Citations

In women with dense breasts, adding molecular breast imaging to digital breast tomosynthesis (DBT) increased both overall and invasive cancer detection rates, while modestly raising the recall rate compared with DBT alone.

Purpose: To determine the factors associated with compliance with recommended intravitreal injections (IVIs) for retinal diseases among out-of-pocket, insured, and fully subsidized (non-paying) patients. Methods: This retrospective observational hospital-based study included patients recommended for IVI in at least one eye between November 2011 and May 2022. Three cohorts of patients were assessed: out-of-pocket payers, insured, and those fully subsidized (non-paying) by the hospital. The main outcome measure was the compliance rate, defined as the proportion of patients receiving an injection after one was recommended. The impact on the visual outcome in each cohort was a secondary outcome. Results: Overall, 50,408 IVI were recommended for at least one eye and were included in the analyses. Male patients were more common (66.72%), and the mean age was 55.36 ± 16.39 years. The overall compliance rate with the first recommended injection was 51.37%, which increased and eventually stabilized with subsequent recommendations to approximately 80% (range: 77.48%–82.93%). Insured patients had a higher compliance rate with the first recommendation compared to the non-insured (100% vs. 49.84%; P < 0.000 01 ), and non-paying patients had a higher compliance rate after the first recommendation compared to paying patients (62.51% vs. 48.66%; P < 0.000 01 ). Patients with insurance achieved a better visual outcome at the last follow-up compared to other cohorts. Conclusion: Insured patients have a much higher compliance rate with recommended IVIs compared to out-of-pocket or non-paying patients. The high non-compliance rate among non-paying patients suggests that factors other than the direct cost of the injections may impact compliance with recommended treatment.

Abstract Context Patients with mild autonomous cortisol secretion (MACS) can develop adrenal insufficiency after unilateral adrenalectomy. Objective This work aimed to determine the prevalence, duration, and predictors of adrenal insufficiency, and compare postoperative basal cortisol and cosyntropin stimulation test (CST). Methods In this multicenter retrospective study of patients with MACS, adrenal insufficiency was diagnosed when postoperative basal cortisol was less than 10 µg/dL and/or CST &lt; 18 µg/dL. The results were concordant when both tests met cutoffs. Biochemical (BSS) and clinical severity scores (CSS) were calculated. Results Among 281 patients with MACS (80% women), postoperative adrenal insufficiency was diagnosed in 153 (54.5%) patients. Adrenal insufficiency inversely correlated with age (odds ratio [OR] 0.67 per 10 years; 95% CI, 0.53-0.84). Low basal cortisol and CST were associated with younger age (OR 0.64 per 10 years for both) and higher BSS (OR 1.17 and 1.22, respectively). Basal cortisol and CST were discordant in 22% of patients, and the discordance rate was more common in patients with bilateral nodules (32% vs 19%; P &lt; .001). The median time to adrenal insufficiency recovery was 3.9 months (IQR, 3-5.9 months), with longer duration associated with higher BSS and CSS: 3 months for mild, 4 to 5 months for moderate, and 12 to 14 months for severe BSS and CSS. Conclusion Approximately half of patients with MACS developed postoperative adrenal insufficiency, with 50% recovering by 3.9 months after surgery. BSS correlated with basal cortisol, CST, and duration of adrenal insufficiency. As discordant results were noted in 22%, performing both basal cortisol and CST postoperatively should be considered.

ABSTRACT Background Acute pulmonary embolism (PE) is one of the most common causes of cardiovascular mortality in the United States. Significant variations in the management of various cardiovascular conditions have previously been reported, but this has been poorly elucidated for pulmonary embolism. Methods During 2016–2020, adult (≥ 18 years) nonelective admissions with PE, admitted to Northeast, Midwest, South, and West geographic regions were identified using the National Inpatient Sample. Outcomes of interest included in‐hospital mortality, utilization of PE therapies, non‐cardiac organ support, total hospitalization costs, and hospitalization duration. Results In this 5‐year duration, 904,260 admissions were identified ‐ Northeast, Midwest, South, and West had 166,050 (18.3%), 225,680 (24.9%), 350,160 (38.7%), and 162,370 (17.9%) admissions, respectively. On average, admissions to the Northeast were less comorbid, from a higher socioeconomic status, privately insured, and more commonly admitted to urban teaching and medium‐sized hospitals (all p < 0.001). The Northeast region also had the lowest rates of definitive PE therapies except surgical thrombectomy. In comparison to the Northeast, the in‐hospital mortality was higher in the South and West and lower in the Midwest region (3.1% vs 2.8% vs 3.2% vs 3.3%, p < 0.001). However, on adjusted analysis with Northeast as a reference, in‐hospital mortality was noted to be lower in the Midwest (adjusted odds ratio [aOR] 0.98, 95% confidence interval [CI] 0.67−0.84; p < 0.001), South (aOR 0.89, 95% CI 0.80−0.98; p < 0.05), and the West (aOR 0.88, 95% CI 0.78−0.99; p < 0.05). Conclusion In this study, we noted significant heterogeneity in the management and outcome of pulmonary embolism across various regions of the United States.

ABSTRACT Herpes simplex virus type 1 replicates in the nucleus of the host cell and utilizes many cellular proteins to facilitate DNA replication. HSV-1 DNA replication is closely linked with homologous recombination, and HSV-1 encodes a two-subunit recombinase consisting of an exonuclease (UL12) and a single-strand DNA-binding protein (ICP8). We identified the cellular deubiquitinating enzyme USP15 as a new UL12-binding partner. USP15 is one of the most enriched proteins on viral DNA and has recently been implicated in regulating cellular homologous recombination. Utilizing isolation of proteins on nascent DNA (iPOND) to compare the proteins on wild-type and UL12-deficient viruses, we observed that USP15 is not recruited to newly replicated DNA in the absence of UL12. We also observed that UL12 and USP15 interact directly in vitro using purified proteins. Together, these data suggest that UL12 directly recruits USP15 to viral DNA. UL12 stimulates a type of homology-directed repair called single-strand annealing (SSA). We generated a USP15 knockout cell line with an integrated GFP-based SSA reporter and observed that UL12 and USP15 both contribute to the maximal induction of SSA. In addition to the reporter cell line, there is a 10-fold reduction in the frequency of marker rescue, and individual replication forks move slower in the absence of USP15. These data support a role for USP15 in facilitating recombination during the virus life cycle and the maintenance of replication fork stability. IMPORTANCE HSV-1 is a ubiquitous pathogen in the global population that causes lifelong latent infection with sporadic reactivation in the host. It has long been appreciated that HSV-1 DNA replication exhibits high rates of recombination and is linked to the host DNA damage response. In this study, we show a novel interaction between UL12, a member of the HSV recombinase, and the deubiquitinating host enzyme USP15. We show that USP15 physically interacts with UL12 and is required for UL12 to maximally stimulate recombination. In the absence of USP15, we also observe an overall reduction in virus growth. This work demonstrated that host proteins facilitate viral-induced recombination. The interaction of USP15 with UL12 represents a potential target for intervention against HSV-1 infection and associated disease.

INTRODUCTION: Treatment of celiac disease (CeD) requires a strict gluten-free diet (GFD). Adherence is difficult to assess and influenced by many factors. Identification of potential gluten exposures is essential, but no validated screening measures exist in pediatrics. The aim of this study was to develop and validate a measure screening for gluten exposure risk in pediatric patients with CeD. METHODS: The Gluten Exposure Risk Assessment (GERA) was developed in 3 phases. First, items were generated and refined by a modified Delphi process. Next, psychometrics, factor structure, and validity were examined in a sample of caregivers of pediatric patients younger than 18 years with CeD at 12 pediatric celiac centers. Finally, the final measure was tested on an independent sample population using confirmatory factor analysis and test-retest data. RESULTS: A total of 134 items were generated representing up to 6 domains, with 36 items selected for initial testing. Based on psychometrics and confirmatory factor analysis data from 484 caregivers, the final measure included a total of a single screening question and 9 validated items representing 2 domains (Home, Outside). Repeat testing on a separate sample (N = 369) confirmed factor structure and validity of the final measure (Comparative Fit Index = 0.96, Tucker–Lewis index = 0.95, root mean square error of approximation = 0.06). DISCUSSION: The GERA is a valid screening measure, completed by caregivers, for assessment of gluten exposure in children and adolescents with CeD following a GFD. GERA is a useful tool for evaluating the potential of risk of gluten exposure and potential need for intervention.

Abstract Front-line pharmaceutical interventions for treating acute graft-versus-host disease (GVHD) are not uniformly effective and have toxic side effects. Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature myeloid cells with potent in vitro and in vivo immunosuppressive functions. Clinical translation of in vitro–generated MDSCs has been limited because of requirements for multiple, high infusion doses, the relatively low yield from peripheral blood–sourced MDSCs (PB-MDSCs), and inconsistent product quality. To circumvent these obstacles, we developed a methodology to generate MDSCs using human induced pluripotent stem cell (iPSC)–derived CD34+ cells. Compared with PB-MDSCs, iPSC-derived MDSCs (iMDSCs) shared similar morphology, phenotype, and suppressive function. We found that the CD14+ iMDSC subset possessed the highest suppressor function. In previous studies, we reported that MDSCs transferred into mice with GVHD lost suppressor function because of inflammasome activation and immature myeloid cell maturation. In striking contrast to human PB-MDSCs, we show herein that iMDSCs retained 95% of suppressor function in vitro despite exposure to lipopolysaccharide (LPS) plus adenosine triphosphate (ATP), which are stimuli that activate the inflammasome via danger-associated molecular patterns released during early posttransplant conditioning and GVHD-induced injury. In an in vivo xenogenic GVHD model with PB mononuclear cells, iMDSCs significantly increased recipient survival without loss of antileukemia effects. iMDSC RNA sequencing and gene knockdown studies revealed that the maintenance of the purine metabolizing enzyme, phosphoglycerate dehydrogenase, during LPS plus ATP treatment, was linked to iMDSC inflammasome resistance. Taken together, these findings provide a platform for translating in vitro–generated, off-the-shelf iMDSCs into the clinic for suppressing a spectrum of adverse immune responses, including GVHD.

Abstract Glioblastoma is the most common type of malignant primary brain tumor and a major cause of morbidity and mortality. In 2021, the World Health Organization updated the classification of Central Nervous System (CNS) tumors to restrict glioblastomas to isocitrate dehydrogenase-wildtype (IDHwt) tumors, improving understanding of the prognosis and optimal therapy for these tumors. This revision also enables more homogeneous populations of patients to be enrolled in clinical trials, facilitating the evaluation of novel therapies. In this updated consensus review from the Society for Neuro-Oncology (SNO) and the European Association of Neuro-Oncology (EANO), the current management of patients with glioblastoma is discussed. In addition, novel therapies such as immunotherapies, viral therapies, targeted molecular therapies, theranostics, and antibody–drug conjugates will be reviewed, as well as the current challenges and future directions for research.