Strengthening the Reporting of Molecular Epidemiology for Infectious Diseases (STROME-ID): an extension of the STROBE statement

Molecular data are now widely used in epidemiological studies to investigate the transmission, distribution, biology, and diversity of pathogens. Our objective was to establish recommendations to support good scientific reporting of molecular epidemiological studies to encourage authors to consider specific threats to valid inference. The statement Strengthening the Reporting of Molecular Epidemiology for Infectious Diseases (STROME-ID) builds upon the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) initiative. The STROME-ID statement was developed by a working group of epidemiologists, statisticians, bioinformaticians, virologists, and microbiologists with expertise in control of infection and communicable diseases. The statement focuses on issues relating to the reporting of epidemiological studies of infectious diseases using molecular data that were not addressed by STROBE. STROME-ID addresses terminology, measures of genetic diversity within pathogen populations, laboratory methods, sample collection, use of molecular markers, molecular clocks, timeframe, multiple-strain infections, non-independence of infectious-disease data, missing data, ascertainment bias, consistency between molecular and epidemiological data, and ethical considerations with respect to infectious-disease research. In total, 20 items were added to the 22 item STROBE checklist. When used, the STROME-ID recommendations should advance the quality and transparency of scientific reporting, with clear benefits for evidence reviews and health-policy decision making.

Antisense-mediated inhibition of papillomavirus type-18 in human squamous cell carcinoma

Numerous co-factors, genetic, environmental and physical, play an important role in development and prognosis of cancer. Each year in the USA, more than 31,000 cases of oral and 13,000 cases of cervical cancer are diagnosed. Substantial epidemiological data supports a high correlation between development of these cancers and the presence of specific types of human papillomaviruses (HPV). Molecular biological studies show that not only are several of the viral genes necessary and sufficient to cause transformation but they also function synergistically with other co-factors. Evidence suggests that prevention of infection or inhibition of viral gene expression may alter the course of malignant transition. The main objective of this project was to test the hypothesis that some human carcinoma cells, containing HPV, behave in malignant manner because the viral genes function in the maintenance of some aspect of the transformed phenotype.^ The specific aims were (1) to select oral and cervical cancer cell lines which were HPV-negative or which harbored transcriptionally active HPV-18, (2) to construct and determine the effects of recombinant sense or antisense expressing vectors, (3) to test the effects of synthetic antisense oligodeoxynucleotides on the transformed behavior of these cells.^ To screen cells, we performed Southern and Northern analysis and polymerase chain reactions. When antisense-expressing vectors were used, cells harboring low numbers of HPV-18 where unable to survive transfection but they were readily transfected with all other constructs. Rare antisense transfectants obtained from HPV-positive cells showed significantly altered characteristics including malignant potential in nude mice. The HPV-negative cells showed no differences in transfection efficiencies or growth characteristics with any construct.^ In addition, treatment of the HPV-positive cells with antisense, but not random oligodeoxynucleotides, resulted in decreased cell proliferation and even cell death. These effects were dose-dependent, synergistic and HPV-specific.^ These results suggest that expression of viral genes play an important role in the maintenance of the transformed phenotype which implies that inhibition of expression, by antisense molecules, may be therapeutic in HPV-induced tumors. ^

Amyotrophic lateral sclerosis and Parkinsonism-dementia complex of Guam: Descriptive epidemiology, secular trends, and birth cohort effects on incidence, 1950--1989

This study describes the patterns of occurrence of amyotrophic lateral sclerosis (ALS) and parkinsonism-dementia complex (PDC) of Guam during 1950-1989. Both ALS and PDC occur with high frequency among the indigenous Chamorro population, first recognized in the early 1950's. Reports in the early 1980's indicated that both ALS and PDC were disappearing, due to a purported reduction in exposure to harmful environmental factors as a result of the dramatic changes in lifestyle that took place after World War II. However, this study provides compelling evidence that ALS and PDC have not disappeared on Guam and that rates for both are higher during 1980-1989 than previously reported.^ The patterns of occurrence for both ALS and PDC overlap in most respects: (1) incidence and mortality are decreasing; (2) median age at onset is increasing; (3) males are at increased risk for developing disease; (4) risk is higher for those residing in the south compared to the non-south; and (5) age-specific incidence is decreasing over time except in the oldest age groups.^ Age-specific incidence of ALS and PDC, separately and together, is generally higher for cohorts born before 1920 than for those born after 1920. A significant birth cohort effect on the incidence of PDC for the 1906-1915 birth cohort was found, but not for ALS and for ALS and PDC together. Whether or not a cohort effect, period effect, or both are associated with incidence of ALS and PDC cannot be determined from the data currently available and will require additional follow-up of individuals born after 1920.^ The epidemiological data amassed over this 40-year period provide evidence that supports an environmental exposure model for disease occurrence as opposed to a simple genetic or infectious disease model. Whether neurodegenerative disease in this population occurs as a consequence of a single exposure or is explained by a multifactorial model such as a genetic predisposition with some environmental interaction is yet to be determined. However, descriptive studies such as this can provide clues concerning timing and location of potential adverse exposures but cannot determine etiology, underscoring the urgent need for analytic studies of ALS and PDC to further investigate existing etiologic hypotheses and to test new hypotheses. ^

A critical evaluation of secondary cancer risk models applied to Monte Carlo dose distributions of 2-dimensional, 3-dimensional conformal and hybrid intensity-modulated radiation therapy for breast cancer

The comparison of radiotherapy techniques regarding secondary cancer risk has yielded contradictory results possibly stemming from the many different approaches used to estimate risk. The purpose of this study was to make a comprehensive evaluation of different available risk models applied to detailed whole-body dose distributions computed by Monte Carlo for various breast radiotherapy techniques including conventional open tangents, 3D conformal wedged tangents and hybrid intensity modulated radiation therapy (IMRT). First, organ-specific linear risk models developed by the International Commission on Radiological Protection (ICRP) and the Biological Effects of Ionizing Radiation (BEIR) VII committee were applied to mean doses for remote organs only and all solid organs. Then, different general non-linear risk models were applied to the whole body dose distribution. Finally, organ-specific non-linear risk models for the lung and breast were used to assess the secondary cancer risk for these two specific organs. A total of 32 different calculated absolute risks resulted in a broad range of values (between 0.1% and 48.5%) underlying the large uncertainties in absolute risk calculation. The ratio of risk between two techniques has often been proposed as a more robust assessment of risk than the absolute risk. We found that the ratio of risk between two techniques could also vary substantially considering the different approaches to risk estimation. Sometimes the ratio of risk between two techniques would range between values smaller and larger than one, which then translates into inconsistent results on the potential higher risk of one technique compared to another. We found however that the hybrid IMRT technique resulted in a systematic reduction of risk compared to the other techniques investigated even though the magnitude of this reduction varied substantially with the different approaches investigated. Based on the epidemiological data available, a reasonable approach to risk estimation would be to use organ-specific non-linear risk models applied to the dose distributions of organs within or near the treatment fields (lungs and contralateral breast in the case of breast radiotherapy) as the majority of radiation-induced secondary cancers are found in the beam-bordering regions.

Patient Safety: What Is It All about?

Patient safety is a major concern in health care systems worldwide. Patients with serious conditions, multimorbidity, and with intense and fragmented health care utilization, like end-stage renal disease (ESRD) patients, are at increased risk for suffering adverse events. In this chapter, the fundamental terms and concepts of patient safety are introduced. Essential epidemiological data relating to the frequency of adverse events and medical errors are provided. The chapter reports important safety threats for ESRD patients and describes examples of key innovations which contribute to patient safety. Recommendations and risk reduction strategies to improve care of ESRD patients are presented. © 2015 S. Karger AG, Basel.

Adiposity and cancer risk: new mechanistic insights from epidemiology

Excess body adiposity, commonly expressed as body mass index (BMI), is a risk factor for many common adult cancers. Over the past decade, epidemiological data have shown that adiposity-cancer risk associations are specific for gender, site, geographical population, histological subtype and molecular phenotype. The biological mechanisms underpinning these associations are incompletely understood but need to take account of the specificities observed in epidemiology to better inform future prevention strategies.

Incidence and causative agents of chemical eye injuries in Switzerland

CONTEXT Chemical eye injuries are ophthalmological emergencies with a high risk of secondary complications and severe visual loss. Only limited epidemiological data for such injuries are available for many countries. PATIENTS AND METHODS We performed two independent studies. The cause of chemical eye injuries was assessed with a prospective questionnaire study. Questionnaires were sent to all ophthalmologists in Switzerland. A total of 163 patients (205 eyes) were included, between December 2012 and October 2014. Independent of the questionnaire study, the incidence of chemical eye injuries was assessed with a retrospective cohort study design using the database of the mandatory accident insurance. RESULTS Ophthalmological questionnaires revealed that plaster/cement (20.5%), alkaline (12.2%) and acid (10.2%) solutions caused the highest number of chemical injuries. Only 2% of all injuries were classified as grade III and none as grade IV (Roper-Hall classification). The official toxicological information phone-hotline was contacted in 4.3% of cases. Using data from the accident insurance, an incidence of chemical eye injuries of about 50/100 000/year was found in the working population. CONCLUSION Here, we present data on the involved agents of chemical eye injuries in Switzerland, and also the incidence of such injuries in the working population. This may also help to assess the need for further education programs and to improve and direct preventive measures.

Analysis of Phenotypic Variation in Childhood Wheezing Disorders

Recurrent wheezing or asthma is a common problem in children that has increased considerably in prevalence in the past few decades. The causes and underlying mechanisms are poorly understood and it is thought that a numb er of distinct diseases causing similar symptoms are involved. Due to the lack of a biologically founded classification system, children are classified according to their observed disease related features (symptoms, signs, measurements) into phenotypes. The objectives of this PhD project were a) to develop tools for analysing phenotypic variation of a disease, and b) to examine phenotypic variability of wheezing among children by applying these tools to existing epidemiological data. A combination of graphical methods (multivariate co rrespondence analysis) and statistical models (latent variables models) was used. In a first phase, a model for discrete variability (latent class model) was applied to data on symptoms and measurements from an epidemiological study to identify distinct phenotypes of wheezing. In a second phase, the modelling framework was expanded to include continuous variability (e.g. along a severity gradient) and combinations of discrete and continuo us variability (factor models and factor mixture models). The third phase focused on validating the methods using simulation studies. The main body of this thesis consists of 5 articles (3 published, 1 submitted and 1 to be submitted) including applications, methodological contributions and a review. The main findings and contributions were: 1) The application of a latent class model to epidemiological data (symptoms and physiological measurements) yielded plausible pheno types of wheezing with distinguishing characteristics that have previously been used as phenotype defining characteristics. 2) A method was proposed for including responses to conditional questions (e.g. questions on severity or triggers of wheezing are asked only to children with wheeze) in multivariate modelling.ii 3) A panel of clinicians was set up to agree on a plausible model for wheezing diseases. The model can be used to generate datasets for testing the modelling approach. 4) A critical review of methods for defining and validating phenotypes of wheeze in children was conducted. 5) The simulation studies showed that a parsimonious parameterisation of the models is required to identify the true underlying structure of the data. The developed approach can deal with some challenges of real-life cohort data such as variables of mixed mode (continuous and categorical), missing data and conditional questions. If carefully applied, the approach can be used to identify whether the underlying phenotypic variation is discrete (classes), continuous (factors) or a combination of these. These methods could help improve precision of research into causes and mechanisms and contribute to the development of a new classification of wheezing disorders in children and other diseases which are difficult to classify.

Longitudinal Dichelobacter nodosus status in 9 sheep flocks free from clinical footrot

Footrot is a widespread problem in Swiss sheep farming. The objectives of this study were to determine whether flocks which were clinically free from footrot carry virulent strains of Dichelobacter nodosus, and to describe the infection dynamics for flocks and individual sheep. To this purpose, a new PCR-diagnostic tool was used, which is able to distinguish benign from virulent D. nodosus. Nine farms were examined three times at intervals of 6 months. Cotton swabs were used to collect samples from the interdigital skin to analyze for the presence of virulent and benign strains of D. nodosus. Additionally, epidemiological data of the farms were collected with the aid of a standardized questionnaire. On four farms, benign strains were diagnosed at each visit; in one farm, benign strains were detected once only. Two flocks revealed sheep infected with virulent D. nodosus throughout the study but without clinical evidence of footrot. In two flocks, the virulent strains of D. nodosus were introduced into the flock during the study period. In one farm, clinical symptoms of virulent footrot were evident only two weeks after the positive finding by PCR. Only individual sheep with previously negative status, but none with previously benign status became infected with virulent strains during the study. The newly developed competitive RT PCR proved to be more sensitive than clinical diagnosis for detecting footrot infection in herds, as it unequivocally classified the four flocks as infected with virulent D. nodosus, even though they did not show clinical signs at the times of sampling. This early detection may be crucial to the success of any control program. Both new infections with virulent strains could be explained by contact with sheep from herds with virulent D. nodosus as evaluated from the questionnaires. These results show that the within-herd eradication of footrot becomes possible using the competitive PCR assay to specifically diagnose virulent D. nodosus.

Medical, psychological and socio-economic implications of chronic hand eczema: a cross-sectional study.

BACKGROUND Hand eczema (HE) is a common skin disease with major medical psychological and socio-economic implications. Onset and prognosis of HE are determined by individual as well as environmental factors. So far, most epidemiological data on HE have been reported from Scandinavian and recently German studies. OBJECTIVE To investigate the characteristics and medical care of patients with chronic HE (CHE) in Switzerland, and identify risk factors. METHODS In this cross-sectional study, data from patients with chronic HE were obtained by means of medical history, dermatological examination and patient questionnaires. Multiple logistic regression analysis was applied to identify risk factors for high severity and dermatology life quality index (DLQI). RESULTS In seven dermatology departments, 199 patients (mean age 40.4 years, 50.8% female) with CHE (mean duration 6.6 years) were enrolled. Moderate to severe HE was reported by 70.9% of patients, and was associated with age <30 or >50 years, localization of lesions and pruritus. Because of the CHE, 37.3% of patients were on sick leave over the past 12 months, 14.8% had changed or lost their job. Practically all patients applied topical therapy, 21% were treated with alitretinoin, and 21% with psoralen plus UVA light (PUVA). The effects on the health-related quality of life was moderate to large in 33.7% and 39.4% of CHE patients, respectively. Factors associated with a high impact on DLQI (mean 9.7 ± 5.8) were female sex, lesions on back of the hands and pruritus as well as mechanical skin irritation and wearing gloves. CONCLUSION In agreement with recent studies, the Swiss data demonstrate the high impact of CHE on medical well-being, patient quality of life and work ability. As it is associated with an intense use of health care services, high rate of sick leave, job loss and change, CHE may cause a high socio-economic burden.

Adolescent tobacco use: Studies of prevalence, factorial validity, and factorial invariance between African Americans and Whites

In the last thirty years, increasing efforts have been made to reduce the prevalence of adolescent tobacco use in the United States. Although the prevalence has declined dramatically over the past decade, there are still sharp differences in adolescent smoking-initiation rates across racial/ethnic groups. Large-scale surveys frequently assess smoking-related attitudes, self-efficacy, and intentions to explain the differences in smoking rates between African Americans and Whites. However, there is little agreement about which constructs are significant. Moreover, the psychometric properties of smoking-related attitude, self-efficacy, and intention constructs have not been fully examined. More studies are needed to understand existing patterns of tobacco use and to validate and fully exploit the constructs' relationship to adolescent smoking initiation across racial/ethnic groups. ^ This dissertation reports on a secondary analysis of data from a large multi-ethnic convenience sample of sixth- through eighth-grade students in 22 schools in East Texas and the city of Houston. The specific aims of this dissertation were to (1) describe smoking and alternate tobacco product use rates by race/ethnicity, gender, age, and grade level (Article 1); (2) test the factorial validity of smoking-related attitudes, self-efficacy, and intentions using confirmatory factor analysis techniques (Article 2); and (3) test the factorial invariance of smoking-related attitudes, self-efficacy, and intentions between African Americans and Whites (Article 3). ^ The prevalence findings confirm the disparities in tobacco use among African American, Hispanic, and White adolescents that other surveys have reported (Article 1). This study also demonstrates the usefulness of examining use patterns of not only cigarettes but also alternative tobacco products in younger multiethnic populations, as well as of providing epidemiological data estimates about different phases of smoking. The confirmatory factor analysis provides evidence of construct validity of attitude, self-efficacy, and intention scales for the multiethnic sample (Article 2). Finally, the factorial invariance analyses indicates that some measures representing smoking-related attitudes, self-efficacy, and intentions may not be appropriate for use among both African Americans and Whites (Article 3). Additional research is needed to further our understanding of the patterns and predictors of youth tobacco use initiation. ^

Prevalence of HIV risk-related behaviors among undocumented Central American immigrant women in Houston, Texas, 2010

The primary aim of this dissertation research is to provide epidemiological data on HIV risk-related behaviors among undocumented Central American immigrant women living in Houston, Texas. Between February and May 2010, we used respondent driven sampling (RDS) to recruit 230 Guatemalan, Honduran, and El Salvadoran women, ages 18 to 50 years, living in Houston without a valid United States visa or residency papers. RDS is a probability-based sampling method that utilizes social networks to access members of hidden populations that lack a sampling frame. Participants completed an interview regarding their demographics, access to and utilization of healthcare services, HIV testing, and sexual behaviors. Data from this study were used 1) to describe the prevalence of sexual HIV risk-related behaviors among undocumented Central American immigrant women, comparing those who recently immigrated to the U.S. (within the past five years) to those with more established residency (of over five years); 2) to describe the prevalence of lifetime HIV testing and evaluate its associated factors in this target population; and 3) to describe the effectiveness of RDS to access members of this target population. ^ As described in Paper 1, there was a generally low prevalence of individual HIV risk-related behaviors (i.e., multiple, concurrent, convenience, and casual sexual partnerships) among the undocumented Central American immigrant women in this study. However, there was evidence of HIV risk due to unprotected sex with male partners who have concurrent sexual partnerships. We identified recent immigrants as the subpopulation at greatest risk, as they were significantly more likely than established immigrants to have multiple and/or concurrent sexual partners. As described in Paper 2, the lifetime prevalence of HIV testing was almost 70%. After adjusting for age, number of years living in the U.S., income security, and resource barriers, lifetime HIV testing was significantly associated with being from Honduras, having more than a sixth grade education, having a regular healthcare provider, and having knowledge of available healthcare resources. Finally, as described in Paper 3, RDS was an effective method for obtaining a diverse sample of Central American immigrant women in Houston. ^ This project is the first to use RDS to conduct an HIV behavioral survey among undocumented Central American immigrant women. Our results will inform the design of future research studies and the implementation of HIV prevention activities among undocumented Central American immigrants in the U.S.^

Addressing teenage pregnancy in rural areas: A case study from Liberty County, Texas

This study explores the issue of teenage pregnancy in a case study of Liberty County, a rural area in Texas with no public health department. It also describes the decision-making process and barriers faced in the beginning phases of adopting a sexual education program, and sets forth an implementation plan for two school districts on disseminating an evidence-based, comprehensive curriculum. Methods include a review of epidemiological data surrounding teenage pregnancy on the national, state, and county level; a literature review of factors related to teenage pregnancy and past interventions implemented in a rural community; a policy review of past and current bills in Legislature; and an analysis of barriers and decision making in implementing an evidence based program through qualitative observations, discussions with community members during meetings, presentations, and discussions. Results of this study indicate that there is a lack of research conducted in rural areas in the field of teenage pregnancy prevention and sexual education programs. Barriers experienced in Liberty County are shown to be consistent in scientific literature such as funding, logistical issues, and problems approaching the School Board in adopting a comprehensive sexual education program. This study fills a large gap in the literature on rural adolescents and attempts to analyze the process of decision-making in a rural area related to adoption of sexual education programming. In order to relieve this health disparity, further research should focus on rural areas to gain insight on the attitudes and behaviors of rural adolescents and beliefs among community stakeholders.^

Estradiol and insulin cross -talk in breast cancer

Approximately 33% of clinical breast carcinomas require estrogens to proliferate. Epidemiological data show that insulin resistance and diabetes mellitus is 2–3 times more prevalent in women with breast cancer than those with benign breast lesions, suggesting a clinical link between insulin and estradiol. Insulin and estradiol have a synergistic effect on the growth of MCF7 breast cancer cells, and long-term estradiol treatment upregulates the expression of the key insulin signaling protein IRS-1. The goal of this study was to further define the mechanism(s) of cross-talk between insulin and estradiol in regulating the growth of breast cancer. Using MCF7 cells, acute treatment with insulin or estradiol alone was found to stimulate two activities associated with growth: Erk MAP kinase and PI 3-kinase. However, combined acute treatment had an antagonistic effect on both activities. Acute estradiol treatment inhibited the insulin-stimulated tyrosine phosphorylation of IRS-1 while increasing its serine phosphorylation; the serine phosphorylation was attenuated by the PI 3-kinase inhibitor wortmannin. The acute antagonism observed with combined estradiol and insulin are not consistent with the long-term synergistic effect on growth. In contrast, chronic estradiol treatment enhanced the insulin-sensitivity of breast cancer cells as measured by increases in total cellular insulin-stimulated tyrosine phosphorylation of IRS-1 and activation of PI 3-kinase. Estradiol stimulation of gene transcription was found to require PI 3-kinase activity but not MAP kinase activity. Insulin alone had no effect on ER transcriptional activity, but chronic treatment in combination with estradiol resulted in synergism of ER transcription. The synergistic effect of insulin and estradiol on MCF7 cell growth was also found to require PI 3-kinase but not MAP kinase activity. Therefore, chronic estradiol treatment increases insulin stimulation of PI 3-kinase, and PI 3-kinase is required for estradiol stimulation of gene transcription alone and in combined synergy with insulin. These data demonstrate that PI 3-kinase is the locus for the cross-talk between insulin and estradiol which results in enhanced breast cancer growth with long-term exposure to both hormones. This may have important clinical implications for women with high risk for breast cancer and/or diabetes mellitus. ^

Human immunodeficiency virus (HIV) type 2-mediated inhibition of HIV type 1: a new approach to gene therapy of HIV-infection.

Human immunodeficiency virus (HIV) type 2, the second AIDS-associated human retrovirus, differs from HIV-1 in its natural history, infectivity, and pathogenicity, as well as in details of its genomic structure and molecular behavior. We report here that HIV-2 inhibits the replication of HIV-1 at the molecular level. This inhibition was selective, dose-dependent, and nonreciprocal. The closely related simian immunodeficiency provirus also inhibited HIV-1. The selectivity of inhibition was shown by the observation that HIV-2 did not significantly downmodulate the expression of the unrelated murine leukemia virus; neither did the murine leukemia virus markedly affect HIV-1 or HIV-2 expression. Moreover, while HIV-2 potently inhibited HIV-1, the reverse did not happen, thus identifying yet another and remarkable difference between HIV-1 and HIV-2. Mutational analysis of the HIV-2 genome suggested that the inhibition follows a complex pathway, possibly involving multiple genes and redundant mechanisms. Introduction of inactivating mutations into the structural and regulatory/accessory genes did not render the HIV-2 provirus ineffective. Some of the HIV-2 gene defects, such as that of tat and rev genes, were phenotypically transcomplemented by HIV-1. The HIV-2 proviruses with deletions in the putative packaging signal and defective for virus replication were effective in inducing the suppressive phenotype. Though the exact mechanism remains to be defined, the inhibition appeared to be mainly due to an intracellular molecular event because it could not be explained solely on the basis of cell surface receptor mediated interference. The results support the notion that the inhibition likely occurred at the level of viral RNA, possibly involving competition between viral RNAs for some transcriptional factor essential for virus replication. Induction of a cytokine is another possibility. These findings might be relevant to the clinical-epidemiological data suggesting that infection with HIV-2 may offer some protection against HIV-1 infection.