Changes in fecal microbiota with CFTR modulator therapy: A pilot study.

Studies have demonstrated that people with CF with pancreatic insufficiency (PI) have fecal dysbioses. Evidence suggests the causes of these dysbioses are multifactorial, and that important drivers include antibiotic exposure, dietary intake, and CF gastrointestinal tract dysfunction, including nutrient malabsorption. In this pilot study, we tested whether initiation of the CFTR modulator treatments ivacaftor (in a cohort of pancreatic sufficient (PS) people with CF and an R117H CFTR variant) or lumacaftor/ivacaftor (in a cohort of PI people with CF and an F508del variant) changed fecal measures of malabsorption or fecal microbiomes. While we identified no statistically significant fecal changes with either treatment, we detected trends in the PI cohort when initiating lumacaftor/ivacaftor towards decreased fecal fat content and towards fecal microbiomes that more closely resembled the fecal microbiota of people without PI. While these findings support a model in which nutrient malabsorption resulting from CF-induced PI drives fecal dysbiosis, they must be validated in future, larger studies of fecal microbiome and malabsorption outcomes with highly effective CFTR modulator therapies.

Improving quality of life in vasculitis patients.

Systemic vasculitis are a complex cluster of diseases with high associated morbidity. As disease-related mortality diminishes, the cumulative impact of poor health-related quality of life becomes more pertinent to patients than the initial pathological insult. In this article we explore health-related quality of life in ANCA-associated vasculitis, large-vessel vasculitis and therapeutic strategies that may enhance this critical outcome.

Multi-axis heterodyne interferometry at MHz frequencies: a short-arm measurement demonstration for LISA with off-the-shelf hardware.

We report the design, construction, and operation of a multi-axis heterodyne interferometry (MAHI) system operating at MHz heterodyne frequencies, which provides a testbed for technologies to be used in the Laser Interferometer Space Antenna (LISA) space-based gravitational wave mission. The system was calibrated for measurement of the piston, pitch, and yaw of a three-axis piezo-actuated mirror, giving measured calibration values that closely match those predicted by a simulation based on Gaussian beam tracing. The piston sensitivity of the MAHI system in the LISA band was measured to be below 10 pm Hz-1/2 for frequencies above 4 mHz and below 1 pm Hz-1/2 for frequencies above 35 mHz. The sensitivity is limited above 2 Hz by the mechanical vibrations of the apparatus and below 1 mHz by dimensional changes caused by temperature fluctuations. Evidence points towards scattered light as the limiting noise source at intermediate frequencies. The angular sensitivity of the MAHI system was measured to be close to or below 10 nrad Hz-1/2 for frequencies above 4 mHz and below 1 nrad Hz-1/2 for frequencies above 100 mHz. Noise budgets for both length and angle were determined, indicating the areas in which improvements must be made in order to reach increased sensitivity. The current operating sensitivity already provides a useful testbed for LISA technologies and a potential blueprint for future ground segment equipment.

Assessing gastrointestinal motility in healthy horses comparing auscultation, ultrasonography and an acoustic gastrointestinal surveillance biosensor: a randomised, blinded, controlled crossover proof of principle study.

BACKGROUND: Auscultation and ultrasonography are noninvasive techniques used to assess gastrointestinal motility in horses. Recently, noninvasive acoustic gastrointestinal surveillance (AGIS) biosensors evaluating intestinal motility have been validated in humans. OBJECTIVES: To compare AGIS to auscultation and ultrasonography for detecting decreased motility after xylazine administration. STUDY DESIGN: Randomised, blinded, controlled cross-over proof of principle study. METHODS: Six healthy horses were evaluated under fasted and nonfasted conditions and randomly assigned to receive treatment with 0.4 mg/kg xylazine or an equivalent volume of 0.9% NaCl intravenously. After a 48-h washout period, the process was repeated with the alternate treatment. Motility was assessed pre and posttreatment. Borborygmi were assessed in each abdominal quadrant and graded on a scale of 0-3, with 3 being continuous borborygmi. Duodenal, jejunal and caecal contractions were assessed ultrasonographically in consistent locations. Four AGIS biosensors were applied in standardised locations (duodenum, caecum, ventral midline, right dorsal colon). The biosensors measure acoustic signals and data were recorded in transport metric. Data were analysed using cross-classified multilevel random effects logistic regression including area under the receiver operator characteristic curve (AUC ROC). Sensitivity, specificity and accuracy were calculated for each modality. RESULTS: All three modalities detected a reduction in gastrointestinal motility following xylazine administration with AUC ROC being 0.85, 0.84 and 0.86 for auscultation, ultrasonography and AGIS respectively. The sensitivity, specificity and accuracy for auscultation was 88, 71 and 75%; for ultrasonography was 67, 63 and 64%; and for AGIS was 69, 70 and 70%, respectively. MAIN LIMITATIONS: The study was performed in normal healthy horses and application of this device to clinical patients warrants further investigation. CONCLUSIONS: In this proof of principle study, AGIS was able to discriminate between horses given xylazine from those given 0.9% NaCl with comparable accuracy as auscultation and ultrasonography. The Summary is available in Spanish - see Supporting Information.

Ten-year outcome of early childhood traumatic brain injury: Diffusion tensor imaging of the ventral striatum in relation to executive functioning.

PRIMARY OBJECTIVE: The long-term effects of TBI on verbal fluency and related structures, as well as the relation between cognition and structural integrity, were evaluated. It was hypothesized that the group with TBI would evidence poorer performance on cognitive measures and a decrease in structural integrity. RESEARCH DESIGN: Between a paediatric group with TBI and a group of typically-developing children, the long-term effects of traumatic brain injury were investigated in relation to both structural integrity and cognition. Common metrics for diffusion tensor imaging (DTI) were used as indicators of white matter integrity. METHODS AND PROCEDURES: Using DTI, this study examined ventral striatum (VS) integrity in 21 patients aged 10-18 years sustaining moderate-to-severe traumatic brain injury (TBI) 5-15 years earlier and 16 demographically comparable subjects. All participants completed Delis-Kaplan Executive Functioning System (D-KEFS) sub-tests. MAIN OUTCOMES AND RESULTS: The group with TBI exhibited lower fractional anisotropy (FA) and executive functioning performance and higher apparent diffusion coefficient (ADC). DTI metrics correlated with D-KEFS performance (right VS FA with Inhibition errors, right VS ADC with Letter Fluency, left VS FA and ADC with Category Switching). CONCLUSIONS: TBI affects VS integrity, even in a chronic phase, and may contribute to executive functioning deficits.

A smartphone app to communicate child passenger safety: an application of theory to practice.

Child passenger safety remains an important public health problem because motor vehicle crashes are the leading cause of death for children, and the majority of children ride improperly restrained. Using a mobile app to communicate with parents about injury prevention offers promise but little information is available on how to create such a tool. The purpose of this article is to illustrate a theory-based approach to developing a tailored, smartphone app for communicating child passenger safety information to parents. The theoretical basis for the tailoring is the elaboration likelihood model, and we utilized the precaution adoption process model (PAPM) to reflect the stage-based nature of behavior change. We created assessment items (written at ≤6th grade reading level) to determine the child's proper type of car seat, the parent's PAPM stage and beliefs on selected constructs designed to facilitate stage movement according to the theory. A message library and template were created to provide a uniform structure for the tailored feedback. We demonstrate how messages derived in this way can be delivered through new m-health technology and conclude with recommendations for the utility of the methods used here for other m-health, patient education interventions.

Associations and propositions: the case for a dual-process account of learning in humans.

We review evidence that supports the conclusion that people can and do learn in two distinct ways - one associative, the other propositional. No one disputes that we solve problems by testing hypotheses and inducing underlying rules, so the issue amounts to deciding whether there is evidence that we (and other animals) also rely on a simpler, associative system, that detects the frequency of occurrence of different events in our environment and the contingencies between them. There is neuroscientific evidence that associative learning occurs in at least some animals (e.g., Aplysia californica), so it must be the case that associative learning has evolved. Since both associative and propositional theories can in principle account for many instances of successful learning, the problem is then to show that there are at least some cases where the two classes of theory predict different outcomes. We offer a demonstration of cue competition effects in humans under incidental conditions as evidence against the argument that all such effects are based on cognitive inference. The latter supposition would imply that if the necessary information is unavailable to inference then no cue competition should occur. We then discuss the case of unblocking by reinforcer omission, where associative theory predicts an irrational solution to the problem, and consider the phenomenon of the Perruchet effect, in which conscious expectancy and conditioned response dissociate. Further discussion makes use of evidence that people will sometimes provide one solution to a problem when it is presented to them in summary form, and another when they are presented in rapid succession with trial-by trial information. We also demonstrate that people trained on a discrimination may show a peak shift (predicted by associative theory), but given the time and opportunity to detect the relationships between S+ and S-, show rule-based behavior instead. Finally, we conclude by presenting evidence that research on individual differences suggests that variation in intelligence and explicit problem solving ability are quite unrelated to variation in implicit (associative) learning, and briefly consider the computational implications of our argument, by asking how both associative and propositional processes can be accommodated within a single framework for cognition.

Rationale and design of a randomized trial of home electronic symptom and lung function monitoring to detect cystic fibrosis pulmonary exacerbations: the early intervention in cystic fibrosis exacerbation (eICE) trial.

BACKGROUND: Acute pulmonary exacerbations are central events in the lives of individuals with cystic fibrosis (CF). Pulmonary exacerbations lead to impaired lung function, worse quality of life, and shorter survival. We hypothesized that aggressive early treatment of acute pulmonary exacerbation may improve clinical outcomes. PURPOSE: Describe the rationale of an ongoing trial designed to determine the efficacy of home monitoring of both lung function measurements and symptoms for early detection and subsequent early treatment of acute CF pulmonary exacerbations. STUDY DESIGN: A randomized, non-blinded, multi-center trial in 320 individuals with CF aged 14 years and older. The study compares usual care to a twice a week assessment of home spirometry and CF respiratory symptoms using an electronic device with data transmission to the research personnel to identify and trigger early treatment of CF pulmonary exacerbation. Participants will be enrolled in the study for 12 months. The primary endpoint is change in FEV1 (L) from baseline to 12 months determined by a linear mixed effects model incorporating all quarterly FEV1 measurements. Secondary endpoints include time to first acute protocol-defined pulmonary exacerbation, number of acute pulmonary exacerbations, number of hospitalization days for acute pulmonary exacerbation, time from the end of acute pulmonary exacerbation to onset of subsequent pulmonary exacerbation, change in health related quality of life, change in treatment burden, change in CF respiratory symptoms, and adherence to the study protocol. CONCLUSIONS: This study is a first step in establishing alternative approaches to the care of CF pulmonary exacerbations. We hypothesize that early treatment of pulmonary exacerbations has the potential to slow lung function decline, reduce respiratory symptoms and improve the quality of life for individuals with CF.

To tell or not to tell - what to do about p.C282Y heterozygotes identified by HFE screening.

Hereditary hemochromatosis (HH) is a common preventable disorder of iron overload that can result in liver cirrhosis and reduced lifespan. Most HH is due to homozygosity for the HFE p.C282Y substitution. We conducted a study of screening for p.C282Y in high schools where p.C282Y heterozygotes (CY) individuals were informed of their genotype by letter. We studied whether these individuals understood the implications of their genotype, whether this resulted in anxiety or reduced health perception and whether cascade testing was higher in families of CY than wild-type homozygous (CC) individuals. We found 586 of 5757 (1 in 10) screened individuals were CY. One month after receiving their result, 83% correctly answered that they have one copy of p.C282Y. There was no adverse change in anxiety or health perception from prior to screening to 1 month after receiving results. Significantly more family members of CY individuals than CC individuals were informed about HH and had testing for HH. In conclusion, we found that informing CY individuals of their genotype does not increase anxiety and the implications are generally well understood. This leads to cascade testing in a minority of families. CY individuals should be informed of their genetic status when identified by population screening.

Cosolvent flushing for the remediation of PAHs from former manufactured gas plants.

Cosolvent flushing is a technique that has been proposed for the removal of hydrophobic organic contaminants in the subsurface. Cosolvents have been shown to dramatically increase the solubility of such compounds compared to the aqueous solubility; however, limited data are available on the effectiveness of cosolvents for field-contaminated media. In this work, we examine cosolvent flushing for the removal of polycyclic aromatic hydrocarbons (PAHs) in soil from a former manufactured gas plant (FMGP). Batch studies confirmed that the relationship between the soil-cosolvent partitioning coefficient (K(i)) and the volume fraction of cosolvent (f(c)) followed a standard log-linear equation. Using methanol at an fc of 0.95, column studies were conducted at varying length scales, ranging from 11.9 to 110 cm. Removal of PAH compounds was determined as a function of pore volumes (PVs) of cosolvent flushed. Despite using a high f(c), rate and chromatographic effects were observed in all the columns. PAH effluent concentrations were modeled using a common two-site sorption model. Model fits were improved by using MeOH breakthrough curves to determine fitted dispersion coefficients. Fitted mass-transfer rates were two to three orders of magnitude lower than predicted values based on published data using artificially contaminated sands.

Occupational all-terrain vehicle deaths among workers 18 years and older in the United States, 1992-2007.

The objective of this study was to summarize basic information on the characteristics of work-related A TV deaths among civilian persons 18 years of age or older in the U.S. from 1992 through 2007. Work-related ATV death data were obtained through the Bureau of Labor Statistics' annual Census of Fatal Occupational Injuries. From 1992 to 2007, 297 work-related ATV deaths occurred among persons over 17 in the U.S. Ninety-two percent were male, 93% were white, 23% were ages 18 to 34, 51% were ages 35 to 64, and 26% were ages > or = 65. Half of the fatal incidents involved overturns resulting in head and chest injuries. Sixty percent of crashes occurred on farms and 20% occurred on highways. The fatality rate among agricultural production workers was significantly higher than the rates in all other industries. While more in-depth analysis of incident and exposure data for this growing problem will more clearly define personal risk and causal factors in the long term, in the short term, stronger emphasis must be placed on the development of prevention strategies, particularly focused on older workers in the agriculture production industry.

Striatal sensitivity to personal responsibility in a regret-based decision-making task.

Regret and relief are complex emotional states associated with the counterfactual processing of nonobtained outcomes in a decision-making situation. In the "actor effect," a sense of agency and personal responsibility is thought to heighten these emotions. Using fMRI, we scanned volunteers (n = 22) as they played a task involving choices between two wheel-of-fortune gambles. We examined how neural responses to counterfactual outcomes were modulated by giving subjects the opportunity to change their minds, as a manipulation of personal responsibility. Satisfaction ratings to the outcomes were highly sensitive to the difference between the obtained and nonobtained outcome, and ratings following losses were lower on trials with the opportunity to change one's mind. Outcome-related activity in the striatum and orbitofrontal cortex was positively related to the satisfaction ratings. The striatal response was modulated by the agency manipulation: Following losses, the striatal signal was significantly lower when the subject had the opportunity to change his/her mind. These results support the involvement of frontostriatal mechanisms in counterfactual thinking and highlight the sensitivity of the striatum to the effects of personal responsibility.

Evaluation of a multi-disease carrier screening programme in Ashkenazi Jewish high schools.

A screening programme for Tay Sachs disease (TSD) carrier status was introduced in high schools in Victoria, Australia in 1997, and was expanded to screen for six other genetic conditions common in the Ashkenazi Jewish population in 2008. The aim of this study was to evaluate the current programme and compare it with an evaluation of the programme when screening was offered for TSD alone. All students from Jewish high schools in Melbourne who offered the programme in 2009 were invited to participate in the study. A purpose-designed questionnaire explored the following domains: knowledge (disease and genetics), reasons for screening, anxiety, and predicted negative feelings if found to be a carrier. Two hundred and seventy-three students were offered screening, and 272 (99.6%) completed the questionnaire. Only two students chose not to have screening. Two hundred and seventy-one students were in the penultimate year of high school (99.6%) and 222 were of Ashkenazi Jewish descent (82.5%). The main reasons for choosing screening were the desire to know carrier status and convenience. Knowledge level decreased and negative feelings increased in the current cohort compared to that when screening was offered for TSD alone. We conclude that the current programme is efficient, although increasing the number of conditions resulted in a decrease in knowledge and increase in predicted negative feelings if found to be a carrier of one of the conditions. This has implications for multi-disease screening programmes that will increase in frequency as more conditions can be screened for and costs diminish.

Implementation of ironXS: a study of the acceptability and feasibility of genetic screening for hereditary hemochromatosis in high schools.

Hereditary hemochromatosis (HH), most often due to HFE C282Y homozygosity, is an iron overload disorder that can result in severe morbidity including hepatic cirrhosis. Predisposition to HH is easily diagnosed and morbidity is preventable by maintaining normal body iron and thus calls have been made to introduce community screening. The current study has been designed to assess the acceptability and feasibility of HH screening in high schools. Students (mostly 15-16 years of age) watched a purpose-designed DVD for education about HH. Those with parental consent were then offered cheek-brush screening for C282Y. Students completed a questionnaire prior to screening. The program was offered to 9187 students at 32 schools and 3489 (38%) had screening. Nineteen C282Y homozygotes (1 in 183) and 376 heterozygotes (1 in 9.3) were identified. More than 90% of students answered each of five knowledge questions correctly. Eight homozygotes (42%) had elevated transferrin saturation, but only two (10.5%) had marginally elevated serum ferritin (SF). We have shown that genetic screening for HH can successfully be offered in the high school setting. Ongoing research in this study will answer questions about the impact of high school students learning that they are at risk of HH.

Patient-reported respiratory symptoms in cystic fibrosis.

BACKGROUND: Cystic fibrosis (CF) specific patient-derived and reported symptom tools are critical steps toward evaluating the outcomes of new therapies for CF. METHODS: We conducted 25 in-depth qualitative interviews using the Day Reconstruction Method and 9 cognitive interviews at two CF programs, the University of Washington and Seattle Children's Hospital and Regional Medical Center. The interviews were audio-recorded and transcribed, and then coded and analyzed for themes relating to pulmonary symptoms and related psychosocial impacts. RESULTS: Six pulmonary symptoms were identified as central to CF: cough, sputum production, wheeze, chest tightness, difficulty breathing/shortness of breath, and fever. Emotional impacts included frustration, sadness/depression, irritability, worry, difficulty sleeping; while activity impacts included time spent sitting or lying down, reduction of usual activities, and missing school or work. In all, 8 symptom items, 4 emotional impacts items, and 4 activity impacts were selected for inclusion on a new daily diary. We also assessed triggers for seeking care. CONCLUSIONS: Using a qualitative inductive methodology, we have obtained patient centered data regarding pulmonary symptoms and burdens and have created a novel patient reported outcome measure for CF. Future studies will assess the validity of the instruments.

Impact of helmets on injuries to riders of all-terrain vehicles.

BACKGROUND: Although helmet use has been shown to be effective in reducing traumatic brain injuries (TBIs) due to motorcycle and bicycle crashes, it is unknown whether helmet use is associated with different injury patterns and severity for users of all-terrain vehicles (ATVs). OBJECTIVES: To compare likelihood of injury and death between helmeted and unhelmeted riders of ATVs. METHODS: The National Trauma Data Bank for years 2002-2006 was used to examine the records of 11 589 patients hospitalized for injuries resulting from ATV use. The likelihood of receiving a TBI diagnosis or a significant injury to other body regions and differences in injury severity and in-hospital mortality between helmeted and unhelmeted ATV riders were compared. RESULTS: After multivariable adjustment, compared with helmeted riders, unhelmeted riders were significantly more likely to sustain any TBI (OR 1.62, 95% CI 1.49 to 1.76, p<0.001) and major/severe TBI (OR 3.19, 95% CI 2.39 to 4.25, p<0.001). Unhelmeted riders were significantly more likely to die while in hospital than were helmeted riders (OR 2.58, 95% CI 1.79 to 3.71, p<0.001). Significant injuries to the neck and face regions were also significantly more likely in unhelmeted riders (OR 3.53, 95% CI 1.28 to 9.71, p = 0.015, and OR 1.94, 95% CI 1.32 to 2.84, p = 0.001, respectively). CONCLUSIONS: ATV riders who do not wear helmets are more likely to receive significant injuries to the head, face, and neck. Prevention strategies and enforceable policy interventions to increase helmet use among ATV riders appear warranted.

Differential effects of insular and ventromedial prefrontal cortex lesions on risky decision-making.

The ventromedial prefrontal cortex (vmPFC) and insular cortex are implicated in distributed neural circuitry that supports emotional decision-making. Previous studies of patients with vmPFC lesions have focused primarily on decision-making under uncertainty, when outcome probabilities are ambiguous (e.g. the Iowa Gambling Task). It remains unclear whether vmPFC is also necessary for decision-making under risk, when outcome probabilities are explicit. It is not known whether the effect of insular damage is analogous to the effect of vmPFC damage, or whether these regions contribute differentially to choice behaviour. Four groups of participants were compared on the Cambridge Gamble Task, a well-characterized measure of risky decision-making where outcome probabilities are presented explicitly, thus minimizing additional learning and working memory demands. Patients with focal, stable lesions to the vmPFC (n = 20) and the insular cortex (n = 13) were compared against healthy subjects (n = 41) and a group of lesion controls (n = 12) with damage predominantly affecting the dorsal and lateral frontal cortex. The vmPFC and insular cortex patients showed selective and distinctive disruptions of betting behaviour. VmPFC damage was associated with increased betting regardless of the odds of winning, consistent with a role of vmPFC in biasing healthy individuals towards conservative options under risk. In contrast, patients with insular cortex lesions failed to adjust their bets by the odds of winning, consistent with a role of the insular cortex in signalling the probability of aversive outcomes. The insular group attained a lower point score on the task and experienced more 'bankruptcies'. There were no group differences in probability judgement. These data confirm the necessary role of the vmPFC and insular regions in decision-making under risk. Poor decision-making in clinical populations can arise via multiple routes, with functionally dissociable effects of vmPFC and insular cortex damage.

Disrupted prediction-error signal in psychosis: evidence for an associative account of delusions.

Delusions are maladaptive beliefs about the world. Based upon experimental evidence that prediction error-a mismatch between expectancy and outcome--drives belief formation, this study examined the possibility that delusions form because of disrupted prediction--error processing. We used fMRI to determine prediction-error-related brain responses in 12 healthy subjects and 12 individuals (7 males) with delusional beliefs. Frontal cortex responses in the patient group were suggestive of disrupted prediction-error processing. Furthermore, across subjects, the extent of disruption was significantly related to an individual's propensity to delusion formation. Our results support a neurobiological theory of delusion formation that implicates aberrant prediction-error signalling, disrupted attentional allocation and associative learning in the formation of delusional beliefs.