This analysis describes the epidemiology and outcomes of invasive candidiasis caused by non-albicans species of Candida in patients enrolled in the Prospective Antifungal Therapy Alliance (PATH ...Alliance) registry from 2004 to 2008. A total of 2,496 patients with non-albicans species of Candida isolates were identified. The identified species were C. glabrata (46.4%), C. parapsilosis (24.7%), C. tropicalis (13.9%), C. krusei (5.5%), C. lusitaniae (1.6%), C. dubliniensis (1.5%) and C. guilliermondii (0.4%); 111 infections involved two or more species of Candida (4.4%). Non-albicans species accounted for more than 50% of all cases of invasive candidiasis in 15 of the 24 sites (62.5%) that contributed more than one case to the survey. Among solid organ transplant recipients, patients with non-transplant surgery, and patients with solid tumors, the most prevalent non-albicans species was C. glabrata at 63.7%, 48.0%, and 53.8%, respectively. In 1,883 patients receiving antifungal therapy on day 3, fluconazole (30.5%) and echinocandins (47.5%) were the most frequently administered monotherapies. Among the 15 reported species, 90-day survival was highest for patients infected with either C. parapsilosis (70.7%) or C. lusitaniae (74.5%) and lowest for patients infected with an unknown species (46.7%) or two or more species (53.2%). In conclusion, this study expands the current knowledge of the epidemiology and outcomes of invasive candidiasis caused by non-albicans species of Candida in North America. The variability in species distribution in these centers underscores the importance of local epidemiology in guiding the selection of antifungal therapy.
Background. Candidemia remains a major cause of morbidity and mortality in the health care setting, and the epidemiology of Candida infection is changing. Methods. Clinical data from patients with ...candidemia were extracted from the Prospective Antifungal Therapy (PATH) Alliance database, a comprehensive registry that collects information regarding invasive fungal infections. A total of 2019 patients, enrolled from 1 July 2004 through 5 March 2008, were identified. Data regarding the candidemia episode were analyzed, including the specific fungal species and patient survival at 12 weeks after diagnosis. Results. The incidence of candidemia caused by non–Candida albicans Candida species (54.4%) was higher than the incidence of candidemia caused by C. albicans (45.6%). The overall, crude 12-week mortality rate was 35.2%. Patients with Candida parapsilosis candidemia had the lowest mortality rate (23.7%; P<.001) and were less likely to be neutropenic (5.1%; P<.001) and to receive corticosteroids (33.5%; P<.001) or other immunosuppressive drugs (7.9%; P=.002), compared with patients infected with other Candida species. Candida krusei candidemia was most commonly associated with prior use of antifungal agents (70.6%; P<.001), hematologic malignancy (52.9%; P<.001) or stem cell transplantation (17.7%; P<.001), neutropenia (45.1%; P<.001), and corticosteroid treatment (60.8%; P<.001). Patients with C. krusei candidemia had the highest crude 12-week mortality in this series (52.9%; P<.001). Fluconazole was the most commonly administered antimicrobial, followed by the echinocandins, and amphotericin B products were infrequently administered. Conclusions. The epidemiology and choice of therapy for candidemia are rapidly changing. Additional study is warranted to differentiate host factors and differences in virulence among Candida species and to determine the best therapeutic regimen.
Background. Invasive candidiasis is an important cause of morbidity and mortality among patients with health care–associated infection. The echinocandins have potent fungicidal activity against most ...Candida species, but there are few data comparing the safety and efficacy of echinocandins in the treatment of invasive candidiasis. Methods. This was an international, randomized, double-blind trial comparing micafungin (100 mg daily) and micafungin (150 mg daily) with a standard dosage of caspofungin (70 mg followed by 50 mg daily) in adults with candidemia and other forms of invasive candidiasis. The primary end point was treatment success, defined as clinical and mycological success at the end of blinded intravenous therapy. Results. A total of 595 patients were randomized to one the treatment groups and received at least 1 dose of study drug. In the modified intent-to-treat population, 191 patients were assigned to the micafungin 100 mg group, 199 to the micafungin 150 mg group, and 188 to the caspofungin group. Demographic characteristics and underlying disorders were comparable across the groups. Approximately 85% of patients had candidemia; the remainder had noncandidemic invasive candidiasis. At the end of blinded intravenous therapy, treatment was considered successful for 76.4% of patients in the micafungin 100 mg group, 71.4% in the micafungin 150 mg group, and 72.3% in the caspofungin group. The median time to culture negativity was 2 days in the micafungin 100 mg group and the caspofungin group, compared with 3 days in the micafungin 150 mg groups. There were no significant differences in mortality, relapsing and emergent infections, or adverse events between the study arms. Conclusions. Dosages of micafungin 100 mg daily and 150 mg daily were noninferior to a standard dosage of caspofungin for the treatment of candidemia and other forms of invasive candidiasis.
In the United States, cardiovascular disease (CVD) is the leading cause of death and disability. Suboptimal diet quality is responsible for a greater percentage of CVD-related morbidity and mortality ...than any other modifiable risk factor. Further troubling are the stark racial/ethnic and socioeconomic disparities in diet quality. This represents a major public health concern that urgently requires a coordinated effort to better characterize the barriers to healthy dietary practices in population groups disproportionally affected by CVD and poor diet quality to inform multifaceted approaches at the government (policy), community environment, sociocultural, and individual levels. This paper reviews the barriers, opportunities, and challenges involved in shifting population behaviors, especially in underserved populations, toward healthy dietary practices. It is imperative that public health policies address the social determinants of nutrition more intensively than previously in order to significantly decrease CVD on a population-wide basis.
The Hedgehog-regulated transcription factors GLI1 and GLI2 play overlapping roles in development and disease; however, the mechanisms underlying their interplay remain elusive. We report for the ...first time that GLI1 and GLI2 physically and functionally interact in cancer cells. GLI1 and GLI2 were shown to co-immunoprecipitate in PANC1 pancreatic cancer cells and RMS13 rhabdomyosarcoma cells. Mapping analysis demonstrated that the zinc finger domains of both proteins are required for their heteromerization. RNAi knockdown of either GLI1 or GLI2 inhibited expression of many well-characterized GLI target genes (BCL2, MYCN, PTCH2, IL7 and CCND1) in PANC1 cells, whereas PTCH1 expression was only inhibited by GLI1 depletion. qPCR screening of a large set of putative canonical and non-canonical Hedgehog/GLI targets identified further genes (e.g. E2F1, BMP1, CDK2) strongly down-regulated by GLI1 and/or GLI2 depletion in PANC1 cells, and demonstrated that ANO1, AQP1 and SOCS1 are up-regulated by knockdown of either GLI1 or GLI2. Chromatin immunoprecipitation showed that GLI1 and GLI2 occupied the same regions at the BCL2, MYCN and CCND1 promoters. Furthermore, depletion of GLI1 inhibited GLI2 occupancy at these promoters, suggesting that GLI1/GLI2 interaction is required for the recruitment of GLI2 to these sites. Together, these findings indicate that GLI1 and GLI2 co-ordinately regulate the transcription of some genes, and provide mechanistic insight into the roles of GLI proteins in carcinogenesis.
Purpose: This review article provides a theoretical overview of the development of spectral resolution in children with normal hearing (cNH) and in those who use cochlear implants (CIs), with an ...emphasis on methodological considerations. The aim was to identify key directions for future research on spectral resolution development in children with CIs. Method: A comprehensive literature review was conducted to summarize and synthesize previously published behavioral research on spectral resolution development in normal and impaired auditory systems. Conclusions: In cNH, performance on spectral resolution tasks continues to improve through the teenage years and is likely driven by gradual maturation of across-channel intensity resolution. A small but growing body of evidence from children with CIs suggests a more complex relationship between spectral resolution development, patient demographics, and the quality of the CI electrode--neuron interface. Future research should aim to distinguish between the effects of patient-specific variables and the underlying physiology on spectral resolution abilities in children of all ages who are hard of hearing and use auditory prostheses.
Twenty years of therapy for HIV-1 infection Pomerantz, Roger J; Horn, David L
Nature medicine,
200307, 2003-Jul, 2003-7-00, 20030701, Letnik:
9, Številka:
7
Journal Article
Recenzirano
Antiretroviral therapy, where available, has transformed HIV-1 disease into a treatable and somewhat chronic infection. This article summarizes the accomplishments thus far and what lies ahead in our ...struggle to improve the treatment of, and possibly eliminate, HIV-1 infection.
Proliferative chronic myelomonocytic leukemia (pCMML), an aggressive CMML subtype, is associated with dismal outcomes. RAS pathway mutations, mainly NRAS
, define the pCMML phenotype as demonstrated ...by our exome sequencing, progenitor colony assays and a Vav-Cre-Nras
mouse model. Further, these mutations promote CMML transformation to acute myeloid leukemia. Using a multiomics platform and biochemical and molecular studies we show that in pCMML RAS pathway mutations are associated with a unique gene expression profile enriched in mitotic kinases such as polo-like kinase 1 (PLK1). PLK1 transcript levels are shown to be regulated by an unmutated lysine methyl-transferase (KMT2A) resulting in increased promoter monomethylation of lysine 4 of histone 3. Pharmacologic inhibition of PLK1 in RAS mutant patient-derived xenografts, demonstrates the utility of personalized biomarker-driven therapeutics in pCMML.
•Loss of function of stereocilin (STRC) produces deficits of active cochlear frequency selectivity and amplifier functions.•Frequency resolution seemed impaired in STRC−/− subjects while their ...temporal resolution was preserved.•Speech in noise understanding in STRC−/− subjects was impaired compared to normal hearing listeners but remained better than in cochlear implanted listeners.•Hearing aid modifications, customized for the spectral deficits could potentially improve speech in noise perception in the STRC−/− population.
Loss of function of stereocilin (STRC) is the second most common cause of inherited hearing loss. The loss of the stereocilin protein, encoded by the STRC gene, induces the loss of connection between outer hair cells and tectorial membrane. This only affects the outer hair cells (OHCs) function, involving deficits of active cochlear frequency selectivity and amplifier functions despite preservation of normal inner hair cells. Better understanding of cochlear features associated with mutation of STRC will improve our knowledge of normal cochlear function, the pathophysiology of hearing impairment, and potentially enhance hearing aid and cochlear implant signal processing. Nine subjects with homozygous or compound heterozygous loss of function mutations in STRC were included, age 7–24 years. Temporal and spectral modulation perception were measured, characterized by spectral and temporal modulation transfer functions. Speech-in-noise perception was studied with spondee identification in adaptive steady-state noise and AzBio sentences with 0 and -5 dB SNR multitalker babble. Results were compared with normal hearing (NH) and cochlear implant (CI) listeners to place STRC−/− listeners’ hearing capacity in context. Spectral ripple discrimination thresholds in the STRC−/− subjects were poorer than in NH listeners (p < 0.0001) but remained better than for CI listeners (p < 0.0001). Frequency resolution appeared impaired in the STRC−/− group compared to NH listeners but did not reach statistical significance (p = 0.06). Compared to NH listeners, amplitude modulation detection thresholds in the STRC−/− group did not reach significance (p= 0.06) but were better than in CI subjects (p < 0.0001). Temporal resolution in STRC−/− subjects was similar to NH (p = 0.98) but better than in CI listeners (p = 0.04). The spondee reception threshold in the STRC−/− group was worse than NH listeners (p = 0.0008) but better than CI listeners (p = 0.0001). For AzBio sentences, performance at 0 dB SNR was similar between the STRC−/− group and the NH group, 88 % and 97 % respectively. For -5 dB SNR, the STRC−/− performance was significantly poorer than NH, 40 % and 85 % respectively, yet much better than with CI who performed at 54 % at +5 dB SNR in children and 53 % at + 10 dB SNR in adults. To our knowledge, this is the first study of the psychoacoustic performance of human subjects lacking cochlear amplification but with normal inner hair cell function. Our data demonstrate preservation of temporal resolution and a trend to impaired frequency resolution in this group without reaching statistical significance. Speech-in-noise perception compared to NH listeners was impaired as well. All measures were better than those in CI listeners. It remains to be seen if hearing aid modifications, customized for the spectral deficits in STRC−/− listeners can improve speech understanding in noise. Since cochlear implants are also limited by deficient spectral selectivity, STRC−/− hearing may provide an upper bound on what could be obtained with better temporal coding in electrical stimulation.
Summary Objectives The study investigated the epidemiology and outcome of invasive aspergillosis (IA), an important cause of morbidity and mortality in immunocompromised patients. Methods Cases of ...proven/probable IA from the Prospective Antifungal Therapy Alliance (PATH Alliance® ) registry – a prospective surveillance network comprising 25 centers in the United States and Canada that collected data on invasive fungal infections from 2004 to 2008 – were analyzed with respect to clinical outcome. Results Nine hundred and sixty patients with IA were enrolled, the most frequent underlying disease being hematologic malignancy ( n = 464 48.3%). Two hundred and eighty patients (29.2%) received solid organ transplant; 268 patients (27.9%) underwent hematopoietic stem cell transplantation. Identified isolates included Aspergillus fumigatus (72.6%), Aspergillus flavus (9.9%), Aspergillus niger (8.7%) and Aspergillus terreus (4.3%). The lung was most frequently affected. Following diagnosis, 47% patients received monotherapy – voriconazole (70%), an amphotericin B formulation (13.8%), or an echinocandin (10.5%) – while 279 patients (29%) received combination therapy. Twelve-week overall survival was 64.4%. Conclusions In this series of patients with IA, the lung was the predominant focus of infection, A. fumigatus was the major species isolated, and overall survival appeared slightly improved compared with previous reports.
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