A Metaontology for Medical Diagnostics of Acute Diseases. Part 1. An Informal Description and Definitions of Basic Terms

The aim of this article is to describe formally a metaontology for medical diagnostics of acute diseases in the language of applied logic. The article includes an informal description of the metaontology, and the part of its model which contains the definitions for basic terms of knowledge and situations and also their integrity restrictions in the form of ontological agreements.

A Metaontology for Medical Diagnostics of Acute Diseases. Part 2. A Formal Description of Cause-and-effect Relations

This article is the continuation of the formal description of the metaontology for medical diagnostics in the language of applied logic. It contains a description of interrelations between terms of knowledge and reality in the form of ontological agreements.

A Metaontology for Medical Diagnostics of Acute Diseases. Part 3. A Formal Description of the Causes of Signs’ Values and of Diseases

This article is the final part of the formal description of the metaontology for medical diagnostics in the language of applied logic. It contains a description of the causes of signs’ values and of the causes of diseases.

Obesity Indicators by Race/Ethnicity for Diagnosis of Cardiometabolic Diseases for a US Representative Sample of Adults

Background: Obesity, a growing epidemic, is a preventable risk factor for cardiometabolic diseases. Obesity and cardiometabolic diseases affect Hispanics and African Americans more than non-Hispanic Caucasians. This study examined the relationship among race/ethnicity, obesity diagnostic measures (body mass index, waist circumference, subscapular and triceps skinfold thickness), and cardiometabolic risk factors (hyperglycemia, high, non-high-density lipoprotein cholesterol, low, high-density lipoprotein cholesterol, and hypertension) for adults across the United States. Methods: Using data from two-cycles of the National Health and Examination Survey (NHANES) 2007-2010, and accounting for the complex sample design, logistic regression models were conducted comparing obesity indicators in Mexican Americans, other Hispanics, and Black non-Hispanics, with White non-Hispanics and their associations with the presence of cardiometabolic diseases. Results: Differences by race/ethnicity were found for subscapular skinfold thickness and hyperglycemia. Waist circumference and subscapular skinfold were positively associated with the presence of hyperglycemia; dyslipidemia, and hypertension across race/ ethnicity, adjusting for age, gender, smoking, physical activity, education, income to poverty index, and health insurance. Race/ ethnicity did not influence the association of any obesity indicators with the tested cardiometabolic diseases. All obesity measures except triceps skinfold were associated with hyperglycemia. Conclusions: We suggest that subscapular skinfold thickness be considered as an inexpensive non-intrusive screening tool for cardiometabolic risk factors in an adult US population

Effects of allergic diseases and age on the composition of serum IgG glycome in children

Glycan analysis was partly supported by European Commission GlycoBioM (contract #259869), IBD-BIOM (contract #305479), HighGlycan (contract #278535), MIMOmics (contract #305280), HTP-GlycoMet (contract #324400) and IntegraLife (contract #315997) grants. The SEATON cohort was partly funded by the UK Medical Research Council (contract #80219) and Asthma UK (contract #00/011 and 02/017) grants.

Chironomid-inferred July-air temperature of Lago Piccolo di Avigliana

Chironomid headcapsules were used to reconstruct late glacial and early-Holocene summer temperatures at Lago Piccolo di Avigliana (LPA). Two training sets (northern Sweden, North America) were used to infer temperatures. The reconstructed patterns of temperature change agreed well with the GRIP and NGRIP d18O records. Inferred temperatures were high during the Bølling (ca 19 °C), slowly decreased to ca 17.5 °C during the Allerød, reached lowest temperatures (ca 16 °C) during the Younger Dryas, and increased to ca. 18.5 °C during the Preboreal. The amplitudes of change at climate transitions (i.e. Oldest Dryas/Bølling: 3 °C, Allerød/Younger Dryas: 1.5 °C, and Younger Dryas/Preboreal: 2.5 °C) were smaller than in the northern Alps but similar to those recorded at another site in northeastern Italy. Our results suggest that (1) Allerød temperatures were higher in the southern Alps and (2) higher during the Preboreal (1 °C) than during the Allerød. These differences might provide an explanation for the different responses of terrestrial-vegetation to late glacial and early-Holocene climatic changes in the two regions. Other sites on both sides of the Alps should be studied to confirm these two hypotheses.

EGFR interacts with the fusion protein of respiratory syncytial virus strain 2-20 and mediates infection and mucin expression.

Respiratory syncytial virus (RSV) is the major cause of viral lower respiratory tract illness in children. In contrast to the RSV prototypic strain A2, clinical isolate RSV 2-20 induces airway mucin expression in mice, a clinically relevant phenotype dependent on the fusion (F) protein of the RSV strain. Epidermal growth factor receptor (EGFR) plays a role in airway mucin expression in other systems; therefore we hypothesized that the RSV 2-20 F protein stimulates EGFR signaling. Infection of cells with chimeric strains RSV A2-2-20F and A2-2-20GF or over-expression of 2-20 F protein resulted in greater phosphorylation of EGFR than infection with RSV A2 or over-expression of A2 F, respectively. Chemical inhibition of EGFR signaling or knockdown of EGFR resulted in diminished infectivity of RSV A2-2-20F but not RSV A2. Over-expression of EGFR enhanced the fusion activity of 2-20 F protein in trans. EGFR co-immunoprecipitated most efficiently with RSV F proteins derived from “mucogenic” strains. RSV 2-20 F and EGFR co-localized in H292 cells, and A2-2-20GF-induced MUC5AC expression was ablated by EGFR inhibitors in these cells. Treatment of BALB/c mice with the EGFR inhibitor erlotinib significantly reduced the amount of RSV A2-2-20F-induced airway mucin expression. Our results demonstrate that RSV F interacts with EGFR in a strain-specific manner, EGFR is a co-factor for infection, and EGFR plays a role in RSV-induced mucin expression, suggesting EGFR is a potential target for RSV disease.

Time-resolved dosimetric verification of respiratory-gated radiotherapy exposures using a high-resolution 2D ionisation chamber array

The aim of this work was to track and verify the delivery of respiratory-gated irradiations, performed with three versions of TrueBeam linac, using a novel phantom arrangement that combined the OCTAVIUS® SRS 1000 array with a moving platform. The platform was programmed to generate sinusoidal motion of the array. This motion was tracked using the real-time position management (RPM) system and four amplitude gating options were employed to interrupt MV beam delivery when the platform was not located within set limits. Time-resolved spatial information extracted from analysis of x-ray fluences measured by the array was compared to the programmed motion of the platform and to the trace recorded by the RPM system during the delivery of the x-ray field. Temporal data recorded by the phantom and the RPM system were validated against trajectory log files, recorded by the linac during the irradiation, as well as oscilloscope waveforms recorded from the linac target signal. Gamma analysis was employed to compare time-integrated 2D x-ray dose fluences with theoretical fluences derived from the probability density function for each of the gating settings applied, where gamma criteria of 2%/2 mm, 1%/1 mm and 0.5%/0.5 mm were used to evaluate the limitations of the RPM system. Excellent agreement was observed in the analysis of spatial information extracted from the SRS 1000 array measurements. Comparisons of the average platform position with the expected position indicated absolute deviations of  <0.5 mm for all four gating settings. Differences were observed when comparing time-resolved beam-on data stored in the RPM files and trajectory logs to the true target signal waveforms. Trajectory log files underestimated the cycle time between consecutive beam-on windows by 10.0  ±  0.8 ms. All measured fluences achieved 100% pass-rates using gamma criteria of 2%/2 mm and 50% of the fluences achieved pass-rates  >90% when criteria of 0.5%/0.5 mm were used. Results using this novel phantom arrangement indicate that the RPM system is capable of accurately gating x-ray exposure during the delivery of a fixed-field treatment beam.

Impact of oral diseases and disorders on oral health-related quality of life of preschool children

BACKGROUND The presence of oral diseases and disorders can produce an impact on the quality of life of preschool children and their parents, affecting their oral health and well-being. However, socioeconomic factors could confound this association, but it has not been yet tested at this age. OBJECTIVE To assess the impact of early childhood caries (ECC), traumatic dental injuries (TDI) and malocclusions on the oral health-related quality of life (OHRQoL) of children between 2 and 5 years of age adjusted by socioeconomic factors. METHODS Parents of 260 children answered the Early Childhood Oral Health Impact Scale (ECOHIS) (six domains) on their perception of the children's OHRQoL and socioeconomic conditions. Two calibrated dentists (κ>0.8) examined the severity of ECC according to dmft index, and children were categorized into: 0=caries free; 1-5=low severity; ≥6=high severity. TDI and malocclusions were examined according to Andreasen & Andreasen (1994) classification and for the presence or absence of three anterior malocclusion traits (AMT), respectively. OHRQoL was measured through ECOHIS domain and total scores, and poisson regression was used to associate the different factors with the outcome. RESULTS In each domain and overall ECOHIS scores, the severity of ECC showed a negative impact on OHRQoL (P<0.001). TDI and AMT did not show a negative impact on OHRQoL nor in each domain (P>0.05). The increase in the child's age, higher household crowding, lower family income and mother working out of home were significantly associated with OHRQoL (P<0.05). The multivariate adjusted model showed that the high severity of ECC (RR=3.81; 95% CI=2.66, 5.46; P<0.001) was associated with greater negative impact on OHRQoL, while high family income was a protective factor for OHRQoL (RR=0.93; 95% CI=0.87, 0.99; P<0.001). CONCLUSIONS The severity of ECC and a lower family income had a negative impact on the OHRQoL of preschool children and their parents.

Air sensitivity of MoS2, MoSe2, MoTe2, HfS2 and HfSe2

A surface sensitivity study was performed on different transition-metal dichalcogenides (TMDs) under ambient conditions in order to understand which material is the most suitable for future device applications. Initially, Atomic Force Microscopy and Scanning Electron Microscopy studies were carried out over a period of 27 days on mechanically exfoliated flakes of 5 different TMDs, namely, MoS2, MoSe2, MoTe2, HfS2, and HfSe2. The most reactive were MoTe2 and HfSe2. HfSe2, in particular, showed surface protrusions after ambient exposure, reaching a height and width of approximately 60 nm after a single day. This study was later supplemented by Transmission Electron Microscopy (TEM) cross-sectional analysis, which showed hemispherical-shaped surface blisters that are amorphous in nature, approximately 180–240 nm tall and 420–540 nm wide, after 5 months of air exposure, as well as surface deformation in regions between these structures, related to surface oxidation. An X-ray photoelectron spectroscopy study of atmosphere exposed HfSe2 was conducted over various time scales, which indicated that the Hf undergoes a preferential reaction with oxygen as compared to the Se. Energy-Dispersive X-Ray Spectroscopy showed that the blisters are Se-rich; thus, it is theorised that HfO2 forms when the HfSe2 reacts in ambient, which in turn causes the Se atoms to be aggregated at the surface in the form of blisters. Overall, it is evident that air contact drastically affects the structural properties of TMD materials. This issue poses one of the biggest challenges for future TMD-based devices and technologies.

DATA DRIVEN APPROACHES TO IDENTIFY DETERMINANTS OF HEART DISEASES AND CANCER RESISTANCE

Cancer and cardio-vascular diseases are the leading causes of death world-wide. Caused by systemic genetic and molecular disruptions in cells, these disorders are the manifestation of profound disturbance of normal cellular homeostasis. People suffering or at high risk for these disorders need early diagnosis and personalized therapeutic intervention. Successful implementation of such clinical measures can significantly improve global health. However, development of effective therapies is hindered by the challenges in identifying genetic and molecular determinants of the onset of diseases; and in cases where therapies already exist, the main challenge is to identify molecular determinants that drive resistance to the therapies. Due to the progress in sequencing technologies, the access to a large genome-wide biological data is now extended far beyond few experimental labs to the global research community. The unprecedented availability of the data has revolutionized the capabilities of computational researchers, enabling them to collaboratively address the long standing problems from many different perspectives. Likewise, this thesis tackles the two main public health related challenges using data driven approaches. Numerous association studies have been proposed to identify genomic variants that determine disease. However, their clinical utility remains limited due to their inability to distinguish causal variants from associated variants. In the presented thesis, we first propose a simple scheme that improves association studies in supervised fashion and has shown its applicability in identifying genomic regulatory variants associated with hypertension. Next, we propose a coupled Bayesian regression approach -- eQTeL, which leverages epigenetic data to estimate regulatory and gene interaction potential, and identifies combinations of regulatory genomic variants that explain the gene expression variance. On human heart data, eQTeL not only explains a significantly greater proportion of expression variance in samples, but also predicts gene expression more accurately than other methods. We demonstrate that eQTeL accurately detects causal regulatory SNPs by simulation, particularly those with small effect sizes. Using various functional data, we show that SNPs detected by eQTeL are enriched for allele-specific protein binding and histone modifications, which potentially disrupt binding of core cardiac transcription factors and are spatially proximal to their target. eQTeL SNPs capture a substantial proportion of genetic determinants of expression variance and we estimate that 58% of these SNPs are putatively causal. The challenge of identifying molecular determinants of cancer resistance so far could only be dealt with labor intensive and costly experimental studies, and in case of experimental drugs such studies are infeasible. Here we take a fundamentally different data driven approach to understand the evolving landscape of emerging resistance. We introduce a novel class of genetic interactions termed synthetic rescues (SR) in cancer, which denotes a functional interaction between two genes where a change in the activity of one vulnerable gene (which may be a target of a cancer drug) is lethal, but subsequently altered activity of its partner rescuer gene restores cell viability. Next we describe a comprehensive computational framework --termed INCISOR-- for identifying SR underlying cancer resistance. Applying INCISOR to mine The Cancer Genome Atlas (TCGA), a large collection of cancer patient data, we identified the first pan-cancer SR networks, composed of interactions common to many cancer types. We experimentally test and validate a subset of these interactions involving the master regulator gene mTOR. We find that rescuer genes become increasingly activated as breast cancer progresses, testifying to pervasive ongoing rescue processes. We show that SRs can be utilized to successfully predict patients' survival and response to the majority of current cancer drugs, and importantly, for predicting the emergence of drug resistance from the initial tumor biopsy. Our analysis suggests a potential new strategy for enhancing the effectiveness of existing cancer therapies by targeting their rescuer genes to counteract resistance. The thesis provides statistical frameworks that can harness ever increasing high throughput genomic data to address challenges in determining the molecular underpinnings of hypertension, cardiovascular disease and cancer resistance. We discover novel molecular mechanistic insights that will advance the progress in early disease prevention and personalized therapeutics. Our analyses sheds light on the fundamental biological understanding of gene regulation and interaction, and opens up exciting avenues of translational applications in risk prediction and therapeutics.

Detection of viral diseases in shrimp Litopenaeus vannamei in Iran with emphasis on white spot disease prevention by using marine alga extract

Nowadays, following was expanded shrimp breeding and culture; viral diseases have been main problem which threatened shrimp industry in the country. Therefore, shrimp samples were obtained from different stages of Litopenaeus vannmei life cycle (larval, post larval, juveniles, adults and broodstocks) based on clinical signs in the breeding center and shrimp farming from Bushehr, Khozestan and Sistan and Baluchestan provinces. Viral diseases were detected by PCR (Polymerase Chain Reaction), histopathology and transmission electron microscopy (TEM) methods. Results of the PCR were indicated present white spot virus (WSV) in juveniles, sub adults and adults shrimp with medium intensity from three provinces, but it was not showed in larval and post larval stages. Histopathological sections were indicated hypertrophy and basophilic Cowdry type A formation in nucleus cells of gill, haematopoietic, lymphoid and epithelial's cuticles and intestinal tissues which was associated with small vacuoles increased in B cells of hepatopancreas tissue of infection shrimps. Transmission electronic microscopic studies were demonstrated that the length and diameter virus was detected, respectively, 300 ± 20 nm and 75 ± 5 nm. Considerable, results of the PCR were only displayed IHHNV in juvenile, adult and broodstock shrimps from breeding and farming center of Bushehr province. The main lesion pathology was formed eosinophilic Cowdry type A in nucleus cells of gill, haematopoietic, lymphoid and epithelial's cuticles and intestinal tissues. Whereas penaeid shrimps are lack specific immune system, hence, in the present study was used of marine alga (Lurensia snideria) collected from along costal Persian Gulf of Bushehr province for viral diseases were prevented. Powder alga extract were added with a ratio of 1 % to shrimp diet. Total haemocyte count (THC) and total protein plasma (TPP) were increased after 5 days of oral administration diets. When shrimps were infected by with spot virus experimentally, THC and TPP gradually were increased in both two groups (shrimps fed with diet containing alga extract and without alga extract) after 48h. Nevertheless; THC, TPP and survival of shrimp fed with diet containing alga extract were more than shrimp control in 15 days. So, oral administration Lurensia snideria extract was capable prevention infected L. vannamei via stimulant specific immune system.

Recommended reporting standards for test accuracy studies of infectious diseases of finfish, amphibians, molluscs and crustaceans: the STRADAS-aquatic checklist

Complete and transparent reporting of key elements of diagnostic accuracy studies for infectious diseases in cultured and wild aquatic animals benefits end-users of these tests, enabling the rational design of surveillance programs, the assessment of test results from clinical cases and comparisons of diagnostic test performance. Based on deficiencies in the Standards for Reporting of Diagnostic Accuracy (STARD) guidelines identified in a prior finfish study (Gardner et al. 2014), we adapted the Standards for Reporting of Animal Diagnostic Accuracy Studies—paratuberculosis (STRADAS-paraTB) checklist of 25 reporting items to increase their relevance to finfish, amphibians, molluscs, and crustaceans and provided examples and explanations for each item. The checklist, known as STRADAS-aquatic, was developed and refined by an expert group of 14 transdisciplinary scientists with experience in test evaluation studies using field and experimental samples, in operation of reference laboratories for aquatic animal pathogens, and in development of international aquatic animal health policy. The main changes to the STRADAS-paraTB checklist were to nomenclature related to the species, the addition of guidelines for experimental challenge studies, and the designation of some items as relevant only to experimental studies and ante-mortem tests. We believe that adoption of these guidelines will improve reporting of primary studies of test accuracy for aquatic animal diseases and facilitate assessment of their fitness-for-purpose. Given the importance of diagnostic tests to underpin the Sanitary and Phytosanitary agreement of the World Trade Organization, the principles outlined in this paper should be applied to other World Organisation for Animal Health (OIE)-relevant species.