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Jamie B Warren,1 William E Lambert,2 Rongwei Fu,2 JoDee M Anderson,1 Alison B Edelman31Department of Pediatrics, 2Department of Public Health and Preventive Medicine, 3Department of Obstetrics and Gynecology, Oregon Health and Science University, Portland, OR, USABackground: Millennium Development Goal 4 calls for the reduction of the under-five mortality rate by two-thirds between 1990 and 2015. To reach this goal, neonatal mortality must be decreased. The lack of information on global neonatal and perinatal mortality impedes appropriate implementation of interventions, as vital registration systems are not available for the majority of the world's neonatal deaths. Verbal autopsy (VA) is a tool that has been used to determine cause of death. Recent studies have attempted to standardize and validate the use of this tool in resource-limited areas. The World Health Organization (WHO) International Standard VA Questionnaire was used to conduct a needs assessment in nine rural Peruvian villages. The goal was to determine the neonatal mortality rate (NMR), perinatal mortality rate (PMR), and causes of, and risk factors for, death in these villages.Methods: Eligible women were interviewed using the WHO International Standard VA Questionnaire or a set of questions based on the WHO VA Questionnaire. NMR and PMR were calculated using a generalized estimating equation model. Three neonatologists independently reviewed VA records to provide cause of death determination. Reviewer agreement was assessed using percent agreement. Fisher's exact test was used to determine risk factors associated with death.Results: The NMR was 31.4 per 1000 live births and the PMR was 49.7 per 1000 pregnancies. The main contributor to neonatal death was infection (43%). Percent agreement among reviewers was 90.5% and 38.9% for cause of neonatal death and stillbirth, respectively. Risk factors for death were pregnancy with twins (P = 0.001), preterm delivery (P = 0.003), and cesarean section delivery (P = 0.049).Conclusion: The WHO VA proved useful for NMR and PMR calculation, cause of death determination, and risk factor identification. Information gathered in this needs assessment will allow for the design and implementation of tailored interventions.Keywords: neonatal mortality, perinatal mortality, verbal autopsy, needs assessment

Adequate adaptions and actions to combat anthropogenic climate change (CC) are significant challenges of the 21st century. In Europe, according to the European Environmental Agency, warming of around 2°C is expected under the moderate climate scenario (RCP 4.5) by the end of the century, but the pessimistic RCP 8.5 scenario project an increase of up to 6°C. In addition to the rise in temperature, changes in precipitation and increased frequency of extreme weather events are predicted. New environmental conditions affect tree species and habitats differently; thus, forest biodiversity and local tree species compositions probably will be altered in many regions in the future. The effects may be manifold: some tree species may persist, locally adapt and migrate, while others may disappear from given regions and be replaced by native or non-native species. The native forests of the Austrian-Hungarian border region are particularly affected by the climate change. To mitigate the consequences of anthropogenic climate change to preserve forest biodiversity for future generations and to enable their use, deliberate and planned human interventions and actions are essential. These require transnational or even global efforts since nature and climate do not recognise man-made borders.The REIN-Forest project (Interreg V-A Austria-Hungary Programme - ATHU150), a bilateral project between Austria and Hungary, aimed to establish harmonised protection measures for the conservation of native forests in Northern, Central and Southern Burgenland, Vienna, Vienna Umland-South, Lower Austria South, Graz and Eastern Styria, Győr-Moson-Sopron, Vas and Zala counties (the so-called programme area). In the scope of this project, international cooperation between three project partners: the Austrian Research Centre for Forests (BFW, Austria), the Forest Research Institute – University of Sopron (SOE ERTI, Hungary) and the Vas County Government Office (VVÖH, Hungary) was established. Previous results and outputs of the SUSTREE project (Interreg Central Europe CE614), such as: a) Transnational delineation model of conservation and forest seed transfer zones in climate change, b) Report of intraspecific response function and derivation of climate transfer limits, SusSelect data, recommendations and c) Application of the species distribution models for the delineation of seed transfer zones/models in Central Europe, were put into practice during the project, focusing on two native deciduous forest tree species of the Austrian-Hungarian border region: European beech (Fagus sylvatica L.) and sessile oak (Quercus petraea (Matt.) Liebl.).During the REIN-Forest project, the following joint documents were prepared and several activities were implemented:1. Model-based document on the current state and future perspectives of European beech and sessile oak forests;2. Bilateral strategy for the transfer of forest reproductive material (FRM) and its use in the Austrian-Hungarian border region;3. Establishment of altogether six demonstration sites (three in each country) with local and climate-adapted FRM of European beech and sessile oak for long-term monitoring;4. Management and monitoring plan of the demonstration sites;5. Joint bilingual communication strategy, which included informative programmes and meetings with professionals, locals and schools and also education material for further use.REIN-Forest focused on using scientific results and outputs in the field of applied forestry and awareness-raising. Besides strategies, recommendations and reports that would facilitate forest managers' decisions for the future in the border region, events and workshops were offered for forestry practitioners, school pupils and the public and a short film and educational materials were published.

Abstract Conifers often occur along steep gradients of diverse climates throughout their natural ranges, which is expected to result in spatially varying selection to local climate conditions. However, signals of climatic adaptation can often be confounded, because unraveled clines covary with signals caused by neutral evolutionary processes such as gene flow and genetic drift. Consequently, our understanding of how selection and gene flow have shaped phenotypic and genotypic differentiation in trees is still limited. A 40‐year‐old common garden experiment comprising 16 Douglas‐fir (Pseudotsuga menziesii) provenances from a north‐to‐south gradient of approx. 1,000 km was analyzed, and genomic information was obtained from exome capture, which resulted in an initial genomic dataset of >90,000 single nucleotide polymorphisms. We used a restrictive and conservative filtering approach, which permitted us to include only SNPs and individuals in environmental association analysis (EAA) that were free of potentially confounding effects (LD, relatedness among trees, heterozygosity deficiency, and deviations from Hardy–Weinberg proportions). We used four conceptually different genome scan methods based on FST outlier detection and gene–environment association in order to disentangle truly adaptive SNPs from neutral SNPs. We found that a relatively small proportion of the exome showed a truly adaptive signal (0.01%–0.17%) when population substructuring and multiple testing was accounted for. Nevertheless, the unraveled SNP candidates showed significant relationships with climate at provenance origins, which strongly suggests that they have featured adaptation in Douglas‐fir along a climatic gradient. Two SNPs were independently found by three of the employed algorithms, and one of them is in close proximity to an annotated gene involved in circadian clock control and photoperiodism as was similarly found in Populus balsamifera. Synthesis. We conclude that despite neutral evolutionary processes, phenotypic and genomic signals of adaptation to climate are responsible for differentiation, which in particular explain disparity between the well‐known coastal and interior varieties of Douglas‐fir.

Abstract Understanding how tree species will respond to a future climate requires reliable and quantitative estimates of intra‐specific variation under current climate conditions. We studied three 10‐year‐old common garden experiments established across a rainfall and drought gradient planted with nearly 10,000 pedunculate oak (Quercus robur L.) trees from ten provenances with known family structure. We aimed at disentangling adaptive and plastic responses for growth (height and diameter at breast height) as well as for leaf and wood functional traits related to adaptation to dry environments. We used restricted maximum likelihood approaches to assess additive genetic variation expressed as narrow‐sense heritability (h2), quantitative trait differentiation among provenances (QST), and genotype‐by‐environment interactions (GxE). We found strong and significant patterns of local adaptation in growth in all three common gardens, suggesting that transfer of seed material should not exceed a climatic distance of approximately 1°C under current climatic conditions, while transfer along precipitation gradients seems to be less stringent. Moreover, heritability reached 0.64 for tree height and 0.67 for dbh at the dry margin of the testing spectrum, suggesting significant additive genetic variation of potential use for future selection and tree breeding. GxE interactions in growth were significant and explained less phenotypic variation than origin of seed source (4% versus 10%). Functional trait variation among provenances was partly related to drought regimes at provenances origins but had moderate explanatory power for growth. We conclude that directional selection, either naturally or through breeding, is the most likely and feasible outcome for pedunculate oak to adapt to warmer and drier climate conditions in the future.

Children of migrant farmworkers are at increased risk of exposure to organophosphate pesticides because of 'carry-home' transport processes and residential location. Although this at-risk status is generally recognized, few available reports describe the extent of this exposure among agricultural communities. We quantified dialkyl phosphate (DAP) levels in serial samples of urine from 176 children, 2-6 years of age, in three Oregon communities hosting differing agricultural industries: pears, cherries, and fruit berries. Up to three spot samples of urine were collected from children at the beginning, mid-point, and end of their parents' work seasons. The median levels of dimethylthiophosphate (DMTP), the most commonly detected metabolite, was significantly higher in urine samples from children in each of the three agricultural communities (17.5, 19.0, and 41.0 ng/mL) relative to a reference group of children who lived in an urban community and whose parents did not work in agriculture (6.5 ng/mL; Kruskal-Wallis, p < 0.001). After controlling for age, sex, and weight, the median level of DMTP in children in the pear community was 1.92 times higher than the level in children of the berry community [95% confidence interval (CI), 1.14-3.23] and 1.75 times higher than the level in children of the cherry community (95% CI, 0.95-3.23). We observed increasing levels of DMTP across the work season only within the berry community. Levels decreased in the cherry community and remained constant in the pear community. Substantial temporal variation within the children followed demonstrates the need for multiple urine samples to most accurately characterize longer term and/or cumulative exposure. The observed variability in urinary DAP levels, between communities and over time, could be attributed to the types and amounts of organophosphate pesticides used, the timing of applications and degradation of residues in the environment, work operations and hygiene practices, the proximity of housing to orchards and fields, or the movement of these working families. Additional studies of variation in pesticide exposure across agricultural regions are needed. [ABSTRACT FROM AUTHOR]

Abstract Background Brimonidine is a common drug for lowering ocular pressure and may directly protect retinal ganglion cells in glaucoma. The disease involves early loss of retinal ganglion cell transport to brain targets followed by axonal and somatic degeneration. We examined whether brimonidine preserves ganglion cell axonal transport and abates degeneration in rats with elevated ocular pressure induced by laser cauterization of the episcleral veins. Results Ocular pressure was elevated unilaterally by 90% for a period of 8 weeks post- cauterization. During this time, brimonidine (1mg/kg/day) or vehicle (phosphate-buffered saline) was delivered systemically and continuously via subcutaneous pump. Animals received bilateral intravitreal injections of fluorescent cholera toxin subunit β (CTB) two days before sacrifice to assess anterograde transport. In retinas from the vehicle group, elevated pressure induced a 44% decrease in the fraction of ganglion cells with intact uptake of CTB and a 14-42% reduction in the number of immuno-labelled ganglion cell bodies, with the worst loss occurring nasally. Elevated pressure also caused a 33% loss of ganglion cell axons in vehicle optic nerves and a 70% decrease in CTB transport to the superior colliculus. Each of these components of ganglion cell degeneration was either prevented or significantly reduced in the brimonidine treatment group. Conclusions Continuous and systemic treatment with brimonidine by subcutaneous injection significantly improved retinal ganglion cell survival with exposure to elevated ocular pressure. This effect was most striking in the nasal region of the retina. Brimonidine treatment also preserved ganglion cell axon morphology, sampling density and total number in the optic nerve with elevated pressure. Consistent with improved outcome in the optic projection, brimonidine also significantly reduced the deficits in axonal transport to the superior colliculus associated with elevated ocular pressure. As transport deficits to and from retinal ganglion cell projection targets in the brain are relevant to the progression of glaucoma, the ability of brimonidine to preserve optic nerve axons and active transport suggests its neuroprotective effects are relevant not only at the cell body, but throughout the entire optic projection.

Abstract Background Ischemia within the optic nerve head (ONH) may contribute to retinal ganglion cell (RGC) loss in primary open angle glaucoma (POAG). Ischemia has been reported to increase neurotrophin and high affinity Trk receptor expression by CNS neurons and glial cells. We have previously demonstrated neurotrophin and Trk expression within the lamina cribrosa (LC) region of the ONH. To determine if ischemia alters neurotrophin and Trk protein expression in cells from the human LC, cultured LC cells and ONH astrocytes were exposed to 48 hours of oxygen-glucose deprivation (OGD). Also cells were exposed to 48 hours of OGD followed by 24 hours of recovery in normal growth conditions. Cell number, neurotrophin and Trk receptor protein expression, neurotrophin secretion, and Trk receptor activation were examined. Results Cell number was estimated using an assay for cell metabolism following 24, 48 and 72 hours of OGD. A statistically significant decrease in LC and ONH astrocyte cell number did not occur until 72 hours of OGD, therefore cellular protein and conditioned media were collected at 48 hours OGD. Protein expression of NGF, BDNF and NT-3 by LC cells and ONH astrocytes increased following OGD, as did NGF secretion. Recovery from OGD increased BDNF protein expression in LC cells. In ONH astrocytes, recovery from OGD increased NGF protein expression, and decreased BDNF secretion. Trk A expression and activation in LC cells was increased following OGD while expression and activation of all other Trk receptors was decreased. A similar increase in Trk A expression and activation was observed in ONH astrocytes following recovery from OGD. Conclusions In vitro conditions that mimic ischemia increase the expression and secretion of neurotrophins by cells from the ONH. Increased Trk A expression and activation in LC cells following OGD and in ONH astrocytes following recovery from OGD suggest autocrine/paracrine neurotrophin signaling could be a response to ONH ischemia in POAG. Also, the increase in NGF, BDNF and NT-3 protein expression and NGF secretion following OGD also suggest LC cells and ONH astrocytes may be a paracrine source of neurotrophins for RGCs.

Trichloroethylene (TCE), a common groundwater contaminant, was found at high levels at an Oregon work site in 1998. According to a recent report released by the National Research Council, 'the evidence on carcinogenic risk and other health hazards from exposure to trichloroethylene has strengthened since 2001.' A convenience sample of 13 former workers from the Oregon work site was recruited for a series of focus groups. Information obtained on plant processes, safety procedures, attitudes regarding medical record access, and opinions about proxy accuracy was subjected to qualitative content analysis. Workers recalled few safety policies and no training or support for control of safety. Most thought co-workers and family members would be the best source of proxy exposure information and favored granting access to medical records. Job-role mobility confirmed the importance of using a job or task exposure matrix. Information obtained will be used in development of an exposure assessment interview tool. [ABSTRACT FROM AUTHOR]

Background: The pork tapeworm (Taenia solium) is a parasitic helminth that imposes a major health and economic burden on poor rural populations around the world. As recognized by the World Health Organization, a key barrier for achieving control of T. solium is the lack of an accurate and validated simulation model with which to study transmission and evaluate available control and elimination strategies. CystiAgent is a spatially-explicit agent based model for T. solium that is unique among T. solium models in its ability to represent key spatial and environmental features of transmission and simulate spatially targeted interventions, such as ring strategy., Methods/principal Findings: We validated CystiAgent against results from the Ring Strategy Trial (RST)-a large cluster-randomized trial conducted in northern Peru that evaluated six unique interventions for T. solium control in 23 villages. For the validation, each intervention strategy was replicated in CystiAgent, and the simulated prevalences of human taeniasis, porcine cysticercosis, and porcine seroincidence were compared against prevalence estimates from the trial. Results showed that CystiAgent produced declines in transmission in response to each of the six intervention strategies, but overestimated the effect of interventions in the majority of villages; simulated prevalences for human taenasis and porcine cysticercosis at the end of the trial were a median of 0.53 and 5.0 percentages points less than prevalence observed at the end of the trial, respectively., Conclusions/significance: The validation of CystiAgent represented an important step towards developing an accurate and reliable T. solium transmission model that can be deployed to fill critical gaps in our understanding of T. solium transmission and control. To improve model accuracy, future versions would benefit from improved data on pig immunity and resistance, field effectiveness of anti-helminthic treatment, and factors driving spatial clustering of T. solium infections including dispersion and contact with T. solium eggs in the environment., Competing Interests: The authors have declared that no competing interests exist.

Background: The pork tapeworm, Taenia solium, is a serious public health problem in rural low-resource areas of Latin America, Africa and Asia, where the associated conditions of nuerocysticercosis (NCC) and porcine cysticercosis cause substantial health and economic harms. An accurate and validated transmission model for T. solium would serve as an important new tool for control and elimination, as it would allow for comparison of available intervention strategies, and prioritization of the most effective strategies for control and elimination efforts., Methods: We developed a spatially-explicit agent-based model (ABM) for T. solium ("CystiAgent") that differs from prior T. solium models by including a spatial framework and behavioral parameters such as pig roaming, open human defecation, and human travel. In this article, we introduce the structure and function of the model, describe the data sources used to parameterize the model, and apply sensitivity analyses (Latin hypercube sampling-partial rank correlation coefficient (LHS-PRCC)) to evaluate model parameters., Results: LHS-PRCC analysis of CystiAgent found that the parameters with the greatest impact on model uncertainty were the roaming range of pigs, the infectious duration of human taeniasis, use of latrines, and the set of "tuning" parameters defining the probabilities of infection in humans and pigs given exposure to T. solium., Conclusions: CystiAgent is a novel ABM that has the ability to model spatial and behavioral features of T. solium transmission not available in other models. There is a small set of impactful model parameters that contribute uncertainty to the model and may impact the accuracy of model projections. Field and laboratory studies to better understand these key components of transmission may help reduce uncertainty, while current applications of CystiAgent may consider calibration of these parameters to improve model performance. These results will ultimately allow for improved interpretation of model validation results, and usage of the model to compare available control and elimination strategies for T. solium.

Both oral disease and middle ear infections are highly prevalent in Pacific Island children. These diseases are multifactorial and likely attributable in part to both social and environmental factors. It has been two decades since these diseases were defined in Palau, and at the time were noted to be among the most common conditions and presented a substantial burden among Palau's children. In 2006, the Ministry of Health in Palau began conducting comprehensive school health screenings in grades 1-11. While primarily used as a referral tool, this survey can also be used in epidemiologic studies to describe health trends. The current study utilized this screening data from the 2011-12 school year to characterize the prevalence of dental caries and otitis media and explore a previously suggested relationship between the two conditions, including common risk factors. It was found that over one-quarter (28.9%) of Palauan students had abnormal tympanometry results, with up to 17% indicating active otitis media. In addition, 85% of students had at least one decayed or filled tooth, with an average of 3.9 decayed or filled teeth in 12-year-olds. Both conditions were found to be more prevalent in public than in private schools; however, the two disorders were not significantly associated with each other. These findings place the prevalence of decayed, missing, and filled teeth, and otitis media in Palauan schoolchildren among the highest reported in the world. The widely recognized consequences of poor oral health and hearing impairment on learning, nutrition, and chronic disease make urgent the need for early intervention., (©Copyright 2020 by University Health Partners of Hawai‘i (UHP Hawai‘i).)

In the United States, there is no reliable data to describe the prevalence of eye diseases leading to visual impairment and little active surveillance to address this knowledge gap. Data that is readily available from many state blind registries may provide helpful information on trends and causes of blindness. We analyzed new registrations with the Oregon Commission for the Blind (OCB) and Oregon State Department of Administrative Services (DAS) from 1961 to 2016 for causes of and trends in blindness. Persons with blindness self-refer into the OCB registry and the Oregon State Department of Administrative Services (DAS) includes those receiving social security disability financial support and other state services. Data for 9,273 blind persons registered were analyzed. The most frequent causes of blindness were age related macular degeneration (AMD) 3,308 (38%), followed by diabetic retinopathy (DR) 729 (8%), congenital conditions 697 (8%), optic nerve atrophy 611 (7%), glaucoma 549 (6%), retinitis pigmentosa 546 (6%), retinopathy of prematurity192 (2%), cataract 180 (2%), and trauma 174 (2%). The mean age of onset of blindness was younger for Blacks (31 years) and Hispanics (33 years) than for Whites (44 years). Analysis of state-based registries can provide useful and locally relevant vision and eye health data where little information is otherwise available., Competing Interests: The authors have declared that no competing interests exist.

Background: Taenia solium (cysticercosis) is a parasitic cestode that is endemic in rural populations where open defecation is common and free-roaming pigs have access to human feces. The purpose of this study was to examine the roaming patterns of free-range pigs, and identify areas where T. solium transmission could occur via contact with human feces. We did this by using GPS trackers to log the movement of 108 pigs in three villages of northern Peru. Pigs were tracked for approximately six days each and tracking was repeated in the rainy and dry seasons. Maps of pig ranges were analyzed for size, distance from home, land type and contact with human defecation sites, which were assessed in a community-wide defecation survey., Results: Consistent with prior GPS studies and spatial analyses, we found that the majority of pigs remained close to home during the tracking period and had contact with human feces in their home areas: pigs spent a median of 79% (IQR: 61-90%) of their active roaming time within 50 m of their homes and a median of 60% of their contact with open defecation within 100 m of home. Extended away-from-home roaming was predominately observed during the rainy season; overall, home range areas were 61% larger during the rainy season compared to the dry season (95% CI: 41-73%). Both home range size and contact with open defecation sites showed substantial variation between villages, and contact with open defecation sites was more frequent among pigs with larger home ranges and pigs living in higher density areas of their village., Conclusions: Our study builds upon prior work showing that pigs predominately roam and have contact with human feces within 50-100 m of the home, and that T. solium transmission is most likely to occur in these concentrated areas of contact. This finding, therefore, supports control strategies that target treatment resources to these areas of increased transmission. Our finding of a seasonal trend in roaming ranges may be useful for control programs relying on pig interventions, and in the field of transmission modeling, which require precise estimates of pig behavior and risk.

The objectives of this study are to evaluate if robotic cystectomy demonstrates reduced complications, readmissions, and cost-to-patient compared to open approach 30-day post-operatively, and to identify predictors of complication, readmission, and cost-to-patient. This retrospective cohort study analyzed 249 patients who underwent open (n = 149) or robotic (n = 100) cystectomy from 2009 to 2015 at our institution. Outcomes included 30-day post-operative complication, readmission, and cost-to-patient charges. We used modified Clavien-Dindo/MSKCC classifications. Multivariable logistic and linear regression models were used to evaluate associations to outcomes and to build predictive models. Patient, clinical, and surgical characteristics differed by open and robotic groups, respectively, only for estimated blood loss (median: 600 versus 150 cc, p < 0.01), operative time (mean: 6.19 versus 6.85 h, p < 0.01), and length of stay (median: 7 versus 5 days, p < 0.01). Complication: frequency of patients with at least one 30-day complication was 85% compared to 66% (p < 0.01). Minor gastrointestinal and bleeding complications were increased in the open group (50% versus 41%, p = 0.01; 52% versus 11%, p < 0.01, respectively). Fifty percent of patients required blood transfusion in open compared to 11% (p < 0.01). Patients in the open group experienced more major complications (19% versus 10%, p = 0.04). Robotic approach was a predictor for fewer complications (OR 0.44, 95% CI 0.20-0.99, p = 0.049). Readmission: no significant difference in number of patients readmitted was found. Cost-to-patient: Robotic approach predicted an 18% reduction in total cost-to-patient compared to open approach (p < 0.01). Robotic cystectomy demonstrated reduced total cost-to-patient when taking into account all 30-day post-operative services with fewer complications compared to open cystectomy.

The aims of this study were to assess the association between gabapentin and suicidality in patients diagnosed with bipolar disorder (BD) and to determine whether the risk is greater relative to patients prescribed lithium. This retrospective observational study utilizes US population-based claims data assembled by PharMetrics Inc., comprising 47 918 patients diagnosed with BD. Patients were included if they were at least 18 years old and initiated a new monotherapy prescription of either gabapentin (n=2421) or lithium (n=3101). Patients were followed for up to 1 year. Gabapentin patients contributed 915.8 person-years (PY) of follow-up time; lithium patients contributed 1421.3 PY. There were 21 suicide/self-harm events in the gabapentin group and 16 in the lithium group. Unadjusted incidence rates were 22.9 and 11.3/1000 PY in the gabapentin and lithium groups, respectively (P=0.03). After adjusting for concomitant medications, comorbid diagnoses, age, sex, and history of suicide/self-harm, the hazard ratio was 2.3 (95% confidence interval: 1.2-4.5). A propensity score-matched analysis accounting for pre-existing illnesses and medications supports this finding, with an adjusted hazard ratio of 2.1 (95% confidence interval: 1.02-4.5). Relative to lithium, the use of gabapentin is significantly associated with a doubling of the risk of suicidality in patients diagnosed with BD.

Objective: Identify factors associated with adherence to nasoalveolar molding (NAM) therapy., Design: Retrospective case-control study., Setting: Tertiary referral center., Patients, Participants: Infants with cleft lip, with or without cleft palate, referred for NAM. One hundred thirty-five patients met criteria., Main Outcome Measure(s): Adherence to NAM therapy, defined as continuous use of the appliance and attendance of NAM adjustment visits., Results: Female sex (OR = 2.85, 95% CI 1.21-6.74), bilateral cleft (OR = 2.88, 95% CI 1.29-6.46), and travel distance (OR = 1.01, 95% CI 1.00-1.01) were independent predictors of nonadherence. Bilateral clefts (OR = 8.35, 95% CI 2.72-25.64) and public-payer insurance (OR = 3.67, 95% CI 1.13-11.91) for male patients were significantly associated with nonadherence, in our sex-stratified multivariate model. The majority of the families (58%) had public health insurance. Males comprised 77.0% of the cohort., Conclusions: NAM treatment adherence is impaired by bilateral clefts, female sex, increased travel distance, and public insurance. Further studies are warranted to investigate how these factors affect adherence, and to develop interventions to improve adherence in families at risk due to economic or psychosocial barriers.

Purpose: This study sought to determine whether respiratory sinus arrhythmia (RSA) and executive functions are associated with stuttered speech disfluencies of young children who do (CWS) and do not stutter (CWNS)., Method: Thirty-six young CWS and 36 CWNS were exposed to neutral, negative, and positive emotion-inducing video clips, followed by their participation in speaking tasks. During the neutral video, we measured baseline RSA, a physiological index of emotion regulation, and during video viewing and speaking, we measured RSA change from baseline, a physiological index of regulatory responses during challenge. Participants' caregivers completed the Children's Behavior Questionnaire from which a composite score of the inhibitory control and attentional focusing subscales served to index executive functioning., Results: For both CWS and CWNS, greater decrease of RSA during both video viewing and speaking was associated with more stuttering. During speaking, CWS with lower executive functioning exhibited a negative association between RSA change and stuttering; conversely, CWNS with higher executive functioning exhibited a negative association between RSA change and stuttering., Conclusion: Findings suggest that decreased RSA during video viewing and speaking is associated with increased stuttering and young CWS differ from CWNS in terms of how their executive functions moderate the relation between RSA change and stuttered disfluencies.

Beta-hydroxybutyric acid (BHB) is a ketone body which is generated from fatty acids as an alternative energy source when glucose is not available. Determination of this compound may be relevant in the forensic laboratory as ketoacidosis - an elevated level of ketone bodies - may contribute to the cause of death. In this study, we aimed at determining the relevance of routinely implementing BHB analysis in the forensic toxicological laboratory, as BHB analysis typically requires an additional workload. We therefore performed an unbiased retrospective analysis of BHB in 599 cases, comprising 553 blood, 232 urine and 62 vitreous humour samples. Cases with BHB concentrations above 100mg/L (in blood, urine and/or vitreous humour) were invariably associated with elevated levels of acetone, another ketone body, the detection of which is already implemented in most forensic laboratories using the gas chromatographic procedure for ethanol quantification. Our retrospective analysis did not reveal any positive case that had been missed initially and confirms that BHB analysis can be limited to acetone positive cases., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Using a matched case-control design, we sought to determine whether the odds of konzo, a distinct spastic paraparesis associated with food (cassava) cyanogenic exposure in the tropics, were associated with lower cyanide detoxification rates (CDR) and malnutrition. Children with konzo (N=122, 5-17 years of age) were age- and sex-matched with presumably healthy controls (N=87) and assessed for motor and cognition performances, cyanogenic exposure, nutritional status, and cyanide detoxification rates (CDR). Cyanogenic exposure was ascertained by thiocyanate (SCN) concentrations in plasma (P-SCN) and urine (U-SCN). Children with a height-for-age z-score (HAZNCHS)<-2 were classified as nutritionally stunted. CDR was measured as time required to convert cyanide to SCN, and expressed as ms/μmol SCN/mg protein or as mmolSCN/ml plasma/min. Mean (SD) U-SCN in children with konzo was 521.9 (353.6) μmol/l and was, significantly higher than 384.6 (223.7) μmol/l in those without konzo. Conditional regression analysis of data for age- and sex- matched case-control pairs showed that konzo was associated with stunting (OR: 5.8; 95% CI: 2.7-12.8; p<0.01; N=83 paired groups) and higher U-SCN (OR: 1.1; 95% CI: 1.02-1.20 per 50-μmol increase in U-SCN; p=0.02; N=47 paired groups). After adjusting for stunting and U-SCN, the odds of developing konzo was reduced by 63% (95% CI: 11-85%, p=0.03; N=41 paired groups) for each 5mmol SCN/(ml plasma/min)-increase in CDR. Linear regression analysis indicated a significant association between BOT-2 or KABC-II scores and both the HAZNCHS z-score and the U-SCN concentration, but not the CDR. Our findings provide evidence in support of interventions to remove cyanogenic compounds from cassava prior to human consumption or, peharps, enhance the detoxification of cyanide in those relying on the cassava as the main source of food., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Introduction: During 2010-2012, Oregon Health & Science University's Prevention Research Center, a Northwest Tribe, and the Northwest Portland Area Indian Health Board, collaborated to evaluate the Healthy & Empowered Youth Project, a school- and community-based positive youth development program for American Indian and Alaska Native high school students., Methods: The Native STAND (Students Together Against Negative Decisions) curriculum was enhanced with hands-on learning activities in media design to engage students in sexual and reproductive health topics covered by the curriculum. Guest speakers, field trips, and extracurricular activities were added to provide academic enrichment, engage students in cultural activities, and offer opportunities for career development. Students completed comprehensive pre- and post-surveys, and the authors conducted focus groups and key informant interviews with students and teachers. Data analysis was conducted during 2013-2014., Results: Survey findings demonstrated improvements in student leadership and achievement, physical and mental health, and protective sexual health behaviors. The percentage of female teens reporting use of a condom the last time they had sex increased from 17% to 30%, and those who reported ever having been tested for sexually transmitted illnesses doubled from 12% to 24%. Focus group and interview findings indicated similar improvements in student self-esteem, life skills, health behavior, and engagement in community., Conclusions: The Healthy & Empowered Youth Project educated and empowered Native high school students on a variety of sensitive health topics. The media enhancements were central to the program's success, reinforcing and personalizing classroom lessons and generating health-related videos and posters that resonated with family and friends., (Copyright © 2016 American Journal of Preventive Medicine. Published by Elsevier Inc. All rights reserved.)

We evaluated the applicability of a validated GC-MS method for the determination of gabapentin in dried blood spots (DBS). Important for the acceptance of DBS sampling as an alternative sampling strategy is the possibility to base solid conclusions on the quantification. Therefore, bridging studies -studies in which the correlation between both DBS and a reference matrix (e.g. serum) is evaluated statistically- need to be conducted. To this end, a comparative study was set up to quantify gabapentin in both blood (DBS) and serum samples. Statistically significant differences between DBS and serum concentrations were found (p<0.001). A mean blood-to-serum ratio of 0.85 was observed, which is in line with expectations. Calculated serum concentrations (obtained by dividing the DBS concentrations by 0.85) demonstrated a good correlation with measured serum concentrations, with 87% of samples fulfilling the criterion for incurred sample reanalysis. Furthermore, our data indicate a good correlation between capillary and venous concentrations. Conclusively, this study demonstrated that DBS are a valid alternative to serum for the determination of gabapentin., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Background: American Indian and Alaska Native (AI/AN) youth face multiple health challenges compared to other racial/ethnic groups, which could potentially be ameliorated by the dissemination of evidence-based adolescent health promotion programs. Previous studies have indicated that limited trained personnel, cultural barriers, and geographic isolation may hinder the reach and implementation of evidence-based health promotion programs among AI/AN youth. Although Internet access is variable in AI/AN communities across the United States, it is swiftly and steadily improving, and it may provide a viable strategy to disseminate evidence-based health promotion programs to this underserved population., Objective: We explored the potential of using the Internet to disseminate evidence-based health promotion programs on multiple health topics to AI/AN youth living in diverse communities across 3 geographically dispersed regions of the United States. Specifically, we assessed the Internet's potential to increase the reach and implementation of evidence-based health promotion programs for AI/AN youth, and to engage AI/AN youth., Methods: This randomized controlled trial was conducted in 25 participating sites in Alaska, Arizona, and the Pacific Northwest. Predominantly AI/AN youth, aged 12-14 years, accessed 6 evidence-based health promotion programs delivered via the Internet, which focused on sexual health, hearing loss, alcohol use, tobacco use, drug use, and nutrition and physical activity. Adult site coordinators completed computer-based education inventory surveys, connectivity and bandwidth testing to assess parameters related to program reach (computer access, connectivity, and bandwidth), and implementation logs to assess barriers to implementation (program errors and delivery issues). We assessed youths' perceptions of program engagement via ratings on ease of use, understandability, credibility, likeability, perceived impact, and motivational appeal, using previously established measures., Results: Sites had sufficient computer access and Internet connectivity to implement the 6 programs with adequate fidelity; however, variable bandwidth (ranging from 0.24 to 93.5 megabits per second; mean 25.6) and technical issues led some sites to access programs via back-up modalities (eg, uploading the programs from a Universal Serial Bus drive). The number of youth providing engagement ratings varied by program (n=40-191; 48-60% female, 85-90% self-identified AI/AN). Across programs, youth rated the programs as easy to use (68-91%), trustworthy (61-89%), likeable (59-87%), and impactful (63-91%). Most youth understood the words in the programs (60-83%), although some needed hints to complete the programs (16-49%). Overall, 37-66% of the participants would recommend the programs to a classmate, and 62-87% found the programs enjoyable when compared to other school lessons., Conclusions: Findings demonstrate the potential of the Internet to enhance the reach and implementation of evidence-based health promotion programs, and to engage AI/AN youth. Provision of back-up modalities is recommended to address possible connectivity or technical issues. The dissemination of Internet-based health promotion programs may be a promising strategy to address health disparities for this underserved population., Trial Registration: Clinicaltrials.gov NCT01303575; https://clinicaltrials.gov/ct2/show/NCT01303575 (Archived by WebCite at http://www.webcitation.org/6m7DO4g7c)., Competing Interests: Conflicts of Interest: None declared., (©Christine M Markham, Stephanie Craig Rushing, Cornelia Jessen, Gwenda Gorman, Jennifer Torres, William E Lambert, Alexander V Prokhorov, Leslie Miller, Kelly Allums-Featherston, Robert C Addy, Melissa F Peskin, Ross Shegog. Originally published in JMIR Research Protocols (http://www.researchprotocols.org), 21.11.2016.)

Dried blood spot (DBS) sampling and analysis is increasingly being applied in bioanalysis. Although the use of DBS has many advantages, it is also associated with some challenges. E.g. given the limited amount of available material, highly sensitive detection techniques are often required to attain sufficient sensitivity. In gas chromatography coupled to mass spectrometry (GC-MS), derivatization can be helpful to achieve adequate sensitivity. Because this additional sample preparation step is considered as time-consuming, we introduce a new derivatization procedure, i.e. "microwave-assisted on-spot derivatization", to minimize sample preparation of DBS. In this approach the derivatization reagents are directly applied onto the DBS and derivatization takes place in a microwave instead of via conventional heating. In this manuscript we evaluated the applicability of this new concept of derivatization for the determination of two polar low molecular weight molecules, gamma-hydroxybutyric acid (GHB) and gabapentin, in DBS using a standard GC-MS configuration. The method was successfully validated for both compounds, with imprecision and bias values within acceptance criteria (<20% at LLOQ, <15% at 3 other QC levels). Calibration lines were linear over the 10-100μg/mL and 1-30μg/mL range for GHB and gabapentin, respectively. Stability studies revealed no significant decrease of gabapentin and GHB in DBS upon storage at room temperature for at least 84 days. Furthermore, DBS-specific parameters, including hematocrit and volume spotted, were evaluated. As demonstrated by the analysis of GHB and gabapentin positive samples, "microwave-assisted on-spot derivatization" proved to be reliable, fast and applicable in routine toxicology. Moreover, other polar low molecular weight compounds of interest in clinical and/or forensic toxicology, including vigabatrin, beta-hydroxybutyric acid, propylene glycol, diethylene glycol, 1,4-butanediol and 1,2-butanediol, can also be detected using this method., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Monitoring of alcohol consumption by living persons takes place in various contexts, amongst which workplace drug testing, driving under the influence of alcohol, driving licence regranting programs, alcohol withdrawal treatment, diagnosis of acute intoxication or fetal alcohol ingestion. The matrices that are mostly used today include blood, breath and urine. The aim of this review is to present alternative sampling strategies that allow monitoring of the alcohol consumption in living subjects. Ethanol itself, indirect (carbohydrate deficient transferrin, CDT%) as well as direct biomarkers (ethyl glucuronide, EtG; ethyl sulphate, EtS; fatty acid ethyl esters, FAEEs and phosphatidylethanol species, PEths) of ethanol consumption will be considered. This review covers dried blood spots (CDT%, EtG/EtS, PEths), dried urine spots (EtG/EtS), sweat and skin surface lipids (ethanol, EtG, FAEEs), oral fluid (ethanol, EtG), exhaled breath (PEths), hair (EtG, FAEEs), nail (EtG), meconium (EtG/EtS, FAEEs), umbilical cord and placenta (EtG/EtS and PEth 16:0/18:1). Main results, issues and considerations specific to each matrix are reported. Details about sample preparation and analytical methods are not within the scope of this review., (Copyright © 2016 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.)

Introduction: About 18% of pregnant women have major or minor depression during pregnancy, but many are neither screened nor treated. Lack of treatment can have serious adverse consequences for the woman and her child. Since 2002, the American College of Nurse-Midwives has advised midwives to integrate prevention, universal screening, treatment, and/or referral for depression into the care they provide. The American College of Obstetricians and Gynecologists' 2015 guidelines recommend screening at least once in the perinatal period using a standardized, validated tool. A consensus has not been reached by professional organizations about the specifics of whether and when to screen for prenatal depression. The objective of this study is to understand the prenatal screening practices of midwives who practice in Oregon., Methods: We surveyed all 162 Oregon-licensed certified nurse-midwives (CNMs). The survey asked about practice characteristics, demographics, screening, and perceived barriers to screening. The survey was administered electronically from October through December 2014., Results: The response rate was 37%. Among the 53 CNM respondents who had provided prenatal care in the previous year, 50 (94%) reported screening for prenatal depression, and 38 (72%) reported the use of a standardized screening tool on more than 90% of prenatal patients. Thirty-five (66%) CNMs reported using the Edinburgh Postnatal Depression Scale. More than 60% of respondents indicated that availability of mental health services and insurance constraints were barriers to screening., Discussion: We explored prenatal depression screening practices of CNMs. Most Oregon CNMs use a standardized screening tool. We suggest 2 strategies to overcome barriers to screening: incorporation of a standardized screening tool into electronic medical records and negotiation with insurance companies. More research is needed to clarify when and how often pregnant women should be screened for depression and how to increase the number of women who receive treatment., (© 2016 by the American College of Nurse-Midwives.)

Background: In Belgium, the analysis of indirect biomarkers such as carbohydrate deficient transferrin (CDT%), gamma-glutamyltransferase (GGT), aspartate aminotransferase/alanine aminotransferase (AST/ALT) and mean corpuscular volume (MCV), is currently used to monitor the alcohol consumption in cases of fitness to drive assessment. We evaluated the use of direct ethanol markers for this purpose, exclusively determined in matrices obtained via non- or minimally invasive sampling., Methods: Three validated quantitative methods (ethylglucuronide (EtG) in hair and urine, ethylsulfate (EtS) in urine, and phosphatidylethanol species (PEth 16:0/18:1, PEth 18:1/18:1 and PEth 16:0/16:0) in capillary dried blood spots (C-DBS)) were used. Fifty volunteers, for whom fitness to drive had to be assessed and for whom a blood analysis for indirect biomarkers was requested, were included in the study. The sampling and analysis of hair, urine and C-DBS were added to the process currently used., Results: Hair EtG (24/50) and C-DBS PEths (29/50) are more sensitive than the currently used indirect biomarkers (13/50 for CDT%) to detect excessive and chronic alcohol consumption and allow to disprove an abstinence period. Urinary EtG and EtS are useful parameters to determine recent alcohol consumption., Conclusion: The combined use of the three strategies allows better inference about the evolution of the alcohol consumption prior to the sampling. Moreover, the exclusive use of non- or minimally invasive sampling (hair, urine and C-DBS) allows this to be performed directly during the fitness to drive assessment by regular staff members. This approach offers the potential to improve the Belgian driver's licence regranting process., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

The degradation and interconversion of a selected set of pterins (dihydroneopterin, hydroxymethyldihydropterin, dihydroxanthopterin, neopterin, hydroxymethylpterin, xanthopterin, 6-formylpterin, 6-carboxypterin and pterin), spiked to charcoal-treated potato and Arabidopsis thaliana matrix was investigated, together with their relative recovery in potato and A. thaliana. As a result, a matrix-specific procedure for the ultra-high performance liquid chromatography-tandem mass spectrometry based determination of 6 aromatic pterins (neopterin, hydroxymethylpterin, xanthopterin, 6-formylpterin, 6-carboxypterin and pterin) is proposed: 1.5ml of an N2-flushed, alkaline (pH=10) extraction solvent is added to 200mg of plant sample. After boiling and homogenization, the samples are incubated: Arabidopsis samples for 30min at room temperature, while shaking, and potato samples for 2h at 37°C (applying a dienzyme treatment with α-amylase and protease). After a final boiling step, the samples are ultrafiltrated and resulting extracts are analyzed by UHPLC-MS/MS., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Interindividual variability in the expression and function of drug metabolizing cytochrome P (CYP) 450 enzymes, determined by a combination of genetic, non-genetic and environmental parameters, is a major source of variable drug response. Phenotyping by administration of a selective enzyme substrate, followed by the determination of a specific phenotyping metric, is an appropriate approach to assess the in vivo activity of CYP450 enzymes as it takes into account all influencing factors. A phenotyping protocol should be as simple and convenient as possible. Typically, phenotyping metrics are determined in traditional matrices, such as blood, plasma or urine. Several sampling strategies have been proposed as an alternative for these traditional sampling techniques. In this review, we provide a comprehensive overview of available methods using dried blood spots (DBS), hair, oral fluid, exhaled breath and sweat for in vivo CYP450 phenotyping. We discuss the relation between phenotyping metrics measured in these samples and those in conventional matrices, along with the advantages and limitations of the alternative sampling techniques. Reliable phenotyping procedures for several clinically relevant CYP450 enzymes, including CYP1A2, CYP2C19 and CYP2D6, are currently available for oral fluid, breath or DBS, while additional studies are needed for other CYP450 isoforms, such as CYP3A4. The role of hair analysis for this purpose remains to be established. Being non- or minimally invasive, these sampling strategies provide convenient and patient-friendly alternatives for classical phenotyping procedures, which may contribute to the implementation of CYP450 phenotyping in clinical practice.

Phosphatidylethanol species (PEths) are promising biomarkers of alcohol consumption. Here, we report on the set-up, validation, and application of a novel UHPLC-ESI-MS/MS method for the quantification of PEth 16:0/18:1, PEth 18:1/18:1, and PEth 16:0/16:0 in whole blood (30 μL) and in venous (V, 30 μL) or capillary (C, 3 punches (3 mm)) dried blood spots (DBS). The methods were linear from 10 (LLOQ) to 2000 ng/mL for PEth 16:0/18:1, from 10 (LLOQ) to 1940 ng/mL for PEth 18:1/18:1, and from 19 (LLOQ) to 3872 ng/mL for PEth 16:0/16:0. Extraction efficiencies were higher than 55% (RSD < 18%) and matrix effects compensated for by IS were between 77 and 125% (RSD < 10%). Accuracy, repeatability, and intermediate precision fulfilled acceptance criteria (bias and RSD below 13%). Validity of the procedure for determination of PEth 16:0/18:1 in blood was demonstrated by the successful participation in a proficiency test. The quantification of PEths in C-DBS was not significantly influenced by the hematocrit, punch localization, or spot volume. The stability of PEths in V-DBS stored at room temperature was demonstrated up to 6 months. The method was applied to authentic samples (whole blood, V-DBS, and C-DBS) from 50 inpatients in alcohol withdrawal and 50 control volunteers. Applying a cut-off value to detect inpatients at 221 ng/mL for PEth 16:0/18:1 provided no false positive results and a good sensitivity (86%). Comparison of quantitative results (Bland-Altman plot, Passing-Bablok regression, and Wilcoxon signed rank test) revealed that V-DBS and C-DBS were valid alternatives to venous blood for the detection of alcohol consumption.

A method for the quantitative determination of folates in rodent diets is very important for correct interpretation of folate intake during feeding trials, given the possible discrepancy between the actual folate concentration in the diet and that mentioned on the product sheet. Liquid chromatography tandem-mass spectrometry is the method of choice to differentiate and quantify the individual folate species present. This discrepancy may be accounted for by, e.g., inaccurate folic acid supplementation and/or the presence of endogenous reduced and substituted folates. We developed a method, validated based on FDA guidelines, that allows the measurement of added and endogenous folates by quantitative determination of 5 folate monoglutamates with linear ranges from 8 μg to 2 mg/kg feed. This information, combined with feed intake data, allows insight into the actual folate intake in animal feeding studies. The relevance of this method was illustrated by the analysis of several feed samples of varying composition, by the investigation of the effect of casein incorporation, and by evaluating the variability of the folate content between pellets and production batches.

Caffeine is the probe drug of choice to assess the phenotype of the drug metabolizing enzyme CYP1A2. Typically, molar concentration ratios of paraxanthine, caffeine's major metabolite, to its precursor are determined in plasma following administration of a caffeine test dose. The aim of this study was to develop and validate an LC-MS/MS method for the determination of caffeine and paraxanthine in hair. The different steps of a hair extraction procedure were thoroughly optimized. Following a three-step decontamination procedure, caffeine and paraxanthine were extracted from 20 mg of ground hair using a solution of protease type VIII in Tris buffer (pH 7.5). Resulting hair extracts were cleaned up on Strata-X™ SPE cartridges. All samples were analyzed on a Waters Acquity UPLC® system coupled to an AB SCIEX API 4000™ triple quadrupole mass spectrometer. The final method was fully validated based on international guidelines. Linear calibration lines for caffeine and paraxanthine ranged from 20 to 500 pg/mg. Precision (%RSD) and accuracy (%bias) were below 12% and 7%, respectively. The isotopically labeled internal standards compensated for the ion suppression observed for both compounds. Relative matrix effects were below 15%RSD. The recovery of the sample preparation procedure was high (>85%) and reproducible. Caffeine and paraxanthine were stable in hair for at least 644 days. The effect of the hair decontamination procedure was evaluated as well. Finally, the applicability of the developed procedure was demonstrated by determining caffeine and paraxanthine concentrations in hair samples of ten healthy volunteers. The optimized and validated method for determination of caffeine and paraxanthine in hair proved to be reliable and may serve to evaluate the potential of hair analysis for CYP1A2 phenotyping., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Purpose: This study investigated the relation among speech-language dissociations, attentional distractibility, and childhood stuttering., Method: Participants were 82 preschool-age children who stutter (CWS) and 120 who do not stutter (CWNS). Correlation-based statistics (Bates, Appelbaum, Salcedo, Saygin, & Pizzamiglio, 2003) identified dissociations across 5 norm-based speech-language subtests. The Behavioral Style Questionnaire Distractibility subscale measured attentional distractibility. Analyses addressed (a) between-groups differences in the number of children exhibiting speech-language dissociations; (b) between-groups distractibility differences; (c) the relation between distractibility and speech-language dissociations; and (d) whether interactions between distractibility and dissociations predicted the frequency of total, stuttered, and nonstuttered disfluencies., Results: More preschool-age CWS exhibited speech-language dissociations compared with CWNS, and more boys exhibited dissociations compared with girls. In addition, male CWS were less distractible than female CWS and female CWNS. For CWS, but not CWNS, less distractibility (i.e., greater attention) was associated with more speech-language dissociations. Last, interactions between distractibility and dissociations did not predict speech disfluencies in CWS or CWNS., Conclusions: The present findings suggest that for preschool-age CWS, attentional processes are associated with speech-language dissociations. Future investigations are warranted to better understand the directionality of effect of this association (e.g., inefficient attentional processes → speech-language dissociations vs. inefficient attentional processes ← speech-language dissociations).

Background: People with multiple sclerosis (MS) fall frequently, and there are few clinically valid tools to measure the risk factors for falls. We assessed the unidimensionality of the 7-item Falls Efficacy Scale-International (FES-I), a measure of fear of falling, and determined whether the 7-item FES-I is associated with recurrent falls in people with MS., Methods: Falls were counted prospectively for 6 months using fall calendars in 58 people with MS (age, 18-50 years; Expanded Disability Status Scale score, 0-6). The FES-I was administered at baseline, and its unidimensionality was assessed by confirmatory factor analysis. The relationship between FES-I score and future falls, after adjusting for recurrent falls in the past year, was assessed by logistic regression., Results: Fifty-four participants who completed all assessments were included in the analysis. Goodness-of-fit indices confirmed a single-factor solution for the 7-item FES-I (discrepancy χ(2), P = .101; Tucker-Lewis index, 0.953; comparative fit index, 0.969; root mean square error of approximation, 0.098). There was a significant association between fear of falling and falls in the following 3 months, independent of recurrent falls in the past year (odds ratio = 1.22, 95% confidence interval, 1.04-1.43, P = .016)., Conclusions: The 7-item FES-I demonstrates good construct validity, allowing the total score to be used as a measure of fear of falling in people with MS. Fear of falling, as measured by the 7-item FES-I, is associated with future recurrent falls independent of past recurrent falls in people with MS.

Background and Objective: Although metabolite-to-parent drug concentration ratios in hair have been suggested as a possible tool to study the metabolism of drugs in a non-invasive way, no studies are available that evaluated this in a systematic way. Cytochrome P450 (CYP) 1A2 is a drug-metabolizing enzyme characterized by large inter-individual differences in its activity. The standard approach for CYP1A2 phenotyping is to determine the paraxanthine/caffeine ratio in plasma at a fixed timepoint after intake of a dose of the CYP1A2 substrate caffeine. The aim of this study was to evaluate whether paraxanthine/caffeine ratios measured in hair samples reflect the plasma-based CYP1A2 phenotype., Methods: Caffeine and paraxanthine concentrations were measured in proximal 3 cm segments of hair samples from 60 healthy volunteers and resulting paraxanthine/caffeine ratios were correlated with CYP1A2 phenotyping indices in plasma., Results: Paraxanthine/caffeine ratios in hair ranged from 0.12 to 0.93 (median 0.41); corresponding ratios in plasma ranged from 0.09 to 0.95 (median 0.40). A statistically significant correlation was found between ratios in hair and plasma (r = 0.41, p = 0.0011). However, large deviations between ratios in both matrices were found in individual cases. Although the influence of several factors on paraxanthine/caffeine ratios and hair-plasma deviations was investigated, no evident factors explaining the observed variability could be identified., Conclusion: The variability between hair and plasma ratios complicates the interpretation of hair paraxanthine/caffeine ratios on an individual basis and, therefore, compromises their practical usefulness as alternative CYP1A2 phenotyping matrix.

Objective: To estimate the effect of oral midazolam on patient pain and anxiety perception during first-trimester surgical abortion., Methods: Between May and December 2013, we conducted a randomized, double-blind, placebo-controlled trial. Patients between 6 0/7 and 10 6/7 weeks of gestation received 10 mg oral midazolam or placebo 30-60 minutes before surgical abortion. All patients received ibuprofen and a paracervical block. We powered the study (power=80%; significance level=.025) to detect a 15-mm difference in our two a priori primary outcomes of pain and anxiety with uterine aspiration on a 100-mm visual analog scale. Secondary outcomes were pain and anxiety at additional time points, memory, satisfaction, side effects, and adverse events., Results: Demographics were similar between groups (placebo=62, midazolam=62). Compared with those randomized to placebo, patients who received midazolam had significantly less anxiety preoperatively (room entry: 51.4 mm compared with 34.5 mm, P<.001; positioning: 56.6 mm compared with 45.4 mm, P=.02). There was no difference in pain (P=.28) or anxiety (P=.14) during uterine aspiration or at other procedural time points. A significantly greater number of patients in the midazolam group reported partial amnesia (31/61 compared with 16/61, P=.005) and dizziness (30/61 compared with 18/61, P=.03). Controlling for baseline differences, patients who received midazolam reported more postoperative sleepiness (P<.001) and less postoperative nausea (P=.004). There was no difference in overall satisfaction (P=.88)., Conclusion: Although oral midazolam reduces preprocedural anxiety, it does not reduce pain or anxiety with uterine aspiration during first-trimester surgical abortions., Clinical Trial Registration: ClinicalTrials.gov, www.clinicaltrials.gov, NCT01830881., Level of Evidence: I.

Volumetric absorptive microsampling (VAMS) is a novel sampling technique that allows the straightforward collection of an accurate volume of blood (approximately 10μL) from a drop or pool of blood by dipping an absorbent polymeric tip into it. The resulting blood microsample is dried and analyzed as a whole. The aim of this study was to evaluate the potential of VAMS to overcome the hematocrit bias, an important issue in the analysis of dried blood microsamples. An LC-MS/MS method for analysis of the model compounds caffeine and paraxanthine in VAMS samples was fully validated and fulfilled all pre-established criteria. In conjunction with previously validated procedures for dried blood spots (DBS) and blood, this allowed us to set up a meticulous comparative study in which both compounds were determined in over 80 corresponding VAMS, DBS and liquid whole blood samples. These originated from authentic human patient samples, covering a wide hematocrit range (0.21-0.50). By calculating the differences with reference whole blood concentrations, we found that analyte concentrations in VAMS samples were not affected by a bias that changed over the evaluated hematocrit range, in contrast to DBS results. However, VAMS concentrations tend to overestimate whole blood concentrations, as a consistent positive bias was observed. A different behavior of VAMS samples prepared from incurred and spiked blood, combined with a somewhat reduced recovery of caffeine and paraxanthine from VAMS tips at high hematocrit values, an effect that was not observed for DBS using a very similar extraction procedure, was found to be at the basis of the observed VAMS-whole blood deviations. Based on this study, being the first in which the validity and robustness of VAMS is evaluated by analyzing incurred human samples, it can be concluded that VAMS effectively assists in eliminating the effect of hematocrit., (Copyright © 2015 The Authors. Published by Elsevier B.V. All rights reserved.)

A stable isotope dilution LC-MS/MS method is the method of choice for the selective quantitative determination of several folate species in clinical samples. By implementing an integrated approach to determine both the plasma and red blood cell (RBC) folate status, the use of consumables and time remains limited. Starting from a single 300μl whole blood sample, the folate status in plasma and RBCs can be determined after separating plasma and RBCs and sequential washing of the latter with isotonic buffer, followed by reproducible lysis using an ammonium-based buffer. Acidification combines both liberation of protein bound folates and protein precipitation. Sample cleanup is performed using a 96-well reversed-phase solid-phase extraction procedure, similar for both plasma and RBC samples. Analyses are performed by UHPLC-MS/MS. Method validation was successfully performed based on EMA-guidelines and encompassed selectivity, carry-over, linearity, accuracy, precision, recovery, matrix effect and stability. Plasma and RBC folates could be quantified in the range of 1-150nmol/l and 5-1500nmol/l, respectively. This method allows for the determination of 6 folate monoglutamates in both plasma and RBCs. It can be used to determine short and long term folate status in both normal and severely deficient subjects in a single analytical sequence., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Therapeutic drug monitoring of antipsychotics is important in optimizing individual therapy. In psychiatric populations, classical venous blood sampling is experienced as frightening. Interest in alternative techniques, like dried blood spots (DBS), has consequently increased. A fast and easy to perform DBS method for quantification of 16 antipsychotics (amisulpride, aripiprazole, asenapine, bromperidol, clozapine, haloperidol, iloperidone, levosulpiride, lurasidone, olanzapine, paliperidone, pipamperone, quetiapine, risperidone, sertindole and zuclopenthixol) and 8 metabolites was developed. DBS were prepared using 25 μL of whole blood and extraction of complete spots was performed using methanol: methyl-t-butyl-ether (4:1). After evaporation, the extract was reconstituted in the mobile phase and 10 μL were injected on an ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). Separation using a C18 column and gradient elution with a flow rate of 0.5 mL/min resulted in a 6-min run-time. Ionization was performed in positive mode and a dynamic MRM method was applied. Median recovery was 66.4 % (range 28.7-84.5%). Accuracy was within the acceptance criteria, except for pipamperone (LLOQ and low concentration) and lurasidone (low concentration). Imprecision was only aberrant for lurasidone at low and medium concentration. All compounds were stable during 1 month at room temperature, 4 °C and -18 °C. Lurasidone was unstable when the extract was stored for 12 h on the autosampler. Absolute matrix effects (ME) (median 66.1%) were compensated by the use of deuterated IS (median 98.8%). The DBS method was successfully applied on 25-μL capillary DBS from patients and proved to be a reliable alternative for quantification of all antipsychotics except for olanzapine and N-desmethylolanzapine., (Copyright © 2014 John Wiley & Sons, Ltd.)

According to Khantzian's (2003) self-medication hypothesis (SMH), substance dependence is a compensatory means to modulate affects and self-soothe in response to distressing psychological states. Khantzian asserts: (1) Drugs become addicting because they have the power to alleviate, remove, or change human psychological suffering, and (2) There is a considerable degree of specificity in a person's choice of drugs because of unique psychological and physiological effects. The SMH has received criticism for its variable empirical support, particularly in terms of the drug-specificity aspect of Khantzian's hypothesis. We posit that previous empirical examinations of the SMH have been compromised by methodological limitations. Also, more recent findings supporting the SMH have yet to be replicated. Addressing previous limitations to the research, this project tested this theory in a treatment sample of treatment-seeking individuals with substance dependence (N = 304), using more heterogeneous, personality-driven measures that are theory-congruent. Using an algorithm based on medical records, individuals were reliably classified as being addicted to a depressant, stimulant, or opiate by two independent raters. Theory-based a priori predictions were that the three groups would exhibit differences in personality characteristics and emotional-regulation strategies. Specifically, our hypotheses entailed that when compared against each other: (1) Individuals with a central nervous system (CNS) depressant as drug of choice (DOC) will exhibit defenses of repression, over-controlling anger, and emotional inhibition to avoid acknowledging their depression; (2) Individuals with an opiate as DOC will exhibit higher levels of aggression, hostility, depression, and trauma, greater deficits in ego functioning, and externalizing/antisocial behavior connected to their use; and (3) Individuals with a stimulant as DOC will experience anhedonia, paranoia, have a propensity to mania, and display lower levels of emotional inhibition. MANOVAs were used to test three hypotheses regarding drug group differences on the personality variables that were in keeping with the SMH. The MANOVAs for Hypothesis I (Depressant group) and Hypothesis II (Opiate group) were statistically significant. Findings partially support the SMH, particularly in its characterization of personality functioning in those addicted to depressants and opiates.

Gamma-hydroxybutyric acid (GHB) is a well-known illicit club and date-rape drug. Dried blood spot (DBS) sampling is a promising alternative for classical venous sampling in cases of (suspected) GHB intoxication since it allows rapid sampling, which is of interest for the extensively metabolized GHB. However, there is limited data if -and how- capillary DBS concentrations correlate with venous concentrations. We conducted a comparative study in 50 patients with suspected GHB intoxication, to determine and to correlate GHB concentrations in venous DBS (vDBS) and capillary DBS (cDBS). This is the first study that evaluates in a large cohort the correlation between capillary and venous concentrations of an illicit drug in real-life samples. Of the 50 paired samples, 7 were excluded: the vDBS concentration was below the LLOQ of 2 µg/mL in 3 cases and 4 samples were excluded after visual inspection of the DBS. Bland-Altman analysis revealed a mean % difference of -2.8% between cDBS and vDBS concentrations, with the zero value included in the 95% confidence interval of the mean difference in GHB concentration. A paired sample t-test confirmed this observation (p = 0.17). Also the requirement for incurred sample reproducibility was fulfilled: for more than two-thirds of the samples the concentrations obtained in cDBS and those in vDBS were within 20% of their mean. Since equivalent concentrations were observed in cDBS and vDBS, blood obtained by fingerprick can be considered a valid alternative for venous blood for GHB determination., (Copyright © 2015 John Wiley & Sons, Ltd.)

Scope: The biological impact of folates from folate rice, a metabolically engineered (biofortified) rice line, rich in folates, was investigated. Its consumption may be helpful to fight folate deficiency. Our objective was to investigate the potential of folate rice to supply the organism with folates and evaluate its biological effectiveness using a rat model., Methods and Results: Five groups of 12 Wistar rats were monitored during a 7/12-wk depletion/repletion trial. Animals receiving folate-free diet (0 μg/rat/day) and those additionally receiving wild-type rice (on average 0.11 μg/rat/day) suffered from decreased hematocrit and lower folate concentrations in both plasma and RBCs. This resulted in serious morbidity and even lethality during the trial. In contrast, all animals receiving a daily supplement of folate rice or folic acid fortified rice (on average 3.00 μg/rat/day and 3.12 μg/rat/day, respectively) and those receiving a positive control diet (11.4 to 25.0 μg/rat/day), survived. In these groups, the hematocrit normalized, plasma and RBC folate concentrations increased and pronounced hyperhomocysteinemia was countered., Conclusion: Using an animal model, we demonstrated that biofortified folate rice is a valuable source of dietary folate, as evidenced by folate determination in plasma and RBCs, the alleviation of anemia and counteraction of pronounced hyperhomocysteinemia., (© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Caffeine, standard treatment for apnea of prematurity, improves brainstem auditory processing. We hypothesized that caffeine also improves cortical differentiation of complex speech sounds. We used event-related potential methodology to measure responses to speech-sound contrasts in 45 intensive care neonates, stratified by cumulative exposure as no-, low-, and high-caffeine groups. Sound differentiation in the low-caffeine group and near-term no-caffeine infants was similar with repeated measures analysis of variance controlling for gestational and postnatal age. However, a generalized estimating equation approach demonstrated that, at equivalent postnatal age, differentiation was reduced in the high-caffeine (gestational age 25 weeks) compared to the low-caffeine group (gestational age 28 weeks), reflecting the importance of maturity at birth (Z = 2.77, P < .006). We conclude that caffeine improves measures of auditory processing associated with improved neurodevelopmental outcomes in preterm infants. However, current usage of caffeine for apnea of prematurity cannot fully compensate for the effects of brain immaturity on speech sound processing., (© The Author(s) 2014.)