Rationale: Sepsis and acute lung injury (ALI) have devastatingly high mortality rates. Both are associated with increased vascular leak, a process regulated by complex molecular mechanisms. Objectives: We hypothesized that integrin avb3 could be an important determinant of vascular leak and endothelial permeability in sepsis and ALI. Methods: b3 subunit knockout mice were tested for lung vascular leak after endotracheal LPS, and systemic vascular leak and mortality after intraperitoneal LPS and cecal ligation and puncture. Possible contributory effects of b3 deficiency in platelets and other hematopoietic cells were excluded by bone marrow reconstitution experiments. Endothelial cells treated with avb3 antibodies were evaluated for sphingosine-1 phosphate (S1P)-mediated alterations in barrier function, cytoskeletal arrangement, and integrin localization. Measurements and Main Results: b3 knockout mice had increased vascular leak and pulmonary edema formation after endotracheal LPS, and increased vascular leak and mortality after intraperitoneal LPS and cecal ligation and puncture. In endothelial cells, avb3 antibodies inhibited barrier-enhancing and cortical actin responses to S1P. Furthermore, S1P induced translocation of avb3 from discrete focal adhesions to cortically distributed sites through Gi-and Rac1-mediated pathways. Cortical avb3 localization after S1P was decreased by avb3 antibodies, suggesting that ligation of the avb3 with its extracellular matrix ligands is required to stabilize cortical avb3 focal adhesions. Conclusions: Our studies identify a novel mechanism by which avb3 mitigates increased vascular leak, a pathophysiologic function central to sepsis and ALI. These studies suggest that drugs designed to block avb3 may have the unexpected side effect of intensifying sepsis-and ALI-associated vascular endothelial leak.Keywords: vascular endothelium; sepsis; acute lung injury; integrin Sepsis and acute lung injury (ALI) are associated with high mortality rates and worldwide healthcare burden (1-4). Development of these syndromes requires complex host responses involving multiple cell types, inflammatory mediators, and coagulation factors. One pathophysiologic hallmark common to both sepsis and ALI is increased vascular leak. Increased vascular leak in sepsis leads to redistribution of intravascular fluid to extravascular compartments, hypovolemia, hemoconcentration, and stasis of blood flow. In ALI, alveolar spaces become flooded with pulmonary edema, resulting in impaired gas exchange, arterial hypoxemia, and respiratory failure (4-6).It is generally believed that increased paracellular passage of solutes through the vascular endothelium occurs during acute inflammatory states (7,8). Frequently cited models suggest that paracellular gaps form because of disrupted homeostasis between cytoskeletal, adhesive cell-cell, and cell-matrix forces (8-10). Integrins, a large family of heterodimeric glycoprotein receptors, are important mediators of these cellular functions and have been shown to participa...

TP-PA results in conjunction with clinical/behavioral assessment helped guide the management of patients with CIA-positive, RPR-negative serology. TP-PA-positive patients were both highly likely to have prior syphilis and major epidemiologic risk factors for syphilis. CIA-positive, RPR-negative, TP-PA-negative serology may represent a false-positive CIA in low-prevalence populations.

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Most pregnant women with discordant serology were CIA(+)/RPR(-)/TP-PA(-); more than half who were retested became CIA(-). CIA(+)/RPR(-)/TP-PA(-) serology in pregnancy is likely to be falsely positive. Reflexive testing of discordant specimens with TP-PA is important to stratify risk given the likelihood of false-positive results in this population.

For the past thirty years, research examining predictors of successful smoking cessation treatment response has focused primarily on clinical variables, such as levels of tobacco dependence, craving, and self-efficacy. Recent research, however, has begun to determine biomarkers (such as genotype, nicotine and metabolite levels, and brain imaging findings) that may have utility in predicting smoking cessation. For genotype, genes associated with nicotinic acetylcholine receptors (nAChRs) and related proteins have been found to predict response to first line medications (e.g., nicotine replacement therapy [NRT], bupropion, or varenicline) or quitting over time without a controlled treatment trial. For nicotine and metabolite levels, function of the CYP 2A6 liver enzyme, which can be assessed with the nicotine metabolite ratio or via genotype, has been found to predict response, with slow nicotine metabolizers having less severe nicotine dependence and a greater likelihood of quitting with NRT than normal metabolizers. And for brain imaging, decreased activation of brain regions associated with emotion regulation and increased connectivity in emotion regulation networks, increased responsiveness to pleasant cues, and altered activation with the Stroop effect have been found in smokers who quit with the first-line medications listed above or counseling. In addition, our group recently demonstrated that lower pre-treatment brain nAChR density is associated with a greater chance of quitting smoking with NRT or placebo. Several of these studies found that specific biomarkers may provide additional information for predicting response beyond subjective symptom or rating scale measures, thereby giving an initial indication that biomarkers may, in the future, be useful for guiding smoking cessation treatment intensity, duration, and type.

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Introduction When microglia become activated (an integral part of neuroinflammation), cellular morphology changes and expression of translocator protein (TSPO) 18 kDa is increased. Over the past several years, [11C]DAA1106 has emerged as a reliable radiotracer for labeling TSPO with high affinity during positron emission tomography (PET) scanning. While [11C]DAA1106 PET scanning has been used in several research studies, a radiation dosimetry study of this radiotracer in humans has not yet been published. Methods Twelve healthy participants underwent full body dynamic [11C]DAA1106 PET scanning, with 8 sequential whole body scans (approximately 12 bed positions each), following a single injection. Regions of interest were drawn manually and time activity curves (TACs) were obtained for 15 organs. OLINDA/EXM 1.1 was used to compute radiation absorbed doses to the target organs, as well as effective dose (ED) and effective dose equivalent (EDE). Results The ED and EDE were 4.06 ± 0.58 μSv/MBq and 5.89 ± 0.83 μSv/MBq, respectively. The highest absorbed doses were to the heart wall, kidney, liver, pancreas, and spleen. TACs revealed that peak dose rates are during the first scan (at 6 min) for all organs other than the urinary bladder wall, which had its peak dose rate during the fourth scan (at 30 min). Conclusions The recently developed radiotracer [11C]DAA1106 has its EDE and target-organ absorbed dose such that, for a single administration, its radiation dosimetry is well within the U.S. FDA guidelines for basic research studies in adults. This dose level implies that the dosimetry for multiple [11C]DAA1106 scans within a given year also falls within FDA guidelines, and this favorable property makes this radiotracer suitable for examining microglial activation repeatedly over time, which may in the future be useful for longitudinal tracking of disease progression and monitoring of therapy response in conditions marked by neuroinflammation (e.g., head trauma and multiple sclerosis).

12026 Background: Informal caregivers are essential partners in the delivery of cancer care, and often can accurately identify and report symptoms and physical function of the patients they care for. We assessed whether such reporting by caregivers is predictive of adverse patient outcomes. Methods: In this prospective study, adult solid cancer patients on active intravenous systemic therapies and their informal caregivers were recruited from 18 Kaiser Permanente Northern California cancer centers. Using a study mobile app (TOGETHERCare), caregivers completed weekly surveys for 4 weeks, which were based on normalized NIH-PROMIS scores to report patients’ physical function and PRO-CTCAE to report patients’ symptoms. Patients’ adverse clinical outcomes were abstracted from the medical record and included: emergency department (ED) visits or hospitalizations, grade 3-4 adverse events (AEs), and treatment delays, up to 1 month following the 4-week study period, as well as mortality and hospice referrals up to 6 months following the study period. Simple univariate logistic regressions were used to correlate caregiver reports (either at baseline or most proximal preceding an adverse outcome) with mortality and hospice referrals, and quasi-Poisson regressions were used for the other adverse outcome measures. Results: Fifty-four patient-caregiver dyads were enrolled, and 52 were included in this analysis. A third of patients had breast cancer and almost 75% had stage 3 or 4 disease. Caregivers predominantly identified as male (61.5%), spouse/partner (76.9%), and non-Hispanic White (63.5%). At least one adverse outcome was experienced by 36.5% of the patients. Caregiver-reported PRO-CTCAE consistently predicted ED/hospitalizations and mortality, and caregiver-reported PROMIS scores predicted hospice referrals (see Table). Conclusions: The results suggest that caregiver reporting of patients’ symptoms and physical function could help provide early predictions of adverse patient outcomes.[Table: see text]