Social Determinants of Health in Idiopathic Intracranial Hypertension.

BACKGROUND: Idiopathic intracranial hypertension (IIH) disproportionately affects women from socioeconomically disadvantaged communities, but specific social determinants of health have not been examined. METHODS: We used data from the National Institutes of Health's All of Us Research Program, an ongoing nationwide study of more than 300,000 diverse individuals in the United States. Height and weight were measured at baseline, and participants completed questionnaires about demographics, health care access, and quality of life. Women aged 18-50 years with IIH were identified through electronic health record data, excluding those with venous thrombosis, meningitis, hydrocephalus, or central nervous system neoplasms. We used logistic regression to compare questionnaire responses for IIH cases and controls, adjusting for age, race, ethnicity, annual income, and body mass index (BMI). RESULTS: We included 416 women with IIH and 107,111 women without IIH. The mean age was 38 years, and 49.3% identified as non-White. After adjusting for age, race/ethnicity, and BMI, women with IIH were more likely to be unemployed (odds ratio [OR] 1.40, 95% confidential interval [CI]: 1.14-1.71) and report delaying care because of difficulty affording copays (OR 1.47, 95% CI: 1.02-2.10) or specialist care (OR 1.52, 95% CI: 1.06-2.18). They also delayed care because of rural residence (OR 2.08, 95% CI: 1.25-3.47) and transportation limitations (OR 2.23, 95% CI: 1.55-3.20). Although women with IIH were more likely to be non-Hispanic Black (OR 1.66, 95% CI: 1.32-2.09), this association lost significance when controlling for BMI and income (OR 1.27, 95% CI: 0.96-1.68). CONCLUSIONS: Women with IIH experience adverse social determinants of health beyond those associated with obesity alone.

Pathway to Independence Awards (K99/R00): Funding Dynamics and Prediction of Future National Institutes of Health Research Project Funding.

PURPOSE: The authors used the National Institutes of Health (NIH) RePORTER (Research Portfolio Online Reporting Tools) to evaluate funding trends and historic NIH investment increase in the K99 award pathway and examine whether R00 to R01 or R21 achievement time correlated with the future success of an early-stage NIH-funded investigator. METHOD: All K99 awards and funding data in this study were limited to all clinical departments. The authors identified all researchers and awards through a K99 search from fiscal years (FYs) 2007 to 2022 across all clinical departments and investigated trends in K99 awards and funding from NIH FYs 2007 to 2022. They generated an R00 data set and analyzed the K99 to R00 achievement statistics from FYs 2007 to 2022. The authors aggregated NIH annual data files for FYs 2007 to 2021 to generate a master data file of all R01 and R21 awards. They linked R01 and R21 award data to the researcher previously identified through the K99 search and focused on the connection between K99/R00 awardees and subsequent R01 or R21 awards. RESULTS: From FY 2008 to FY 2022, the NIH K99 budget increased 127.0%, whereas the NIH program-level budget increased 17.3%. A principal investigator's mean funding per year significantly decreased as time from R00 to R01 or R21 increased ( P < .001); 7 of 15 comparisons differed significantly (2 at P < .01 and 5 at P < .001). CONCLUSIONS: NIH investment in the K99 award pathway has substantially outpaced the NIH program-level budget increase, and there is a strong association between mean funding per year since the start of the R00 phase and time from R00 to R01 or R21. This analysis may be useful to clinical departments as they evaluate selecting new and retaining current biomedical scientists for independent research positions.

National Institutes of Health Funding Gaps for Principal Investigators.

Importance: Early-stage and established investigators compete for a limited supply of funds from the National Institutes of Health (NIH). Regardless of their previous funding success, many principal investigators (PIs) encounter a funding gap in which they no longer receive ongoing funding from the NIH. Objective: To determine incidence rates of PI-level funding gaps, the mean funding gap length, and whether these 2 metrics are associated with previous funding success. Design, Setting, and Participants: This study was conducted using data from NIH RePORTER. Historical datafiles for fiscal year (FY) 2011 to FY 2021 were aggregated to generate 2 master datafiles for this period: all NIH awards and only R01 awards. PIs with no funding in FY 2011 or FY 2021 were removed. PIs were sorted by FY 2011 total funding amounts and grouped by quarter of amount. Results: A total of 39 944 unique researchers were awarded 220 131 NIH awards, of which 103 753 were R01 awards. For all NIH awards, there was an overall linear increase from top quarter to bottom quarter in the percentage of PIs who had at least 1 year without funding (from 27% to 75%), percentage of these gap PIs who had at least 2 consecutive years without funding (from 56% to 68%), and mean maximum consecutive years without funding for gap PIs (2.2 years to 3.1 years). For only R01 awards, there was an overall linear increase from top quarter to bottom quarter in the percentage of PIs who had at least 1 year without funding (50% to 74%), percentage of gap PIs who had at least 2 consecutive years without funding (59% to 71%), and mean maximum consecutive years without funding for gap PIs (2.4 years to 3.1 years). Conclusions and Relevance: In this cohort study of NIH-funded investigators, PIs with higher NIH funding were less likely to experience a funding gap. Additionally, when these PIs encountered a funding gap, this period without funding was shorter; however, among all PIs, funding gaps typically lasted 2 to 3 years. These associations were found inclusive of all NIH awards and when analysis was limited to only R01 awards. These findings may be useful to PIs and academic institutions as they prepare, structure, and project research resource allocations.

Identifying breast cancer recurrence histories via patient-reported outcomes.

PURPOSE: To test accuracy of patient self-report of breast cancer recurrence for enhancing standard population-based cancer registries that do not routinely collect cancer recurrence data despite the importance of this outcome. METHODS: Potential research subjects were identified in the Breast Cancer Research Database (BCRD) of the Swedish Cancer Institute (SCI). The BCRD has collected data within 45 days of each medical encounter on new primary breast cancer patients receiving all or part of their initial care at SCI. Females diagnosed with a new primary breast cancer 2004-2016, Stages I-III, and alive at the time of study initiation (2018) were identified. Recurrent breast cancer patients were matched 1:1 to surviving non-recurrent patients by patient age, date of diagnosis, and single or multiple primary tumors. Consented research subjects were surveyed about their initial and subsequent diagnostic, therapeutic, and recurrent events. PRO survey responses were compared with BCRD information for each individual participant. Discrepancies were reviewed in medical records. RESULTS: A matched sample of 88 recurrent and 88 non-recurrent patients were used in analyses. Respondents correctly identified the date of diagnosis of first primary breast cancer within 1 year 94% (165/176). Recurrence was reported by 97% (85/88) of recurrent patients. No recurrence was reported by 100% (88/88) of non-recurrent patients. Recurrence date within 1 year was correctly identified in 79% (67/85). Recurrence site was correctly identified in 82% (70/85). Medical record review of survey-registry discrepancies led to BCRD corrections in 4.5% (8/176) of cases. IMPLICATIONS FOR CANCER SURVIVORS: Breast cancer patients can accurately report their disease characteristics, treatments, and recurrence history. Patient-reported information would enhance cancer registry data.

Cellular and humoral immune responses following SARS-CoV-2 mRNA vaccination in patients with multiple sclerosis on anti-CD20 therapy.

SARS-CoV-2 messenger RNA vaccination in healthy individuals generates immune protection against COVID-19. However, little is known about SARS-CoV-2 mRNA vaccine-induced responses in immunosuppressed patients. We investigated induction of antigen-specific antibody, B cell and T cell responses longitudinally in patients with multiple sclerosis (MS) on anti-CD20 antibody monotherapy (n = 20) compared with healthy controls (n = 10) after BNT162b2 or mRNA-1273 mRNA vaccination. Treatment with anti-CD20 monoclonal antibody (aCD20) significantly reduced spike-specific and receptor-binding domain (RBD)-specific antibody and memory B cell responses in most patients, an effect ameliorated with longer duration from last aCD20 treatment and extent of B cell reconstitution. By contrast, all patients with MS treated with aCD20 generated antigen-specific CD4 and CD8 T cell responses after vaccination. Treatment with aCD20 skewed responses, compromising circulating follicular helper T (TFH) cell responses and augmenting CD8 T cell induction, while preserving type 1 helper T (TH1) cell priming. Patients with MS treated with aCD20 lacking anti-RBD IgG had the most severe defect in circulating TFH responses and more robust CD8 T cell responses. These data define the nature of the SARS-CoV-2 vaccine-induced immune landscape in aCD20-treated patients and provide insights into coordinated mRNA vaccine-induced immune responses in humans. Our findings have implications for clinical decision-making and public health policy for immunosuppressed patients including those treated with aCD20.

Correction: Incorporating Breast Cancer Recurrence Events Into Population-Based Cancer Registries Using Medical Claims: Cohort Study.

[This corrects the article DOI: 10.2196/18143.].

Incorporating Breast Cancer Recurrence Events Into Population-Based Cancer Registries Using Medical Claims: Cohort Study.

BACKGROUND: There is a need for automated approaches to incorporate information on cancer recurrence events into population-based cancer registries. OBJECTIVE: The aim of this study is to determine the accuracy of a novel data mining algorithm to extract information from linked registry and medical claims data on the occurrence and timing of second breast cancer events (SBCE). METHODS: We used supervised data from 3092 stage I and II breast cancer cases (with 394 recurrences), diagnosed between 1993 and 2006 inclusive, of patients at Kaiser Permanente Washington and cases in the Puget Sound Cancer Surveillance System. Our goal was to classify each month after primary treatment as pre- versus post-SBCE. The prediction feature set for a given month consisted of registry variables on disease and patient characteristics related to the primary breast cancer event, as well as features based on monthly counts of diagnosis and procedure codes for the current, prior, and future months. A month was classified as post-SBCE if the predicted probability exceeded a probability threshold (PT); the predicted time of the SBCE was taken to be the month of maximum increase in the predicted probability between adjacent months. RESULTS: The Kaplan-Meier net probability of SBCE was 0.25 at 14 years. The month-level receiver operating characteristic curve on test data (20% of the data set) had an area under the curve of 0.986. The person-level predictions (at a monthly PT of 0.5) had a sensitivity of 0.89, a specificity of 0.98, a positive predictive value of 0.85, and a negative predictive value of 0.98. The corresponding median difference between the observed and predicted months of recurrence was 0 and the mean difference was 0.04 months. CONCLUSIONS: Data mining of medical claims holds promise for the streamlining of cancer registry operations to feasibly collect information about second breast cancer events.

Microtubule-targeting agents can sensitize cancer cells to ionizing radiation by an interphase-based mechanism.

BACKGROUND: The cytotoxic effects of microtubule-targeting agents (MTAs) are often attributed to targeted effects on mitotic cells. In clinical practice, MTAs are combined with DNA-damaging agents such as ionizing radiation (IR) with the rationale that mitotic cells are highly sensitive to DNA damage. In contrast, recent studies suggest that MTAs synergize with IR by interfering with the trafficking of DNA damage response (DDR) proteins during interphase. These studies, however, have yet to demonstrate the functional consequences of interfering with interphase microtubules in the presence of IR. To address this, we combined IR with an established MTA, mebendazole (MBZ), to treat glioma cells exclusively during interphase. MATERIALS AND METHODS: To test whether MTAs can sensitize interphase cells to IR, we treated GL261 and GBM14 glioma cells with MBZ during 3-9 hours post IR (when the mitotic index was 0%). Cell viability was measured using a WST-1 assay, and radiosensitization was quantified using the dose enhancement factor (DEF). The effect of MBZ on the DDR was studied via Western blot analysis of H2AX phosphorylation. To examine the effects of MTAs on intracellular transport of DDR proteins, Nbs1 and Chk2, cytoplasmic and nuclear fractionation studies were conducted following treatment of glioma cells with MBZ. RESULTS: Treatment with MBZ sensitized interphase cells to the effects of IR, with a maximal DEF of 1.34 in GL261 cells and 1.69 in GBM14 cells. Treatment of interphase cells with MBZ led to more sustained γH2AX levels post IR, indicating a delay in the DDR. Exposure of glioma cells to MBZ resulted in a dose-dependent sequestration of Chk2 and Nbs1 in the cytoplasm. CONCLUSION: This study demonstrates that MBZ can sensitize cancer cells to IR independently of the induction of mitotic arrest. In addition, evidence is provided supporting the hypothesis that MTA-induced radiosensitization is mediated by inhibiting DDR protein accumulation into the nucleus.

Increased putamen hypercapnic vasoreactivity in levodopa-induced dyskinesia.

In a rodent model of Parkinson's disease (PD), levodopa-induced involuntary movements have been linked to striatal angiogenesis - a process that is difficult to document in living human subjects. Angiogenesis can be accompanied by localized increases in cerebral blood flow (CBF) responses to hypercapnia. We therefore explored the possibility that, in the absence of levodopa, local hypercapnic CBF responses are abnormally increased in PD patients with levodopa-induced dyskinesias (LID) but not in their nondyskinetic (NLID) counterparts. We used H215O PET to scan 24 unmedicated PD subjects (12 LID and 12 NLID) and 12 matched healthy subjects in the rest state under normocapnic and hypercapnic conditions. Hypercapnic CBF responses were compared to corresponding levodopa responses from the same subjects. Group differences in hypercapnic vasoreactivity were significant only in the posterior putamen, with greater CBF responses in LID subjects compared with the other subjects. Hypercapnic and levodopa-mediated CBF responses measured in this region exhibited distinct associations with disease severity: the former correlated with off-state motor disability ratings but not symptom duration, whereas the latter correlated with symptom duration but not motor disability. These are the first in vivo human findings linking LID to microvascular changes in the basal ganglia.

Compact Intraoperative MRI: Stereotactic Accuracy and Future Directions.

BACKGROUND: Intraoperative imaging must supply data that can be used for accurate stereotactic navigation. This information should be at least as accurate as that acquired from diagnostic imagers. OBJECTIVES: The aim of this study was to compare the stereotactic accuracy of an updated compact intraoperative MRI (iMRI) device based on a 0.15-T magnet to standard surgical navigation on a 1.5-T diagnostic scan MRI and to navigation with an earlier model of the same system. METHODS: The accuracy of each system was assessed using a water-filled phantom model of the brain. Data collected with the new system were compared to those obtained in a previous study assessing the older system. The accuracy of the new iMRI was measured against standard surgical navigation on a 1.5-T MRI using T1-weighted (W) images. RESULTS: The mean error with the iMRI using T1W images was lower than that based on images from the 1.5-T scan (1.24 vs. 2.43 mm). T2W images from the newer iMRI yielded a lower navigation error than those acquired with the prior model (1.28 vs. 3.15 mm). CONCLUSIONS: Improvements in magnet design can yield progressive increases in accuracy, validating the concept of compact, low-field iMRI. Avoiding the need for registration between image and surgical space increases navigation accuracy.

Repurposing Mebendazole as a Replacement for Vincristine for the Treatment of Brain Tumors.

The microtubule inhibitor vincristine is currently used to treat a variety of brain tumors, including low-grade glioma and anaplastic oligodendroglioma. Vincristine, however, does not penetrate well into brain tumor tissue, and moreover, it displays dose-limiting toxicities, including peripheral neuropathy. Mebendazole, a Food and Drug Administration-approved anthelmintic drug with a favorable safety profile, has recently been shown to display strong therapeutic efficacy in animal models of both glioma and medulloblastoma. Importantly, appropriate formulations of mebendazole yield therapeutically effective concentrations in the brain. Mebendazole has been shown to inhibit microtubule formation, but it is not known whether its potency against tumor cells is mediated by this inhibitory effect. To investigate this, we examined the effects of mebendazole on GL261 glioblastoma cell viability, microtubule polymerization and metaphase arrest, and found that the effective concentrations to inhibit these functions are very similar. In addition, using mebendazole as a seed for the National Cancer Institute (NCI) COMPARE program revealed that the top-scoring drugs were highly enriched in microtubule-targeting drugs. Taken together, these results indicate that the cell toxicity of mebendazole is indeed caused by inhibiting microtubule formation. We also compared the therapeutic efficacy of mebendazole and vincristine against GL261 orthotopic tumors. We found that mebendazole showed a significant increase in animal survival time, whereas vincristine, even at a dose close to its maximum tolerated dose, failed to show any efficacy. In conclusion, our results strongly support the clinical use of mebendazole as a replacement for vincristine for the treatment of brain tumors.

Pharmacological Inhibition of the Protein Kinase MRK/ZAK Radiosensitizes Medulloblastoma.

Medulloblastoma is a cerebellar tumor and the most common pediatric brain malignancy. Radiotherapy is part of the standard care for this tumor, but its effectiveness is accompanied by significant neurocognitive sequelae due to the deleterious effects of radiation on the developing brain. We have previously shown that the protein kinase MRK/ZAK protects tumor cells from radiation-induced cell death by regulating cell-cycle arrest after ionizing radiation. Here, we show that siRNA-mediated MRK depletion sensitizes medulloblastoma primary cells to radiation. We have, therefore, designed and tested a specific small molecule inhibitor of MRK, M443, which binds to MRK in an irreversible fashion and inhibits its activity. We found that M443 strongly radiosensitizes UW228 medulloblastoma cells as well as UI226 patient-derived primary cells, whereas it does not affect the response to radiation of normal brain cells. M443 also inhibits radiation-induced activation of both p38 and Chk2, two proteins that act downstream of MRK and are involved in DNA damage-induced cell-cycle arrest. Importantly, in an animal model of medulloblastoma that employs orthotopic implantation of primary patient-derived UI226 cells in nude mice, M443 in combination with radiation achieved a synergistic increase in survival. We hypothesize that combining radiotherapy with M443 will allow us to lower the radiation dose while maintaining therapeutic efficacy, thereby minimizing radiation-induced side effects. Mol Cancer Ther; 15(8); 1799-808. ©2016 AACR.