Exonuclease activity and P nucleotide addition in the generation of the expressed immunoglobulin repertoire

BACKGROUND: Immunoglobulin rearrangement involves random and imprecise processes that act to both create and constrain diversity. Two such processes are the loss of nucleotides through the action of unknown exonuclease(s) and the addition of P nucleotides. The study of such processes has been compromised by difficulties in reliably aligning immunoglobulin genes and in the partitioning of nucleotides between segment ends, and between N and P nucleotides. RESULTS: A dataset of 294 human IgM sequences was created and partitioned with the aid of a probabilistic model. Non-random removal of nucleotides is seen between the three IGH gene types with the IGHV gene averaging removals of 1.2 nucleotides compared to 4.7 for the other gene ends (p < 0.001). Individual IGHV, IGHD and IGHJ gene subgroups also display statistical differences in the level of nucleotide loss. For example, within the IGHJ group, IGHJ3 has average removals of 1.3 nucleotides compared to 6.4 nucleotides for IGHJ6 genes (p < 0.002). Analysis of putative P nucleotides within the IgM and pooled datasets revealed only a single putative P nucleotide motif (GTT at the 3' D-REGION end) to occur at a frequency significantly higher then would be expected from random N nucleotide addition. CONCLUSIONS: The loss of nucleotides due to the action of exonucleases is not random, but is influenced by the nucleotide composition of the genes. P nucleotides do not make a significant contribution to diversity of immunoglobulin sequences. Although palindromic sequences are present in 10% of immunologlobulin rearrangements, most of the 'palindromic' nucleotides are likely to have been inserted into the junction during the process of N nucleotide addition. P nucleotides can only be stated with confidence to contribute to diversity of less than 1% of sequences. Any attempt to identify P nucleotides in immunoglobulins is therefore likely to introduce errors into the partitioning of such sequences

MC-Simulation of the Transverse Double Spin Asymmetry for RHIC

Using {\sc Sphinx tt}, a new MC simulation program for transverse polarized nucleon--nucleon scattering based on {\sc Pythia~5.6}, we calculate the transverse double spin asymmetry $A^{TT}$ in the Drell-Yan process. If one assumes (quite arbitrarily) that the transversity parton distribution $\delta q(x,Q^2)$ equals the helicity distribution $\Delta q(x,Q^2)$ at some low $Q_0^2$ scale, the resulting asymmetry is of order 1\%. In this case is $A^{TT}$ would hardly be be measurable with PHENIX at RHIC.Comment: 17 pages, 5 figure

Comparison of techniques for handling missing covariate data within prognostic modelling studies: a simulation study

Background: There is no consensus on the most appropriate approach to handle missing covariate data within prognostic modelling studies. Therefore a simulation study was performed to assess the effects of different missing data techniques on the performance of a prognostic model. Methods: Datasets were generated to resemble the skewed distributions seen in a motivating breast cancer example. Multivariate missing data were imposed on four covariates using four different mechanisms; missing completely at random (MCAR), missing at random (MAR), missing not at random (MNAR) and a combination of all three mechanisms. Five amounts of incomplete cases from 5% to 75% were considered. Complete case analysis (CC), single imputation (SI) and five multiple imputation (MI) techniques available within the R statistical software were investigated: a) data augmentation (DA) approach assuming a multivariate normal distribution, b) DA assuming a general location model, c) regression switching imputation, d) regression switching with predictive mean matching (MICE-PMM) and e) flexible additive imputation models. A Cox proportional hazards model was fitted and appropriate estimates for the regression coefficients and model performance measures were obtained. Results: Performing a CC analysis produced unbiased regression estimates, but inflated standard errors, which affected the significance of the covariates in the model with 25% or more missingness. Using SI, underestimated the variability; resulting in poor coverage even with 10% missingness. Of the MI approaches, applying MICE-PMM produced, in general, the least biased estimates and better coverage for the incomplete covariates and better model performance for all mechanisms. However, this MI approach still produced biased regression coefficient estimates for the incomplete skewed continuous covariates when 50% or more cases had missing data imposed with a MCAR, MAR or combined mechanism. When the missingness depended on the incomplete covariates, i.e. MNAR, estimates were biased with more than 10% incomplete cases for all MI approaches. Conclusion: The results from this simulation study suggest that performing MICE-PMM may be the preferred MI approach provided that less than 50% of the cases have missing data and the missing data are not MNAR

Heatwave–blocking relation change likely dominates over decrease in blocking frequency under global warming

This is the final version. Available on open access from Nature Research via the DOI in this recordData availability; CMIP6 model data are available from https://esgf-node.llnl.gov/projects/cmip6. We acknowledge the World Climate Research Programme, which, through its Working Group on Coupled Modelling, coordinated and promoted CMIP6. We thank the climate modelling groups for producing and making available their model output, the Earth System Grid Federation (ESGF) for archiving the data and providing access, and the multiple funding agencies that support CMIP6 and ESGF.Code availability: Computer code to repeat the results is available on Zenodo. The D13 blocking index code is provided by Etienne Dunn-Sigouin. This study uses xarray and scikit-learn.Extra-tropical continental summer heatwaves often occur under persistent anticyclones or blocking. Here we partition heatwave changes into contributions from blocking changes, heatwave–blocking relation change and mean temperature increase, under global warming in climate models. We employ an optimized blocking index that best correlates with heatwaves (Pearson correlation of 0.7) and find heatwave-driving blocking decreases but the change in heatwave–blocking relation likely dominates. Over Europe, with a historical heatwave frequency of 2.5%, less blocking will cause 0.6% fewer heatwaves, steepened heatwave–blocking relation will cause 1.4% more heatwaves, and the mean temperature increase will cause 60% more heatwaves. Over Greenland, flattened heatwave–blocking relation will dominate over the insignificant decrease in blocking. The future increase in heatwave frequency is not caused by changes in blocking frequency, but by factors such as thermodynamics, that enhance the capacity of blocking to drive heatwaves.Natural Environment Research Council (NERC

Clinical characteristics of emergency department heart failure patients initially diagnosed as non-heart failure

BACKGROUND: Since previous studies suggest the emergency department (ED) misdiagnosis rate of heart failure is 10–20% we sought to describe the characteristics of ED patients misdiagnosed as non-decompensated heart failure in the ED. METHODS: We analyzed a prospective convenience sample of 439 patients at 4 emergency departments who presented with signs or symptoms of decompensated heart failure. Patients with a cardiology criterion standard diagnosis of decompensated heart failure and an ED diagnosis of decompensated heart failure were compared to patients with a criterion standard of decompensated heart failure but no ED diagnosis of decompensated heart failure. Two senior cardiology fellows retrospectively determined the patient's heart failure status during their acute ED presentation. The Mann-Whitney u-test for two groups, the Kruskall-Wallis test for multiple groups, or Chi-square tests, were used as appropriate. RESULTS: There were 173 (39.4%) patients with a criterion standard diagnosis of decompensated heart failure. Among those with this criterion standard diagnosis of decompensated heart failure, discordant patients without an ED diagnosis of decompensated heart failure (n = 58) were more likely to have a history of COPD (p = 0.017), less likely to have a previous history of heart failure (p = 0.014), and less likely to have an elevated b-type natriuretic peptide (BNP) level (median 518 vs 764 pg/ml; p = 0.038) than those who were given a concordant ED diagnosis of decompensated heart failure. BNP levels were higher in those with a criterion standard diagnosis of decompensated heart failure than in those without a criterion standard diagnosis (median 657 vs 62.7 pg/ml). However, 34.6% of patients with decompensated heart failure had BNP levels in the normal (<100 pg/ml; 6.1%) or indeterminate range (100–500 pg/ml; 28.5%). CONCLUSION: We found the ED diagnoses of decompensated heart failure to be discordant with the criterion standard in 14.3% of patients, the vast majority of which were due to a failure to diagnose heart failure when it was present. Patients with a previous history of COPD, without a previous history of heart failure and with lower BNP levels were more likely to have an ED misdiagnosis of non-decompensated heart failure. Readily available, accurate, objective ED tests are needed to improve the early diagnosis of decompensated heart failure in ED patients

An international internet survey of the experiences of 1,714 mothers with a late stillbirth: The STARS cohort study

Background: Stillbirth occurring after 28 weeks gestation affects between 1.5-4.5 per 1,000 births in high-income countries. The majority of stillbirths in this setting occur in women without risk factors. In addition, many established risk factors such as nulliparity and maternal age are not amenable to modification during pregnancy. Identification of other risk factors which could be amenable to change in pregnancy should be a priority in stillbirth prevention research. Therefore, this study aimed to utilise an online survey asking women who had a stillbirth about their pregnancy in order to identify any common symptoms and experiences. Methods: A web-based survey. Results: A total of 1,714 women who had experienced a stillbirth >3 weeks prior to enrolment completed the survey. Common experiences identified were: perception of changes in fetal movement (63 % of respondents), reports of a "gut instinct" that something was wrong (68 %), and perceived time of death occurring overnight (56 %). A quarter of participants believed that their baby's death was due to a cord issue and another 18 % indicated that they did not know the reason why their baby died. In many cases (55 %) the mother believed the cause of death was different to that told by clinicians. Conclusions: This study confirms the association between altered fetal movements and stillbirth and highlights novel associations that merit closer scrutiny including a maternal gut instinct that something was wrong. The potential importance of maternal sleep is highlighted by the finding of more than half the mothers believing their baby died during the night. This study supports the importance of listening to mothers' concerns and symptoms during pregnancy and highlights the need for thorough investigation of stillbirth and appropriate explanation being given to parents

Prompt atmospheric neutrino fluxes: perturbative QCD models and nuclear effects

We evaluate the prompt atmospheric neutrino flux at high energies using three different frameworks for calculating the heavy quark production cross section in QCD: NLO perturbative QCD, $k_T$ factorization including low-$x$ resummation, and the dipole model including parton saturation. We use QCD parameters, the value for the charm quark mass and the range for the factorization and renormalization scales that provide the best description of the total charm cross section measured at fixed target experiments, at RHIC and at LHC. Using these parameters we calculate differential cross sections for charm and bottom production and compare with the latest data on forward charm meson production from LHCb at $7$ TeV and at $13$ TeV, finding good agreement with the data. In addition, we investigate the role of nuclear shadowing by including nuclear parton distribution functions (PDF) for the target air nucleus using two different nuclear PDF schemes. Depending on the scheme used, we find the reduction of the flux due to nuclear effects varies from $10\%$ to $50 \%$ at the highest energies. Finally, we compare our results with the IceCube limit on the prompt neutrino flux, which is already providing valuable information about some of the QCD models.Comment: 61 pages, 25 figures, 11 table

Grand Challenges: Improving HIV Treatment Outcomes by Integrating Interventions for Co-Morbid Mental Illness.

In the fourth article of a five-part series providing a global perspective on integrating mental health, Sylvia Kaaya and colleagues discuss the importance of integrating mental health interventions into HIV prevention and treatment platforms. Please see later in the article for the Editors' Summary