-specific constraints. This method detected 80.1 and 92.8% more centered arbor points, and 53.5 and 55.5% fewer spurious points than existing vesselness and LoG-based methods, respectively, and the traces were 13.1 and 15.5% more accurate based on the DIADEM metric. The arbor morphologies were quantified using Scorcioni’s L-measure. Coifman’s harmonic co-clustering revealed four morphologically distinct classes that concord with known microglia activation patterns. This enabled us to map spatial distributions of microglial activation and cell abundances. Availability and implementation: Experimental protocols, sample datasets, scalable open-source multi-threaded software implementation (C++, MATLAB) in the electronic supplement, and website (www.farsight-toolkit.org). http://www.farsight-toolkit.org/wiki/Population-scale_Three-dimensional_Reconstruction_and_Quanti-tative_Profiling_of_Microglia_Arbors Contact: broysam@central.uh.edu Supplementary information: Supplementary data are available at Bioinformatics online.

OBJECTIVELumboperitoneal (LP) shunts have a role not only in pseudotumor cerebri, but also in patients with slit-like ventricles who are treated with CSF shunting on a chronic basis. Hesitation to utilize LP shunts is based on previous conventional beliefs including the tendency for overdrainage, difficulties accessing the shunt to tap or revise, and risk of progressive cerebellar tonsillar herniation. The authors hypothesized that the use of horizontal-vertical (HV) valves may reduce the risk of these complications, particularly overdrainage and development of Chiari malformation.METHODSAll pediatric cases involving patients treated with an LP shunt at the Children’s Hospital of Michigan were reviewed in this retrospective case series. A total of 143 patients with hydrocephalus were treated with LP shunts from 1997–2015 (follow-up range 8 months–8 years, median 4.2 years). Patients with pseudotumor cerebri underwent placement of an LP shunt as a primary procedure. In patients with slit ventricles from chronically treated hydrocephalus or repeated shunt malfunctions from proximal catheter obstruction, a lumbar drain was inserted to assess candidacy for conversion to an LP shunt. In patients who tolerated the lumbar drain and demonstrated communication of the ventricles with the spinal cisterns, treatment was converted to an LP shunt. All patients included in the series had undergone initial shunt placement between birth and age 16 years.RESULTSIn 30% of patients (n = 43), LP shunts were placed as the initial shunt treatment; in 70% (n = 100), treatment was converted to LP shunts from ventriculoperitoneal (VP) shunts. The patients’ age at insertion of or conversion to an LP shunt ranged from 1 to 43 years (median 8.5 years). Of the patients with clear pre-LP and post-LP shunt follow-up imaging, none were found to develop an acquired Chiari malformation. In patients with pre-existing tonsillar ectopia, no progression was noted on follow-up MRIs of the brain in these patients after LP shunt insertion. In our LP shunt case series, no patient presented with acute deterioration from shunt malfunction.CONCLUSIONSConversion to an LP shunt may minimize acute deterioration from shunt malfunction and decrease morbidity of repeated procedures in patients with chronically shunt-treated hydrocephalus and small ventricles. In comparison to previously published case series of LP shunt treatment, the use of LP shunts in conjunction with HV valves may decrease the overall risk of cerebellar tonsillar herniation. The use of an LP shunt may be an alternative in the management of slit ventricles when VP shunting repeatedly fails.

Rhabdoid tumors are highly malignant tumors predominantly affecting the pediatric population. When these tumors occur outside of the kidneys, they are referred to as malignant extrarenal rhabdoid tumors (MERT), a rare highly aggressive subtype. Less commonly, these tumors involve the neuro-axis. Here we present a case of a 15-year-old girl with intradural MERT of the lumbosacral spine who presented with back pain, sudden worsening of lower extremity strength, and complete loss of bowel and bladder control. The patient’s tumor showed loss of INI-1 and negative staining for cytokeratin AE1AE3, CD99, and SOX10. To our knowledge, there are no previous case reports of MERT with intradural lumbosacral spinal involvement.

Hydrocephalus, a disorder of excess cerebrospinal fluid, affects roughly 1 in 500 live births per year. Communicating, or extra-ventricular hydrocephalus, is a subset of the disorder that is, in part, a result of arachnoid granulation dysfunction. Arachnoid granulations are innate one-way valves that allow for pressure dependent absorption of cerebrospinal fluid from the subarachnoid space into the venous blood flow of the superior sagittal sinus. This study investigates a bead-based microfluidic diode as a self-regulated shunt valve for mimicking the physiological functions of arachnoid granulations. The proposed device has been fabricated using assembly of several parts manufactured by 3D printing (stereolithography). The additive manufacturing allows layer-by-layer deposition of soft polymer with high precision. The performance of bead-based arachnoid granulations has been preliminarily tested, including penetration into biological tissues and benchtop flow tests.