Phase informed model for motion and susceptibility

Field inhomogeneities caused by variations in magnetic susceptibility throughout the head lead to geometric distortions, mainly in the phase‐encode direction of echo‐planar images (EPI). The magnitude and spatial characteristics of the distortions depend on the orientation of the head in the magnetic field and will therefore vary with head movement. A new method is presented, based on a phase informed model for motion and susceptibility (PIMMS), which estimates the change in geometric distortion associated with head motion. This method fits a model of the head motion parameters and scanner hardware characteristics to EPI phase time series. The resulting maps of the model fit parameters are used to correct for susceptibility artifacts in the magnitude images. Results are shown for EPI‐based fMRI time‐series acquired at 3T, demonstrating that compared with conventional rigid body realignment, PIMMS removes residual variance associated with motion‐related distortion effects. Furthermore, PIMMS can lead to a reduction in false negatives compared with the widely accepted approach which uses standard rigid body realignment and includes the head motion parameters in the statistical model. The PIMMS method can be used with any standard EPI sequence for which accurate phase information is available. Hum Brain Mapp 34:3086–3100, 2013. © 2012 The Authors. Human Brain Mapping Published byWiley Periodicals, Inc.     

The zebrafish reveals dependence of the mast cell lineage on Notch signaling in vivo

We used the opportunities afforded by the zebrafish to determine upstream pathways regulating mast cell development in vivo and identify their cellular origin. Colocalization studies demonstrated zebrafish notch receptor expression in cells expressing carboxypeptidase A5 (cpa5), a zebrafish mast cell-specific marker. Inhibition of the Notch pathway resulted in decreased cpa5 expression in mindbomb mutants and wild-type embryos treated with the γ-secretase inhibitor, Compound E. A series of morpholino knockdown studies specifically identified notch1b and gata2 as the critical factors regulating mast cell fate. Moreover, hsp70::GAL4;UAS::nicd1a transgenic embryos overexpressing an activated form of notch1, nicd1a, displayed increased cpa5, gata2, and pu.1 expression. This increase in cpa5 expression could be reversed and reduced below baseline levels in a dose-dependent manner using Compound E. Finally, evidence that cpa5 expression colocalizes with lmo2 in the absence of hematopoietic stem cells revealed that definitive mast cells initially delineate from erythromyeloid progenitors. These studies identify a master role for Notch signaling in vertebrate mast cell development and establish developmental origins of this lineage. Moreover, these findings postulate targeting the Notch pathway as a therapeutic strategy in mast cell diseases.     

‘Sometimes they fail to keep their faith in us’: community health worker perceptions of structural barriers to quality of care and community utilisation of services in Bangladesh

Community health workers (CHWs) have strong potential to extend health and nutrition services to underserved populations. However, CHWs face complex challenges when working within weak health systems and among communities with limited abilities to access and utilise CHW services. It is crucial to understand these challenges to improve programme support mechanisms. This study describes the results of qualitative investigations into CHW perceptions of barriers to quality of care among two groups of workers implementing community case management of acute respiratory infection, diarrhoea and severe acute malnutrition in southern Bangladesh. We explored systemic barriers to service delivery, pertaining to communities and health systems, which limited the usefulness and effectiveness of CHW services. Focus group discussions (n = 10) were conducted in March 2010. Discussions were analysed for themes related to CHWs' work challenges. Findings highlight several perceived barriers to effective service provision, including community poverty constraining uptake of recommended practices, irregular supplies of medicine from the health facility and poor quality of care for CHW referrals sent there. This study further documents interactions between demand‐side and supply‐side constraints including the influence of health system resource constraints on community trust in CHW services, and the influence of community resource constraints on the utilisation and effectiveness of CHW services. By documenting service delivery challenges from the perspective of the frontline workers themselves, this article contributes evidence to help identify appropriate support mechanisms for these workers, in order to develop scalable and sustainable CHW programmes in countries with under‐resourced public health care infrastructure.     

Pan-cancer association of HLA gene expression with cancer prognosis and immunotherapy efficacy

Background The function of major histocompatibility complex (MHC) molecules is to bind peptide fragments derived from genomic mutations or pathogens and display them on the cell surface for recognition by cognate T cells to initiate an immune response.Methods In this study, we provide a comprehensive investigation of HLA gene expression in a pan-cancer manner involving 33 cancer types. We utilised gene expression data from several databases and immune checkpoint blockade-treated patient cohorts.Results We show that MHC expression varies strongly among cancer types and is associated with several genomic and immunological features. While immune cell infiltration was generally higher in tumours with higher HLA gene expression, CD4+ T cells showed significantly different correlations among cancer types, separating them into two clusters. Furthermore, we show that increased HLA gene expression is associated with prolonged survival in the majority of cancer types. Lastly, HLA gene expression is associated with patient response to immune checkpoint blockade, which is especially prominent for HLA class II expression in tumour biopsies taken during treatment.Conclusion We show that HLA gene expression is an important feature of tumour biology that has significant impact on patient prognosis.Subject terms: Tumour immunology, MHC     

Regulatory polymorphisms in the interleukin-18 promoter are associated with hepatitis C virus clearance

The immune response is critical in determining the outcome of hepatitis C virus (HCV) infection. Interleukin (IL)-18 is a pivotal mediator of the Th1/Th2-driven immune response. Two IL-18 promoter polymorphisms (-607C/A and -137G/C) and their haplotypes were known to affect IL-18 expression. We examined the role played by these polymorphisms in determining HCV clearance or persistence. Genotyping was performed among African American injection drug users with HCV clearance (n = 91) or HCV persistence (n = 182) and among European Americans with hemophilia who were mainly infected through plasma transfusion. Among injection drug users, IL18 -607A (odds ratio [OR], 3.68 [95% confidence interval {CI},1.85-7.34]) and IL18 -137C (OR, 2.33 [95% CI, 1.24-4.36]) were significantly associated with HCV clearance. A haplotype carrying -607A and -137C (OR, 4.53 [95% CI, 1.77-11.6]) was also strongly associated with viral clearance. No association was found among those with hemophilia. These results suggest that IL18 promoter polymorphism may affect the outcome of HCV infection in certain groups.     

Host genetic factors and antiviral immune responses to hepatitis C virus

Human genome variations explain some of the heterogeneity in the immune response to antigenic stimuli. Such differences in response to hepatitis C virus (HCV) antigens can account for the ability of the immune response to clear HCV after an acute infection or to develop more rapidly progressive liver disease. Several studies have examined polymorphisms in several candidate immune-response genes for their relation to these HCV outcomes. Results of some of these studies complement knowledge gained from immunology studies, and others offer new insights into HCV biology. This review summarizes published studies on variation in immune-response genes and HCV outcomes.