Estimating between-country migration in pneumococcal populations.

Streptococcus pneumoniae (the pneumococcus) is a globally distributed, human obligate opportunistic bacterial pathogen which, although often carried commensally, is also a significant cause of invasive disease. Apart from multi-drug resistant and virulent clones, the rate and direction of pneumococcal dissemination between different countries remains largely unknown. The ability for the pneumococcus to take a foothold in a country depends on existing population configuration, the extent of vaccine implementation, as well as human mobility since it is a human obligate bacterium. To shed light on its international movement, we used extensive genome data from the Global Pneumococcal Sequencing project and estimated migration parameters between multiple countries in Africa. Data on allele frequencies of polymorphisms at housekeeping-like loci for multiple different lineages circulating in the populations of South Africa, Malawi, Kenya, and The Gambia were used to calculate the fixation index (Fst) between countries. We then further used these summaries to fit migration coalescent models with the likelihood-free inference algorithms available in the ELFI software package. Synthetic datawere additionally used to validate the inference approach. Our results demonstrate country-pair specific migration patterns and heterogeneity in the extent of migration between different lineages. Our approach demonstrates that coalescent models can be effectively used for inferring migration rates for bacterial species and lineages provided sufficiently granular population genomics surveillance data. Further, it can demonstrate the connectivity of respiratory disease agents between countries to inform intervention policy in the longer term.

Modulation of multidrug-resistant clone success in Escherichia coli populations: a longitudinal, multi-country, genomic and antibiotic usage cohort study.

BACKGROUND: The effect of antibiotic usage on the success of multidrug-resistant (MDR) clones in a population remains unclear. With this genomics-based molecular epidemiology study, we aimed to investigate the contribution of antibiotic use to Escherichia coli clone success, relative to intra-strain competition for colonisation and infection. METHODS: We sequenced all the available E coli bloodstream infection isolates provided by the British Society for Antimicrobial Chemotherapy (BSAC) from 2012 to 2017 (n=718) and combined these with published data from the UK (2001-11; n=1090) and Norway (2002-17; n=3254). Defined daily dose (DDD) data from the European Centre for Disease Prevention and Control (retrieved on Sept 21, 2021) for major antibiotic classes (ß-lactam, tetracycline, macrolide, sulfonamide, quinolone, and non-penicillin ß-lactam) were used together with sequence typing, resistance profiling, regression analysis, and non-neutral Wright-Fisher simulation-based modelling to enable systematic comparison of resistance levels, clone success, and antibiotic usage between the UK and Norway. FINDINGS: Sequence type (ST)73, ST131, ST95, and ST69 accounted for 892 (49·3%) of 1808 isolates in the BSAC collection. In the UK, the proportion of ST69 increased between 2001-10 and 2011-17 (p=0·0004), whereas the proportions of ST73 and ST95 did not vary between periods. ST131 expanded quickly after its emergence in 2003 and its prevalence remained consistent throughout the study period (apart from a brief decrease in 2009-10). The extended-spectrum ß-lactamase (ESBL)-carrying, globally disseminated MDR clone ST131-C2 showed overall greater success in the UK (154 [56·8%] of 271 isolates in 2003-17) compared with Norway (51 [18·3%] of 278 isolates in 2002-17; p<0·0001). DDD data indicated higher total use of antimicrobials in the UK, driven mainly by the class of non-penicillin ß-lactams, which were used between 2·7-times and 5·1-times more in the UK per annum (ratio mean 3·7 [SD 0·8]). This difference was associated with the higher success of the MDR clone ST131-C2 (pseudo-R2 69·1%). A non-neutral Wright-Fisher model replicated the observed expansion of non-MDR and MDR sequence types under higher DDD regimes. INTERPRETATION: Our study indicates that resistance profiles of contemporaneously successful clones can vary substantially, warranting caution in the interpretation of correlations between aggregate measures of resistance and antibiotic usage. Our study further suggests that in countries with low-to-moderate use of antibiotics, such as the UK and Norway, the extent of non-penicillin ß-lactam use modulates rather than determines the success of widely disseminated MDR ESBL-carrying E coli clones. Detailed understanding of underlying causal drivers of success is important for improved control of resistant pathogens. FUNDING: Trond Mohn Foundation, Marie Sklodowska-Curie Actions, European Research Council, Royal Society, and Wellcome Trust.

Identification of multiplicatively acting modulatory mutational signatures in cancer.

BACKGROUND: A deep understanding of carcinogenesis at the DNA level underpins many advances in cancer prevention and treatment. Mutational signatures provide a breakthrough conceptualisation, as well as an analysis framework, that can be used to build such understanding. They capture somatic mutation patterns and at best identify their causes. Most studies in this context have focused on an inherently additive analysis, e.g. by non-negative matrix factorization, where the mutations within a cancer sample are explained by a linear combination of independent mutational signatures. However, other recent studies show that the mutational signatures exhibit non-additive interactions. RESULTS: We carefully analysed such additive model fits from the PCAWG study cataloguing mutational signatures as well as their activities across thousands of cancers. Our analysis identified systematic and non-random structure of residuals that is left unexplained by the additive model. We used hierarchical clustering to identify cancer subsets with similar residual profiles to show that both systematic mutation count overestimation and underestimation take place. We propose an extension to the additive mutational signature model-multiplicatively acting modulatory processes-and develop a maximum-likelihood framework to identify such modulatory mutational signatures. The augmented model is expressive enough to almost fully remove the observed systematic residual patterns. CONCLUSION: We suggest the modulatory processes biologically relate to sample specific DNA repair propensities with cancer or tissue type specific profiles. Overall, our results identify an interesting direction where to expand signature analysis.

Pulse modulation by Bloch surface wave excitation.

Considering dielectric multilayers with N identical bilayers and an additional terminating layer, we address the effect of Bloch surface wave excitation on the temporal characteristics of short optical pulses. When such a resonant excitation occurs within the spectrum of the incident pulse, the reflected pulse splits into leading and trailing parts, the latter having an exponentially decaying tail. The role of the number of bilayers and the level of absorption in the multilayer stack is illustrated.

Apparent nosocomial adaptation of Enterococcus faecalis predates the modern hospital era.

Enterococcus faecalis is a commensal and nosocomial pathogen, which is also ubiquitous in animals and insects, representing a classical generalist microorganism. Here, we study E. faecalis isolates ranging from the pre-antibiotic era in 1936 up to 2018, covering a large set of host species including wild birds, mammals, healthy humans, and hospitalised patients. We sequence the bacterial genomes using short- and long-read techniques, and identify multiple extant hospital-associated lineages, with last common ancestors dating back as far as the 19th century. We find a population cohesively connected through homologous recombination, a metabolic flexibility despite a small genome size, and a stable large core genome. Our findings indicate that the apparent hospital adaptations found in hospital-associated E. faecalis lineages likely predate the "modern hospital" era, suggesting selection in another niche, and underlining the generalist nature of this nosocomial pathogen.

Event timing in human vision: Modulating factors and independent functions.

Essential for successful interaction with the environment is the human capacity to resolve events in time. Typical event timing paradigms are judgements of simultaneity (SJ) and of temporal order (TOJ). It remains unclear whether SJ and TOJ are based on the same underlying mechanism and whether there are fixed thresholds for resolution. The current study employed four visual event timing task versions: horizontal and vertical SJ and TOJ. Binary responses were analysed using multilevel binary regression modelling. Modulatory effects of potential explanatory variables on event timing perception were investigated: (1) Individual factors (sex and age), (2) temporal factors (SOA, trial number, order of experiment, order of stimuli orientation, time of day) and (3) spatial factors (left or right stimulus first, top or bottom stimulus first, horizontal vs. vertical orientation). The current study directly compares for the first time, performance on SJ and TOJ tasks using the same paradigm and presents evidence that a variety of factors and their interactions selectively modulate event timing functions in humans, explaining the variance found in previous studies. We conclude that SJ and TOJ are partially independent functions, because they are modulated differently by individual and contextual variables.

Temporal coherence and polarization modulation of pulse trains by resonance gratings.

We analyze the effects of subwavelength-period resonance gratings on temporally partially coherent optical plane-wave pulse trains. The interaction of the grating with pulses is simulated with the Fourier modal method and finite-difference time-domain method whose performances are compared. Both TE and TM linearly polarized Gaussian Schell-model pulse trains are examined, and partial temporal coherence is modeled with the identical elementary-pulse method. The polarization-dependent response of the grating is seen to lead to significant variations in the average intensity, polarization properties, and degree of temporal coherence of the reflected (and transmitted) pulse trains when the coherence time and polarization state of the incident field are altered. As an important example, we demonstrate that a fully polarized incident pulse train can become partially polarized in grating reflection. The results find use in tailoring of random electromagnetic pulse trains.

Childhood physical abuse and emotional neglect are specifically associated with adult mental disorders.

Background: Childhood adversities and trauma (CAT) are associated with adult mental disorders. Nevertheless, although CAT of different domains mostly co-occurs, and co-morbidity is common, the associations between CAT and mental disorders, when taking these interrelations into account, are not well known.Aims: We aimed to study differential associations between the five core domains of CAT and current axis-I disorders, taking into consideration their interrelations.Methods: Four hundred and fifteen outpatients attending adult primary (n = 255) and psychiatric care (n = 160) were assessed with the Trauma and Distress Scale (TADS) and the Mini International Neuropsychiatric Interview (MINI). Associations between CAT core domains and diagnostic categories were examined by path analyses.Results: At least some infrequent experience of CAT (83.6%), mostly of neglect, and current mental disorders (49.4%), mostly depression, was frequent, as were co-morbidities and co-occurrence of CAT domains. Considering these interrelations in a path model of excellent fit, physical abuse predicted depressive, manic, psychotic and anxiety disorders, whereas emotional neglect predicted depressive, anxiety and substance misuse disorders.Conclusions: Of all five CAT core domains, physical abuse and emotional neglect had the strongest association with adult psychiatric disorders and might have transmitted earlier reported main effects of other CAT domains onto mental disorders.

Maternal Depressive Symptoms During the Pre- and Postnatal Periods and Infant Attention to Emotional Faces.

We examined how infants' attentional disengagement from happy, fearful, neutral, and phase-scrambled faces at 8 months, as assessed by eye tracking, is associated with trajectories of maternal depressive symptoms from early pregnancy to 6 months postpartum (decreasing n = 48, increasing n = 34, and consistently low symptom levels n = 280). The sample (mother-infant dyads belonging to a larger FinnBrain Birth Cohort Study) was collected between 5/2013-6/2016. The overall disengagement probability from faces to distractors was not related to maternal depressive symptoms, but fear bias was heightened in infants whose mothers reported decreasing or increasing depressive symptoms. Exacerbated attention to fearful faces in infants of mothers with depressive symptoms may be independent of the timing of the symptoms in the pre- and postnatal stages.

Temporal coherence modulation of pulsed, scalar light with a Fabry-Pérot interferometer.

We analyze the effect of a high-finesse Fabry-Pérot interferometer on the temporal coherence properties of scalar optical plane-wave pulse trains. We focus on the cases of single-peak and double-peak transmissions of Gaussian Schell-model (GSM) and supercontinuum (SC) pulses. For the GSM light, we show how the characteristics of the average intensity and temporal degree of coherence of the transmitted pulses depend on the coherence parameters of the incident field. Regarding the SC light, the output is found to depend specifically on the location of the transmission peak(s) within the average spectrum. The results demonstrate that a Fabry-Pérot etalon can act as a simple passive element for tailoring the temporal (and spectral) coherence properties of optical pulse trains.

Single-subject analysis of N400 event-related potential component with five different methods.

There are several different approaches to analyze event-related potentials (ERPs) at single-subject level, and the aim of the current study is to provide information for choosing a method based on its ability to detect ERP effects and factors influencing the results. We used data from 79 healthy participants with EEG referenced to mastoid average and investigated the detection rate of auditory N400 effect in single-subject analysis using five methods: visual inspection of participant-wise averaged ERPs, analysis of variance (ANOVA) for amplitude averages in a time window, cluster-based non-parametric testing, a novel Bayesian approach and Studentized continuous wavelet transform (t-CWT). Visual inspection by three independent raters yielded N400 effect detection in 85% of the participants in at least one paradigm (active responding or passive listening), whereas ANOVA identified the effect in 68%, the cluster-method in 59%, the Bayesian method in 89%, and different versions of t-CWT in 22-59% of the participants. Thus, the Bayesian method was the most liberal and also showed the greatest concordance between the experimental paradigms (active/passive). ANOVA detected significant effect only in cases with converging evidence from other methods. The t-CWT and cluster-based method were the most conservative methods. As we show in the current study, different analysis methods provide results that do not completely overlap. The method of choice for determining the presence of an ERP component at single-subject level thus remains unresolved. Relying on a single statistical method may not be sufficient for drawing conclusions on single-subject ERPs.

Prenatal maternal distress associates with a blunted cortisol response in rhinovirus-positive infants.

INTRODUCTION: Prenatal exposure to maternal psychological distress (PD) may have programming effects on the fetus/infant hypothalamic-pituitary-adrenal (HPA) axis and subsequently on the development of the fetus' immune function. Therefore, our aim was to study whether prenatal exposure to PD is related to early infant HPA axis reactivity in the context of a subclinical rhinovirus infection that challenges infants HPA axis postnatally. METHODS: This study included 336 10-week-old infants from the nested case control Focus Cohort of the FinnBrain Birth Cohort Study. The outcome was infant HPA axis reactivity in a stress test. The acute stressor comprised of pediatric examination with venipuncture and nasal swabs for virus assessment. Saliva cortisol samples were collected at 5 time points: baseline, 0, 15, 25 and 35 min after the stressor. HPA axis reactivity was defined by the cumulative post-stressor cortisol concentration. RESULTS: HPA axis reactivity was blunted in the PD/rhinovirus + group compared to the average of control/rhinovirus+, PD/rhinovirus-, and control/rhinovirus- groups (difference: 14.7 ln [nmol/L] × min, 95% confidence interval 3.8-25.6, p = .008). HPA axis reactivity was significantly blunted only in boys with rhinovirus detected when separately tested for boys and girls (p = .04). CONCLUSION: Our finding of PD-exposed rhinovirus-positive infants having blunted cortisol secretion gives rise to a hypothesis that maternal PD during pregnancy influences infant HPA axis functioning and the functioning of the immune system. Future studies are needed to test whether this suppression of the HPA axis that co-occurs with rhinovirus infection associates with later disease development (e.g., asthma).

PYLFIRE: Python implementation of likelihood-free inference by ratio estimation.

Likelihood-free inference for simulator-based models is an emerging methodological branch of statistics which has attracted considerable attention in applications across diverse fields such as population genetics, astronomy and economics. Recently, the power of statistical classifiers has been harnessed in likelihood-free inference to obtain either point estimates or even posterior distributions of model parameters. Here we introduce PYLFIRE, an open-source Python implementation of the inference method LFIRE (likelihood-free inference by ratio estimation) that uses penalised logistic regression. PYLFIRE is made available as part of the general ELFI inference software http://elfi.ai to benefit both the user and developer communities for likelihood-free inference.

Maternal pre- and postnatal anxiety symptoms and infant attention disengagement from emotional faces.

BACKGROUND: Biases in socio-emotional attention may be early markers of risk for self-regulation difficulties and mental illness. We examined the associations between maternal pre- and postnatal anxiety symptoms and infant attention patterns to faces, with particular focus on attentional biases to threat, across male and female infants. METHODS: A general population, Caucasian sample of eight-month old infants (N = 362) were tested using eye-tracking and an attention disengagement (overlap) paradigm, with happy, fearful, neutral, and phase-scrambled faces and distractors. Maternal self-reported anxiety symptoms were assessed with the Symptom Checklist-90/anxiety subscale at five time points between gestational week 14 and 6 months postpartum. RESULTS: Probability of disengagement was lowest for fearful faces in the whole sample. Maternal pre- but not postnatal anxiety symptoms associated with higher threat bias in infants, and the relation between maternal anxiety symptoms in early pregnancy and higher threat bias in infants remained significant after controlling for maternal postnatal symptoms. Maternal postnatal anxiety symptoms, in turn, associated with higher overall probability of disengagement from faces to distractors, but the effects varied by child sex. LIMITATIONS: The small number of mothers suffering from very severe symptoms. No control for the comorbidity of depressive symptoms. CONCLUSIONS: Maternal prenatal anxiety symptoms associate with infant's heightened attention bias for threat. Maternal postnatal anxiety symptoms, in turn, associate with infant's overall disengagement probability differently for boys and girls. Boys may show enhanced vigilance for distractors, except when viewing fearful faces, and girls enhanced vigilance for all socio-emotional stimuli. Long-term implications of these findings remain to be explored.

Peace of mind and anxiety in the waking state are related to the affective content of dreams.

Waking mental well-being is assumed to be tightly linked to sleep and the affective content of dreams. However, empirical research is scant and has mostly focused on ill-being by studying the dreams of people with psychopathology. We explored the relationship between waking well-being and dream affect by measuring not only symptoms of ill-being but also different types and components of well-being. Importantly, this is the first time peace of mind was investigated as a distinct aspect of well-being in a Western sample and in relation to dream content. Healthy participants completed a well-being questionnaire, followed by a three-week daily dream diary and ratings of dream affect. Multilevel analyses showed that peace of mind was related to positive dream affect, whereas symptoms of anxiety were related to negative dream affect. Moreover, waking measures were better related to affect expressed in dream reports rather than participants' self-ratings of dream affect. We propose that whereas anxiety may reflect affect dysregulation in waking and dreaming, peace of mind reflects enhanced affect regulation in both states of consciousness. Therefore, dream reports may possibly serve as markers of mental health. Finally, our study shows that peace of mind complements existing conceptualizations and measures of well-being.

Gut Microbiota Composition in Mid-Pregnancy Is Associated with Gestational Weight Gain but Not Prepregnancy Body Mass Index.

BACKGROUND: Pregnancy is a time of numerous hormonal, metabolic, and immunological changes for both the mother and the fetus. Furthermore, maternal gut microbiota composition (GMC) is altered during pregnancy. One major factor affecting GMC in pregnant and nonpregnant populations is obesity. The aim was to analyze associations between maternal overweight/obesity, as well as gestational weight gain (GWG) and GMC. Moreover, the modifying effect of depression and anxiety symptom scores on weight and GMC were investigated. METHODS: Study included 46 women from the FinnBrain Birth Cohort study, of which 36 were normal weight, and 11 overweight or obese according to their prepregnancy body mass index (BMI). Stool samples were collected in gestational week 24, and the GMC was sequenced with Illumina MiSeq approach. Hierarchical clustering was executed to illuminate group formation according to the GMC. The population was divided according to Firmicutes and Bacteroidetes dominance. Symptoms of depression, general anxiety, and pregnancy-related anxiety were measured by using standardized questionnaires. RESULTS: Excessive GWG was associated with distinct GMC in mid-pregnancy as measured by hierarchical clustering and grouping according to Firmicutes or Bacteroidetes dominance, with Bacteroidetes being prominent and Firmicutes being less prominent in the GMC among those with increased GWG. Reduced alpha diversity was observed among the Bacteroidetes-dominated subjects. There were no zero-order effects between the abundances of bacterial genera or phyla, alpha or beta diversity, and prepregnancy BMI or GWG. CONCLUSION: Bacteroidetes-dominated GMC in mid-pregnancy is associated with increased GWG and reduced alpha diversity.

Human milk cortisol concentration predicts experimentally induced infant fear reactivity: moderation by infant sex.

Little consideration has been given to the possibility of human infant development being shaped via lactocrine programming, and by breast milk cortisol levels specifically. Despite animal models indicating that glucocorticoid (GC) exposure via lactation might modify brain development and behavior, only one study has reported that milk cortisol levels were positively associated with infant negative affectivity, especially fearfulness and sadness-early emerging risk factors for internalizing difficulties such as anxiety. The aim of the current study was to investigate whether human milk cortisol is associated with mother-reported fearfulness and experimentally induced infant fear reactivity. Mother-infant dyads (n = 65) enrolled in the FinnBrain Cohort Study participated. Breast milk samples were obtained 2.5 months postpartum, and milk cortisol concentrations were ascertained using validated luminescence immunoassay methodology. Infant fear reactivity was assessed using maternal reports 6 months postpartum and in a laboratory 8 months postpartum. There was a significant interaction between infant sex and milk cortisol such that higher milk cortisol was related to higher infant fear reactivity in a laboratory setting in girls (ß = 0.36, p = .04) but not in boys (ß = -0.15, p = .40). Milk cortisol was not associated with mother-reported infant fearfulness. Results suggest that higher human milk cortisol concentrations are associated with elevated experimentally induced fear in infancy. Findings support lactocrine programming, and suggest that mothers may "communicate" vital information about stressful environments via cortisol contained in breast milk, shaping girls' early emotional reactivity.

Dynamic Changes in Cortical Effective Connectivity Underlie Transsaccadic Integration in Humans.

Due to saccadic eye movements the retinal image is abruptly displaced 2-4 times a second, yet we experience a stable and continuous stream of vision. It is known that saccades modulate neural processing in various local brain areas, but the question of how saccades influence neural communication between different areas in the thalamo-cortical system has remained unanswered. By combining transcranial magnetic stimulation with electroencephalography, we found that saccades were accompanied by dynamic changes in causal communication between different brain areas in humans. These changes were anticipatory; they began before the actual eye movement. Compared with fixation, communication between posterior cortical areas was first briefly enhanced during saccades, but subsequently peri-saccadic information did not ignite sustained activity in fronto-parietal cortices. This suggests that the brain constructs a spatially stable and temporally continuous stream of conscious vision from discrete fixations by restricting the access of peri-saccadic visual information to sustained processing in fronto-parietal cortices.

Rapid and accurate processing of multiple objects in briefly presented scenes.

Humans can detect multiple objects in briefly presented natural visual scenes, but the mechanisms through which the objects are segmented from the background and consciously accessed remain open. By asking participants to report how many humans natural photos presented for 50 ms contain, we show that up to three items can be rapidly enumerated from natural scenes without compromising speed or accuracy. In contrast to standard parallel and serial models of object selection, our results revealed that the participants were fastest in enumerating two objects; even enumerating one single item required additional processing time. Also enumeration accuracy slightly increased in the subitizing range as number increased. Our results suggest that the visual system is tuned to process multiple items, which may underlie spatial and numerical cognition, and be beneficial in real-world situations that often require dealing with more than one object at a time.