Emergency Department Process Times and Door-In-Door-Out Times in Interhospital Transfers After Acute Ischemic Stroke.

Importance: Stroke treatment is exquisitely time sensitive. The door-in-door-out (DIDO) time, defined as the total time spent in the emergency department (ED) at a transferring hospital, is an important quality metric for the care of acute stroke. However, little is known about the contributions of specific process steps to delays and disparities in DIDO time. Objective: To quantify process steps and their association with DIDO times at transferring hospitals among patients with acute ischemic stroke (AIS). Design, Setting, and Participants: This retrospective cohort study analyzed patients in the American Heart Association Get With the Guidelines-Stroke registry with AIS presenting between January 1, 2019, to December 31, 2021, and transferred from the presenting hospital ED to another acute care hospital for evaluation of thrombolytics, endovascular therapy, or postthrombolytic care. Data were analyzed from July 8 to October 13, 2023. Exposures: Intervals of ED care of ischemic stroke: door-to-imaging and imaging-to-door times. Main Outcomes and Measures: The primary outcome was DIDO time. Multivariate generalized estimating equations regression models were performed to compare contributions of interval process times to explain variation in DIDO time, controlling for patient- and hospital-level characteristics. Results: Among 28 887 patients (50.5% male; mean [SD] age, 68.3 [14.8] years; 5.5% Hispanic, 14.7% non-Hispanic Black, and 73.2% non-Hispanic White), mean (SD) DIDO time was 171.4 (149.5) minutes, mean (SD) door-to-imaging time was 18.3 (34.1) minutes, and mean (SD) imaging-to-door time was 153.1 (141.5) minutes. In the model adjusting for door-to-imaging time, the following were associated with longer DIDO time: age 80 years or older (compared with 18-59 years; 5.97 [95% CI, 1.02-10.92] minutes), female sex (5.21 [95% CI, 1.55-8.87] minutes), and non-Hispanic Black race (compared with non-Hispanic White 10.09 [95% CI, 4.21-15.96] minutes). In the model including imaging-to-door time as a covariate, disparities in DIDO by age and female sex became nonsignificant, and the disparity by Black race was attenuated (2.32 [95% CI, 1.09-3.56] minutes). Conclusions and Relevance: In this national cohort study of interhospital transfer of patients with AIS, delays in DIDO time by Black race, older age (≥80 years), and female sex were largely explained by the imaging-to-door period, suggesting that future systems interventions should target this interval to reduce these disparities. While existing guidelines and care resources heavily focus on reducing door-to-imaging times, further attention is warranted to reduce imaging-to-door times in the management of patients with AIS who require interhospital transfer.

Understanding Opportunities for Prescribing Pre-exposure Prophylaxis (PrEP) at Two Academic Medical Centers in a High Priority Jurisdiction for Ending the HIV Epidemic.

Introduction: Pre-exposure prophylaxis (PrEP) is an effective, yet underutilized tool for HIV prevention. We sought to understand practice patterns and opportunities for prescribing PrEP across two large, urban, academic healthcare institutions in Chicago, Illinois. Methods: We analyzed electronic medical record data from two institutions including encounters for persons ≥18 years of age with ≥1 negative HIV test between 1/1/2015-12/31/2021 who had indications for PrEP. Eligible encounters were those within a six-month window after STI diagnosis, or as long as injection drug use (IDU) was documented. We categorized encounters as inpatient, emergency department (ED), primary care, infectious disease (ID), obstetrics and gynecology/women's health (OBGYN) and other outpatient settings. We performed bivariable and multivariable mixed effects regression models to examine associations, reporting odds ratios (or adjusted odds ratios) and 95% confidence intervals (OR, aOR, 95% CI). Results: In total, 9644 persons contributed 53031 encounters that resulted in 4653 PrEP prescriptions. The two healthcare institutions had differing patient demographics; institution A had more 18-24 year-olds (58.3% vs 31.3%), more African Americans (83.8% vs 27.9%), and more women (65.7% vs 46.3%). Institution B had more White (40.6% vs 7.1%) and Hispanic persons (14.0% vs 4.2%), and more men who have sex with men (MSM) (15.2% vs 3.3%). Institution A had more eligible encounters in the ED (30.8% vs 7.3%) as well as in infectious disease, inpatient, OBYGN, and primary care settings. Institution B accounted for the majority of PrEP prescriptions (97.0%).Adjusted models found lower odds of PrEP prescriptions in non-Hispanic Black (aOR 0.23 [0.16, 0.32]) and Latino (aOR 0.62 [0.44, 0.89]) patients, those with injection drug use (aOR 0.01 [0.00, 0.09]), men who have sex with women (aOR 0.36 [0.23, 0.56]), women who have sex with men (aOR 0.11 [0.06, 0.19]), and in the ED (ref) or OBGYN (0.11 [0.04, 0.27]) settings; while increased odds of PrEP prescription were associated with non-Hispanic White (ref) and MSM (aOR 24.87 [15.79, 39.15]) patients, and encounters at Institution B (aOR 1.78 [1.25, 2.53]) and in infectious disease (aOR [11.92 [7.65, 18.58]), primary care (aOR 2.76 [1.90, 4.01]), and other outpatient subspecialty settings (aOR 2.67 [1.84, 3.87]). Conclusions: Institution A contained persons historically underrepresented in PrEP prescriptions, while institution B accounted for most PrEP prescriptions. Opportunities exist to improve equity in PrEP prescribing and across ED and OBGYN settings.

Quantification of Collateral Supply with Local-AIF Dynamic Susceptibility Contrast MRI Predicts Infarct Growth.

BACKGROUND AND PURPOSE: In ischemic stroke, leptomeningeal collaterals can provide delayed and dispersed compensatory blood flow to tissue-at-risk despite an occlusion and can impact treatment response and infarct growth. The purpose of this work is to test the hypothesis that inclusion of this delayed and dispersed flow with an appropriately calculated Local Arterial Input Function (Local-AIF) is needed to quantify the degree of collateral blood supply in tissue distal to an occlusion. MATERIALS AND METHODS: Seven experiments were conducted in a pre-clinical middle cerebral artery occlusion model. Dynamic susceptibility contrast MRI was imaged and post-processed to yield quantitative cerebral blood flow (qCBF) maps with both a traditionally chosen single arterial input function applied globally to the whole brain (i.e. "Global-AIF") and a delay and dispersion corrected AIF (i.e. "Local-AIF") that is sensitive to retrograde flow. Leptomeningeal collateral arterial recruitment was quantified with a pial collateral score from x-ray angiograms, and infarct growth calculated from serially acquired diffusion weighted MRI scans. RESULTS: The degree of collateralization at x-ray correlated more strongly with qCBF using the Local-AIF in the ischemic penumbra (R2=0.81) than traditionally chosen Global-AIF (R2=0.05). qCBF using a Local-AIF was negatively correlated (less infarct progression as perfusion increased) with infarct growth (R2 = 0.79) more strongly than a Global-AIF (R2=0.02). CONCLUSIONS: In acute stroke, qCBF calculated with a Local-AIF is more accurate for assessing tissue status and collateral supply than traditionally chosen Global-AIFs. These findings support use of a Local-AIF that corrects for delayed and dispersed retrograde flow in determining quantitative tissue perfusion with collateral supply in occlusive disease. ABBREVIATIONS: MRI = magnetic resonance imaging; DSC = dynamic susceptibility contrast; PCS = pial collateral score; MCAO = middle cerebral artery occlusion; MCA = middle cerebral artery; AIF = arterial input function; rCBF = relative cerebral blood flow; qCBF = quantitative cerebral blood flow.

Multiparametric quantitative magnetic resonance imaging of uterine fibroids for prediction of growth rate-a pilot study.

Background: Uterine fibroid (UF) growth rate and future morbidity cannot be predicted. This can lead to sub-optimal clinical management, with women being lost to follow-up and later presenting with severe disease that may require hospitalization, transfusions, and urgent surgical interventions. Multi-parametric quantitative magnetic resonance imaging (MRI) could provide a biomarker to predict growth rate facilitating better-informed disease management and better clinical outcomes. We assessed the ability of putative quantitative and qualitative MRI predictive factors to predict UF growth rate. Methods: Twenty women with UFs were recruited and completed baseline and follow-up MRI exams, 1-2.5 years apart. The subjects filled out symptom severity and health-related quality of life questionnaires at each visit. A standard clinical pelvic MRI non-contrast exam was performed at each visit, followed by a contrast-enhanced multi-parametric quantitative MRI (mp-qMRI) exam with T2, T2*, and apparent diffusion coefficient (ADC) mapping and dynamic contrast-enhanced MRI. Up to 3 largest fibroids were identified and outlined on the T2-weighted sequence. Fibroid morphology and enhancement patterns were qualitatively assessed on dynamic contrast-enhanced MRI. The UFs' volumes and average T2, T2*, and ADC values were calculated. Pearson correlation coefficients were calculated between UF growth rate and T2, T2*, ADC, and baseline volume. Multiple logistic regression and receiver operating characteristic (ROC) analysis were performed to predict fast-growing UFs using combinations of up to 2 significant predictors. A significance level of alpha =0.05 was used. Results: Forty-four fibroids in 20 women had growth rate measurement available, and 36 fibroids in 16 women had follow-up quantitative MRI available. The distribution of fibroid growth rate was skewed, with approximately 20% of the fibroids exhibiting fast growth (>10 cc/year). However, there were no significant changes in median baseline and follow-up values of symptom severity and health-related quality of life scores. There was no change in average T2, T2*, and ADC at follow-up exams and there was a moderate to strong correlation to the fibroid growth rate in baseline volume and average T2 and ADC in slow-growing fibroids (<10 cc/year). A multiple logistic regression to identify fast growing UFs (>10 cc/year) achieved an area under the curve (AUC) of 0.80 with specificity of 69% at 100% sensitivity. Conclusions: The mp-qMRI parameters T2, ADC, and UF volume obtained at the time of initial fibroid diagnosis may be able to predict UF growth rate. Mp-qMRI could be integrated into the management of UFs, for individualized care and improved clinical outcomes.

Quantification of Collateral Supply with Local-AIF Dynamic Susceptibility Contrast MRI Predicts Infarct Growth.

Background and purpose: In ischemic stroke, leptomeningeal collaterals can provide compensatory blood flow to tissue at risk despite an occlusion, and impact treatment response and infarct growth. The purpose of this work is to test the hypothesis that local perfusion with an appropriate Local Arterial Input Function (AIF) is needed to quantify the degree of collateral blood supply in tissue distal to an occlusion. Materials and methods: Seven experiments were conducted in a pre-clinical middle cerebral artery occlusion model. Magnetic resonance dynamic susceptibility contrast (DSC) was imaged and post-processed as cerebral blood flow maps with both a traditionally chosen single arterial input function (AIF) applied globally to the whole brain (i.e. "Global-AIF") and a novel automatic delay and dispersion corrected AIF (i.e. "Local AIF") that is sensitive to retrograde flow. Pial collateral recruitment was assessed from x-ray angiograms and infarct growth via serially acquired diffusion weighted MRI scans both blinded to DSC. Results: The degree of collateralization at x-ray correlated strongly with quantitative perfusion determined using the Local AIF in the ischemic penumbra (R2=0.81) compared to a traditionally chosen Global-AIF (R2=0.05). Quantitative perfusion calculated using a Local-AIF was negatively correlated (less infarct progression as local perfusion increased) with infarct growth (R2 = 0.79) compared to Global-AIF (R2=0.02). Conclusions: Local DSC perfusion with a Local-AIF is more accurate for assessing tissue status and degree of leptomeningeal collateralization than traditionally chosen AIFs. These findings support use of a Local-AIF in determining quantitative tissue perfusion with collateral supply in occlusive disease.

Quantitative perfusion and water transport time model from multi b-value diffusion magnetic resonance imaging validated against neutron capture microspheres.

Purpose: Quantification of perfusion in ml/100 g/min, rather than comparing relative values side-to-side, is critical at the clinical and research levels for large longitudinal and multi-center trials. Intravoxel incoherent motion (IVIM) is a non-contrast magnetic resonance imaging diffusion-based scan that uses a multitude of b-values to measure various speeds of molecular perfusion and diffusion, sidestepping inaccuracy of arterial input functions or bolus kinetics. Questions remain as to the original of the signal and whether IVIM returns quantitative and accurate perfusion in a pathology setting. This study tests a novel method of IVIM perfusion quantification compared with neutron capture microspheres. Approach: We derive an expression for the quantification of capillary blood flow in ml/100 g/min by solving the three-dimensional Gaussian probability distribution and defining water transport time (WTT) as when 50% of the original water remains in the tissue of interest. Calculations were verified in a six-subject pre-clinical canine model of normocapnia, CO2 induced hypercapnia, and middle cerebral artery occlusion (ischemic stroke) and compared with quantitative microsphere perfusion. Results: Linear regression analysis of IVIM and microsphere perfusion showed agreement (slope = 0.55, intercept = 52.5, R2=0.64) with a Bland-Altman mean difference of -11.8 [-78,54] ml/100 g/min. Linear regression between dynamic susceptibility contrast mean transit time and IVIM WTT asymmetry in infarcted tissue was excellent (slope=0.59, intercept = 0.3, R2=0.93). Strong linear agreement was found between IVIM and reference standard infarct volume (slope = 1.01, R2=0.79). The simulation of cerebrospinal fluid (CSF) suppression via inversion recovery returned a blood signal reduced by 82% from combined T1 and T2 effects. Conclusions: The accuracy and sensitivity of IVIM provides evidence that observed signal changes reflect cytotoxic edema and tissue perfusion and can be quantified with WTT. Partial volume contamination of CSF may be better removed during post-processing rather than with inversion recovery.

Corrigendum: Absolute oxygen-guided radiation therapy improves tumor control in three preclinical tumor models.

[This corrects the article DOI: 10.3389/fmed.2023.1269689.].

Preconception care utilization: Self-report versus claims-based measures among women with Medicaid.

The objective of this study is to compare self-reported preconception care utilization (PCU) among Medicaid-covered births to Medicaid claims. We identified all Medicaid-covered births to women ages 15-45 in 26 states in the year 2012 among the Pregnancy Risk Assessment and Monitoring System (PRAMS) survey and Medicaid Analytic eXtract (MAX) claims data, and identified preconception services in the latter using diagnosis codes published by Health and Human Services' Office of Population Affairs. We fit mixed-effects logistic regression models for the probability of PCU on sociodemographic factors (age, race, and ethnicity) and clinical diagnoses (depression, diabetes, or hypertension), separately for each dataset. Among 652,929 women delivering in MAX, 28.1% received at least one claims-based preconception service while an estimated 23.6% (95% CI 22.1-25.3) of PRAMS respondents reported receiving preconception care. Adjusting for age, chronic diseases, and state, PCU rates in both MAX and PRAMS were higher for non-Hispanic Black versus non-Hispanic White women (OR 1.51, 95% CI 1.49-1.54 and OR 2.05, 95% CI 1.60-2.62, respectively). Adjusting for differences in age, race and ethnicity, and state, PCU rates were higher for patients with diabetes (OR 1.34, 95% CI 1.29-1.40 and OR 1.82, 95% CI 1.16-2.85) or hypertension (OR 1.22, 95% CI 1.18-1.27 and OR 1.85, 95% CI 1.41-2.44). While Hispanic and Asian women were also more likely to report PCU than their non-Hispanic White counterparts (OR 2.07, 95% CI 1.53-2.80 and OR 3.37, 95% CI 2.28-4.98), they were less likely to have received it (OR 0.74, 95% CI 0.73-0.75 and OR 0.65, 95% CI 0.63-0.67). In conclusion, comparing self-report to claims measures of PCU, we found similar trends in the differences between non-Hispanic Black and White women, and between those with vs. without diabetes and hypertension. However, the two data sources differed in trends in other racial/ethnic groups (differences between Hispanic vs. non-Hispanic White women, and between Asian vs. non-Hispanic White women), and in those with vs. without depression. This suggests that while Medicaid claims can be a useful tool for studying preconception care, they may miss certain types of care among some sub-groups of the population or be subject to reporting differences that are hard to surmise. Both data sets have potential benefits and drawbacks as research tools.

Vulnerable and Stabilized States After Cerebral Ischemic Events: Implications of Kinetic Modeling in the SOCRATES, POINT, and THALES Trials.

BACKGROUND AND OBJECTIVES: Trials of acute secondary prevention after minor stroke or transient ischemic attack (TIA), such as SOCRATES, POINT, and THALES, demonstrate a high initial rate of recurrence after ischemic events that drop quickly to a lower rate, suggesting a transient vulnerable clinical state, which may call for different treatments than the subsequent stabilized state. A kinetic model incorporating vulnerable and stabilized states provides estimates of the distinct kinetic rates reflecting the temporal features of underlying stroke mechanisms. We aimed to compare these kinetic rates between treatments and across trials, asking whether these features point to common pathophysiologic processes underlying stroke recurrence, and inform the targeting and timing of enhanced antiplatelet therapy in recurrent stroke prevention. METHODS: Kaplan-Meier recurrence-free survival curves in the SOCRATES, POINT, and THALES trials were estimated for each treatment group and fitted by nonlinear regression to the 2-state kinetic model, producing estimates of kinetic parameters, with standard errors estimated using the nonparametric bootstrap with repetitive resampling. RESULTS: For each trial, the 2-state kinetic model fit the survival curves better than did the null (single-state) kinetic model or the Weibull model (p < 0.05). Recurrence rates in the vulnerable state (k 1 ) were 100-fold higher than in the stabilized state (k 2 ). Transition rates from the vulnerable to stabilized state (k 0 ) were still more rapid. Kinetic parameters were consistent across the trials, without significant differences between the trials. Enhanced antiplatelet regimens produced significant reductions in k 1 (aspirin alone: 0.030 ± 0.004 d-1; active treatment: 0.016 ± 0.003 d-1; p < 0.01) but did not affect k 0 or k 2 , suggesting that active treatment only affected risk in the vulnerable state. Modeling based on these kinetic parameters suggests that most of the benefit of active treatment occurred within 3 days. DISCUSSION: Across multiple trials of acute secondary prevention after minor stroke or TIA, recurrence of stroke is well-described by a 2-state kinetic model postulating vulnerable and stabilized states, with similar kinetic parameters across trials. Enhanced antiplatelet regimens only affected the recurrence rates in the vulnerable state, over a brief period. This analysis suggests that 2 distinct states follow acute cerebral ischemic events, subject to differential impact of immediate or delayed therapies.

Absolute oxygen-guided radiation therapy improves tumor control in three preclinical tumor models.

Background: Clinical attempts to find benefit from specifically targeting and boosting resistant hypoxic tumor subvolumes have been promising but inconclusive. While a first preclinical murine tumor type showed significant improved control with hypoxic tumor boosts, a more thorough investigation of efficacy from boosting hypoxic subvolumes defined by electron paramagnetic resonance oxygen imaging (EPROI) is necessary. The present study confirms improved hypoxic tumor control results in three different tumor types using a clonogenic assay and explores potential confounding experimental conditions. Materials and methods: Three murine tumor models were used for multi-modal imaging and radiotherapy: MCa-4 mammary adenocarcinomas, SCC7 squamous cell carcinomas, and FSa fibrosarcomas. Registered T2-weighted MRI tumor boundaries, hypoxia defined by EPROI as pO2 ≤ 10 mmHg, and X-RAD 225Cx CT boost boundaries were obtained for all animals. 13 Gy boosts were directed to hypoxic or equal-integral-volume oxygenated tumor regions and monitored for regrowth. Kaplan-Meier survival analysis was used to assess local tumor control probability (LTCP). The Cox proportional hazards model was used to assess the hazard ratio of tumor progression of Hypoxic Boost vs. Oxygenated Boost for each tumor type controlling for experimental confounding variables such as EPROI radiofrequency, tumor volume, hypoxic fraction, and delay between imaging and radiation treatment. Results: An overall significant increase in LTCP from Hypoxia Boost vs. Oxygenated Boost treatments was observed in the full group of three tumor types (p < 0.0001). The effects of tumor volume and hypoxic fraction on LTCP were dependent on tumor type. The delay between imaging and boost treatments did not have a significant effect on LTCP for all tumor types. Conclusion: This study confirms that EPROI locates resistant tumor hypoxic regions for radiation boost, increasing clonogenic LTCP, with potential enhanced therapeutic index in three tumor types. Preclinical absolute EPROI may provide correction for clinical hypoxia images using additional clinical physiologic MRI.

Variation in HIV Transmission Behaviors Among People Who Use Drugs in Rural US Communities.

Importance: People who use drugs (PWUD) continue to be at risk of HIV infection, but the frequency and distribution of transmission-associated behaviors within various rural communities is poorly understood. Objective: To examine the association of characteristics of rural PWUD with HIV transmission behaviors. Design, Setting, and Participants: In this cross-sectional study, surveys of PWUD in rural communities in 10 states (Illinois, Kentucky, New Hampshire, Massachusetts, North Carolina, Ohio, Oregon, Vermont, West Virginia, and Wisconsin) were collected January 2018 through March 2020 and analyzed August through December 2022. A chain-referral sampling strategy identified convenience sample seeds who referred others who used drugs. Rural PWUD who reported any past 30-day injection drug use or noninjection opioid use "to get high" were included. Exposures: Individual characteristics, including age, race, gender identity, sexual orientation, partnership status, drug of choice, and location, were collected. Main Outcomes and Measures: Past 30-day frequency of behaviors associated with HIV transmission, including drug injection, syringe sharing, opposite- and same-gender partners, transactional sex, and condomless sex, was assessed. Results: Of 3048 rural PWUD (mean [SD] age, 36.1 [10.3] years; 225 American Indian [7.4%], 96 Black [3.2%], and 2576 White [84.5%] among 3045 with responses; and 1737 men [57.0%] among 3046 with responses), most participants were heterosexual (1771 individuals [86.8%] among 2040 with responses) and single (1974 individuals [68.6%] among 2879 with responses). Opioids and stimulants were reported as drug of choice by 1636 individuals (53.9%) and 1258 individuals (41.5%), respectively, among 3033 individuals with responses. Most participants reported recent injection (2587 of 3046 individuals [84.9%] with responses) and condomless sex (1406 of 1757 individuals [80.0%] with responses), among whom 904 of 1391 individuals (65.0%) with responses indicated that it occurred with people who inject drugs. Syringe sharing (1016 of 2433 individuals [41.8%] with responses) and transactional sex (230 of 1799 individuals [12.8%] with responses) were reported less frequently. All characteristics and behaviors, except the number of men partners reported by women, varied significantly across locations (eg, mean [SD] age ranged from 34.5 [10.0] years in Wisconsin to 39.7 [11.0] years in Illinois; P < .001). In multivariable modeling, younger age (adjusted odds ratio [aOR] for ages 15-33 vs ≥34 years, 1.36; 95% CI, 1.08-1.72) and being single (aOR, 1.37; 95% CI, 1.08-1.74) were associated with recent injection; younger age (aOR, 1.49; 95% CI, 1.20-1.85) and bisexual orientation (aOR vs heterosexual orientation, 2.27; 95% CI, 1.60-3.23) with syringe sharing; gender identity as a woman (aOR vs gender identity as a man, 1.46; 95% CI, 1.01-2.12), bisexual orientation (aOR vs heterosexual orientation, 2.59; 95% CI, 1.67-4.03), and being single (aOR, 1.71; 95% CI, 1.15-2.55) with transactional sex; and bisexual orientation (aOR vs heterosexual orientation, 1.60; 95% CI, 1.04-2.46) and stimulants as the drug of choice (aOR vs opioids, 1.45; 95 CI, 1.09-1.93) with condomless sex with someone who injects drugs. Conclusions and Relevance: This study found that behaviors associated with HIV transmission were common and varied across communities. These findings suggest that interventions to reduce HIV risk among rural PWUD may need to be tailored to locally relevant factors.

Door-in-Door-out Times for Interhospital Transfer of Patients With Stroke.

Importance: Treatments for time-sensitive acute stroke are not available at every hospital, often requiring interhospital transfer. Current guidelines recommend hospitals achieve a door-in-door-out time of no more than 120 minutes at the transferring emergency department (ED). Objective: To evaluate door-in-door-out times for acute stroke transfers in the American Heart Association Get With The Guidelines-Stroke registry and to identify patient and hospital factors associated with door-in-door-out times. Design, Setting, and Participants: US registry-based, retrospective study of patients with ischemic or hemorrhagic stroke from January 2019 through December 2021 who were transferred from the ED at registry-affiliated hospitals to other acute care hospitals. Exposure: Patient- and hospital-level characteristics. Main Outcomes and Measures: The primary outcome was the door-in-door-out time (time of transfer out minus time of arrival to the transferring ED) as a continuous variable and a categorical variable (≤120 minutes, >120 minutes). Generalized estimating equation (GEE) regression models were used to identify patient and hospital-level characteristics associated with door-in-door-out time overall and in subgroups of patients with hemorrhagic stroke, acute ischemic stroke eligible for endovascular therapy, and acute ischemic stroke transferred for reasons other than endovascular therapy. Results: Among 108 913 patients (mean [SD] age, 66.7 [15.2] years; 71.7% non-Hispanic White; 50.6% male) transferred from 1925 hospitals, 67 235 had acute ischemic stroke and 41 678 had hemorrhagic stroke. Overall, the median door-in-door-out time was 174 minutes (IQR, 116-276 minutes): 29 741 patients (27.3%) had a door-in-door-out time of 120 minutes or less. The factors significantly associated with longer median times were age 80 years or older (vs 18-59 years; 14.9 minutes, 95% CI, 12.3 to 17.5 minutes), female sex (5.2 minutes; 95% CI, 3.6 to 6.9 minutes), non-Hispanic Black vs non-Hispanic White (8.2 minutes, 95% CI, 5.7 to 10.8 minutes), and Hispanic ethnicity vs non-Hispanic White (5.4 minutes, 95% CI, 1.8 to 9.0 minutes). The following were significantly associated with shorter median door-in-door-out time: emergency medical services prenotification (-20.1 minutes; 95% CI, -22.1 to -18.1 minutes), National Institutes of Health Stroke Scale (NIHSS) score exceeding 12 vs a score of 0 to 1 (-66.7 minutes; 95% CI, -68.7 to -64.7 minutes), and patients with acute ischemic stroke eligible for endovascular therapy vs the hemorrhagic stroke subgroup (-16.8 minutes; 95% CI, -21.0 to -12.7 minutes). Among patients with acute ischemic stroke eligible for endovascular therapy, female sex, Black race, and Hispanic ethnicity were associated with a significantly higher door-in-door-out time, whereas emergency medical services prenotification, intravenous thrombolysis, and a higher NIHSS score were associated with significantly lower door-in-door-out times. Conclusions and Relevance: In this US registry-based study of interhospital transfer for acute stroke, the median door-in-door-out time was 174 minutes, which is longer than current recommendations for acute stroke transfer. Disparities and modifiable health system factors associated with longer door-in-door-out times are suitable targets for quality improvement initiatives.

Improving reader accuracy and specificity with the addition of hybrid multidimensional-MRI to multiparametric-MRI in diagnosing clinically significant prostate cancers.

PURPOSE: Compare reader performance when adding the Hybrid Multidimensional-MRI (HM-MRI) map to multiparametric MRI (mpMRI+HM-MRI) versus mpMRI alone and inter-reader agreement in diagnosing clinically significant prostate cancers (CSPCa). METHODS: All 61 patients who underwent mpMRI (T2-, diffusion-weighted (DWI), and contrast-enhanced scans) and HM-MRI (with multiple TE/b-value combinations) before prostatectomy or MRI-fused-transrectal ultrasound-guided biopsy between August, 2012 and February, 2020, were retrospectively analyzed. Two experienced readers (R1, R2) and two less-experienced readers (less than 6-year MRI prostate experience) (R3, R4) interpreted mpMRI without/with HM-MRI in the same sitting. Readers recorded the PI-RADS 3-5 score, lesion location, and change in score after adding HM-MRI. Each radiologist's mpMRI+HM-MRI and mpMRI performance measures (AUC, sensitivity, specificity, PPV, NPV, and accuracy) based on pathology, and Fleiss' kappa inter-reader agreement was calculated and compared. RESULTS: Per-sextant R3 and R4 mpMRI+HM-MRI accuracy (82% 81% vs. 77%, 71%; p=.006, <.001) and specificity (89%, 88% vs. 84%, 75%; p=.009, <.001) were higher than with mpMRI. Per-patient R4 mpMRI+HM-MRI specificity improved (48% from 7%; p<.001). R1 and R2 mpMRI+HM-MRI specificity per-sextant (80%, 93% vs. 81%, 93%; p=.51,>.99) and per-patient (37%, 41% vs. 48%, 37%; p=.16, .57) remained similar to mpMRI. R1 and R2 per-patient AUC with mpMRI+HM-MRI (0.63, 0.64 vs. 0.67, 0.61; p=.33, .36) remained similar to mpMRI, but R3 and R4 mpMRI+HM-MRI AUC (0.73, 0.62) approached R1 and R2 AUC. Per-patient inter-reader agreement, mpMRI+HM-MRI Fleiss Kappa, was higher than mpMRI (0.36 [95% CI 0.26, 0.46] vs. 0.17 [95% CI 0.07, 0.27]); p=.009). CONCLUSION: Adding HM-MRI to mpMRI (mpMRI+HM-MRI) improved specificity and accuracy for less-experienced readers, improving overall inter-reader agreement.

Subsampling based variable selection for generalized linear models.

A novel variable selection method for low-dimensional generalized linear models is introduced. The new approach called AIC OPTimization via STABility Selection (OPT-STABS) repeatedly subsamples the data, minimizes Akaike's Information Criterion (AIC) over a sequence of nested models for each subsample, and includes in the final model those predictors selected in the minimum AIC model in a large fraction of the subsamples. New methods are also introduced to establish an optimal variable selection cutoff over repeated subsamples. An extensive simulation study examining a variety of proposec variable selection methods shows that, although no single method uniformly outperforms the others in all the scenarios considered, OPT-STABS is consistently among the best-performing methods in most settings while it performs competitively for the rest. This is in contrast to other candidate methods which either have poor performance across the board or exhibit good performance in some settings, but very poor in others. In addition, the asymptotic properties of the OPT-STABS estimator are derived, and its root-n consistency and asymptotic normality are proved. The methods are applied to two datasets involving logistic and Poisson regressions.

A population-based evaluation of tunica vaginalis mesothelioma: An analysis of the National Cancer Database.

PURPOSE: Primary mesothelioma of the tunica vaginalis (TVM) is a rare and poorly understood malignancy with insufficient population-level data to guide management decisions. MATERIALS AND METHODS: A retrospective analysis of TVM cases recorded in the National Cancer Database from 2004 to 2015 was performed. Cases were identified using International Classification of Diseases for Oncology histology codes. Associations between demographic, clinical and therapeutic factors were analyzed using Kaplan-Meier survival estimates for overall survival (OS) and Cox proportional hazard modeling. Propensity score matching for receipt of systemic chemotherapy was performed to assess the impact on OS. RESULTS: One hundred fifty-one men with a median age of 65 years (interquartile range [IQR] 51-78) were included. Median OS from diagnosis was 72.5 months (IQR 20.2-Not Reached [NR]) after a median follow up of 34.9 months. Multivariate analysis demonstrated an increased risk of death for patients in the fourth quartile of age (hazard ratio [HR] 5.57, 95% confidence interval [CI] 1.70-18.17, P = 0.004), those with biphasic or fibrous histology (HR 2.59, 95% CI 1.15-6.42, P = 0.04) and positive surgical margins (HR 3.27, 95% CI 1.61-6.63, P = 0.001). There was no significant difference in OS associated with receiving chemotherapy (P = 0.5) even after propensity score matching (P = 0.07). CONCLUSIONS: Margin-negative surgical resection is paramount to improving OS. There are insufficient data to recommend for or against adjuvant systemic chemotherapy or RT, although the limited available data does not suggest apparent benefit in terms of OS.

Immunomodulatory fecal metabolites are associated with mortality in COVID-19 patients with respiratory failure.

Respiratory failure and mortality from COVID-19 result from virus- and inflammation-induced lung tissue damage. The intestinal microbiome and associated metabolites are implicated in immune responses to respiratory viral infections, however their impact on progression of severe COVID-19 remains unclear. We prospectively enrolled 71 patients with COVID-19 associated critical illness, collected fecal specimens within 3 days of medical intensive care unit admission, defined microbiome compositions by shotgun metagenomic sequencing, and quantified microbiota-derived metabolites (NCT #04552834). Of the 71 patients, 39 survived and 32 died. Mortality was associated with increased representation of Proteobacteria in the fecal microbiota and decreased concentrations of fecal secondary bile acids and desaminotyrosine (DAT). A microbiome metabolic profile (MMP) that accounts for fecal secondary bile acids and desaminotyrosine concentrations was independently associated with progression of respiratory failure leading to mechanical ventilation. Our findings demonstrate that fecal microbiota composition and microbiota-derived metabolite concentrations can predict the trajectory of respiratory function and death in patients with severe SARS-Cov-2 infection and suggest that the gut-lung axis plays an important role in the recovery from COVID-19.

Racial and ethnic disparities in the observed COVID-19 case fatality rate among the U.S. population.

PURPOSE: During the initial 12 months of the pandemic, racial and ethnic disparities in COVID-19 death rates received considerable attention but it has been unclear whether disparities in death rates were due to disparities in case fatality rates (CFRs), incidence rates or both. We examined differences in observed COVID-19 CFRs between U.S. White, Black/African American, and Latinx individuals during this period. METHODS: Using data from the COVID Tracking Project and the Centers for Disease Control and Prevention COVID-19 Case Surveillance Public Use dataset, we calculated CFR ratios comparing Black and Latinx to White individuals, both overall and separately by age group. We also used a model of monthly COVID-19 deaths to estimate CFR ratios, adjusting for age, gender, and differences across states and time. RESULTS: Overall Black and Latinx individuals had lower CFRs than their White counterparts. However, when adjusting for age, Black and Latinx had higher CFRs than White individuals among those younger than 65. CFRs varied substantially across states and time. CONCLUSIONS: Disparities in COVID-19 case fatality among U.S. Black and Latinx individuals under age 65 were evident during the first year of the pandemic. Understanding racial and ethnic differences in COVID-19 CFRs is challenging due to limitations in available data.

Comparing Radiologist Performance in Diagnosing Clinically Significant Prostate Cancer with Multiparametric versus Hybrid Multidimensional MRI.

Background Variability of acquisition and interpretation of prostate multiparametric MRI (mpMRI) persists despite implementation of the Prostate Imaging Reporting and Data System (PI-RADS) version 2.1 due to the range of reader experience and subjectivity of lesion characterization. A quantitative method, hybrid multidimensional MRI (HM-MRI), may introduce objectivity. Purpose To compare performance, interobserver agreement, and interpretation time of radiologists using mpMRI versus HM-MRI to diagnose clinically significant prostate cancer. Materials and Methods In this retrospective analysis, men with prostatectomy or MRI-fused transrectal US biopsy-confirmed prostate cancer underwent mpMRI (triplanar T2-weighted, diffusion-weighted, and dynamic contrast-enhanced imaging) and HM-MRI (with multiple echo times and b value combinations) from August 2012 to February 2020. Four readers with 1-20 years of experience interpreted mpMRI and HM-MRI examinations independently, with a 4-week washout period between interpretations. PI-RADS score, lesion location, and interpretation time were recorded. mpMRI and HM-MRI interpretation time, interobserver agreement (Cronbach alpha), and performance of area under the receiver operating characteristic curve (AUC) analysis were compared for each radiologist with use of bootstrap analysis. Results Sixty-one men (mean age, 61 years ± 8 [SD]) were evaluated. Per-patient AUC was higher for HM-MRI for reader 4 compared with mpMRI (AUCs for readers 1-4: 0.61, 0.71, 0.59, and 0.64 vs 0.66, 0.60, 0.50, and 0.46; P = .57, .20, .32, and .04, respectively). Per-patient specificity was higher for HM-MRI for readers 2-4 compared with mpMRI (specificity for readers 1-4: 48%, 78%, 48%, and 46% vs 37%, 26%, 0%, and 7%; P = .34, P < .001, P < .001, and P < .001, respectively). Diagnostic performance improved for the reader least experienced with HM-MRI, reader 4 (AUC, 0.64 vs 0.46; P = .04). HM-MRI interobserver agreement (Cronbach alpha = 0.88 [95% CI: 0.82, 0.92]) was higher than that of mpMRI (Cronbach alpha = 0.26 [95% CI: 0.10, 0.52]; α > .60 indicates reliability; P = .03). HM-MRI mean interpretation time (73 seconds ± 43 [SD]) was shorter than that of mpMRI (254 seconds ± 133; P = .03). Conclusion Radiologists had similar or improved diagnostic performance, higher interobserver agreement, and lower interpretation time for clinically significant prostate cancer with hybrid multidimensional MRI than multiparametric MRI. © RSNA, 2022 Online supplemental material is available for this article. See also the editorial by Turkbey in this issue.

Directional and inter-acquisition variability in diffusion-weighted imaging and editing for restricted diffusion.

PURPOSE: To evaluate and quantify inter-directional and inter-acquisition variation in diffusion-weighted imaging (DWI) and emphasize signals that report restricted diffusion to enhance cancer conspicuity, while reducing the effects of local microscopic motion and magnetic field fluctuations. METHODS: Ten patients with biopsy-proven prostate cancer were studied under an Institutional Review Board-approved protocol. Individual acquisitions of DWI signal intensities were reconstructed to calculate inter-acquisition distributions and their statistics, which were compared for healthy versus cancer tissue. A method was proposed to detect and filter the acquisitions affected by motion-induced signal loss. First, signals that reflect restricted diffusion were separated from the acquisitions that suffer from signal loss, likely due to microscopic motion, by imposing a cutoff value. Furthermore, corrected apparent diffusion coefficient maps were calculated by employing a weighted sum of the multiple acquisitions, instead of conventional averaging. These weights were calculated by applying a soft-max function to the set of acquisitions per-voxel, making the analysis immune to acquisitions with significant signal loss, even if the number of such acquisitions is high. RESULTS: Inter-acquisition variation is much larger than the Rician noise variance, local spatial variations, and the estimates of diffusion anisotropy based on the current data, as well as the published values of anisotropy. The proposed method increases the contrast for cancers and yields a sensitivity of 98 . 8 % $$ 98.8\% $$ with a false positive rate of 3 . 9 % $$ 3.9\% $$ . CONCLUSION: Motion-induced signal loss makes conventional signal-averaging suboptimal and can obscure signals from areas with restricted diffusion. Filtering or weighting individual acquisitions prior to image analysis can overcome this problem.

The optimal 18F-fluoromisonidazole PET threshold to define tumor hypoxia in preclinical squamous cell carcinomas using pO2 electron paramagnetic resonance imaging as reference truth.

PURPOSE: To identify the optimal threshold in 18F-fluoromisonidazole (FMISO) PET images to accurately locate tumor hypoxia by using electron paramagnetic resonance imaging (pO2 EPRI) as ground truth for hypoxia, defined by pO2 [Formula: see text] 10 mmHg. METHODS: Tumor hypoxia images in mouse models of SCCVII squamous cell carcinoma (n = 16) were acquired in a hybrid PET/EPRI imaging system 2 h post-injection of FMISO. T2-weighted MRI was used to delineate tumor and muscle tissue. Dynamic contrast enhanced (DCE) MRI parametric images of Ktrans and ve were generated to model tumor vascular properties. Images from PET/EPR/MRI were co-registered and resampled to isotropic 0.5 mm voxel resolution for analysis. PET images were converted to standardized uptake value (SUV) and tumor-to-muscle ratio (TMR) units. FMISO uptake thresholds were evaluated using receiver operating characteristic (ROC) curve analysis to find the optimal FMISO threshold and unit with maximum overall hypoxia similarity (OHS) with pO2 EPRI, where OHS = 1 shows perfect overlap and OHS = 0 shows no overlap. The means of dice similarity coefficient, normalized Hausdorff distance, and accuracy were used to define the OHS. Monotonic relationships between EPRI/PET/DCE-MRI were evaluated with the Spearman correlation coefficient ([Formula: see text]) to quantify association of vasculature on hypoxia imaged with both FMISO PET and pO2 EPRI. RESULTS: FMISO PET thresholds to define hypoxia with maximum OHS (both OHS = 0.728 [Formula: see text] 0.2) were SUV [Formula: see text] 1.4 [Formula: see text] SUVmean and SUV [Formula: see text] 0.6 [Formula: see text] SUVmax. Weak-to-moderate correlations (|[Formula: see text]|< 0.70) were observed between PET/EPRI hypoxia images with vascular permeability (Ktrans) or fractional extracellular-extravascular space (ve) from DCE-MRI. CONCLUSION: This is the first in vivo comparison of FMISO uptake with pO2 EPRI to identify the optimal FMISO threshold to define tumor hypoxia, which may successfully direct hypoxic tumor boosts in patients, thereby enhancing tumor control.