Responsiveness and sensitivity of PROMs to change in disease activity status in early and established rheumatoid arthritis.

OBJECTIVES: To determine whether patient reported outcome measures (PROMs) capturing activity limitations, health impact, pain, fatigue and work ability are responsive and sensitive to changes in disease activity status in patients with early and established rheumatoid arthritis (RA). METHODS: All early RA patients (n = 557) from the tREACH-trial and established RA patients (n = 188) from the TARA-trial were included. Both studies were multicentre, single-blinded trials with a treat-to-target management approach. The following PROMs were studied: Health Assessment Questionnaire Disability Index(HAQ-DI), morning stiffness severity, EQ-5D, general health, 36-item short form(SF-36), joint pain, fatigue and productivity loss. Mean changes in PROMs between two consecutive visits were compared with changes in disease activity status(remission, low disease activity and active disease) using linear mixed models and standardised response means. Additionally, the proportion of individual observations that showed an expected PROM response to disease activity status alterations was calculated. RESULTS: HAQ-DI, morning stiffness severity, general health, EQ-5D and joint pain demonstrated responsiveness to improvement or worsening of disease activity status in both early and established RA. SF-36 physical and mental component scale, fatigue and productivity loss did not show this effect in both groups. Across nearly all PROMs, the magnitude of change and the proportion of individual observations that reflect a shift from and to active disease remained low. CONCLUSION: HAQ-DI, morning stiffness severity, EQ-5D, general health and joint pain are responsive to disease activity status alterations on a group level in both early and established RA. For the individual patient the responsiveness of these PROMs is poor. CLINICAL TRIAL REGISTRATION: tREACH trial (www.isrctn.com, ISRCTN26791028) and TARA trial (www.onderzoekmetmensen.nl, NTR2754).

Associations of the placental metabolome with immune maturation up to one year of age in the Swedish NICE-cohort.

INTRODUCTION: Allergies and other immune-mediated diseases are thought to result from incomplete maturation of the immune system early in life. We previously showed that infants' metabolites at birth were associated with immune cell subtypes during infancy. The placenta supplies the fetus with nutrients, but may also provide immune maturation signals. OBJECTIVES: To examine the relationship between metabolites in placental villous tissue and immune maturation during the first year of life and infant and maternal characteristics (gestational length, birth weight, sex, parity, maternal age, and BMI). METHODS: Untargeted metabolomics was measured using Liquid Chromatography-Mass Spectrometry. Subpopulations of T and B cells were measured using flow cytometry at birth, 48 h, one, four, and 12 months. Random forest analysis was used to link the metabolomics data with the T and B cell sub populations as well as infant and maternal characteristics. RESULTS: Modest associations (Q2 = 0.2-0.3) were found between the placental metabolome and kappa-deleting recombination excision circles (KREC) at birth and naïve B cells and memory T cells at 12 months. Weak associations were observed between the placental metabolome and sex and parity. Still, most metabolite features of interest were of low intensity compared to associations previously found in cord blood, suggesting that underlying metabolites were not of placental origin. CONCLUSION: Our results indicate that metabolomic measurements of the placenta may not effectively recognize metabolites important for immune maturation.

Toxic metals and essential trace elements in placenta and their relation to placental function.

INTRODUCTION: Placental function is essential for fetal development, but it may be susceptible to malnutrition and environmental stressors. OBJECTIVE: To assess the impact of toxic and essential trace elements in placenta on placental function. METHODS: Toxic metals (cadmium, lead, mercury, cobalt) and essential elements (copper, manganese, zinc, selenium) were measured in placenta of 406 pregnant women in northern Sweden using ICP-MS. Placental weight and birth weight were obtained from hospital records and fetoplacental weight ratio was used to estimate placental efficiency. Placental relative telomere length (TL) and mitochondrial DNA copy number (mtDNAcn) were determined by quantitative PCR (n = 285). Single exposure-outcome associations were evaluated using linear or spline regression, and joint associations and interactions with Bayesian kernel machine regression (BKMR), all adjusted for sex, maternal smoking, and age or BMI. RESULTS: Median cadmium, mercury, lead, cobalt, copper, manganese, zinc, and selenium concentrations in placenta were 3.2, 1.8, 4.3, 2.3, 1058, 66, 10626, and 166 µg/kg, respectively. In the adjusted regression, selenium (>147 µg/kg) was inversely associated with placental weight (B: -158; 95 % CI: -246, -71, per doubling), as was lead at low selenium (B: -23.6; 95 % CI: -43.2, -4.0, per doubling). Manganese was positively associated with placental weight (B: 41; 95 % CI: 5.9, 77, per doubling) and inversely associated with placental efficiency (B: -0.01; 95 % CI: -0.019, -0.004, per doubling). Cobalt was inversely associated with mtDNAcn (B: -11; 95 % CI: -20, -0.018, per doubling), whereas all essential elements were positively associated with mtDNAcn, individually and joint. CONCLUSION: Among the toxic metals, lead appeared to negatively impact placental weight and cobalt decreased placental mtDNAcn. Joint essential element concentrations increased placental mtDNAcn. Manganese also appeared to increase placental weight, but not birth weight. The inverse association of selenium with placental weight may reflect increased transport of selenium to the fetus in late gestation.

Increased Pulmonary-Aortic Interspace in Fetal Right Aortic Arch: A Matched Case-Control Study.

INTRODUCTION: The prenatal detection rate of a right aortic arch (RAA) has increased with the implementation of the three-vessel view (3VV) to the second-trimester anomaly scan formed by the pulmonary artery (PA), aorta (Ao), and superior vena cava (SVC). We examined the value of measuring the distance between PA and Ao in the 3VV in cases with an RAA. METHODS: We conducted a case-control study in which fetuses with an isolated RAA were matched to 3 healthy controls. Using 3VV images, the distances between PA, Ao, and SVC were measured and the ratio between PA to Ao (PAAo) distance and Ao to SVC (AoSVC) distance was calculated. RESULTS: Fifty-four RAA cases and 162 matched controls were included. The mean absolute distance PAAo was 3.1 mm in cases and 1.8 mm in controls (p < 0.001), and the mean PAAo/AoSVC ratio was 2.9 and 1.4, respectively (p < 0.001). The ROC curve of PAAo/AoSVC ratio showed a cut-off point of 1.9 with sensitivity and specificity over 87% for the diagnosis of RAA. CONCLUSIONS: The pulmonary-aortic interspace and the PAAo/AoSVC ratio were significantly larger for RAA cases as compared to controls. If an increased pulmonary-aortic interspace is observed, a PAAo/AoSVC of ≥1.9 can be helpful in the diagnosis of an RAA.

Oxidation Chemistry of Bicarbonate and Peroxybicarbonate: Implications for Carbonate Management in Energy Storage.

Carbonate formation presents a major challenge to energy storage applications based on low-temperature CO2 electrolysis and recyclable metal-air batteries. While direct electrochemical oxidation of (bi)carbonate represents a straightforward route for carbonate management, knowledge of the feasibility and mechanisms of direct oxidation is presently lacking. Herein, we report the isolation and characterization of the bis(triphenylphosphine)iminium salts of bicarbonate and peroxybicarbonate, thus enabling the examination of their oxidation chemistry. Infrared spectroelectrochemistry combined with time-resolved infrared spectroscopy reveals that the photoinduced oxidation of HCO3- by an Ir(III) photoreagent results in the generation of the short-lived bicarbonate radical in less than 50 ns. The highly acidic bicarbonate radical undergoes proton transfer with HCO3- to furnish the carbonate radical anion and H2CO3, leading to the eventual release of CO2 and H2O, thus accounting for the appearance of H2O and CO2 in both electrochemical and photochemical oxidation experiments. The back reaction of the carbonate radical subsequently oxidizes the Ir(II) photoreagent, leading to carbonate. In the absence of this back reaction, dimerization of the carbonate radical provides entry into peroxybicarbonate, which we show undergoes facile oxidation to O2 and CO2. Together, the results reported identify tangible pathways for the design of catalysts for the management of carbonate in energy storage applications.

Rheumatoid arthritis presenting with mono- or oligo-arthritis and high VAS remains most fatigued during 5-years follow-up.

OBJECTIVES: The severity of fatigue in rheumatoid arthritis (RA) has hardly improved in recent decades, leaving a large unmet need. Fortunately, not all RA-patients suffer from persistent fatigue, but the subgroup of patients who suffer the most is insufficiently recognizable at diagnosis. As disease activity is partly coupled to fatigue, Disease-Activity-Score (DAS)-components may associate with the course of fatigue. We aimed to identify the RA-patients who remain fatigued by studying DAS-components at diagnosis in relation to the course of fatigue over a 5-year follow-up period in two independent early RA-cohorts. METHODS: 1560 consecutive RA-patients included in the Leiden Early Arthritis Cohort and 415 RA-patients included in the tREACH-Cohort were studied. Swollen joint count, tender joint count, ESR and Patient Global Assessment (Visual Analogue Scale(VAS),0-100 mm) were studied in relation to fatigue(VAS, 0-100mm) during 5-years using linear mixed models. RESULTS: Higher TJC and PGA at diagnosis were associated with a more severe course of fatigue. The SJC, in contrast, showed an inverse association; patients with mono- or oligo-arthritis at diagnosis remained more fatigued. The combination of aforementioned characteristics revealed that patients presenting with a mono- or oligo-arthritis and PGA ≥ 50 remained the most fatigued over time(+20mm vs polyarthritis with PGA < 50), whilst the DAS-course over time was not different. This subgroup comprised 14% of the early RA-population. Data from the tREACH-cohort showed similar findings. CONCLUSION: RA-patients who remain the most fatigued are characterized by mono- or oligo-arthritis and high PGA(VAS ≥ 50) at diagnosis. This understanding may enable early-intervention with non-pharmacological approaches in dedicated patient groups.

Staphylococcus aureus sequence type (ST) 45, ST30, and ST15 in the gut microbiota of healthy infants - persistence and population counts in relation to ST and virulence gene carriage.

Staphylococcus aureus colonizes the anterior nares, and also the gut, particularly in infants. S. aureus is divided into lineages, termed clonal complexes (CCs), which comprise closely related sequence types (STs). While CC30 and CC45 predominate among nasal commensals, their prevalence among gut-colonizing S. aureus is unknown. Here, 67 gut commensal S. aureus strains from 49 healthy Swedish infants (aged 3 days to 12 months) were subjected to multi-locus sequence typing. The STs of these strains were related to their virulence gene profiles, time of persistence in the microbiota, and fecal population counts. Three STs predominated: ST45 (22% of the strains); ST15 (21%); and ST30 (18%). In a logistic regression, ST45 strains showed higher fecal population counts than the others, independent of virulence gene carriage. The lower fecal counts of ST15 were linked to the carriage of fib genes (encoding fibrinogen-binding proteins), while those of ST30 were linked to fib and sea (enterotoxin A) carriage. While only 11% of the ST15 and ST30 strains were acquired after 2 months of age, this was true of 53% of the ST45 strains (p = 0.008), indicating that the former may be less fit for establishment in a more mature microbiota. None of the ST45 strains was transient (persisting < 3 weeks), and persistent ST45 strains colonized for significantly longer periods than persistent strains of other STs (mean, 34 vs 22 weeks, p = 0.04). Our results suggest that ST45 strains are well-adapted for commensal gut colonization in infants, reflecting yet-unidentified traits of these strains.

Biomarkers of seafood intake during pregnancy - Pollutants versus fatty acids and micronutrients.

Intake of fish and seafood during pregnancy may have certain beneficial effects on fetal development, but measurement of intake using questionnaires is unreliable. Here, we assessed several candidate biomarkers of seafood intake, including long-chain omega 3 fatty acids (n-3 LCPUFA), selenium, iodine, methylmercury, and different arsenic compounds, in 549 pregnant women (gestational week 29) in the prospective birth cohort NICE (Nutritional impact on Immunological maturation during Childhood in relation to the Environment). Proportions of the fatty acids eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA), and docosahexaenoic acid (DHA) in erythrocytes were measured using gas chromatography with flame ionization detector. Selenium was measured in blood plasma and erythrocytes, mercury and arsenic in erythrocytes, and iodine and several arsenic compounds in urine, using inductively coupled plasma mass spectrometry, arsenic compounds after first being separated by ion exchange high-performance liquid chromatography (HPLC). Each biomarker was related to intake of total seafood and to intake of fatty and lean fish, and shellfish in third trimester, estimated from a semi-quantitative food frequency questionnaire filled out in gestational week 34. The pregnant women reported a median total seafood intake of 184 g/week (5th-95th percentiles: 34-465 g/week). This intake correlated most strongly with erythrocyte mercury concentrations (rho = 0.49, p < 0.001), consisting essentially of methylmercury, followed by total arsenic in erythrocytes (rho = 0.34, p < 0.001), and arsenobetaine in urine (rho = 0.33, p < 0.001), the main form of urinary arsenic. These biomarkers correlated well with intake of both fatty fish, lean fish, and shellfish. Erythrocyte DHA and plasma selenium correlated, although weakly, mainly with fatty fish (rho = 0.25 and 0.22, respectively, both p < 0.001). In conclusion, elevated concentrations of erythrocyte mercury and urinary arsenobetaine can be useful indicators of seafood intake, more so than the n-3 LCPUFAs. However, the relative importance of the biomarkers may differ depending on the type and amount of seafood consumed.

Frequent Occurrence of Perianal Disease and Granuloma Formation in Patients with Crohn's Disease and Coexistent Orofacial Granulomatosis.

BACKGROUND: Orofacial granulomatosis (OFG) is an inflammatory disorder of the perioral region and oral cavity. Crohn's disease (CD) in conjunction with OFG (CD-OFG), has been suggested to constitute a phenotype of CD with distinct features at diagnosis. AIMS: The aim of this project was to investigate whether the distinct phenotypic features of CD-OFG persist in the years following the initial diagnosis of CD. METHODS: Clinical data were extracted from medical records covering the first 5 years post-diagnosis for a cohort of patients with CD-OFG, and were compared to those of references with CD without OFG. RESULTS: The clinical characteristics of our cohort of patients with CD-OFG (N = 25) were evaluated in comparison to references with CD without OFG (ratio 1:2). Five years post-diagnosis, more patients with CD-OFG had a phenotype with perianal disease (cumulative incidence: 16/25, 64% vs 13/50, 26%, P = 0.002) and intestinal granulomas (cumulative incidence: 22/25, 88% vs 24/50, 48%, P = 0.0009) than patients in the CD reference group. The patients with CD-OFG were also more likely to have undergone perianal surgery (12/25, 48% vs 4/50, 8%, P = 0.0002). At the end of the observation period, more of the patients with CD-OFG were receiving combination therapy, i.e., immunomodulators and tumor necrosis factor antagonists, than those in the CD reference group (9/25, 36% vs 5/50, 10%, P = 0.01). CONCLUSION: The results support the notion that CD in conjunction with OFG represents a specific phenotype of CD that is characterized by frequent perianal disease, pronounced intestinal granuloma formation and a need for extensive therapy.

The Tmod cellular logic gate as a solution for tumor-selective immunotherapy.

Immune cells that are engineered with receptors to integrate signals from multiple antigens offer a promising route to achieve the elusive property of therapeutic selectivity in cancer patients. Several types of multi-signal integrators have been described, among them mechanisms that pair activating and inhibitory receptors which are termed NOT gates by analogy to logical operations performed by machines. Here we review one such NOT-gated signal integrator called the Tmod system which is being developed for patients with solid tumors. Coupled with rigorous selection for patients with defined lesions in their tumor genomes (loss of heterozygosity), the Tmod approach presents an unusual opportunity to create truly selective therapies for certain cancer patients. Several of these agents are advancing toward the clinic, supported by a large body of quantitative preclinical data.

Assessment of Joint Impact of Iodine, Selenium, and Zinc Status on Women's Third-Trimester Plasma Thyroid Hormone Concentrations.

BACKGROUND: Iodine is essential for synthesizing thyroid hormones, but other micronutrients are also required for optimal thyroid function. However, there is a lack of data on combined micronutrient status in relation to thyroid hormones in pregnancy. OBJECTIVES: We aimed to assess the joint associations of iodine, selenium, and zinc status with plasma concentrations of thyroid hormones and thyroid-stimulating hormone (TSH) in pregnancy. METHODS: We included 531 pregnant women (aged 22-40 y) participating in a Swedish birth cohort who provided blood and spot urine samples in gestational weeks 27-33 (mean: 29). Associations of urinary iodine concentration (UIC), plasma selenium concentration, and plasma zinc concentration (measured by inductively coupled plasma mass spectrometry) with plasma hormone concentrations [total and free thyroxine (tT4, fT4), total and free triiodothyronine (tT3, fT3), and TSH] were explored with Bayesian kernel machine regression (BKMR; n = 516; outliers excluded) and multivariable-adjusted linear regression (n = 531; splined for nonlinear associations). RESULTS: Median (IQR) micronutrient concentrations were 112 µg/L (80-156 µg/L) for UIC, 67 µg/L (58-76 µg/L) for plasma selenium, and 973 µg/L (842-1127 µg/L) for plasma zinc; the former 2 median values were below recommended concentrations (150 µg/L and 70 µg/L, respectively). Mean ± SD TSH concentration was 1.7 ± 0.87 mIU/L, with 98% < 4 mIU/L. BKMR showed a positive trend of joint micronutrient concentrations in relation to TSH. Plasma zinc was most influential for all hormones but tT3, for which plasma selenium was most influential. In adjusted linear regression models, zinc was positively associated with tT4, tT3, and TSH, and <1200 µg/L also with fT4 and fT3. Selenium was inversely associated with fT3, and <85 µg/L with tT3. CONCLUSIONS: Pregnant women's plasma TSH concentrations in the early third trimester increased with increasing joint status of iodine, selenium, and zinc. Zinc and selenium were more influential than iodine for the hormone concentrations. Multiple micronutrients need consideration in future studies of thyroid hormone status.

Low Concentration of Fecal Valeric Acid at 1 Year of Age Is Linked with Eczema and Food Allergy at 13 Years of Age: Findings from a Swedish Birth Cohort.

BACKGROUND: Short-chain fatty acids (SCFAs) are abundant bacterial metabolites in the gut, with immunomodulatory properties. Hence, they may influence allergy development. Previous studies have linked fecal SCFA pattern during infancy with allergy. However, the association of SCFAs to allergic outcomes in adolescence is not well established. Here, we examined how the fecal SCFA pattern at 1 year of age related to allergy at 13 years of age. METHODS: Levels of 8 SCFAs in fecal samples collected at 1 year of age from 110 children were quantified using gas chromatography. The same individuals were evaluated at 13 years of age for allergic symptoms, allergy diagnosis and allergy medication by questionnaire, and for sensitization using skin prick test against egg, milk, fish, wheat and soy, cat, dog, horse, birch, and timothy grass. RESULTS: The concentration of fecal valeric acid at 1 year of age was inversely associated with eczema at 13 years of age (OR 0.6, 95% CI: 0.4-1.0, p = 0.049) and showed a trend for inverse association with food allergy at 13 years of age (OR 0.6, 95% CI: 0.4-1.0, p = 0.057). In a sub-group analysis of children with eczema at 1 year of age, a higher concentration of fecal valeric acid was linked with reduced risk of their eczema remaining at 13 years of age (OR 0.2, 95% CI: 0.0-1.5), although this latter analysis did not reach statistical significance (p = 0.12). CONCLUSIONS: Our findings lend further support to the notion of early childhood as a critical period when allergy may be programmed via the gut microbiota. Higher levels of fecal valeric acid may be characteristic of a protective gut microbiota and/or actively contribute to protection from eczema and food allergy.

Metal-Organic Framework Magnets.

Metal-organic frameworks represent the ultimate chemical platform on which to develop a new generation of designer magnets. In contrast to the inorganic solids that have dominated permanent magnet technology for decades, metal-organic frameworks offer numerous advantages, most notably the nearly infinite chemical space through which to synthesize predesigned and tunable structures with controllable properties. Moreover, the presence of a rigid, crystalline structure based on organic linkers enables the potential for permanent porosity and postsynthetic chemical modification of the inorganic and organic components. Despite these attributes, the realization of metal-organic magnets with high ordering temperatures represents a formidable challenge, owing largely to the typically weak magnetic exchange coupling mediated through organic linkers. Nevertheless, recent years have seen a number of exciting advances involving frameworks based on a wide range of metal ions and organic linkers. This review provides a survey of structurally characterized metal-organic frameworks that have been shown to exhibit magnetic order. Section 1 outlines the need for new magnets and the potential role of metal-organic frameworks toward that end, and it briefly introduces the classes of magnets and the experimental methods used to characterize them. Section 2 describes early milestones and key advances in metal-organic magnet research that laid the foundation for structurally characterized metal-organic framework magnets. Sections 3 and 4 then outline the literature of metal-organic framework magnets based on diamagnetic and radical organic linkers, respectively. Finally, Section 5 concludes with some potential strategies for increasing the ordering temperatures of metal-organic framework magnets while maintaining structural integrity and additional function.

Association of maternal urinary fluoride concentrations during pregnancy with size at birth and the potential mediation effect by maternal thyroid hormones: The Swedish NICE birth cohort.

BACKGROUND: Observational studies have indicated that elevated maternal fluoride exposure during pregnancy may impair child neurodevelopment but a potential impact on birth outcomes is understudied. OBJECTIVES: To evaluate the impact of gestational fluoride exposure on birth outcomes (birth size and gestational age at birth) and to assess the potential mediating role of maternal thyroid hormones. METHODS: We studied 583 mother-child dyads in the NICE cohort in northern Sweden. Maternal fluoride exposure was assessed by measuring urinary concentrations at late pregnancy (median: 29th gestational week) using an ion selective electrode. Plasma levels of free and total thyroxine (fT4, tT4) and triiodothyronine (fT3, tT3), and thyroid stimulating hormone (TSH) were measured with electrochemiluminescence immunoassays. The infant's weight, length, head circumference, and gestational age at birth were extracted from hospital records. RESULTS: Median urinary fluoride concentration was 0.71 mg/L (5th-95th percentile 0.31-1.9 mg/L; specific gravity adjusted). In multivariable-adjusted regression models, every 1 mg/L increase of maternal urinary fluoride was associated with a mean increase in birth weight by 84 g (95%CI: 30, 138), length by 0.41 cm (95%CI: 0.18, 0.65), head circumference by 0.3 cm (95%CI: 0.1, 0.4), and with increased odds of being born large for gestational age (OR = 1.39, 95%CI: 1.03, 1.89). Every 1 mg/L increase of maternal urinary fluoride was also associated with a mean increase of the plasma fT3:fT4 ratio (B = 0.007, 95%CI: 0.000, 0.014), but not with the hormones or TSH. In mediation analyses, the maternal fT3:fT4 ratio did not explain the urinary fluoride-birth size relationships. DISCUSSION: Gestational urinary fluoride concentrations were associated with increased size at birth and even with increased odds of being born large for gestational age. The fluoride-related associations with increased size at birth were not explained by changes in maternal thyroid hormone levels.

A New 1,5-Disubstituted Triazole DNA Backbone Mimic with Enhanced Polymerase Compatibility.

Triazole linkages (TLs) are mimics of the phosphodiester bond in oligonucleotides with applications in synthetic biology and biotechnology. Here we report the RuAAC-catalyzed synthesis of a novel 1,5-disubstituted triazole (TL2) dinucleoside phosphoramidite as well as its incorporation into oligonucleotides and compare its DNA polymerase replication competency with other TL analogues. We demonstrate that TL2 has superior replication kinetics to these analogues and is accurately replicated by polymerases. Derived structure-biocompatibility relationships show that linker length and the orientation of a hydrogen bond acceptor are critical and provide further guidance for the rational design of artificial biocompatible nucleic acid backbones.

Khoe-San Genomes Reveal Unique Variation and Confirm the Deepest Population Divergence in Homo sapiens.

The southern African indigenous Khoe-San populations harbor the most divergent lineages of all living peoples. Exploring their genomes is key to understanding deep human history. We sequenced 25 full genomes from five Khoe-San populations, revealing many novel variants, that 25% of variants are unique to the Khoe-San, and that the Khoe-San group harbors the greatest level of diversity across the globe. In line with previous studies, we found several gene regions with extreme values in genome-wide scans for selection, potentially caused by natural selection in the lineage leading to Homo sapiens and more recent in time. These gene regions included immunity-, sperm-, brain-, diet-, and muscle-related genes. When accounting for recent admixture, all Khoe-San groups display genetic diversity approaching the levels in other African groups and a reduction in effective population size starting around 100,000 years ago. Hence, all human groups show a reduction in effective population size commencing around the time of the Out-of-Africa migrations, which coincides with changes in the paleoclimate records, changes that potentially impacted all humans at the time.

Bacterial Carriage of Genes Encoding Fibronectin-Binding Proteins Is Associated with Long-Term Persistence of Staphylococcus aureus in the Nasal and Gut Microbiota of Infants.

Staphylococcus aureus can colonize both the anterior nares and the gastrointestinal tract. However, colonization at these sites in the same individuals has not been studied, and the traits that facilitate colonization and persistence at these sites have not been compared. Samples from the nostrils and feces collected on 9 occasions from 3 days to 3 years of age in 65 infants were cultured; 54 samples yielded S. aureus. The numbers of nasal and fecal S. aureus strains increased rapidly during the first weeks and were similar at 1 month of age (>40% of infants colonized). Thereafter, nasal carriage declined, while fecal carriage remained high during the first year of life. Individual strains were identified, and their colonization patterns were related to their carriage of genes encoding adhesins and superantigenic toxins. Strains retrieved from both the nose and gut (n = 44) of an infant were 4.5 times more likely to colonize long term (≥3 weeks at both sites) than strains found only in the rectum/feces (n = 56) or only in the nose (n = 32) (P ≤ 0.001). Gut colonization was significantly associated with carriage of the fnbA gene, and long-term colonization at either site was associated with carriage of fnbA and fnbB. In summary, gut colonization by S. aureus was more common than nasal carriage by S. aureus in the studied infants. Gut strains may provide a reservoir for invasive disease in vulnerable individuals. Fibronectin-binding adhesins and other virulence factors may facilitate commensal colonization and confer pathogenic potential. IMPORTANCE S. aureus may cause severe infections and frequently colonizes the nose. Nasal carriage of S. aureus increases 3-fold the risk of invasive S. aureus infection. S. aureus is also commonly found in the gut microbiota of infants and young children. However, the relationships between the adhesins and other virulence factors of S. aureus strains and its abilities to colonize the nostrils and gut of infants are not well understood. Our study explores the simultaneous colonization by S. aureus of the nasal and intestinal tracts of newborn infants through 3 years of follow-up. We identify bacterial virulence traits that appear to facilitate persistent colonization of the nose and gut by S. aureus. This expands our current knowledge of the interplay between bacterial commensalism and pathogenicity. Moreover, it may contribute to the development of targeted strategies for combating S. aureus infection.

Circulating proteins associated with allergy development in infants-an exploratory analysis.

BACKGROUND: Protein profiles that can predict allergy development in children are lacking and the ideal sampling age is unknown. By applying an exploratory proteomics approach in the prospective FARMFLORA birth cohort, we sought to identify previously unknown circulating proteins in early life that associate to protection or risk for development of allergy up to 8 years of age. METHODS: We analyzed plasma prepared from umbilical cord blood (n = 38) and blood collected at 1 month (n = 42), 4 months (n = 39), 18 months (n = 42), 36 months (n = 42) and 8 years (n = 44) of age. We profiled 230 proteins with a multiplexed assay and evaluated the global structure of the data with principal component analysis (PCA). Protein profiles informative to allergic disease at 18 months, 36 months and/or 8 years were evaluated using Lasso logistic regression and random forest. RESULTS: Two clusters emerged in the PCA analysis that separated samples obtained at birth and at 1 month of age from samples obtained later. Differences between the clusters were mostly driven by abundant plasma proteins. For the prediction of allergy, both Lasso logistic regression and random forest were most informative with samples collected at 1 month of age. A Lasso model with 27 proteins together with farm environment differentiated children who remained healthy from those developing allergy. This protein panel was primarily composed of antigen-presenting MHC class I molecules, interleukins and chemokines. CONCLUSION: Sampled at one month of age, circulating proteins that reflect processes of the immune system may predict the development of allergic disease later in childhood.

Stereoscopic three-dimensional visualisation technology in anatomy learning: A meta-analysis.

OBJECTIVES: The features that contribute to the apparent effectiveness of three-dimensional visualisation technology [3DVT] in teaching anatomy are largely unknown. The aim of this study was to conduct a systematic review and meta-analysis of the role of stereopsis in learning anatomy with 3DVT. METHODS: The review was conducted and reported according to PRISMA Standards. Literature search of English articles was performed using EMBASE, MEDLINE, CINAHL EBSCOhost, ERIC EBSCOhost, Cochrane CENTRAL, Web of Science and Google Scholar databases until November 2019. Study selection, data extraction and study appraisal were performed independently by two authors. Articles were assessed for methodological quality using the Medical Education Research Study Quality Instrument and the Cochrane Collaboration's tool for assessing the risk of bias. For quantitative analysis, studies were grouped based on relative between-intervention differences in instructional methods and type of control conditions. RESULTS: A total of 3934 citations were obtained of which 67 underwent a full-text review. Ultimately, 13 randomised controlled trials were included in the meta-analysis. When interactive, stereoscopic 3D models were compared to interactive, monoscopic 3D models within a single level of instructional design, for example isolating stereopsis as the only true manipulated element in the experimental design, an effect size [ES] of 0.53 (95% confidence interval [CI] 0.26-0.80; P < .00001) was found. In comparison with 2D images within multiple levels of instructional design, an effect size of 0.45 (95% CI 0.10-0.81; P < .002) was found. Stereopsis had no effect on learning when utilised with non-interactive 3D images (ES = -0.87, 95% CI -2.09-0.35; P = .16). CONCLUSION: Stereopsis is an important distinguishing element of 3DVT that has a significant positive effect on acquisition of anatomical knowledge when utilised within an interactive 3D environment. A distinction between stereoscopic and monoscopic 3DVT is essential to make in anatomical education and research.

Candida species as commensal gut colonizers: A study of 133 longitudinally followed Swedish infants.

The gut microbiota harbor a wide range of bacterial species, but also yeasts may be part of this ecosystem. Infants who are being treated in intensive care units are often colonized by Candida species. However, little is known regarding commensal yeast colonization of healthy infants and young children. Here the acquisition of yeast species was studied in a birth-cohort including 133 healthy Swedish infants. A rectal swab sample was obtained on day 3 of life, and fresh fecal samples were obtained at regular intervals up to 3 years of age; the samples were cultured quantitatively for yeasts. Colonization with yeasts increased rapidly in the first months of life, with 73/133 infants (55%) colonized at 6 months of age. The yeast numbers in positive samples decreased from an average of 105 cfu/g in infants aged 0-2 months to 103.5 cfu/g at 3 years of age. Candida albicans was the most frequently isolated species and reached higher population counts than the other species in culture-positive infants. The yeast colonization rate did not differ between infants who were delivered vaginally and those birthed via Caesarean section, whereas breastfed infants showed a lower colonization rate (p < 0.05 for 1 year of age compared to the other infants). The results demonstrate that yeasts, particularly C. albicans and C. parapsilosis (sensu lato), are common commensals in the gut microbiota of healthy infants and young children.