What Goes into Patient Selection for Lung Cancer Screening? Factors Associated with Clinician Judgments of Suitability for Screening.

Rationale: Achieving the net benefit of lung cancer screening (LCS) depends on optimizing patient selection. Objective: To identify factors associated with clinician assessments that a patient was unlikely to benefit from LCS ("LCS-inappropriate") because of comorbidities or limited life expectancy. Methods: Retrospective analysis of patients assessed for LCS at 30 Veterans Health Administration facilities from January 1, 2015 to February 1, 2021. We conducted hierarchical mixed-effects logistic regression analyses to determine factors associated with clinicians' designations of LCS inappropriateness (primary outcome), accounting for 3-year predicted probability (i.e., competing risk) of non-lung cancer death. Measurements and Main Results: Among 38,487 LCS-eligible patients, 1,671 (4.3%) were deemed LCS-inappropriate by clinicians, whereas 4,383 (11.4%) had an estimated 3-year competing risk of non-lung cancer death greater than 20%. Patients with higher competing risks of non-lung cancer death were more likely to be deemed LCS-inappropriate (odds ratio [OR], 2.66; 95% confidence interval [CI], 2.32-3.05). Older patients (ages 75-80; OR, 1.45; 95% CI, 1.18-1.78) and those with interstitial lung disease (OR, 1.98; 95% CI, 1.51-2.59) were more likely to be deemed LCS-inappropriate than would be explained by competing risk of non-lung cancer death, whereas patients currently smoking (OR, 0.65; 95% CI, 0.58-0.73) were less likely to be deemed LCS-inappropriate, suggesting that clinicians over- or underweighted these factors. The probability of being deemed LCS-inappropriate varied from 0.4% to 74%, depending on the clinician making the assessment (median OR, 3.07; 95% CI, 2.89-3.25). Conclusion: Concerningly, the likelihood that a patient is deemed LCS-inappropriate is more strongly associated with the clinician making the assessment than with patient characteristics. Patient selection may be optimized by providing decision support to help clinicians assess net LCS benefit.

Early Mortality After the First Dose of COVID-19 Vaccination: A Target Trial Emulation.

BACKGROUND: Vaccine hesitancy persists alongside concerns about the safety of coronavirus disease 2019 (COVID-19) vaccines. We aimed to examine the effect of COVID-19 vaccination on risk of death among US veterans. METHODS: We conducted a target trial emulation to estimate and compare risk of death up to 60 days under two COVID-19 vaccination strategies: vaccination within 7 days of enrollment versus no vaccination through follow-up. The study cohort included individuals aged ≥18 years enrolled in the Veterans Health Administration system and eligible to receive a COVID-19 vaccination according to guideline recommendations from 1 March 2021 through 1 July 2021. The outcomes of interest included deaths from any cause and excluding a COVID-19 diagnosis. Observations were cloned to both treatment strategies, censored, and weighted to estimate per-protocol effects. RESULTS: We included 3 158 507 veterans. Under the vaccination strategy, 364 993 received vaccine within 7 days. At 60 days, there were 156 deaths per 100 000 veterans under the vaccination strategy versus 185 deaths under the no vaccination strategy, corresponding to an absolute risk difference of -25.9 (95% confidence limit [CL], -59.5 to 2.7) and relative risk of 0.86 (95% CL, .7 to 1.0). When those with a COVID-19 infection in the first 60 days were censored, the absolute risk difference was -20.6 (95% CL, -53.4 to 16.0) with a relative risk of 0.88 (95% CL, .7 to 1.1). CONCLUSIONS: Vaccination against COVID-19 was associated with a lower but not statistically significantly different risk of death in the first 60 days. These results agree with prior scientific knowledge suggesting vaccination is safe with the potential for substantial health benefits.

Selective Uptake of Macromolecules to the Brain in Microfluidics and Animal Models Using the HAVN1 Peptide as a Blood-Brain Barrier Modulator.

Monoclonal antibodies (mAbs) possess favorable pharmacokinetic properties, high binding specificity and affinity, and minimal off-target effects, making them promising therapeutic agents for central nervous system (CNS) disorders. However, their development as effective therapeutic and diagnostic agents for brain disorders is hindered by their limited ability to efficiently penetrate the blood-brain barrier (BBB). Therefore, it is crucial to develop efficient delivery methods that enhance the penetration of antibodies into the brain. Previous studies have demonstrated the potential of cadherin-derived peptides (i.e., ADTC5, HAVN1 peptides) as BBB modulators (BBBMs) to increase paracellular porosities for penetration of molecules across the BBB. Here, we test the effectiveness of the leading BBBM peptide, HAVN1 (Cyclo(1,6)SHAVSS), in enhancing the permeation of various monoclonal antibodies through the BBB using both in vitro and in vivo systems. In vitro, HAVN1 has been shown to increase the permeability of fluorescently labeled macromolecules, such as a 70 kDa dextran, 50 kDa Fab1, and 150 kDa mAb1, by 4- to 9-fold in a three-dimensional blood-brain barrier (3D-BBB) microfluidics model using a human BBB endothelial cell line (i.e., hCMEC/D3). HAVN1 was selective in modulating the BBB endothelial cell, compared to the pulmonary vascular endothelial (PVE) cell barrier. Co-administration of HAVN1 significantly improved brain depositions of mAb1, mAb2, and Fab1 in C57BL/6 mice after 15 min in the systemic circulation. Furthermore, HAVN1 still significantly enhanced brain deposition of mAb2 when it was administered 24 h after the administration of the mAb. Lastly, we observed that multiple doses of HAVN1 may have a cumulative effect on the brain deposition of mAb2 within a 24-h period. These findings offer promising insights into optimizing HAVN1 and mAb dosing regimens to control or modulate mAb brain deposition for achieving desired mAb dose in the brain to provide its therapeutic effects.

Occupational Radiation Dose Trends in U.S. Radiologic Technologists Assisting with Fluoroscopically Guided Interventional Procedures, 1980-2020.

PURPOSE: To summarize dose trends from 1980 to 2020 for 19,651 U.S. Radiologic Technologists who reported assisting with fluoroscopically guided interventional procedures (FGIPs), overall and by work history characteristics. MATERIALS AND METHODS: A total of 762,310 annual personal dose equivalents at a 10-mm reference depth (doses) during 1980-2020 for 43,823 participants of the U.S. Radiologic Technologists (USRT) cohort who responded to work history questionnaires administered during 2012-2014 were summarized. This population included 19,651 technologists who reported assisting with FGIP (≥1 time per month for ≥12 consecutive months) at any time during the study period. Doses corresponding to assistance with FGIP were estimated in terms of proximity to patients, monthly procedure frequency, and procedure type. Box plots and summary statistics (eg, medians and percentiles) were used to describe annual doses and dose trends. RESULTS: Median annual dose corresponding to assistance with FGIP was 0.65 mSv (interquartile range [IQR], 0.60-1.40 mSv; 95th percentile, 6.80). Higher occupational doses with wider variability were associated with close proximity to patients during assistance with FGIP (median, 1.20 mSv [IQR, 0.60-4.18 mSv]; 95th percentile, 12.66), performing ≥20 FGIPs per month (median, 0.75 mSv [IQR, 0.60-2.40 mSv]; 95th percentile, 9.44), and assisting with high-dose FGIP (median, 0.70 mSv [IQR, 0.60-1.90 mSv]; 95th percentile, 8.30). CONCLUSIONS: Occupational doses corresponding to assistance with FGIP were generally low but varied with exposure frequency, procedure type, and proximity to patients. These results highlight the need for vigilant dose monitoring, radiation safety training, and proper protective equipment.

Cone photoreceptor dysfunction in retinitis pigmentosa revealed by optoretinography.

Retinitis pigmentosa (RP) is the most common group of inherited retinal degenerative diseases, whose most debilitating phase is cone photoreceptor death. Perimetric and electroretinographic methods are the gold standards for diagnosing and monitoring RP and assessing cone function. However, these methods lack the spatial resolution and sensitivity to assess disease progression at the level of individual photoreceptor cells, where the disease originates and whose degradation causes vision loss. High-resolution retinal imaging methods permit visualization of human cone cells in vivo but have only recently achieved sufficient sensitivity to observe their function as manifested in the cone optoretinogram. By imaging with phase-sensitive adaptive optics optical coherence tomography, we identify a biomarker in the cone optoretinogram that characterizes individual cone dysfunction by stimulating cone cells with flashes of light and measuring nanometer-scale changes in their outer segments. We find that cone optoretinographic responses decrease with increasing RP severity and that even in areas where cone density appears normal, cones can respond differently than those in controls. Unexpectedly, in the most severely diseased patches examined, we find isolated cones that respond normally. Short-wavelength-sensitive cones are found to be more vulnerable to RP than medium- and long-wavelength-sensitive cones. We find that decreases in cone response and cone outer-segment length arise earlier in RP than changes in cone density but that decreases in response and length are not necessarily correlated within single cones.

NCRP commentary no. 33-recommendations for stratification of equipment use and radiation safety training for fluoroscopy.

National Council on Radiation Protection and Measurements Commentary No. 33 'Recommendations for Stratification of Equipment Use and Radiation Safety Training for Fluoroscopy' defines an evidence-based, radiation risk classification for fluoroscopically guided procedures (FGPs), provides radiation-related recommendations for the types of fluoroscopes suitable for each class of procedure, and indicates the extent and content of training that ought to be provided to different categories of facility staff who might enter a room where fluoroscopy is or may be performed. For FGP, radiation risk is defined by the type and likelihood of radiation hazards that could be incurred by a patient undergoing a FGP. The Commentary also defines six training groups of facility staff based on their role in the fluoroscopy room. The training groups are based on a combination of job descriptions and the procedures in which these individuals might be involved. The Commentary recommends the extent and content of training that should be provided to each of these training groups. It also provides recommendations on training formats, training frequency, and methods for demonstrating that the learner has acquired the necessary knowledge.

Oral Antiviral Therapy Utilization Among Adults with Recent COVID-19 in the United States.

BACKGROUND: This is the first study, to our knowledge, to assess uptake of oral antiviral treatment (OAV) for COVID-19 in the US and assess whether it is reaching recommended groups. OBJECTIVE: The study evaluated uptake among persons of all ages, with emphasis on utilization among individuals ages 65 + who comprise 75% of all COVID-19 deaths. To maximize public health outreach and benefit, we sought to understand reasons for use and non-use of OAV among individuals 65 + with at least mild COVID-19 symptoms. DESIGN: Data were collected from phase 3.5 of the US Census Household Pulse Survey, during three 2022 time periods: June 1-13, June 29-July 11, and July 27-August 8. PARTICIPANTS: Respondents (n = 12,299) were ages 18 + with active or resolved COVID-19 within the last 4 weeks of their survey participation. MAIN MEASURE(S): Comparisons of demographic variables were made for OAV uptake using the chi-square test of independence. A logistic regression was conducted to identify characteristics of participants independently associated with receipt of an OAV. Comparisons were made with chi-square testing, between those ages 65 + with at least mild symptoms who endorsed one of a number of specific reasons for not using OAV. KEY RESULTS: Utilization was low-17.9% of all respondents, 20.5% of respondents ages 50-64, and 33.9% of respondents 65 years and older received guideline-concordant treatment for their infection. Receipt did not differ by income or sex. The average response across the three phases was 5.4%. Most common reasons for not receiving treatment included having minimal symptoms, not thinking that they needed treatment, and not receiving a recommendation from their healthcare provider. CONCLUSIONS: A minority of increased-risk US residents have accessed early therapy for COVID-19 despite being made available without cost. Responses suggest that efforts to improve patient and provider knowledge could improve utilization to mitigate future COVID-19 hospitalizations.

Patient Radiation Doses in IR Procedures: The American College of Radiology Dose Index Registry-Fluoroscopy Pilot.

PURPOSE: To update normative data on fluoroscopy dose indices in the United States for the first time since the Radiation Doses in Interventional Radiology study in the late 1990s. MATERIALS AND METHODS: The Dose Index Registry-Fluoroscopy pilot study collected data from March 2018 through December 2019, with 50 fluoroscopes from 10 sites submitting data. Primary radiation dose indices including fluoroscopy time (FT), cumulative air kerma (Ka,r), and kerma area product (PKA) were collected for interventional radiology fluoroscopically guided interventional (FGI) procedures. Clinical facility procedure names were mapped to the American College of Radiology (ACR) common procedure lexicon. Distribution parameters including the 10th, 25th, 50th, 75th, 95th, and 99th percentiles were computed. RESULTS: Dose indices were collected for 70,377 FGI procedures, with 50,501 ultimately eligible for analysis. Distribution parameters are reported for 100 ACR Common IDs. FT in minutes, Ka,r in mGy, and PKA in Gy-cm2 are reported in this study as (n; median) for select ACR Common IDs: inferior vena cava filter insertion (1,726; FT: 2.9; Ka,r: 55.8; PKA: 14.19); inferior vena cava filter removal (464; FT: 5.7; Ka,r: 178.6; PKA: 34.73); nephrostomy placement (2,037; FT: 4.1; Ka,r: 39.2; PKA: 6.61); percutaneous biliary drainage (952; FT: 12.4; Ka,r: 160.5; PKA: 21.32); gastrostomy placement (1,643; FT: 3.2; Ka,r: 29.1; PKA: 7.29); and transjugular intrahepatic portosystemic shunt placement (327; FT: 34.8; Ka,r: 813.0; PKA: 181.47). CONCLUSIONS: The ACR DIR-Fluoro pilot has provided state-of-the-practice statistics for radiation dose indices from IR FGI procedures. These data can be used to prioritize procedures for radiation optimization, as demonstrated in this work.

Patient Radiation Doses in Interventional Radiology Procedures: Comparison of Fluoroscopy Dose Indices between the American College of Radiology Dose Index Registry-Fluoroscopy Pilot and the Radiation Doses in Interventional Radiology Study.

PURPOSE: To compare radiation dose index distributions for fluoroscopically guided interventions in interventional radiology from the American College of Radiology (ACR) Fluoroscopy Dose Index Registry (DIR-Fluoro) pilot to those from the Radiation Doses in Interventional Radiology (RAD-IR) study. MATERIALS AND METHODS: Individual and grouped ACR Common identification numbers (procedure types) from the DIR-Fluoro pilot were matched to procedure types in the RAD-IR study. Fifteen comparisons were made. Distribution parameters, including the 10th, 25th, 50th, 75th, and 95th percentiles, were compared for fluoroscopy time (FT), cumulative air kerma (Ka,r), and kerma area product (PKA). Two derived indices were computed using median dose indices. The procedure-averaged reference air kerma rate (Ka,r¯) was computed as Ka,r / FT. The procedure-averaged x-ray field size at the reference point (Ar) was computed as PKA / (Ka,r × 1,000). RESULTS: The median FT was equally likely to be higher or lower in the DIR-Fluoro pilot as it was in the RAD-IR study, whereas the maximum FT was almost twice as likely to be higher in the DIR-Fluoro pilot than it was in the RAD-IR study. The median Ka,r was lower in the DIR-Fluoro pilot for all procedures, as was median PKA. The maximum Ka,r and PKA were more often higher in the DIR-Fluoro pilot than in the RAD-IR study. Ka,r¯ followed the same pattern as Ka,r, whereas Ar was often greater in DIR-Fluoro. CONCLUSIONS: The median dose indices have decreased since the RAD-IR study. The typical Ka,r rates are lower, a result of the use of lower default dose rates. However, opportunities for quality improvement exist, including renewed focus on tight collimation of the imaging field of view.

Juvenile idiopathic epilepsy in Arabian horses is not a single-gene disorder.

Valued for their temperament, beauty, athletic ability, and exhibition in the show ring, Arabian horses are an important component of the horse industry. Juvenile idiopathic epilepsy (JIE), a seizure disorder, is most often reported in Arabian foals from birth to 6 months of age. Affected foals exhibit tonic-clonic seizures lasting as long as 5 min and risking secondary complications like temporary blindness and disorientation. Some foals outgrow this condition, while others die or suffer lifelong complications if not treated. Previous work suggested a strong genetic component to JIE and proposed JIE to be a single-gene trait. In this work, we conducted a genome wide association study (GWAS) in 60 cases of JIE and 120 genetically matched controls, identifying loci suggesting JIE is not caused by a single locus. Coat color (chestnut, gray) phenotypes were used as positive control traits to assess the efficacy of GWAS in this population. Future work will attempt to future define candidate regions and explore a polygenic mode of inheritance.

CEBPß regulation of endogenous IGF-1 in adult sensory neurons can be mobilized to overcome diabetes-induced deficits in bioenergetics and axonal outgrowth.

Aberrant insulin-like growth factor 1 (IGF-1) signaling has been proposed as a contributing factor to the development of neurodegenerative disorders including diabetic neuropathy, and delivery of exogenous IGF-1 has been explored as a treatment for Alzheimer's disease and amyotrophic lateral sclerosis. However, the role of autocrine/paracrine IGF-1 in neuroprotection has not been well established. We therefore used in vitro cell culture systems and animal models of diabetic neuropathy to characterize endogenous IGF-1 in sensory neurons and determine the factors regulating IGF-1 expression and/or affecting neuronal health. Single-cell RNA sequencing (scRNA-Seq) and in situ hybridization analyses revealed high expression of endogenous IGF-1 in non-peptidergic neurons and satellite glial cells (SGCs) of dorsal root ganglia (DRG). Brain cortex and DRG had higher IGF-1 gene expression than sciatic nerve. Bidirectional transport of IGF-1 along sensory nerves was observed. Despite no difference in IGF-1 receptor levels, IGF-1 gene expression was significantly (P < 0.05) reduced in liver and DRG from streptozotocin (STZ)-induced type 1 diabetic rats, Zucker diabetic fatty (ZDF) rats, mice on a high-fat/ high-sugar diet and db/db type 2 diabetic mice. Hyperglycemia suppressed IGF-1 gene expression in cultured DRG neurons and this was reversed by exogenous IGF-1 or the aldose reductase inhibitor sorbinil. Transcription factors, such as NFAT1 and CEBPß, were also less enriched at the IGF-1 promoter in DRG from diabetic rats vs control rats. CEBPß overexpression promoted neurite outgrowth and mitochondrial respiration, both of which were blunted by knocking down or blocking IGF-1. Suppression of endogenous IGF-1 in diabetes may contribute to neuropathy and its upregulation at the transcriptional level by CEBPß can be a promising therapeutic approach.

A new clinical opportunity: Rechallenging penicillin allergy in an outpatient pharmacy.

In the United States, approximately 27 million people have a documented penicillin allergy, but 90% of the allergies are falsely labeled. By rechallenging suspected allergies, a pharmacist can optimize patient care, fulfill antimicrobial stewardship objectives, and educate patients on true allergies. We suggest a protocol that allows pharmacists to investigate the presence of an allergy and conduct a challenge when indicated. The protocol consists of a patient interview, a risk assessment, an oral rechallenge, and the potential for a skin test. The testing and delabeling of penicillin allergies will enhance the practice of antimicrobial stewardship in the outpatient setting. In the changing landscape of pharmacy, community pharmacists can increase their services and improve patient care. Owing to limited documented experience in the outpatient pharmacy, an opportunity to set the standard and be a leader in the field is present.

The epidemiology of mild cognitive impairment, Alzheimer's disease and related dementia in U.S. veterans.

INTRODUCTION: US veterans have a unique dementia risk profile that may be evolving over time. METHODS: Age-standardized incidence and prevalence of Alzheimer's disease (AD), AD and related dementias (ADRD), and mild cognitive impairment (MCI) was estimated from electronic health records (EHR) data for all veterans aged 50 years and older receiving Veterans Health Administration (VHA) care from 2000 to 2019. RESULTS: The annual prevalence and incidence of AD declined, as did ADRD incidence. ADRD prevalence increased from 1.07% in 2000 to 1.50% in 2019, primarily due to an increase in the prevalence of dementia not otherwise specified. The prevalence and incidence of MCI increased sharply, especially after 2010. The prevalence and incidence of AD, ADRD, and MCI were highest in the oldest veterans, in female veterans, and in African American and Hispanic veterans. DISCUSSION: We observed 20-year trends of declining prevalence and incidence of AD, increasing prevalence of ADRD, and sharply increasing prevalence and incidence of MCI.

Clinical pharmacy practitioners' semi-visible labor: building referral relationships in interprofessional collaborative care.

Clinical pharmacy practitioners (CPP) in the Veterans Health Administration (VHA) prescribe medications and help manage chronic conditions such as diabetes, and they are increasingly working as part of interprofessional clinical teams. The challenges of integrating a new role in a clinical team are documented, but we know less about strategies new healthcare providers use to overcome these challenges. We studied how clinical pharmacy practitioners integrated into clinical teams. We conducted telephone interviews with clinical pharmacy practitioners (n = 53) and members of their clinical teams (n = 74), which were recorded, transcribed, and coded for concepts and themes. We identified four major themes. We found CPP perceived VHA as a "safe haven" for interprofessional care but found it necessary to build other prescribers' trust and confidence in their clinical skills to establish the referral relationships they needed for full integration. To facilitate their integration, CPP engaged in relational, untracked labor, which we characterize as semi-visible labor. While both CPP and clinical team members perceived CPPs' semi-visible labor as vital for implementing and maintaining strong interprofessional collaborations, such labor may be unsustainable as a long-term strategy for integrating CPP in clinical teams.

Inequities in coronavirus disease 2019 (COVID-19) Vaccination Rates Among Adolescents in Massachusetts: A Cross-sectional Study.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic has disproportionately affected more socioeconomically disadvantaged persons and areas. We sought to determine how certain sociodemographic factors were correlated to adolescents' COVID-19 vaccination rates in towns and cities ("communities") in the Commonwealth of Massachusetts. METHODS: Data on COVID-19 vaccination rates were obtained over a 20-week period from 30 March 2021 to 10 August 2021. Communities' adolescent (ages 12-19) vaccination rates were compared across quintiles of community-level income, COVID-19 case rate, and proportion of non-Hispanic Black or Hispanic individuals. Other variables included population density and earlier COVID-19 vaccination rates of adolescents and adults, averaged from 30 March to 11 May to determine their effects on vaccination rates on 10 August. Linear and logistic regression was used to estimate individual effects of variables on adolescent vaccination rates. RESULTS: Higher median household income, lower proportion of Black or Hispanic individuals, higher early adolescent COVID-19 vaccination rates, and higher early adult COVID-19 vaccination rates were associated with higher later adolescent COVID-19 vaccination rates. Income per $10 000 (adjusted odds ratio [aOR] = 1.01 [95% confidence interval [CI] = 1.01-1.02]), proportion of Hispanic individuals (aOR = 1.33 [95% CI: 1.13-1.56]), early adolescent COVID-19 vaccination rates (aOR = 5.28 [95% CI: 4.67-5.96]), and early adult COVID-19 vaccination rates (aOR = 2.31 [95% CI: 2.02-2.64]) were associated with higher adolescent COVID-19 vaccination on 10 August, whereas proportion of Black individuals approached significance (aOR = 1.26 [95% CI: .98-1.61]). CONCLUSIONS: Vaccination efforts for adolescents in Massachusetts should focus on boosting vaccination rates early in communities with the lowest incomes and greatest proportion of Hispanic individuals and consider targeting communities with a greater proportion of Black individuals.

Stereotactic radiosurgery for melanoma brain metastases: dose-size response relationship in the era of immunotherapy.

PURPOSE/OBJECTIVE(S): To determine, for intact melanoma brain metastases (MBM) treated with single-fraction stereotactic radiosurgery (SRS), whether planning parameter peripheral dose per lesion diameter (PDLDm, Gy/mm) and lesion control (LC) differs with versus without immunotherapy (IO). MATERIALS/METHODS: We performed a retrospective analysis of patients with intact MBM treated with SRS from 2008 to 2019. Cox-frailty models were constructed to include confounders selected by penalized Cox regression models with a LASSO selector. Interaction effect testing was used to determine whether a significant effect between IO and PDLDm could be demonstrated with respect to LC. RESULTS: The study cohort comprised 67 patients with 244 MBMs treated with SRS (30 patients with 122 lesions treated with both SRS and IO) were included. The logarithm of PDLDm was selected as a predictor of LC (HR 0.307, 95% CI 0.098-0.441), adjusting for IO receipt (HR 0.363, 95% CI 0.108-1.224). Interaction effect testing demonstrated a differential effect of PDLDm by IO receipt, with respect to LC (p = 0.048). Twelve-month LC rates for a 7.5 mm lesion receiving SRS (18 Gy) with IO versus without IO were 87.8% (95% CI 69.0-98.3%) versus 79.8% (95% CI 55.1-93.8%) respectively. CONCLUSION: PDLDm predicted LC in patients with small MBMs treated with single-fraction SRS. We found a differential effect of dose per lesion size and LC by immunotherapy receipt. Future studies are needed to determine whether lower doses of single-fraction SRS afford similarly effective LC for patients with small MBMs receiving immunotherapy.

Is intraoperative MRI use in malignant brain tumor surgery a health care burden? A matched analysis of MarketScan Database.

BACKGROUND: Intraoperative magnetic resonance imaging (iMRI) is a useful adjunct for resection of primary malignant brain tumors (MBTs). The aim of our study is to investigate the impact of iMRI on health care utilization in patients who underwent craniotomy for resection of MBTs. MATERIALS AND METHODS: MarketScan database were queried using the ICD-9/10 and CPT 4th edition, from 2008 to 2020. We included patients ≥ 18 years of age who underwent a craniotomy with at-least one year follow-up. Outcomes were length of stay (LOS), discharge disposition, hospital/emergency room (ER) re-admissions, outpatient services, medication refills and corresponding payments. RESULTS: Of 6,640 patients who underwent craniotomy for MBTs, 465 patients (7%) had iMRI used during the procedure with 0.7% per year increase in iMRI use during the study period. Patients without iMRI use had higher complications at index hospitalization compared to those with iMRI use (19% vs. 14%, p = 0.04). There was no difference in the ER admission rates among the patients who underwent surgery with and without iMRI use at 6-months and 1-year after the index procedure. In terms of post-discharge payments, no significant differences were noted among the patients without and with iMRI use at 6-months ($81,107 vs. $ 81,458, p = 0.26) and 1-year ($132,657 vs. $ 118,113, p = 0.12). CONCLUSION: iMRI use during craniotomy for MBT gradually increased during the study period. iMRI did not result in higher payments at index hospitalization, 6-months, and 1-year after the index procedure.

Mendelian Randomization Analysis of Hemostatic Factors and Their Contribution to Peripheral Artery Disease-Brief Report.

BACKGROUND AND OBJECTIVE: Peripheral artery disease (PAD) is the third most common form of atherosclerotic vascular disease and is characterized by significant functional disability and increased cardiovascular mortality. Recent genetic data support a role for a procoagulation protein variant, the factor V Leiden mutation, in PAD. The role of other hemostatic factors in PAD remains unknown. We evaluated the role of hemostatic factors in PAD using Mendelian randomization. Approach and Results: Two-sample Mendelian randomization to evaluate the roles of FVII (factor VII), FVIII (factor VIII), FXI (factor XI), VWF (von Willebrand factor), and fibrinogen in PAD was performed using summary statistics from GWAS for hemostatic factors performed within the Cohorts for Heart and Aging Research in the Genome Epidemiology Consortium and from GWAS performed for PAD within the Million Veteran Program. Genetically determined FVIII and VWF, but not FVII, FXI, or fibrinogen, were associated with PAD in Mendelian randomization experiments (FVIII: odds ratio, 1.41 [95% CI, 1.23-1.62], P=6.0×10-7, VWF: odds ratio, 1.28 [95% CI, 1.07-1.52], P=0.0073). In single variant sensitivity analysis, the ABO locus was the strongest genetic instrument for both FVIII and VWF. CONCLUSIONS: Our results suggest a role for hemostasis, and by extension, thrombosis in PAD. Further study is warranted to determine whether VWF and FVIII independently affect the biology of PAD.

Cone photoreceptor classification in the living human eye from photostimulation-induced phase dynamics.

Human color vision is achieved by mixing neural signals from cone photoreceptors sensitive to different wavelengths of light. The spatial arrangement and proportion of these spectral types in the retina set fundamental limits on color perception, and abnormal or missing types are responsible for color vision loss. Imaging provides the most direct and quantitative means to study these photoreceptor properties at the cellular scale in the living human retina, but remains challenging. Current methods rely on retinal densitometry to distinguish cone types, a prohibitively slow process. Here, we show that photostimulation-induced optical phase changes occur in cone cells and carry substantial information about spectral type, enabling cones to be differentiated with unprecedented accuracy and efficiency. Moreover, these phase dynamics arise from physiological activity occurring on dramatically different timescales (from milliseconds to seconds) inside the cone outer segment, thus exposing the phototransduction cascade and subsequent downstream effects. We captured these dynamics in cones of subjects with normal color vision and a deuteranope, and at different macular locations by: (i) marrying adaptive optics to phase-sensitive optical coherence tomography to avoid optical blurring of the eye, (ii) acquiring images at high speed that samples phase dynamics at up to 3 KHz, and (iii) localizing phase changes to the cone outer segment, where photoactivation occurs. Our method should have broad appeal for color vision applications in which the underlying neural processing of photoreceptors is sought and for investigations of retinal diseases that affect cone function.

Impact of Wnt/ß-catenin signaling on ethanol-induced changes in brain endothelial cell permeability.

Chronic exposure to ethanol is associated with enhanced leakiness in the brain microvessel endothelial cells that form the blood-brain barrier (BBB). As previous studies suggested Wnt/ß-catenin signaling could improve the BBB phenotype of brain endothelial cells, we examined the extent to which Wnt signaling is altered following ethanol exposure, using both a cell culture model of the BBB and mice exposed to ethanol, and the ability of Wnt activation to reverse the permeability effects of ethanol. The human brain endothelial cells, hCMEC/D3, were exposed to ethanol (17-200 mM) for various periods of time (0-96 hr) and Wnt signaling, as well as expression of downstream genes influencing BBB integrity in the cell monolayers were monitored. Determination of Wnt signaling in both brain homogenates and brain microvessels from mice exposed to ethanol was also performed. The effects of ethanol on the permeability of the hCMEC/D3 monolayers were examined using both small molecular weight (sodium fluorescein) and large molecular weight (IRdye 800CW PEG) fluorescent markers. Exposure of hCMEC/D3 to ethanol (50 mM) caused a down-regulation of Wnt/ß-catenin signaling, a reduction of tight junction protein expression and up-regulation of plasmalemma vesicle associated protein (PLVAP). A similar reduction in Wnt/ß-catenin activity in both cortical brain homogenates and isolated cortical cerebral microvessels were observed in mice. Other areas such as cerebellum and striatum displayed as much as 3-6 fold increases in Dkk-1, an endogenous Wnt inhibitor. Ethanol exposure caused significant changes in both sodium fluorescein and IRdye 800CW PEG permeability (2-fold compared to control). The ethanol-induced increases in permeability were attenuated by treatment with known Wnt activators (i.e. LiCl or Wnt3a). Additional screens of CNS active agents with possible Wnt activity indicated fluoxetine could also prevent the permeability effects of ethanol. These studies suggest that ethanol-induced changes in brain microvessel permeability can be reversed through activation of Wnt signaling.