Twenty years' experience with the Swiss data registry for assisted reproductive medicine: outcomes, key trends and recommendations for improved practice.

QUESTIONS UNDER STUDY The impact of assisted reproductive technology (ART) on Swiss demography was quantified. From 1993 to 2012 the number of deliveries, including multiples, generated by ART was compared with overall delivery numbers. Swiss experts in ART collaborated in a consensus to increase successful outcomes, to reduce the incidence of complications of ART and to validate recommendations through statistical review of available data. METHODS Data generated between 1993 and 2012 and published by the Federal Office of Statistics (BfS) were compared with the Swiss database on ART (FIVNAT-CH) as organised by the Swiss Society of Reproductive Medicine (SGRM). From these analyses a panel of Swiss experts in ART extracted recommendations to improve current practice, to prevent complications related to ART and to recommend changes in current Swiss legislation dealing with ART. RESULTS Since 1993 the age of women giving birth rose together with the number of women asking for ART. This demographic trend was reflected in a rise in the number of deliveries generated by ART (in 2012: 2.2%) and the proportion of multiple births (in 2012: 17.6%). The outcome of ART was most negatively influenced by the age of the treated patient. The number of retrieved oocytes decisively impacted the likelihood of delivery, the risk of multiple births and the incidence of ovarian hyperstimulation syndrome. CONCLUSIONS Optimal ovarian stimulation should be designed for the retrieval of 10 to 15 oocytes per treatment. Swiss legislation should enable and stimulate a policy of elective single embryo transfer to avoid multiple births.

Differential diagnosis of the honey bee trypanosomatids Crithidia mellificae and Lotmaria passim

Trypanosomatids infecting honey bees have been poorly studied with molecular methods until recently. After the description of Crithidia mellificae (Langridge and McGhee, 1967) it took about forty years until molecular data for honey bee trypanosomatids became available and were used to identify and describe a new trypanosomatid species from honey bees, Lotmaria passim (Evans and Schwarz, 2014). However, an easy method to distinguish them without sequencing is not yet available. Research on the related bumble bee parasites Crithidia bombi and Crithidia expoeki revealed a fragment length polymorphism in the internal transcribed spacer 1 (ITS1), which enabled species discrimination. In search of fragment length polymorphisms for differential diagnostics in honey bee trypanosomatids, we studied honey bee trypanosomatid cell cultures of C. mellificae and L. passim. This research resulted in the identification of fragment length polymorphisms in ITS1 and ITS1-2 markers, which enabled us to develop a diagnostic method to differentiate both honey bee trypanosomatid species without the need for sequencing. However, the amplification success of the ITS1 marker depends probably on the trypanosomatid infection level. Further investigation confirmed that L. passim is the dominant species in Belgium, Japan and Switzerland. We found C. mellificae only rarely in Belgian honey bee samples, but not in honey bee samples from other countries. C. mellificae was also detected in mason bees (Osmia bicornis and Osmia cornuta) besides in honey bees. Further, the characterization and comparison of additional markers from L. passim strain SF (published as C. mellificae strain SF) and a Belgian honey bee sample revealed very low divergence in the 18S rRNA, ITS1-2, 28S rRNA and cytochrome b sequences. Nevertheless, a variable stretch was observed in the gp63 virulence factor.

Environmental and behavioral risk factors for moderate or severe rotavirus diarrhea in children less than 24 months

On a global basis rotaviruses are the most important agents involved in childhood diarrhea. In developing countries they account for 6% of all diarrheas and 20% of all diarrhea related deaths of children under 5 years of age, with over 1 billion episodes and over 4 million deaths annually. Given the disease burden, there is a need for better understanding the risk factors involved in rotavirus disease, to identify areas of intervention. In order to provide this information, two areas were developed: a review of the literature, examining the causal evidence for rotavirus diarrhea and a case comparison study. The case comparison study analyzed two areas: identifying climate factors and, identifying environmental and behavioral risk factors. The literature review showed that few analytical studies have identified specific risk factors such as home environment, and a winter seasonal trend for temperate areas, but in key areas evidence is contradictory. The case comparison study for climate factors demonstrated that seasonality occurs in a tropical country like Venezuela and that a complex interplay between weather conditions contribute to the seasonal pattern. A positive association between rain fall (OR 4.1); dew point (OR 2.3) and temperature differential during the day (OR 1.4) and, an inverse association with temperature (OR 0.5) and relative humidity (OR 0.8) was found. This information is useful in understanding the seasonal pattern of rotavirus and for planning health care needs. The second analysis demonstrated that environmental variables such as crowding (OR 14.3), contact with someone with an infectious disease (OR 4.9) and animal ownership (OR 2.3) were important. Restricting the analysis to animal owners demonstrated that living In a rural settling (OR 13.8), defecating in inappropriate places (OR 7.2), crowding(4.2) and indoor animals (4.0) are of importance. Behavioral variables identified were: lack of breast feeding (OR 4.0) and visiting when someone was sick (OR 3.4). Biological and demographic variables of importance were: age, with a dose response relationship; undernurishment (OR 11.3) and household per capita monthly income less than US $ 16.30 (OR 8.5). Using a diarrhea compeer group we found that, although some of the previous variables were of importance, no major differences were found. These findings are important in identifying paths for prevention and further research. ^

Issues related to HIV stigma: An embedded case study of PLHAS and community in Nepal

Little is known about HIV stigma in Nepal. Findings from other parts of the world suggest that HIV related stigma acts as a limiting factor for People Living with HIV & AIDS (PLHAs) from accessing needed health care and the subsequent psychological outcomes make PLHAs and their immediate family members more vulnerable. The purpose of this study is to understand and describe Nepalese PLHA's and community peoples' experiences regarding sources, types, causes and mechanism of HIV-associated stigma. This study aimed to best utilize the existing data. Study participants were recruited through local Community Based Organizations working in the field of HIV. The data, collected in the form of focus group discussions in workshop settings, were coded and analyzed. Study has revealed key issues related to HIV stigma in Nepal: hierarchy of stigma, denial and rejection, death as a form of punishment and Mumbaiya disease. A conceptual model was developed to explain the HIV stigma in Nepal. Our hope is that this finding, stigma being a contextual variable, will be helpful in triggering a novel public health discourse in the field of HIV stigma in Nepal, which will eventually be helpful for developing policies and interventions to eliminate HIV-associated stigma.^

Determining appropriate measurement methods for etiological research of computing-related musculoskeletal symptoms and disorders

Two studies among college students were conducted to evaluate appropriate measurement methods for etiological research on computing-related upper extremity musculoskeletal disorders (UEMSDs). ^ A cross-sectional study among 100 graduate students evaluated the utility of symptoms surveys (a VAS scale and 5-point Likert scale) compared with two UEMSD clinical classification systems (Gerr and Moore protocols). The two symptom measures were highly concordant (Lin's rho = 0.54; Spearman's r = 0.72); the two clinical protocols were moderately concordant (Cohen's kappa = 0.50). Sensitivity and specificity, endorsed by Youden's J statistic, did not reveal much agreement between the symptoms surveys and clinical examinations. It cannot be concluded self-report symptoms surveys can be used as surrogate for clinical examinations. ^ A pilot repeated measures study conducted among 30 undergraduate students evaluated computing exposure measurement methods. Key findings are: temporal variations in symptoms, the odds of experiencing symptoms increased with every hour of computer use (adjOR = 1.1, p < .10) and every stretch break taken (adjOR = 1.3, p < .10). When measuring posture using the Computer Use Checklist, a positive association with symptoms was observed (adjOR = 1.3, p < 0.10), while measuring posture using a modified Rapid Upper Limb Assessment produced unexpected and inconsistent associations. The findings were inconclusive in identifying an appropriate posture assessment or superior conceptualization of computer use exposure. ^ A cross-sectional study of 166 graduate students evaluated the comparability of graduate students to College Computing & Health surveys administered to undergraduate students. Fifty-five percent reported computing-related pain and functional limitations. Years of computer use in graduate school and number of years in school where weekly computer use was ≥ 10 hours were associated with pain within an hour of computing in logistic regression analyses. The findings are consistent with current literature on both undergraduate and graduate students. ^

The movement toward patient safety: State action related to reporting and disclosure of healthcare-associated infections

Increasing attention has been given to the problem of medical errors over the past decade. Included within that focused attention has been a strong interest in reducing the occurrence of healthcare-associated infections (HAIs). Acting concurrently with federal initiatives, the majority of U.S. states have statutorily required reporting and public disclosure of HAI data. Although the occurrence of these state statutory enactments and other state initiatives represent a recognition of the strong concern pertaining to HAIs, vast differences in each state’s HAI reporting and public disclosure requirements creates a varied and unequal response to what has become a national problem.^ The purpose of this research was to explore the variations in state HAI legal requirements and other state mandates. State actions, including statutory enactments, regulations, and other initiatives related to state reporting and public disclosure mechanisms were compared, discussed, and analyzed in an effort to illustrate the impact of the lack of uniformity as a public health concern.^ The HAI statutes, administrative requirements, and other mandates of each state and two U.S. territories were reviewed to answer the following seven research questions: How far has the state progressed in its HAI initiative? If the state has a HAI reporting requirement, is it mandatory or voluntary? What healthcare entities are subject to the reporting requirements? What data collection system is utilized? What measures are required to be reported? What is the public disclosure mechanism? How is the underlying reported information protected from public disclosure or other legal release?^ Secondary publicly available data, including state statutes, administrative rules, and other initiatives, were utilized to examine the current HAI-related legislative and administrative activity of the study subjects. The information was reviewed and analyzed to determine variations in HAI reporting and public disclosure laws. Particular attention was given to the seven key research questions.^ The research revealed that considerable progress has been achieved in state HAI initiatives since 2004. Despite this progress, however, when reviewing the state laws and HAI programs comparatively, considerable variations were found to exist with regards to the type of reporting requirements, healthcare facilities subject to the reporting laws, data collection systems utilized, reportable measures, public disclosure requirements, and confidentiality and privilege provisions. The wide variations in state statutes, administrative rules, and other agency directives create a fragmented and inconsistent approach to addressing the nationwide occurrence of HAIs in the U.S. healthcare system. ^

The prevention of catheter related bloodstream infections in a pediatric population

Catheter related bloodstream infections are a significant barrier to success in many inpatient healthcare facilities. The goal of this study was to analyze and determine if an evidence based methodology to reduce the number of catheter related bloodstream infections in a pediatric inpatient healthcare facility had significant impact on the infection rate. Catheter related bloodstream infection rates were compared before and after program implementation. The patient population was selected based upon a recommendation in the 2010 National Healthcare Safety Network report on device related infections. This report indicated a need for more data on pediatric populations requiring admission to a long term care facility. The study design is a retrospective cohort study. Catheter related bloodstream infection data was gathered between 2008 and 2011. In October of 2008 a program implementation began to reduce the number of catheter related bloodstream infections. The key components of this initiative were to implement a standardized catheter maintenance checklist, introduce the usage of a chlorhexadine gluconate based product for catheter maintenance and skin antisepsis, and a multidisciplinary education plan that focused on hand hygiene and aseptic technique. The catheter related bloodstream infection rate in 2008 was 21.21 infections per 1000 patient-line days. After program implementation the 2009 catheter related bloodstream infection rate dropped to 1.11 per 1000 patient-line days. The infection rates in 2010 and 2011 were 2.19 and 1.47 respectively. Additionally, this study demonstrated that there was a potential cost savings of $620,000 to $1,240,000 between 2008 and 2009. In conclusion, an evidence based program based upon CDC guidelines can have a significant impact on catheter related bloodstream infection rates. ^

Functional analysis of the sea urchin {\it orthodenticle\/} -related gene, {\it SPOTX\/}, in aboral ectoderm-specific gene activation and aboral ectoderm cell fate specification

An important question in developmental biology is how embryonic cell types are derived from a fertilized egg. To address this question, this thesis investigates the mechanisms by which the aboral ectoderm-specific Spec2a gene is spatially and temporally regulated during sea urchin embryogenesis. The Spec2a gene of the sea urchin Strongylocentratus purpuratus has served as a valuable maker to understand the basis of lineage-specific gene activation and the role of transcription factors in cell fate specification. The hypothesis is that transcription factors responsible for cell type-specific gene activation are key components in the initial cell specification step. The Spec2a gene, which encodes a small cytosolic calcium-binding protein, is expressed exclusively in aboral ectoderm cell lineages. The 1516-bp control region of the Spec2a gene contains a 188-bp enhancer element required for temporal activation and aboral ectoderm/mesenchyme cell expression, while an unidentified element upstream of the enhancer represses expression in mesenchyme cells. Using an enhancer activation assay, combined with site-directed mutagenesis, I showed that three TAATCC/T sites within the enhancer are responsible for enhancer activity. Mutagenizing these sites and a fourth one just upstream abolished all activity from the Spec2a control region. A 77-bp DNA fragment from the Spec2a enhancer containing two of the TAATCC/T sites is sufficient for aboral ectoderm/mesenchyme cell expression. A cDNA encoding SpOtx, an orthodenticle-related protein, was cloned from S. purpuratus and shown to bind with high affinity to the TAATCC/T sequences within the Spec2a control region. SpOtx transcripts were found initially in all cells of the cleaving embryo, but they gradually became restricted to oral ectoderm and endoderm cells, suggesting that SpOtx might play a role in the initial temporal activation of the Spec2a gene and most likely has additional functions in the developing embryo. To reveal the broader biological functions of SpOtx, I injected SpOtx mRNA into living sea urchin eggs to determine what effects overexpressing the SpOtx protein might have on embryo development. SpOtx mRNA-injected embryos displayed dramatic alterations in development. Instead of developing into pluteus larvae with 15 different cell types, uniform epithelia balls were formed. These balls consisted of a thin layer of squamous cells with short cilia highly reminiscent of aboral ectoderm. Immunohistochemical staining and RT-PCR demonstrated that the SpOtx-injected embryoids expressed aboral ectoderm markers uniformly, but showed very weak or no expression of markers for non-aboral ectoderm cell types. These data strongly suggested that overexpression of SpOtx redirected the normal fate of non-aboral ectoderm cells to that of aboral ectoderm. These results show that SpOtx is involved in aboral ectoderm differentiation by activating aboral ectoderm-specific genes and that modulating its expression can lead to changes in cell fate. ^

Genetic analysis of Pitx2 in left -right asymmetry and cardiovascular development

Pitx2, a paired-related homeobox gene that is mutated in human Rieger Syndrome, plays a key role in transferring the early asymmetric signals to individual organs. Pitx2 encodes three isoforms, Pitx2a, Pitx2b and Pitx2c. I found that Pitx2c was the Pitx2 isoform for regulating left-right asymmetry in heart, lung and the predominant isoform in guts. Previous studies suggested that the generation of left-right asymmetry within individual organs is an all or none, random event. Phenotypic analysis of various Pitx2 allelic combinations, that encode graded levels of Pitx2c, reveals an organ-intrinsic mechanism for regulating left-right asymmetric morphogenesis based on differential response to Pitx2c levels. The heart needs low Pitx2c levels, while the lungs and duodenum require higher doses of Pitx2c. In addition, the duodenal rotation is under strict control of Pitx2c activity. Left-right asymmetry development for aortic arch arteries involves complex vascular remodeling. Left-sided expression of Pitx2c in these developing vessels implied its potential function in this process. In order to determine if Pitx2c also can regulate the left-right asymmetry of the aortic arch arteries, a Pitx2c-specific loss of function mutation is generated. Although in wild type mice, the direction of the aortic arch is always oriented toward the left side, the directions of the aortic arches in the mutants were randomized, showing that Pitx2c also determined the left-right asymmetry of these vessels. I have further showed that the cardiac neural crest wasn't involved in this vascular remodeling process. In addition, all mutant embryos had Double Outlet Right Ventricle (DORV), a common congenital heart disease. This study provided insight into the mechanism of Pitx2c-mediated late stages of left-right asymmetry development and identified the roles of Pitx2c in regulation of aortic arch remodeling and heart development. ^

Methodologies for estimating abortion incidence and abortion-related morbidity: a review.

The objective of the following chapters is to contribute to addressing these data quality issues by improving research on the measurement of abortion incidence and abortion related morbidity. To do so, they provide over- views of existing methods of and approaches to estimating abortion incidence and morbidity. The volume supplies detailed descriptions and examples of key methods. Its goal is to provide a clear understanding of the relative merits of available study designs to quantify abortion incidence and abortion related morbidity. Information on methodologies will greatly assist researchers worldwide in carrying out studies on these topics, particularly in settings where abortion is legally restricted.

Geochemistry, physical properties, diatom abundance and datums of ODP Site 186-1150 and Hole 186-1151A

Detection of climate response to orbital forcing during Cenozoic long-term global cooling is a key to understanding the behavior of Earth's icehouse climate. Sedimentary rhythm, which is a rhythmic or cyclic variation in the sequence of sediments and sedimentary rocks, is useful for quantitative reconstruction of Earth's evolution during geological time. In this study, we attempt to (1) identify sources of natural gamma ray (NGR) emissions of core recovered during Ocean Drilling Program (ODP) Leg 186 by analyses of physical properties, major element concentrations, diatom abundances, and total organic carbon contents, (2) integrate whole-core NGR intensity of recovered core with wireline logging NGR measurements in order to construct a continuous sedimentary sequence, and (3) discuss changes in the NGR signal in the time domain. This attempt gives us preliminary information to discuss climate stability in relation to orbital forcing thorough geologic time. NGR values are obtained mainly by indirectly measuring the amount of terrigenous minerals including potassium and related elements in the sediments. NGR intensity is also affected by high porosity, which in these sediments was related to the amount of diatom valves. NGR signals might be a proxy of the intensity of the East Asian monsoon off Sanriku. A continuous sedimentary record was constructed by integration of the whole-core NGR intensity measured in sediments obtained from the drilled holes with that measured directly in the borehole by wireline logging, then using a stratigraphic age model to convert to a time series covering 1.3-9.7 Ma with a short break at ~5 Ma. High sedimentation rate (H) stages were identified in the sequence, related to intervals of low-amplitude precession and eccentricity variations. The transition of the dominant periodicities through the four H stages may correlate to major shifts in the climate system, including the onset of major Northern Hemisphere glaciation, the initial stage of the East Asian monsoon intensification, and the onset of the East Asian monsoon with uplift of the Himalayas and the Tibetan Plateau.

Fig. S1. Loci of possible event locations based on differential ts - tp arrival times at the single functioning geophone

Geological storage of CO2 that has been captured at large, point source emitters represents a key potential method for reduction of anthropogenic greenhouse gas emissions. However, this technology will only be viable if it can be guaranteed that injected CO2 will remain trapped in the subsurface for thousands of years or more. A signi?cant issue for storage security is the geomechanical response of the reservoir. Concerns have been raised that geomechanical deformation induced by CO2 injection will create or reactivate fracture networks in the sealing caprocks, providing a pathway for CO2 leakage. In this paper, we examine three large-scale sites where CO2 is injected at rates of ab. 1 megatonne/y or more: Sleipner, Weyburn, and In Salah. We compare and contrast the observed geomechanical behavior of each site, with particular focus on the risks to storage security posed by geomechanical deformation. At Sleipner, the large, high-permeability storage aquifer has experienced little pore pressure increase over 15 y of injection, implying little possibility of geomechanical deformation. At Weyburn, 45 y of oil production has depleted pore pressures before increases associated with CO2 injection. The long history of the ?eld has led to complicated, sometimes nonintuitive geomechanical deformation. At In Salah, injection into the water leg of a gas reservoir has increased pore pressures, leading to uplift and substantial microseismic activity. The differences in the geomechanical responses of these sites emphasize the need for systematic geomechanical appraisal before injection in any potential storage site.