ViVaMBC: estimating viral sequence variation in complex populations from illumina deep-sequencing data using model-based clustering.

BACKGROUND: Deep-sequencing allows for an in-depth characterization of sequence variation in complex populations. However, technology associated errors may impede a powerful assessment of low-frequency mutations. Fortunately, base calls are complemented with quality scores which are derived from a quadruplet of intensities, one channel for each nucleotide type for Illumina sequencing. The highest intensity of the four channels determines the base that is called. Mismatch bases can often be corrected by the second best base, i.e. the base with the second highest intensity in the quadruplet. A virus variant model-based clustering method, ViVaMBC, is presented that explores quality scores and second best base calls for identifying and quantifying viral variants. ViVaMBC is optimized to call variants at the codon level (nucleotide triplets) which enables immediate biological interpretation of the variants with respect to their antiviral drug responses. RESULTS: Using mixtures of HCV plasmids we show that our method accurately estimates frequencies down to 0.5%. The estimates are unbiased when average coverages of 25,000 are reached. A comparison with the SNP-callers V-Phaser2, ShoRAH, and LoFreq shows that ViVaMBC has a superb sensitivity and specificity for variants with frequencies above 0.4%. Unlike the competitors, ViVaMBC reports a higher number of false-positive findings with frequencies below 0.4% which might partially originate from picking up artificial variants introduced by errors in the sample and library preparation step. CONCLUSIONS: ViVaMBC is the first method to call viral variants directly at the codon level. The strength of the approach lies in modeling the error probabilities based on the quality scores. Although the use of second best base calls appeared very promising in our data exploration phase, their utility was limited. They provided a slight increase in sensitivity, which however does not warrant the additional computational cost of running the offline base caller. Apparently a lot of information is already contained in the quality scores enabling the model based clustering procedure to adjust the majority of the sequencing errors. Overall the sensitivity of ViVaMBC is such that technical constraints like PCR errors start to form the bottleneck for low frequency variant detection.

unifiedWMWqPCR: the unified Wilcoxon-Mann-Whitney test for analyzing RT-qPCR data in R.

MOTIVATION: Recently, De Neve et al. proposed a modification of the Wilcoxon-Mann-Whitney (WMW) test for assessing differential expression based on RT-qPCR data. Their test, referred to as the unified WMW (uWMW) test, incorporates a robust and intuitive normalization and quantifies the probability that the expression from one treatment group exceeds the expression from another treatment group. However, no software package for this test was available yet. RESULTS: We have developed a Bioconductor package for analyzing RT-qPCR data with the uWMW test. The package also provides graphical tools for visualizing the effect sizes. AVAILABILITY AND IMPLEMENTATION: The unifiedWMWqPCR package and its user documentation can be obtained through Bioconductor.

Risks associated with bacterial vaginosis in infertility patients: a systematic review and meta-analysis.

STUDY QUESTION: Is bacterial vaginosis (BV) associated with the cause of infertility and does BV impinge on conception rates and early pregnancy loss following IVF? SUMMARY ANSWER: The incidence of BV is significantly higher among patients with tubal infertility when compared with patients with non-tubal infertility. BV does not impinge on conception rates but is significantly associated with preclinical pregnancy loss, though not with first trimester abortion. WHAT IS KNOWN ALREADY: BV is prevalent in patients with infertility, as evident from studies across the world. STUDY DESIGN, SIZE, DURATION: This study is a meta-analysis of data on the prevalence of BV in women with infertility, the association between BV and the cause of infertility, and the associations between BV and conception rates and early pregnancy loss following IVF. The meta-analyses of the various topics involved different numbers of studies: prevalence of BV with infertility--12 studies, association with tubal infertility--3 studies and associations with conception rates--6 studies, with early preclinical pregnancy loss--2 studies and with clinical pregnancy loss--4 studies. PARTICIPANTS/MATERIALS, SETTING, METHODS: Systematic literature searches of the electronic databases, PubMed, EMBASE, CINAHL, the Cochrane Library and ISI Web of Knowledge were performed up to September 2012. Studies were included if they reported on, at least, one of the following: prevalence of BV in infertility patients, association between BV and the cause of infertility, association between BV and conception rates with IVF or association between BV and early pregnancy loss. Studies were considered eligible if BV was diagnosed through standardized criteria like Nugent's criteria or Hay-Ison's criteria. In none of the studies, infertility as such was defined, but patients were described as unselected patients undergoing IVF. MAIN RESULTS AND THE ROLE OF CHANCE: The estimated prevalence of BV (Nugent score >6) in infertile women is 19% [95% confidence interval (CI): 14-25%]. Abnormal microflora including BV and intermediate microflora (Nugent scores 4-10) occurs in 39% of the infertile patients (95% CI: 26-52%). BV is significantly more prevalent in women with infertility compared with antenatal women in the same population [OR (odds ratio) 3.32, 95% CI 1.53-7.20]. BV is significantly more prevalent in women with tubal infertility compared with women with other causes of infertility (OR 2.77, 95% CI 1.62-4.75). BV is not associated with decreased conception rates (OR 1.03, 95% CI 0.79-1.33). Similarly, none of the studies found an association between abnormal vaginal flora and conception rates following IVF treatment. BV is associated with a significantly elevated risk of preclinical pregnancy loss (OR 2.36, 95% CI: 1.24-4.51). BV is not associated with an increased risk of first trimester miscarriage (OR 1.20, 95%CI: 0.53-2.75). LIMITATIONS, REASONS FOR CAUTION: All included studies were centre based. In addition, publication bias cannot be ruled out. Furthermore, all estimates are obtained using an absolute minimum of studies. The standard error on the estimates is so large that it does not allow for any formal statistical conclusions regarding heterogeneity between the effects reported in different studies. WIDER IMPLICATIONS OF THE FINDINGS: It needs to be recognized that most inferences drawn in our study rely on a limited number of studies, potentially, endangering the generalizability of our findings. Moreover, all studies on cause of infertility in relation to BV included had a cross-sectional design and, therefore, do not allow for causal inferences. Still, there is strong circumstantial evidence that supports a causal link between BV and tubal infertility. Studies with a longitudinal design, on the other hand, strongly support a relation between BV and early pregnancy loss. Unfortunately, no study looked beyond first trimester fetal loss, although it is plausible that the high preterm birth rates with IVF are, at least, in part attributable to BV.

Mobility and the spatial spread of sars-cov-2 in Belgium.

We analyse and mutually compare time series of covid-19-related data and mobility data across Belgium's 43 arrondissements (NUTS 3). In this way, we reach three conclusions. First, we could detect a decrease in mobility during high-incidence stages of the pandemic. This is expressed as a sizeable change in the average amount of time spent outside one's home arrondissement, investigated over five distinct periods, and in more detail using an inter-arrondissement "connectivity index" (CI). Second, we analyse spatio-temporal covid-19-related hospitalisation time series, after smoothing them using a generalise additive mixed model (GAMM). We confirm that some arrondissements are ahead of others and morphologically dissimilar to others, in terms of epidemiological progression. The tools used to quantify this are time-lagged cross-correlation (TLCC) and dynamic time warping (DTW), respectively. Third, we demonstrate that an arrondissement's CI with one of the three identified first-outbreak arrondissements is correlated to a substantial local excess mortality some five to six weeks after the first outbreak. More generally, we couple results leading to the first and second conclusion, in order to demonstrate an overall correlation between CI values on the one hand, and TLCC and DTW values on the other. We conclude that there is a strong correlation between physical movement of people and viral spread in the early stage of the sars-cov-2 epidemic in Belgium, though its strength weakens as the virus spreads.

Bacterial vaginosis is associated with uterine cervical human papillomavirus infection: a meta-analysis.

BACKGROUND: Bacterial vaginosis (BV), an alteration of vaginal flora involving a decrease in Lactobacilli and predominance of anaerobic bacteria, is among the most common cause of vaginal complaints for women of childbearing age. It is well known that BV has an influence in acquisition of certain genital infections. However, association between BV and cervical human papillomavirus (HPV) infection has been inconsistent among studies. The objective of this meta-analysis of published studies is to clarify and summarize published literature on the extent to which BV is associated with cervical HPV infection. METHODS: Medline and Web of Science were systematically searched for eligible publications until December 2009. Articles were selected based on inclusion and exclusion criteria. After testing heterogeneity of studies, meta-analysis was performed using random effect model. RESULTS: Twelve eligible studies were selected to review the association between BV and HPV, including a total of 6,372 women. The pooled prevalence of BV was 32%. The overall estimated odds ratio (OR) showed a positive association between BV and cervical HPV infection (OR, 1.43; 95% confidence interval, 1.11-1.84). CONCLUSION: This meta-analysis of available literature resulted in a positive association between BV and uterine cervical HPV infection.

Whose clock makes yours tick? How maternal cardiorespiratory physiology influences newborns' heart rate variability.

This study examined the existence of direct maternal-infant physiological relatedness in respiratory sinus arrhythmia (RSA) when the infant was age 1, 2, 4, 8, and 12 weeks. We instructed mothers to breathe at 6, 12, 15, 20, and 6 cycles per minute while their infants lay on their body. The mother-infant ECG and respiration were registered and video recordings were made. RR-interval (RRI), respiration rate (fR) and RSA were calculated and mother-infant RSA response-patterns were analyzed. The results revealed that infants adjusted their RSA levels to their mothers' levels during the first 2 months of life, but not at 3 months of age, which could be interpreted as a continuing intra-uterine effect. The attenuation between 2 and 3 months could be a reflection of the 2-month developmental shift of social orientation.

Environmental estrogens interact with and modulate the properties of plasma sex steroid-binding proteins in juvenile Atlantic salmon (Salmo salar).

Environmental chemicals may modulate the endocrine system through interaction with plasma sex steroid-binding proteins (SBP) and SBP-regulated processes. Some of these chemicals, which are known to interact with the estrogen receptor (ER), were found to bind competitively to the Atlantic salmon (Salmo salar) SBP and potentially disrupt the endocrine function of these proteins. Furthermore, both weakly acting (di-n-butyl phthalate) and potent estrogen mimics (ethynylestradiol), were able to induce a substantial up-regulation of circulating levels of SBP in vivo. Interestingly, modulation of SBP-levels was found to be a more sensitive endpoint than chemically induced interference with classical ER-mediated mechanisms for weakly acting estrogen mimics like di-(n-butyl) phthalate. Interference with the endocrine function of SBPs may thus introduce a novel mechanism for endocrine disruption. and give additional answers to the question why some weakly acting xenoestrogens are causing "estrogen-like" reproductive disturbances in developing males.

High frequency of genital human papillomavirus infections and related cervical dysplasia in adolescent girls in Belgium.

Human papillomavirus (HPV) infections are causally related to cervical cancer and a range of other diseases, both in adults and in minors. Information on the frequency of genital HPV infections in adolescents is sparse. The aim of this study was to gain insight into the genotype-specific distribution of HPV genotypes in patients younger than 18 years of age. This observational retrospective study included 4807 samples of patients presenting for opportunistic screening in Belgium between June 2006 and January 2012. For statistical analysis, only the first visits of patients were withheld, reducing the sample to 4180. Samples were collected in liquid-based cytology medium and analyzed using a series of genotype-specific real-time PCR reactions. Cytology was read with previous knowledge of HPV infection and scored using the Bethesda classification. The mean age was 16.9 years. Most youngsters had no complaints (88.4%), were using hormonal contraception (79.5%), and clinical examination did not show any abnormalities (96.0%). The overall HPV frequency was 15.7%, with the most frequently found types being HPV16 (16.7%), HPV51 (14.6%), HPV66 (10.4%), HPV31 (9.9%), and HPV39 (9.1%). More than one-third (39.0%) of the infected girls harbored an infection with at least two HPV genotypes. Cytological abnormalities were found in 8.2% of samples. L-SIL (4.2%) was most frequently observed, followed by ASC-US (3.6%), HSIL (0.3%), and ASC-H (0.1%). The severity of lesions worsened with increasing age. Our findings indicate that an aberrant HPV genotype profile can be found in adolescent girls; moreover, this group shows a high rate of cervical abnormalities.

Do you hear the same? Cardiorespiratory responses between mothers and infants during tonal and atonal music.

This study examined the effects of tonal and atonal music on respiratory sinus arrhythmia (RSA) in 40 mothers and their 3-month-old infants. The tonal music fragment was composed using the structure of a harmonic series that corresponds with the pitch ratio characteristics of mother-infant vocal dialogues. The atonal fragment did not correspond with a tonal structure. Mother-infant ECG and respiration were registered along with simultaneous video recordings. RR-interval, respiration rate, and RSA were calculated. RSA was corrected for any confounding respiratory and motor activities. The results showed that the infants' and the mothers' RSA-responses to the tonal and atonal music differed. The infants showed significantly higher RSA-levels during the tonal fragment than during the atonal fragment and baseline, suggesting increased vagal activity during tonal music. The mothers showed RSA-responses that were equal to their infants only when the infants were lying close to their bodies and when they heard the difference between the two fragments, preferring the tonal above the atonal fragment. The results are discussed with regard to music-related topics, psychophysiological integration and mother-infant vocal interaction processes.

Combined exposure to cyanobacteria and carbaryl results in antagonistic effects on the reproduction of Daphnia pulex.

In aquatic ecosystems, Daphnia are exposed to a wide variety of natural and chemical stressors that can cause interactive effects resulting in an increased impact on aquatic ecosystems. The authors therefore investigated the interactive effects of harmful cyanobacteria (cyanoHABs) with carbaryl in Daphnia pulex, because cyanobacteria have become an important concern for aquatic ecosystems. Daphnia were exposed for 21 d to 4 selected cyanobacteria (Aphanizomenon sp., Cylindrospermopsis raciborskii, Microcystis aeruginosa, and Oscillatoria sp), carbaryl, and all binary combinations of carbaryl and each individual cyanobacterium. Results were analyzed with both the independent action and the concentration addition model. The estimated median effect concentration (EC50) for carbaryl was comparable between the experiments, ranging from 2.28 µg/L to 5.94 µg/L. The EC50 for cyanobacteria ranged from 13.45% of the total diet ratio for Microcystis to 66.69% of the diet ratio for Oscillatoria. In combination with carbaryl, the response of Daphnia to 3 of the 4 cyanobacteria demonstrated antagonistic deviation patterns (p < 0.05). Exposure to combinations of carbaryl and Cylindrospermopsis did not result in statistically significant deviations from both reference models. The results may have important implications for pesticide risk assessment, underlining the impact of interactive effects on aquatic organisms. Based on these results, the authors suggest that both the independent action and the concentration addition model can serve as a protective approach in risk assessment of carbaryl in the presence of cyanobacterial blooms.

Transmission of carcinogenic human papillomavirus types from mother to child: a meta-analysis of published studies.

Currently, human papillomavirus (HPV) research focuses on HPV infection in adults and sexual transmission. Data on HPV infection in children are slowly becoming available. It is a matter of debate whether mother-to-child transmission of HPV is an important infection route and whether children born to HPV-positive mothers are at a higher risk of HPV infection compared with children born to HPV-negative mothers. The objective of this meta-analysis is to summarize the published literature on the extent to which genital HPV infection is vertically transmitted from mother to child. Medline, Web of Science, and CINAHL were searched for eligible reports published before January 2011. Differences in the risk of HPV infection between newborns from HPV-positive and HPV-negative mothers were pooled using a random-effects model. Twenty eligible studies, including 3128 women/children pairs, fulfilled the selection criteria. High heterogeneity could be found (I=96%). The overall estimated risk difference was 33% (95% confidence interval: 22-44%). On restricting to high-risk HPV-positive mothers only (n=4; women=231), the difference in risk was 45% (95% confidence interval: 33-56%). The heterogeneity was found to be low (I=15%). This meta-analysis indicates a significantly higher risk for children born to HPV-positive mothers to become HPV positive themselves. Plausible explanations include vertical transmission of HPV during pregnancy and/or birth or a higher infection rate during early nursing from mother to child. More research is required to gain an insight into the precise mode of transmission and the clinical effects of infection on the child.

Association between bacterial vaginosis and cervical intraepithelial neoplasia: systematic review and meta-analysis.

OBJECTIVE: Bacterial vaginosis (BV), the most common vaginal disorder among women of reproductive age, has been suggested as co-factor in the development of cervical cancer. Previous studies examining the relationship between BV and cervical intra-epithelial neoplasia (CIN) provided inconsistent and conflicting results. The aim of this study is to clarify the association between these two conditions. METHODS: A systematic review and meta-analysis were conducted to summarize published literature on the association between BV and cervical pre-cancerous lesions. An extensive search of electronic databases Medline (Pubmed) and Web of Science was performed. The key words 'bacterial vaginosis' and 'bacterial infections and vaginitis' were used in combination with 'cervical intraepithelial neoplasia', 'squamous intraepithelial lesions', 'cervical lesions', 'cervical dysplasia', and 'cervical screening'. Eligible studies required a clear description of diagnostic methods used for detecting both BV and cervical pre-cancerous lesions. Publications were included if they either reported odds ratios (OR) and corresponding 95% confidence intervals (CI) representing the magnitude of association between these two conditions, or presented data that allowed calculation of the OR. RESULTS: Out of 329 articles, 17 cross-sectional and 2 incidence studies were selected. In addition, two studies conducted in The Netherlands, using the national KOPAC system, were retained. After testing for heterogeneity and publication bias, meta-analysis and meta-regression were performed, using a random effects model. Although heterogeneity among studies was high (χ(2) = 164.7, p<0.01, I(2) = 88.5), a positive association between BV and cervical pre-cancerous lesions was found, with an overall estimated odds ratio of 1.51 (95% CI, 1.24-1.83). Meta-regression analysis could not detect a significant difference between studies based on BV diagnosis, CIN diagnosis or study population. CONCLUSIONS: Although most studies were cross-sectional and heterogeneity was high, this meta-analysis confirms a connection between BV and CIN.