Mortality from HIV-associated meningitis in sub-Saharan Africa: a systematic review and meta-analysis.

INTRODUCTION: HIV-associated cryptococcal, TB and pneumococcal meningitis are the leading causes of adult meningitis in sub-Saharan Africa (SSA). We performed a systematic review and meta-analysis with the primary aim of estimating mortality from major causes of adult meningitis in routine care settings, and to contrast this with outcomes from clinical trial settings. METHODS: We searched PubMed, EMBASE and the Cochrane Library for published clinical trials (defined as randomized-controlled trials (RCTs) or investigator-managed prospective cohorts) and observational studies that evaluated outcomes of adult meningitis in SSA from 1 January 1990 through 15 September 2019. We performed random effects modelling to estimate pooled mortality, both in clinical trial and routine care settings. Outcomes were stratified as short-term (in-hospital or two weeks), medium-term (up to 10 weeks) and long-term (up to six months). RESULTS AND DISCUSSION: Seventy-nine studies met inclusion criteria. In routine care settings, pooled short-term mortality from cryptococcal meningitis was 44% (95% confidence interval (95% CI):39% to 49%, 40 studies), which did not differ between amphotericin (either alone or with fluconazole) and fluconazole-based induction regimens, and was twofold higher than pooled mortality in clinical trials using amphotericin based treatment (21% (95% CI:17% to 25%), 17 studies). Pooled short-term mortality of TB meningitis was 46% (95% CI: 33% to 59%, 11 studies, all routine care). For pneumococcal meningitis, pooled short-term mortality was 54% in routine care settings (95% CI:44% to 64%, nine studies), with similar mortality reported in two included randomized-controlled trials. Few studies evaluated long-term outcomes. CONCLUSIONS: Mortality rates from HIV-associated meningitis in SSA are very high under routine care conditions. Better strategies are needed to reduce mortality from HIV-associated meningitis in the region

High success and low mortality rates with non-invasive ventilation in influenza A H1N1 patients in a tertiary hospital

<p>Abstract</p> <p>Background</p> <p>In 2009, an outbreak of respiratory illness caused by influenza A H1N1 virus occurred worldwide. Some patients required Intensive Care Unit (ICU) admission. The use of non-invasive ventilation (NIV) in these patients is controversial, as the aerosol dispersion may contaminate the environment and health-care co-workers.</p> <p>Methods</p> <p>Describe the respiratory profile, the mortality rate, and the benefit of using NIV in patients with confirmed diagnosis of influenza AH1N1 who were admitted in the ICU during the year 2009.</p> <p>Results</p> <p>A total of 1, 401 cases of influenza A H1N1 were confirmed in our hospital by real-time RT-PCR in 2009, and 20 patients were admitted to the ICU. The patients' ages ranged from 18 to 74 years (median of 42). Acute Respiratory Failure (ARF) was present in 70% of patients. The median Acute Physiology and Chronic Health Evaluation II score was 7 (range 7 to 25). Of the 14 patients who developed ARF, 85.7% needed NIV and 14% needed invasive MV at admission. Our success rate (41.6%) with NIV was higher than that described by others. The hospital mortality rate was 2.1%. When influenza A H1N1 arrived in Brazil, the disease was already on endemic alert in other countries. The population was already aware of the symptoms and the health-care system of the treatment. This allowed patients to be properly and promptly treated for influenza A H1N1, while health-care workers took protective measures to avoid contamination.</p> <p>Conclusion</p> <p>In our study we found a high success and low mortality rates with non-invasive ventilation in patients with influenza A H1N1.</p

Backpack-mounted satellite transmitters do not affect reproductive performance in a migratory bustard

Backpack-mounted satellite transmitters (PTTs) are used extensively in the study of avian habitat use and of the movements and demography of medium- to large-bodied species, but can affect individuals’ performance and fitness. Transparent assessment of potential transmitter effects is important for both ethical accountability and confidence in, or adjustment to, life history parameter estimates. We assessed the influence of transmitters on seven reproductive parameters in Asian houbara Chlamydotis macqueenii, comparing 114 nests of 38 females carrying PTTs to 184 nests of untagged birds (non-PTT) over seven breeding seasons (2012‒2018) in Uzbekistan. There was no evidence of any influence of PTTs on: lay date (non-PTT x̅ = 91.7 Julian day ± 12.3 SD; PTT x̅ = 95.1 Julian day ± 15.7 SD); clutch size (non-PTT x̅ = 3.30 ± 0.68 SD; PTT x̅ = 3.25 ± 0.65 SD); mean egg weight at laying (non-PTT x̅ = 66.1g ± 5.4 SD; PTT x̅ = 66.4g ± 5.4 SD); nest success (non-PTT x̅ = 57.08% ± 4.3 SE; PTT x̅ = 58.24% ± 4.5 SE for nests started 2 April); egg hatchability (non-PTT x̅ = 88.3% ± 2.2 SE; PTT x̅ = 88.3% ± 2.6 SE); or chick survival to fledging from broods that had at least one surviving chick (non-PTT x̅ = 63.4% ± 4.2 SE; PTT x̅= 64.4% ± 4.7 SE). High nesting propensity (97.3% year-1 ± 1.9% SE) of tagged birds indicated minimal PTT effect on breeding probability. These findings show harness-mounted transmitters can give unbiased measures of demographic parameters of this species, and are relevant to other large-bodied, cursorial, ground-nesting birds of open habitats, particularly other bustards

Characterization of the Contradictory Chromatin Signatures at the 3′ Exons of Zinc Finger Genes

The H3K9me3 histone modification is often found at promoter regions, where it functions to repress transcription. However, we have previously shown that 3′ exons of zinc finger genes (ZNFs) are marked by high levels of H3K9me3. We have now further investigated this unusual location for H3K9me3 in ZNF genes. Neither bioinformatic nor experimental approaches support the hypothesis that the 3′ exons of ZNFs are promoters. We further characterized the histone modifications at the 3′ ZNF exons and found that these regions also contain H3K36me3, a mark of transcriptional elongation. A genome-wide analysis of ChIP-seq data revealed that ZNFs constitute the majority of genes that have high levels of both H3K9me3 and H3K36me3. These results suggested the possibility that the ZNF genes may be imprinted, with one allele transcribed and one allele repressed. To test the hypothesis that the contradictory modifications are due to imprinting, we used a SNP analysis of RNA-seq data to demonstrate that both alleles of certain ZNF genes having H3K9me3 and H3K36me3 are transcribed. We next analyzed isolated ZNF 3′ exons using stably integrated episomes. We found that although the H3K36me3 mark was lost when the 3′ ZNF exon was removed from its natural genomic location, the isolated ZNF 3′ exons retained the H3K9me3 mark. Thus, the H3K9me3 mark at ZNF 3′ exons does not impede transcription and it is regulated independently of the H3K36me3 mark. Finally, we demonstrate a strong relationship between the number of tandemly repeated domains in the 3′ exons and the H3K9me3 mark. We suggest that the H3K9me3 at ZNF 3′ exons may function to protect the genome from inappropriate recombination rather than to regulate transcription

Tumour macrophages as potential targets of bisphosphonates

Tumour cells communicate with the cells of their microenvironment via a series of molecular and cellular interactions to aid their progression to a malignant state and ultimately their metastatic spread. Of the cells in the microenvironment with a key role in cancer development, tumour associated macrophages (TAMs) are among the most notable. Tumour cells release a range of chemokines, cytokines and growth factors to attract macrophages, and these in turn release numerous factors (e.g. VEGF, MMP-9 and EGF) that are implicated in invasion-promoting processes such as tumour cell growth, flicking of the angiogenic switch and immunosuppression. TAM density has been shown to correlate with poor prognosis in breast cancer, suggesting that these cells may represent a potential therapeutic target. However, there are currently no agents that specifically target TAM's available for clinical use

deFuse: An Algorithm for Gene Fusion Discovery in Tumor RNA-Seq Data

Gene fusions created by somatic genomic rearrangements are known to play an important role in the onset and development of some cancers, such as lymphomas and sarcomas. RNA-Seq (whole transcriptome shotgun sequencing) is proving to be a useful tool for the discovery of novel gene fusions in cancer transcriptomes. However, algorithmic methods for the discovery of gene fusions using RNA-Seq data remain underdeveloped. We have developed deFuse, a novel computational method for fusion discovery in tumor RNA-Seq data. Unlike existing methods that use only unique best-hit alignments and consider only fusion boundaries at the ends of known exons, deFuse considers all alignments and all possible locations for fusion boundaries. As a result, deFuse is able to identify fusion sequences with demonstrably better sensitivity than previous approaches. To increase the specificity of our approach, we curated a list of 60 true positive and 61 true negative fusion sequences (as confirmed by RT-PCR), and have trained an adaboost classifier on 11 novel features of the sequence data. The resulting classifier has an estimated value of 0.91 for the area under the ROC curve. We have used deFuse to discover gene fusions in 40 ovarian tumor samples, one ovarian cancer cell line, and three sarcoma samples. We report herein the first gene fusions discovered in ovarian cancer. We conclude that gene fusions are not infrequent events in ovarian cancer and that these events have the potential to substantially alter the expression patterns of the genes involved; gene fusions should therefore be considered in efforts to comprehensively characterize the mutational profiles of ovarian cancer transcriptomes

Genomic analyses identify recurrent MEF2D fusions in acute lymphoblastic leukaemia

Chromosomal rearrangements are initiating events in acute lymphoblastic leukaemia (ALL). Here using RNA sequencing of 560 ALL cases, we identify rearrangements between MEF2D (myocyte enhancer factor 2D) and five genes (BCL9, CSF1R, DAZAP1, HNRNPUL1 and SS18) in 22 B progenitor ALL (B-ALL) cases with a distinct gene expression profile, the most common of which is MEF2D-BCL9. Examination of an extended cohort of 1,164 B-ALL cases identified 30 cases with MEF2D rearrangements, which include an additional fusion partner, FOXJ2; thus, MEF2D-rearranged cases comprise 5.3% of cases lacking recurring alterations. MEF2D-rearranged ALL is characterized by a distinct immunophenotype, DNA copy number alterations at the rearrangement sites, older diagnosis age and poor outcome. The rearrangements result in enhanced MEF2D transcriptional activity, lymphoid transformation, activation of HDAC9 expression and sensitive to histone deacetylase inhibitor treatment. Thus, MEF2D-rearranged ALL represents a distinct form of high-risk leukaemia, for which new therapeutic approaches should be considered