Fcgr2b and Fcgr3 are the major genetic factors for cartilage antibody-induced arthritis, overriding the effect of Hc encoding complement C5.

Like rheumatoid arthritis (RA) in humans, collagen-induced arthritis (CIA) in mice is associated with not only MHC class II genetic polymorphism but also, to some extent, with other loci including genes encoding Fc gamma receptors (FCGRs) and complement C5. In this study, we used a cartilage antibody-induced arthritis (CAIA) model in which arthritis develops within a 12-h timeframe, to determine the relative importance of FCGRs and C5 (Hc). In CAIA, inhibiting or deleting FCGR3 substantially hindered arthritis development, underscoring the crucial role of this receptor. Blocking FCGR3 also reduced the levels of FCGR4, and vice versa. When employing an IgG1 arthritogenic cocktail that exclusively interacts with FCGR2B and FCGR3, joint inflammation was promptly initiated in Fcgr2b-- mice but not in Fcgr3-- mice, suggesting that FCGR3 is sufficient for CAIA development. Regarding complement activation, Fcgr2b++.Hc** mice with C5 mutated were fully resistant to CAIA, whereas Fcgr2b--.Hc** mice developed arthritis rapidly. We conclude that FCGR3 is essential and sufficient for CAIA development, particularly when induced by IgG1 antibodies. The human ortholog of mouse FCGR3, FCGR2A, may be associated with RA pathogenesis. FCGR2B deficiency allows for rapid arthritis progression and overrides the resistance conferred by C5 deficiency.

Transposable elements drive intron gain in diverse eukaryotes.

There is massive variation in intron numbers across eukaryotic genomes, yet the major drivers of intron content during evolution remain elusive. Rapid intron loss and gain in some lineages contrast with long-term evolutionary stasis in others. Episodic intron gain could be explained by recently discovered specialized transposons called Introners, but so far Introners are only known from a handful of species. Here, we performed a systematic search across 3,325 eukaryotic genomes and identified 27,563 Introner-derived introns in 175 genomes (5.2%). Species with Introners span remarkable phylogenetic diversity, from animals to basal protists, representing lineages whose last common ancestor dates to over 1.7 billion years ago. Aquatic organisms were 6.5 times more likely to contain Introners than terrestrial organisms. Introners exhibit mechanistic diversity but most are consistent with DNA transposition, indicating that Introners have evolved convergently hundreds of times from nonautonomous transposable elements. Transposable elements and aquatic taxa are associated with high rates of horizontal gene transfer, suggesting that this combination of factors may explain the punctuated and biased diversity of species containing Introners. More generally, our data suggest that Introners may explain the episodic nature of intron gain across the eukaryotic tree of life. These results illuminate the major source of ongoing intron creation in eukaryotic genomes.

Treenome Browser: co-visualization of enormous phylogenies and millions of genomes.

SUMMARY: Treenome Browser is a web browser tool to interactively visualize millions of genomes alongside huge phylogenetic trees. AVAILABILITY AND IMPLEMENTATION: Treenome Browser for SARS-CoV-2 can be accessed at cov2tree.org, or at taxonium.org for user-provided trees. Source code and documentation are available at github.com/theosanderson/taxonium and docs.taxonium.org/en/latest/treenome.html. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Online Phylogenetics with matOptimize Produces Equivalent Trees and is Dramatically More Efficient for Large SARS-CoV-2 Phylogenies than de novo and Maximum-Likelihood Implementations.

Phylogenetics has been foundational to SARS-CoV-2 research and public health policy, assisting in genomic surveillance, contact tracing, and assessing emergence and spread of new variants. However, phylogenetic analyses of SARS-CoV-2 have often relied on tools designed for de novo phylogenetic inference, in which all data are collected before any analysis is performed and the phylogeny is inferred once from scratch. SARS-CoV-2 data sets do not fit this mold. There are currently over 14 million sequenced SARS-CoV-2 genomes in online databases, with tens of thousands of new genomes added every day. Continuous data collection, combined with the public health relevance of SARS-CoV-2, invites an "online" approach to phylogenetics, in which new samples are added to existing phylogenetic trees every day. The extremely dense sampling of SARS-CoV-2 genomes also invites a comparison between likelihood and parsimony approaches to phylogenetic inference. Maximum likelihood (ML) and pseudo-ML methods may be more accurate when there are multiple changes at a single site on a single branch, but this accuracy comes at a large computational cost, and the dense sampling of SARS-CoV-2 genomes means that these instances will be extremely rare because each internal branch is expected to be extremely short. Therefore, it may be that approaches based on maximum parsimony (MP) are sufficiently accurate for reconstructing phylogenies of SARS-CoV-2, and their simplicity means that they can be applied to much larger data sets. Here, we evaluate the performance of de novo and online phylogenetic approaches, as well as ML, pseudo-ML, and MP frameworks for inferring large and dense SARS-CoV-2 phylogenies. Overall, we find that online phylogenetics produces similar phylogenetic trees to de novo analyses for SARS-CoV-2, and that MP optimization with UShER and matOptimize produces equivalent SARS-CoV-2 phylogenies to some of the most popular ML and pseudo-ML inference tools. MP optimization with UShER and matOptimize is thousands of times faster than presently available implementations of ML and online phylogenetics is faster than de novo inference. Our results therefore suggest that parsimony-based methods like UShER and matOptimize represent an accurate and more practical alternative to established ML implementations for large SARS-CoV-2 phylogenies and could be successfully applied to other similar data sets with particularly dense sampling and short branch lengths.

matOptimize: a parallel tree optimization method enables online phylogenetics for SARS-CoV-2.

MOTIVATION: Phylogenetic tree optimization is necessary for precise analysis of evolutionary and transmission dynamics, but existing tools are inadequate for handling the scale and pace of data produced during the coronavirus disease 2019 (COVID-19) pandemic. One transformative approach, online phylogenetics, aims to incrementally add samples to an ever-growing phylogeny, but there are no previously existing approaches that can efficiently optimize this vast phylogeny under the time constraints of the pandemic. RESULTS: Here, we present matOptimize, a fast and memory-efficient phylogenetic tree optimization tool based on parsimony that can be parallelized across multiple CPU threads and nodes, and provides orders of magnitude improvement in runtime and peak memory usage compared to existing state-of-the-art methods. We have developed this method particularly to address the pressing need during the COVID-19 pandemic for daily maintenance and optimization of a comprehensive SARS-CoV-2 phylogeny. matOptimize is currently helping refine on a daily basis possibly the largest-ever phylogenetic tree, containing millions of SARS-CoV-2 sequences. AVAILABILITY AND IMPLEMENTATION: The matOptimize code is freely available as part of the UShER package (https://github.com/yatisht/usher) and can also be installed via bioconda (https://bioconda.github.io/recipes/usher/README.html). All scripts we used to perform the experiments in this manuscript are available at https://github.com/yceh/matOptimize-experiments. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Pathogenic antibody response to glucose-6-phosphate isomerase targets a modified epitope uniquely exposed on joint cartilage.

OBJECTIVES: To identify the arthritogenic B cell epitopes of glucose-6-phosphate isomerase (GPI) and their association with rheumatoid arthritis (RA). METHODS: IgG response towards a library of GPI peptides in patients with early RA, pre-symptomatic individuals and population controls, as well as in mice, were tested by bead-based multiplex immunoassays and ELISA. Monoclonal IgG were generated, and the binding specificity and affinity were determined by ELISA, gel size exclusion chromatography, surface plasma resonance and X-ray crystallography. Arthritogenicity was investigated by passive transfer experiments. Antigen-specific B cells were identified by peptide tetramer staining. RESULTS: Peptide GPI293-307 was the dominant B cell epitope in K/BxN and GPI-immunised mice. We could detect B cells and low levels of IgM antibodies binding the GPI293-307 epitopes, and high affinity anti-GPI293-307 IgG antibodies already 7 days after GPI immunisation, immediately before arthritis onset. Transfer of anti-GPI293-307 IgG antibodies induced arthritis in mice. Moreover, anti-GPI293-307 IgG antibodies were more frequent in individuals prior to RA onset (19%) than in controls (7.5%). GPI293-307-specific antibodies were associated with radiographic joint damage. Crystal structures of the Fab-peptide complex revealed that this epitope is not exposed in native GPI but requires conformational change of the protein in inflamed joint for effective recognition by anti-GPI293-307 antibodies. CONCLUSIONS: We have identified the major pathogenic B cell epitope of the RA-associated autoantigen GPI, at position 293-307, exposed only on structurally modified GPI on the cartilage surface. B cells to this neo-epitope escape tolerance and could potentially play a role in the pathogenesis of RA.

A Daily-Updated Database and Tools for Comprehensive SARS-CoV-2 Mutation-Annotated Trees.

The vast scale of SARS-CoV-2 sequencing data has made it increasingly challenging to comprehensively analyze all available data using existing tools and file formats. To address this, we present a database of SARS-CoV-2 phylogenetic trees inferred with unrestricted public sequences, which we update daily to incorporate new sequences. Our database uses the recently proposed mutation-annotated tree (MAT) format to efficiently encode the tree with branches labeled with parsimony-inferred mutations, as well as Nextstrain clade and Pango lineage labels at clade roots. As of June 9, 2021, our SARS-CoV-2 MAT consists of 834,521 sequences and provides a comprehensive view of the virus' evolutionary history using public data. We also present matUtils-a command-line utility for rapidly querying, interpreting, and manipulating the MATs. Our daily-updated SARS-CoV-2 MAT database and matUtils software are available at http://hgdownload.soe.ucsc.edu/goldenPath/wuhCor1/UShER_SARS-CoV-2/ and https://github.com/yatisht/usher, respectively.

Health of Syrian unaccompanied asylum seeking adolescents (UASA) at first medical examination in Germany in comparison to UASA from other world regions.

BACKGROUND: The war in Syria has led to the biggest refugee crisis of our time. Unaccompanied asylum seeking adolescents (UASA) are a particularly vulnerable subgroup of refugees. This study aims to describe the weight status, health behaviour and disease spectrum of Syrian UASA in comparison to UASA from other world regions. METHODS: The study was conducted as a prospective cross-sectional analysis of health metrics and diagnoses from 346 UASA (78% male; mean age 16 years) between 2011 and 2017. The data was collected in an outpatient clinic for internal and tropical medicine during a systematic medical examination after arrival. Descriptive and bivariate analyses stratified by gender and region/country of origin were performed. RESULTS: The general health status of the UASA in most cases was good. Compared to other UASA Syrian UASA had the highest underweight prevalence (16.7%) (p = .013) and the second highest smoking prevalence (37.9%) (p < .001). Diseases at first medical examination mostly were infections and diseases of the digestive system, with significant differences between the regions/countries of origin (p < .001; p < .001, respectively). Syrian UASA had a lower prevalence of infections (28%) and a similar prevalence of mental and behavioural problems (10.3%) than the average of all regions/countries of origin (48.6%; 11%, respectively). CONCLUSION: Tailored screening for diseases as well as for health behaviour immediately after arrival in Germany is needed to reduce the individual burden of disease and to offer targeted preventive measures.

[Assessment of health risks due to heat and fine particles in Germany: an epidemiological study approach]. / Erfassung von hitze- und feinstaubbedingten Gesundheitsrisiken in Deutschland: Ein epidemiologischer Studienansatz.

BACKGROUND: Exposure to heat and particulate matter is a cause of increased mortality. Climate change and increasing climate variability exacerbate these problems. Experts require assessments with which health risks and the success of preventative measures can be estimated. We implemented an ecological study approach to assess these risks at both small and large scales of reference levels (Federal Republic of Germany and territorial authority). METHODS: We utilised a case-crossover design to investigate the relationship between exposure and mortality. This study design uses a logistic regression model. Analogously to a matched case-control study, the odds ratio maps the effect strength. The study period included the years 2002-2006. RESULTS: The analysis demonstrated health risks from exposure to heat for the German population (OR 1.1529, 95% CI 1.1517-1.1541; adjusted OR 1.0658). Significant evidence of a health risk was also documented for exposure to particulate matter (PM10; OR 1.2987, 95% CI 1.2951-1.3024; adjusted OR 1.0128). The risk does not significantly differ for women versus men; the variable age was also not significant at the level of the country-wide analysis, but for a few subordinate units of space. This study approach can be adapted for assessments at varying levels of reference and periods of time as well as for different populations. DISCUSSION: The methodological approach is useful for a reproducible study design. Nevertheless, other influencing factors such as ozone or PM2.5 should be incorporated in subsequent analyses to clarify whether these factors skew the results. Further analysis would also be useful to investigate if and to what extent socio-structural and socio-economic factors affect the associated risk.

[INTRAOPERATIVE RADIOTHERAPY (IORT) IN EARLY BREAST CANCER - 500 PATIENTS, ONE CENTER'S EXPERIENCE].

AIMS: To present our Institute's experience with intraoperative radiotherapy in this selected population by collecting and analyzing clinical data, including long-term follow-up. BACKGROUND: Breast-conserving therapy is the standard treatment for early-stage breast cancer. The treatment includes tumor resection and a whole breast irradiation. Intraoperative radiotherapy is a single dose of irradiation given to the tumor bed immediately after it is removed. This treatment is suitable for a selected population of patients with early stage breast cancer, which constitutes about 20% of all breast cancer patients and is supposed to replace the standard whole breast radiation treatment. METHODS: Between the years 2006-2017, 737 women with early breast cancer were treated in Carmel Medical Center with intraoperative radiotherapy. We herein report the results of the first 500 patients who were treated until 2015. RESULTS: In 13.8% of the patients, additional breast treatment was recommended due to poor pathological characteristics of the disease in final pathological examination. During a median follow-up period of 74 months (1-136), recurrence was observed in 22 patients (4.4%), and in 7 patients (1.4%) recurrence was observed in regional lymph nodes; 13 patients (2.6%) developed metastatic disease. Risk factors for regional recurrence were identified: tumor size greater than 2 cm, lack of adjuvant therapy and poor genetic profile of the disease. CONCLUSIONS: Intraoperative radiotherapy is feasible and may offer an alternative to the standard whole breast radiotherapy, in low risk early breast cancer patients. The patients should be selected according to known risk factors.

Atrazine affects craniofacial chondrogenesis and axial skeleton mineralization in zebrafish ( Danio rerio).

Atrazine is a commonly used herbicide that has previously been implicated as an endocrine-disrupting compound. Previous studies have shown that estrogenic endocrine-disrupting compounds affect the development of the heart, cartilage, and bone in zebrafish ( Danio rerio). To determine whether atrazine has effects similar to other endocrine disruptors, zebrafish embryos were treated with a range of atrazine concentrations. Atrazine treatment at a low concentration of 0.1 µM resulted in significant differences in craniofacial cartilage elements, while concentrations ≥1 µM led to decreased survival and increased heart rates. Fish treated with ≥1 µM atrazine also developed with delayed vertebrae mineralization. Higher concentrations of atrazine caused gross craniofacial defects and decreased hatching rates. Further studies into the molecular pathways disrupted in these developmental processes could shed light on a link between endocrine-disrupting compounds and developmental abnormalities.

[Recommendations for Academic Profiling of Global Public Health in Germany]. / Empfehlungen zur akademischen Profilierung von Global Public Health in Deutschland.

Many dimensions of public health are now global. Therefore, global public health is essential for facing cross-border health problems, promoting health chances and reducing health inequalities on a global level. The aim of this interdisciplinary research field is to improve the health of the population and its subgroups in a global context, taking into account a variety of factors. The importance of global public health is shown in this paper. Central topics, concepts and methods, as well as challenges for global public health are identified and recommendations for the academic profiling of global public health in Germany are given.

Cost-effectiveness of human papillomavirus vaccination in Germany.

BACKGROUND: The aim of this study was to assess the cost-effectiveness of human papillomavirus (HPV) vaccination in addition to the current cervical cancer screening programme in Germany using a dynamic transmission model. METHODS: Based on a mathematical model simulating the transmission dynamics and the natural history of HPV infection and associated diseases (cervical intraepithelial neoplasia, cervical cancer, and genital warts), we estimated the epidemiological and economic consequences of HPV vaccination with both the quadrivalent and bivalent vaccines. In our base case analysis, we assessed the cost-effectiveness of vaccinating 12-year-old girls with a 3-dose schedule. In sensitivity analysis, we also evaluated the use of a 2-dose schedule and assessed the impact of vaccinating boys. RESULTS: From a health care payer perspective, incremental cost-effectiveness ratios (ICERs) of a 3-dose schedule were €34,249 per quality-adjusted life year (QALY) for the bivalent and €14,711 per QALY for the quadrivalent vaccine. Inclusion of indirect costs decreased ICERs by up to 40%. When adopting a health care payer perspective, ICERs of a 2-dose approach decreased to €19,450 per QALY for the bivalent and to €3645 per QALY for the quadrivalent vaccine. From a societal perspective, a 2-dose approach using the quadrivalent vaccine was a cost-saving strategy while using the bivalent vaccine resulted in an ICER of €13,248 per QALY. Irrespective of the perspective adopted, additional vaccination of boys resulted in ICERs exceeding €50,000 per QALY, except for scenarios with low coverage (20%) in girls. CONCLUSIONS: Our model results suggest that routine HPV vaccination of 12-year-old girls with three doses is likely to be cost-effective in Germany. Due to the additional impact on genital warts, the quadrivalent vaccine appeared to be more cost-effective than the bivalent vaccine. A 2-dose schedule of the quadrivalent vaccine might even lead to cost savings when adopting a societal perspective. The cost-effectiveness of additional vaccination of boys was highly dependent on the coverage in girls.

[The health situation and health care needs of unaccompanied minor refugees - an approximation based on qualitative and quantitative studies from Bielefeld, Germany]. / Gesundheitliche Situation und Versorgung unbegleiteter minderjähriger Flüchtlinge - eine Näherung anhand qualitativer und quantitativer Forschung in der Stadt Bielefeld.

Unaccompanied minor refugees are children or adolescents below the age of 18 years who are not accompanied by their parents. International studies show that unaccompanied minor refugees represent a special risk group. Currently, empirical study results about the health status of unaccompanied minor refugees barely exist for Germany. Therefore, the goal of this article is an assessment of the health status and health care of unaccompanied minor refugees in Bielefeld, Germany. For this purpose, two qualitative studies and one quantitative study from Bielefeld are used.Results demonstrate that the health care of unaccompanied minor refugees underlies certain peculiarities that indicate major medical needs: Firstly, the need for psychological/psychiatric care and secondly the need for health care regarding infectious diseases. Further challenges in the health care needs of this population group result from its specific situation, and comprise legal conditions, as well as language and cultural competencies on behalf of the health care providers and the unaccompanied minor refugees themselves.

Disease profile and health-related quality of life (HRQoL) using the EuroQol (EQ-5D + C) questionnaire for chronic metallic mercury vapor intoxication.

BACKGROUND: Toxic mercury is still being used today for example by workers mining gold, resulting in diverse health symptoms in users and individuals in proximity. A considerable burden of disease (BoD) can be assumed, while previous analyses were limited by data scarcity. Besides limited epidemiological data, neither data about the health-related quality of life (HRQoL) nor about the disease severity (disability weight, DW) is available. The aim of the project was to develop disease profiles of chronic metallic mercury vapor intoxication (CMMVI) by including the HRQoL to improve the data basis for BoD analyses of gold miners exposed to mercury. METHODS: Disease profiles comprising the disease label [a], differentiation into disease stages [b], description of the cause of exposure [c], a list of common symptoms [d], and an assessment of the HRQoL [e] were developed using expert elicitation and literature search. The HRQoL was assessed by experts using the five EuroQol dimensions accompanied by the cognition add-on questionnaire (EQ-5D + C). RESULTS: The ten sources used for the analyses (interview transcript, presentation, and eight literature reviews) identified more than 250 terms describing 85 distinguishable health effects of CMMVI. The analysis revealed 29 common symptoms that were frequently mentioned. Moderate and severe CMMVI cases differ regarding their symptoms and/or symptom severity and HRQoL, resulting in the EQ-5D + C-3L codes 121222 and 233333, respectively. CONCLUSIONS: The profiles should be used to facilitate the ascertainment of CMMVI cases, to compare the HRQoL with other diseases, to derive DWs for improving BoD estimates, and to foster discussions about how to reduce the associated burden.

Sociodemographic and health-(care-)related characteristics of online health information seekers: a cross-sectional German study.

BACKGROUND: Although the increasing dissemination and use of health-related information on the Internet has the potential to empower citizens and patients, several studies have detected disparities in the use of online health information. This is due to several factors. So far, only a few studies have examined the impact of socio-economic status (SES) on health information seeking on the Internet. This study was designed to identify sociodemographic and health-(care-)related differences between users and non-users of health information gleaned from the Internet with the aim of detecting hard-to-reach target groups. METHODS: This study analyzed data from the NRW Health Survey LZG.NRW 2011 (n = 2,000; conducted in North Rhine-Westphalia, Germany, via telephone interviews). Logistic regression analysis was used to examine the determinants of online health information seeking behavior. RESULTS: 68% of Internet users refer to the Internet for health-related purposes. Of the independent variables tested, SES proved to exert the strongest influence on searching the Internet for health information. The final multivariate regression model shows that people from the middle (OR: 2.2, 95% CI: 1.6-3.2) and upper (OR: 4.0, 95% CI: 2.7-6.2) social classes are more likely to seek health information on the Internet than those from the lower class. Also, women are more likely to look for health information on the Internet than men (OR: 1.5, 95% CI: 1.1-2.1). Individuals with a migration background are less likely to conduct health searches on the Internet (OR: 0.6, 95% CI: 0.4-0.8). Married people or individuals in a stable relationship search the Internet more often for health information than do singles (OR: 1.9, 95% CI: 1.2-2.9). Also, heavy use of health-care services compared to non-use is associated with a higher likelihood of using the Internet for health-related matters (OR: 1.7, 95% CI: 1.2-2.5). CONCLUSIONS: In order to achieve equity in health, health-related Internet use by the socially deprived should be promoted through measures to increase their level of e-health literacy. Furthermore, longitudinal studies are needed in order to gain reliable data/results on determinants of health-related Internet use.

Meeting the International Health Regulations (2005) surveillance core capacity requirements at the subnational level in Europe: the added value of syndromic surveillance.

BACKGROUND: The revised World Health Organization's International Health Regulations (2005) request a timely and all-hazard approach towards surveillance, especially at the subnational level. We discuss three questions of syndromic surveillance application in the European context for assessing public health emergencies of international concern: (i) can syndromic surveillance support countries, especially the subnational level, to meet the International Health Regulations (2005) core surveillance capacity requirements, (ii) are European syndromic surveillance systems comparable to enable cross-border surveillance, and (iii) at which administrative level should syndromic surveillance best be applied? DISCUSSION: Despite the ongoing criticism on the usefulness of syndromic surveillance which is related to its clinically nonspecific output, we demonstrate that it was a suitable supplement for timely assessment of the impact of three different public health emergencies affecting Europe. Subnational syndromic surveillance analysis in some cases proved to be of advantage for detecting an event earlier compared to national level analysis. However, in many cases, syndromic surveillance did not detect local events with only a small number of cases. The European Commission envisions comparability of surveillance output to enable cross-border surveillance. Evaluated against European infectious disease case definitions, syndromic surveillance can contribute to identify cases that might fulfil the clinical case definition but the approach is too unspecific to comply to complete clinical definitions. Syndromic surveillance results still seem feasible for comparable cross-border surveillance as similarly defined syndromes are analysed. We suggest a new model of implementing syndromic surveillance at the subnational level. In this model, syndromic surveillance systems are fine-tuned to their local context and integrated into the existing subnational surveillance and reporting structure. By enhancing population coverage, events covering several jurisdictions can be identified at higher levels. However, the setup of decentralised and locally adjusted syndromic surveillance systems is more complex compared to the setup of one national or local system. SUMMARY: We conclude that syndromic surveillance if implemented with large population coverage at the subnational level can help detect and assess the local and regional effect of different types of public health emergencies in a timely manner as required by the International Health Regulations (2005).

Girl-child marriage and its association with morbidity and mortality of children under 5 years of age in a nationally-representative sample of Pakistan.

OBJECTIVE: To determine the relationship between child marriage (before age 18 years) and morbidity and mortality of children under 5 years of age in Pakistan beyond those attributed to social vulnerabilities. STUDY DESIGN: Nationally-representative cross-sectional observational survey data from Pakistan Demographic and Health Survey, 2006-2007 was limited to children from the past 5 years, reported by ever-married women aged 15-24 years (n = 2630 births of n = 2138 mothers) to identify differences in infectious diseases in past 2 weeks (diarrhea, acute respiratory infection [ARI], ARI with fever), under 5 years of age and infant mortality, and low birth weight by early (<18) vs adult (≥ 18) age at marriage. Associations between child marriage and mortality and morbidity of children under 5 years of age were assessed by calculating adjusted OR using logistic regression models after controlling for maternal and child demographics. RESULTS: Majority (74.5%) of births were from mothers aged <18 years. Marriage before age 18 years increased the likelihood of recent diarrhea among children born to young mothers (adjusted OR = 1.59; 95% CI: 1.18-2.14). Even though maternal child marriage was associated with infant mortality and mortality of children under 5 years of age in unadjusted models, association was lost in the adjusted models. We did not find a relation between girl-child marriage and low birth weight infants, and ARI. CONCLUSIONS: Girl-child marriage increases the likelihood of recent diarrhea among children born to young mothers. Further qualitative and prospective quantitative studies are needed to understand the factors that may drive child morbidity and mortality among those married as children vs adults in Pakistan.

Knowledge and attitude towards child marriage practice among women married as children-a qualitative study in urban slums of Lahore, Pakistan.

BACKGROUND: Child marriage (<18 years) is prevalent in Pakistan which is associated with negative health outcomes. Our aim is to describe women's knowledge and attitude towards child marriage practice who themselves were married as children. METHODS: Women of reproductive age (15-49 years) who were married prior to 18 years, for at least 5 years and had at least one child birth were recruited from most populous slum areas of Lahore, Pakistan. Themes for the interview were developed using published literature and everyday observations of the researchers. Interviews were conducted by trained interviewers in Urdu language and were translated into English. The interviews were tape-recorded, transcribed, analyzed and categorized into themes. RESULTS: Nineteen of 20 participants who agreed to participate were married between 11-17 years. Most respondents were uneducated, poor and were working as housemaids. The majority participants were unaware of the negative health outcomes of child marriages. They appeared satisfied by the decision of their parents of marrying them before 18 years, and even condemned banning child marriages in Pakistan. Strong influence of culture and community perceptions, varying interpretation of religion, and protecting family honor are some of the reasons that were narrated by the participants, which seems playing a role in continuation of child marriage practice in Pakistan. CONCLUSION: Raising awareness of the negative health outcomes of child marriage, implementing and enforcing strict laws against child marriage practice, promoting civil, sexual and reproductive health rights for women, can help eliminate child marriages in Pakistan.

Clustering of developmental delays in Bavarian preschool children - a repeated cross-sectional survey over a period of 12 years.

BACKGROUND: While most children display a normal development, some children experience developmental delays compared to age specific development milestones assessed during school entry examination. Data exist on prevalence of delays in single areas, but there is lack of knowledge regarding the clustering patterns of developmental delays and their determinants. METHODS: During the observation period 1997-2008, 12 399 preschool children (5-7 years of age) in one district of Bavaria, Germany, were assessed in twelve schooling-relevant development areas. The co-occurrence of developmental delays was studied by means of Pearson's correlation. Subsequently, a two-step cluster algorithm was applied to identify patterns of developmental delays, and multinomial logistic regression was conducted to identify variables associated with the specific patterns. RESULTS: Fourteen percent of preschool children displayed developmental delays in one and 19% in two or more of the studied areas. Among those with at least two developmental delays, most common was the combination of delays in "fine motor skills" + "grapho-motor coordination" (in 9.1% of all children), followed by "memory/concentration" + "endurance" (5.8%) and "abstraction" + "visual perception" (2.1%). In the cluster analysis, five distinct patterns of delays were identified, which displayed different associations with male gender and younger age. CONCLUSIONS: While developmental delays can affect single areas, clustering of multiple developmental delays is common. Such clustering should be taken into account when developing diagnostic tests, in pediatric practice and considering interventions to reduce delays.