Exploring and Analyzing the Systemic Delivery Barriers for Nanoparticles.

Most nanomedicines require efficient in vivo delivery to elicit diagnostic and therapeutic effects. However, en route to their intended tissues, systemically administered nanoparticles often encounter delivery barriers. To describe these barriers, we propose the term "nanoparticle blood removal pathways" (NBRP), which summarizes the interactions between nanoparticles and the body's various cell-dependent and cell-independent blood clearance mechanisms. We reviewed nanoparticle design and biological modulation strategies to mitigate nanoparticle-NBRP interactions. As these interactions affect nanoparticle delivery, we studied the preclinical literature from 2011-2021 and analyzed nanoparticle blood circulation and organ biodistribution data. Our findings revealed that nanoparticle surface chemistry affected the in vivo behavior more than other nanoparticle design parameters. Combinatory biological-PEG surface modification improved the blood area under the curve by ~418%, with a decrease in liver accumulation of up to 47%. A greater understanding of nanoparticle-NBRP interactions and associated delivery trends will provide new nanoparticle design and biological modulation strategies for safer, more effective, and more efficient nanomedicines.

Exposure to Secondhand Smoke Extract Increases Cisplatin Resistance in Head and Neck Cancer Cells.

Chemotherapy and radiotherapy resistance are major obstacles in the long-term efficacy of head and neck squamous cell carcinoma (HNSCC) treatment. Secondhand smoke (SHS) exposure is common and has been proposed as an independent predictor of HNSCC recurrence and disease-free survival. However, the underlying mechanisms responsible for these negative patient outcomes are unknown. To assess the effects of SHS exposure on cisplatin efficacy in cancer cells, three distinct HNSCC cell lines were exposed to sidestream (SS) smoke, the main component of SHS, at concentrations mimicking the nicotine level seen in passive smokers' saliva and treated with cisplatin (0.01-100 µM) for 48 h. Compared to cisplatin treatment alone, cancer cells exposed to both cisplatin and SS smoke extract showed significantly lower cisplatin-induced cell death and higher cell viability, IC50, and indefinite survival capacity. However, SS smoke extract exposure alone did not change cancer cell viability, cell death, or cell proliferation compared to unexposed control cancer cells. Mechanistically, exposure to SS smoke extract significantly reduced the expression of cisplatin influx transporter CTR1, and increased the expression of multidrug-resistant proteins ABCG2 and ATP7A. Our study is the first to document that exposure to SHS can increase cisplatin resistance by altering the expression of several proteins involved in multidrug resistance, thus increasing the cells' capability to evade cisplatin-induced cell death. These findings emphasize the urgent need for clinicians to consider the potential role of SHS on treatment outcomes and to advise cancer patients and caregivers on the potential benefits of avoiding SHS exposure.

Vaginal-perianal or vaginal-perineal compared with vaginal-rectal culture-based screening for Group B Streptococci (GBS) colonization during the third trimester of pregnancy: a systematic review and meta-analysis.

BACKGROUND: Screening for maternal anogenital Group B streptococci (GBS) colonization in pregnancy with initiation of intravenous intrapartum antibiotic prophylaxis as indicated has led to a significant reduction in the incidence of neonatal GBS infection. This study aims to evaluate the agreement between vaginal-perianal or vaginal-perineal culture and the more typically used vaginal-rectal culture for screening for maternal anogenital GBS colonization in the third trimester of pregnancy. METHODS: Eligible English-language studies published until January 2020 were retrieved from Scopus, Web of Science, PubMed, Embase, and ClinicalTrials.gov databases. Studies were compiled that assessed for GBS colonization utilizing vaginal-perianal or vaginal-perineal culture and vaginal-rectal culture during the third trimester of pregnancy. Nonoriginal research articles and studies that did not assess pregnant patients, did not use culture-based screening, or did not compare vaginal-perianal or vaginal-perineal culture with vaginal-rectal culture were excluded. The search identified 559 articles with three prospective cohort studies that met inclusion criteria, including 643 participants. Quality was assessed using the Newcastle-Ottawa Scale, and risk of bias was assessed using the Risk of Bias In Non-randomized Studies of Interventions (ROBINS-I) tool. Patient characteristics and associated pain with specimen collection were abstracted. Meta-analyses of both the raw agreement and the Cohen's kappa statistic were performed. RESULTS: Within the three included studies, the range of GBS detection was 17.6-34.0%, consistent with the anticipated prevalence of GBS colonization reported in earlier publications. For both raw agreement and Cohen's kappa coefficient, the test for heterogeneity was not significant, indicating low heterogeneity among studies. The pooled estimate of the raw agreement was 0.97 (95%CI 0.95-0.98) and of the Cohen's kappa coefficient was 0.91 (95% CI: 0.87-0.95), indicating (according to the Landis and Koch criteria) an "almost perfect" agreement between the compared clinical tests. In the two studies that assessed procedure-related patient discomfort, vaginal-rectal swabbing caused more discomfort. CONCLUSION: Use of vaginal-perineal culture for assessment of maternal GBS colonization is comparable to the more typically utilized vaginal-rectal culture and is associated with less discomfort.

Effects of Low-Level Tragus Stimulation on Endothelial Function in Heart Failure With Reduced Ejection Fraction.

BACKGROUND: Autonomic dysregulation in heart failure with reduced ejection fraction plays a major role in endothelial dysfunction. Low-level tragus stimulation (LLTS) is a novel, noninvasive method of autonomic modulation. METHODS AND RESULTS: We enrolled 50 patients with heart failure with reduced ejection fraction (left ventricular ejection fraction of ≤40%) in a randomized, double-blinded, crossover study. On day 1, patients underwent 60 minutes of LLTS with a transcutaneous stimulator (20 Hz, 200 µs pulse width) or sham (ear lobule) stimulation. Macrovascular function was assessed using flow-mediated dilatation in the brachial artery and cutaneous microcirculation with laser speckle contrast imaging in the hand and nail bed. On day 2, patients were crossed over to the other study arm and underwent sham or LLTS; vascular tests were repeated before and after stimulation. Compared with the sham, LLTS improved flow-mediated dilatation by increasing the percent change in the brachial artery diameter (from 5.0 to 7.5, LLTS on day 1, P = .02; and from 4.9 to 7.1, LLTS on day 2, P = .003), compared with no significant change in the sham group (from 4.6 to 4.7, P = .84 on day 1; and from 5.6 to 5.9 on day 2, P = .65). Cutaneous microcirculation in the hand showed no improvement and perfusion of the nail bed showed a trend toward improvement. CONCLUSIONS: Our study demonstrated the beneficial effects of acute neuromodulation on macrovascular function. Larger studies to validate these findings and understand mechanistic links are warranted.

Potential and mechanism of mebendazole for treatment and maintenance of ovarian cancer.

OBJECTIVE: Mebendazole and other anti-parasitic drugs are being used off-prescription based on social media and unofficial accounts of their anti-cancer activity. The purpose of this study was to conduct a controlled evaluation of mebendazole's therapeutic efficacy in cell culture and in vivo models of ovarian cancer. The majority of ovarian cancers harbor p53 null or missense mutations, therefore the effects of p53 mutations and a mutant p53 reactivator, PRIMA-1MET (APR246) on mebendazole activity were evaluated. METHODS: Mebendazole was evaluated in cisplatin-resistant high grade serous stage 3C ovarian cancer patient derived xenograft (PDX) models: PDX-0003 (p53 null) and PDX-0030 (p53 positive), and on ovarian cancer cell lines: MES-OV (p53 R282W), ES2 (p53 S241F), A2780 (p53 wild type), SKOV3 parental (p53 null) and isogenic sublines, SKOV3 R273H p53 and SKOV3 R248W p53. Drug synergy and mechanisms were evaluated in cell cultures using isobolograms, clonogenic assays and western blots. Prevention of tumor establishment was studied in a MES-OV orthotopic model. RESULTS: Mebendazole inhibited growth of ovarian cancer cell cultures at nanomolar concentrations and PDXs at doses up to 50 mg/kg, and reduced orthotopic tumor establishment at 50 mg/kg. The mechanism of mebendazole was associated with p53-independent induction of p21 and tubule depolymerization. PRIMA-1MET also inhibited tumor establishment and worked synergistically with mebendazole in cell culture to inhibit growth and induce intrinsic apoptosis through a p53- and tubule destabilization-independent mechanism. CONCLUSION: This work demonstrates the therapeutic potential of repurposing mebendazole and supports clinical development of mebendazole for ovarian cancer therapy and maintenance.

Assessment of Streptococcus mutans biofilms on orthodontic adhesives over 7 days.

INTRODUCTION: The purpose of this study was to compare the metabolism of Streptococcus mutans biofilms after 1-7 days of growth on different orthodontic adhesives. METHODS: Specimens of 6 commercial orthodontic adhesives were fabricated in custom-made molds and polymerized using a light-emitting diode light-curing unit. Bioluminescent S mutans (UA159:JM10) biofilms were grown on ultraviolet-sterilized specimens for 1, 3, 5, and 7 days (n = 18 biofilms/d/product) in anaerobic conditions at 37°C. The metabolism of biofilms (relative luminescence unit [RLU]) was measured 0, 2, 4, and 6 minutes after exposure to D-luciferin solution using a microplate reader. A linear mixed-effects model was used to analyze the logarithm of RLU (log RLU). The model included fixed effects of products, days, and minutes. Tukey-Kramer post-hoc tests were then performed on the significant predictors of log RLU (α = 0.05). RESULTS: Days (P <0.0001) and minutes (P <0.0001) were independent predictors of log RLU, but the products were not (P = 0.5869). After adjusting for minutes, the log RLU was analyzed with a post-hoc test, and all differences between days were significant with the exceptions of day 3 from day 5 (P = 0.0731) and day 5 from day 7 (P = 0.8802). After adjusting for day, log RLU was analyzed with a post-hoc test and all differences in minutes were significant. CONCLUSIONS: No significant differences in the metabolism of S mutans biofilms were observed among the 6 orthodontic adhesives. Biofilms that were grown for 3 days demonstrated the highest levels of biofilm metabolism as evidenced by higher mean log RLU values relative to 1, 5, and 7-day growth durations.

Novel ovarian cancer maintenance therapy targeted at mortalin and mutant p53.

Current ovarian cancer maintenance therapy is limited by toxicity and no proven impact on overall survival. To study a maintenance strategy targeted at missense mutant p53, we hypothesized that the release of mutant p53 from mortalin inhibition by the SHetA2 drug combined with reactivation of mutant p53 with the PRIMA-1MET drug inhibits growth and tumor establishment synergistically in a mutant-p53 dependent manner. The Cancer Genome Atlas (TCGA) data and serous ovarian tumors were evaluated for TP53 and HSPA9/mortalin status. SHetA2 and PRIMA-1MET were tested in ovarian cancer cell lines and fallopian tube secretory epithelial cells using isobolograms, fluorescent cytometry, Western blots and ELISAs. Drugs were administered to mice after peritoneal injection of MESOV mutant p53 ovarian cancer cells and prior to tumor establishment, which was evaluated by logistic regression. Fifty-eight percent of TP53 mutations were missense and there were no mortalin mutations in TCGA high-grade serous ovarian cancers. Mortalin levels were sequentially increased in serous benign, borderline and carcinoma tumors. SHetA2 caused p53 nuclear and mitochondrial accumulation in cancer, but not in healthy, cells. Endogenous or exogenous mutant p53 increased SHetA2 resistance. PRIMA-1MET decreased this resistance and interacted synergistically with SHetA2 in mutant and wild type p53-expressing cell lines in association with elevated reactive oxygen species/ATP ratios. Tumor-free rates in animals were 0% (controls), 25% (PRIMA1MET ), 42% (SHetA2) and 67% (combination). SHetA2 (p = 0.004) and PRIMA1MET (p = 0.048) functioned additively in preventing tumor development with no observed toxicity. These results justify the development of SHetA2 and PRIMA-1MET alone and in combination for ovarian cancer maintenance therapy.

A TMEFF2-regulated cell cycle derived gene signature is prognostic of recurrence risk in prostate cancer.

BACKGROUND: The clinical behavior of prostate cancer (PCa) is variable, and while the majority of cases remain indolent, 10% of patients progress to deadly forms of the disease. Current clinical predictors used at the time of diagnosis have limitations to accurately establish progression risk. Here we describe the development of a tumor suppressor regulated, cell-cycle gene expression based prognostic signature for PCa, and validate its independent contribution to risk stratification in several radical prostatectomy (RP) patient cohorts. METHODS: We used RNA interference experiments in PCa cell lines to identify a gene expression based gene signature associated with Tmeff2, an androgen regulated, tumor suppressor gene whose expression shows remarkable heterogeneity in PCa. Gene expression was confirmed by qRT-PCR. Correlation of the signature with disease outcome (time to recurrence) was retrospectively evaluated in four geographically different cohorts of patients that underwent RP (834 samples), using multivariate logistical regression analysis. Multivariate analyses were adjusted for standard clinicopathological variables. Performance of the signature was compared to previously described gene expression based signatures using the SigCheck software. RESULTS: Low levels of TMEFF2 mRNA significantly (p < 0.0001) correlated with reduced disease-free survival (DFS) in patients from the Memorial Sloan Kettering Cancer Center (MSKCC) dataset. We identified a panel of 11 TMEFF2 regulated cell cycle related genes (TMCC11), with strong prognostic value. TMCC11 expression was significantly associated with time to recurrence after prostatectomy in four geographically different patient cohorts (2.9 ≤ HR ≥ 4.1; p ≤ 0.002), served as an independent indicator of poor prognosis in the four RP cohorts (1.96 ≤ HR ≥ 4.28; p ≤ 0.032) and improved the prognostic value of standard clinicopathological markers. The prognostic ability of TMCC11 panel exceeded previously published oncogenic gene signatures (p = 0.00017). CONCLUSIONS: This study provides evidence that the TMCC11 gene signature is a robust independent prognostic marker for PCa, reveals the value of using highly heterogeneously expressed genes, like Tmeff2, as guides to discover prognostic indicators, and suggests the possibility that low Tmeff2 expression marks a distinct subclass of PCa.

Chemo-biologic combinatorial drug delivery using folate receptor-targeted dendrimer nanoparticles for lung cancer treatment.

Co-administration of functionally distinct anti-cancer agents has emerged as an efficient strategy in lung cancer treatment. However, a specially designed drug delivery system is required to co-encapsulate functionally different agents, such as a combination of siRNA and chemotherapy, for targeted delivery. We developed a folic acid (FA)-conjugated polyamidoamine dendrimer (Den)-based nanoparticle (NP) system for co-delivery of siRNA against HuR mRNA (HuR siRNA) and cis-diamine platinum (CDDP) to folate receptor-α (FRA) -overexpressing H1299 lung cancer cells. The co-delivery of HuR siRNA and CDDP using the FRA-targeted NP had a significantly greater therapeutic effect than did individual therapeutics. Further, the FRA-targeted NP exhibited improved cytotoxicity compared to non-targeted NP against lung cancer cells. Finally, the NP showed negligible toxicity towards normal MRC9 lung fibroblast cells. Thus, the present study demonstrates FRA-targeted Den nanoparticle system as a suitable carrier for targeted co-delivery of siRNA and chemotherapy agents in lung cancer cells.

Association between daily walking and antioxidant capacity in patients with symptomatic peripheral artery disease.

OBJECTIVE: The primary aim of the study was to assess whether both the amount and pace of daily walking were associated with circulating antioxidant capacity in symptomatic patients with peripheral artery disease (PAD). METHODS: Community-based walking was measured in 244 men and women who were limited by symptomatic PAD during a 1-week period in which they wore an ankle-mounted step activity monitor. Patients were further characterized by circulating antioxidant capacity with the OxiSelect (Cell Biolabs Inc, San Diego, Calif) hydroxyl radical antioxidant capacity (HORAC) activity assay. RESULTS: To assess the amount of walking, patients were grouped into low (≤2440 strides/d), middle (2441-3835 strides/d), and high (>3835 strides/d) stride tertiles. HORAC was higher in the middle (P = .03) and high (P = .01) stride tertiles than in the low tertile, but there was no difference between middle and high tertiles (P = .44). To assess the pace of walking, patients were grouped into slow (<25.0 strides/min), middle (25.0-31.6 strides/min), and fast (>31.6 strides/min) cadence tertiles. HORAC was higher in the high cadence tertile than in the low (P < .01) and middle (P < .01) tertiles, but there was no difference between low and middle tertiles (P = .48). Similar findings were obtained on group differences in HORAC after adjusting for age, sex, race, and ankle-brachial index for both the amount and pace of daily walking. CONCLUSIONS: Walking >2440 strides each day and walking at a cadence faster than 31.6 strides/min for 30 minutes each day are both associated with greater circulating antioxidant capacity in symptomatic patients with PAD. The clinical significance is that a home-based walking program may be one approach to increase endogenous antioxidant capacity.

RIG-I overexpression decreases mortality of cigarette smoke exposed mice during influenza A virus infection.

BACKGROUND: Retinoic acid-inducible gene I (RIG-I) is an important regulator of virus-induced antiviral interferons (IFNs) and proinflammatory cytokines which participate in clearing viral infections. Cigarette smoke (CS) exposure increases the frequency and severity of respiratory tract infections. METHODS: We generated a RIG-I transgenic (TG) mouse strain that expresses the RIG-I gene product under the control of the human lung specific surfactant protein C promoter. We compared the mortality and host immune responses of RIG-I TG mice and their litter-matched wild type (WT) mice following challenge with influenza A virus (IAV). RESULTS: RIG-I overexpression increased survival of IAV-infected mice. CS exposure increased mortality in WT mice infected with IAV. Remarkably, the effect of RIG-I overexpression on survival during IAV infection was enhanced in CS-exposed animals. CS-exposed IAV-infected WT mice had a suppressed innate response profile in the lung compared to sham-exposed IAV-infected WT mice in terms of the protein concentration, total cell count and inflammatory cell composition in the bronchoalveolar lavage fluid. RIG-I overexpression restored the innate immune response in CS-exposed mice to that seen in sham-exposed WT mice during IAV infection, and is likely responsible for enhanced survival in RIG-I TG mice as restoration preceded death of the animals. CONCLUSIONS: Our results demonstrate that RIG-I overexpression in mice is protective for CS enhanced susceptibility of smokers to influenza infection, and that CS mediated RIG-I suppression may be partially responsible for the increased morbidity and mortality of the mice exposed to IAV. Thus, optimizing the RIG-I response may be an important treatment strategy for CS-enhanced lung infections, particularly those due to IAV.

The Impact on Endoscopic Resource Utilization After a Targeted Intervention for Cost-Minimization of EGD and Colonoscopy.

OBJECTIVES: The need to define the cost of endoscopic procedures becomes increasingly important in an era of providing low-cost, high-quality care. We examined the impact of informing endoscopists of the cost of accessories and pathology specimens as a cost-minimization strategy. METHODS: We conducted a prospective observational cohort study of therapeutic outpatient esophagogastroduodenoscopy (EGD) and colonoscopy. During the pre-intervention phase (phase 1), the endoscopists were not briefed on the cost of accessories or pathology specimens obtained during the procedure. During a 3-week intervention phase and the post-intervention phase (phase 2) endoscopists were informed of the dollar value of accessories and pathology specimens after the completion of all procedures. In all cases the institutional costs (not charges) were used. The endoscopists were blinded to their observation. RESULTS: A total of 969 EGD, colonoscopy, and EGD+colonoscopy performed by 6 endoscopists were reviewed, 456 procedures in phase 1 and 513 procedures in phase 2. There was no significant difference between phases 1 and 2 in total device and pathology cost in dollars (188.8±151.4 vs. 188.9±151.8, P=0.99), total device cost (36.2±107.9 vs. 39.0±95.96, P=0.67) and total pathology cost (152.6±101.3 vs. 149.9±112.5, P=0.70). There was not a significant difference in total device and pathology cost when examined by specific procedures performed, or for any of the endoscopists between phases 1 and 2. CONCLUSIONS: Making endoscopists more cost conscious by informing them of the costs of each procedure during EGD and colonoscopy does not result in lower procedural costs. Analysis of cost-minimization strategies involving procedures in other health-care settings and procedures using high-cost accessories are warranted.

Altered type II interferon precedes autoantibody accrual and elevated type I interferon activity prior to systemic lupus erythematosus classification.

OBJECTIVES: The relationship of immune dysregulation and autoantibody production that may contribute to systemic lupus erythematosus (SLE) pathogenesis is unknown. This study evaluates the individual and combined contributions of autoantibodies, type I interferon (IFN-α) activity, and IFN-associated soluble mediators to disease development leading to SLE. METHODS: Serial serum specimens from 55 individuals collected prior to SLE classification (average timespan=4.3 years) and unaffected healthy controls matched by age (±5 years), gender, race and time of sample procurement were obtained from the Department of Defense Serum Repository. Levels of serum IFN-α activity, IFN-associated mediators and autoantibodies were evaluated and temporal relationships assessed by growth curve modelling, path analysis, analysis of covariance and random forest models. RESULTS: In cases, but not matched controls, autoantibody specificities and IFN-associated mediators accumulated over a period of years, plateauing near the time of disease classification (p<0.001). Autoantibody positivity coincided with or followed type II IFN dysregulation, preceding IFN-α activity in growth curve models, with elevated IFN-α activity and B-lymphocyte stimulator levels occurring shortly before SLE classification (p≤0.005). Cases were distinguished by multivariate random forest models incorporating IFN-γ, macrophage chemoattractant protein (MCP)-3, anti-chromatin and anti-spliceosome antibodies (accuracy 93% >4 years pre-classification; 97% within 2 years of SLE classification). CONCLUSIONS: Years before SLE classification, enhancement of the type II IFN pathway allows for accumulation of autoantibodies and subsequent elevations in IFN-α activity immediately preceding SLE classification. Perturbations in select immunological processes may help identify at-risk individuals for further clinical evaluation or participation in prospective intervention trials.

Effect of cognitive status on exercise performance and quality of life in patients with symptomatic peripheral artery disease.

BACKGROUND: We determined whether scores on a cognitive screening measure were associated with the primary outcome measure of peak walking time (PWT) and with secondary outcome measures related to mobility, community-based ambulation, health-related quality of life (QoL), and vascular function in patients with claudication and peripheral artery disease (PAD). METHODS: Gross cognitive status of 246 PAD patients was assessed with the Mini-Mental State Examination (MMSE) questionnaire. Patients were grouped according to whether they had a perfect MMSE score of 30 points (n = 123) or whether they missed one or more points (n = 123). Patients were characterized on numerous outcomes, including PWT during a treadmill test and QoL. RESULTS: Compared with the group with the higher MMSE scores, there was a trend for lower PWT in the group with the lower MMSE scores (P = .06) after adjusting for age, sex, race, and education level (model 1), which became significant (380 ± 250 seconds vs 460 ± 270 seconds; P < .05) after adjusting for model 1 plus coronary artery disease, chronic obstructive pulmonary disease, and arthritis (model 2). Multiple domains of QoL were lower (P < .05) in the group with the lower MMSE scores after adjusting for model 1, but only mental health remained lower (75 ± 20% vs 80 ± 5%; P = .02) after further adjustment with model 2. CONCLUSIONS: In symptomatic patients with PAD, lower cognitive screening scores were associated with greater ambulatory impairment than in patients with higher MMSE scores. Furthermore, worse cognitive status was associated with lower scores in multiple dimensions of health-related QoL, all of which except mental health were explained by the comorbid conditions of coronary artery disease, chronic obstructive pulmonary disease, and arthritis. The clinical significance is that there is a need for enhanced cognitive and mental health screening as potential indicators of poor outcome among symptomatic patients with PAD. Furthermore, patients identified as having worse cognitive status might be in greatest need of intervention to improve ambulation and QoL related to mental health.

Blocking the adhesion cascade at the premetastatic niche for prevention of breast cancer metastasis.

Shear-resistant adhesion and extravasation of disseminated cancer cells at the target organ is a crucial step in hematogenous metastasis. We found that the vascular adhesion molecule E-selectin preferentially promoted the shear-resistant adhesion and transendothelial migration of the estrogen receptor (ER)(-)/CD44(+) hormone-independent breast cancer cells, but not of the ER(+)/CD44(-/low) hormone-dependent breast cancer cells. Coincidentally, CD44(+) breast cancer cells were abundant in metastatic lung and brain lesions in ER(-) breast cancer, suggesting that E-selectin supports hematogenous metastasis of ER(-)/CD44(+) breast cancer. In an attempt to prevent hematogenous metastasis through the inhibition of a shear-resistant adhesion of CD44(+) cancer cells to E-selectin-expressing blood vessels on the premetastatic niche, an E-selectin targeted aptamer (ESTA) was developed. We demonstrated that a single intravenous injection of ESTA reduced metastases to a baseline level in both syngeneic and xenogeneic forced breast cancer metastasis models without relocating the site of metastasis. The effect of ESTA was absent in E-selectin knockout mice, suggesting that E-selectin is a molecular target of ESTA. Our data highlight the potential application of an E-selectin antagonist for the prevention of hematogenous metastasis of ER(-)/CD44(+) breast cancer.

Knowledge Translation of the Gross Motor Function Classification System Among Pediatric Physical Therapists.

PURPOSE: To learn where pediatric physical therapists in the United States are in the process of knowledge translation of the Gross Motor Function Classification System (GMFCS). METHODS: Links to an online survey were distributed electronically. RESULTS: All 283 respondents reported hearing about the GMFCS, 95% agreed it was useful, 81% reported they were confident in their ability to use it, 77% reported they use it, and 42% reported they use it consistently. Therapists primarily used the GMFCS to predict gross motor function, set realistic goals, and anticipate need for assistive technology. The American Physical Therapy Association Section on Pediatrics members were more likely than nonmembers to agree the GMFCS is useful, they are able to use it, that they use it, and that they use it consistently. CONCLUSIONS: The majority of therapists responding use the GMFCS, but not consistently. VIDEO ABSTRACT: For more insights from the authors, see Supplemental Digital Content 1, available at http://links.lww.com/PPT/A91.

Cigarette smoke attenuates the RIG-I-initiated innate antiviral response to influenza infection in two murine models.

Cigarette smoke (CS) exposure increases the frequency and severity of respiratory tract infections. Despite this association, the mechanisms underlying the increased susceptibility to respiratory virus infection are poorly understood. Retinoic acid-inducible gene I (RIG-I) is an important regulator of influenza virus-induced expression of antiviral cytokines, mainly interferons (IFNs), which are necessary to clear viral infections. In this study, we compared the innate cytokine responses of two mouse CS exposure models following a challenge with influenza A virus (IAV): 1) exposure of the mice to cigarette smoke extract (CSE) intratracheally and 2) exposure of the mice to CS in a whole body exposure chamber. Both intratracheal CSE treatment and whole body CS exposure caused antiviral immunosuppression in these mice, and both CS exposure methods inhibited RIG-I induction. CS attenuated influenza-induced antiviral IFNs and IP-10 expression in vivo. However, we did not find that CS inhibited induction of the proinflammatory cytokines IL-6 and TNF-α, whose expression was induced by IAV. Interestingly, IAV infection also increased Toll-like receptor 3 (TLR3) expression in mouse lung, but CS exposure did not impact TLR3 induction in these mice. Together, the results support our previous finding in a human lung organ culture model that the suppression of RIG-I induction and antiviral cytokine responses by CS are likely important in the enhanced susceptibility of smokers to influenza infection in the lung.

Testing homogeneity of stratum effects in stratified paired binary data.

For paired binary data, McNemar's test is widely used to test marginal homogeneity or symmetry for a 2 by 2 contingency table. In this article, we extend McNemar's test by considering a series of paired binary data in which the series is defined by a stratification factor. We provide a test for testing homogeneous stratum effects. For illustration, we apply our test to a cancer epidemiology study. Finally, we conduct simulations to show that our test preserves the nominal type I error level and evaluate the power of our test under various scenarios.

Systematic Review and Meta-Analysis of Endovascular Therapy Effectiveness for Unruptured Saccular Intracranial Aneurysms.

Background: Currently, endovascular treatment of intracranial aneurysms (ICAs) is limited by low complete occlusion rates. The advent of novel endovascular technology has expanded the applicability of endovascular therapy; however, the superiority of novel embolic devices over the traditional Guglielmi detachable coils (GDCs) is still debated. We performed a systematic review of literature that reported Raymond-Roy occlusion classification (RROC) rates of modern endovascular devices to determine their immediate and follow-up occlusion effectiveness for the treatment of unruptured saccular ICAs. Methods: A search was conducted using electronic databases (PUBMED, Cochrane, ClinicalTrials.gov, Web of Science). We retrieved studies published between 2000-2022 reporting immediate and follow-up RROC rates of subjects treated with different endovascular ICA therapies. We extracted demographic information of the treated patients and their reported angiographic RROC rates. Results: A total of 80 studies from 15 countries were included for data extraction. RROC rates determined from angiogram were obtained for 21,331 patients (72.5% females, pooled mean age: 58.2 (95% CI: 56.8-59.6), harboring 22,791 aneurysms. The most frequent aneurysm locations were the internal carotid artery (46.4%, 95% CI: 41.9%-50.9%), the anterior communicating artery (26.4%, 95% CI: 22.5%-30.8%), the middle cerebral artery (24.5%, 95% CI:19.2%-30.8%) and the basilar tip (14.4%, 95% CI:11.3%-18.3%). The complete occlusion probability (RROC-I) was analyzed for GDCs, the Woven EndoBridge (WEB), and flow diverters. The RROC-I rate was the highest in balloon-assisted coiling (73.9%, 95% CI: 65.0%-81.2%) and the lowest in the WEB (27.8%, 95% CI:13.2%-49.2%). The follow-up RROC-I probability was homogenous in all analyzed devices. Conclusions: We observed that the coil-based endovascular therapy provides acceptable rates of complete occlusion, and these rates are improved in balloon-assisted coils. Out of the analyzed devices, the WEB exhibited the shortest time to achieve >90% probability of follow-up complete occlusion (~18 months). Overall, the GDCs remain the gold standard for endovascular treatment of unruptured saccular aneurysms.

Estimation of the common risk difference in stratified paired binary data with homogeneous stratum effect.

McNemar's test is commonly used to test for the risk difference between two binary variables on matched pairs. For stratified paired binary data, recently a test for the homogeneous stratum effect (HSE) has been developed. If HSE is rejected, then McNemar's test should be applied by stratum; otherwise, in this article we propose a concept of common risk difference (CRD) across the strata and derive point estimators and confidence intervals for CRD. We use a cancer study for illustration and conduct simulations to recommend point estimators and associated confidence intervals with good statistical properties.