Cryptococcal meningitis (CM) causes significant morbidity and mortality globally; however, recent national trends have not been described. Incidence and trends for CM-associated hospitalizations in ...18 states were estimated using the Agency for Healthcare and Research Quality (AHRQ) State Inpatient Databases (SID) datasets for 1997 through 2009. We identified 30,840 hospitalizations coded for CM, of which 21.6% were among HIV-uninfected patients. CM in-hospital mortality was significant (12.4% for women and 10.8% for men) with a total of 3,440 deaths over the study period. Co-morbidities of CM coded at increased frequency in HIV-uninfected CM hospitalized populations included hydrocephalus and acute/chronic renal failure as well as possible predispositions including transplantation, combined T and B cell defects, Cushing's syndrome, liver disease and hypogammaglobulinemia. Median hospitalization costs were significant for CM and higher for HIV-uninfected patients (16,803.01 vs. 15,708.07; p<0.0001). Cryptococcal meningitis remains a disease with significant morbidity and mortality in the U.S. and the relative burden among persons without HIV infection is increasing.
HIV-associated cryptococcal meningitis is by far the most common cause of adult meningitis in many areas of the world that have high HIV seroprevalence. In most areas in Sub-Saharan Africa, the ...incidence of cryptococcal meningitis is not decreasing despite availability of antiretroviral therapy, because of issues of adherence and retention in HIV care. In addition, cryptococcal meningitis in HIV-seronegative individuals is a substantial problem: the risk of cryptococcal infection is increased in transplant recipients and other individuals with defects in cell-mediated immunity, and cryptococcosis is also reported in the apparently immunocompetent. Despite therapy, mortality rates in these groups are high. Over the past 5 years, advances have been made in rapid point-of-care diagnosis and early detection of cryptococcal antigen in the blood. These advances have enabled development of screening and pre-emptive treatment strategies aimed at preventing the development of clinical infection in patients with late-stage HIV infection. Progress in optimizing antifungal combinations has been aided by evaluation of the clearance rate of infection by using serial quantitative cultures of cerebrospinal fluid (CSF). Measurement and management of raised CSF pressure, a common complication, is a vital component of care. In addition, we now better understand protective immune responses in HIV-associated cases, immunogenetic predisposition to infection, and the role of immune-mediated pathology in patients with non-HIV associated infection and in the context of HIV-associated immune reconstitution reactions.
...survival and growth of latent fungal organisms within the brain meningeal immune cells might be facilitated by the presence of a latent HIV viral infection, stubbornly persistent within ...macrophages and the CNS.12 This persistent HIV reservoir, which is postulated to contribute to neurocognitive decline in patients on ART, might thus also have a role in the development of cryptococcal meningitis in patients on ART because fungal macrophage residence is key to survival and virulence of the pathogen.13 Thus, passive approaches to cryptococcal meningitis centred exclusively on HIV treatment might need to be reconsidered. Living Art Enterprises, Llc/Science Photo Library 1 V Pyrgos, AE Seitz, CA Steiner, DR Prevots, PR Williamson, Epidemiology of cryptococcal meningitis in the US: 1997-2009, PloS One, Vol. 8, 2013, e56269 2 RL Castelblanco, M Lee, R Hasbun, Epidemiology of bacterial meningitis in the USA from 1997 to 2010: a population-based observational study, Lancet Infect Dis, Vol. 14, 2014, 813-819 3 BJ Park, KA Wannemuehler, BJ Marston, N Govender, PG Pappas, TM Chiller, Aids, Vol. 23, 2009, 525-530 4 DL Goldman, H Khine, J Abadi, Serologic evidence for Cryptococcus neoformans infection in early childhood, Pediatrics, Vol. 107, 2001, E66 5 S Patel, GY Shin, I Wijewardana, The prevalence of cryptococcal antigenemia in newly diagnosed HIV patients in a Southwest London cohort, J Infect, Vol. 66, 2013, 75-79 6 F Dromer, S Mathoulin-Pelissier, A Fontanet, O Ronin, B Dupont, O Lortholary, Epidemiology of HIV-associated cryptococcosis in France (1985-2001): comparison of the pre- and post-HAART eras, Aids, Vol. 18,...
Exoplanets that orbit close to their host stars are much more highly irradiated than their solar system counterparts. Understanding the thermal structures and appearances of these planets requires ...investigating how their atmospheres respond to such extreme stellar forcing. We present spectroscopic thermal emission measurements as a function of orbital phase ("phase-curve observations") for the highly irradiated exoplanet WASP-43b spanning three full planet rotations using the Hubble Space Telescope. With these data, we construct a map of the planet's atmospheric thermal structure, from which we find large day-night temperature variations at all measured altitudes and a monotonically decreasing temperature with pressure at all longitudes. We also derive a Bond albedo of ${0.18}_{-0.12}^{+0.07}$ and an altitude dependence in the hot-spot offset relative to the substellar point.
•Drug combinations improve efficacy and permit dose reductions of each drug.•Lowering the dose of combined drugs prevents concentration-associated toxicity.•Drug combinations can overcome the growing ...resistance to antibiotics.•Real-time screens, using patient isolates, identify treatments for severe infections.•Drug repurposing and combinations can identify treatments for emerging pathogens.
Infections from multidrug resistant (MDR) pathogens and emerging viruses present challenges for effective clinical treatments. Drug repurposing and combination screens may provide therapies at a fraction of the time and cost of traditional methods of drug development. Synergistic combinations of two or three known compounds can increase therapeutic efficacy and reduce concentrations required for individual drugs, in turn, reducing the risk of drug toxicity. Using libraries of approved drugs, traditionally non-antibiotic compounds identified in repurposing screens can quickly move into clinical trials, since safety profiles have been previously established. Herein we summarize recent advances in identifying synergistic drug combinations and the use of drug screens for personalized medicine treatments of infections caused by MDR pathogens and emerging viruses.
Innate lymphoid cells (ILCs) are lymphocyte-like cells that lack T cell or B cell antigen receptors and mediate protective and repair functions through cytokine secretion. Among these, type 2 ILCs ...(ILC2 cells) are able to produce type 2 cytokines. We report the existence of an inflammatory ILC2 (iILC2) population responsive to interleukin 25 (IL-25) that complemented IL-33-responsive natural ILC2 (nILC2) cells. iILC2 cells developed into nILC2-like cells in vitro and in vivo and contributed to the expulsion of Nippostrongylus brasiliensis. They also acquired IL-17-producing ability and provided partial protection against Candida albicans. We propose that iILC2 cells are transient progenitors of ILCs mobilized by inflammation and infection that develop into nILC2-like cells or ILC3-like cells and contribute to immunity to both helminths and fungi.
The water abundance in a planetary atmosphere provides a key constraint on the planet's primordial origins because water ice is expected to play an important role in the core accretion model of ...planet formation. However, the water content of the solar system giant planets is not well known because water is sequestered in clouds deep in their atmospheres. By contrast, short-period exoplanets have such high temperatures that their atmospheres have water in the gas phase, making it possible to measure the water abundance for these objects. We present a precise determination of the water abundance in the atmosphere of the 2 M sub(Jup) short-period exoplanet WASP-43b based on thermal emission and transmission spectroscopy measurements obtained with the Hubble Space Telescope. We find the water content is consistent with the value expected in a solar composition gas at planetary temperatures (0.4-3.5 x solar at 1sigma confidence). The metallicity of WASP-43b's atmosphere suggested by this result extends the trend observed in the solar system of lower metal enrichment for higher planet masses.
Cryptococcal Disease in Diverse Hosts Meya, David B.; Williamson, Peter R.
The New England journal of medicine,
05/2024, Volume:
390, Issue:
17
Journal Article
Peer reviewed
Cryptococcus accounts for up to 180,000 deaths annually and 68% of HIV-related meningitis cases. The authors discuss diagnostic, preventive, and therapeutic strategies and the pathophysiological role ...of inflammatory syndromes.
The fungus Cryptococcus is a major cause of meningoencephalitis in HIV-infected as well as HIV-uninfected individuals with mortalities in developed countries of 20% and 30%, respectively. In ...HIV-related disease, defects in T-cell immunity are paramount, whereas there is little understanding of mechanisms of susceptibility in non-HIV related disease, especially that occurring in previously healthy adults. The present description is the first detailed immunological study of non-HIV-infected patients including those with severe central nervous system (s-CNS) disease to 1) identify mechanisms of susceptibility as well as 2) understand mechanisms underlying severe disease. Despite the expectation that, as in HIV, T-cell immunity would be deficient in such patients, cerebrospinal fluid (CSF) immunophenotyping, T-cell activation studies, soluble cytokine mapping and tissue cellular phenotyping demonstrated that patients with s-CNS disease had effective microbiological control, but displayed strong intrathecal expansion and activation of cells of both the innate and adaptive immunity including HLA-DR+ CD4+ and CD8+ cells and NK cells. These expanded CSF T cells were enriched for cryptococcal-antigen specific CD4+ cells and expressed high levels of IFN-γ as well as a lack of elevated CSF levels of typical T-cell specific Th2 cytokines -- IL-4 and IL-13. This inflammatory response was accompanied by elevated levels of CSF NFL, a marker of axonal damage, consistent with ongoing neurological damage. However, while tissue macrophage recruitment to the site of infection was intact, polarization studies of brain biopsy and autopsy specimens demonstrated an M2 macrophage polarization and poor phagocytosis of fungal cells. These studies thus expand the paradigm for cryptococcal disease susceptibility to include a prominent role for macrophage activation defects and suggest a spectrum of disease whereby severe neurological disease is characterized by immune-mediated host cell damage.
Cryptococcal meningoencephalitis is responsible for upwards of 15% of HIV-related deaths worldwide and is currently the most common cause of non-viral meningitis in the US, affecting both previously ...healthy and people with immune suppression caused by cancer chemotherapy, transplantation, and biologic therapies. Despite a continued 30-50% attributable mortality, recommended therapeutic strategies have remained largely unchanged since the 1950s. Recent murine models and human studies examining the role of the immune system in both susceptibility to the infection as well as host damage have begun to influence patient care decisions. The Damage Framework Response, originally proposed in 1999, was recently used to discuss dichotomous etiologies of host damage in cryptococcal disease. These include patients suffering microbiological damage with low host immunity (especially those immunosuppressed with HIV) and those having low (live) microbiological burden but high immune-mediated damage (HIV-related immune reconstitution syndrome and non-HIV-related postinfectious inflammatory response syndrome). Cryptococcal disease in previously healthy hosts, albeit rare, has been known for a long time. Immunophenotyping and dendritic cell-T cell signaling studies on cerebral spinal fluid of these rare patients reveal immune capacity for recognition and T-cell activation pathways including increased levels of HLA-DR and CD56. However, despite effective T-cell signals, brain biopsy and autopsy specimens demonstrated an M2 alternative macrophage polarization and poor phagocytosis of fungal cells. These studies expand the paradigm for cryptococcal disease susceptibility to include a prominent role for immune-mediated damage and suggest a need for careful individual consideration of immune activation during therapy of cryptococcal disease in diverse hosts.
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