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Factors that Influence the Continuous Pursuit of Education, Training, and Employment among Young Adults with Serious Mental Health ConditionsYoung adults (ages 18–30) with serious mental health conditions (SMHC) often face challenges in their education, training, and employment pursuits. The study presented in this brief study describes young adult patterns of education, training, and employment activities for individuals with SMHC in the United States and identifies modifiable factors that hinder or facilitate their ability to consistently pursue these activities. Based on first-person narratives from young adults (ages 25–30) with SMHC, these findings should inform psychiatric rehabilitation efforts that support the school, training, and work activities of young adults with SMHC to improve their long-term career trajectories. To learn more about this research project and find additional materials please visit our website: https://www.umassmed.edu/TransitionsACR/research/projects-by-grant/rtc/careerdevSMHC/
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My “Must Have” Papers [English and Spanish versions]2023-03-10Tip sheet for youth and young adults with serious mental health conditions with tips about keeping and protecting important personal records and information. A Spanish translation of this publication is available for download. Originally published as a: Transitions RTC Northeast Massachusetts Community of Practice Tip Sheet, 2011.
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Endemic Burkitt lymphoma avatar mouse models for exploring inter-patient tumor variation and testing targeted therapiesEndemic Burkitt lymphoma (BL) is a childhood cancer in sub-Saharan Africa characterized by Epstein-Barr virus and malaria-associated aberrant B-cell activation and MYC chromosomal translocation. Survival rates hover at 50% after conventional chemotherapies; therefore, clinically relevant models are necessary to test additional therapies. Hence, we established five patient-derived BL tumor cell lines and corresponding NSG-BL avatar mouse models. Transcriptomics confirmed that our BL lines maintained fidelity from patient tumors to NSG-BL tumors. However, we found significant variation in tumor growth and survival among NSG-BL avatars and in Epstein-Barr virus protein expression patterns. We tested rituximab responsiveness and found one NSG-BL model exhibiting direct sensitivity, characterized by apoptotic gene expression counterbalanced by unfolded protein response and mTOR pro-survival pathways. In rituximab-unresponsive tumors, we observed an IFN-α signature confirmed by the expression of IRF7 and ISG15. Our results demonstrate significant inter-patient tumor variation and heterogeneity, and that contemporary patient-derived BL cell lines and NSG-BL avatars are feasible tools to guide new therapeutic strategies and improve outcomes for these children.
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Use of expert consensus to develop a shared list of procedures with potential for aerosol generation during the coronavirus disease 2019 (COVID-19) pandemicThe coronavirus disease 2019 (COVID-19) pandemic highlighted the lack of agreement regarding the definition of aerosol-generating procedures and potential risk to healthcare personnel. We convened a group of Massachusetts healthcare epidemiologists to develop consensus through expert opinion in an area where broader guidance was lacking at the time.
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Monitoring the Implementation of Tobacco Cessation Support Tools: Using Novel Electronic Health Record Activity MetricsBackground: Clinical decision support (CDS) tools in electronic health records (EHRs) are often used as core strategies to support quality improvement programs in the clinical setting. Monitoring the impact (intended and unintended) of these tools is crucial for program evaluation and adaptation. Existing approaches for monitoring typically rely on health care providers' self-reports or direct observation of clinical workflows, which require substantial data collection efforts and are prone to reporting bias. Objective: This study aims to develop a novel monitoring method leveraging EHR activity data and demonstrate its use in monitoring the CDS tools implemented by a tobacco cessation program sponsored by the National Cancer Institute's Cancer Center Cessation Initiative (C3I). Methods: We developed EHR-based metrics to monitor the implementation of two CDS tools: (1) a screening alert reminding clinic staff to complete the smoking assessment and (2) a support alert prompting health care providers to discuss support and treatment options, including referral to a cessation clinic. Using EHR activity data, we measured the completion (encounter-level alert completion rate) and burden (the number of times an alert was fired before completion and time spent handling the alert) of the CDS tools. We report metrics tracked for 12 months post implementation, comparing 7 cancer clinics (2 clinics implemented the screening alert and 5 implemented both alerts) within a C3I center, and identify areas to improve alert design and adoption. Results: The screening alert fired in 5121 encounters during the 12 months post implementation. The encounter-level alert completion rate (clinic staff acknowledged completion of screening in EHR: 0.55; clinic staff completed EHR documentation of screening results: 0.32) remained stable over time but varied considerably across clinics. The support alert fired in 1074 encounters during the 12 months. Providers acted upon (ie, not postponed) the support alert in 87.3% (n=938) of encounters, identified a patient ready to quit in 12% (n=129) of encounters, and ordered a referral to the cessation clinic in 2% (n=22) of encounters. With respect to alert burden, on average, both alerts fired over 2 times (screening alert: 2.7; support alert: 2.1) before completion; time spent postponing the screening alert was similar to completing (52 vs 53 seconds) the alert, and time spent postponing the support alert was more than completing (67 vs 50 seconds) the alert per encounter. These findings inform four areas where the alert design and use can be improved: (1) improving alert adoption and completion through local adaptation, (2) improving support alert efficacy by additional strategies including training in provider-patient communication, (3) improving the accuracy of tracking for alert completion, and (4) balancing alert efficacy with the burden. Conclusions: EHR activity metrics were able to monitor the success and burden of tobacco cessation alerts, allowing for a more nuanced understanding of potential trade-offs associated with alert implementation. These metrics can be used to guide implementation adaptation and are scalable across diverse settings.
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Career self-efficacy disparities in underrepresented biomedical scientist traineesThe present study examines racial, ethnic, and gender disparities in career self-efficacy amongst 6077 US citizens and US naturalized graduate and postdoctoral trainees. Respondents from biomedical fields completed surveys administered by the National Institutes of Health Broadening Experiences in Scientific Training (NIH BEST) programs across 17 US institutional sites. Graduate and postdoctoral demographic and survey response data were examined to evaluate the impact of intersectional identities on trainee career self-efficacy. The study hypothesized that race, ethnicity and gender, and the relations between these identities, would impact trainee career self-efficacy. The analysis demonstrated that racial and ethnic group, gender, specific career interests (academic principal investigator vs. other careers), and seniority (junior vs. senior trainee level) were, to various degrees, all associated with trainee career self-efficacy and the effects were consistent across graduate and postdoctoral respondents. Implications for differing levels of self-efficacy are discussed, including factors and events during training that may contribute to (or undermine) career self-efficacy. The importance of mentorship for building research and career self-efficacy of trainees is discussed, especially with respect to those identifying as women and belonging to racial/ethnic populations underrepresented in biomedical sciences. The results underscore the need for change in the biomedical academic research community in order to retain a diverse biomedical workforce.
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Prospective study on embolization of intracranial aneurysms with the pipeline device (PREMIER study): 3-year results with the application of a flow diverter specific occlusion classificationBACKGROUND: The pipeline embolization device (PED; Medtronic) has presented as a safe and efficacious treatment for small- and medium-sized intracranial aneurysms. Independently adjudicated long-term results of the device in treating these lesions are still indeterminate. We present 3-year results, with additional application of a flow diverter specific occlusion scale. METHODS: PREMIER (prospective study on embolization of intracranial aneurysms with pipeline embolization device) is a prospective, single-arm trial. Inclusion criteria were patients with unruptured wide-necked intracranial aneurysms < /=12 mm. Primary effectiveness (complete aneurysm occlusion) and safety (major neurologic event) endpoints were independently monitored and adjudicated. RESULTS: As per the protocol, of 141 patients treated with a PED, 25 (17.7%) required angiographic follow-up after the first year due to incomplete aneurysm occlusion. According to the Core Radiology Laboratory review, three (12%) of these patients progressed to complete occlusion, with an overall rate of complete aneurysm occlusion at 3 years of 83.3% (115/138). Further angiographic evaluation using the modified Cekirge-Saatci classification demonstrated that complete occlusion, neck residual, or aneurysm size reduction occurred in 97.1%. The overall combined safety endpoint at 3 years was 2.8% (4/141), with only one non-debilitating major event occurring after the first year. There was one case of aneurysm recurrence but no cases of delayed rupture in this series. CONCLUSIONS: The PED device presents as a safe and effective modality in treating small- and medium-sized intracranial aneurysms. The application of a flow diverter specific occlusion classification attested the long-term durability with higher rate of successful aneurysm occlusion and no documented aneurysm rupture. TRIAL REGISTRATION: NCT02186561.
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UMCCTS Newsletter, March 2023This is the March 2023 issue of the UMass Center for Clinical and Translational Science Newsletter containing news and events of interest.
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Social Determinants, Blood Pressure Control, and Racial Inequities in Childbearing Age Women With Hypertension, 2001 to 2018Background Hypertension is an important modifiable risk factor of serious maternal morbidity and mortality. Social determinants of health (SDoH) influence hypertension outcomes and may contribute to racial and ethnic differences in hypertension control. Our objective was to assess SDoH and blood pressure (BP) control by race and ethnicity in US women of childbearing age with hypertension. Methods and Results We studied women (aged 20-50 years) with hypertension (systolic BP ≥140 mm Hg or diastolic BP ≥90 mm Hg or use of antihypertensive medication) in the National Health and Nutrition Examination Surveys 2001 to 2018. SDoH and BP control (systolic BP <140 mm Hg and diastolic BP <90 mm Hg) were examined by race and ethnicity (White race, Black race, Hispanic ethnicity, and Asian race). Using multivariable logistic regression, odds of uncontrolled BP by race and ethnicity were modeled, adjusting for SDoH, health factors, and modifiable health behaviors. Responses on hunger and affording food determined food insecurity status. Across women of childbearing age with hypertension (N=1293), 59.2% were White race, 23.4% were Black race, 15.8% were Hispanic ethnicity, and 1.7% were Asian race. More Hispanic and Black women experienced food insecurity than White women (32% and 25% versus 13%; both P<0.001). After SDoH, health factor, and modifiable health behavior adjustment, Black women maintained higher odds of uncontrolled BP than White women (odds ratio, 2.31 [95% CI, 1.08-4.92]), whereas Asian and Hispanic women showed no difference. Conclusions We identified racial inequities in uncontrolled BP and food insecurity among women of childbearing age with hypertension. Further exploration beyond the SDoH measured is needed to understand the inequity in hypertension control in Black women.
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Performance of Rapid Antigen Tests Based on Symptom Onset and Close Contact Exposure: A secondary analysis from the Test Us At Home prospective cohort study [preprint]Background: The performance of rapid antigen tests for SARS-CoV-2 (Ag-RDT) in temporal relation to symptom onset or exposure is unknown, as is the impact of vaccination on this relationship. Objective: To evaluate the performance of Ag-RDT compared with RT-PCR based on day after symptom onset or exposure in order to decide on 'when to test'. Design setting and participants: The Test Us at Home study was a longitudinal cohort study that enrolled participants over 2 years old across the United States between October 18, 2021 and February 4, 2022. All participants were asked to conduct Ag-RDT and RT-PCR testing every 48 hours over a 15-day period. Participants with one or more symptoms during the study period were included in the Day Post Symptom Onset (DPSO) analyses, while those who reported a COVID-19 exposure were included in the Day Post Exposure (DPE) analysis. Exposure: Participants were asked to self-report any symptoms or known exposures to SARS-CoV-2 every 48-hours, immediately prior to conducting Ag-RDT and RT-PCR testing. The first day a participant reported one or more symptoms was termed DPSO 0, and the day of exposure was DPE 0. Vaccination status was self-reported. Main outcome and measures: Results of Ag-RDT were self-reported (positive, negative, or invalid) and RT-PCR results were analyzed by a central laboratory. Percent positivity of SARS-CoV-2 and sensitivity of Ag-RDT and RT-PCR by DPSO and DPE were stratified by vaccination status and calculated with 95% confidence intervals. Results: A total of 7,361 participants enrolled in the study. Among them, 2,086 (28.3%) and 546 (7.4%) participants were eligible for the DPSO and DPE analyses, respectively. Unvaccinated participants were nearly twice as likely to test positive for SARS-CoV-2 than vaccinated participants in event of symptoms (PCR+: 27.6% vs 10.1%) or exposure (PCR+: 43.8% vs. 22.2%). The highest proportion of vaccinated and unvaccinated individuals tested positive on DPSO 2 and DPE 5-8. Performance of RT-PCR and Ag-RDT did not differ by vaccination status. Ag-RDT detected 78.0% (95% Confidence Interval: 72.56-82.61) of PCR-confirmed infections by DPSO 4. For exposed participants, Ag-RDT detected 84.9% (95% CI: 75.0-91.4) of PCR-confirmed infections by day five post-exposure (DPE 5). Conclusions and relevance: Performance of Ag-RDT and RT-PCR was highest on DPSO 0-2 and DPE 5 and did not differ by vaccination status. These data suggests that serial testing remains integral to enhancing the performance of Ag-RDT.
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Chronic Wound Image Augmentation and Assessment Using Semi-Supervised Progressive Multi-Granularity EfficientNetGoal: Augment a small, imbalanced, wound dataset by using semi-supervised learning with a secondary dataset. Then utilize the augmented wound dataset for deep learning-based wound assessment. Methods: The clinically-validated Photographic Wound Assessment Tool (PWAT) scores eight wound attributes: Size, Depth, Necrotic Tissue Type, Necrotic Tissue Amount, Granulation Tissue type, Granulation Tissue Amount, Edges, Periulcer Skin Viability to comprehensively assess chronic wound images. A small corpus of 1639 wound images labeled with ground truth PWAT scores was used as reference. A Semi-Supervised learning and Progressive Multi-Granularity training mechanism were used to leverage a secondary corpus of 9870 unlabeled wound images. Wound scoring utilized the EfficientNet Convolutional Neural Network on the augmented wound corpus. Results: Our proposed Semi-Supervised PMG EfficientNet (SS-PMG-EfficientNet) approach estimated all 8 PWAT sub-scores with classification accuracies and F1 scores of about 90% on average, and outperformed a comprehensive list of baseline models and had a 7% improvement over the prior state-of-the-art (without data augmentation). We also demonstrate that synthetic wound image generation using Generative Adversarial Networks (GANs) did not improve wound assessment. Conclusions: Semi-supervised learning on unlabeled wound images in a secondary dataset achieved impressive performance for deep learning-based wound grading.
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Exploring the Phenomenon of MNNG Dose-Dependent Death PolypharmacologyRegulated cell death (RCD) is composed of several pathways that control cell fate. While each pathway is mechanistically distinct, these pathways have been shown to interact. Most of these interactions tend to be antagonistic, such that activation of one pathway blocks the subsequent activation of another pathway. This highlights that death pathways tend to be mutually exclusive. Thus, combining two cytotoxic drugs that activate different death pathways could result in less cell death than predicted, hampering therapeutic efficacy. As such, it is necessary to characterize which death pathways are activated by clinically relevant drugs, particularly for drug combination studies. However, studies of death pathway engagement are complicated by the fact that many drugs are capable of activating multiple RCD pathways. In order to improve annotations of RCD pathway activation by specific stimuli, we need to learn what features dictate which death pathway is activated. To study this phenomenon, we focused on characterizing RCD execution after treatment with methylnitronitrosoguanidine (MNNG), a DNA alkylating agent. MNNG is the canonical activator of parthanatos, an inflammatory form of RCD dependent on PARP-1 hyper-activation. We found that MNNG exhibits dose-dependent changes in death features, such as death onset time and death rate, indicative of a death mechanism change. As such we hypothesized that MNNG can induce multiple RCD pathways in a dose-dependent fashion. We found that this dose-dependent change in death features was generalizable to multiple cell lines. Moreover, we established that the phenotype was not due to PARP-trapping effects. Importantly, we uncovered that MNNG does induce a death mechanism switch. We found that MNNG is capable of inducing either parthanatos or apoptosis, depending on the dose. We also found evidence that the two death pathways induced by MNNG were mutually exclusive. And lastly, we established that the death mechanism switch was not due to altered mismatch repair (MMR). The information from this study could help to shed light on clinical outcomes from drug combination trials, specifically combinations with DNA damaging agents and PARP inhibitors.
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The flutter of an aching heartIntroduction: I do not have an original offering for this week. In honour of February being American Heart Month, I offer up a story I wrote 12 years ago about an incident in my early years fresh out of residency in private practice. Heart disease is complicated. We do so many "rule outs" proving that a person did not have a heart attack and then we send them on their way. While true heart disease is incredibly prevalent and serious, so too are the many other things that break our hearts. This story is about this latter kind of heart disease.
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Infertility Services for Veterans Enrolled in Veterans Health Administration CareBackground: Infertility care is provided to Veterans through the Veterans Health Administration (VHA) medical benefits package and includes infertility evaluation and many infertility treatments. Objective: Our objective was to examine the incidence and prevalence of infertility diagnoses and the receipt of infertility healthcare among Veterans using Veterans Health Administration (VHA) healthcare from 2018 to 2020. Methods: Veterans using the VHA and diagnosed with infertility during October 2017-September 2020 (FY18-20) were identified in VHA administrative data and through VA-purchased care (i.e., community care) claims. Infertility was categorized among men as azoospermia, oligospermia, and other and unspecified male infertility, and among women as anovulation, infertility of tubal origin, infertility of uterine origin, and other and unspecified female infertility using diagnosis and procedure codes (ICD-10, CPT). Key results: A total of 17,216 Veterans had at least one VHA infertility diagnosis in FY18, FY19, or FY20, including 8766 male Veterans and 8450 female Veterans. Incident diagnoses of infertility were observed in 7192 male Veterans (10.8/10,000 person (p)-years) and 5563 female Veterans (93.6/10,000 p-years). A large proportion of Veterans who were diagnosed with infertility received an infertility-related procedure in the year of their incident diagnosis (males: 74.7, 75.3, 65.0%, FY18-20 respectively; females: 80.9, 80.8, 72.9%, FY18-20 respectively). Conclusions: In comparison to a recent study of active duty servicemembers, we found a lower rate of infertility among Veteran men and a higher rate among Veteran women. Further work is needed to investigate military exposures and circumstances that may lead to infertility. Given the rates of infertility among Veterans and active duty servicemembers, enhancing communications between Department of Defense and VHA systems regarding sources of and treatment for infertility is essential to help more men and women benefit from infertility care during military service or as Veterans.
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Mesh modeling of system geometry and anatomy phantoms for realistic GATE simulations and their inclusion in SPECT reconstructionObjective: Monte-Carlo simulation studies have been essential for advancing various developments in SPECT imaging, such as system design and accurate image reconstruction. Among the simulation software available, GATE is one of the most used simulation toolkits in nuclear medicine, which allows building systems and attenuation phantom geometries based on the combination of idealized volumes. However, these idealized volumes are inadequate for modeling free-form shape components of such geometries. Recent GATE versions alleviate these major limitations by allowing users to import triangulated surface meshes. Approach: In this study, we describe our mesh-based simulations of a next-generation multi-pinhole SPECT system dedicated to clinical brain imaging, called AdaptiSPECT-C. To simulate realistic imaging data, we incorporated in our simulation the XCAT phantom, which provides an advanced anatomical description of the human body. An additional challenge with the AdaptiSPECT-C geometry is that the default voxelized XCAT attenuation phantom was not usable in our simulation due to intersection of objects of dissimilar materials caused by overlap of the air containing regions of the XCAT beyond the surface of the phantom and the components of the imaging system. Main results: We validated our mesh-based modeling against the one constructed by idealized volumes for a simplified single vertex configuration of AdaptiSPECT-C through simulated projection data of 123I-activity distributions. We resolved the overlap conflict by creating and incorporating a mesh-based attenuation phantom following a volume hierarchy. We then evaluated our reconstructions with attenuation and scatter correction for projections obtained from simulation consisting of mesh-based modeling of the system and the attenuation phantom for brain imaging. Our approach demonstrated similar performance as the reference scheme simulated in air for uniform and clinical-like 123I-IMP brain perfusion source distributions. Significance: This work enables the simulation of complex SPECT acquisitions and reconstructions for emulating realistic imaging data close to those of actual patients.
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Changes in Stage at Presentation among Lung and Breast Cancer Patients During the COVID-19 PandemicBackground: The COVID-19 pandemic altered access to healthcare by decreasing number of patients able to receive preventative care and cancer screening. We hypothesized that given these changes in access to care, radiologic screening for breast and lung cancer would be decreased, and patients with these cancers would consequently present at later stages of their disease. Design: Retrospective cross-sectional study of 2017-September 2021 UMass Memorial Tumor Registry for adult breast and lung cancer patients. Changes in stage at presentation of breast and lung cancer during the COVID-19 pandemic were measured, defined as prior to and during COVID-19. Results: There were no statistically significant changes in the overall stage of presentation before or during the COVID-19 pandemic for either breast or lung cancer patients. Analysis of case presentation and stage during periods of COVID-19 surges that occurred over the time of this study compared to pre-pandemic data demonstrated a statistically significant decrease in overall presentation of breast cancer patients in the first surge, with no other statistically significant changes in breast cancer presentation. A non-statistically significant decrease in lung cancer presentations was seen during the initial surge of COVID-19. There was also a statistically significant increase in early-stage presentation of lung cancer during the second and third COVID-19 surges. Conclusions: In the two years after the COVID-19 pandemic we were not able to demonstrate stage migration at presentation of breast and lung cancer patients to later stages despite decreases in overall presentation during the initial two years of the COVID pandemic. An increase in early-stage lung cancer during the second and third surges is interesting and could be related to increased chest imaging for COVID pneumonia.
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Diagnoses Associated with Intellectual and Developmental Disabilities in Adult Decedents: A Secondary Analysis of Healthcare Cost and Utilization Project National Inpatient Sample (HCUP/NIS) DataPurpose: To identify primary and secondary diagnoses preceding death among adults with and without IDD who died during hospitalization. Specific Aims: 1) to describe the commonly reported base diagnostic related groups preceding death among decedents with and without IDD who died during hospitalization in 2019, 2) to determine which base-DRGs had a higher prevalence rate among adults with IDD than among adults without IDD, controlling for age, gender, race, urbanicity of person’s residence, US census division of hospital, and mean income of person’s zip code, and 3) to use the base-DRGs and ICD-10-CMs to examine the conditions of the Fatal Four/Five as conditions of concern preceding death in decedents with and without IDD. Framework: The NIMHD Minority Health and Health Disparities Research Framework. Design: A secondary data analysis using the 2019 Healthcare Cost and Utilization Project National (Nationwide) Inpatient Sample (HCUP-NIS). Results: Identified fourteen primary diagnoses at the time of death for decedents with IDD that are represented at a higher percentage than for decedents without IDD and have a significant odds ratio for IDD diagnosis. Conclusion: A new set of conditions is proposed to assist nurses in reducing preventable deaths in decedents with IDD. Dehydration, GI obstruction, respiratory infection, seizures, and sepsis, will be known as the IDD Concerning Conditions. Aspiration, constipation, and GERD, the IDD Contributing Conditions, are conditions that do not cause death in themselves but contribute to the development of at least one of the IDD Concerning Conditions, which do cause death.
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Data quality considerations for evaluating COVID-19 treatments using real world data: learnings from the National COVID Cohort Collaborative (N3C)Background: Multi-institution electronic health records (EHR) are a rich source of real world data (RWD) for generating real world evidence (RWE) regarding the utilization, benefits and harms of medical interventions. They provide access to clinical data from large pooled patient populations in addition to laboratory measurements unavailable in insurance claims-based data. However, secondary use of these data for research requires specialized knowledge and careful evaluation of data quality and completeness. We discuss data quality assessments undertaken during the conduct of prep-to-research, focusing on the investigation of treatment safety and effectiveness. Methods: Using the National COVID Cohort Collaborative (N3C) enclave, we defined a patient population using criteria typical in non-interventional inpatient drug effectiveness studies. We present the challenges encountered when constructing this dataset, beginning with an examination of data quality across data partners. We then discuss the methods and best practices used to operationalize several important study elements: exposure to treatment, baseline health comorbidities, and key outcomes of interest. Results: We share our experiences and lessons learned when working with heterogeneous EHR data from over 65 healthcare institutions and 4 common data models. We discuss six key areas of data variability and quality. (1) The specific EHR data elements captured from a site can vary depending on source data model and practice. (2) Data missingness remains a significant issue. (3) Drug exposures can be recorded at different levels and may not contain route of administration or dosage information. (4) Reconstruction of continuous drug exposure intervals may not always be possible. (5) EHR discontinuity is a major concern for capturing history of prior treatment and comorbidities. Lastly, (6) access to EHR data alone limits the potential outcomes which can be used in studies. Conclusions: The creation of large scale centralized multi-site EHR databases such as N3C enables a wide range of research aimed at better understanding treatments and health impacts of many conditions including COVID-19. As with all observational research, it is important that research teams engage with appropriate domain experts to understand the data in order to define research questions that are both clinically important and feasible to address using these real world data.
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Abdominal UltrasoundThis presentation is part of the PEER Liberia Radiology Lecture Series. It provides an overview of abdominal ultrasound.
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The choroid plexus links innate immunity to CSF dysregulation in hydrocephalusThe choroid plexus (ChP) is the blood-cerebrospinal fluid (CSF) barrier and the primary source of CSF. Acquired hydrocephalus, caused by brain infection or hemorrhage, lacks drug treatments due to obscure pathobiology. Our integrated, multi-omic investigation of post-infectious hydrocephalus (PIH) and post-hemorrhagic hydrocephalus (PHH) models revealed that lipopolysaccharide and blood breakdown products trigger highly similar TLR4-dependent immune responses at the ChP-CSF interface. The resulting CSF "cytokine storm", elicited from peripherally derived and border-associated ChP macrophages, causes increased CSF production from ChP epithelial cells via phospho-activation of the TNF-receptor-associated kinase SPAK, which serves as a regulatory scaffold of a multi-ion transporter protein complex. Genetic or pharmacological immunomodulation prevents PIH and PHH by antagonizing SPAK-dependent CSF hypersecretion. These results reveal the ChP as a dynamic, cellularly heterogeneous tissue with highly regulated immune-secretory capacity, expand our understanding of ChP immune-epithelial cell cross talk, and reframe PIH and PHH as related neuroimmune disorders vulnerable to small molecule pharmacotherapy.
