Poor long-term outcomes despite improved hospital survival for patients with cryptococcal meningitis in rural, Northern Uganda.

Background: Cryptococcal meningitis (CM) remains a major cause of death among people living with HIV in rural sub-Saharan Africa. We previously reported that a CM diagnosis and treatment program (CM-DTP) improved hospital survival for CM patients in rural, northern Uganda. This study aimed to evaluate the impact on long-term survival.

Impact of a Cryptococcal meningitis diagnosis and treatment program at Lira Regional Referral Hospital in rural, Northern Uganda.

In rural areas of sub-Saharan Africa, infrastructure and resources for treatment of cryptococcal meningitis (CM) are often lacking. We introduced a CM diagnosis and treatment program (CM-DTP) at Lira Regional Referral Hospital (LRRH) in rural Uganda to determine if implementing high-quality standard of care protocols would improve outcomes. Information extracted from hospital charts and clinical record forms at LRRH were used to compare diagnoses, treatments, and outcomes for all patients diagnosed with meningitis (n = 281) over a two-year period after initiation of the CM-DTP in February of 2017 to all patients diagnosed with meningitis (n = 215) in the two preceding years.

High Burden of Cryptococcal Meningitis Among Antiretroviral Therapy-Experienced Human Immunodeficiency Virus-Infected Patients in Northern Uganda in the Era of "Test and Treat": Implications for Cryptococcal Screening Programs.

Background: The impact of the "test and treat" program for human immunodeficiency virus (HIV) treatment in rural areas of Uganda on cryptococcal antigen (CrAg) screening or cryptococcal meningitis (CM) is poorly understood.

Methods: We retrospectively evaluated clinical factors in 212 HIV-infected patients diagnosed with CM from February of 2017 to November of 2019 at Lira Regional Referral Hospital in northern Uganda.

Results: Among 212 patients diagnosed with CM, 58.

Neuromyelitis Optica Spectrum Disorders in Africa: A Systematic Review.

Background And Objectives: Neuromyelitis optica (NMO) is a CNS inflammatory disease that predominantly affects the optic nerves and the spinal cord. It is more frequent in Asian and African populations than in European ones. Data on epidemiology, clinical presentation, additional investigations, and treatment in the African continent are scarce.

Transcriptomic biomarker pathways associated with death in HIV-infected patients with cryptococcal meningitis.

Background: Cryptococcal meningitis (CM) is a major cause of death in HIV-infected patients in sub-Saharan Africa. Many CM patients experience cryptococcosis-associated immune reconstitution inflammatory syndrome (C-IRIS), which is often fatal. We sought to identify transcriptomic biomarker pathways in peripheral blood that are associated with or predict the development of death or fatal C-IRIS among patients with CM who were enrolled in the Cryptococcal Optimal ART Timing Trial.

B Cell Compartmentalization in Blood and Cerebrospinal Fluid of HIV-Infected Ugandans with Cryptococcal Meningitis.

Activated B cells modulate infection by differentiating into pathogen-specific antibody-producing effector plasmablasts/plasma cells, memory cells, and immune regulatory B cells. In this context, the B cell phenotypes that infiltrate the central nervous system during human immunodeficiency virus (HIV) and cryptococcal meningitis coinfection are ill defined. We characterized clinical parameters, mortality, and B cell phenotypes in blood and cerebrospinal fluid (CSF) by flow cytometry in HIV-infected adults with cryptococcal ( = 31) and noncryptococcal ( = 12) meningitis and in heathy control subjects with neither infection ( = 10).

Epidemiology of non-traumatic spinal cord injury in Uganda: a single center, prospective study with MRI evaluation.

Background: A few reliable national data concerning the etiology of non-traumatic spinal cord injury (SCI) in sub-Sahara Africa exists, mainly because of the limitations of diagnostic imaging. These are both expensive and mostly unavailable in several resource-limited settings. Only a few studies have employed the magnetic resonance imaging (MRI) in documenting non-traumatic SCI and most of these studies are from South Africa.

Blood neutrophil counts in HIV-infected patients with cryptococcal meningitis: Association with mortality.

Background: The mortality from cryptococcal meningitis remains high, despite the availability of antiretroviral therapy (ART) and amphotericin-based fungal regimens. The role of neutrophils in cryptococcosis is controversial. Our objective was to examine the association between blood neutrophil counts and outcomes in terms of mortality, the incidence of bacterial infections (including Mycobacterium tuberculosis) and hospitalization among HIV-infected patients presenting with cryptococcal meningitis.

Reovirus infection induces stabilization and up-regulation of cellular transcripts that encode regulators of TGF-β signaling.

Reovirus infection induces dramatic changes in host mRNA expression. We utilized oligonucleotide microarrays to measure cellular mRNA decay rates in mock- or reovirus-infected murine L929 cells to determine if changes in host mRNA expression are a consequence of reovirus-induced alterations in cellular mRNA stability. Our analysis detected a subset of cellular transcripts that were coordinately induced and stabilized following infection with the reovirus isolates c87 and c8, strains that led to an inhibition of cellular translation, but not following infection with Dearing, a reovirus isolate that did not negatively impact cellular translation.

Transcriptomic Predictors of Paradoxical Cryptococcosis-Associated Immune Reconstitution Inflammatory Syndrome.

Background: Paradoxical cryptococcosis-associated immune reconstitution inflammatory syndrome (C-IRIS) affects ~25% of human immunodeficiency virus (HIV)-infected patients with cryptococcal meningitis (CM) after they commence antiretroviral therapy (ART) resulting in significant morbidity and mortality. Genomic studies in cryptococcal meningitis and C-IRIS are rarely performed.

Methods: We assessed whole blood transcriptomic profiles in 54 HIV-infected subjects with CM who developed C-IRIS (27) and compared the results with control subjects (27) who did not experience neurological deterioration over 24 weeks after ART initiation.

Viral manipulation of host mRNA decay.

Viruses alter host-cell gene expression at many biochemical levels, such as transcription, translation, mRNA splicing and mRNA decay in order to create a cellular environment suitable for viral replication. In this review, we discuss mechanisms by which viruses manipulate host-gene expression at the level of mRNA decay in order to enable the virus to evade host antiviral responses to allow viral survival and replication. We discuss different cellular RNA decay pathways, including the deadenylation-dependent mRNA decay pathway, and various strategies that viruses exploit to manipulate these pathways in order to create a virus-friendly cellular environment.

The hepatitis C viral nonstructural protein 5A stabilizes growth-regulatory human transcripts.

Numerous mammalian proto-oncogene and other growth-regulatory transcripts are upregulated in malignancy due to abnormal mRNA stabilization. In hepatoma cells expressing a hepatitis C virus (HCV) subgenomic replicon, we found that the viral nonstructural protein 5A (NS5A), a protein known to bind to viral RNA, also bound specifically to human cellular transcripts that encode regulators of cell growth and apoptosis, and this binding correlated with transcript stabilization. An important subset of human NS5A-target transcripts contained GU-rich elements, sequences known to destabilize mRNA.

A Systematic Review of Non-Traumatic Spinal Cord Injuries in Sub-Saharan Africa and a Proposed Diagnostic Algorithm for Resource-Limited Settings.

Background: Non-traumatic myelopathy is common in Africa and there are geographic differences in etiology. Clinical management is challenging due to the broad differential diagnosis and the lack of diagnostics. The objective of this systematic review is to determine the most common etiologies of non-traumatic myelopathy in sub-Saharan Africa to inform a regionally appropriate diagnostic algorithm.

Monocyte Phenotype and IFN-γ-Inducible Cytokine Responses Are Associated with Cryptococcal Immune Reconstitution Inflammatory Syndrome.

A third of adults with AIDS and cryptococcal meningitis (CM) develop immune reconstitution inflammatory syndrome (IRIS) after initiating antiretroviral therapy (ART), which is thought to result from exaggerated inflammatory antigen-specific T cell responses. The contribution of monocytes to the immunopathogenesis of cryptococcal IRIS remains unclear. We compared monocyte subset frequencies and immune responses in HIV-infected Ugandans at time of CM diagnosis (IRIS-Baseline) for those who later developed CM-IRIS, controls who did not develop CM-IRIS (Control-Baseline) at CM-IRIS (IRIS-Event), and for controls at a time point matched for ART duration (Control-Event) to understand the association of monocyte distribution and immune responses with cryptococcal IRIS.

Neurocognitive function in HIV-infected persons with asymptomatic cryptococcal antigenemia: a comparison of three prospective cohorts.

Background: HIV-infected persons with detectable cryptococcal antigen (CrAg) in blood have increased morbidity and mortality compared with HIV-infected persons who are CrAg-negative. This study examined neurocognitive function among persons with asymptomatic cryptococcal antigenemia.

Methods: Participants from three prospective HIV cohorts underwent neurocognitive testing at the time of antiretroviral therapy (ART) initiation.

Evolving Failures in the Delivery of Human Immunodeficiency Virus Care: Lessons From a Ugandan Meningitis Cohort 2006-2016.

Background: Because of investments in human immunodeficiency virus (HIV) care in sub-Saharan Africa, the number of people aware of their status and receiving antiretroviral therapy (ART) has increased; however, HIV/acquired immune deficiency syndrome (AIDS) mortality still remains high.

Methods: We performed retrospective analysis of 3 sequential prospective cohorts of HIV-infected Ugandan adults presenting with AIDS and meningitis from 2006 to 2009, 2010 to 2012, and 2013 to 2016. Participants were categorized as follows: (1) unknown HIV status; (2) known HIV without ART; (3) known HIV with previous ART.

Mechanisms of Accelerated Liver Fibrosis Progression during HIV Infection.

With the introduction of antiretroviral therapy (ART), a dramatic reduction in HIV-related morbidity and mortality has been observed. However, it is now becoming increasingly clear that liver-related complications, particularly rapid fibrosis development from ART as well as from the chronic HIV infection itself, are of serious concern to HIV patients. The pathophysiology of liver fibrosis in patients with HIV is a multifactorial process whereby persistent viral replication, and bacterial translocation lead to chronic immune activation and inflammation, which ART is unable to fully suppress, promoting production of fibrinogenic mediators and fibrosis.

Different Lymphocyte Populations Direct Dichotomous Eosinophil or Neutrophil Responses to Pulmonary Cryptococcus Infection.

Many pulmonary infections elicit lymphocyte responses that lead to an accumulation of granulocytes in the lungs. A variety of lymphocytes are capable of directing eosinophils or neutrophils to the lungs, but the contribution of each subset remains enigmatic. In this study, we used a murine model to examine lymphocyte subsets that ultimately drive the eosinophil or neutrophil response to infection with the fungal pathogen Cryptococcus neoformans.

Post-transcriptional regulation of cytokine and growth factor signaling in cancer.

Cytokines and growth factors regulate cell proliferation, differentiation, migration and apoptosis, and play important roles in coordinating growth signal responses during development. The expression of cytokine genes and the signals transmitted through cytokine receptors are tightly regulated at several levels, including transcriptional and post-transcriptional levels. A majority of cytokine mRNAs, including growth factor transcripts, contain AU-rich elements (AREs) in their 3' untranslated regions that control gene expression by regulating mRNA degradation and changing translational rates.

Increased Hepatitis E Virus Seroprevalence Correlates with Lower CD4+ Cell Counts in HIV-Infected Persons in Argentina.

Hepatitis E virus (HEV) is a single-stranded RNA virus that can cause hepatitis in an epidemic fashion. HEV usually causes asymptomatic or limited acute infections in immunocompetent individuals, whereas in immunosuppressed individuals such as transplant recipients, HEV can cause chronic infections. The risks and outcomes of HEV co-infection in patients infected with human immunodeficiency virus (HIV) are poorly characterized.