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.
...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,...
Ecosystem Advantage Williamson, Peter James; De Meyer, Arnoud
California management review,
10/2012, Volume:
55, Issue:
1
Journal Article
Peer reviewed
Open access
Changes in the global environment are generating opportunities for companies to build advantage by creating loosely coupled networks or ecosystems. Ecosystems are larger, more diverse, and more fluid ...than a traditional set of bilateral partnerships or complementors. By leveraging ecosystems, companies can deliver complex solutions while maintaining corporate focus. This article describes six keys to unlock ecosystem advantage: pinpointing where value is created, defining an architecture of differentiated partner roles, stimulating complementary partner investments, reducing the transaction costs, facilitating joint learning across the network, and engineering effective ways to capture profit.
A growing recognition of the importance of disruptive innovation has led researchers to examine the question of how disruptive innovation comes about and to what extent it reflects “discovery” versus ...“creation” of opportunities. Earlier research has focused on the organisational preconditions for disruptive innovation to arise. Much less attention has been paid to the role of innovation processes, including their goals and design, in promoting disruptive innovation. In this paper we aim to begin to fill this gap by better understanding how new innovation processes can act as antecedents for disruptive innovation.
We adopt an inductive theory-building methodology using a set of case studies of Chinese firms to develop propositions about how novel R&D and production processes can foster disruptive innovation. We find that in the case of China the adoption of new innovation processes that re-define the focus of innovation and re-engineer traditional R&D processes in ways that allow the novel deployment of Chinese cost advantages can create offerings that incorporate the key elements of disruptive innovation in the sense that they challenge incumbents׳ established business models. Realising disruptive innovation opportunities requires proactive initiatives. We conclude by discussing the managerial implications and possible responses as well as directions for future research.
•We explore how new innovation processes act as antecedents for disruptive innovation.•We use inductive theory-building based on a set of case studies of Chinese firms.•China is a significant source of disruptive innovation.•Novel R&D and production processes can foster disruptive innovation.•Realising disruptive innovation opportunities requires proactive initiatives.
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.
•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 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.
Abstract Follow-up of previously healthy patients surviving cryptococcal meningitis found that cryptococcal antigen could be detected for >1 year in serum from 38 of 44 (86%) patients and in ...cerebrospinal fluid (CSF) from 20 of 31 patients (67%), far beyond the time of culture conversion. The speed of titer decline, measured as the number of days for a 2-fold drop in titer to occur, was slower in serum than in CSF. The speed of decline of antigen titers was much slower in serum and CSF for patients infected with Cryptococcus gattii than Cryptococcus neoformans. The speed of decline in CSF and serum titers was also much slower in patients who had received a ventriculoperitoneal shunt for increased intracranial pressure. The variable and extraordinarily slow rate of clearance in our patients did not appear to reflect differences in disease control but rather differences in species and shunting for increased intracranial pressure.
Cryptococcal Disease in Diverse Hosts Meya, David B; Williamson, Peter R
The New England journal of medicine,
2024-May-02, Volume:
390, Issue:
17
Journal Article
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