Disease progression model using the integrated Alzheimer's Disease Rating Scale.

INTRODUCTION: An Alzheimer's disease (AD) dementia disease progression model was developed based on the integrated Alzheimer's Disease Rating Scale (iADRS). METHODS: Data from 3483 placebo participants in six AD trials were used to develop the disease progression model with NONMEM (version 7.4.2) and examined for mild cognitive impairment, and mild and moderate dementia due to AD. RESULTS: Baseline iADRS score was significantly influenced by AD symptomatic medication use, EXPEDITION2 enrollment (included moderate AD participants), age, and baseline Mini-Mental State Examination (MMSE) score. Rate of disease progression increased across disease stage and was significantly influenced by AD medication use, age, and baseline MMSE score. Apolipoprotein E ε4 carrier status did not influence baseline iADRS score or disease progression. DISCUSSION: These results demonstrate a disease progression model describing the time course of the iADRS across the AD severity spectrum. This model can assist future clinical trials in study design optimization and treatment effect interpretation. HIGHLIGHTS: A disease progression model described the integrated Alzheimer's Disease Rating Scale (iADRS) time course in mild cognitive impairment to moderate Alzheimer's disease. Using the linear regression model, iADRS scores can be calculated for Mini-Mental State Examination scores. Results can help optimize future clinical trial design and aid in understanding treatment effects.

Measuring and exploring mental health determinants: a closer look at co-residents' effect using a multilevel structural equations model.

OBJECTIVE: Previous research has demonstrated that individual risk of mental illness is associated with individual, co-resident, and household risk factors. However, modelling the overall effect of these risk factors presents several methodological challenges. In this study we apply a multilevel structural equation model (MSEM) to address some of these challenges and the impact of the different determinants when measuring mental health risk. STUDY DESIGN AND SETTING: Two thousand, one hundred forty-three individuals aged 16 and over from 888 households were analysed based on the Household Survey for England-2014 dataset. We applied MSEM to simultaneously measure and identify psychiatric morbidity determinants while accounting for the dependency among individuals within the same household and the measurement errors. RESULTS: Younger age, female gender, non-working status, headship of the household, having no close relationship with other people, having history of mental illness and obesity were all significant (p < 0.01) individual risk factors for psychiatric morbidity. A previous history of mental illness in the co-residents, living in a deprived household, and a lack of closeness in relationships among residents were also significant predictors. Model fit indices showed a very good model specification (CFI = 0.987, TLI = 0.980, RMSEA = 0.023, GFI = 0.992). CONCLUSION: Measuring and addressing mental health determinants should consider not only an individual's characteristics but also the co-residents and the households in which they live.

Comparing outcomes from tailored meta-analysis with outcomes from a setting specific test accuracy study using routine data of faecal calprotectin testing for inflammatory bowel disease.

BACKGROUND: Meta-analyses of test accuracy studies may provide estimates that are highly improbable in clinical practice. Tailored meta-analysis produces plausible estimates for the accuracy of a test within a specific setting by tailoring the selection of included studies compatible with a specific setting using information from the target setting. The aim of this study was to validate the tailored meta-analysis approach by comparing outcomes from tailored meta-analysis with outcomes from a setting specific test accuracy study. METHODS: A retrospective cohort study of primary care electronic health records provided setting-specific data on the test positive rate and disease prevalence. This was used to tailor the study selection from a review of faecal calprotectin testing for inflammatory bowel disease for meta-analysis using the binomial method and the Mahalanobis distance method. Tailored estimates were compared to estimates from a study of test accuracy in primary care using the same routine dataset. RESULTS: Tailoring resulted in the inclusion of 3/14 (binomial method) and 9/14 (Mahalanobis distance method) studies in meta-analysis. Sensitivity and specificity from tailored meta-analysis using the binomial method were 0.87 (95% CI 0.77 to 0.94) and 0.65 (95% CI 0.60 to 0.69) and 0.98 (95% CI 0.83 to 0.999) and 0.68 (95% CI 0.65 to 0.71), respectively using the Mahalanobis distance method. The corresponding estimates for the conventional meta-analysis were 0.94 (95% CI 0.90 to 0.97) and 0.67 (95% CI 0.57 to 0.76) and for the FC test accuracy study of primary care data 0.93 (95%CI 0.89 to 0.96) and 0.61 (95% CI 0.6 to 0.63) to detect IBD at a threshold of 50 µg/g. Although the binomial method produced a plausible estimate, the tailored estimates of sensitivity and specificity were not closer to the primary study estimates than the estimates from conventional meta-analysis including all 14 studies. CONCLUSIONS: Tailored meta-analysis does not always produce estimates of sensitivity and specificity that lie closer to the estimates derived from a primary study in the setting in question. Potentially, tailored meta-analysis may be improved using a constrained model approach and this requires further investigation.

An integrated PK-PD model for cortisol and the 17-hydroxyprogesterone and androstenedione biomarkers in children with congenital adrenal hyperplasia.

AIMS: The aim of this study was to characterize the pharmacokinetic/pharmacodynamic relationships of cortisol and the adrenal biomarkers 17-hydroxyprogesterone and androstenedione in children with congenital adrenal hyperplasia (CAH). METHODS: A nonlinear mixed-effect modelling approach was used to analyse cortisol, 17-hydroxyprogesterone and androstenedione concentrations obtained over 6 hours from children with CAH (n = 50). A circadian rhythm was evident and the model leveraged literature information on circadian rhythm in untreated children with CAH. Indirect response models were applied in which cortisol inhibited the production rate of all three compounds using an Imax model. RESULTS: Cortisol was characterized by a one-compartment model with apparent clearance and volume of distribution estimated at 22.9 L/h/70 kg and 41.1 L/70 kg, respectively. The IC50 values of cortisol concentrations for cortisol, 17-hydroxyprogesterone and androstenedione were estimated to be 1.36, 0.45 and 0.75 µg/dL, respectively. The inhibitory effect was found to be more potent on 17OHP than D4A, and the IC50 values were higher in salt-wasting subjects than simple virilizers. Production rates of cortisol, 17-hydroxyprogesterone and androstenedione were higher in simple-virilizer subjects. Half-lives of cortisol, 17-hydroxyprogesterone and androstenedione were 60, 47 and 77 minutes, respectively. CONCLUSION: Rapidly changing biomarker responses to cortisol concentrations highlight that single measurements provide volatile information about a child's disease control. Our model closely captured observed cortisol, 17-hydroxyprogesterone and androstenedione concentrations. It can be used to predict concentrations over 24 hours and allows many novel exposure metrics to be calculated, e.g., AUC, AUC-above-threshold, time-within-range, etc. Our long-range goal is to uncover dose-exposure-outcome relationships that clinicians can use in adjusting hydrocortisone dose and timing.

The incidence and prevalence of inflammatory bowel disease in UK primary care: a retrospective cohort study of the IQVIA Medical Research Database.

BACKGROUND: Our knowledge of the incidence and prevalence of inflammatory bowel disease (IBD) is uncertain. Recent studies reported an increase in prevalence. However, they excluded a high proportion of ambiguous cases from general practice. Estimates are needed to inform health care providers who plan the provision of services for IBD patients. We aimed to estimate the IBD incidence and prevalence in UK general practice. METHODS: We undertook a retrospective cohort study of routine electronic health records from the IQVIA Medical Research Database covering 14 million patients. Adult patients from 2006 to 2016 were included. IBD was defined as an IBD related Read code or record of IBD specific medication. Annual incidence and 12-month period prevalence were calculated. RESULTS: The prevalence of IBD increased between 2006 and 2016 from 106.2 (95% CI 105.2-107.3) to 142.1 (95% CI 140.7-143.5) IBD cases per 10,000 patients which is a 33.8% increase. Incidence varied across the years. The incidence across the full study period was 69.5 (95% CI 68.6-70.4) per 100,000 person years. CONCLUSIONS: In this large study we found higher estimates of IBD incidence and prevalence than previously reported. Estimates are highly dependent on definitions of disease and previously may have been underestimated.

Classification of Tea Aromas Using Multi-Nanoparticle Based Chemiresistor Arrays.

Nanoparticle based chemical sensor arrays with four types of organo-functionalized gold nanoparticles (AuNPs) were introduced to classify 35 different teas, including black teas, green teas, and herbal teas. Integrated sensor arrays were made using microfabrication methods including photolithography and lift-off processing. Different types of nanoparticle solutions were drop-cast on separate active regions of each sensor chip. Sensor responses, expressed as the ratio of resistance change to baseline resistance (ΔR/R0), were used as input data to discriminate different aromas by statistical analysis using multivariate techniques and machine learning algorithms. With five-fold cross validation, linear discriminant analysis (LDA) gave 99% accuracy for classification of all 35 teas, and 98% and 100% accuracy for separate datasets of herbal teas, and black and green teas, respectively. We find that classification accuracy improves significantly by using multiple types of nanoparticles compared to single type nanoparticle arrays. The results suggest a promising approach to monitor the freshness and quality of tea products.

Preferred Reporting Items for a Systematic Review and Meta-analysis of Diagnostic Test Accuracy Studies: The PRISMA-DTA Statement.

Importance: Systematic reviews of diagnostic test accuracy synthesize data from primary diagnostic studies that have evaluated the accuracy of 1 or more index tests against a reference standard, provide estimates of test performance, allow comparisons of the accuracy of different tests, and facilitate the identification of sources of variability in test accuracy. Objective: To develop the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) diagnostic test accuracy guideline as a stand-alone extension of the PRISMA statement. Modifications to the PRISMA statement reflect the specific requirements for reporting of systematic reviews and meta-analyses of diagnostic test accuracy studies and the abstracts for these reviews. Design: Established standards from the Enhancing the Quality and Transparency of Health Research (EQUATOR) Network were followed for the development of the guideline. The original PRISMA statement was used as a framework on which to modify and add items. A group of 24 multidisciplinary experts used a systematic review of articles on existing reporting guidelines and methods, a 3-round Delphi process, a consensus meeting, pilot testing, and iterative refinement to develop the PRISMA diagnostic test accuracy guideline. The final version of the PRISMA diagnostic test accuracy guideline checklist was approved by the group. Findings: The systematic review (produced 64 items) and the Delphi process (provided feedback on 7 proposed items; 1 item was later split into 2 items) identified 71 potentially relevant items for consideration. The Delphi process reduced these to 60 items that were discussed at the consensus meeting. Following the meeting, pilot testing and iterative feedback were used to generate the 27-item PRISMA diagnostic test accuracy checklist. To reflect specific or optimal contemporary systematic review methods for diagnostic test accuracy, 8 of the 27 original PRISMA items were left unchanged, 17 were modified, 2 were added, and 2 were omitted. Conclusions and Relevance: The 27-item PRISMA diagnostic test accuracy checklist provides specific guidance for reporting of systematic reviews. The PRISMA diagnostic test accuracy guideline can facilitate the transparent reporting of reviews, and may assist in the evaluation of validity and applicability, enhance replicability of reviews, and make the results from systematic reviews of diagnostic test accuracy studies more useful.

Visual and radiographic caries detection: a tailored meta-analysis for two different settings, Egypt and Germany.

BACKGROUND: Diagnostic meta-analyses on caries detection methods should assist practitioners in their daily practice. However, conventional meta-analysis estimates may be inapplicable due to differences in test conduct, applied thresholds and assessed population between settings. Our aim was to demonstrate the impact of tailored meta-analysis of visual and radiographic caries detection to different settings using setting-specific routine data. METHODS: Published systematic reviews and meta-analyses on the accuracy of visual and radiographic caries detection were used. In two settings (a private practice in Germany and a public health clinic in Egypt), routine data of a total of 100 (n = 50/practice) consecutive 12-14 year-olds were collected. Test-positive rates of visual and radiographic detection for initial and advanced carious lesions on occlusal or proximal surfaces of molars were used to tailor meta-analyses. If prevalence data were available, these were also used for tailoring. RESULTS: From the original reviews, 210 and 100 heterogeneous studies on visual and radiographic caries detection were included in our meta-analyses. For radiographic detection, sensitivity and specificity estimates derived from conventional and tailored meta-analysis were similar. For visual detection of advanced occlusal carious lesions, the conventional meta-analysis yielded a sensitivity and specificity (95% CI) of 64.6% (57-71) and 90.9% (88-93), whereas the tailored estimates for Egypt were 75.1% (70-81) and 84.9% (82-89), respectively, and 43.7% (37-51) and 96.5% (95-97) for Germany, respectively. CONCLUSION: Conventional test accuracy meta-analyses may yield aggregate estimates which are inapplicable to specific settings. Routine data may be used to produce a meta-analysis estimate which is tailored to the setting and thereby improving its applicability.

Type 1 diabetes mellitus and risk of incident epilepsy: a population-based, open-cohort study.

AIMS/HYPOTHESIS: The aim of this research was to explore the relationship between incident epilepsy and type 1 diabetes in British participants. METHODS: Using The Health Improvement Network database, we conducted a retrospective, open-cohort study. Patients who were newly diagnosed with type 1 diabetes mellitus at the age of ≤40 years were identified and followed-up from 1 January 1990 to 15 September 2015. These patients, identified as not suffering from epilepsy at the time of diagnosis, were randomly matched with up to four individuals without type 1 diabetes mellitus, based on age, sex and participating general practice. A Cox regression analysis was subsequently performed using Townsend deprivation index, cerebral palsy, head injury and learning disabilities as model covariates. RESULTS: The study population consisted of a total of 24,610 individuals (4922 with type 1 diabetes and 19,688 controls). These individuals were followed up for a mean of 5.4 years (approximately 132,000 person-years of follow up). Patients with type 1 diabetes were significantly more likely to be diagnosed with epilepsy during the observation period compared with controls (crude HR [95% CI]: 3.02 [1.95, 4.69]). The incidence rate was estimated to be 132 and 44 per 100,000 person-years in patients and controls, respectively. This finding persisted after adjusting for model covariates (adjusted HR [95% CI]: 3.01 [1.93, 4.68]) and was also robust to sensitivity analysis, excluding adult-onset type 1 diabetes mellitus. CONCLUSIONS/INTERPRETATION: Patients with type 1 diabetes are at approximately three-times greater risk of developing epilepsy compared with matched controls without type 1 diabetes. This should be considered when investigating seizure-related disorders in patients with type 1 diabetes mellitus.

Mismatch repair status and PD-L1 expression in clear cell carcinomas of the ovary and endometrium.

Clear cell carcinoma represents a distinct histologic type of müllerian carcinoma that is resistant to conventional chemotherapy. Expression of programmed cell death ligand (PD-L1) has been associated with immune evasion in numerous tumor types and may be used to identify patients who will benefit from targeted immunotherapy, particularly in the setting of mismatch repair defects. We evaluated PD-L1 expression in 23 ovarian clear cell carcinomas and 21 endometrial clear cell carcinomas, and correlated expression with mismatch repair status. Tumor PD-L1 staining was seen in 43% of ovarian tumors and 76% of endometrial tumors, including 71% of cases (67% of ovarian and 75% of endometrial) with mismatch repair defects. Extensive tumoral staining (>50%) was seen in only one case (an endometrial case with MSH6 loss). However, tumoral PD-L1 expression remained common in mismatch repair-intact tumors and mismatch repair status was not significantly correlated with PD-L1 expression. The increased incidence of PD-L1 positivity in tumor cells (P=0.04) in endometrial vs ovarian clear cell carcinomas suggests differences in the tumor microenvironment of these histologically and molecularly similar tumors that may inform treatment options. These results suggest that clear cell histology may be a useful susceptibility marker for immunotherapy targeting the PD-1/PD-L1 axis irrespective of mismatch repair status, particularly in endometrial carcinomas.

Measuring the statistical validity of summary meta-analysis and meta-regression results for use in clinical practice.

An important question for clinicians appraising a meta-analysis is: are the findings likely to be valid in their own practice-does the reported effect accurately represent the effect that would occur in their own clinical population? To this end we advance the concept of statistical validity-where the parameter being estimated equals the corresponding parameter for a new independent study. Using a simple ('leave-one-out') cross-validation technique, we demonstrate how we may test meta-analysis estimates for statistical validity using a new validation statistic, Vn, and derive its distribution. We compare this with the usual approach of investigating heterogeneity in meta-analyses and demonstrate the link between statistical validity and homogeneity. Using a simulation study, the properties of Vn and the Q statistic are compared for univariate random effects meta-analysis and a tailored meta-regression model, where information from the setting (included as model covariates) is used to calibrate the summary estimate to the setting of application. Their properties are found to be similar when there are 50 studies or more, but for fewer studies Vn has greater power but a higher type 1 error rate than Q. The power and type 1 error rate of Vn are also shown to depend on the within-study variance, between-study variance, study sample size, and the number of studies in the meta-analysis. Finally, we apply Vn to two published meta-analyses and conclude that it usefully augments standard methods when deciding upon the likely validity of summary meta-analysis estimates in clinical practice. © 2017 The Authors. Statistics in Medicine published by John Wiley & Sons Ltd.

The potent BACE1 inhibitor LY2886721 elicits robust central Aß pharmacodynamic responses in mice, dogs, and humans.

BACE1 is a key protease controlling the formation of amyloid ß, a peptide hypothesized to play a significant role in the pathogenesis of Alzheimer's disease (AD). Therefore, the development of potent and selective inhibitors of BACE1 has been a focus of many drug discovery efforts in academia and industry. Herein, we report the nonclinical and early clinical development of LY2886721, a BACE1 active site inhibitor that reached phase 2 clinical trials in AD. LY2886721 has high selectivity against key off-target proteases, which efficiently translates in vitro activity into robust in vivo amyloid ß lowering in nonclinical animal models. Similar potent and persistent amyloid ß lowering was observed in plasma and lumbar CSF when single and multiple doses of LY2886721 were administered to healthy human subjects. Collectively, these data add support for BACE1 inhibition as an effective means of amyloid lowering and as an attractive target for potential disease modification therapy in AD.

Causes of maternal and child mortality among Cambodian sex workers and their children: a cross sectional study.

BACKGROUND: To reach global and national goals for maternal and child mortality, countries must identify vulnerable populations, which includes sex workers and their children. The objective of this study was to identify and describe maternal deaths of female sex workers in Cambodia and causes of death among their children. METHODS: A convenience sample of female sex workers were recruited by local NGOs that provide support to sex workers. We modified the maternal mortality section of the 2010 Cambodia Demographic and Health Survey and collected reports of all deaths of female sex workers. For each death we ask the 'sisterhood' methodology questions to identify maternal deaths. For child deaths we asked each mother who reported the death of a child about the cause of death. We also asked all participants about the cause of deaths of children of other female sex workers. RESULTS: We interviewed 271 female sex workers in the four largest Cambodian cities between May and September 2013. Participants reported 32 deaths of other female sex workers that met criteria for maternal death. The most common reported causes of maternal deaths were abortion (n = 13;40%) and HIV (n = 5;16%). Participants report deaths of 8 of their children and 50 deaths of children of other female sex workers. HIV was the reported cause of death for 13 (36%) children under age five. CONCLUSION: This is the first report of maternal deaths of sex workers in Cambodia or any other country. This modification of the sisterhood methodology has not been validated and did not allow us to calculate maternal mortality rates so the results are not generalizable, however these deaths may represent unrecognized maternal deaths in Cambodia. The results also indicate that children of sex workers in Cambodia are at risk of HIV and may not be accessing treatment. These issues require additional studies but in the meantime we must assure that sex workers in Cambodia and their children have access to quality health services.

Two Case Reports of Nodular Fasciitis: A Newly Recognized Placental Lesion.

We describe two occurrences of nontrophoblastic mesenchymal tumors of the placenta. The first placental tumor was found along the placental margin, and the second was identified close to the insertion of the fetal membranes along the placental disc. Microscopically both lesions demonstrated bland fibroblastic cells with intricate vasculature and inflammatory cells. Both lesions were negative for estrogen receptor (ER), progesterone receptor (PR), beta-HCG, PLAP, CD34, desmin, h-caldesmin, and smooth muscle actin by immunohistochemistry. Some cells were weakly positive for CD10, a nonspecific finding. The morphologic and immunohistochemical characteristics of these lesions were most consistent with nodular fasciitis, a tumor most commonly found in the soft tissues. FISH positive for USP6 gene rearrangement in our two patients confirmed the molecular similarity of these lesions to nodular fasciitis of soft tissue. Such lesions can be easily dismissed on gross placental examination as infarcts or thrombi, thus these rare entities are likely underreported.

Summarising and validating test accuracy results across multiple studies for use in clinical practice.

Following a meta-analysis of test accuracy studies, the translation of summary results into clinical practice is potentially problematic. The sensitivity, specificity and positive (PPV) and negative (NPV) predictive values of a test may differ substantially from the average meta-analysis findings, because of heterogeneity. Clinicians thus need more guidance: given the meta-analysis, is a test likely to be useful in new populations, and if so, how should test results inform the probability of existing disease (for a diagnostic test) or future adverse outcome (for a prognostic test)? We propose ways to address this. Firstly, following a meta-analysis, we suggest deriving prediction intervals and probability statements about the potential accuracy of a test in a new population. Secondly, we suggest strategies on how clinicians should derive post-test probabilities (PPV and NPV) in a new population based on existing meta-analysis results and propose a cross-validation approach for examining and comparing their calibration performance. Application is made to two clinical examples. In the first example, the joint probability that both sensitivity and specificity will be >80% in a new population is just 0.19, because of a low sensitivity. However, the summary PPV of 0.97 is high and calibrates well in new populations, with a probability of 0.78 that the true PPV will be at least 0.95. In the second example, post-test probabilities calibrate better when tailored to the prevalence in the new population, with cross-validation revealing a probability of 0.97 that the observed NPV will be within 10% of the predicted NPV.

Modeling and simulations to confirm a controlled hypoglycemic stress test in healthy subjects is not associated with clinically significant QT prolongations.

OBJECTIVES: A modified insulin tolerance test (ITT) can be used to simulate a physiological stress state through the induction of controlled hypoglycemia in healthy volunteers. This allows for evaluation of hypothalamic-pituitary-adrenocortical axis response to stress via a surge in cortical release. However, a consequence of severe, prolonged hypoglycemia is QT interval prolongation. The aim of this analysis was to confirm that blood glucose lowering to 60 mg/dL (previously identified as adequate for inducing stress) has low risk of inducing clinically significant QT prolongation. MATERIALS AND METHODS: Continuous ECG monitoring was conducted as a planned sub study of an open-label, 2-period study involving 18 healthy male subjects. The QTcF response to hypoglycemia was measured over 2 identical periods, ~ 7 days apart. RESULTS: An indirect- response model adequately described the pharmacological relationship between blood glucose and QTcF intervals over the time-course of the ITT. The model correctly identified the steep glucose-QT relationship as an on-off response with a large Hill coefficient of 59 and the threshold glucose, EC50, as ~ 57 mg/dL with narrow between-subject variability of 10%. Simulated QTcF profiles over the course of an ITT did not demonstrate any QTcF interval changes of clinical concern, defined as QTcF observation > 500 ms, if hypoglycemia did not reach below 60 mg/dL. The statistical prediction that the chance of a mean QTcF observation > 500 ms was < 0.0001. CONCLUSIONS: Results support that an ITT maintained at or above 60 mg/dL is unlikely to cause QT prolongation in healthy volunteers and does not warrant continuous ECG monitoring in this group of subjects.

Causes of preventable death among children of female sex worker mothers in low- and middle-income countries: A community knowledge approach investigation.

Background: Female sex workers (FSW) in low- and middle-income countries (LMIC) are disproportionately vulnerable to poor health, social, and economic outcomes. The children of female sex workers (CFSW) experience health risks based on these challenging circumstances and the unique conditions to which they are exposed. Although country child mortality data exist, little is known about the causes of death among CFSW specifically, thereby severely limiting an effective public health response to the needs of this high-risk group of children. Methods: The Community Knowledge Approach (CKA) was employed between January and October 2019 to survey a criterion sample of 1280 FSW participants across 24 cities in eight LMIC countries. Participants meeting pre-determined criteria provided detailed reports of deaths among the CFSW within their community of peers. Newborn deaths were gleaned from FSW maternal death reports where the infants also died following birth. Results: Of the 668 child deaths reported, 589 were included in the analysis. Nutritional deficiencies comprised the leading cause of mortality accounting for 20.7% of deaths, followed closely by accidents (20.0%), particularly house fires, overdoses (19.4%), communicable diseases (18.5%), and homicides (9.8%). Other reported causes of death included neonatal conditions, respiratory illnesses, and suicides. Conclusions: The causes of CFSW death in these eight countries are preventable with improved protections. Governments, intergovernmental organisations like the United Nations, nongovernmental stakeholder organisations (e.g. sex worker organisations), and funders can implement targeted policies and programmes to protect CFSW and assist vulnerable FSW who are pregnant and raising children. Further research is needed to identify effective child welfare safeguards for CFSW.

DNA gold nanoparticle nanocomposite films for chemiresistive vapor sensing.

Chemiresistive vapor sensors combining functionalized gold nanoparticles and single-stranded DNA oligomers are investigated to enhance specificity in chemical sensing. Sensors are made by depositing DNA-functionalized gold nanoparticles onto microfabricated electrodes using four distinct sequences. Sensor performance is evaluated for response to relative humidity and exposure to vapor analytes including ethanol, methanol, hexane, dimethyl methylphosphonate, and toluene under different relative humidity. It is found that sensors display a nonmonotonic resistance change toward increasing humidity due to the combined effects of hydration induced swelling and ionic conduction. Responses to vapor analytes show sequence-dependent patterns as well as a strong influence of humidity. Overall, the findings are encouraging for using DNA oligomers to enhance specificity in chemical sensing.

Subscale validation of the neuropsychiatric inventory questionnaire: comparison of Alzheimer's disease neuroimaging initiative and national Alzheimer's coordinating center cohorts.

OBJECTIVE: Neuropsychiatric symptoms are prevalent in mild cognitive impairment (MCI) and Alzheimer disease (AD) and commonly measured using the Neuropsychiatric Inventory (NPI). Based on existing exploratory literature, we report preliminary validation of three NPI Questionnaire (NPI-Q-10) subscales that measure clinically meaningful symptom clusters. METHODS: Cross-sectional results for three subscales (NPI-Q-4-Frontal, NPI-Q-4-Agitation/Aggression, NPI-Q-3-Mood) in amnestic MCI and AD dementia cases from the National Alzheimer's Coordinating Center (NACC) and Alzheimer's Disease Neuroimaging Initiative (ADNI) databases were analyzed using confirmatory unrotated principal component analysis. RESULTS: ADNI contributed 103 MCI, 90 MCI converters, and 112 AD dementia cases, whereas NACC contributed 1,042 MCI, 763 MCI converters, and 3,048 AD dementia cases. NACC had higher baseline mean age (75.7 versus 74.6), and more impaired mean scores (at month 24) on Mini-Mental State Exam (19.5 versus 22.4) and NPI-Q-10 (5.0 versus 4.3), and all NPI-Q subscales than ADNI. Medians were not different between cohorts for NPI-Q-4-Agitation/Aggression, and NPI-Q-3-Mood, however. Each item on all scales/subscales contributed variance in principal component analysis Pareto plots. All items in Factor (F) 1 for each scale/subscale projected in a positive direction on biplots (revealing coherence), whereas F2 and F3 items showed more spatial separation (revealing independence). There were remarkable similarities between cohorts for factor loadings and spatial patterns of item projections, although factor item identities varied somewhat, especially beyond F1. CONCLUSION: The similar pattern of results across two cohorts support validity of these subscales, which are worthy of further psychometric evaluation in MCI and AD patients and preliminary application in clinical settings.