Availability of long-acting and permanent family-planning methods leads to increase in use in conflict-affected northern Uganda: evidence from cross-sectional baseline and endline cluster surveys

Humanitarian assistance standards require specific attention to address the reproductive health (RH) needs of conflict-affected populations. Despite these internationally recognised standards, access to RH services is still often compromised in war. We assessed the effectiveness of our programme in northern Uganda to provide family planning (FP) services through mobile outreach and public health centre strengthening. Baseline (n=905) and endline (n=873) cross-sectional surveys using a multistage cluster sampling design were conducted in the catchment areas of four public health centres in 2007 and 2010. Current use of any modern FP method increased from 7.1% to 22.6% (adjusted odds ratio [OR] 3.34 [95% confidence interval (CI) 2.27–4.92]); current use of long-acting and permanent methods increased from 1.2% to 9.8% (adjusted OR 9.45 [95%CI 3.99–22.39]). The proportion of women with unmet need for FP decreased from 52.1% to 35.7%. This study demonstrates that when comprehensive FP services are provided among conflict-affected populations, women will choose to use them. The combination of mobile teams and health systems strengthening can make a full range of methods quickly available while supporting the health system to continue to provide those services in challenging and resource-constrained settings

Barriers and facilitators when implementing midwifery continuity of carer:a narrative analysis of the international literature

Background: Midwifery continuity of carer (MCoC) is a model of care in which the same midwife or small team of midwives supports women throughout pregnancy, birth and the postnatal period. The model has been prioritised by policy makers in a number of high-income countries, but widespread implementation and sustainability has proved challenging. Methods: In this narrative review and synthesis of the global literature on the implementation and sustainability of midwifery continuity of carer, we identify barriers to, and facilitators of, this model of delivering maternity care. By mapping existing research evidence onto the Consolidated Framework for Implementation Research (CFIR), we identify factors for organisations to consider when planning and implementing midwifery continuity of carer as well as gaps in the current research evidence. Results: Analysing international evidence using the CFIR shows that evidence around midwifery continuity of carer implementation is patchy and fragmented, and that the impetus for change is not critically examined. Existing literature pays insufficient attention to core aspects of the innovation such as the centrality of on call working arrangements and alignment with the professional values of midwifery. There is also limited attention to the political and structural contexts into which midwifery continuity of carer is introduced. Conclusions: By synthesizing international research evidence with the CFIR, we identify factors for organisations to consider when planning and implementing midwifery continuity of carer. We also call for more systematic and contextual evidence to aid understanding of the implementation or non-implementation of midwifery continuity of carer. Existing evidence should be critically evaluated and used more cautiously in support of claims about the model of care and its implementation, especially when implementation is occurring in different settings and contexts to the research being cited

The initiator methionine tRNA drives secretion of type II collagen from stromal fibroblasts to promote tumor growth and angiogenesis

Summary: Expression of the initiator methionine tRNA (tRNAi Met) is deregulated in cancer. Despite this fact, it is not currently known how tRNAi Met expression levels influence tumor progression. We have found that tRNAi Met expression is increased in carcinoma-associated fibroblasts, implicating deregulated expression of tRNAi Met in the tumor stroma as a possible contributor to tumor progression. To investigate how elevated stromal tRNAi Met contributes to tumor progression, we generated a mouse expressing additional copies of the tRNAi Met gene (2+tRNAi Met mouse). Growth and vascularization of subcutaneous tumor allografts was enhanced in 2+tRNAi Met mice compared with wild-type littermate controls. Extracellular matrix (ECM) deposited by fibroblasts from 2+tRNAi Met mice supported enhanced endothelial cell and fibroblast migration. SILAC mass spectrometry indicated that elevated expression of tRNAi Met significantly increased synthesis and secretion of certain types of collagen, in particular type II collagen. Suppression of type II collagen opposed the ability of tRNAi Metoverexpressing fibroblasts to deposit pro-migratory ECM. We used the prolyl hydroxylase inhibitor ethyl- 3,4-dihydroxybenzoate (DHB) to determine whether collagen synthesis contributes to the tRNAi Met-driven pro-tumorigenic stroma in vivo. DHB had no effect on the growth of syngeneic allografts in wild-type mice but opposed the ability of 2+tRNAi Met mice to support increased angiogenesis and tumor growth. Finally, collagen II expression predicts poor prognosis in high-grade serous ovarian carcinoma. Taken together, these data indicate that increased tRNAi Met levels contribute to tumor progression by enhancing the ability of stromal fibroblasts to synthesize and secrete a type II collagen-rich ECM that supports endothelial cell migration and angiogenesis

Retrograde optogenetic characterization of the pontospinal module of the locus coeruleus with a canine adenoviral vector

AbstractNoradrenergic neurons of the brainstem extend projections throughout the neuraxis to modulate a wide range of processes including attention, arousal, autonomic control and sensory processing. A spinal projection from the locus coeruleus (LC) is thought to regulate nociceptive processing. To characterize and selectively manipulate the pontospinal noradrenergic neurons in rats, we implemented a retrograde targeting strategy using a canine adenoviral vector to express channelrhodopsin2 (CAV2-PRS-ChR2-mCherry). LC microinjection of CAV2-PRS-ChR2-mCherry produced selective, stable, transduction of noradrenergic neurons allowing reliable opto-activation in vitro. The ChR2-transduced LC neurons were opto-identifiable in vivo and functional control was demonstrated for >6 months by evoked sleep-wake transitions. Spinal injection of CAV2-PRS-ChR2-mCherry retrogradely transduced pontine noradrenergic neurons, predominantly in the LC but also in A5 and A7. A pontospinal LC (ps:LC) module was identifiable, with somata located more ventrally within the nucleus and with a discrete subset of projection targets. These ps:LC neurons had distinct electrophysiological properties with shorter action potentials and smaller afterhyperpolarizations compared to neurons located in the core of the LC. In vivo recordings of ps:LC neurons showed a lower spontaneous firing frequency than those in the core and they were all excited by noxious stimuli. Using this CAV2-based approach we have demonstrated the ability to retrogradely target, characterise and optogenetically manipulate a central noradrenergic circuit and show that the ps:LC module forms a discrete unit.This article is part of a Special Issue entitled SI: Noradrenergic System

Central role of JC virus-specific CD4+ lymphocytes in progressive multi-focal leucoencephalopathy-immune reconstitution inflammatory syndrome

Progressive multi-focal leucoencephalopathy and progressive multi-focal leucoencephalopathy-immune reconstitution inflammatory syndrome are caused by infection of the central nervous system with the JC polyoma virus. Both are complications of monoclonal antibody therapy in multiple sclerosis and other autoimmune diseases. Progressive multi-focal leucoencephalopathy-immune reconstitution inflammatory syndrome can obscure the diagnosis of progressive multi-focal leucoencephalopathy and lead to severe clinical disability and possibly death. Different from progressive multi-focal leucoencephalopathy, in which demyelination results from oligodendrocyte lysis by JC virus in the absence of an immune response, tissue destruction in progressive multi-focal leucoencephalopathy-immune reconstitution inflammatory syndrome is caused by a vigorous immune response within the brain. The cells and mediators that are involved in progressive multi-focal leucoencephalopathy-immune reconstitution inflammatory syndrome are as yet poorly understood. We examined two patients with multiple sclerosis, who developed progressive multi-focal leucoencephalopathy and later progressive multi-focal leucoencephalopathy-immune reconstitution inflammatory syndrome under natalizumab therapy. Due to initially negative JC viral deoxyribonucleic acid testing in the cerebrospinal fluid, a diagnostic brain biopsy was performed in one patient. Histopathology revealed brain inflammation characterized by a prominent T cell infiltrate (CD4+ > CD8+ T cells), but also B/plasma cells and monocytes. Despite very low JC viral load, both patients showed high intrathecal anti-JC virus antibodies. Brain-infiltrating CD4+ T cells were studied regarding antigen specificity and function. CD4+ T cells were highly specific for peptides from several JC virus proteins, particularly the major capsid protein VP1. T cell phenotyping revealed CD4+ Th1 and bifunctional Th1-2 cells. The latter secrete large amounts of interferon-γ and interleukin-4 explaining the strong brain inflammation, presence of plasma cells and secretion of intrathecal anti-VP1 antibodies. The functional phenotype of brain-infiltrating JC virus-specific CD4+ T cells was confirmed and extended by examining brain-derived JC virus-specific CD4+ T cell clones. Our data provide novel insight into the pathogenesis of progressive multi-focal leucoencephalopathy-immune reconstitution inflammatory syndrome and indicate that JC virus-specific CD4+ T cells play an important role in both eliminating JC virus from the brain, but also in causing the massive inflammation with often fatal outcom

Structure of Class Feeling / Feeling of Class Structure:Laura Wade’s Posh and Katherine Soper’s Wish List

Theatre’s counter-hegemonic resistance to the “demonization of the working class” (Owen Jones) is the subject of this article. This resistance is analysed through case studies of two “class acts”: the elite Oxford boys in Laura Wade’s Posh (2010) and poverty-stricken youth in Katherine Soper’s Wish List (2016). My close reading of these two plays involves a reprise of Raymond Williams’s “structure of feeling”: the conjugation of “structure” and “feeling” allows me to engage with and advocate a dual concern with systems of classification, and the affective, experiential (lived) dimension of being “classified.” Moving between the class-fuelled feelings of entitlement in Posh and those of alienation in Wish List, I elucidate how, under the UK’s regime of neoliberal austerity, the label “working class” has become “sticky” (Sara Ahmed) with disgust-making properties (Pierre Bourdieu). Overall, what emerges is a critical feeling for the UK as a class-divided nation and the urgent need to resist the entrenched classifying gaze of the neoliberalist imagination

A single-cell atlas enables mapping of homeostatic cellular shifts in the adult human breast

A.D.R. performed the majority of the bioinformatic analysis and interpretation of the data. S.P. contributed to the study design, sample processing, analysis and interpretation of the data. J.S. contributed to the sample processing. D.J.K. and P.H. contributed to the data processing, batch correction and cell cluster identification. A.S. contributed to the design of the sample batches and contributed to the analysis of the raw data. A.J.T. contributed to the analysis of the data and Figure design. L.J.P. performed the immune histochemistry validations. K.H. assisted A.D.R. with the inferCNV analysis and interpretation. P.H. assisted with the subclustering of immune cells and scVI integration analysis. A.Q.S. performed the immunofluorescence quantification. K.K. performed all the scRNA-seq library preparation and sequencing. R.B.M., I.G., J.J.G., V.S. and J.L.J. provided the human tissues and the metadata from the 55 donors. A.D.R., S.P., J.C.M. and W.T.K. wrote the paper. J.C.M. and W.T.K. conceptualized and supervised the study.Peer reviewe

A mutation in the mitochondrial fission gene Dnm1l leads to cardiomyopathy

Mutations in a number of genes have been linked to inherited dilated cardiomyopathy (DCM). However, such mutations account for only a small proportion of the clinical cases emphasising the need for alternative discovery approaches to uncovering novel pathogenic mutations in hitherto unidentified pathways. Accordingly, as part of a large-scale N-ethyl-N-nitrosourea mutagenesis screen, we identified a mouse mutant, Python, which develops DCM. We demonstrate that the Python phenotype is attributable to a dominant fully penetrant mutation in the dynamin-1-like (Dnm1l) gene, which has been shown to be critical for mitochondrial fission. The C452F mutation is in a highly conserved region of the M domain of Dnm1l that alters protein interactions in a yeast two-hybrid system, suggesting that the mutation might alter intramolecular interactions within the Dnm1l monomer. Heterozygous Python fibroblasts exhibit abnormal mitochondria and peroxisomes. Homozygosity for the mutation results in the death of embryos midway though gestation. Heterozygous Python hearts show reduced levels of mitochondria enzyme complexes and suffer from cardiac ATP depletion. The resulting energy deficiency may contribute to cardiomyopathy. This is the first demonstration that a defect in a gene involved in mitochondrial remodelling can result in cardiomyopathy, showing that the function of this gene is needed for the maintenance of normal cellular function in a relatively tissue-specific manner. This disease model attests to the importance of mitochondrial remodelling in the heart; similar defects might underlie human heart muscle disease

Comparison of real-world treatment outcomes of systemic immunomodulating therapy in atopic dermatitis patients with dark and light skin types

Background Few data exist on differences in treatment effectiveness and safety in atopic dermatitis patients of different skin types. Objective To investigate treatment outcomes of dupilumab, methotrexate, and ciclosporin, and morphological phenotypes in atopic dermatitis patients, stratified by Fitzpatrick skin type. Methods In an observational prospective cohort study, pooling data from the Dutch TREAT (TREatment of ATopic eczema) NL (treatregister.nl) and UK-Irish A-STAR (Atopic eczema Systemic TherApy Register; astar-register.org) registries, data on morphological phenotypes and treatment outcomes were investigated. Results A total of 235 patients were included (light skin types [LST]: Fitzpatrick skin type 1-3, n = 156 [Ethnicity, White: 94.2%]; dark skin types [DST]: skin type 4-6, n = 68 [Black African/Afro-Caribbean: 25%, South-Asian: 26.5%, and Hispanics: 0%]). DST were younger (19.5 vs 29.0 years; P .05). Limitations Unblinded, non-randomized. Conclusion Atopic dermatitis differs in several characteristics between LST and DST. Skin type may influence treatment effectiveness of dupilumab