Synthesis of fluorinated carbocyclic pyrimidine nucleoside analogues.

Analogues of the canonical nucleosides have a longstanding presence and proven capability within medicinal chemistry and drug discovery research. The synthesis reported herein successfully replaces furanose oxygen with CF2 and CHF in pyrimidine nucleosides, granting access to an alternative pharmacophore space. Key diastereoselective conjugate addition and fluorination methodologies are developed from chiral pool materials, establishing a robust gram-scale synthesis of 6'-(R)-monofluoro- and 6'-gem-difluorouridines. Vital intermediate stereochemistries are confirmed using X-ray crystallography and NMR analysis, providing an indicative conformational preference for these fluorinated carbanucleosides. Utilising these 6'-fluorocarbauridine scaffolds enables synthesis of related cytidine, ProTide and 2'-deoxy analogues alongside a preliminary exploration of their biological capabilities in cancer cell viability assays. This synthetic blueprint offers potential to explore fluorocarbanucleoside scaffolds, indicatively towards triphosphate analogues and as building blocks for oligonucleotide synthesis

Core components for effective infection prevention and control programmes: new WHO evidence-based recommendations

Abstract Health care-associated infections (HAI) are a major public health problem with a significant impact on morbidity, mortality and quality of life. They represent also an important economic burden to health systems worldwide. However, a large proportion of HAI are preventable through effective infection prevention and control (IPC) measures. Improvements in IPC at the national and facility level are critical for the successful containment of antimicrobial resistance and the prevention of HAI, including outbreaks of highly transmissible diseases through high quality care within the context of universal health coverage. Given the limited availability of IPC evidence-based guidance and standards, the World Health Organization (WHO) decided to prioritize the development of global recommendations on the core components of effective IPC programmes both at the national and acute health care facility level, based on systematic literature reviews and expert consensus. The aim of the guideline development process was to identify the evidence and evaluate its quality, consider patient values and preferences, resource implications, and the feasibility and acceptability of the recommendations. As a result, 11 recommendations and three good practice statements are presented here, including a summary of the supporting evidence, and form the substance of a new WHO IPC guideline

Cognitive reserve in granulin-related frontotemporal dementia: from preclinical to clinical stages

OBJECTIVE Consistent with the cognitive reserve hypothesis, higher education and occupation attainments may help persons with neurodegenerative dementias to better withstand neuropathology before developing cognitive impairment. We tested here the cognitive reserve hypothesis in patients with frontotemporal dementia (FTD), with or without pathogenetic granulin mutations (GRN+ and GRN-), and in presymptomatic GRN mutation carriers (aGRN+). METHODS Education and occupation attainments were assessed and combined to define Reserve Index (RI) in 32 FTD patients, i.e. 12 GRN+ and 20 GRN-, and in 17 aGRN+. Changes in functional connectivity were estimated by resting state fMRI, focusing on the salience network (SN), executive network (EN) and bilateral frontoparietal networks (FPNs). Cognitive status was measured by FTD-modified Clinical Dementia Rating Scale. RESULTS In FTD patients higher level of premorbid cognitive reserve was associated with reduced connectivity within the SN and the EN. EN was more involved in FTD patients without GRN mutations, while SN was more affected in GRN pathology. In aGRN+, cognitive reserve was associated with reduced SN. CONCLUSIONS This study suggests that cognitive reserve modulates functional connectivity in patients with FTD, even in monogenic disease. In GRN inherited FTD, cognitive reserve mechanisms operate even in presymptomatic to clinical stages

Genome-Wide Screen in Saccharomyces cerevisiae Identifies Vacuolar Protein Sorting, Autophagy, Biosynthetic, and tRNA Methylation Genes Involved in Life Span Regulation

The study of the chronological life span of Saccharomyces cerevisiae, which measures the survival of populations of non-dividing yeast, has resulted in the identification of homologous genes and pathways that promote aging in organisms ranging from yeast to mammals. Using a competitive genome-wide approach, we performed a screen of a complete set of approximately 4,800 viable deletion mutants to identify genes that either increase or decrease chronological life span. Half of the putative short-/long-lived mutants retested from the primary screen were confirmed, demonstrating the utility of our approach. Deletion of genes involved in vacuolar protein sorting, autophagy, and mitochondrial function shortened life span, confirming that respiration and degradation processes are essential for long-term survival. Among the genes whose deletion significantly extended life span are ACB1, CKA2, and TRM9, implicated in fatty acid transport and biosynthesis, cell signaling, and tRNA methylation, respectively. Deletion of these genes conferred heat-shock resistance, supporting the link between life span extension and cellular protection observed in several model organisms. The high degree of conservation of these novel yeast longevity determinants in other species raises the possibility that their role in senescence might be conserved

Retrospective analysis of nosocomial infections in the intensive care unit of a tertiary hospital in China during 2003 and 2007

<p>Abstract</p> <p>Background</p> <p>Nosocomial infections are a major threat to patients in the intensive care unit (ICU). Limited data exist on the epidemiology of ICU-acquired infections in China. This retrospective study was carried out to determine the current status of nosocomial infection in China.</p> <p>Methods</p> <p>A retrospective review of nococomial infections in the ICU of a tertiary hospital in East China between 2003 and 2007 was performed. Nosocomial infections were defined according to the definitions of Centers for Disease Control and Prevention. The overall patient nosocomial infection rate, the incidence density rate of nosocomial infections, the excess length of stay, and distribution of nosocomial infection sites were determined. Then, pathogen and antimicrobial susceptibility profiles were further investigated.</p> <p>Results</p> <p>Among 1980 patients admitted over the period of time, the overall patient nosocomial infection rate was 26.8% or 51.0 per 1000 patient days., Lower respiratory tract infections (LRTI) accounted for most of the infections (68.4%), followed by urinary tract infections (UTI, 15.9%), bloodstream (BSI, 5.9%), and gastrointestinal tract (GI, 2.5%) infections. There was no significant change in LRTI, UTI and BSI infection rates during the 5 years. However, GI rate was significantly decreased from 5.5% in 2003 to 0.4% in 2007. In addition, <it>A. baumannii, C. albicans </it>and <it>S. epidermidis </it>were the most frequent pathogens isolated in patients with LRTIs, UTIs and BSIs, respectively. The rates of isolates resistant to commonly used antibiotics ranged from 24.0% to 93.1%.</p> <p>Conclusion</p> <p>There was a high and relatively stable rate of nosocomial infections in the ICU of a tertiary hospital in China through year 2003–2007, with some differences in the distribution of the infection sites, and pathogen and antibiotic susceptibility profiles from those reported from the Western countries. Guidelines for surveillance and prevention of nosocomial infections must be implemented in order to reduce the rate.</p

A Profile Likelihood Analysis of the Constrained MSSM with Genetic Algorithms

The Constrained Minimal Supersymmetric Standard Model (CMSSM) is one of the simplest and most widely-studied supersymmetric extensions to the standard model of particle physics. Nevertheless, current data do not sufficiently constrain the model parameters in a way completely independent of priors, statistical measures and scanning techniques. We present a new technique for scanning supersymmetric parameter spaces, optimised for frequentist profile likelihood analyses and based on Genetic Algorithms. We apply this technique to the CMSSM, taking into account existing collider and cosmological data in our global fit. We compare our method to the MultiNest algorithm, an efficient Bayesian technique, paying particular attention to the best-fit points and implications for particle masses at the LHC and dark matter searches. Our global best-fit point lies in the focus point region. We find many high-likelihood points in both the stau co-annihilation and focus point regions, including a previously neglected section of the co-annihilation region at large m_0. We show that there are many high-likelihood points in the CMSSM parameter space commonly missed by existing scanning techniques, especially at high masses. This has a significant influence on the derived confidence regions for parameters and observables, and can dramatically change the entire statistical inference of such scans.Comment: 47 pages, 8 figures; Fig. 8, Table 7 and more discussions added to Sec. 3.4.2 in response to referee's comments; accepted for publication in JHE

Disparities in the Burden of HIV/AIDS in Canada

Background We aimed to characterize changes in patterns of new HIV diagnoses, HIV-related mortality, and HAART use in Canada from 1995 to 2008. Methods Data on new HIV diagnoses were obtained from Health Canada, HIV-related mortality statistics were obtained from Statistics Canada, and information on the number of people on HAART was obtained from the single antiretroviral distribution site in British Columbia (BC), and the Intercontinental Marketing Services Health for Ontario and Quebec. Trends of new HIV-positive tests were assessed using Spearman rank correlations and the association between the number of individuals on HAART and new HIV diagnoses were estimated using generalized estimating equations (GEE). Results A total of 34,502 new HIV diagnoses were observed. Rates of death in BC are higher than those in Ontario and Quebec with the rate being 2.03 versus 1.06 and 1.21 per 100,000 population, respectively. The number of HIV infected individuals on HAART increased from 5,091 in 1996 to 20,481 in 2008 in the three provinces (4 fold increase). BC was the only province with a statistically significant decrease (trend test p&lt;0.0001) in the rate of new HIV diagnoses from 18.05 to 7.94 new diagnoses per 100,000 population. Our analysis showed that for each 10% increment in HAART coverage the rate of new HIV diagnoses decreased by 8% (95% CI: 2.4%, 13.3%) Interpretation Except for British Columbia, the number of new HIV diagnoses per year has remained relatively stable across Canada over the study period. The decline in the rate of new HIV diagnoses per year may be in part attributed to the greater expansion of HAART coverage in this province

The usefulness of arbekacin compared to vancomycin

The bacteriological efficacy response (improved, arbekacin vs. vancomycin; 71.2% vs. 79.5%) and clinical efficacy response (improved, arbekacin vs. vancomycin; 65.3% vs. 76.1%) were not statistically different between the two groups. The complication rate was significantly higher in the vancomycin group (32.9%) compared to the arbekacin group (15.1%) (p = 0.019). Arbekacin was not inferior to vancomycin, and it could be a good alternative drug for vancomycin in methicillin-resistant Staphylococcus aureus (MRSA) treatment