Contrast-enhanced ultrasonography-CT/MRI fusion guidance for percutaneous ablation of inconspicuous, small liver tumors: improving feasibility and therapeutic outcome.

BACKGROUND: Percutaneous radiofrequency ablation (RFA) is pivotal for treating small malignant liver tumors, but tumors often remain inconspicuous on B-mode ultrasound (US). This study evaluates the potential of CEUS-CT/MRI fusion imaging (FI) to improve tumor visibility and the associated RFA outcomes for small (≤ 3 cm) malignant liver tumors that were inconspicuous on US. METHODS: Between January 2019 and April 2021, a prospective study enrolled 248 patients with liver malignancies (≤ 3 cm) that were poorly visible on B-mode US. Tumor visibility and ablation feasibility were assessed using B-mode US, US-CT/MRI FI, and CEUS-CT/MRI FI, and graded on a 4-point scale. CEUS was employed post-registration of US and CT/MRI images, utilizing either SonoVue or Sonazoid. Comparisons between US-based and CEUS-based fusion visibility and feasibility scores were undertaken using the Friedman test. Moreover, rates of technical success, technique efficacy, local tumor progression (LTP), and major complications were assessed. RESULTS: The cohort included 223 hepatocellular carcinomas (HCCs) (89.9%) and 23 metastases (9.3%), with an average tumor size of 1.6 cm. CEUS-CT/MRI FI demonstrated a significant advantage in tumor visibility (3.4 ± 0.7 vs. 1.9 ± 0.6, P < 0.001) and technical feasibility (3.6 ± 0.6 vs. 2.9 ± 0.8, P < 0.001) compared to US-FI. In 85.5% of patients, CEUS addition to US-FI ameliorated tumor visibility. Technical success was achieved in 99.6% of cases. No severe complications were reported. One and two-year post CEUS-CT/MRI FI-guided RFA estimates for LTP were 9.3% and 10.9%, respectively. CONCLUSIONS: CEUS-CT/MRI FI significantly improves the visualization of tumors not discernible on B-mode US, thus augmenting percutaneous RFA success and delivering improved therapeutic outcomes. TRIAL REGISTRATION: ClinicalTrials.gov, NCT05445973. Registered 17 June 2022 - Retrospectively registered, http://clinicaltrials.gov/study/NCT05445973?id=NCT05445973&rank=1 .

Leveraging Patients' Creative Ideas for Innovation in Health Care.

Policy Points Patients' creative ideas may inform learning and innovation that improve patient-centered care. Routinely collected patient experience surveys provide an opportunity to invite patients to share their creative ideas for improvement. We develop and assess a methodological strategy that validates question wording designed to elicit creative ideas from patients. Health care organizations should consider how to report and use these data in health care delivery and quality improvement, and policymakers should consider promoting the use of narrative feedback to better understand and respond to patients' experiences. CONTEXT: Learning health systems (LHSs) have been promoted for a decade to achieve high-quality, patient-centered health care. Innovation driven by knowledge generated through day-to-day health care delivery, including patient insights, is critical to LHSs. However, the pace of translating patient insights into innovation is slow and effectiveness inadequate. This study aims to evaluate a method for systematically eliciting patients' creative ideas, examine the value of such ideas as a source of insight, and examine patients' creative ideas regarding how their experiences could be improved within the context of their own health systems. METHODS: The first stage of the study developed a survey and tested strategies for elicitation of patients' creative ideas with 600 patients from New York State. The second stage deployed the survey with the most generative open-ended question sequence within a health care system and involved analysis of 1,892 patients' responses, including 2,948 creative ideas. FINDINGS: Actionable, creative feedback was fostered by incorporating a request for transformative feedback into a sequence of narrative elicitation questions. Patients generate more actionable and creative ideas when explicitly invited to share such ideas, especially patients with negative health care experiences, those from minority racial/ethnic backgrounds, and those with chronic illness. The most frequently elicited creative ideas focused on solving challenges, proposing interventions, amplifying exceptional practices, and conveying hopes for the future. CONCLUSIONS: A valid and reliable method for eliciting creative ideas from patients can be deployed as part of routine patient experience surveys that include closed-ended survey items and open-ended narrative items in which patients share their experiences in their own words. The elicited creative ideas are promising for patient engagement and innovation efforts. This study highlights the benefits of engaging patients for quality improvement, offers a rigorously tested method for cultivating innovation using patient-generated knowledge, and outlines how creative ideas can enable organizational learning and innovation.

Prenatal and postnatal exposure to polychlorinated biphenyls alter follicle numbers, gene expression, and a proliferation marker in the rat ovary.

Polychlorinated biphenyls (PCBs) were used in industrial applications until they were banned in the 1970s, but they still persist in the environment. Little is known about the long-term effects of exposure to PCB mixtures on the rat ovary during critical developmental periods. Thus, this study tested whether prenatal and postnatal exposures to PCBs affect follicle numbers and gene expression in the ovaries of F1 offspring. Sprague-Dawley rats were treated with vehicle or Aroclor 1221 (A1221) at 1 mg/kg/day during embryonic days 8-18 and/or postnatal days (PND) 1-21. Ovaries from F1 rats were collected for assessment of follicle numbers and differential expression of estrogen receptor 1 (Esr1), estrogen receptor 2 (Esr2), androgen receptor (Ar), progesterone receptor (Pgr), and Ki-67 (Ki67) at PNDs 8, 32, and 60. Sera were collected for measurement of estradiol concentrations. Prenatal exposure to A1221 significantly decreased the number of primordial follicles and the total number of follicles at PND 32 compared to control. Postnatal PCB exposure borderline increased Ki67 gene expression and significantly increased Ki67 protein levels (PND 60) compared to control. Combined prenatal and postnatal PCB exposure borderline decreased Ar expression (PND 8) compared to control. However, PCB exposure did not significantly affect the expression of Pgr, Esr1, and Esr2 or serum estradiol concentrations compared to control at any time point. In conclusion, these data suggest that PCB exposure affects follicle numbers and levels of the proliferation marker Ki67, but it does not affect expression of some sex steroid hormone receptors in the rat ovary.

The spectrum of imaging manifestations of Gorham-Stout disease: a novel dynamic contrast-enhanced MR lymphangiography.

BACKGROUND: To describe the radiological features of Gorham-Stout disease (GSD) as evaluated using plain radiography and dynamic contrast-enhanced magnetic resonance lymphangiography (DCMRL) imaging techniques. METHODS: Clinical and conventional imaging data were retrospectively reviewed for 15 patients with GSD between January 2001 and December 2020. After December 2018, DCMRL examinations were performed for lymphatic vessel evaluation in patients with GSD and reviewed in four patients. RESULTS: The median age at diagnosis was 9 years (range: 2 months-53 years). The clinical manifestations were dyspnea in seven patients (46.7%), sepsis in 12 (80.0%), orthopedic problems in seven (46.7%), and bloody chylothorax in seven (46.7%). The common sites of osseous involvement were the spine (73.3%) and pelvic bone (60.0%). Among the non-osseous involvements, peri-osseous infiltrative soft-tissue abnormalities adjacent to the area of bone involvement were the most common (86.7%), followed by splenic cysts (26.7%) and interstitial thickening (26.7%). DCMRL demonstrated weak central conducting lymphatic flow in two patients with abnormal giant tortuous thoracic ducts and no flow in one patient. All patients who underwent DCMRL in this study presented with altered anatomical lymphatics and functional flow with collateralization. CONCLUSION: DCMRL imaging and plain radiography are very useful for determining the extent of GSD. DCMRL is a novel imaging tool for the visualization of abnormal lymphatics in patients with GSD, which helps in further treatment. Therefore, in patients with GSD, it might be necessary to obtain not only plain radiographs but also MR and DCMRL images.

Perfluorooctanoic Acid Disrupts Ovarian Steroidogenesis and Folliculogenesis in Adult Mice.

Perfluorooctanoic acid (PFOA) is a synthetic fluorosurfactant used in the manufacturing of fluorotelomers. Although PFOA is no longer produced in the United States, it is environmentally persistent and found in imported food packaging, cookware, and textiles. Previous studies have identified developmental toxicity of PFOA, but little is known about the effects of PFOA on the adult ovary. Thus, this study examined the effects of PFOA on hormone levels, ovarian steroidogenic gene expression, and folliculogenesis in mice in vitro and in vivo. For the in vitro studies, antral follicles from adult female mice were cultured with vehicle control or 1, 10, or 100 µg/ml PFOA for 96 h. For the in vivo studies, adult CD-1 female mice were orally dosed with vehicle control or 1, 5, 10, or 20 mg/kg/day PFOA for 10 days. Gene expression of steroidogenic enzymes, levels of sex steroid hormones, and follicle counts were analyzed. In vitro, PFOA (100 µg/ml) significantly decreased follicle growth, estradiol and estrone levels, and gene expression of StaR, Cyp11a1, and Hsd3b1 compared with controls. In vivo, exposure to PFOA significantly decreased progesterone and pregnenolone levels (5 mg/kg), increased testosterone levels (1 mg/kg), and increased gene expression of Cyp19a1 (1 mg/kg) compared with controls. Exposure to PFOA also significantly altered follicle counts by decreasing primordial follicles and increasing preantral and antral follicles (5 and 10 mg/kg) compared with controls. Collectively, these data show that PFOA disrupts adult ovarian function in a nonmonotonic matter and may pose a risk for premature ovarian failure.

Reducing Sedative-Hypnotics Among Hospitalized Patients: a Multi-centered Study.

BACKGROUND: Sedative-hypnotics are frequently prescribed for insomnia in hospital but are associated with preventable harms. OBJECTIVE, DESIGN, AND PARTICIPANTS: We aimed to examine whether a sedative-hypnotic reduction quality improvement bundle decreases the rate of sedative-hypnotic use among hospitalized patients, who were previously naïve to sedative-hypnotics. This interrupted time series study occurred between May 2016 and January 2019. Control data for 1 year prior to implementation and intervention data for at least 16 months were collected. The study occurred on 7 inpatient wards (general medicine, cardiology, nephrology, general surgery, and cardiovascular surgery wards) across 5 teaching hospitals in Toronto, Canada. INTERVENTION: Participating wards implemented a sedative-hypnotic reduction bundle (i.e., order set changes, audit-feedback, pharmacist-enabled medication reviews, sleep hygiene, daily sleep huddles, and staff/patient/family education) aimed to reduce in-hospital sedative-hypnotic initiation for insomnia in patients who were previously naïve to sedative-hypnotics. Each inpatient ward adapted the bundle prior to sustaining the intervention for a minimum of 16 months. MAIN MEASURES: The primary outcome measure was the proportion of sedative-hypnotic-naïve inpatients newly prescribed a sedative-hypnotic for sleep in hospital. Secondary measures include prescribing rates of other sedating medications, fall rates, length of stay, and mortality. KEY RESULTS: We included 8,970 patient discharges in the control period and 10,120 in the intervention period. Adjusted sedative-hypnotic prescriptions among naïve patients decreased from 15.48% (95% CI: 6.09-19.42) to 9.08% (p<0.001) (adjusted OR 0.814; 95% CI: 0.667-0.993, p=0.042). Unchanged secondary outcomes included mortality (adjusted OR 1.089; 95% CI: 0.786-1.508, p=0.608), falls (adjusted rate ratio 0.819; 95% CI: 0.625-1.073, p=0.148), or other sedating drug prescriptions (adjusted OR 1.046; 95% CI: 0.873-1.252, p=0.627). CONCLUSIONS: A sedative-hypnotic reduction quality improvement bundle implemented across 5 hospitals was associated with a sustained reduction in sedative-hypnotic prescriptions.

In vitro and in silico characterization of adiponectin-receptor agonist dipeptides.

The aim of this study is to develop a dipeptide showing an adiponectin receptor 1 (AdipoR1) agonistic effect in skeletal muscle L6 myotubes. Based on the structure of the AdipoR1 agonist, AdipoRon, 15 synthetic dipeptides were targeted to promote glucose uptake in L6 myotubes. Tyr-Pro showed a significant increase in glucose uptake among the dipeptides, while other dipeptides, including Pro-Tyr, failed to exert this effect. Tyr-Pro induces glucose transporter 4 (Glut4) expression in the plasma membrane, along with adenosine monophosphate-activated protein kinase (AMPK) activation. In AdipoR1-knocked down cells, the promotion by Tyr-Pro was ameliorated, indicating that Tyr-Pro may directly interact with AdipoR1 as an agonist, followed by the activation of AMPK/Glut4 translocation in L6 myotubes. Molecular dynamics simulations revealed that a Tyr-Pro molecule was stably positioned in the two potential binding pockets (sites 1 and 2) of the seven-transmembrane receptor, AdipoR1, anchored in a virtual 1-palmitoyl-2-oleoyl-phosphatidylcholine membrane. In conclusion, we demonstrated the antidiabetic function of the Tyr-Pro dipeptide as a possible AdipoR1 agonist.

Association between chronic bladder catheterisation and bladder cancer incidence and mortality: a population-based retrospective cohort study in Ontario, Canada.

OBJECTIVES: To compare the risk of bladder cancer and bladder cancer mortality among patients with chronic bladder catheterisation (indwelling or intermittent) to patients from the general population. DESIGN: Retrospective cohort study. SETTING: Population-based study in Ontario, Canada between 2003 and 2018. PARTICIPANTS: Adult patients 18-90 years of age with chronic bladder catheterisation were hard matched to patients from the general population without a history of bladder catheterisation. INTERVENTIONS: The presence of a chronic catheter was defined as a minimum of two physician encounters for bladder catheterisation, suprapubic tube insertion or home care for catheter care separated by at least 28 days. Urinary tract infection (UTI) rates were collected. MAIN OUTCOME MEASURES: Bladder cancer and bladder cancer-specific mortality after a 1-year lag period were compared between groups. RESULTS: We identified 36 903 patients with chronic catheterisation matched to 110 709 patients without a history of catheterisation. Patients were followed for a median of 8.8 years (IQR: 5.2-11.9 years). The median age was 62 years (IQR: 50-71) and 52% were female. More patients in the catheter group developed bladder cancer (393 (1.1%) vs 304 (0.3%),p<0.001). There were 106 (0.3%) bladder cancer deaths in the catheter group and 59 (0.1%) in the comparison group (p<0.001). Chronic catheterisation (adjusted subdistribution HR (sdHR)=4.80, 95% CI: 4.26 to 5.42,p<0.001) and the number of UTIs (adjusted sdHR=1.04 per UTI, 95% CI: 1.04 to 1.05,p<0.001) were independent predictors of bladder cancer. The relative rate of bladder cancer-specific death was more than eightfold higher among patients with chronic catheterisation (adjusted sdHR=8.68, 95% CI: 6.97 to 10.81,p<0.001). Subgroup analysis among patients with neurogenic bladder and bladder calculi similarly revealed an increased risk of bladder cancer diagnosis and mortality. Bladder cancer risk was highest among patients in the two longest catheter duration quintiles (2.9-5.9 and 5.9-15.5 years). CONCLUSIONS: This is the first study to quantify the increase in bladder cancer incidence and mortality in a large, diverse cohort of patients with chronic indwelling or intermittent bladder catheterisation. The risk was highest among patients with a chronic catheter beyond 2.9 years.

AI-based improvement in lung cancer detection on chest radiographs: results of a multi-reader study in NLST dataset.

OBJECTIVE: Assess if deep learning-based artificial intelligence (AI) algorithm improves reader performance for lung cancer detection on chest X-rays (CXRs). METHODS: This reader study included 173 images from cancer-positive patients (n = 98) and 346 images from cancer-negative patients (n = 196) selected from National Lung Screening Trial (NLST). Eight readers, including three radiology residents, and five board-certified radiologists, participated in the observer performance test. AI algorithm provided image-level probability of pulmonary nodule or mass on CXRs and a heatmap of detected lesions. Reader performance was compared with AUC, sensitivity, specificity, false-positives per image (FPPI), and rates of chest CT recommendations. RESULTS: With AI, the average sensitivity of readers for the detection of visible lung cancer increased for residents, but was similar for radiologists compared to that without AI (0.61 [95% CI, 0.55-0.67] vs. 0.72 [95% CI, 0.66-0.77], p = 0.016 for residents, and 0.76 [95% CI, 0.72-0.81] vs. 0.76 [95% CI, 0.72-0.81, p = 1.00 for radiologists), while false-positive findings per image (FPPI) was similar for residents, but decreased for radiologists (0.15 [95% CI, 0.11-0.18] vs. 0.12 [95% CI, 0.09-0.16], p = 0.13 for residents, and 0.24 [95% CI, 0.20-0.29] vs. 0.17 [95% CI, 0.13-0.20], p < 0.001 for radiologists). With AI, the average rate of chest CT recommendation in patients positive for visible cancer increased for residents, but was similar for radiologists (54.7% [95% CI, 48.2-61.2%] vs. 70.2% [95% CI, 64.2-76.2%], p < 0.001 for residents and 72.5% [95% CI, 68.0-77.1%] vs. 73.9% [95% CI, 69.4-78.3%], p = 0.68 for radiologists), while that in cancer-negative patients was similar for residents, but decreased for radiologists (11.2% [95% CI, 9.6-13.1%] vs. 9.8% [95% CI, 8.0-11.6%], p = 0.32 for residents and 16.4% [95% CI, 14.7-18.2%] vs. 11.7% [95% CI, 10.2-13.3%], p < 0.001 for radiologists). CONCLUSIONS: AI algorithm can enhance the performance of readers for the detection of lung cancers on chest radiographs when used as second reader. KEY POINTS: • Reader study in the NLST dataset shows that AI algorithm had sensitivity benefit for residents and specificity benefit for radiologists for the detection of visible lung cancer. • With AI, radiology residents were able to recommend more chest CT examinations (54.7% vs 70.2%, p < 0.001) for patients with visible lung cancer. • With AI, radiologists recommended significantly less proportion of unnecessary chest CT examinations (16.4% vs. 11.7%, p < 0.001) in cancer-negative patients.

Streamlined selection of cancer antigens for vaccine development through integrative multi-omics and high-content cell imaging.

Identification of tumor antigens that induce cytotoxic T lymphocytes (CTLs) is crucial for cancer-vaccine development. Despite their predictive ability, current algorithmic approaches and human leukocyte antigen (HLA)-peptidomic analysis allow limited selectivity. Here, we optimized a method to rapidly screen and identify highly immunogenic epitopes that trigger CTL responses. We used a combined application of this method involving immune-specific signature analysis and HLA-associated peptidomics using samples from six patients with triple-negative breast cancer (TNBC) in order to select immunogenic HLA epitopes for in vitro testing. Additionally, we applied high-throughput imaging at the single-cell level in order to confirm the immunoreactivity of the selected peptides. The results indicated that this method enabled identification of promising CTL peptides capable of inducing antitumor immunity. This platform combining high-resolution computational analysis, HLA-peptidomics, and high-throughput immunogenicity testing allowed rapid and robust identification of highly immunogenic epitopes and represents a powerful technique for cancer-vaccine development.

Genetic and pathogenic characteristics of clade 2.3.2.1c H5N1 highly pathogenic avian influenza viruses isolated from poultry outbreaks in Laos during 2015-2018.

Since 2004, there have been multiple outbreaks of H5 highly pathogenic avian influenza (HPAI) viruses in Laos. Here, we isolated H5N1 HPAI viruses from poultry outbreaks in Laos during 2015-2018 and investigated their genetic characteristics and pathogenicity in chickens. Phylogenetic analysis revealed that the isolates belonged to clade 2.3.2.1c and that they differed from previous Laos viruses with respect to genetic composition. In particular, the isolates were divided into two genotypes, each of which had a different NS segments. The results of possible migration analysis suggested a high likelihood that the Laos isolates were introduced from neighbouring countries, particularly Vietnam. The recent Laos isolate, A/Duck/Laos/NL-1504599/2018, had an intravenous pathogenicity index score of 3.0 and showed a 50% chicken lethal dose of 102.5 EID50 /0.1 ml, indicating high pathogenicity. The isolated viruses exhibited no critical substitution in the markers associated with mammalian adaptation, but possess markers related to neuraminidase inhibitor resistance. These results emphasize the need for ongoing surveillance of circulating influenza virus in South-East Asia, including Laos, to better prepare for and mitigate global spread of H5 HPAI.

NIH3T3 Directs Memory-Fated CTL Programming and Represses High Expression of PD-1 on Antitumor CTLs.

Memory CD8+ T cells have long been considered a promising population for adoptive cell therapy (ACT) due to their long-term persistence and robust re-stimulatory response. NIH3T3 is an immortalized mouse embryonic fibroblast cell line. We report that NIH3T3-conditioned medium (CM) can augment effector functions of CTLs following antigen priming and confer phenotypic and transcriptional properties of central memory cells. After NIH3T3-CM-educated CTLs were infused into naïve mice, they predominantly developed to central memory cells. A large number of NIH3T3-CM-educated CTLs with high functionality persisted and infiltrated to tumor mass. In addition, NIH3T3-CM inhibited CTLs expression of PD-1 in vitro and repressed their high expression of PD-1 in tumor microenvironment after adoptive transfer. Consequently, established tumor models showed that infusion of NIH3T3-CM-educated CTLs dramatically improved CTL mediated-antitumor immunity. Furthermore, NIH3T3-CM also promoted human CD8+ T cells differentiation into memory cells. These results suggest that NIH3T3-CM-programmed CTLs are good candidates for adoptive transfer in tumor therapy.

Overcoming ineffective resistance modulation in p-type NiO gas sensor by nanoscale Schottky contacts.

We present a gas sensor having nanoscale Schottky contacts on an array of helical-shaped p-type NiO to overcome intrinsically ineffective resistance modulation in the bulk of p-type metal oxides upon gas exposure. The Schottky device shows an abnormal n-type sensing behavior despite using the p-type NiO under reducing gas, with the sensitivity of 142.9% at 200 ppm of hydrogen, much higher than the reference Ohmic device with 0.7% sensitivity. Based on our equivalent circuit model with the quantitative estimation of the modulations in both carrier concentration and Schottky barrier height upon gas exposure, such a high sensitivity and the abnormal sensing behavior are attributed to the predominant modulation in the barrier height at the nanoscale Schottky contacts which are uniquely designed to have top-and-bottom electrodes configuration for efficient gas adsorption and sensitive Schottky barrier height modulation.

Chemical analysis techniques and investigation of polycyclic aromatic hydrocarbons in fruit, vegetables and meats and their products.

The current investigation was performed to evaluate the chemical analytical techniques for PAHs (organic, carcinogenic and mutagenic compounds) in food. It also determines the content of eight polycyclic aromatic hydrocarbons (PAHs) in frequently consumed fruit, vegetables, meats and their products. The methodology included saponification or ultrasonication, liquid-liquid extraction with solvents like n-hexane, clean-up using a silica solid phase extraction cartridge and a gas chromatography-mass spectrometry technique. A good linearity (R2 > 0.99) was achieved for the PAHs at different concentrations. Recovery results for PAHs extended from 88.75 to ∼100.00%. The limit of detection was 0.08-0.25 µg/kg and the limit of quantification was 0.24-0.75 µg/kg. The mean concentration (n = 3) of benzo[a]pyrene was not identified in fruits, was 0.05 µg/kg in vegetables, and 0.64 µg/kg in meat products. Overall concentration of the eight PAHs was 0.67 µg/kg in fruits, 0.82 µg/kg in vegetables, and 3.37 µg/kg in meat products.

Highly Pathogenic Avian Influenza A(H5N6) in Domestic Cats, South Korea.

In December 2016, highly pathogenic avian influenza (HPAI) infection with systemic pathologic lesions was found in cats in South Korea. Genetic analyses indicated that the feline isolates were similar to HPAI H5N6 viruses isolated in chicken farms nearby. This finding highlights the need for monitoring of domestic mammals during HPAI outbreaks.

Association Between Use of Antithrombotic Medication and Hematuria-Related Complications.

Importance: Antithrombotic medications are among the most commonly prescribed medications. Objective: To characterize rates of hematuria-related complications among patients taking antithrombotic medications. Design, Setting, and Participants: Population-based, retrospective cohort study including all citizens in Ontario, Canada, aged 66 years and older between 2002 and 2014. The final follow-up date was December 31, 2014. Exposures: Receipt of an oral anticoagulant or antiplatelet medication. Main Outcomes and Measures: Hematuria-related complications, defined as emergency department visit, hospitalization, or a urologic procedure to investigate or manage gross hematuria. Results: Among 2 518 064 patients, 808 897 (mean [SD] age, 72.1 [6.8] years; 428 531 [53%] women) received at least 1 prescription for an antithrombotic agent over the study period. Over a median follow-up of 7.3 years, the rates of hematuria-related complications were 123.95 events per 1000 person-years among patients actively exposed to antithrombotic agents vs 80.17 events per 1000 person-years among patients not exposed to these drugs (difference, 43.8; 95% CI, 43.0-44.6; P < .001, and incidence rate ratio [IRR], 1.44; 95% CI, 1.42-1.46). The rates of complications among exposed vs unexposed patients (80.17 events/1000 person-years) were 105.78 for urologic procedures (difference, 33.5; 95% CI, 32.8-34.3; P < .001, and IRR, 1.37; 95% CI, 1.36-1.39), 11.12 for hospitalizations (difference, 5.7; 95% CI, 5.5-5.9; P < .001, and IRR, 2.03; 95% CI, 2.00-2.06), and 7.05 for emergency department visits (difference, 4.5; 95% CI, 4.3-4.7; P < .001, and IRR, 2.80; 95% CI, 2.74-2.86). Compared with patients who were unexposed to thrombotic agents, the rates of hematuria-related complications were 191.61 events per 1000 person-years (difference, 117.3; 95% CI, 112.8-121.8) for those exposed to both an anticoagulant and antiplatelet agent (IRR, 10.48; 95% CI, 8.16-13.45), 140.92 (difference, 57.7; 95% CI, 56.9-58.4) for those exposed to anticoagulants (IRR, 1.55; 95% CI, 1.52-1.59), and 110.72 (difference, 26.5; 95% CI, 25.9-27.0) for those exposed to antiplatelet agents (IRR, 1.31; 95% CI, 1.29-1.33). Patients exposed to antithrombotic agents, compared with patients not exposed to these drugs, were more likely to be diagnosed as having bladder cancer within 6 months (0.70% vs 0.38%; odds ratio, 1.85; 95% CI, 1.79-1.92). Conclusions and Relevance: Among older adults in Ontario, Canada, use of antithrombotic medications, compared with nonuse of these medications, was significantly associated with higher rates of hematuria-related complications (including emergency department visits, hospitalizations, and urologic procedures to manage gross hematuria).

Cellular Immune Correlates Preventing Disease Against Respiratory Syncytial Virus by Vaccination with Virus-Like Nanoparticles Carrying Fusion Proteins.

Cellular immune correlates conferring protection against respiratory syncytial virus (RSV) but preventing vaccine-enhanced respiratory disease largely remain unclear. We investigated cellular immune correlates that contribute to preventing disease against human respiratory syncytial virus (RSV) by nanoparticle vaccine delivery. Formalin-inactivated RSV (FI-RSV) vaccines and virus-like nanoparticles carrying RSV fusion proteins (F VLP) were investigated in mice. The FI-RSV vaccination caused severe weight loss and histopathology by inducing interleukin (IL)-4+, interferon (IFN)-γ+, IL-4+IFN-γ+ CD4+ T cells, eosinophils, and lung plasmacytoid dendritic cells (DCs), CD103+ DCs, and CD11b+ DCs. In contrast, the F VLP-immune mice induced protection against RSV without disease by inducing natural killer cells, activated IFN-γ+, and IFN-γ+ tumor necrosis factor (TNF)-α+ CD8+ T cells in the lung and bronchiolar airways during RSV infection but not disease-inducing DCs and effector T cells. Clodronate-mediated depletion studies provided evidence that alveolar macrophages that were present at high levels in the F VLP-immune mice play a role in modulating protective cellular immune phenotypes. There was an intrinsic difference between the F VLP and FI-RSV treatments in stimulating proinflammatory cytokines. The F VLP nanoparticle vaccination induced distinct innate and adaptive cellular subsets that potentially prevented lung disease after RSV infection.

Roles of Aluminum Hydroxide and Monophosphoryl Lipid A Adjuvants in Overcoming CD4+ T Cell Deficiency To Induce Isotype-Switched IgG Antibody Responses and Protection by T-Dependent Influenza Vaccine.

Vaccine adjuvant effects in the CD4-deficient condition largely remain unknown. We investigated the roles of combined monophosphoryl lipid A (MPL) and aluminum hydroxide (Alum) adjuvant (MPL+Alum) in inducing immunity after immunization of CD4 knockout (CD4KO) and wild-type (WT) mice with T-dependent influenza vaccine. MPL+Alum adjuvant mediated IgG isotype-switched Abs, IgG-secreting cell responses, and protection in CD4KO mice, which were comparable to those in WT mice. In contrast, Alum adjuvant effects were dependent on CD4+ T cells. MPL+Alum adjuvant was effective in recruiting monocytes and neutrophils as well as in protecting macrophages from Alum-mediated cell loss at the injection site in CD4KO mice. MPL+Alum appeared to attenuate MPL-induced inflammatory responses in WT mice, likely improving the safety. Additional studies in CD4-depleted WT mice and MHC class II KO mice suggest that MHC class II+ APCs contribute to providing alternative B cell help in the CD4-deficient condition in the context of MPL+Alum-adjuvanted vaccination.

Performance of the Angle Labor Pain Questionnaire During Initiation of Epidural Analgesia in Early Active Labor.

BACKGROUND: The Angle Labor Pain Questionnaire (A-LPQ) is a new, 22-item multidimensional psychometric questionnaire that measures the 5 most important dimensions of women's childbirth pain experiences using 5 subscales: The Enormity of the Pain, Fear/Anxiety, Uterine Contraction Pain, Birthing Pain, and Back Pain/Long Haul. Previous work showed that the A-LPQ has overall good psychometric properties and performance during early active labor in women without pain relief. The current study assessed the tool's sensitivity to change during initiation of labor epidural analgesia with the standardized response mean (SRM, primary outcome). METHODS: Two versions of the A-LPQ were administered once, in each of 2 test sessions, by the same trained interviewer during early active labor. The sequence of administration was randomized (ie, standard question order version [Test 1] followed by mixed version [Test 2] or vice versa). Test 1 was completed before epidural insertion; Test 2 commenced 20 to 30 minutes after the test dose. Providers assessed/treated pain independently of the study. Sensitivity to change was assessed using SRMs, Cohen's d, and paired t tests. Overall pain intensity was concurrently examined using Numeric Rating Scale and the Verbal Rating Scale (VRS); coping was assessed with the Pain Mastery Scale. Changes in pain were measured with the Patient Global Impression of Change Scale. Internal consistency was assessed with Cronbach's α. Concurrent validity with other tools was assessed using Spearman's rank correlation coefficient. RESULTS: A total of 51 complete datasets were analyzed. Most women reported moderate (63%, 32/51) or severe (18%, 9/51) baseline pain on VRS scores during Test 1; 29% (15/51) reported mild pain, and 6% (3/51) reported moderate pain during Test 2. Approximately 90% (46/51) of women reported much or very much improved pain at the end of testing. Cronbach's α for A-LPQ summary scores was excellent (0.94) and ranged from 0.78 (acceptable) to 0.92 (excellent) for subscales (Test 1). Large SRMs were found for A-LPQ summary scores (1.6, 95% CI: 1.2, 2.1) and all subscales except the Birthing Pain subscale (moderate, 0.60, 95% CI: 0.23, 0.97). Significant (P < .001) differences were found between A-LPQ summary scores and between all subscales on paired t tests. Correlations between A-LPQ summary and Numeric Rating Scale scores (overall pain intensity) were strong (ρ > 0.73), correlations were moderate (ρ > 0.5) with VRS scores and coping scores (ρ > 0.67). CONCLUSIONS: Findings support A-LPQ use for measurement of women's childbirth pain experiences during initiation of labor epidural analgesia during early active labor. Combined with our previous work, they also support the use of the A-LPQ in late labor and at delivery.

Cardiovascular and Skeletal-related Events Following Localized Prostate Cancer Treatment: Role of Surgery, Radiotherapy, and Androgen Deprivation.

OBJECTIVE: To examine the impact of androgen deprivation therapy (ADT) and primary treatment modality on cardiovascular and skeletal-related events and to investigate potential effect modification in a contemporary cohort of patients treated for clinically localized prostate cancer. SUBJECTS AND METHODS: We conducted a retrospective cohort study using Surveillance, Epidemiology, and End Results-Medicare linked databases for men aged 65-79 years who underwent radical prostatectomy or radiotherapy for cT1 or cT2 prostate cancer from 2000 to 2008. We categorized treatment according to primary therapy and receipt of ADT. We described the cumulative incidence of cardiovascular and skeletal-related events. RESULTS: Among 60,156 men, 14,403 underwent surgery and 45,753 underwent radiotherapy. Median follow-up was 6.0 years. After adjusting for baseline differences, treatments with radiotherapy (adjusted hazard ratios [aHR] 1.16-1.28, P <.0001-.04) and ADT (aHR 1.18-1.32, P <.0001-.008) were each independently associated with increased risk of coronary heart disease, sudden cardiac death, fracture, and fracture requiring hospitalization. Radiotherapy was associated with an increased risk of myocardial infarction (aHR 1.20, P = .02), whereas ADT was not (P = .5). We did not identify a significant statistical interaction between primary and hormonal treatment. CONCLUSION: Care for cardiovascular and skeletal-related events is an important part of the survivorship phase for a significant proportion of patients with localized prostate cancer. Increasing use of ADT for patients with localized disease undergoing radiotherapy and the observed higher prevalence of these events in these patients should be considered when discussing the risks and benefits of treatment for localized prostate cancer and when formulating a survivorship plan.