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This paper describes the deployment of a large-scale study designed to measure human interactions across a variety of communication channels, with high temporal resolution and spanning multiple years-the Copenhagen Networks Study. Specifically, we collect data on face-to-face interactions, telecommunication, social networks, location, and background information (personality, demographics, health, politics) for a densely connected population of 1000 individuals, using state-of-the-art smartphones as social sensors. Here we provide an overview of the related work and describe the motivation and research agenda driving the study. Additionally, the paper details the data-types measured, and the technical infrastructure in terms of both backend and phone software, as well as an outline of the deployment procedures. We document the participant privacy procedures and their underlying principles. The paper is concluded with early results from data analysis, illustrating the importance of multi-channel high-resolution approach to data collection.

Background Improving immune competence (IC) in livestock could reduce the incidence of disease and reliance on the use of antibiotics. In Australian Angus cattle, IC is a measure of an animal’s combined ability to mount antibody and cell-mediated immune responses (AMIR and CMIR). Immune competence may affect traits such as growth and related phenotypes as well as the variability of such phenotypes. However, the genetic relationship between IC and genetic sensitivity to individual environments, measured as micro-genetic environmental sensitivity (GES), is yet to be reported. In this study the genetic parameters of, and correlations between, AMIR or CMIR and micro-GES of live weaning weight (WW) and ultrasound scan records of rib (RIB) and rump (RUMP) fat depth and eye muscle area (EMA) measured between 501 and 900 days of age were estimated. This was accomplished by fitting eight multivariate models with AMIR or CMIR and a double hierarchical generalised linear model on a production trait. Results The heritabilities were 0.35 and 0.36 for AMIR and CMIR, respectively, and 0.25–0.70 for the production traits. The heritabilities and the genetic coefficient of variation of micro-GES of the production traits ranged from 0.01–0.04 and 18–82%, respectively, and were higher in RIB and RUMP than WW and EMA. The genetic correlations between AMIR and WW, RIB, RUMP, or EMA were -0.35 (SE 0.11), 0.11 (0.12), 0.06 (0.12) and -0.13 (0.12), respectively, while the genetic correlations between CMIR and WW, RIB, RUMP, or EMA were -0.26 (0.12), 0.15 (0.13), 0.16 (0.12) and 0.04 (0.13), respectively. The genetic correlations between IC and micro-GES of WW, RIB, RUMP or EMA were moderately negative to lowly positive and had large SEs rendering them non-significant. Conclusions The unfavourable genetic correlation between the IC traits and WW supports the hypothesis that mounting an effective immune response can direct resources away from growth when resources are limited. Based on the heritabilities and genetic coefficient of variation of micro-GES, selection to increase uniformity is possible for WW, RIB, RUMP and EMA. The standard errors of the genetic correlations between IC and micro-GES of the production traits were too large to draw any definite conclusions about their relationships. Standard errors are expected to reduce as more IC records are collected.

The endocytic receptor cubam formed by the 460-kDa protein cubilin and the 45-kDa transmembrane protein amnionless (AMN), is essential for intestinal vitamin B 12 (B 12 ) uptake and for protein (e.g. albumin) reabsorption from the kidney filtrate. Loss of function of any of the two components ultimately leads to serious B 12 deficiency and urinary protein loss in humans (Imerslund-Gräsbeck’s syndrome, IGS). Here, we present the crystal structure of AMN in complex with the amino-terminal region of cubilin, revealing a sophisticated assembly of three cubilin subunits combining into a single intertwined β-helix domain that docks to a corresponding three-faced β-helix domain in AMN. This β-helix-β-helix association thereby anchors three ligand-binding cubilin subunits to the transmembrane AMN. Electron microscopy of full-length cubam reveals a 700–800 Å long tree-like structure with the potential of dimerization into an even larger complex. Furthermore, effects of known human mutations causing IGS are explained by the structural information. Cubilin and the transmembrane protein amnionless (AMN) form the endocytic receptor cubam that is essential for intestinal vitamin B 12 uptake. Here the authors present the 2.3 Å crystal structure of AMN in complex with the amino-terminal region of cubilin and discuss cubam architecture and disease causing mutations.

The aim of this study was to examine (i) the genetic variation in macro-environmental sensitivity (macro-ES) for ADG in Danish Duroc pigs, (ii) the genetic heterogeneity among sexes, and (iii) residual variance heterogeneity among herds. Record of ADG for 32,297 boars (19 herds) and 42,724 gilts (16 herds) was used for analysis. The data were provided by the National Danish Pig Research Centre. The analysis was performed by fitting univariate reaction norm models with the herd-year-month on test (HYM) effect as environmental covariates and herd-specific residual variance for boars and gilts separately under a Bayesian setting. The environmental covariate was inferred simultaneously with other parameters of the model. Gibbs sampling was used to sample model dispersion and location parameters. The posterior means and highest posterior density intervals of the additive genetic variance, genetic correlations for ADG, and heritability were calculated over the continuous environmental range of -3σh to +3σh (SD of the HYM effect). The coheritability of ADG at the average environmental level and ADG in the environments along the -3σh to +3σh environmental gradient were also calculated. The analysis showed significant variation in macro-ES, revealing genotype by environment interactions (G × E) for ADG. The presence of G × E resulted in changes in additive genetic variance and heritability across the -3σh to +3σh range. The genetic correlations were high and positive between ADG in environments differing by 1σh units or less and decreased to moderately positive between ADG in the extreme environments in both sexes. The coheritability of ADG in the environment at the average level and the -3σh environment for boars were greater than the heritability in the environment at the average level, while it was less for gilts. The coheritability of ADG in the environment at the average level and the +3σh environment for boars was less than heritability in the environment at the average level, while it was either the same or greater for gilts, depending on the residual variance. Boars had larger additive genetic and residual variances than gilts. Heterogeneity of residual variances across herds was shown for both sexes. In conclusion, this study shows the presence of macro-ES, genetic variance heterogeneity among sexes for ADG in pigs, and residual variance heterogeneity across herds.

The access to portal circulation is possible during the implantation of a transjugular intrahepatic portosystemic shunt (TIPS). [...]we characterised the circulating microbiome in portal vein (first venous outflow in gut–liver axis), liver outflow, central venous blood and peripheral venous blood from seven patients with decompensated liver cirrhosis receiving TIPS for either variceal bleeding (n=3) or refractory ascites (n=4) (mean Model for End-stage Liver Disease (MELD) 8.4 (range 6–13), Child-Pugh-Score (CHILD) A: n=4, CHILD B: n=3) (figure 1A). Blood microbiome phylum compositions identified in our study agreed with previous findings investigating the peripheral blood microbiome in buffy coat samples from patients with liver fibrosis2 as well as healthy individuals3 but differed from the gut microbiome measured in faecal samples, where Bacteroidetes and Firmicutes are predominant.2 SP110.1136/gutjnl-2018-316227.supp1 Supplementary data Figure 1. Bacterial infections are frequent in cirrhotics, often trigger acute-on-chronic liver failure and are associated with high mortality.5 A number of cytokines, which might show immune dysfunction, systemic inflammation and oxidative stress, have been linked to decompensation, acute-on-chronic liver failure and mortality.6–10 To elaborate on the relationship with systemic inflammation, we measured cytokine levels in serum of the same patients and compartments except central venous blood.

Background Postpartum haemorrhage (PPH) remains a leading cause of maternal mortality worldwide. In Denmark 2% of parturients receive blood transfusion. During the course of bleeding fibrinogen (coagulation factor I) may be depleted and fall to critically low levels, impairing haemostasis and thus worsening the ongoing bleeding. A plasma level of fibrinogen below 2 g/L in the early phase of postpartum haemorrhage is associated with subsequent development of severe haemorrhage. Use of fibrinogen concentrate allows high-dose substitution without the need for blood type crossmatch. So far no publications of randomised controlled trials involving acutely bleeding patients in the obstetrical setting have been published. This trial aims to investigate if early treatment with fibrinogen concentrate reduces the need for blood transfusion in women suffering severe PPH. Methods/Design In this randomised placebo-controlled double-blind multicentre trial, parturients with primary PPH are eligible following vaginal delivery in case of: manual removal of placenta (blood loss ≥ 500 ml) or manual exploration of the uterus after the birth of placenta (blood loss ≥ 1000 ml). Caesarean sections are also eligible in case of perioperative blood loss ≥ 1000 ml. The exclusion criteria are known inherited haemostatic deficiencies, prepartum treatment with antithrombotics, pre-pregnancy weight <45 kg or refusal to receive blood transfusion. Following informed consent, patients are randomly allocated to either early treatment with 2 g fibrinogen concentrate or 100 ml isotonic saline (placebo). Haemostatic monitoring with standard laboratory coagulation tests and thromboelastography (TEG, functional fibrinogen and Rapid TEG) is performed during the initial 24 hours. Primary outcome is the need for blood transfusion. To investigate a 33% reduction in the need for blood transfusion, a total of 245 patients will be included. Four university-affiliated public tertiary care hospitals will include patients during a two-year period. Adverse events including thrombosis are assessed in accordance with International Conference on Harmonisation (ICH) good clinical practice (GCP). Discussion A widespread belief in the benefits of early fibrinogen substitution in cases of PPH has led to increased off-label use. The FIB-PPH trial is investigator-initiated and aims to provide an evidence-based platform for the recommendations of the early use of fibrinogen concentrate in PPH. Trial registration ClincialTrials.gov NCT01359878.

This study aims to translate and cross-culturally adapt the standard version of the World Endometriosis Research Foundation (WERF) EPHect Endometriosis Patient Questionnaire (EPQ) into Danish and to ensure equivalence of a Danish electronic version. The translation, cultural adaption, and electronic migration followed recommendations from the International Society for Pharmacoeconomics and Outcomes Research (ISPOR) and the Critical Path Institute. Ten women with endometriosis were enrolled for cognitive debriefing of the paper version (pEPQ) after translation and back translation. The questionnaire was then migrated into an electronic version (eEPQ) and subsequently tested for usability and measurement equivalence by five women with endometriosis. Cross-cultural alterations were needed for medical terms, response options for ethnicity, the educational system, and measurement units. Thirteen questions were altered after back translation, while 21 underwent minor changes after cognitive debriefing. After testing the eEPQ, 13 questions were altered. Questions tested for measurement equivalence across the two modes of administration were found comparable. The median time-to-complete the pEPQ and eEPQ was 62 min (range: 29-110) and 63 min (range: 31-88), respectively. General comments included the questionnaire being relevant but long and repetitive. We find the the Danish pEPQ and eEPQ similar and comparable to the original English instrument. However, attention must be drawn to questions regarding measurement units, ethnicity, and educational systems before cross-country comparison. The Danish pEPQ and eEPQ are suitable for obtaining subjective data on women with endometriosis.

Background: Multiple endocrine neoplasia type 2A (MEN 2A) is a rare hereditary cancer syndrome caused by pathogenic variants in the rearranged during transfection (RET) gene and is characterized by medullary thyroid carcinoma (MTC), pheochromocytoma (PHEO), primary hyperparathyroidism (PHPT), cutaneous lichen amyloidosis (CLA), and Hirschsprung’s disease. Phenotypic data on the RET C611Y variant remain sparse. Consequently, we aimed to establish a clinical risk profile. Methods: We conducted a nationwide study of all cases (n = 128) born after 1 January 1930 and recognized as carrying the RET C611Y variant in Denmark before 1 April 2021. Results: The median follow-up after birth was 47 years (range, 3–92). Age-related penetrance at age 70 years for MTC was 98% (CI, 91–100), for PHEO 24% (CI, 16–37), and for PHPT 10% (CI, 5–20). None had CLA or Hirschsprung’s disease. The age-related progression of MTC was significant (p < 0.001). The mean age at T0N0M0 was 16 years (CI, 12–20), at T1-4N0M0 38 years (CI, 34–42), at TxN1M0 45 years (CI, 38–53) and at TxNxM1 49 years (CI, 36–61). At the last follow-up, 56% of thyroidectomized cases (n = 103) were biochemically cured. Overall survival at 70 years was 74% (CI, 59–84). Conclusions: RET C611Y is associated with a very high penetrance of MTC and a low penetrance of PHEO and PHPT. CLA and Hirschsprung’s disease almost never occur. MTC seems moderately aggressive, but large variability can be seen. Overall survival may be comparable to that of the general population.

Getting to grips with vitamin B 12 Vitamin B 12 , or cobalamin (Cbl), is an essential coenzyme in mammals that has to be taken up from the diet. Intestinal uptake of the 'extrinsic factor' Cbl is a highly specific process, dependent on gastric intrinsic factor (IF) and the ileal endocytic cubam receptor formed by cubilin and amnionless. Loss of function of any of these proteins ultimately leads to Cbl deficiency in humans. The crystal structure of the complex between IF–Cbl and the cubilin IF–Cbl-binding region (CUB 5–8 ) has now been determined at 3.3 Å resolution. The structure illuminates how multiple CUB domains collectively function as modular ligand-binding regions, and how two distant CUB domains bind the two IF domains in a Ca 2+ -dependent fashion. Vitamin B 12 (cobalamin) is an essential coenzyme in mammals, and is taken up from the diet. The proteins required for its uptake are the gastric intrinsic factor (IF) and the ileal endocytic cubam receptor, which is in turn formed from the proteins cubilin and amnionless. Here, the crystal structure is presented of the complex between IF–cobalamin and the IF–cobalamin-binding region (CUB) of cubilin. The structure illustrates how numerous CUB domains function together as modular ligand-binding regions. Cobalamin (Cbl, vitamin B 12 ) is a bacterial organic compound and an essential coenzyme in mammals, which take it up from the diet. This occurs by the combined action of the gastric intrinsic factor (IF) and the ileal endocytic cubam receptor formed by the 460-kilodalton (kDa) protein cubilin and the 45-kDa transmembrane protein amnionless 1 , 2 . Loss of function of any of these proteins ultimately leads to Cbl deficiency in man 3 , 4 . Here we present the crystal structure of the complex between IF–Cbl and the cubilin IF–Cbl-binding-region (CUB 5–8 ) 5 determined at 3.3 Å resolution. The structure provides insight into how several CUB (for ‘complement C1r/C1s, Uegf, Bmp1’) domains collectively function as modular ligand-binding regions, and how two distant CUB domains embrace the Cbl molecule by binding the two IF domains in a Ca 2+ -dependent manner. This dual-point model provides a probable explanation of how Cbl indirectly induces ligand–receptor coupling. Finally, the comparison of Ca 2+ -binding CUB domains and the low-density lipoprotein (LDL) receptor-type A modules suggests that the electrostatic pairing of a basic ligand arginine/lysine residue with Ca 2+ -coordinating acidic aspartates/glutamates is a common theme of Ca 2+ -dependent ligand–receptor interactions.

IntroductionChildren and adolescents with recent-onset type 1 diabetes (T1D) commonly maintain a certain level of insulin production during the remission phase, which can last months to years. Preserving β-cell function can reduce T1D complications and improve glycaemic control. Influenza vaccination has pleiotropic effects and administration of the vaccine during the early phases of T1D may offer β-cell protection. This study aims to assess the effect of influenza vaccination on preserving β-cell function in children and adolescents with recent-onset T1D.Methods and analysisThe INfluenza VaccInation To mitigate typE 1 Diabetes trial is a randomised, double-blind, placebo-controlled, multicentre trial in paediatric patients with recent-onset T1D aged 7–17 years. 100 participants will be randomised in a 1:1 ratio to receive either a standard inactivated quadrivalent influenza vaccine or a placebo within 14 days of diagnosis. The primary outcome is a difference in mean change (from baseline to 12 months) in C-peptide level between groups during a 2-hour mixed-meal tolerance test. Secondary outcomes include mean change (from baseline to 6 months) in C-peptide levels, haemoglobin A1c, ambulatory glucose profiles and insulin requirements. Exploratory outcomes are diabetes-related autoantibodies, inflammatory markers and serum haemagglutinin inhibition antibody titres against the influenza viruses. The current treatment for T1D is largely symptomatic, relying on insulin administration. There is a pressing need for novel pharmacological approaches aimed at modulating the immune system to preserve residual β-cell function. Existing immunotherapies are cost-prohibitive and associated with multiple side effects, whereas influenza vaccination is inexpensive and generally well tolerated. A positive outcome of this study holds potential for immediate implementation into standard care for children and adolescents with recent-onset T1D and may guide future research on immune modulation in T1D.Ethics and disseminationEthical approval was obtained from Danish Health Authorities prior to participant enrollment. The trial results will be submitted to a peer-reviewed journal.Trial registration numberClinicalTrials.gov NCT05585983 and EudraCT Number 2022-500906-17-01.