Detecting dementia in patients with normal neuropsychological screening by Short Smell Test and Palmo-Mental Reflex Test: an observational study

BACKGROUND General practitioners (GPs) are in best position to suspect dementia. Mini-Mental State Examination (MMSE) and Clock Drawing Test (CDT) are widely used. Additional neurological tests may increase the accuracy of diagnosis. We aimed to evaluate diagnostic ability to detect dementia with a Short Smell Test (SST) and Palmo-Mental Reflex (PMR) in patients whose MMSE and CDT are normal, but who show signs of cognitive dysfunction. METHODS This was a 3.5-year cross-sectional observational study in the Memory Clinic of the University Department of Geriatrics in Bern, Switzerland. Participating patients with normal MMSE (>26 points) and CDT (>5 points) were referred by GPs because they suspected dementia. All were examined according to a standardized protocol. Diagnosis of dementia was based on DSM-IV TR criteria. We used SST and PMR to determine if they accurately detected dementia. RESULTS In our cohort, 154 patients suspected of dementia had normal MMSE and CDT test results. Of these, 17 (11 %) were demented. If SST or PMR were abnormal, sensitivity was 71 % (95 % CI 44-90 %), and specificity 64 % (95 % CI 55-72 %) for detecting dementia. If both tests were abnormal, sensitivity was 24 % (95 % CI 7-50 %), but specificity increased to 93 % (95 % CI 88-97 %). CONCLUSION Patients suspected of dementia, but with normal MMSE and CDT results, may benefit if SST and PMR are added as diagnostic tools. If both SST and PMR are abnormal, this is a red flag to investigate these patients further, even though their negative neuropsychological screening results.

Stereoselective virtual screening of the ZINC database using atom pair 3D-fingerprints

Background Tools to explore large compound databases in search for analogs of query molecules provide a strategically important support in drug discovery to help identify available analogs of any given reference or hit compound by ligand based virtual screening (LBVS). We recently showed that large databases can be formatted for very fast searching with various 2D-fingerprints using the city-block distance as similarity measure, in particular a 2D-atom pair fingerprint (APfp) and the related category extended atom pair fingerprint (Xfp) which efficiently encode molecular shape and pharmacophores, but do not perceive stereochemistry. Here we investigated related 3D-atom pair fingerprints to enable rapid stereoselective searches in the ZINC database (23.2 million 3D structures). Results Molecular fingerprints counting atom pairs at increasing through-space distance intervals were designed using either all atoms (16-bit 3DAPfp) or different atom categories (80-bit 3DXfp). These 3D-fingerprints retrieved molecular shape and pharmacophore analogs (defined by OpenEye ROCS scoring functions) of 110,000 compounds from the Cambridge Structural Database with equal or better accuracy than the 2D-fingerprints APfp and Xfp, and showed comparable performance in recovering actives from decoys in the DUD database. LBVS by 3DXfp or 3DAPfp similarity was stereoselective and gave very different analogs when starting from different diastereomers of the same chiral drug. Results were also different from LBVS with the parent 2D-fingerprints Xfp or APfp. 3D- and 2D-fingerprints also gave very different results in LBVS of folded molecules where through-space distances between atom pairs are much shorter than topological distances. Conclusions 3DAPfp and 3DXfp are suitable for stereoselective searches for shape and pharmacophore analogs of query molecules in large databases. Web-browsers for searching ZINC by 3DAPfp and 3DXfp similarity are accessible at www.gdb.unibe.ch webcite and should provide useful assistance to drug discovery projects.

Tuberculosis in Pediatric Antiretroviral Therapy Programs in Low- and Middle-Income Countries: Diagnosis and Screening Practices.

BACKGROUND The global burden of childhood tuberculosis (TB) is estimated to be 0.5 million new cases per year. Human immunodeficiency virus (HIV)-infected children are at high risk for TB. Diagnosis of TB in HIV-infected children remains a major challenge. METHODS We describe TB diagnosis and screening practices of pediatric antiretroviral treatment (ART) programs in Africa, Asia, the Caribbean, and Central and South America. We used web-based questionnaires to collect data on ART programs and patients seen from March to July 2012. Forty-three ART programs treating children in 23 countries participated in the study. RESULTS Sputum microscopy and chest Radiograph were available at all programs, mycobacterial culture in 40 (93%) sites, gastric aspiration in 27 (63%), induced sputum in 23 (54%), and Xpert MTB/RIF in 16 (37%) sites. Screening practices to exclude active TB before starting ART included contact history in 41 sites (84%), symptom screening in 38 (88%), and chest Radiograph in 34 sites (79%). The use of diagnostic tools was examined among 146 children diagnosed with TB during the study period. Chest Radiograph was used in 125 (86%) children, sputum microscopy in 76 (52%), induced sputum microscopy in 38 (26%), gastric aspirate microscopy in 35 (24%), culture in 25 (17%), and Xpert MTB/RIF in 11 (8%) children. CONCLUSIONS Induced sputum and Xpert MTB/RIF were infrequently available to diagnose childhood TB, and screening was largely based on symptom identification. There is an urgent need to improve the capacity of ART programs in low- and middle-income countries to exclude and diagnose TB in HIV-infected children.

Future water quality monitoring--adapting tools to deal with mixtures of pollutants in water resource management.

Environmental quality monitoring of water resources is challenged with providing the basis for safeguarding the environment against adverse biological effects of anthropogenic chemical contamination from diffuse and point sources. While current regulatory efforts focus on monitoring and assessing a few legacy chemicals, many more anthropogenic chemicals can be detected simultaneously in our aquatic resources. However, exposure to chemical mixtures does not necessarily translate into adverse biological effects nor clearly shows whether mitigation measures are needed. Thus, the question which mixtures are present and which have associated combined effects becomes central for defining adequate monitoring and assessment strategies. Here we describe the vision of the international, EU-funded project SOLUTIONS, where three routes are explored to link the occurrence of chemical mixtures at specific sites to the assessment of adverse biological combination effects. First of all, multi-residue target and non-target screening techniques covering a broader range of anticipated chemicals co-occurring in the environment are being developed. By improving sensitivity and detection limits for known bioactive compounds of concern, new analytical chemistry data for multiple components can be obtained and used to characterise priority mixtures. This information on chemical occurrence will be used to predict mixture toxicity and to derive combined effect estimates suitable for advancing environmental quality standards. Secondly, bioanalytical tools will be explored to provide aggregate bioactivity measures integrating all components that produce common (adverse) outcomes even for mixtures of varying compositions. The ambition is to provide comprehensive arrays of effect-based tools and trait-based field observations that link multiple chemical exposures to various environmental protection goals more directly and to provide improved in situ observations for impact assessment of mixtures. Thirdly, effect-directed analysis (EDA) will be applied to identify major drivers of mixture toxicity. Refinements of EDA include the use of statistical approaches with monitoring information for guidance of experimental EDA studies. These three approaches will be explored using case studies at the Danube and Rhine river basins as well as rivers of the Iberian Peninsula. The synthesis of findings will be organised to provide guidance for future solution-oriented environmental monitoring and explore more systematic ways to assess mixture exposures and combination effects in future water quality monitoring.

THE USE OF ARM CIRCUMFERENCE FOR SIMPLIFIED SCREENING FOR MALNUTRITION BY MINIMALLY TRAINED HEALTH WORKERS

Because of its simplicity and low cost, arm circumference (AC) is being used increasingly in screening for protein energy malnutrition among pre-school children in many parts of the developing world, especially where minimally trained health workers are employed. The objectives of this study were as follows: (1) To determine the relationship of the AC measure with weight for age and weight for height in the detection of malnutrition among pre-school children in a Guatemalan Indian village. (2) To determine the performance of minimally trained promoters under field conditions in measuring AC, weight and height. (3) To describe the practical aspects of taking AC measures versus weight, age and height.^ The study was conducted in San Pablo La Laguna, one of four villages situated on the shores of Lake Atitlan, Guatemala, in which a program of simplified medical care was implemented by the Institute for Nutrition for Central America and Panama (INCAP). Weight, height, AC and age data were collected for 144 chronically malnourished children. The measurements obtained by the trained investigator under the controlled conditions of the health post were correlated against one another and AC was found to have a correlation with weight for age of 0.7127 and with weight for height of 0.7911, both well within the 0.65 to 0.80 range reported in the literature. False positive and false negative analysis showed that AC was more sensitive when compared with weight for height than with weight for age. This was fortunate since, especially in areas with widespread chronic malnutrition, weight for height detects those acute cases in immediate danger of complicating illness or death. Moreover, most of the cases identified as malnourished by AC, but not by weight for height (false positives), were either young or very stunted which made their selection by AC better than weight for height. The large number of cases detected by weight for age, but not by AC (false negative rate--40%) were, however, mostly beyond the critical age period and had normal weight for heights.^ The performance of AC, weight for height and weight for age under field conditions in the hands of minimally trained health workers was also analyzed by correlating these measurements against the same criterion measurements taken under ideally controlled conditions of the health post. AC had the highest correlation with itself indicating that it deteriorated the least in the move to the field. Moreover, there was a high correlation between AC in the field and criterion weight for height (0.7509); this correlation was almost as high as that for field weight for height versus the same measure in the health post (0.7588). The implication is that field errors are so great for the compounded weight for height variable that, in the field, AC is about as good a predictor of the ideal weight for height measure.^ Minimally trained health workers made more errors than the investigator as exemplified by their lower intra-observer correlation coefficients. They consistently measured larger than the investigator for all measures. Also there was a great deal of variability between these minimally trained workers indicating that careful training and followup is necessary for the success of the AC measure.^ AC has many practical advantages compared to the other anthropometric tools. It does not require age data, which are often unreliable in these settings, and does not require sophisticated subtraction and two dimensional table-handling skills that weight for age and weight for height require. The measure is also more easily applied with less disturbance to the child and the community. The AC tape is cheap and not easily damaged or jarred out of calibration while being transported in rugged settings, as is often the case with weight scales. Moreover, it can be kept in a health worker's pocket at all times for continual use in a widespread range of settings. ^

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Includes index.

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Includes index.

Validity of the portable piko-6 spirometer used for screening obstructive airway diseases in community pharmacy practice

Background: Obstructive airway diseases (OADs) are among the leading causes of morbidity and mortality worldwide. Shortness of breath (SOB) is the main symptom associated with OADs. International guidelines from the Global Initiative for Chronic Lung Disease (GOLD) and the Global Initiative for Asthma (GINA) have recommended spirometry as an indispensable tool for the diagnosis of asthma and chronic obstructive pulmonary diseases (COPD), but spirometry is rarely used in family practice. Simple and reliable diagnostic tools are necessary for screening community patients with onset of OADs for timely management. Purpose: This thesis examined screening utility of the PiKo-6 forced expiratory volume in one second (pFEV₁) , in six second (pFEV₆), and the pRatio ( pFEV₁/pFEV₆) in SOB patients for OADs in community pharmacy settings. FEV₆ has recently been suggested an excellent surrogate for Forced Vital Capacity (FVC), which requires maximum exhalation of the lungs. Methods: Patients with SOB symptoms who were prescribed pulmonary inhalers, by their family physicians, were recruited via community pharmacies. Trained pharmacists collected two PiKo-6 tests to assess the repeatability of the PiKo-6 device. All patients performed laboratory spirometry ( FEV₁, FVC and FEV₁/FVC) to obtain physician diagnosis of their OADs. The results of the PiKo-6 spirometer and laboratory spirometer were compared. In addition, the PiKo-6 pRatio and laboratory FEV₁/FVC were assessed against physician diagnosed COPD. Results: Sixty three patients volunteered to perform the PiKo-6 spirometry. Of these, 52.4 % were men (age 53.9 ± 15.3 years; BMI 31.9 ± 7.40 kg/m2). Repeated testing with pFEV₁, pFEV6 and pRatio correlated significantly (within correlation, r = 0.835, p-Value≤ 0.05 ; 0.872, p- Value≤ 0.05; and 0.664, p-Value≤ 0.05). In addition, pFEV₁, pFEV6 and pRatio correlated significantly with FEV₁, FVC and FEV₁/FVC, respectively (between correlation = 0.630, p- Value≤ 0.05 ; 0.660, p-Value≤ 0.05 and 0.580, p-Value≤ 0.05). The cut-off value corresponding to the greatest sum of sensitivity and specificity of pRatio for physician-diagnosed COPD was <0.80, the sensitivity and specificity were 84 % and 50%, respectively. Conclusions The portable PiKo-6 correlates moderately well with the standard spirometry, when delivered by community pharmacists to patients with OADs. The PiKo-6 spirometer may play a role in screening patients suspected of having an OAD in community pharmacies that may benefit from early physician diagnosis and appropriate management.

Electronic health records: essential tools in integrating substance abuse treatment with primary care.

While substance use problems are considered to be common in medical settings, they are not systematically assessed and diagnosed for treatment management. Research data suggest that the majority of individuals with a substance use disorder either do not use treatment or delay treatment-seeking for over a decade. The separation of substance abuse services from mainstream medical care and a lack of preventive services for substance abuse in primary care can contribute to under-detection of substance use problems. When fully enacted in 2014, the Patient Protection and Affordable Care Act 2010 will address these barriers by supporting preventive services for substance abuse (screening, counseling) and integration of substance abuse care with primary care. One key factor that can help to achieve this goal is to incorporate the standardized screeners or common data elements for substance use and related disorders into the electronic health records (EHR) system in the health care setting. Incentives for care providers to adopt an EHR system for meaningful use are part of the Health Information Technology for Economic and Clinical Health Act 2009. This commentary focuses on recent evidence about routine screening and intervention for alcohol/drug use and related disorders in primary care. Federal efforts in developing common data elements for use as screeners for substance use and related disorders are described. A pressing need for empirical data on screening, brief intervention, and referral to treatment (SBIRT) for drug-related disorders to inform SBIRT and related EHR efforts is highlighted.

Molecular docking and geographical information systems as tools to assess the potential impact of veterinary medicines on non-target organisms and the environment

Veterinary medicines (VMs) from agricultural industry can enter the environment in a number of ways. This includes direct exposure through aquaculture, accidental spillage and disposal, and indirect entry by leaching from manure or runoff after treatment. Many compounds used in animal treatments have ecotoxic properties that may have chronic or sometimes lethal effects when they come into contact with non-target organisms. VMs enter the environment in mixtures, potentially having additive effects. Traditional ecotoxicology tests are used to determine the lethal and sometimes reproductive effects on freshwater and terrestrial organisms. However, organisms used in ecotoxicology tests can be unrepresentative of the populations that are likely to be exposed to the compound in the environment. Most often the tests are on single compound toxicity but mixture effects may be significant and should be included in ecotoxicology testing. This work investigates the use, measured environmental concentrations (MECs) and potential impact of sea lice treatments on salmon farms in Scotland. Alternative methods for ecotoxicology testing including mixture toxicity, and the use of in silico techniques to predict the chronic impact of VMs on different species of aquatic organisms were also investigated. The Scottish Environmental Protection Agency (SEPA) provided information on the use of five sea lice treatments from 2008-2011 on Scottish salmon farms. This information was combined with the recently available data on sediment MECs for the years 2009-2012 provided by SEPA using ArcGIS 10.1. In depth analysis of this data showed that from a total of 55 sites, 30 sites had a MEC higher than the maximum allowable concentration (MAC) as set out by SEPA for emamectin benzoate and 7 sites had a higher MEC than MAC for teflubenzuron. A number of sites that were up to 16 km away from the nearest salmon farm reported as using either emamectin benzoate or teflubenzuron measured positive for the two treatments. There was no relationship between current direction and the distribution of the sea lice treatments, nor was there any evidence for alternative sources of the compounds e.g. land treatments. The sites that had MECs higher than the MAC could pose a risk to non-target organisms and disrupt the species dynamics of the area. There was evidence that some marine protected sites might be at risk of exposure to these compounds. To complement this work, effects on acute mixture toxicity of the 5 sea lice treatments, plus one major metabolite 3-phenoxybenzoic acid (3PBA), were measured using an assay using the bioluminescent bacteria Aliivibrio fischeri. When exposed to the 5 sea lice treatments and 3PBA A. fischeri showed a response to 3PBA, emamectin benzoate and azamethiphos as well as combinations of the three. In order to establish any additive effect of the sea lice treatments, the efficacy of two mixture prediction equations, concentration addition (CA) and independent action ii(IA) were tested using the results from single compound dose response curves. In this instance IA was the more effective prediction method with a linear regression confidence interval of 82.6% compared with 22.6% of CA. In silico molecular docking was carried out to predict the chronic effects of 15 VMs (including the five used as sea lice control). Molecular docking has been proposed as an alternative screening method for the chronic effects of large animal treatments on non-target organisms. Oestrogen receptor alpha (ERα) of 7 non-target bony fish and the African clawed frog Xenopus laevis were modelled using SwissModel. These models were then ‘docked’ to oestradiol, the synthetic oestrogen ethinylestradiol, two known xenoestrogens dichlorodiphenyltrichloroethane (DDT) and bisphenol A (BPA), the antioestrogen breast cancer treatment tamoxifen and 15 VMs using Auto Dock 4. Based on the results of this work, four VMs were identified as being possible xenoestrogens or anti-oestrogens; these were cypermethrin, deltamethrin, fenbendazole and teflubenzuron. Further investigation, using in vitro assays, into these four VMs has been suggested as future work. A modified recombinant yeast oestrogen screen (YES) was attempted using the cDNA of the ERα of the zebrafish Danio rerio and the rainbow trout Oncorhynchus mykiss. Due to time and difficulties in cloning protocols this work was unable to be completed. Use of such in vitro assays would allow for further investigation of the highlighted VMs into their oestrogenic potential. In conclusion, VMs used as sea lice treatments, such as teflubenzuron and emamectin benzoate may be more persistent and have a wider range in the environment than previously thought. Mixtures of sea lice treatments have been found to persist together in the environment, and effects of these mixtures on the bacteria A. fischeri can be predicted using the IA equation. Finally, molecular docking may be a suitable tool to predict chronic endocrine disrupting effects and identify varying degrees of impact on the ERα of nine species of aquatic organisms.

Systems Modeling of Lung Cancer Screening Programs to Improve Quality

Thesis (Master's)--University of Washington, 2016-08

Evaluating conservation and fisheries management strategies by linking spatial prioritization software and ecosystem and fisheries modelling tools

Well-designed marine protected area (MPA) networks can deliver a range of ecological, economic and social benefits, and so a great deal of research has focused on developing spatial conservation prioritization tools to help identify important areas. However, whilst these software tools are designed to identify MPA networks that both represent biodiversity and minimize impacts on stakeholders, they do not consider complex ecological processes. Thus, it is difficult to determine the impacts that proposed MPAs could have on marine ecosystem health, fisheries and fisheries sustainability. Using the eastern English Channel as a case study, this paper explores an approach to address these issues by identifying a series of MPA networks using the Marxan and Marxan with Zones conservation planning software and linking them with a spatially explicit ecosystem model developed in Ecopath with Ecosim. We then use these to investigate potential trade-offs associated with adopting different MPA management strategies. Limited-take MPAs, which restrict the use of some fishing gears, could have positive benefits for conservation and fisheries in the eastern English Channel, even though they generally receive far less attention in research on MPA network design. Our findings, however, also clearly indicate that no-take MPAs should form an integral component of proposed MPA networks in the eastern English Channel, as they not only result in substantial increases in ecosystem biomass, fisheries catches and the biomass of commercially valuable target species, but are fundamental to maintaining the sustainability of the fisheries. Synthesis and applications. Using the existing software tools Marxan with Zones and Ecopath with Ecosim in combination provides a powerful policy-screening approach. This could help inform marine spatial planning by identifying potential conflicts and by designing new regulations that better balance conservation objectives and stakeholder interests. In addition, it highlights that appropriate combinations of no-take and limited-take marine protected areas might be the most effective when making trade-offs between long-term ecological benefits and short-term political acceptability.

Glasgow Psychosis Screening tool for use in adults with Intellectual Disabilities (GPS-ID): development and psychometric properties

Background: Prevalence of psychosis is known to be higher in adults with intellectual disabilities (ID) than in the general adult population. However, there have been no attempts to develop a psychosis screening tool specifically for the adult ID population. The present study describes the development and preliminary evaluation of a new measure, the Glasgow Psychosis Screening tool for use in Adults with Intellectual Disabilities (GPS-ID). Method: An item pool was generated following: 1) focus groups with adults with ID and psychosis, and their carers and/or workers; 2) expert input from clinicians. A draft scale was compiled and refined following expert feedback. The new scale, along with the Psychotic Symptom Rating Scales was administered to 20 adults with ID (10 with and 10 without psychosis) and their relative or carers. Results: The GPS-ID total score, self-report subscale and informant rating-subscale differentiated psychosis and non-psychosis groups. The tool had good internal consistency (Cronbach’s α=0.91), and a cut-off score ≥4 yielded high sensitivity (90%) and specificity (100%). The method of tool development supports face and content validity. Criterion validity was not supported. Conclusions: Preliminary investigation of the tool’s psychometric properties is positive, although further investigation is required. The tool is accessible to adults with mild to moderate ID and can be completed in 15-30 minutes. The GPS-ID is not a diagnostic tool, therefore any adult exceeding the cut-off score of ≥4 should receive further assessment.