A Multidisciplinary Intervention to Reduce Infections of ESBL- and AmpC-Producing,Gram-Negative Bacteria at a University Hospital

In response to a considerable increase in the infections caused by ESBL/AmpC-producing Klebsiella pneumonia in 2008, a multidisciplinary intervention, with a main focus on antimicrobial stewardship, was carried out at one university hospital. Four other hospitals were used as controls. Stringent guidelines for antimicrobial treatment and prophylaxis were disseminated throughout the intervention hospital; cephalosporins were restricted for prophylaxis use only, fluoroquinolones for empiric use in septic shock only, and carbapenems were selected for penicillin-allergic patients, infections due to ESBL/AmpC-producing and other resistant bacteria, in addition to their use in severe sepsis/septic shock. Piperacillin-tazobactam ± gentamicin was recommended for empiric treatments of most febrile conditions. The intervention also included education and guidance on infection control, as well as various other surveillances. Two year follow-up data on the incidence rates of patients with selected bacterial infections, outcomes, and antibiotic consumption were assessed, employing before-and-after analysis and segmented regression analysis of interrupted time series, using the other hospitals as controls. The intervention led to a sustained change in antimicrobial consumption, and the incidence of patients infected with ESBL-producing K. pneumoniae decreased significantly (p<0.001). The incidences of other hospital-associated infections also declined (p’s<0.02), but piperacillin-tazobactam-resistant Pseudomonas aeruginosa and Enterococcus faecium infections increased (p’s<0.033). In wards with high antimicrobial consumption, the patient gut carrier rate of ESBL-producing bacteria significantly decreased (p = 0.023). The unadjusted, all-cause 30-day mortality rates of K. pneumoniae and E. coli were unchanged over the four-year period, with similar results in all five hospitals. Although not statistically significant, the 30-day mortality rate of patients with ESBL-producing K. pneumoniae decreased, from 35% in 2008–2009, to 17% in 2010–2011. The two-year follow-up data indicated that this multidisciplinary intervention led to a statistically significant decrease in the incidence of ESBL/AmpC-resistant K. pneumoniae infections, as well as in the incidences of other typical hospital-associated bacterial infections.     

Effect of BDNF Val66Met on Memory Decline and Hippocampal Atrophy in Prodromal Alzheimer’s Disease: A Preliminary Study

Objective

Cross-sectional genetic association studies have reported equivocal results on the relationship between the brain-derived neurotrophic factor (BDNF) Val66Met and risk of Alzheimer’s disease (AD). As AD is a neurodegenerative disease, genetic influences may become clearer from prospective study. We aimed to determine whether BDNF Val66Met polymorphism influences changes in memory performance, hippocampal volume, and Aβ accumulation in adults with amnestic mild cognitive impairment (aMCI) and high Aβ.

Methods

Thirty-four adults with aMCI were recruited from the Australian, Imaging, Biomarkers and Lifestyle (AIBL) Study. Participants underwent PiB-PET and structural MRI neuroimaging, neuropsychological assessments and BDNF genotyping at baseline, 18 month, and 36 month assessments.

Results

In individuals with aMCI and high Aβ, Met carriers showed significant and large decline in episodic memory (d = 0.90, p = .020) and hippocampal volume (d = 0.98, p = .035). BDNF Val66Met was unrelated to the rate of Aβ accumulation (d = −0.35, p = .401).

Conclusions

Although preliminary due to the small sample size, results of this study suggest that high Aβ levels and Met carriage may be useful prognostic markers of accelerated decline in episodic memory, and reductions in hippocampal volume in individuals in the prodromal or MCI stage of AD.     

The consequences of linear growth stunting: Influence on body composition among youth in the bolivian amazon

Stunting, or linear growth retardation, has been documented in up to half of all children in rural indigenous populations of South America. Stunting is well understood as a signal of adverse conditions during growth, and has been associated with developmentally induced modifications to body composition, including body fat and muscularity, that stem from early growth restriction. This article examines the relation between short stature and three anthropometric indicators of body composition during childhood and adolescence among a rural, indigenous population of forager‐horticulturalists. Anthropometric data were collected annually from 483 Tsimane' youth, ages 2–10 years, in 13 communities in the Beni region of Bolivia for 6 consecutive years (2002–2007). Baseline height‐for‐age was used to indicate stunting (HAZ < ?2.0) and compared with z‐scores of body mass index (BMI), sum of two skinfolds, and arm muscle area. Multilevel regression models indicate baseline stunting is associated with lower BMI z‐scores (B = ?0.386; P < 0.001), body fatness (ZSkinfold, B = ?0.164; P < 0.001), and arm muscularity (AMAZ, B = ?0.580; P < 0.001) in youth across a period of 6 years. When split by sex, there was a stronger relation between baseline stunting and lower skinfold body fat scores among girls (B = ?0.244; P < 0.001) than boys (B = ?0.080; P = 0.087). In contrast, baseline stunting was associated with lower arm muscularity in both girls (B = ?0.498; P < 0.001) and boys (B = ?0.646; P < 0.001). The relation between linear growth restriction and indicators of body composition persist into adolescence, providing additional insight into the influence of adverse conditions during growth. Am J Phys Anthropol 153:92–102, 2014. © 2013 Wiley Periodicals, Inc.     

Sequencing,annotation and comparative analysis of nine BACs of the giant panda(Ailuropoda melanoleuca)

A 10-fold BAC library for the giant panda was constructed and nine BACs were selected to generate finish sequences.These BACs could be used as a validation resource for the de novo assembly accuracy of the whole genome shotgun sequencing reads of the giant panda newly generated by Illumina GA sequencing technology.Complete Sanger sequencing,assembly,annotation and comparative analysis were carried out on the selected BACs of a joint length 878 kb.Homologue search and de novo prediction methods were used to ...     

大鼠眶额叶皮质受损破坏新异性探索行为

利用旷场测试和Y-迷宫测试两种行为模型检测了双侧眶额叶（orbitofrontal cortex, OFC）电损伤或假损伤雄性SD大鼠的新异性探索行为, 探讨了OFC在大鼠探索新异环境中的作用。旷场测试的结果发现,OFC损伤大鼠的行走距离和直立次数较假损组有明显降低;同时,在Y-迷宫测试中与假损伤组大鼠相比,OFC损伤大鼠在新异臂的访问时间和穿梭次数明显降低。提示眶额叶皮质在大鼠新异性探索行为中起着重要作用。     

Multilocus Sequence Typing as a Replacement for Serotyping in Salmonella enterica

Salmonella enterica subspecies enterica is traditionally subdivided into serovars by serological and nutritional characteristics. We used Multilocus Sequence Typing (MLST) to assign 4,257 isolates from 554 serovars to 1092 sequence types (STs). The majority of the isolates and many STs were grouped into 138 genetically closely related clusters called eBurstGroups (eBGs). Many eBGs correspond to a serovar, for example most Typhimurium are in eBG1 and most Enteritidis are in eBG4, but many eBGs contained more than one serovar. Furthermore, most serovars were polyphyletic and are distributed across multiple unrelated eBGs. Thus, serovar designations confounded genetically unrelated isolates and failed to recognize natural evolutionary groupings. An inability of serotyping to correctly group isolates was most apparent for Paratyphi B and its variant Java. Most Paratyphi B were included within a sub-cluster of STs belonging to eBG5, which also encompasses a separate sub-cluster of Java STs. However, diphasic Java variants were also found in two other eBGs and monophasic Java variants were in four other eBGs or STs, one of which is in subspecies salamae and a second of which includes isolates assigned to Enteritidis, Dublin and monophasic Paratyphi B. Similarly, Choleraesuis was found in eBG6 and is closely related to Paratyphi C, which is in eBG20. However, Choleraesuis var. Decatur consists of isolates from seven other, unrelated eBGs or STs. The serological assignment of these Decatur isolates to Choleraesuis likely reflects lateral gene transfer of flagellar genes between unrelated bacteria plus purifying selection. By confounding multiple evolutionary groups, serotyping can be misleading about the disease potential of S. enterica. Unlike serotyping, MLST recognizes evolutionary groupings and we recommend that Salmonella classification by serotyping should be replaced by MLST or its equivalents.     

Deaths from Symptomatically Identifiable Furious Rabies in India: A Nationally Representative Mortality Survey

Background

It is estimated that India has more deaths from rabies than any other country. However, existing estimates are indirect and rely on non-representative studies.

Methods and Principal Findings

We examined rabies deaths in the ongoing Million Death Study (MDS), a representative survey of over 122,000 deaths in India that uses enhanced types of verbal autopsy. We estimated the age-specific mortality rates of symptomatically identifiable furious rabies and its geographic and demographic distributions. A total of 140 deaths in our sample were caused by rabies, suggesting that in 2005 there were 12,700 (99% CI 10,000 to 15,500) symptomatically identifiable furious rabies deaths in India. Most rabies deaths were in males (62%), in rural areas (91%), and in children below the age of 15 years (50%). The overall rabies mortality rate was 1.1 deaths per 100,000 population (99%CI 0.9 to 1.4). One third of the national rabies deaths were found in Uttar Pradesh (4,300) and nearly three quarters (8,900) were in 7 central and south-eastern states: Chhattisgarh, Uttar Pradesh, Odisha, Andhra Pradesh, Bihar, Assam, and Madhya Pradesh.

Conclusions and Significance

Rabies remains an avoidable cause of death in India. As verbal autopsy is not likely to identify atypical or paralytic forms of rabies, our figure of 12,700 deaths due to classic and clinically identifiable furious rabies underestimates the total number of deaths due to this virus. The concentrated geographic distribution of rabies in India suggests that a significant reduction in the number of deaths or potentially even elimination of rabies deaths is possible.     

Red Blood Cell Transfusion and Mortality in Trauma Patients: Risk-Stratified Analysis of an Observational Study

Background

Haemorrhage is a common cause of death in trauma patients. Although transfusions are extensively used in the care of bleeding trauma patients, there is uncertainty about the balance of risks and benefits and how this balance depends on the baseline risk of death. Our objective was to evaluate the association of red blood cell (RBC) transfusion with mortality according to the predicted risk of death.

Methods and Findings

A secondary analysis of the CRASH-2 trial (which originally evaluated the effect of tranexamic acid on mortality in trauma patients) was conducted. The trial included 20,127 trauma patients with significant bleeding from 274 hospitals in 40 countries. We evaluated the association of RBC transfusion with mortality in four strata of predicted risk of death: <6%, 6%–20%, 21%–50%, and >50%. For this analysis the exposure considered was RBC transfusion, and the main outcome was death from all causes at 28 days. A total of 10,227 patients (50.8%) received at least one transfusion. We found strong evidence that the association of transfusion with all-cause mortality varied according to the predicted risk of death (p-value for interaction <0.0001). Transfusion was associated with an increase in all-cause mortality among patients with <6% and 6%–20% predicted risk of death (odds ratio [OR] 5.40, 95% CI 4.08–7.13, p<0.0001, and OR 2.31, 95% CI 1.96–2.73, p<0.0001, respectively), but with a decrease in all-cause mortality in patients with >50% predicted risk of death (OR 0.59, 95% CI 0.47–0.74, p<0.0001). Transfusion was associated with an increase in fatal and non-fatal vascular events (OR 2.58, 95% CI 2.05–3.24, p<0.0001). The risk associated with RBC transfusion was significantly increased for all the predicted risk of death categories, but the relative increase was higher for those with the lowest (<6%) predicted risk of death (p-value for interaction <0.0001). As this was an observational study, the results could have been affected by different types of confounding. In addition, we could not consider haemoglobin in our analysis. In sensitivity analyses, excluding patients who died early; conducting propensity score analysis adjusting by use of platelets, fresh frozen plasma, and cryoprecipitate; and adjusting for country produced results that were similar.

Conclusions

The association of transfusion with all-cause mortality appears to vary according to the predicted risk of death. Transfusion may reduce mortality in patients at high risk of death but increase mortality in those at low risk. The effect of transfusion in low-risk patients should be further tested in a randomised trial.

Trial registration

www.ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01746953","term_id":"NCT01746953"}}NCT01746953 Please see later in the article for the Editors'' Summary     

Longitudinal Analysis Is More Powerful than Cross-Sectional Analysis in Detecting Genetic Association with Neuroimaging Phenotypes

Most existing genome-wide association analyses are cross-sectional, utilizing only phenotypic data at a single time point, e.g. baseline. On the other hand, longitudinal studies, such as Alzheimer''s Disease Neuroimaging Initiative (ADNI), collect phenotypic information at multiple time points. In this article, as a case study, we conducted both longitudinal and cross-sectional analyses of the ADNI data with several brain imaging (not clinical diagnosis) phenotypes, demonstrating the power gains of longitudinal analysis over cross-sectional analysis. Specifically, we scanned genome-wide single nucleotide polymorphisms (SNPs) with 56 brain-wide imaging phenotypes processed by FreeSurfer on 638 subjects. At the genome-wide significance level () or a less stringent level (e.g. ), longitudinal analysis of the phenotypic data from the baseline to month 48 identified more SNP-phenotype associations than cross-sectional analysis of only the baseline data. In particular, at the genome-wide significance level, both SNP rs429358 in gene APOE and SNP rs2075650 in gene TOMM40 were confirmed to be associated with various imaging phenotypes in multiple regions of interests (ROIs) by both analyses, though longitudinal analysis detected more regional phenotypes associated with the two SNPs and indicated another significant SNP rs439401 in gene APOE. In light of the power advantage of longitudinal analysis, we advocate its use in current and future longitudinal neuroimaging studies.     

Genetic Variants in the Fat and Obesity Associated (FTO) Gene and Risk of Alzheimer's Disease

Background

Recent studies showed that polymorphisms in the Fat and Obesity-Associated (FTO) gene have robust effects on obesity, obesity-related traits and endophenotypes associated with Alzheimer''s disease (AD).

Methods

We used 1,877 Caucasian cases and controls from the NIA-LOAD study and 1,093 Caribbean Hispanics to further explore the association of FTO with AD. Using logistic regression, we assessed 42 SNPs in introns 1 and 2, the region previously reported to be associated with AD endophenotypes, which had been derived by genome-wide screenings. In addition, we performed gene expression analyses of neuropathologically confirmed AD cases and controls of two independent datasets (19 AD cases, 10 controls; 176 AD cases, 188 controls) using within- and between-group factors ANOVA of log₁₀ transformed rank invariant normalized expression data.

Results

In the NIALOAD study, one SNP was significantly associated with AD and three additional markers were close to significance (rs6499640, rs10852521, rs16945088, rs8044769, FDR p-value: 0.05<p<0.09). Two of the SNPs are in strong LD (D′>0.9) with the previously reported SNPs. In the Caribbean Hispanic dataset, we identified three SNPs (rs17219084, rs11075996, rs11075997, FDR p-value: 0.009<p<0.01) that were associated with AD. These results were confirmed by haplotype analyses and in a metaanalysis in which we included the ADNI dataset. FTO had a significantly lower expresssion in AD cases compared to controls in two independent datasets derived from human cortex and amygdala tissue, respectively (p = 2.18×10−5 and p<0.0001).

Conclusions

Our data support the notion that genetic variation in Introns 1 and 2 of the FTO gene may contribute to AD risk.