Inaccuracy of Death Certificate Diagnosis of Tuberculosis and Potential Underdiagnosis of TB in a Region of High HIV Prevalence

Despite the South African antiretroviral therapy rollout, which should reduce the incidence of HIV-associated tuberculosis (TB), the number of TB-attributable deaths in KwaZuluNatal (KZN) remains high. TB is often diagnosed clinically, without microbiologic confirmation, leading to inaccurate estimates of TB-attributed deaths. This may contribute to avoidable deaths, and impact population-based TB mortality estimates. Objectives. (1) To measure the number of cases with microbiologically confirmed TB in a retrospective cohort of deceased inpatients with TB-attributed hospital deaths. (2) To estimate the rates of multi-drug resistant (MDR) and extensively drug resistant (XDR) TB in this cohort. Results. Of 2752 deaths at EDH between September 2006 and March 2007, 403 (15%) were attributed to TB on the death certificate. 176 of the TB-attributed deaths (44%) had a specimen sent for smear or culture; only 64 (36%) had a TB diagnosis confirmed by either test. Of the 39 culture-confirmed cases, 27/39 (69%) had fully susceptible TB and 27/39 (69%) had smear-negative culture-positive TB (SNTB). Two patients had drug monoresistance, three patients had MDR-TB, and one had XDR-TB. Conclusions. Most TB-attributed deaths in this cohort were not microbiologically confirmed. Of confirmed cases, most were smear-negative, culture positive and were susceptible to all first line drugs

WDFY4 deficiency in NOD mice ameliorates autoimmune diabetes and insulitis

The events that initiate autoimmune diabetes in nonobese diabetic (NOD) mice remain poorly understood. CD

Cis interactions in the Irf8 locus regulate stage-dependent enhancer activation

Individual elements within a superenhancer can act in a cooperative or temporal manner, but the underlying mechanisms remain obscure. We recently identified a

The Killing of African Trypanosomes by Ethidium Bromide

Introduced in the 1950s, ethidium bromide (EB) is still used as an anti-trypanosomal drug for African cattle although its mechanism of killing has been unclear and controversial. EB has long been known to cause loss of the mitochondrial genome, named kinetoplast DNA (kDNA), a giant network of interlocked minicircles and maxicircles. However, the existence of viable parasites lacking kDNA (dyskinetoplastic) led many to think that kDNA loss could not be the mechanism of killing. When recent studies indicated that kDNA is indeed essential in bloodstream trypanosomes and that dyskinetoplastic cells survive only if they have a compensating mutation in the nuclear genome, we investigated the effect of EB on kDNA and its replication. We here report some remarkable effects of EB. Using EM and other techniques, we found that binding of EB to network minicircles is low, probably because of their association with proteins that prevent helix unwinding. In contrast, covalently-closed minicircles that had been released from the network for replication bind EB extensively, causing them, after isolation, to become highly supertwisted and to develop regions of left-handed Z-DNA (without EB, these circles are fully relaxed). In vivo, EB causes helix distortion of free minicircles, preventing replication initiation and resulting in kDNA loss and cell death. Unexpectedly, EB also kills dyskinetoplastic trypanosomes, lacking kDNA, by inhibiting nuclear replication. Since the effect on kDNA occurs at a >10-fold lower EB concentration than that on nuclear DNA, we conclude that minicircle replication initiation is likely EB's most vulnerable target, but the effect on nuclear replication may also contribute to cell killing

A New Approach to Analyzing Patterns of Collaboration in Co-authorship Networks - Mesoscopic Analysis and Interpretation

This paper focuses on methods to study patterns of collaboration in co-authorship networks at the mesoscopic level. We combine qualitative methods (participant interviews) with quantitative methods (network analysis) and demonstrate the application and value of our approach in a case study comparing three research fields in chemistry. A mesoscopic level of analysis means that in addition to the basic analytic unit of the individual researcher as node in a co-author network, we base our analysis on the observed modular structure of co-author networks. We interpret the clustering of authors into groups as bibliometric footprints of the basic collective units of knowledge production in a research specialty. We find two types of coauthor-linking patterns between author clusters that we interpret as representing two different forms of cooperative behavior, transfer-type connections due to career migrations or one-off services rendered, and stronger, dedicated inter-group collaboration. Hence the generic coauthor network of a research specialty can be understood as the overlay of two distinct types of cooperative networks between groups of authors publishing in a research specialty. We show how our analytic approach exposes field specific differences in the social organization of research.Comment: An earlier version of the paper was presented at ISSI 2009, 14-17 July, Rio de Janeiro, Brazil. Revised version accepted on 2 April 2010 for publication in Scientometrics. Removed part on node-role connectivity profile analysis after finding error in calculation and deciding to postpone analysis

IL-6 selectively suppresses cDC1 specification via C/EBPβ

Cytokines produced in association with tumors can impair antitumor immune responses by reducing the abundance of type 1 conventional dendritic cells (cDC1), but the mechanism remains unclear. Here, we show that tumor-derived IL-6 generally reduces cDC development but selectively impairs cDC1 development in both murine and human systems through the induction of C/EBPβ in the common dendritic cell progenitor (CDP). C/EBPβ and NFIL3 compete for binding to sites in the Zeb2 -165 kb enhancer and support or repress Zeb2 expression, respectively. At homeostasis, pre-cDC1 specification occurs upon Nfil3 induction and consequent Zeb2 suppression. However, IL-6 strongly induces C/EBPβ expression in CDPs. Importantly, the ability of IL-6 to impair cDC development is dependent on the presence of C/EBPβ binding sites in the Zeb2 -165 kb enhancer, as this effect is lost in Δ1+2+3 mutant mice in which these binding sites are mutated. These results explain how tumor-associated IL-6 suppresses cDC1 development and suggest therapeutic approaches preventing abnormal C/EBPβ induction in CDPs may help reestablish cDC1 development to enhance antitumor immunity

Zbtb46 expression distinguishes classical dendritic cells and their committed progenitors from other immune lineages

Distinguishing dendritic cells (DCs) from other cells of the mononuclear phagocyte system is complicated by the shared expression of cell surface markers such as CD11c. In this study, we identified Zbtb46 (BTBD4) as a transcription factor selectively expressed by classical DCs (cDCs) and their committed progenitors but not by plasmacytoid DCs (pDCs), monocytes, macrophages, or other lymphoid or myeloid lineages. Using homologous recombination, we replaced the first coding exon of Zbtb46 with GFP to inactivate the locus while allowing detection of Zbtb46 expression. GFP expression in Zbtb46(gfp/+) mice recapitulated the cDC-specific expression of the native locus, being restricted to cDC precursors (pre-cDCs) and lymphoid organ- and tissue-resident cDCs. GFP(+) pre-cDCs had restricted developmental potential, generating cDCs but not pDCs, monocytes, or macrophages. Outside the immune system, Zbtb46 was expressed in committed erythroid progenitors and endothelial cell populations. Zbtb46 overexpression in bone marrow progenitor cells inhibited granulocyte potential and promoted cDC development, and although cDCs developed in Zbtb46(gfp/gfp) (Zbtb46 deficient) mice, they maintained expression of granulocyte colony-stimulating factor and leukemia inhibitory factor receptors, which are normally down-regulated in cDCs. Thus, Zbtb46 may help enforce cDC identity by restricting responsiveness to non-DC growth factors and may serve as a useful marker to identify rare cDC progenitors and distinguish between cDCs and other mononuclear phagocyte lineages

Measurement Bias in Caregiver-Report of Early Childhood Behavior Problems across Demographic Factors in an Echo-Wide Diverse Sample

BACKGROUND: Research and clinical practice rely heavily on caregiver-report measures, such as the Child Behavior Checklist 1.5-5 (CBCL/1.5-5), to gather information about early childhood behavior problems and to screen for child psychopathology. While studies have shown that demographic variables influence caregiver ratings of behavior problems, the extent to which the CBCL/1.5-5 functions equivalently at the item level across diverse samples is unknown. METHODS: Item-level data of CBCL/1.5-5 from a large sample of young children ( RESULTS: Items with the most impactful DIF across child and caregiver groupings were identified for Internalizing, Externalizing, and total Problems. The robust item sets, excluding the high DIF items, showed good reliability and high correlation with the original Internalizing and total Problems scales, with lower reliability for Externalizing. Language version of CBCL administration, education level and sex of the caregiver respondent showed the most significant impact on MI, followed by child age. Sensitivity analyses revealed that child race has a unique impact on DIF over and above socioeconomic status. CONCLUSIONS: The CBCL/1.5-5, a caregiver-report measure of early childhood behavior problems, showed bias across demographic groups. Robust item sets with less DIF can measure Internalizing and total Problems equally as well as the full item sets, with slightly lower reliability for Externalizing, and can be crosswalked to the metric of the full item set, enabling calculation of normed T scores based on more robust item sets

Targeting of B and T lymphocyte associated (BTLA) prevents graft-versus-host disease without global immunosuppression

One-time treatment with an antibody against BTLA provides long-term protection against graft-versus-host disease without affecting effector T cell responses to tumors or pathogens

Pan-cancer Alterations of the MYC Oncogene and Its Proximal Network across the Cancer Genome Atlas

Although theMYConcogene has been implicated incancer, a systematic assessment of alterations ofMYC, related transcription factors, and co-regulatoryproteins, forming the proximal MYC network (PMN),across human cancers is lacking. Using computa-tional approaches, we define genomic and proteo-mic features associated with MYC and the PMNacross the 33 cancers of The Cancer Genome Atlas.Pan-cancer, 28% of all samples had at least one ofthe MYC paralogs amplified. In contrast, the MYCantagonists MGA and MNT were the most frequentlymutated or deleted members, proposing a roleas tumor suppressors.MYCalterations were mutu-ally exclusive withPIK3CA,PTEN,APC,orBRAFalterations, suggesting that MYC is a distinct onco-genic driver. Expression analysis revealed MYC-associated pathways in tumor subtypes, such asimmune response and growth factor signaling; chro-matin, translation, and DNA replication/repair wereconserved pan-cancer. This analysis reveals insightsinto MYC biology and is a reference for biomarkersand therapeutics for cancers with alterations ofMYC or the PMN