The Effectors of the Transient Receptor Vanilloid Potential Type 4 in the Choroid Plexus

poster abstractHydrocephalus is a deadly disease that affects 1-2 births in 1000. When severe, this disease can result in irreversible brain damage. There are no drugs to treat hydrocephalus and the standard therapy is to surgically implant shunts to drain the excess cerebrospinal fluid (CSF) into other parts of the body. However this approach often results in a less than optimal outcomes. Shunt failures due to blockage, infection, and other causes are as high as 50% even in major medical centers which specialize in these procedures. Our laboratory is using a Meckel-Gruber syndrome rat model to study the development of severe hydrocephalus. Immunohistochemistry has been used to show the overexpression of Transient Receptor Vanilloid Potential Type 4, TRPV4 on the choroid plexus epithelial membrane. Because the choroid plexus is responsible for the majority of the cerebrospinal fluid that contributes to the progression of hydrocephalus, the TRPV4 calcium channel is a potential target that could contribute to the disease development. The endogenous activators of this channel in the choroid plexus are yet to be determined. Consequently, the current study is using a cultured choroid plexus cell line to identify endogenous activators of this channel. Potential activators include homovanillic acid (HVA), lysophosphatidic acid, and arachidonic acid. In addition, the introduction of novel compounds that act as sensitizers of the channel led to a set of experiments that were conducted to confirm the existence and identification of the sensitizers such as inflammatory cytokines. The effect of these compounds on the activation of the TRPV4 channel are being investigated using electrophysiological techniques in a porcine choroid plexus cell line with the characteristics of the in vivo choroid plexus. This cell line exhibits a robust increase in ion transport in response to a TRPV4 agonist. . The determination of the endogenous TRPV4 activators and sensitizers will provide important information in the development of a drug that can be used to treat hydrocephalus with minimal side effects by altering the activity of TRPV4

Electronic clinical decision support for children with minor head trauma and intracranial injuries: A sociotechnical analysis

BACKGROUND: Current management of children with minor head trauma (MHT) and intracranial injuries is not evidence-based and may place some children at risk of harm. Evidence-based electronic clinical decision support (CDS) for management of these children may improve patient safety and decrease resource use. To guide these efforts, we evaluated the sociotechnical environment impacting the implementation of electronic CDS, including workflow and communication, institutional culture, and hardware and software infrastructure, among other factors. METHODS: Between March and May, 2020 semi-structured qualitative focus group interviews were conducted to identify sociotechnical influences on CDS implementation. Physicians from neurosurgery, emergency medicine, critical care, and pediatric general surgery were included, along with information technology specialists. Participants were recruited from nine health centers in the United States. Focus group transcripts were coded and analyzed using thematic analysis. The final themes were then cross-referenced with previously defined sociotechnical dimensions. RESULTS: We included 28 physicians and four information technology specialists in seven focus groups (median five participants per group). Five physicians were trainees and 10 had administrative leadership positions. Through inductive thematic analysis, we identified five primary themes: (1) clinical impact; (2) stakeholders and users; (3) tool content; (4) clinical practice integration; and (5) post-implementation evaluation measures. Participants generally supported using CDS to determine an appropriate level-of-care for these children. However, some had mixed feelings regarding how the tool could best be used by different specialties (e.g. use by neurosurgeons versus non-neurosurgeons). Feedback from the interviews helped refine the tool content and also highlighted potential technical and workflow barriers to address prior to implementation. CONCLUSIONS: We identified key factors impacting the implementation of electronic CDS for children with MHT and intracranial injuries. These results have informed our implementation strategy and may also serve as a template for future efforts to implement health information technology in a multidisciplinary, emergency setting

Translating data analytics into improved spine surgery outcomes: A roadmap for biomedical informatics research in 2021

STUDY DESIGN: Narrative review. OBJECTIVES: There is growing interest in the use of biomedical informatics and data analytics tools in spine surgery. Yet despite the rapid growth in research on these topics, few analytic tools have been implemented in routine spine practice. The purpose of this review is to provide a health information technology (HIT) roadmap to help translate data assets and analytics tools into measurable advances in spine surgical care. METHODS: We conducted a narrative review of PubMed and Google Scholar to identify publications discussing data assets, analytical approaches, and implementation strategies relevant to spine surgery practice. RESULTS: A variety of data assets are available for spine research, ranging from commonly used datasets, such as administrative billing data, to emerging resources, such as mobile health and biobanks. Both regression and machine learning techniques are valuable for analyzing these assets, and researchers should recognize the particular strengths and weaknesses of each approach. Few studies have focused on the implementation of HIT, and a variety of methods exist to help translate analytic tools into clinically useful interventions. Finally, a number of HIT-related challenges must be recognized and addressed, including stakeholder acceptance, regulatory oversight, and ethical considerations. CONCLUSIONS: Biomedical informatics has the potential to support the development of new HIT that can improve spine surgery quality and outcomes. By understanding the development life-cycle that includes identifying an appropriate data asset, selecting an analytic approach, and leveraging an effective implementation strategy, spine researchers can translate this potential into measurable advances in patient care

Electronic clinical decision support for children with minor head trauma and intracranial injuries: a sociotechnical analysis.

BackgroundCurrent management of children with minor head trauma (MHT) and intracranial injuries is not evidence-based and may place some children at risk of harm. Evidence-based electronic clinical decision support (CDS) for management of these children may improve patient safety and decrease resource use. To guide these efforts, we evaluated the sociotechnical environment impacting the implementation of electronic CDS, including workflow and communication, institutional culture, and hardware and software infrastructure, among other factors.MethodsBetween March and May, 2020 semi-structured qualitative focus group interviews were conducted to identify sociotechnical influences on CDS implementation. Physicians from neurosurgery, emergency medicine, critical care, and pediatric general surgery were included, along with information technology specialists. Participants were recruited from nine health centers in the United States. Focus group transcripts were coded and analyzed using thematic analysis. The final themes were then cross-referenced with previously defined sociotechnical dimensions.ResultsWe included 28 physicians and four information technology specialists in seven focus groups (median five participants per group). Five physicians were trainees and 10 had administrative leadership positions. Through inductive thematic analysis, we identified five primary themes: (1) clinical impact; (2) stakeholders and users; (3) tool content; (4) clinical practice integration; and (5) post-implementation evaluation measures. Participants generally supported using CDS to determine an appropriate level-of-care for these children. However, some had mixed feelings regarding how the tool could best be used by different specialties (e.g. use by neurosurgeons versus non-neurosurgeons). Feedback from the interviews helped refine the tool content and also highlighted potential technical and workflow barriers to address prior to implementation.ConclusionsWe identified key factors impacting the implementation of electronic CDS for children with MHT and intracranial injuries. These results have informed our implementation strategy and may also serve as a template for future efforts to implement health information technology in a multidisciplinary, emergency setting

Acquired hydrocephalus is associated with neuroinflammation, progenitor loss, and cellular changes in the subventricular zone and periventricular white matter

Abstract Background Hydrocephalus is a neurological disease with an incidence of 80–125 per 100,000 births in the United States. Neuropathology comprises ventriculomegaly, periventricular white matter (PVWM) alterations, inflammation, and gliosis. We hypothesized that hydrocephalus in a pig model is associated with subventricular and PVWM cellular alterations and neuroinflammation that could mimic the neuropathology described in hydrocephalic infants. Methods Hydrocephalus was induced by intracisternal kaolin injections in 35-day old female pigs (n = 7 for tissue analysis, n = 10 for CSF analysis). Age-matched sham controls received saline injections (n = 6). After 19–40 days, MRI scanning was performed to measure the ventricular volume. Stem cell proliferation was studied in the Subventricular Zone (SVZ), and cell death and oligodendrocytes were examined in the PVWM. The neuroinflammatory reaction was studied by quantifying astrocytes and microglial cells in the PVWM, and inflammatory cytokines in the CSF. Results The expansion of the ventricles was especially pronounced in the body of the lateral ventricle, where ependymal disruption occurred. PVWM showed a 44% increase in cell death and a 67% reduction of oligodendrocytes. In the SVZ, the number of proliferative cells and oligodendrocyte decreased by 75% and 57% respectively. The decrease of the SVZ area correlated significantly with ventricular volume increase. Neuroinflammation occurred in the hydrocephalic pigs with a significant increase of astrocytes and microglia in the PVWM, and high levels of inflammatory interleukins IL-6 and IL-8 in the CSF. Conclusion The induction of acquired hydrocephalus produced alterations in the PVWM, reduced cell proliferation in the SVZ, and neuroinflammation

Usability and Acceptability of Clinical Decision Support Based on the KIIDS-TBI Tool for Children with Mild Traumatic Brain Injuries and Intracranial Injuries

BackgroundThe Kids Intracranial Injury Decision Support tool for Traumatic Brain Injury (KIIDS-TBI) tool is a validated risk prediction model for managing children with mild traumatic brain injuries (mTBI) and intracranial injuries. Electronic clinical decision support (CDS) may facilitate the clinical implementation of this evidence-based guidance.ObjectiveOur objective was to evaluate the acceptability and usability of an electronic CDS tool for managing children with mTBI and intracranial injuries.MethodsEmergency medicine and neurosurgery physicians (10 each) from 10 hospitals in the United States were recruited to participate in usability testing of a novel CDS prototype in a simulated electronic health record environment. Testing included a think-aloud protocol, an acceptability and usability survey, and a semi-structured interview. The prototype was updated twice during testing to reflect user feedback. Usability problems recorded in the videos were categorized using content analysis. Interview transcripts were analyzed using thematic analysis.ResultsAmong the 20 participants, most worked at teaching hospitals (80%), freestanding children's hospitals (95%), and level-1 trauma centers (75%). During the two prototype updates, problems with clarity of terminology and navigating through the CDS interface were identified and corrected. Corresponding to these changes, the number of usability problems decreased from 35 in phase 1 to 8 in phase 3 and the number of mistakes made decreased from 18 (phase 1) to 2 (phase 3). Through the survey, participants found the tool easy to use (90%), useful for determining a patient's level of care (95%), and likely to improve resource use (90%) and patient safety (79%). Interview themes related to the CDS's ability to support evidence-based decision-making and improve clinical workflow proposed implementation strategies and potential pitfalls.ConclusionAfter iterative evaluation and refinement, the KIIDS-TBI CDS tool was found to be highly usable and useful for aiding the management of children with mTBI and intracranial injuries

Biochemical profile of human infant cerebrospinal fluid in intraventricular hemorrhage and post-hemorrhagic hydrocephalus of prematurity

Abstract Background Intraventricular hemorrhage (IVH) and post-hemorrhagic hydrocephalus (PHH) have a complex pathophysiology involving inflammatory response, ventricular zone and cell–cell junction disruption, and choroid-plexus (ChP) hypersecretion. Increased cerebrospinal fluid (CSF) cytokines, extracellular matrix proteins, and blood metabolites have been noted in IVH/PHH, but osmolality and electrolyte disturbances have not been evaluated in human infants with these conditions. We hypothesized that CSF total protein, osmolality, electrolytes, and immune cells increase in PHH. Methods CSF samples were obtained from lumbar punctures of control infants and infants with IVH prior to the development of PHH and any neurosurgical intervention. Osmolality, total protein, and electrolytes were measured in 52 infants (18 controls, 10 low grade (LG) IVH, 13 high grade (HG) IVH, and 11 PHH). Serum electrolyte concentrations, and CSF and serum cell counts within 1-day of clinical sampling were obtained from clinical charts. Frontal occipital horn ratio (FOR) was measured for estimating the degree of ventriculomegaly. Dunn or Tukey’s post-test ANOVA analysis were used for pair-wise comparisons. Results CSF osmolality, sodium, potassium, and chloride were elevated in PHH compared to control (p = 0.012 − < 0.0001), LGIVH (p = 0.023 − < 0.0001), and HGIVH (p = 0.015 − 0.0003), while magnesium and calcium levels were higher compared to control (p = 0.031) and LGIVH (p = 0.041). CSF total protein was higher in both HGIVH and PHH compared to control (p = 0.0009 and 0.0006 respectively) and LGIVH (p = 0.034 and 0.028 respectively). These differences were not reflected in serum electrolyte concentrations nor calculated osmolality across the groups. However, quantitatively, CSF sodium and chloride contributed 86% of CSF osmolality change between control and PHH; and CSF osmolality positively correlated with CSF sodium (r, p = 0.55,0.0015), potassium (r, p = 0.51,0.0041), chloride (r, p = 0.60,0.0004), but not total protein across the entire patient cohort. CSF total cells (p = 0.012), total nucleated cells (p = 0.0005), and percent monocyte (p = 0.016) were elevated in PHH compared to control. Serum white blood cell count increased in PHH compared to control (p = 0.042) but there were no differences in serum cell differential across groups. CSF total nucleated cells also positively correlated with CSF osmolality, sodium, potassium, and total protein (p = 0.025 − 0.0008) in the whole cohort. Conclusions CSF osmolality increased in PHH, largely driven by electrolyte changes rather than protein levels. However, serum electrolytes levels were unchanged across groups. CSF osmolality and electrolyte changes were correlated with CSF total nucleated cells which were also increased in PHH, further suggesting PHH is a neuro-inflammatory condition