Using Genetic Variation to Explore the Causal Effect of Maternal Pregnancy Adiposity on Future Offspring Adiposity: A Mendelian Randomisation Study

Background: It has been suggested that greater maternal adiposity during pregnancy affects lifelong risk of offspring fatness via intrauterine mechanisms. Our aim was to use Mendelian randomisation (MR) to investigate the causal effect of intrauterine exposure to greater maternal body mass index (BMI) on offspring BMI and fat mass from childhood to early adulthood. Methods and Findings: We used maternal genetic variants as instrumental variables (IVs) to test the causal effect of maternal BMI in pregnancy on offspring fatness (BMI and dual-energy X-ray absorptiometry [DXA] determined fat mass index [FMI]) in a MR approach. This was investigated, with repeat measurements, from ages 7 to 18 in the Avon Longitudinal Study of Parents and Children (ALSPAC; n = 2,521 to 3,720 for different ages). We then sought to replicate findings with results for BMI at age 6 in Generation R (n = 2,337 for replication sample; n = 6,057 for total pooled sample). In confounder-adjusted multivariable regression in ALSPAC, a 1 standard deviation (SD, equivalent of 3.7 kg/m2) increase in maternal BMI was associated with a 0.25 SD (95% CI 0.21–0.29) increase in offspring BMI at age 7, with similar results at later ages and when FMI was used as the outcome. A weighted genetic risk score was generated from 32 genetic variants robus

Volumes of polytopes in spaces of constant curvature

We overview the volume calculations for polyhedra in Euclidean, spherical and hyperbolic spaces. We prove the Sforza formula for the volume of an arbitrary tetrahedron in $H^3$ and $S^3$. We also present some results, which provide a solution for Seidel problem on the volume of non-Euclidean tetrahedron. Finally, we consider a convex hyperbolic quadrilateral inscribed in a circle, horocycle or one branch of equidistant curve. This is a natural hyperbolic analog of the cyclic quadrilateral in the Euclidean plane. We find a few versions of the Brahmagupta formula for the area of such quadrilateral. We also present a formula for the area of a hyperbolic trapezoid.Comment: 22 pages, 9 figures, 58 reference

Leukocyte populations in human preterm and term breast milk identified by multicolour flow cytometry

Background Extremely preterm infants are highly susceptible to bacterial infections but breast milk provides some protection. It is unknown if leukocyte numbers and subsets in milk differ between term and preterm breast milk. This study serially characterised leukocyte populations in breast milk of mothers of preterm and term infants using multicolour flow cytometry methods for extended differential leukocyte counts in blood. Methods Sixty mothers of extremely preterm (<28 weeks gestational age), very preterm (28–31 wk), and moderately preterm (32–36 wk), as well as term (37–41 wk) infants were recruited. Colostrum (d2–5), transitional (d8–12) and mature milk (d26–30) samples were collected, cells isolated, and leukocyte subsets analysed using flow cytometry. Results The major CD45+ leukocyte populations circulating in blood were also detectable in breast milk but at different frequencies. Progression of lactation was associated with decreasing CD45+ leukocyte concentration, as well as increases in the relative frequencies of neutrophils and immature granulocytes, and decreases in the relative frequencies of eosinophils, myeloid and B cell precursors, and CD16- monocytes. No differences were observed between preterm and term breast milk in leukocyte concentration, though minor differences between preterm groups in some leukocyte frequencies were observed. Conclusions Flow cytometry is a useful tool to identify and quantify leukocyte subsets in breast milk. The stage of lactation is associated with major changes in milk leukocyte composition in this population. Fresh preterm breast milk is not deficient in leukocytes, but shorter gestation may be associated with minor differences in leukocyte subset frequencies in preterm compared to term breast milk

Mixed marriages and transnational families in the intercultural context : a case study of African-Spanish couples in Catalonia, Spain

Premi a l'excel·lència investigadora. Àmbit de les Ciències Socials. 2008One of the consequences of international migration and the permanent settlement of immigrants in southern EU countries is the growing number of inter-country marriages and the formation of transnational families. Using both quantitative and qualitative data, this article examines patterns of endogamy and exogamy (i.e. marriage within/outside a particular group or category) among African immigrants in Catalonia, focusing on bi-national Senegalese- and Gambian-Spanish couples. Socio-demographic profiles, transnationality, the dynamics of cultural change or retention, and the formation of transcultural identities are explored. The evidence presented suggests that social-class factors are more important than cultural origins in patterns of endogamy and exogamy, in the dynamics of living together and in the bringing-up of children of mixed unions. Such a conclusion negates culturalists' explanations of endogamy and exogamy while, at the same time, emphasising the role of social actors as active subjects in these processes. I further argue that mixed couples and their offspring deal-to a greater or lesser extent-with multiple localisations and cultural backgrounds (i.e. here and there), rather than experiencing a 'clash between two cultures'. Therefore, it would be a mistake to pretend that multicultural links do not exist and that they cannot be revitalised and functional. The paper starts and ends by addressing the complexities of processes of interculturalism, resisting an interpretation of hybridity and segregation as contradictory or exclusive realities

Long-acting intramuscular cabotegravir and rilpivirine in adults with HIV-1 infection (LATTE-2): 96-week results of a randomised, open-label, phase 2b, non-inferiority trial

Background Cabotegravir and rilpivirine are antiretroviral drugs in development as long-acting injectable formulations. The LATTE-2 study evaluated long-acting cabotegravir plus rilpivirine for maintenance of HIV-1 viral suppression through 96 weeks. Methods In this randomised, phase 2b, open-label study, treatment-naive adults infected with HIV-1 initially received oral cabotegravir 30 mg plus abacavir–lamivudine 600–300 mg once daily. The objective of this study was to select an intramuscular dosing regimen based on a comparison of the antiviral activity, tolerability, and safety of the two intramuscular dosing regimens relative to oral cabotegravir plus abacavir–lamivudine. After a 20-week induction period on oral cabotegravir plus abacavir–lamivudine, patients with viral suppression (plasma HIV-1 RNA 90%). Difference in proportions and associated 95% CIs were supportive to the primary analysis. The trial is registered at ClinicalTrials.gov, number NCT02120352. Findings Among 309 enrolled patients, 286 were randomly assigned to the maintenance period (115 to each of the 4-week and 8-week groups and 56 to the oral treatment group). This study is currently ongoing. At 32 weeks following randomisation, both long-acting regimens met primary criteria for comparability in viral suppression relative to the oral comparator group. Viral suppression was maintained at 32 weeks in 51 (91%) of 56 patients in the oral treatment group, 108 (94%) of 115 patients in the 4-week group (difference 2·8% [95% CI −5·8 to 11·5] vs oral treatment), and 109 (95%) of 115 patients in the 8-week group (difference 3·7% [−4·8 to 12·2] vs oral treatment). At week 96, viral suppression was maintained in 47 (84%) of 56 patients receiving oral treatment, 100 (87%) of 115 patients in the 4-week group, and 108 (94%) of 115 patients in the 8-week group. Three patients (1%) experienced protocol-defined virological failure (two in the 8-week group; one in the oral treatment group). Injection-site reactions were mild (3648 [84%] of 4360 injections) or moderate (673 [15%] of 4360 injections) in intensity and rarely resulted in discontinuation (two [<1%] of 230 patients); injection-site pain was reported most frequently. Serious adverse events during maintenance were reported in 22 (10%) of 230 patients in the intramuscular groups (4-week and 8-week groups) and seven (13%) of 56 patients in the oral treatment group; none were drug related. Interpretation The two-drug combination of all-injectable, long-acting cabotegravir plus rilpivirine every 4 weeks or every 8 weeks was as effective as daily three-drug oral therapy at maintaining HIV-1 viral suppression through 96 weeks and was well accepted and tolerated. Funding ViiV Healthcare and Janssen R&D

Hamstring muscles: Architecture and innervation

Knowledge of the anatomical organization of the hamstring muscles is necessary to understand their functions, and to assist in the development of accurate clinical and biomechanical models. The hamstring muscles were examined by dissection in six embalmed human lower limbs with the purpose of clarifying their gross morphology. In addition to obtaining evidence for or against anatomical partitioning ( as based on muscle architecture and pattern of innervation), data pertaining to architectural parameters such as fascicular length, volume, physiological cross-sectional area, and tendon length were collected. For each muscle, relatively consistent patterns of innervation were identified between specimens, and each was unique with respect to anatomical organization. On the basis of muscle architecture, three regions were identified within semimembranosus. However, this was not completely congruent with the pattern of innervation, as a primary nerve branch supplied only two regions, with the third region receiving a secondary branch. Semitendinosus comprised two distinct partitions arranged in series that were divided by a tendinous inscription. A singular muscle nerve or a primary nerve branch innervated each partition. In the biceps femoris long head the two regions were supplied via a primary nerve branch which divided into two primary branches or split into a series of branches. Being the only muscle to cross a single joint, biceps femoris short head consisted of two distinct regions demarcated by fiber direction, with each innervated by a separate muscle nerve. Architecturally, each muscle differed with respect to parameters such as physiological cross-sectional area, fascicular length and volume, but generally all partitions within an individual muscle were similar in fascicular length. The long proximal and distal tendons of these muscles extended into the muscle bellies thereby forming elongated musculotendinous junctions. Copyright (C) 2005 S. Karger AG, Basel

TIC 172900988: A transiting circumbinary planet detected in one sector of TESS data

We report the first discovery of a transiting circumbinary planet detected from a single sector of Transiting Exoplanet Survey Satellite (TESS) data. During Sector 21, the planet TIC 172900988b transited the primary star and then five days later it transited the secondary star. The binary is itself eclipsing, with a period P ≈ 19.7 days and an eccentricity e ≈ 0.45. Archival data from ASAS-SN, Evryscope, KELT, and SuperWASP reveal a prominent apsidal motion of the binary orbit, caused by the dynamical interactions between the binary and the planet. A comprehensive photodynamical analysis of the TESS, archival and follow-up data yields stellar masses and radii of M1 = 1.2384 ± 0.0007 Me and R1 = 1.3827 ± 0.0016 Re for the primary and M2 = 1.2019 ± 0.0007 Me and R2 = 1.3124 ± 0.0012 Re for the secondary. The radius of the planet is R3 = 11.25 ± 0.44 R (1.004 ± 0.039RJup). The planet's mass and orbital properties are not uniquely determined-there are six solutions with nearly equal likelihood. Specifically, we find that the planet's mass is in the range of 824 M3 981 M (2.65 M3 3.09MJup), its orbital period could be 188.8, 190.4, 194.0, 199.0, 200.4, or 204.1 days, and the eccentricity is between 0.02 and 0.09. At V = 10.141 mag, the system is accessible for high-resolution spectroscopic observations, e.g., the Rossiter-McLaughlin effect and transit spectroscopy

The evolving SARS-CoV-2 epidemic in Africa: Insights from rapidly expanding genomic surveillance

INTRODUCTION Investment in Africa over the past year with regard to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) sequencing has led to a massive increase in the number of sequences, which, to date, exceeds 100,000 sequences generated to track the pandemic on the continent. These sequences have profoundly affected how public health officials in Africa have navigated the COVID-19 pandemic. RATIONALE We demonstrate how the first 100,000 SARS-CoV-2 sequences from Africa have helped monitor the epidemic on the continent, how genomic surveillance expanded over the course of the pandemic, and how we adapted our sequencing methods to deal with an evolving virus. Finally, we also examine how viral lineages have spread across the continent in a phylogeographic framework to gain insights into the underlying temporal and spatial transmission dynamics for several variants of concern (VOCs). RESULTS Our results indicate that the number of countries in Africa that can sequence the virus within their own borders is growing and that this is coupled with a shorter turnaround time from the time of sampling to sequence submission. Ongoing evolution necessitated the continual updating of primer sets, and, as a result, eight primer sets were designed in tandem with viral evolution and used to ensure effective sequencing of the virus. The pandemic unfolded through multiple waves of infection that were each driven by distinct genetic lineages, with B.1-like ancestral strains associated with the first pandemic wave of infections in 2020. Successive waves on the continent were fueled by different VOCs, with Alpha and Beta cocirculating in distinct spatial patterns during the second wave and Delta and Omicron affecting the whole continent during the third and fourth waves, respectively. Phylogeographic reconstruction points toward distinct differences in viral importation and exportation patterns associated with the Alpha, Beta, Delta, and Omicron variants and subvariants, when considering both Africa versus the rest of the world and viral dissemination within the continent. Our epidemiological and phylogenetic inferences therefore underscore the heterogeneous nature of the pandemic on the continent and highlight key insights and challenges, for instance, recognizing the limitations of low testing proportions. We also highlight the early warning capacity that genomic surveillance in Africa has had for the rest of the world with the detection of new lineages and variants, the most recent being the characterization of various Omicron subvariants. CONCLUSION Sustained investment for diagnostics and genomic surveillance in Africa is needed as the virus continues to evolve. This is important not only to help combat SARS-CoV-2 on the continent but also because it can be used as a platform to help address the many emerging and reemerging infectious disease threats in Africa. In particular, capacity building for local sequencing within countries or within the continent should be prioritized because this is generally associated with shorter turnaround times, providing the most benefit to local public health authorities tasked with pandemic response and mitigation and allowing for the fastest reaction to localized outbreaks. These investments are crucial for pandemic preparedness and response and will serve the health of the continent well into the 21st century

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2,3,4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease