Ophthalmic signs in Ugandan adults with HIV-associated cryptococcal meningitis: A nested analysis of the ASTRO-CM cohort.

Cryptococcal meningitis is a leading cause of morbidity and mortality among HIV-infected persons, accounting for 15% of AIDS-related deaths. Visual disturbance is commonly reported, and a wide range of ophthalmic signs may be present on examination. There is limited published literature to date describing the range and incidence of ophthalmic signs in HIV-associated cryptococcal meningitis. Nested within the Adjunctive Sertraline for the Treatment of HIV-Associated Cryptococcal Meningitis (ASTRO-CM) trial (ClinicalTrials.gov number: NCT01802385), we conducted an observational study of 696 Ugandan adults with HIV-associated cryptococcal meningitis. Patients were screened for visual disturbance and external ophthalmic signs at initial presentation and at follow-up appointments over 18 weeks. Assessment comprised simple clinical history and basic examination and required no specialist equipment. More than a quarter of our cohort demonstrated ocular signs or symptoms, which were observed throughout the study period.  A broad range of ocular signs were demonstrated: these included neurological signs (10.9%), localized ocular pathology (4.5%), and evidence of concurrent systemic disease (12.9%). The range of signs observed demonstrates the complexities of case management in patients with advanced HIV and cryptococcosis and also the importance of basic ocular examination in low resource settings. There remains an urgent need for studies conducting comprehensive ocular examination in patients with HIV-associated cryptococcal meningitis; these studies should include formal assessment of visual acuity, slit lamp examination and dilated indirect ophthalmoscopy. Prospective studies should investigate whether there is a correlation between reported visual disturbance and objective signs, in order to further clarify the underlying mechanisms and to guide effective diagnosis, follow-up and management

Cryptococcal Meningitis and Tuberculous Meningitis Co-infection in HIV-Infected Ugandan Adults.

We report 5 HIV-infected Ugandan adults with cryptococcal and tuberculous (TB) meningitis co-infection. All unmasked meningitis occurred within 5 weeks of starting HIV therapy. Xpert MTB/RIF Ultra facilitated prompt diagnosis; however, 60% in-hospital mortality occurred. TB meningitis coinfection prevalence was 0.8% (5/586) among cryptococcal meningitis, 2 during second cryptococcal episodes

Flow cytometry to assess CSF fungal burden in cryptococcal meningitis

Fungal burden in the cerebrospinal fluid is an important determinant of mortality in cryptococcal meningitis but its use to aid clinical decision-making is hampered by the time involved to perform quantitative cultures. Here we demonstrate the potential of flow cytometry as a novel and rapid technique to address this

Clinical Features and Serum Biomarkers in HIV Immune Reconstitution Inflammatory Syndrome after Cryptococcal Meningitis: A Prospective Cohort Study

David Boulware and colleagues investigate clinical features in a prospective cohort with AIDS and recent cryptococcal meningitis after initiation of antiretroviral therapy to identify biomarkers for prediction and diagnosis of CM-IRIS (cryptococcal meninigitis-related immune reconstitution inflammatory syndrome)

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. At baseline, stimulation with IFN-γ ex vivo induced a higher frequency of TNF-α- and IL-6-producing monocytes among those who later developed IRIS. Among participants who developed IRIS, ex vivo IFN-γ stimulation induced higher frequencies of activated monocytes, IL-6⁺, TNF-α⁺ classical, and IL-6⁺ intermediate monocytes compared with controls. In conclusion, we have demonstrated that monocyte subset phenotype and cytokine responses prior to ART are associated with and may be predictive of CM-IRIS. Larger studies to further delineate innate immunological responses and the efficacy of immunomodulatory therapies during cryptococcal IRIS are warranted

The CSF immune response in HIV-1-associated cryptococcal meningitis: macrophage activation, correlates of disease severity and effect of antiretroviral therapy.

Immune modulation may improve outcome in HIV-associated cryptococcal meningitis. Animal studies suggest alternatively activated macrophages are detrimental but human studies are limited. We performed a detailed assessment of the cerebrospinal fluid (CSF) immune response and examined immune correlates of disease severity and poor outcome, and the effects of antiretroviral therapy (ART). We enrolled persons ≥18 years with first episode of HIV-associated cryptococcal meningitis. CSF immune response was assessed using flow cytometry and multiplex cytokine analysis. Principal component analysis was used to examine relationships between immune response, fungal burden, intracranial pressure and mortality, and the effects of recent ART initiation (<12 weeks). CSF was available from 57 persons (median CD4 34/μL). CD206 (alternatively activated macrophage marker) was expressed on 54% CD14+ and 35% CD14- monocyte-macrophages. High fungal burden was not associated with CD206 expression but with a paucity of CD4+, CD8+ and CD4-CD8- T cells and lower IL-6, G-CSF and IL-5 concentrations. High intracranial pressure (≥30cmH2O) was associated with fewer T cells, a higher fungal burden and larger Cryptococcus organisms. Mortality was associated with reduced interferon-gamma concentrations and CD4-CD8- T cells but lost statistical significance when adjusted for multiple comparisons. Recent ART was associated with increased CSF CD4/CD8 ratio and a significantly increased macrophage expression of CD206. Paucity of CSF T cell infiltrate rather than alternative macrophage activation was associated with severe disease in HIV-associated cryptococcosis. ART had a pronounced effect on the immune response at the site of disease

Performance of Lipoarabinomannan Assay using Cerebrospinal fluid for the diagnosis of Tuberculous meningitis among HIV patients.

Background: The diagnostic utility of the Mycobacteria tuberculosis lipoarabinomannan (TB-LAM) antigen lateral flow assay on cerebrospinal fluid (CSF) for the diagnosis of tuberculous meningitis (TBM) has not been extensively studied and the few published studies have conflicting results. Methods: Lumbar CSF from 59 HIV-positive patients with suspected TBM was tested with TB-LAM and Xpert MTB/Rif Ultra. The diagnostic performance of CSF TB-LAM was compared to positive CSF Xpert MTB/Rif Ultra (definite TBM) and a composite reference of probable or definite TBM according to the uniform case definition.  Results: Of 59 subjects, 12 (20%) had definite TBM and five (9%) had probable TBM. With reference to definite TBM, CSF TB-LAM assay had a diagnostic sensitivity of 33% and specificity of 96%. When compared to a composite reference of definite or probable TBM, the sensitivity was 24% and specificity was 95%. There were two false positive tests with TB-LAM (3+ grade). In-hospital mortality in CSF TB-LAM positive patients was 17% compared to 0% in those with definite TBM by Xpert MTB/Rif Ultra but negative LAM. Conclusions: Lumbar CSF TB-LAM has a poor performance in diagnosing TBM. Both urine TB-LAM and Xpert Ultra should be further investigated in the diagnosis of TBM

Path Integrals, Density Matrices, and Information Flow with Closed Timelike Curves

Two formulations of quantum mechanics, inequivalent in the presence of closed timelike curves, are studied in the context of a soluable system. It illustrates how quantum field nonlinearities lead to a breakdown of unitarity, causality, and superposition using a path integral. Deutsch's density matrix approach is causal but typically destroys coherence. For each of these formulations I demonstrate that there are yet further alternatives in prescribing the handling of information flow (inequivalent to previous analyses) that have implications for any system in which unitarity or coherence are not preserved.Comment: 25 pages, phyzzx, CALT-68-188

Point-of-Care Lung Ultrasound for COVID-19: Findings and Prognostic Implications From 105 Consecutive Patients

Background: The prognostic value of point-of-care lung ultrasound has not been evaluated in a large cohort of patients with COVID-19 admitted to general medicine ward in the United States. The aim of this study was to describe lung ultrasound findings and their prognostic value in patients with COVID-19 admitted to internal medicine ward. Method: This prospective observational study consecutively enrolled 105 hospitalized participants with COVID-19 at 2 tertiary care centers. Ultrasound was performed in 12 lung zones within 24 hours of admission. Findings were assessed relative to 4 outcomes: intensive care unit (ICU) need, need for intensive respiratory support, length of stay, and death. Results: We detected abnormalities in 92% (97/105) of participants. The common findings were confluent B-lines (92%), non-homogenous pleural lines (78%), and consolidations (54%). Large confluent B-lines, consolidations, bilateral involvement, and any abnormality in ≥ 6 areas were associated with a longer hospitalization and need for intensive respiratory support. Large confluent B-lines and bilateral involvement were also associated with ICU stay. A total lung ultrasound score \u3c5 had a negative predictive value of 100% for the need of intensive respiratory support. A higher total lung ultrasound score was associated with ICU need (median total 18 in the ICU group vs. 11 non-ICU, p = 0.004), a hospitalization ≥ 9d (15 vs 10, p = 0.016) and need for intensive respiratory support (18 vs. 8.5, P \u3c 0.001). Conclusions: Most patients hospitalized with COVID-19 had lung ultrasound abnormalities on admission and a higher lung ultrasound score was associated with worse clinical outcomes except death. A low total lung ultrasound score (\u3c5) had a negative predictive value of 100% for the need of intensive respiratory support. Point-of-care ultrasound can aid in the risk stratification for patients with COVID-19 admitted to general wards

Simple Quantum Systems in Spacetimes with Closed Timelike Curves

Three simple examples illustrate properties of path integral amplitudes in fixed background spacetimes with closed timelike curves: non-relativistic potential scattering in the Born approximation is non-unitary, but both an example with hard spheres and the exact solution of a totally discrete model are unitary.Comment: 15 pages, CALT-68-180