Immune profiling of adeno-associated virus response identifies B cell-specific targets that enable vector re-administration in mice.

Adeno-associated virus (AAV) vector-based gene therapies can be applied to a wide range of diseases. AAV expression can last for months to years, but vector re-administration may be necessary to achieve life-long treatment. Unfortunately, immune responses against these vectors are potentiated after the first administration, preventing the clinical use of repeated administration of AAVs. Reducing the immune response against AAVs while minimizing broad immunosuppression would improve gene delivery efficiency and long-term safety. In this study, we quantified the contributions of multiple immune system components of the anti-AAV response in mice. We identified B-cell-mediated immunity as a critical component preventing vector re-administration. Additionally, we found that IgG depletion alone was insufficient to enable re-administration, suggesting IgM antibodies play an important role in the immune response against AAV. Further, we found that AAV-mediated transduction is improved in µMT mice that lack functional IgM heavy chains and cannot form mature B-cells relative to wild-type mice. Combined, our results suggest that B-cells, including non-class switched B-cells, are a potential target for therapeutics enabling AAV re-administration. Our results also suggest that the µMT mice are a potentially useful experimental model for gene delivery studies since they allow repeated dosing for more efficient gene delivery from AAVs.

Membrane-bound MMP-14 protease-activatable adeno-associated viral vectors for gene delivery to pancreatic tumors.

Adeno-associated virus' (AAV) relatively simple structure makes it accommodating for engineering into controllable delivery platforms. Cancer, such as pancreatic ductal adenocarcinoma (PDAC), are often characterized by upregulation of membrane-bound proteins, such as MMP-14, that propagate survival integrin signaling. In order to target tumors, we have engineered an MMP-14 protease-activatable AAV vector that responds to both membrane-bound and extracellularly active MMPs. This "provector" was generated by inserting a tetra-aspartic acid inactivating motif flanked by the MMP-14 cleavage sequence IPESLRAG into the capsid subunits. The MMP-14 provector shows lower background transduction than previously developed provectors, leading to a 9.5-fold increase in transduction ability. In a murine model of PDAC, the MMP-14 provector shows increased delivery to an allograft tumor. This proof-of-concept study illustrates the possibilities of membrane-bound protease-activatable gene therapies to target tumors.

A pilot school-based health center intervention to improve asthma chronic care in high-poverty schools.

OBJECTIVE: To test the feasibility and effectiveness of a multifaceted intervention administered through school-based health centers (SBHCs) to improve asthma control for children in high-poverty schools with not well controlled asthma. METHODS: Students 4-14 years old with persistent asthma were enrolled from three SBHCs. The centers' advanced practice providers received training on evidence-based asthma guidelines. Students randomized to the intervention received directly observed therapy of their asthma controller medication, medication adjustments as needed by the centers' providers, and daily self-management support. Students randomized to usual care were referred back to their primary care provider (PCP) for routine asthma care. RESULTS: We enrolled 29 students. Students in the intervention group received their controller medication 92% of days they were in school. Ninety-four percent of follow-up assessments were completed. During the study, 11 of 12 intervention students had a step-up in medication; 2 of 15 usual care students were stepped up by their PCP. Asthma Control Test scores did not differ between groups, although there were significant improvements from baseline to the 7 month follow-up within each group (both p < .01). Both FEV1% predicted and FEV1/FVC ratio significantly worsened in the usual care group (both p = .001), but did not change in the intervention group (p = .76 and .28 respectively). CONCLUSIONS: Our pilot data suggest that a multifaceted intervention can be feasibly administered through SBHCs in communities with health disparities. Despite the small sample size, spirometry detected advantages in the intervention group. Further study is needed to optimize the intervention and evaluate outcomes. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT03032744.

Frustration and Direct-Coupling Analyses to Predict Formation and Function of Adeno-Associated Virus.

Adeno-associated virus (AAV) is a promising gene therapy vector because of its efficient gene delivery and relatively mild immunogenicity. To improve delivery target specificity, researchers use combinatorial and rational library design strategies to generate novel AAV capsid variants. These approaches frequently propose high proportions of nonforming or noninfective capsid protein sequences that reduce the effective depth of synthesized vector DNA libraries, thereby raising the discovery cost of novel vectors. We evaluated two computational techniques for their ability to estimate the impact of residue mutations on AAV capsid protein-protein interactions and thus predict changes in vector fitness, reasoning that these approaches might inform the design of functionally enriched AAV libraries and accelerate therapeutic candidate identification. The Frustratometer computes an energy function derived from the energy landscape theory of protein folding. Direct-coupling analysis (DCA) is a statistical framework that captures residue coevolution within proteins. We applied the Frustratometer to select candidate protein residues predicted to favor assembled or disassembled capsid states, then predicted mutation effects at these sites using the Frustratometer and DCA. Capsid mutants were experimentally assessed for changes in virus formation, stability, and transduction ability. The Frustratometer-based metric showed a counterintuitive correlation with viral stability, whereas a DCA-derived metric was highly correlated with virus transduction ability in the small population of residues studied. Our results suggest that coevolutionary models may be able to elucidate complex capsid residue-residue interaction networks essential for viral function, but further study is needed to understand the relationship between protein energy simulations and viral capsid metastability.

The Effectiveness of Eye Movement Desensitization and Reprocessing Therapy to Treat Symptoms Following Trauma in Timor Leste.

The effectiveness of eye movement desensitization and reprocessing (EMDR) therapy for treating trauma symptoms was examined in a postwar/conflict, developing nation, Timor Leste. Participants were 21 Timorese adults with symptoms of posttraumatic stress disorder (PTSD), assessed as those who scored ≥2 on the Harvard Trauma Questionnaire (HTQ). Participants were treated with EMDR therapy. Depression and anxiety symptoms were assessed using the Hopkins Symptom Checklist. Symptom changes post-EMDR treatment were compared to a stabilization control intervention period in which participants served as their own waitlist control. Sessions were 60-90 mins. The average number of sessions was 4.15 (SD = 2.06). Despite difficulties providing treatment cross-culturally (i.e., language barriers), EMDR therapy was followed by significant and large reductions in trauma symptoms (Cohen's d = 2.48), depression (d = 2.09), and anxiety (d = 1.77). At posttreatment, 20 (95.2%) participants scored below the HTQ PTSD cutoff of 2. Reliable reductions in trauma symptoms were reported by 18 participants (85.7%) posttreatment and 16 (76.2%) at 3-month follow-up. Symptoms did not improve during the control period. Findings support the use of EMDR therapy for treatment of adults with PTSD in a cross-cultural, postwar/conflict setting, and suggest that structured trauma treatments can be applied in Timor Leste.

Reliability of the penetration aspiration scale with flexible endoscopic evaluation of swallowing.

OBJECTIVES: The Penetration Aspiration Scale (PAS), although designed for videofluoroscopy, has been utilized with flexible endoscopic evaluation of swallowing (FEES) in both research and clinical practice. The purpose of this investigation was to determine inter- and intrarater reliability of the PAS with FEES as a function of clinician FEES experience and retest interval. METHODS: Three groups of 3 clinicians (N=9) with varying FEES experience (beginning, intermediate, and advanced) assigned PAS scores to 35 swallows. Initial ratings were repeated following short-term (ie, 1 day) and long-term (ie, 1 week) retest intervals. RESULTS: Intraclass correlation coefficients were calculated to assess interrater reliability on the first rating for each group. The coefficients were .91, .82, and .89 for the beginning, intermediate, and advanced clinicians, respectively. Overall interrater reliability across all 9 clinicians, irrespective of experience, was .85. Intraclass correlation coefficients were also calculated to assess intrarater reliability. The intrarater reliability for short- and long-term ratings was .90, .94, and .96 and .96, .97, and .94 for the beginning, intermediate, and advanced clinicians, respectively. Overall intrarater reliability across all 9 clinicians and all 3 ratings was .94. CONCLUSIONS: Excellent inter- and intrarater reliability was evidenced with the application of the PAS for FEES regardless of clinician experience and retest interval.

Use of topical nasal anesthesia during flexible endoscopic evaluation of swallowing in dysphagic patients.

OBJECTIVE: This study aimed to determine the effect of topical lidocaine on Penetration-Aspiration Scale (PAS) scores and patient comfort and tolerance of flexible endoscopic evaluation of swallowing (FEES) examinations in dysphagic patients. METHODS: Adults with dysphagia referred for swallowing evaluation were recruited to participate in consecutive nonanesthetized and then anesthetized FEES examinations. Under endoscopic visualization, participants consumed 6 swallows consisting of graduated volumes of milk, pudding, and cracker in each condition and recorded their discomfort and tolerance in the 2 conditions. Penetration-Aspiration Scale scores were assigned in blinded fashion for each swallow. RESULTS: Twenty-five adults participated in the study. Although there was no statistically significant effect of anesthesia on PAS scores (P=.065), the odds of a higher PAS score were 33% higher during anesthetized swallows. The anesthetized condition yielded significantly less discomfort and pain during the examination, significantly less pain and discomfort during insertion and removal of the endoscope, and significantly greater overall tolerance than the nonanesthetized condition. CONCLUSION: The use of topical lidocaine during FEES may impair swallowing ability in patients with dysphagia, but this result does not achieve statistical significance. Topical nasal anesthesia significantly reduces subjective pain and discomfort and improves tolerance during FEES.

Effect of Lidocaine on Swallowing During FEES in Patients With Dysphagia.

PURPOSE: The aims of this study were to assess the effects of 0.2 mL of 4% atomized lidocaine on swallowing and tolerability during Fiberoptic Endoscopic Evaluation of Swallowing (FEES). METHODS: A single blinded study was conducted with 17 dysphagic patients, who received 4 standardized boluses in 2 sequential FEES exams under 2 conditions: non-anesthetized (decongestant only) and anesthetized (lidocaine 4%+decongestant). After each procedure, patients rated their pain on the Wong Baker FACES Pain Rating Scale. Clinicians scored each swallow with the Penetration Aspiration Scale (PAS) and an author-developed Residue Rating Scale. Because the assessments were ordinal, a series of Wilcoxon signed-rank tests were conducted to detect differences between the 2 conditions. RESULTS: No significant differences were detected between groups on PAS or residue in the 4 boluses. Pain scores, however, were significantly lower in the anesthetized condition than the decongested-only condition (P=.035). CONCLUSION: The findings of this study indicated that 0.2 mL of 4% lidocaine enhanced exam tolerability and did not impair the swallow in dysphagic patients.

Effect of Quencher, Denaturants, Temperature and pH on the Fluorescent Properties of BSA Protected Gold Nanoclusters.

In this paper, we have synthesized BSA protected gold nanoclusters (BSA Au nanocluster) and studied the effect of quencher, protein denaturant, pH and temperature on the fluorescence properties of the tryptophan molecule of the BSA Au nanocluster and native BSA. We have also studied their effect on the peak emission of BSA Au nanoclusters (650 nm). The phtophysical characterization of a newly developed fluorophore in different environments is absolutely necessary to futher develop their biomedical and analytical applications. It was observed from our experiments that the tryptophan in BSA Au nanoclusters is better shielded from the polar environment. Tryptophan in native BSA showed a red shift in its peak emission wavelength position. Tryptophan is a highly polarity sensitive dye and a minimal change in its microenvironment can be easily observed in its photophysical properties.

Deep vs shallow: GPS tags reveal a dichotomy in movement patterns of loggerhead turtles foraging in a coastal bay.

BACKGROUND: Individual variation in movement strategies of foraging loggerhead turtles have been documented on the scale of tens to hundreds of kilometers within single ocean basins. Use of different strategies among individuals may reflect variations in resources, predation pressure or competition. It is less common for individual turtles to use different foraging strategies on the scale of kilometers within a single coastal bay. We used GPS tags capable of back-filling fine-scale locations to document movement patterns of loggerhead turtles in a coastal bay in Northwest Florida, U.S.A. METHODS: Iridium-linked GPS tags were deployed on loggerhead turtles at a neritic foraging site in Northwest Florida. After filtering telemetry data, point locations were transformed to movement lines and then merged with the original point file to define travel paths and assess travel speed. Home ranges were determined using kernel density function. Diurnal behavioral shifts were examined by examining turtle movements compared to solar time. RESULTS: Of the 11 turtles tagged, three tracked turtles remained in deep (~ 6 m) water for almost the entire tracking period, while all other turtles undertook movements from deep water locations, located along edges and channels, to shallow (~ 1-2 m) shoals at regular intervals and primarily at night. Three individuals made short-term movements into the Gulf of Mexico when water temperatures dropped, and movement speeds in the Gulf were greater than those in the bay. Turtles exhibited a novel behavior we termed drifting. CONCLUSIONS: This study highlighted the value provided to fine-scale movement studies for species such as sea turtles that surface infrequently by the ability of these GPS tags to store and re-upload data. Future use of these tags at other loggerhead foraging sites, and concurrent with diving and foraging data, would provide a powerful tool to better understand fine-scale movement patterns of sea turtles.

Cross study analyses of SEND data: toxicity profile classification.

A SEND toxicology data transformation, harmonization, and analysis platform were created to improve the identification of unique findings related to the intended target, species, and duration of dosing using data from multiple studies. The lack of a standardized digital format for data analysis had impeded large-scale analysis of in vivo toxicology studies. The CDISC SEND standard enables the analysis of data from multiple studies performed by different laboratories. This work describes methods to analyze data and automate cross-study analysis of toxicology studies. Cross-study analysis can be used to understand a single compound's toxicity profile across all studies performed and/or to evaluate on-target versus off-target toxicity for multiple compounds intended for the same pharmacological target. This work involved development of data harmonization/transformation strategies to enable cross-study analysis of both numerical and categorical SEND data. Four de-identified SEND datasets from the BioCelerate database were used for the analyses. Toxicity profiles for key organ systems were developed for liver, kidney, male reproductive tract, endocrine system, and hematopoietic system using SEND domains. A cross-study analysis dashboard with a built-in user-defined scoring system was created for custom analyses, including visualizations to evaluate data at the organ system level and drill down into individual animal data. This data analysis provides the tools for scientists to compare toxicity profiles across multiple studies using SEND. A cross-study analysis of 2 different compounds intended for the same pharmacological target is described and the analyses indicate potential on-target effects to liver, kidney, and hematopoietic systems.

Stability of aspiration status in healthy adults.

OBJECTIVES: In multiple separate studies, we consistently found that approximately 30% of asymptomatic healthy older adults silently aspirated liquids during flexible endoscopic evaluation of swallowing (FEES). We subsequently questioned whether aspiration status remained stable in healthy older adults over time. The purpose of this study was to determine the stability of aspiration status in healthy older adults over time. METHODS: Eighteen healthy older participants, comprising of 9 aspirators and 9 nonaspirators whose aspiration status was identified in a previous study, underwent a second FEES approximately 6 to 21 months later. The participants contributed 36 swallows, comprising 5-, 10-, 15-, and 20-mL boluses of milk (ie, 1 bolus of each volume of skim, 2%, whole, and soy milk) and water via cup and straw delivery, during the original FEES. An abbreviated protocol was administered for the repeat FEES. The Penetration-Aspiration Scale was used to rate all swallows. RESULTS: A McNemar test demonstrated no change in aspiration status among participants between the initial test and the retest (p > 0.999). CONCLUSIONS: In this cohort, the aspiration status was stable over about 12 months. This finding lends credence to the premise that trace aspiration of liquids may be a normal and consistent finding in some healthy older adults.

Implementing Centering Parenting Model With an Urban Pediatric Population to Measure and Improve Clinical Outcomes and Parent Satisfaction.

INTRODUCTION: For CenteringParenting-a patient-centered, group family approach to child health-this study aimed to determine how the CenteringParenting model affects clinical outcomes compared with the traditional well-child care model and how the CenteringParenting model affect parent satisfaction as compared with the traditional well-child care model. This study was conducted at the Children's Health Center in West Reading, PA-a single-site pediatric practice that serves primarily an inner city with a population currently at 95,112. METHOD: Quantitative data collection was obtained from a retrospective chart review for both groups of patients to obtain outcome data. Phone interviews were completed, and participants were asked to respond to a series of questions using a 5-point Likert scale and several open-ended questions. All statistical analyses for this research were performed using SPSS (version 25.0; IBM Corp., Armonk, NY). Two groups were coded as the centering group and control group. Significance testing was performed using chi-square analysis for categorical data and t test for continuous data. RESULTS: CenteringParenting children are more likely to be UTD with their scheduled visits and vaccines than those receiving the traditional model of well-child care. Maternal depression screenings were more likely to be completed and documented and open discussions about maternal depression. Parents involved with group visits found it to be great care, liked being with other parents, learned a lot, and would recommend it to other parents. DISCUSSION: Limitations of the study include being a new site offering the CHI program for group well-child visits. As the program has continued to progress over the years, it has continued to grow and is now offered in both English and Spanish. Another limitation was not having trained breastfeeding professionals such as lactation counselors, consultants, or breastfeeding resource nurses. Future research is needed to study the implementation of breastfeeding in minority populations. In addition, a more in-depth study about triage calls and if parents feel more comfortable calling if they have a better connection to their provider and health care team. This issue was not addressed or questioned in this research and would be very beneficial to understand in the future how it relates to CPGs.

Low doses of lipopolysaccharide and minimally oxidized low-density lipoprotein cooperatively activate macrophages via nuclear factor kappa B and activator protein-1: possible mechanism for acceleration of atherosclerosis by subclinical endotoxemia.

RATIONALE: Oxidized low-density lipoprotein (LDL) is an important determinant of inflammation in atherosclerotic lesions. It has also been documented that certain chronic infectious diseases, such as periodontitis and chlamydial infection, exacerbate clinical manifestations of atherosclerosis. In addition, low-level but persistent metabolic endotoxemia is often found in diabetic and obese subjects and is induced in mice fed a high-fat diet. OBJECTIVE: In this study, we examined cooperative macrophage activation by low levels of bacterial lipopolysaccharide (LPS) and by minimally oxidized LDL (mmLDL), as a model for subclinical endotoxemia-complicated atherosclerosis. METHODS AND RESULTS: We found that both in vitro and in vivo, mmLDL and LPS (Kdo2-LipidA) cooperatively activated macrophages to express proinflammatory cytokines Cxcl2 (MIP-2), Ccl3 (MIP-1alpha), and Ccl4 (MIP-1beta). Importantly, the mmLDL and LPS cooperative effects were evident at a threshold LPS concentration (1 ng/mL) at which LPS alone induced only a limited macrophage response. Analyzing microarray data with a de novo motif discovery algorithm, we found that genes transcribed by promoters containing an activator protein (AP)-1 binding site were significantly upregulated by costimulation with mmLDL and LPS. In a nuclear factor-DNA binding assay, the cooperative effect of mmLDL and LPS costimulation on c-Jun and c-Fos DNA binding, but not on p65 or p50, was dependent on mmLDL-induced activation of extracellular signal-regulated kinase (ERK) 1/2. In addition, mmLDL induced c-Jun N-terminal kinase (JNK)-dependent derepression of AP-1 by removing nuclear receptor corepressor (NCoR) from the chemokine promoters. CONCLUSIONS: The cooperative engagement of AP-1 and nuclear factor (NF)-kappaB by mmLDL and LPS may constitute a mechanism of increased transcription of inflammatory cytokines within atherosclerotic lesions.

Use of complementary and alternative medicine among men with prostate cancer in a rural setting.

UNLABELLED: The purpose of this study was to examine the prevalence and predictors of complementary and alternative medicine (CAM) use among rural patients with localized prostate cancer. The study also examined the participants' disclosure of CAM use to their physicians. Baseline and 6-month follow-up data were taken from a study examining the factors that influence treatment choice and quality of life among men diagnosed with and being treated for localized prostate cancer residing in rural southwest Georgia (N = 321). A total of 291 participants were interviewed at baseline and 6-month follow-up. FINDINGS: At baseline, 26.4% reported ever using CAM. Among them, dietary supplements were the most commonly used (75%), and 56% of patients did not disclose their CAM use to their physicians. At 6-month follow-up, 11% of the study sample reported using CAM since starting treatment (half of these were new users). The proportions of CAM users who reported taking dietary supplements after treatment were significantly lower than the corresponding proportions before treatment. CAM use after treatment was more common among those who selected surgery and watchful waiting. While 44% of the sample disclosed using CAM to their doctors before treatment, 61% after treatment began (P = 0.05). We found that CAM use after cancer treatment in this population was markedly less common than in nationally reported data for cancer patients. In line with national patterns, younger and more educated rural patients were significantly more likely to have ever used CAM and to use it after treatment.

Effects of liquid type, delivery method, and bolus volume on penetration-aspiration scores in healthy older adults during flexible endoscopic evaluation of swallowing.

OBJECTIVES: The type of liquid (eg, water or milk) that should be used during flexible endoscopic evaluation of swallowing (FEES) has received little investigation. Aspiration may vary as a function of the thin liquid type used during FEES. METHODS: We measured the effects of liquid type (water, skim milk, 2% milk, and whole milk; all dyed with green food coloring), delivery method (cup and straw), and bolus volume (5, 10, 15, and 20 mL) on Penetration-Aspiration Scale (PAS) scores in 14 healthy older adults (mean, 75 years; range, 69 to 85 years). Each participant generated 32 swallows. RESULTS: The PAS scores differed significantly by liquid type (p = 0.003) and by bolus volume (p = 0.017), but not by delivery method (p = 0.442). The PAS scores were significantly greater for 2% milk and whole milk than for skim milk and water (p < 0.05), and for 20 mL versus smaller volumes. Penetration and aspiration were observed on 113 (25%) and 15 (3%) of 448 swallows, respectively. CONCLUSIONS: These findings suggest that both milk and water should be used during FEES for an accurate assessment of aspiration status.

The effects of aspiration status, liquid type, and bolus volume on pharyngeal peak pressure in healthy older adults.

The reasons for aspiration in healthy adults remain unknown. Given that the pharyngeal phase of swallowing is a key component of the safe swallow, it was hypothesized that healthy older adults who aspirate are likely to generate less pharyngeal peak pressures when swallowing. Accordingly, pharyngeal and upper esophageal sphincter pressures were examined as a function of aspiration status (i.e., nonaspirator vs. aspirator), sensor location (upper vs. lower pharynx), liquid type (i.e., water vs. milk), and volume (i.e., 5 vs. 10 ml) in healthy older adults. Manometric measurements were acquired with a 2.1-mm catheter during flexible endoscopic evaluation. Participants (N = 19, mean age = 79.2 years) contributed 28 swallows; during 8 swallows, simultaneous manometric measurements of upper and lower pharyngeal and upper esophageal pressures were obtained. Pharyngeal manometric peak pressure was significantly less for aspirators (mean = 82, SD = 31 mmHg) than for nonaspirators (mean = 112, SD = 20 mmHg), and upper pharyngeal pressures (mean = 85, SD = 32 mmHg) generated less pressure than lower pharyngeal pressures (mean = 116, SD = 38 mmHg). Manometric measurements vary with respect to aspiration status and sensor location. Lower pharyngeal pressures in healthy older adults may predispose them to aspiration.

Pulmonary fibrosis inducer, bleomycin, causes redox-sensitive activation of phospholipase D and cytotoxicity through formation of bioactive lipid signal mediator, phosphatidic acid, in lung microvascular endothelial cells.

The mechanisms of lung microvascular complications and pulmonary hypertension known to be associated with idiopathic pulmonary fibrosis (IPF), a debilitating lung disease, are not known. Therefore, we investigated whether bleomycin, the widely used experimental IPF inducer, would be capable of activating phospholipase D (PLD) and generating the bioactive lipid signal-mediator phosphatidic acid (PA) in our established bovine lung microvascular endothelial cell (BLMVEC) model. Our results revealed that bleomycin induced the activation of PLD and generation of PA in a dose-dependent (5, 10, and 100 µg) and time-dependent (2-12 hours) fashion that were significantly attenuated by the PLD-specific inhibitor, 5-fluoro-2-indolyl des-chlorohalopemide (FIPI). PLD activation and PA generation induced by bleomycin (5 µg) were significantly attenuated by the thiol protectant (N-acetyl-L-cysteine), antioxidants, and iron chelators suggesting the role of reactive oxygen species (ROS), lipid peroxidation, and iron therein. Furthermore, our study demonstrated the formation of ROS and loss of glutathione (GSH) in cells following bleomycin treatment, confirming oxidative stress as a key player in the bleomycin-induced PLD activation and PA generation in ECs. More noticeably, PLD activation and PA generation were observed to happen upstream of bleomycin-induced cytotoxicity in BLMVECs, which was protected by FIPI. This was also supported by our current findings that exposure of cells to exogenous PA led to internalization of PA and cytotoxicity in BLMVECs. For the first time, this study revealed novel mechanism of the bleomycin-induced redox-sensitive activation of PLD that led to the generation of PA, which was capable of inducing lung EC cytotoxicity, thus suggesting possible bioactive lipid-signaling mechanism/mechanisms of microvascular disorders encountered in IPF.

Looking behind: Turning cards in the selection task.

Wason's selection task requires that one imagine which of four cards, each of which has a letter on one side and a number on the other, one would have to turn over to determine whether a statement about the cards is true or false. For example, one might see four cards showing T, H, 6, and 4 and be asked to say which card or cards one would have to turn over to determine whether a statement in the form of If a card has T on one side, it has 4 on the other is true. In the great majority of experiments with this task no cards are actually turned. This limits the conclusions that can be drawn from experimental results. In two experiments participants actually turned (had a computer turn) virtual cards so as to show what they contained on their originally hidden sides. Participants were given a monetary incentive to do well on the task, and they performed it, with trial-by-trial feedback, many times. Performance was much better than is typically obtained with the more common way of performing the task. Results also demonstrate the importance of the precise wording of the statement to be evaluated and how a misinterpretation could help account for a tendency for people to turn only a single card even when the turning of two is required. Results prompt several questions of a theoretical nature and are discussed as they relate to recent theoretical treatments of the selection task.

Increased prevalence of left-sided skin cancers.

BACKGROUND: Previous research has shown an increase in photodamage and precancers on the left side of the face. OBJECTIVE: We sought to determine whether there is a higher frequency of skin cancer development on the left side of the body than the right. METHODS: The study was a retrospective review of patients with skin cancer referred to our Mohs micrographic surgery and cutaneous oncology unit in 2004. RESULTS: When including all types of skin cancers and both sexes, more cancers occurred on the left (52.6%) than the right (47.4%) (P = .059), with a stronger trend in men (P = .042). There were significantly more malignant melanoma in situ on the left (31/42, 74%) than the right (11/42, 26%) (P = .002). LIMITATIONS: Population was comprised of patients referred to an academic medical center and often for Mohs micrographic surgery. CONCLUSIONS: There were significantly more skin cancers on the left than the right side in men. This discrepancy was even more profound in malignant melanoma in situ.