Soluble receptor for advanced glycation end products (sRAGE) and endogenous secretory RAGE (esRAGE) in amniotic fluid: modulation by infection and inflammation

Abstract Objective: The receptor for advanced glycation end products (RAGE) has been proposed to participate in the innate and adaptive immune responses. RAGE can induce production of pro-inflammatory cytokines and chemokines, as well as neutrophil chemotaxis in a manner that may be suppressed or stimulated by soluble, truncated forms of RAGE including the soluble form of RAGE (sRAGE) and endogenous secretory RAGE (esRAGE). The objective of this study was to determine whether intra-amniotic infection/inflammation (IAI) is associated with changes in the amniotic fluid concentration of sRAGE and esRAGE. Study design: Amniotic fluid (AF) was retrieved from patients in the following groups: 1) mid-trimester (14-18 weeks of gestation; n=68); 2) term not in labor (n=24); 3) term in labor (n=51); 4) preterm labor and intact membranes (n=124); and 5) preterm PROM (n=80). Intra-amniotic infection and inflammation were defined as the presence of a positive amniotic fluid culture for microorganisms and an AF interleukin-6 concentration >/=2.6 ng/mL, respectively. The AF concentration of sRAGE and esRAGE were determined using specific and sensitive ELISAs which measured total immunoreactive sRAGE and esRAGE, respectively. Patients were matched for gestational age at amniocentesis to compare the AF concentration of sRAGE and esRAGE in patients with and without IAI. Non-parametric statistics were used for analysis and a P<0.05 was considered significant. Results: 1) Patients at term not in labor had higher median AF concentrations of sRAGE and esRAGE than those in the mid-trimester (P<0.001 for both comparisons) and those at term in labor (P=0.03 and P=0.04, respectively); 2) patients with preterm labor and intact membranes with intra-amniotic infection/inflammation (IAI) had higher median AF concentrations of sRAGE and esRAGE than those without IAI (P=0.02 and P=0.005, respectively); 3) similarly, patients with preterm PROM with IAI had higher median AF concentrations of sRAGE and esRAGE than those without IAI (P=0.03 and P=0.02, respectively). Conclusion: Intra-amniotic infection/inflammation is associated with increased amniotic fluid concentrations of sRAGE and esRAGE. Changes in the amniotic fluid concentration of sRAGE and esRAGE may represent part of the immune response to intra-amniotic infection/inflammation.     

Sleep architecture based on sleep depth and propensity: patterns in different demographics and sleep disorders and association with health outcomes

Study ObjectivesConventional metrics of sleep quantity/depth have serious shortcomings. Odds-Ratio-Product (ORP) is a continuous metric of sleep depth ranging from 0 (very deep sleep) to 2.5 (full-wakefulness). We describe an ORP-based approach that provides information on sleep disorders not apparent from traditional metrics.MethodsWe analyzed records from the Sleep-Heart-Health-Study and a study of performance deficit following sleep deprivation. ORP of all 30-second epochs in each PSG and percent of epochs in each decile of ORPs range were calculated. Percentage of epochs in deep sleep (ORP < 0.50) and in full-wakefulness (ORP > 2.25) were each assigned a rank, 1–3, representing first and second digits, respectively, of nine distinct types (“1,1”, “1,2” … ”3,3”). Prevalence of each type in clinical groups and their associations with demographics, sleepiness (Epworth-Sleepiness-Scale, ESS) and quality of life (QOL; Short-Form-Health-Survey-36) were determined.ResultsThree types (“1,1”, “1,2”, “1,3”) were prevalent in OSA and were associated with reduced QOL. Two (“1,3” and “2,3”) were prevalent in insomnia with short-sleep-duration (insomnia-SSD), but only “1,3” was associated with poor sleep depth and reduced QOL, suggesting two phenotypes in insomnia-SSD. ESS was high in types “1,1” and “1,2”, and low in “1,3” and “2,3”. Prevalence of some types increased with age while in others it decreased. Other types were either rare (“1,1” and “3,3”) or high (“2,2”) at all ages.ConclusionsThe proposed ORP histogram offers specific and unique information on the underlying neurophysiological characteristics of sleep disorders not captured by routine metrics, with potential of advancing diagnosis and management of these disorders.     

3D Printed Customized Facemask for Maxillary Protraction in the Early Treatment of a Class III Malocclusion: Proof-of-Concept Clinical Case

In order to improve fit and comfort, a maxillary protraction facemask customized to the patient’s anatomy was produced by means of 3D face scanning, digital design and additive manufacturing. An 8-year-old patient in need of early treatment for the Class III malocclusion received a rapid palatal expander and a Petit-type facemask, whose components were digitally designed on a 3D scan of the patient’s face. For face scanning, the iPad Pro 2018 tablet (Apple, Cupertino, CA, USA) with the Bellus3D DentalPro application (Bellus3D, Campbell, CA, USA) was used. Facemask components were modelled with 3D Blender software. The rests were 3D printed in BioMed Clear biocompatible resin (Formlabs, Somerville, MA, USA), and the bar in stainless steel. For greater comfort, the internal surface of the rests was lined with a polymer gel pad (Silipos, Niagara Falls, NY, USA). The manufacturing procedure of the customized facemask is patented. The patient wore the facemask at night for a period of 9 months. The patient’s experience was evaluated with a questionnaire at 1 week, 3, 6, and 10 months of treatment. The customized facemask was well accepted by the patient and obtained the expected treatment outcome. Furthermore, 3D face scanning, 3D modelling and 3D printing allow for the manufacturing of customized facemasks with improved fit and comfort, favoring patient compliance and treatment success.     

Reactive vaccination as control strategy for an outbreak of invasive meningococcal disease caused by Neisseria meningitidis C:P1.5-1,10-8:F3-6:ST-11(cc11), Bergamo province,Italy, December 2019 to January 2020

In Italy, serogroup C meningococci of the clonal complex cc11 (MenC/cc11) have caused several outbreaks of invasive meningococcal disease (IMD) during the past 20 years. Between December 2019 and January 2020, an outbreak of six cases of IMD infected with MenC/cc11 was identified in a limited area in the northern part of Italy. All cases presented a severe clinical picture, and two of them were fatal. This report is focused on the microbiological and molecular analysis of meningococcal isolates with the aim to reconstruct the chain of transmission. It further presents the vaccination strategy adopted to control the outbreak. The phylogenetic evaluation demonstrated the close genetic proximity between the strain involved in this outbreak and a strain responsible for a larger epidemic that had occurred in 2015 and 2016 in the Tuscany Region. The rapid identification and characterisation of IMD cases and an extensive vaccination campaign contributed to the successful control of this outbreak caused by a hyperinvasive meningococcal strain.     

Population interconnectivity over the past 120,000 years explains distribution and diversity of Central African hunter-gatherers

The evolutionary history of African hunter-gatherers holds key insights into modern human diversity. Here, we combine ethnographic and genetic data on Central African hunter-gatherers (CAHG) to show that their current distribution and density are explained by ecology rather than by a displacement to marginal habitats due to recent farming expansions, as commonly assumed. We also estimate the range of hunter-gatherer presence across Central Africa over the past 120,000 years using paleoclimatic reconstructions, which were statistically validated by our newly compiled dataset of dated archaeological sites. Finally, we show that genomic estimates of divergence times between CAHG groups match our ecological estimates of periods favoring population splits, and that recoveries of connectivity would have facilitated subsequent gene flow. Our results reveal that CAHG stem from a deep history of partially connected populations. This form of sociality allowed the coexistence of relatively large effective population sizes and local differentiation, with important implications for the evolution of genetic and cultural diversity in Homo sapiens.

The evolutionary history of African hunter-gatherers may hold key insights into patterns and processes behind the evolution of modern human diversity. Recent genomic studies have revealed that these populations represent the oldest and most diverse human genetic lineages and have been genetically differentiated from one another since the origin of humans (1–3) (SI Appendix, Table S1). Therefore, a first question is whether their current ecological niches were also characteristic of early Homo sapiens populations. However, genetic data alone can neither determine the geographic distribution of hunter-gatherers in the past nor demonstrate a deep history of adaptation of hunter-gatherers to their current environments. In fact, various studies have proposed that farming expansions within the past 5,000 years (in particular by the ancestors of Bantu speakers) would have only recently displaced hunter-gatherers to marginalized regions less favorable to agriculture (such as rainforests and deserts) (4–7).For example, the central part of Africa, between latitudes 5°N and 5°S currently is inhabited by ∼20 scattered hunter-gatherer ethnic groups (8). These Central African hunter-gatherers (CAHG) form a genetic clade thought to have diverged from other African populations as far back as 120,000 to 200,000 years ago (2, 9). The lack of any major linguistic specificity between them is often implied to reflect extensive contacts with surrounding farmer populations (8, 10), and seen as evidence of recent displacement into marginal forest environments by expanding farming populations. However, anthropologists have remarked on the huge variability in lifestyle, habitat, techniques, and tools between CAHG (11), suggestive of long-term cultural diversification and adaptation to forest environments. Research on the drivers of demography and adaptation of CAHG populations remains extremely limited, which can be partially attributed to the lack of archaeological and osteological data resulting from a rapid disintegration of fossil remains in the rainforest’s acidic soils, in addition to social instability in the region (12). Therefore, we are still left with crucial questions regarding the time depth of occupation of Central Africa by hunter-gatherers, the breadth of the niche exploited by earlier populations in the region, and variations in levels of interconnectivity at different points in time.To address those questions, we first compiled ethnographic data on the distribution of 749 camps from 11 hunter-gatherer groups extending from West to East Central Africa. We used them as inputs for environmental niche models (ENMs) to determine the relative influence of several bioclimatic and ecological factors, as well as the presence of farming populations, on the distribution and abundance of CAHG (13, 14). Then, we used high-resolution paleoclimatic reconstructions and topographic maps to make continuous predictions about where CAHG could have lived over the past 120,000 years and the potential extension of their interaction networks. Next, we compiled all reliably dated archaeological assemblages ascribed to hunter-gatherer groups in the Congo Basin (n = 168) and confirmed the model’s ability to predict the location and date of the sites. We further contextualized genomic estimates of population divergences with changes in population densities and interpopulation connectivity predicted by our model. Last, we complemented these analyses with a detailed assessment of present and historical gene flow between nine CAHG populations (n = 265 individuals), which we used to assess recent interactions between previously diverged CAHG populations, after farming expansions. Our study therefore provides a causal link between past environmental changes and human population dynamics over evolutionary time, by predicting where and when populations across Central Africa could have exchanged genetic and/or cultural information throughout their evolutionary history.     

Renal function and clinical outcome of patients with cancer-associated venous thromboembolism randomized to receive apixaban or dalteparin. Results from the Caravaggio trial

The effect of renal impairment (RI) on risk of bleeding and recurrent thrombosis in cancer patients treated with direct oral anticoagulants for venous thromboembolism (VTE) is undefined. We ran a prespecified analysis of the randomized Caravaggio study to evaluate the role of RI as a risk factor for bleeding or recurrence in patients treated with dalteparin or apixaban for cancer-associated VTE. RI was graded as moderate (creatinine clearance between 30-59 mL/minute; 275 patients) and mild (between 60-89 mL/minute; 444 patients). In the 1142 patients included in this analysis, the incidence of major bleeding was similar in patients with moderate vs. no or mild RI (HR 1.06-95% CI: 0.53-2.11), with no difference in the relative safety of apixaban and dalteparin. Recurrent VTE was not different in moderate vs. no or mild RI (HR=0.67, 95% CI: 0.38-1.20); in moderate RI, apixaban reduced recurrent VTE compared to dalteparin (HR=0.27, 95% CI: 0.08-0.96; P for interaction 0.1085). At multivariate analysis, no association was found between variation of renal function over time and major bleeding or recurrent VTE. Advanced or metastatic cancer was the only independent predictor of major bleeding (HR=2.84, 95% CI: 1.20-6.71), with no effect of treatment with apixaban or dalteparin. In our study, in cancer patients treated with apixaban or dalteparin, moderate RI was not associated with major bleeding or recurrent VTE. In patients with moderate renal failure, the safety profile of apixaban was confirmed with the potential for improved efficacy in comparison to dalteparin. ClinicalTrials.gov identifier: {"type":"clinical-trial","attrs":{"text":"NCT03045406","term_id":"NCT03045406"}}NCT03045406.     

Differential Effects of Three Nutritional Supplements on the Nutrient Intake of Pregnant Women Enrolled in a Conditional Cash Transfer Program in Mexico: A Cluster Randomized Trial

Supplementation in malnourished pregnant women should not displace natural healthy foods. Objective: To estimate the differential effects of three nutritional supplements on macro- and micronutrient intake of pregnant women beneficiaries of the conditional cash transfer program Prospera (CCT-POP). Methods: Prospective cluster randomized trial. Communities were randomly assigned to receive a fortified beverage (Beverage), micronutrient tablets (Tablets), or micronutrient powder (MNP). Pregnant women (at <25 weeks) were recruited. The food frequency questionnaire was applied at 25 and 37 weeks of pregnancy and at one and three months postpartum (mpp). Differential effects of the three supplements on the median change in nutrient intake from baseline to each follow-up stage were estimated. Results: Median change in protein intake from dietary and supplement sources were significantly lower for MNP and Tablets than for Beverages (baseline to 37 w: −7.80 ± 2.90 and −11.54 ± 3.00, respectively; baseline to 1 mpp: −7.34 ± 2.90 for MNP, p < 0.001). Compared to Beverages, median increases were higher for the MNP for vitamins C (31.2 ± 11.7, p < 0.01), E (1.67 ± 0.81, p < 0.05), and B12 (0.83 ± 0.27, p < 0.01) from baseline to 37 wk; from baseline to 1 mpp, there was a higher median increase in B12 (0.55 ± 0.25, p < 0.05) and folate (63.4 ± 24.3, p < 0.01); and from baseline to 3 mpp, a higher median increase in iron (2.38 ± 1.06, p < 0.05) and folate (94.4 ± 38.1, p < 0.05). Conclusions: Intake of micronutrients was higher for MNP and Tablets, likely due to food displacement among Beverage consumers. Although iron bioavailability and absorption inhibitors were not considered for the present analyses, the distribution of Tablets or MNP had several advantages in this context where micronutrient deficiency remains high among pregnant women, but macronutrient intake is generally adequate or even high.