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Objective: Limited reports have described ketamine’s role as an adjunct sedative. The purpose was to describe ketamine’s role as an adjunct to achieve goal sedation in mechanically ventilated children.Design: Retrospective, descriptive study.Setting: Thirteen-bed pediatric intensive care unit (ICU) and 12-bed pediatric cardiovascular ICU.Participants: Seventy-three ketamine courses were included, representing 62 mechanically ventilated children

Ketamine is an N-methyl-D-aspartate receptor antagonist that has been used as an adjunct analgesic and sedative in critically ill children. Previous reports noted that ketamine has been used for a variable duration of 12 to 408 hours for this indication. We report on the use of ketamine infusions for >720 hours as a second-line sedative in addition to an opioid and dexmedetomidine infusion in a 2-month old and 17-month old. The purpose of this case report and review of the literature is to highlight the prolonged ketamine exposure of these two patients and to provide awareness to clinicians on the potential of withdrawal with extended ketamine administration. These children were started on initials doses of 5 and 15 µg/kg/min and titrated to peak doses of 20 and 25 µg/kg/min, respectively. They were continued for a total of 987 and 792 hours, respectively. No adverse events were noted during the ketamine infusions. One patient developed possible withdrawal symptoms 17 hours after ketamine discontinuation despite tapering of the infusion. These symptoms resolved with administration of as needed intravenous opioids and benzodiazepines, and the agitation normalized within 24 hours after ketamine discontinuation. Clinicians should consider tapering ketamine infusions in children receiving >72 hours of a continuous infusion by 5 µg/kg/min every 8 to 12 hours. Patients should be monitored for potential withdrawal symptoms including anxiety, allodynia, hyperalgesia, sweating, and drowsiness.

The poultry (broiler) industry is continuously increasing all over the world, therefore, the amount of waste generated in these facilities is also increasing. As a consequence of the above mentioned, the more efficient conversion of chicken manure to organic fertilizer is a key problem. The aims of the study are to investigate the changes in temperature and moisture content during composting of chicken manure in the oval tank fermentation system and to create a model for the evaluation of the performance of biodegradation processes. The moisture and temperature distribution models of the oval tank were created in Hydrus software. The results showed that the oval tank fermenter can be divided into two main zones. In the first zone, where the rate of biodegradation was relatively high, a heterogeneous temperature zone was found with continuously decreasing moisture content. The second zone was more homogenous in both temperature and moisture content. This stage represents the weak fermentation part of the technology and results in an elongated post fermentation section. Furthermore, statistically significant correlations were found between composting key parameters, such as ammonium content with temperature and organic matter content with organic nitrogen content. It was also concluded that the exact location of the manure turning and chopping mechanical system (MTCM) used for aeration had a high effect on the composting processes, as well as on the quality parameters of the mature compost.

Simple Summary Breast cancer is the most common cancer in females worldwide. To date, many gene-environment interaction (GxE) studies have been conducted to better understand how genetic factors combine with environmental factors to influence risk. However, previous studies have not found or found only a few interactions by using SNPs which were discovered from genome-wide association studies and have been conducted, for the most part, within European populations. In this study, we focused on estrogen-related lifestyle factors that have been identified for breast cancer, including several well-established reproductive factors that are mediated by hormonal mechanisms. We aimed to examine whether there are any gene and environmental factor interactions related to estrogen exposure or metabolism using a candidate approach in Korean women. We found two interactions in this study, although they were not replicated in the independent large consortium data. These findings suggest specificity in Koreans for breast cancer risk. In this study we aim to examine gene-environment interactions (GxEs) between genes involved with estrogen metabolism and environmental factors related to estrogen exposure. GxE analyses were conducted with 1970 Korean breast cancer cases and 2052 controls in the case-control study, the Seoul Breast Cancer Study (SEBCS). A total of 11,555 SNPs from the 137 candidate genes were included in the GxE analyses with eight established environmental factors. A replication test was conducted by using an independent population from the Breast Cancer Association Consortium (BCAC), with 62,485 Europeans and 9047 Asians. The GxE tests were performed by using two-step methods in GxEScan software. Two interactions were found in the SEBCS. The first interaction was shown between rs13035764 of NCOA1 and age at menarche in the GE|2df model (p-2df = 1.2 x 10(-3)). The age at menarche before 14 years old was associated with the high risk of breast cancer, and the risk was higher when subjects had homozygous minor allele G. The second GxE was shown between rs851998 near ESR1 and height in the GE|2df model (p-2df = 1.1 x 10(-4)). Height taller than 160 cm was associated with a high risk of breast cancer, and the risk increased when the minor allele was added. The findings were not replicated in the BCAC. These results would suggest specificity in Koreans for breast cancer risk.

Summary Background Germline pathogenic variants in the E-cadherin gene ( CDH1 ) are strongly associated with the development of hereditary diffuse gastric cancer. There is a paucity of data to guide risk assessment and management of families with hereditary diffuse gastric cancer that do not carry a CDH1 pathogenic variant, making it difficult to make informed decisions about surveillance and risk-reducing surgery. We aimed to identify new candidate genes associated with predisposition to hereditary diffuse gastric cancer in affected families without pathogenic CDH1 variants. Methods We did whole-exome sequencing on DNA extracted from the blood of 39 individuals (28 individuals diagnosed with hereditary diffuse gastric cancer and 11 unaffected first-degree relatives) in 22 families without pathogenic CDH1 variants. Genes with loss-of-function variants were prioritised using gene-interaction analysis to identify clusters of genes that could be involved in predisposition to hereditary diffuse gastric cancer. Findings Protein-affecting germline variants were identified in probands from six families with hereditary diffuse gastric cancer; variants were found in genes known to predispose to cancer and in lesser-studied DNA repair genes. A frameshift deletion in PALB2 was found in one member of a family with a history of gastric and breast cancer. Two different MSH2 variants were identified in two unrelated affected individuals, including one frameshift insertion and one previously described start-codon loss. One family had a unique combination of variants in the DNA repair genes ATR and NBN . Two variants in the DNA repair gene RECQL5 were identified in two unrelated families: one missense variant and a splice-acceptor variant. Interpretation The results of this study suggest a role for the known cancer predisposition gene PALB2 in families with hereditary diffuse gastric cancer and no detected pathogenic CDH1 variants. We also identified new candidate genes associated with disease risk in these families. Funding UK Medical Research Council (Sackler programme), European Research Council under the European Union's Seventh Framework Programme (2007–13), National Institute for Health Research Cambridge Biomedical Research Centre, Experimental Cancer Medicine Centres, and Cancer Research UK.

Background and purpose This study was designed to identify common single nucleotide polymorphisms (SNPs) associated with toxicity 2years after radiotherapy. Materials and methods A genome wide association study was performed in 1850 patients from the RAPPER study: 1217 received adjuvant breast radiotherapy and 633 had radical prostate radiotherapy. Genotype associations with both overall and individual endpoints of toxicity were tested via univariable and multivariable regression. Replication of potentially associated SNPs was carried out in three independent patient cohorts who had radiotherapy for prostate (516 RADIOGEN and 862 Gene-PARE) or breast (355 LeND) cancer. Results Quantile–quantile plots show more associations at the P −7 level than expected by chance (164 vs. 9 for the prostate cases and 29 vs. 4 for breast cases), providing evidence that common genetic variants are associated with risk of toxicity. Strongest associations were for individual endpoints rather than an overall measure of toxicity in all patients . However, in general, significant associations were not validated at a nominal 0.05 level in the replication cohorts. Conclusions This largest GWAS to date provides evidence of true association between common genetic variants and toxicity. Associations with toxicity appeared to be tumour site-specific. Future GWAS require higher statistical power, in particular in the validation stage, to test clinically relevant effect sizes of SNP associations with individual endpoints, but the required sample sizes are achievable.

Genome-wide association studies have found SNPs at 17q22 to be associated with breast cancer risk. To identify potential causal variants related to breast cancer risk, we performed a high resolution fine-mapping analysis that involved genotyping 517 SNPs using a custom Illumina iSelect array (iCOGS) followed by imputation of genotypes for 3,134 SNPs in more than 89,000 participants of European ancestry from the Breast Cancer Association Consortium (BCAC). We identified 28 highly correlated common variants, in a 53 Kb region spanning two introns of the STXBP4 gene, that are strong candidates for driving breast cancer risk (lead SNP rs2787486 (OR = 0.92; CI 0.90–0.94; P = 8.96 × 10−15)) and are correlated with two previously reported risk-associated variants at this locus, SNPs rs6504950 (OR = 0.94, P = 2.04 × 10−09, r2 = 0.73 with lead SNP) and rs1156287 (OR = 0.93, P = 3.41 × 10−11, r2 = 0.83 with lead SNP). Analyses indicate only one causal SNP in the region and several enhancer elements targeting STXBP4 are located within the 53 kb association signal. Expression studies in breast tumor tissues found SNP rs2787486 to be associated with increased STXBP4 expression, suggesting this may be a target gene of this locus., published version, peerReviewed

Staphylococcus aureus is an important nosocomial and community-acquired pathogen. Its genetic plasticity has facilitated the evolution of many virulent and drug-resistant strains, presenting a major and constantly changing clinical challenge. We sequenced the ≈2.8-Mbp genomes of two disease-causing S. aureus strains isolated from distinct clinical settings: a recent hospital-acquired representative of the epidemic methicillin-resistant S. aureus EMRSA-16 clone (MRSA252), a clinically important and globally prevalent lineage; and a representative of an invasive community-acquired methicillin-susceptible S. aureus clone (MSSA476). A comparative-genomics approach was used to explore the mechanisms of evolution of clinically important S. aureus genomes and to identify regions affecting virulence and drug resistance. The genome sequences of MRSA252 and MSSA476 have a well conserved core region but differ markedly in their accessory genetic elements. MRSA252 is the most genetically diverse S. aureus strain sequenced to date: ≈6% of the genome is novel compared with other published genomes, and it contains several unique genetic elements. MSSA476 is methicillin-susceptible, but it contains a novel Staphylococcal chromosomal cassette (SCC) mec -like element (designated SCC 476 ), which is integrated at the same site on the chromosome as SCC mec elements in MRSA strains but encodes a putative fusidic acid resistance protein. The crucial role that accessory elements play in the rapid evolution of S. aureus is clearly illustrated by comparing the MSSA476 genome with that of an extremely closely related MRSA community-acquired strain; the differential distribution of large mobile elements carrying virulence and drug-resistance determinants may be responsible for the clinically important phenotypic differences in these strains.

The African trypanosome, Trypanosoma brucei, causes sleeping sickness in humans in sub-Saharan Africa. Here we report the sequence and analysis of the 1.1 Mb chromosome I, which encodes approximately 400 predicted genes organised into directional clusters, of which more than 100 are located in the largest cluster of 250 kb. A 160-kb region consists primarily of three gene families of unknown function, one of which contains a hotspot for retroelement insertion. We also identify five novel gene families. Indeed, almost 20% of predicted genes are members of families. In some cases, tandemly arrayed genes are 99–100% identical, suggesting an active process of amplification and gene conversion. One end of the chromosome consists of a putative bloodstream-form variant surface glycoprotein (VSG) gene expression site that appears truncated and degenerate. The other chromosome end carries VSG and expression site-associated genes and pseudogenes over 50 kb of subtelomeric sequence where, unusually, the telomere-proximal VSG gene is oriented away from the telomere. Our analysis includes the cataloguing of minor genetic variations between the chromosome I homologues and an estimate of crossing-over frequency during genetic exchange. Genetic polymorphisms are exceptionally rare in sequences located within and around the strand-switches between several gene clusters.

Mycobacterium bovis is the causative agent of tuberculosis in a range of animal species and man, with worldwide annual losses to agriculture of $3 billion. The human burden of tuberculosis caused by the bovine tubercle bacillus is still largely unknown. M. bovis was also the progenitor for the M. bovis bacillus Calmette–Guérin vaccine strain, the most widely used human vaccine. Here we describe the 4,345,492-bp genome sequence of M. bovis AF2122/97 and its comparison with the genomes of Mycobacterium tuberculosis and Mycobacterium leprae . Strikingly, the genome sequence of M. bovis is >99.95% identical to that of M. tuberculosis , but deletion of genetic information has led to a reduced genome size. Comparison with M. leprae reveals a number of common gene losses, suggesting the removal of functional redundancy. Cell wall components and secreted proteins show the greatest variation, indicating their potential role in host–bacillus interactions or immune evasion. Furthermore, there are no genes unique to M. bovis , implying that differential gene expression may be the key to the host tropisms of human and bovine bacilli. The genome sequence therefore offers major insight on the evolution, host preference, and pathobiology of M. bovis .