Subtyping cognitive profiles in Autism Spectrum Disorder using a Functional Random Forest algorithm.

DSM-5 Autism Spectrum Disorder (ASD) comprises a set of neurodevelopmental disorders characterized by deficits in social communication and interaction and repetitive behaviors or restricted interests, and may both affect and be affected by multiple cognitive mechanisms. This study attempts to identify and characterize cognitive subtypes within the ASD population using our Functional Random Forest (FRF) machine learning classification model. This model trained a traditional random forest model on measures from seven tasks that reflect multiple levels of information processing. 47 ASD diagnosed and 58 typically developing (TD) children between the ages of 9 and 13 participated in this study. Our RF model was 72.7% accurate, with 80.7% specificity and 63.1% sensitivity. Using the random forest model, the FRF then measures the proximity of each subject to every other subject, generating a distance matrix between participants. This matrix is then used in a community detection algorithm to identify subgroups within the ASD and TD groups, and revealed 3 ASD and 4 TD putative subgroups with unique behavioral profiles. We then examined differences in functional brain systems between diagnostic groups and putative subgroups using resting-state functional connectivity magnetic resonance imaging (rsfcMRI). Chi-square tests revealed a significantly greater number of between group differences (p < .05) within the cingulo-opercular, visual, and default systems as well as differences in inter-system connections in the somato-motor, dorsal attention, and subcortical systems. Many of these differences were primarily driven by specific subgroups suggesting that our method could potentially parse the variation in brain mechanisms affected by ASD.

Association between Giardia and arthritis or joint pain in a large health insurance cohort: could it be reactive arthritis?

This study aimed to assess the association between giardiasis and subsequent development of arthritis or joint pain using a retrospective cohort of individuals from a large administrative claims database in the United States. Using 2006-2010 data from MarketScan Commercial Claims and Encounters, we conducted a retrospective cohort study in people with an ICD-9-CM code for giardiasis (n = 3301) and persons without giardiasis (n = 14 612) individually matched on age, sex, and enrolment length. We used conditional logistic regression to model the association between giardiasis and arthritis or joint pain documented in the 6 months following initial giardiasis diagnosis or index date for matched controls. After adjusting for healthcare utilization rate, giardiasis was associated with a 51% increase in claims for arthritis or joint pain (odds ratio 1·51, 95% confidence interval 1·26-1·80). In age- and sex-stratified adjusted analyses, the association remained significant across all subgroups (age 0-19 years, age 20-64 years, males, and females). Findings from this study lend epidemiological support for the association between giardiasis and subsequent development of arthritis. Reactive arthritis might occur more frequently than has been reported in the literature. Further research is necessary to determine the mechanisms by which giardiasis could lead to arthritis.

Evolving epidemiology of reported cryptosporidiosis cases in the United States, 1995-2012.

Cryptosporidium is the leading aetiology of waterborne disease outbreaks in the United States. This report briefly describes the temporal and geographical distribution of US cryptosporidiosis cases and presents analyses of cryptosporidiosis case data reported in the United States for 1995-2012. The Cochran-Armitage test was used to assess changes in the proportions of cases by case status (confirmed vs. non-confirmed), sex, race, and ethnicity over the study period. Negative binomial regression models were used to estimate rate ratios (RR) and 95% confidence intervals (CI) for comparing rates across three time periods (1995-2004, 2005-2008, 2009-2012). The proportion of confirmed cases significantly decreased (P < 0·0001), and a crossover from male to female predominance in case-patients occurred (P < 0·0001). Overall, compared to 1995-2004, rates were higher in 2005-2008 (RR 2·92, 95% CI 2·08-4·09) and 2009-2012 (RR 2·66, 95% CI 1·90-3·73). However, rate changes from 2005-2008 to 2009-2012 varied by age group (P interaction < 0·0001): 0-14 years (RR 0·55, 95% CI 0·42-0·71), 15-44 years (RR 0·99, 95% CI 0·82-1·19), 45-64 years (RR 1·47, 95% CI 1·21-1·79) and ⩾65 years (RR 2·18, 95% CI 1·46-3·25). The evolving epidemiology of cryptosporidiosis necessitates further identification of risk factors in population subgroups. Adding systematic molecular typing of Cryptosporidium specimens to US national cryptosporidiosis surveillance would help further identify risk factors and markedly expand understanding of cryptosporidiosis epidemiology in the United States.

Development and validation of the Learning Disabilities Needs Assessment Tool (LDNAT), a HoNOS-based needs assessment tool for use with people with intellectual disability.

BACKGROUND: In meeting the needs of individuals with intellectual disabilities (ID) who access health services, a brief, holistic assessment of need is useful. This study outlines the development and testing of the Learning Disabilities Needs Assessment Tool (LDNAT), a tool intended for this purpose. METHOD: An existing mental health (MH) tool was extended by a multidisciplinary group of ID practitioners. Additional scales were drafted to capture needs across six ID treatment domains that the group identified. LDNAT ratings were analysed for the following: item redundancy, relevance, construct validity and internal consistency (n = 1692); test-retest reliability (n = 27); and concurrent validity (n = 160). RESULTS: All LDNAT scales were deemed clinically relevant with little redundancy apparent. Principal component analysis indicated three components (developmental needs, challenging behaviour, MH and well-being). Internal consistency was good (Cronbach alpha 0.80). Individual item test-retest reliability was substantial-near perfect for 20 scales and slight-fair for three scales. Overall reliability was near perfect (intra-class correlation = 0.91). There were significant associations with five of six condition-specific measures, i.e. the Waisman Activities of Daily Living Scale (general ability/disability), Threshold Assessment Grid (risk), Behaviour Problems Inventory for Individuals with Intellectual Disabilities-Short Form (challenging behaviour) Social Communication Questionnaire (autism) and a bespoke physical health questionnaire. Additionally, the statistically significant correlations between these tools and the LDNAT components made sense clinically. There were no statistically significant correlations with the Psychiatric Assessment Schedules for Adults with Developmental Disabilities (a measure of MH symptoms in people with ID). CONCLUSIONS: The LDNAT had clinically utility when rating the needs of people with ID prior to condition-specific assessment(s). Analyses of internal and external validity were promising. Further evaluation of its sensitivity to changes in needs is now required.

Pre-existing medical conditions associated with Vibrio vulnificus septicaemia.

Vibrio vulnificus (Vv) can result in severe disease. Although pre-existing liver disease is a recognized risk factor for serious infection, the relative importance of other comorbidities has not been fully assessed. We analysed reports of Vv infections submitted to CDC from January 1988 to September 2006 in order to assess the role of pre-existing conditions contributing to severe outcomes. A total of 1212 patients with Vv infection were reported. Only patients with liver disease [adjusted odds ratio (aOR) 5.1)] were more likely to become septic when exposure was due to contaminated food. Patients with liver disease (aOR 4.1), a haematological disease (aOR 3.2), or malignancy (aOR 3.2) were more likely to become septic when infection was acquired via a non-foodborne exposure. As such, patients with these pre-existing medical conditions should be advised of the risk of life-threatening illness after eating undercooked contaminated seafood or exposing broken skin to warm seawater.

Optimal skin simulant for ballistic testing.

An extensive literature review, combined with practical experience of forensic testing, has identified several concerns regarding existing studies into skin simulants. These can be summarised as arising due to human skin being a highly complex, multi-layered and anisotropic material whose mechanical properties depend on many factors such as age and gender of the host. In many studies (and papers) essential information is missing. Although there is some parallelism between the studies, the reported energy density at perforation is very inconsistent (a function of the natural variation of skin properties alluded to above) and differs from 0,113 J/mm2 [1] to 0,239 J/mm2 [2]. Which is, in fact, a more than 100 % variation. Such a variation is arguably insufficient to enable accurate replication with a single simulant material. Combined with the missing common agreement about the energy density threshold between countries, laboratories and researchers, this analysis clearly identifies the need for an adjustable and / or customizable skin simulant. To-date, the most often used simulation material for human skin in ballistic testing is 'Chrome crusted cow hide' [3]. However, this is a natural material and, consequently therefore, inevitably physically variable in nature - both inter and intra hide. Ballistic tests on 10 chrome crusted cow hides using 4,5 mm BB's gave v50% ranging from 113 m/s to 200 m/s, an uncontrolled variability for forensic experiments. Hence, the authors examined a skin analogue that could be produced in-house, enabling tailoring to match the desired properties, and with improved consistency. To this end, a thin, 4 mm thick, layer of gelatine (30 - 45 wt%, increasing per 1 wt%) was studied. The ballistic resistance of the gelatine skin analogue was compared to the v50%'s published values in literature, with good agreement found as the gelatine concentration was varied. In comparison to the chrome crusted cow hides this suggests that this relatively simple and accessible approach has potential to provide a more consistent standard.

Inhibition of transforming growth factor-ß-activated kinase-1 blocks cancer cell adhesion, invasion, and metastasis.

BACKGROUND: Tumour cell metastasis involves cell adhesion and invasion, processes that depend on signal transduction, which can be influenced by the tumour microenvironment. N-6 polyunsaturated fatty acids, found both in the diet and in response to inflammatory responses, are important components of this microenvironment. METHODS: We used short hairpin RNA (shRNA) knockdown of TGF-ß-activated kinase-1 (TAK1) in human tumour cells to examine its involvement in fatty acid-stimulated cell adhesion and invasion in vitro. An in vivo model of metastasis was developed in which cells, stably expressing firefly luciferase and either a control shRNA or a TAK1-specific shRNA, were injected into the mammary fat pads of mice fed diets, rich in n-6 polyunsaturated fatty acids. Tumour growth and spontaneous metastasis were monitored with in vivo and in situ imaging of bioluminescence. RESULTS: Arachidonic acid activated TAK1 and downstream kinases in MDA-MB-435 breast cancer cells and led to increased adhesion and invasion. Knockdown of TAK1 blocked this activation and inhibited both cell adhesion and invasion in vitro. Tumour growth at the site of injection was not affected by TAK1 knockdown, but both the incidence and extent of metastasis to the lung were significantly reduced in mice injected with TAK1 knockdown cells compared with mice carrying control tumour cells. CONCLUSION: These data demonstrate the importance of TAK1 signalling in tumour metastasis in vivo and suggest an opportunity for antimetastatic therapies.

Immunohistochemical features of 3,3',4,4'-tetrachloroazobenzene-induced rat gingival lesions.

Gingival lesions of squamous hyperplasia, cystic keratinizing hyperplasia (CKH), and squamous cell carcinoma (SCC) can be induced in rats treated by chronic gavage with 10-100 mg/kg 3,3',4,4'-tetrachloroazobenzene. We evaluated gingival squamous hyperplasia (GSH), CKH, and SCC for the immunohistochemical pattern of expression of carcinogenesis-associated markers. The 3 types of lesions and controls were stained with proliferation markers (proliferating cell nuclear antigen [PCNA] and cyclin-D1), tumor-suppressor markers (ß-catenin and mammary serine protease inhibitor [maspin]) and stroma-related markers (α-smooth muscle actin [SMA] and osteonectin/SPARC). The lesions had common immunohistochemical characteristics that differed in their expression patterns among the various diagnoses. PCNA and cyclin-D1 expression was higher in GSH, CKH, and SCC than in controls. The normal membranous expression of ß-catenin was lower in GSH, and almost absent in CKH and SCC. Maspin expression was similar in GSH and controls, whereas both CKH and SCC showed decreased expression. SMA and/or osteonectin/SPARC were seen in stromal cells in CKH and SCC. Collectively, there appears to be a progression from hyperplastic and cystic lesions toward malignancy based on the morphological changes, supported by the expression of carcinogenesis-associated proteins. The exact sequence of events leading to SCC remains to be defined in a time-dependent manner.

Intestinal lymphangiectasis and lipidosis in rats following subchronic exposure to indole-3-carbinol via oral gavage.

To investigate the toxicity and carcinogenic potential of indole-3-carbinol (I3C), the National Toxicology Program has conducted 13-week subchronic studies in Fisher 344 rats and B6C3F1 mice, and chronic 2-year bioassays in Sprague-Dawley rats and B6C3F1 mice. While the chronic study results are not yet available, subchronic study results and short-term special evaluations of interim sacrifices in the 2-year rat bioassay are presented. F344 rats were orally gavaged ≤300 mg I3C/kg body weight 5 days a week for 13 weeks. Rats treated with ≥150 mg/kg demonstrated a dose-related dilation of lymphatics (lymphangiectasis) of the duodenum, jejunum, and mesenteric lymph nodes. Material within dilated lacteals stained positively for Oil Red O and Sudan Black, consistent with lipid. Electron microscopic evaluation confirmed extracellular lipid accumulation within the villar lamina propria, lacteals, and within villar macrophages. Analyses of hepatic and pulmonary CYP1A enzymes demonstrated dose-dependent I3C induction of CYP1A1 and 1A2. B6C3F1 mice orally gavaged ≤250 mg I3C/kg body weight did not demonstrate histopathological changes; however, hepatic CYP induction was similar to that in rats. The histopathologic changes of intestinal lymphangiectasis and lipidosis in this study share similarities with intestinal lymphangiectasia as observed in humans and dogs. However, the resultant clinical spectrum of protein-losing enteropathy was not present.

The effect of pistachio shells as a visual cue in reducing caloric consumption.

UNLABELLED: It was hypothesized that pistachio shells left in sight as visual cues of consumption will cause individuals to consume less. A convenience sample of faculty and staff at a mid-western university (n=118) were recruited as subjects for the study. The subjects were told they were going to evaluate a variety of brands of pistachios and were surveyed at the end of each day to determine their fullness and satisfaction. The subjects were offered pistachios on their desks for an 8-h period on two separate days and were able to consume the pistachios at their leisure during that time. Subjects began each day with a sixteen ounce bowl filled with four ounces of pistachios in the shell. They were also provided with a second sixteen ounce bowl, in which they were instructed to place the empty shells from the pistachios they consumed. Every 2 h throughout the day pistachios were added in two ounce increments. In condition one, the shells remained in the bowls until the end of the day, whereas in condition two, the shell bowls were emptied every 2 h throughout the day. In condition one, subjects consumed an average of 216 calories. In condition two, subjects consumed an average of 264 calories, a difference of 48 calories. Subjects in condition one consumed significantly (p≤.05) fewer calories, yet fullness and satisfaction ratings were not significantly (p≥.05) different between conditions. Leaving pistachio shells as a visual cue to consumption may help consumers consume fewer calories. LEARNING OUTCOMES: Individuals will be aware of the impact of visual cues of dietary intake on total food consumption.

Useful immunohistochemical markers of tumor differentiation.

Immunohistochemistry (IHC) has been somewhat underutilized in the practice of toxicological pathology but can be a valuable tool for the evaluation of rodent neoplasms, both in a diagnostic and an investigational role. Determining an exact tumor type using standard hematoxylin and eosin (H&E) staining of formalin-fixed tissues can be challenging, especially with metastatic and/or poorly differentiated tumors. Successful IHC is dependent on many factors, including species and tissue type, type and duration of fixation, quality fresh or frozen sectioning, and antibody specificity. The initial approach of most tumor diagnosis IHC applications is distinguishing epithelial from mesenchymal differentiation using vimentin and cytokeratin markers, although false-negative and/or false-positive results may occur. Experimentally, IHC can be employed to investigate the earliest changes in transformed tissues, identifying cellular changes not normally visible with H&E. Individual markers for proliferation, apoptosis, and specific tumor proteins can be used to help distinguish hyperplasia from neoplasia and determine specific tumor origin/type. IHC provides a relatively rapid and simple method to better determine the origin of neoplastic tissue or investigate the behavior or progression of a given neoplasm. Several experimental and diagnostic examples will be presented to illustrate the utility of IHC as a supplement to standard staining techniques.

Genome-wide association and epidemiological analyses reveal common genetic origins between uterine leiomyomata and endometriosis.

Uterine leiomyomata (UL) are the most common neoplasms of the female reproductive tract and primary cause for hysterectomy, leading to considerable morbidity and high economic burden. Here we conduct a GWAS meta-analysis in 35,474 cases and 267,505 female controls of European ancestry, identifying eight novel genome-wide significant (P < 5 × 10-8) loci, in addition to confirming 21 previously reported loci, including multiple independent signals at 10 loci. Phenotypic stratification of UL by heavy menstrual bleeding in 3409 cases and 199,171 female controls reveals genome-wide significant associations at three of the 29 UL loci: 5p15.33 (TERT), 5q35.2 (FGFR4) and 11q22.3 (ATM). Four loci identified in the meta-analysis are also associated with endometriosis risk; an epidemiological meta-analysis across 402,868 women suggests at least a doubling of risk for UL diagnosis among those with a history of endometriosis. These findings increase our understanding of genetic contribution and biology underlying UL development, and suggest overlapping genetic origins with endometriosis.

Prevalence and clinical association of clonal T-cell expansions in Myelodysplastic Syndrome.

Selected patients with Myelodysplastic Syndromes (MDS) are responsive to immunosuppressive therapy, suggesting that hematopoietic suppressive T cells have a pathogenic role in ineffective hematopoiesis. We assessed T-cell receptor (TCR) clonality through combined flow cytometry and molecular analysis of the complementarity determining region (CDR)-3 of the T-cell receptor-Vbeta gene. We identified clonal T cells in 50% of MDS patients (n=52) compared to 5% of age-matched normal controls (n=20). The presence of T-cell clones was not associated with features linked previously to immunosuppression response, including WHO diagnostic category, karyotype, marrow cellularity, IPSS category, sex or age

On differences in the equation-of-state for a selection of seven representative mammalian tissue analogue materials.

Tissue analogues employed for ballistic purposes are often monolithic in nature, e.g. ballistic gelatin and soap, etc. However, such constructs are not representative of real-world biological systems. Further, ethical considerations limit the ability to test with real-world tissues. This means that availability and understanding of accurate tissue simulants is of key importance. Here, the shock response of a wide range of ballistic simulants (ranging from dermal (protective/bulk) through to skeletal simulant materials) determined via plate-impact experiments are discussed, with a particular focus on the classification of the behaviour of differing simulants into groups that exhibit a similar response under high strain-rate loading. Resultant Hugoniot equation-of-state data (Us-up; P-v) provides appropriate feedstock materials data for future hydrocode simulations of ballistic impact events.

Economic analysis of CDC's culture- and smear-based tuberculosis instructions for Filipino immigrants.

SETTING: In 2007, the US Centers for Disease Control and Prevention (CDC) revised its tuberculosis (TB) technical instructions for panel physicians who administer mandatory medical examinations among US-bound immigrants. Many US-bound immigrants come from the Philippines, a high TB prevalence country. OBJECTIVE: To quantify economic and health impacts of smear- vs. culture-based TB screening. DESIGN: Decision tree modeling was used to compare three Filipino screening programs: 1) no screening, 2) smear-based screening, and 3) culture-based screening. The model incorporated pre-departure TB screening results from Filipino panel physicians and CDC databases with post-arrival follow-up outcomes. Costs (2013 $US) were examined from societal, immigrant, US Public Health Department and hospitalization perspectives. RESULTS: With no screening, an annual cohort of 35 722 Filipino immigrants would include an estimated 450 TB patients with 264 hospitalizations, at a societal cost of US$9.90 million. Culture-based vs. smear-based screening would result in fewer imported cases (80.9 vs. 310.5), hospitalizations (19.7 vs. 68.1), and treatment costs (US$1.57 million vs. US$4.28 million). Societal screening costs, including US follow-up, were greater for culture-based screening (US$5.98 million) than for smear-based screening (US$3.38 million). Culture-based screening requirements increased immigrant costs by 61% (US$1.7 million), but reduced costs for the US Public Health Department (22%, US$750 000) and of hospitalization (70%, US$1 020 000). CONCLUSION: Culture-based screening reduced imported TB and US costs among Filipino immigrants.

Syphilis Among U.S.-Bound Refugees, 2009-2013.

U.S. immigration regulations require clinical and serologic screening for syphilis for all U.S.-bound refugees 15 years of age and older. We reviewed syphilis screening results for all U.S.-bound refugees from January 1, 2009 through December 31, 2013. We calculated age-adjusted prevalence by region and nationality and assessed factors associated with syphilis seropositivity using multivariable log binomial regression models. Among 233,446 refugees, we identified 874 syphilis cases (373 cases per 100,000 refugees). The highest overall age-adjusted prevalence rates of syphilis seropositivity were observed among refugees from Africa (1340 cases per 100,000), followed by East Asia and the Pacific (397 cases per 100,000). In most regions, male sex, increasing age, and living in non-refugee camp settings were associated with syphilis seropositivity. Future analysis of test results, stage of infection, and treatment delivery overseas is warranted in order to determine the extent of transmission risk and benefits of the screening program.

Atherosclerosis in angiographically "normal" coronary artery reference segments: an intravascular ultrasound study with clinical correlations.

OBJECTIVES: This study evaluated the magnitude, patterns and clinical correlates of atherosclerosis in angiographically "normal" reference segments in patients undergoing transcatheter therapy for symptomatic coronary artery disease. BACKGROUND: Pathologic studies indicate that the extent of coronary atherosclerosis is underestimated by visual analysis of angiographically normal coronary artery segments. Intravascular ultrasound allows detailed, high quality cross-sectional imaging of the coronary arteries in vivo. METHODS: Intravascular ultrasound was used to study angiographically normal coronary artery reference segments in 884 patients evaluated for transcatheter therapy for symptomatic native coronary artery disease. The reference segment was the most visually normal intravascular ultrasound cross section within 10 mm proximal to the target lesion but distal to any major side branch. Results are presented as mean value +/- 1 SD. RESULTS: Only 60 (6.8%) of 884 angiographically normal reference segments were normal by intravascular ultrasound. Reference segment percent cross-sectional narrowing measured 51 +/- 13% and correlated poorly with the target lesion percent cross-sectional narrowing (r = 0.166, p < 0.0001). Reference segments contained less calcific and dense fibrotic plaque and proportionately more soft plaque elements. Independent predictors of reference segment percent cross-sectional narrowing were male gender, patient age, diabetes mellitus, hypercholesterolemia and presence of multivessel disease. Independent predictors of reference segment calcification were patient age and serum creatinine levels. Reference segment percent cross-sectional narrowing in 723 patients undergoing transcatheter therapy was similar to that in patients studied for diagnostic purposes; however, reference segment arc of calcium was greater in treated patients (43 +/- 81 vs. 25 +/- 57, p = 0.015). Reference segment disease was not an independent predictor of subsequent angiographic restenosis or clinical events within 12 months of follow-up. CONCLUSIONS: Atherosclerosis is ubiquitous in angiographically normal coronary artery reference segments. Reference segment disease parallels the severity of target lesion disease and is associated with many of the conventional risk factors for coronary artery disease. Because of its sensitivity in detecting atherosclerosis in angiographically normal reference segments, intravascular ultrasound should enhance the study of risk factors for atherosclerosis and the results of therapies to control disease progression.

Circulating insulin-like growth factor II and colorectal adenomas.

Circulating insulin-like growth factor I (IGF-I) and IGF-binding protein-3 (IGFBP-3) may be risk factors for the development of colorectal cancer. On the other hand, IGF-II and IGFBP-2 are overexpressed in colorectal carcinomas. These contrasting backgrounds led us to investigate the relationship between serum IGF-I, IGF-II, IGFBP-2, and IGFBP-3 and the presence of colorectal adenomas, known precursors of colorectal carcinoma, in 345 volunteers attending a screening flexible sigmoidoscopy trial (entry criteria: healthy, aged 55-64 yr). The most striking finding was an elevated mean serum IGF-II in individuals with adenomas (n = 52) compared with controls (mean difference, 139 ng/mL; 95% confidence intervals, 82, 196; P < 0.0001). Logistic regression adjusting for confounding factors confirmed the significant association between IGF-II and adenoma occurrence (P < 0.0001) and revealed an additional positive association with serum IGFBP-2 (P < 0.0001). However, there was no association found between either serum IGF-I and/or IGFBP-3 and the presence of adenomas. Additionally, in 31 individuals with adenomas in whom levels were determined pre- and postpolypectomy, there was a significant fall in mean IGF-II (P < 0.001) and IGFBP-2 (P < 0.001) after adenoma removal, but no difference in IGF-II and IGFBP-2 concentrations between repeated samples in 20 individuals without adenomas. Immunohistochemical studies demonstrated IGF-II expression in 83% of all adenomas, which contrasted with absent expression in normal colonic expression and hyperplastic polyps. This study has shown for the first time that serum IGF-II may be a tumor marker in individuals with colorectal adenomas. Further studies are needed to validate these relationships in larger populations, including individuals undergoing colonoscopy.