Postoperative delirium continues to pose major clinical difficulties. While unmodifiable factors (e.g. age and comorbidity burden) are commonly studied risk factors for delirium, the role of ...modifiable factors, such as anaesthesia type and commonly used perioperative medications, remains understudied. This study aims to evaluate the role of modifiable factors for delirium after hip and knee arthroplasties.
We performed a retrospective study of 41 766 patients who underwent hip or knee arthroplasties between 2005 and 2014 at a single institution. Data were collected as part of routine patient care. Multivariable logistic regression models assessed associations between anaesthesia type and commonly used perioperative medications (opioids, benzodiazepines, and ketamine) and postoperative delirium. Odds ratios (OR) and 95% confidence intervals (CI) are reported. Various sensitivity analyses are also considered, including multiple imputation methods to address missing data.
Postoperative delirium occurred in 2.21% (n=922) of all patients. While patients who received neuraxial anaesthesia were at lower risk for postoperative delirium (compared with general anaesthesia; epidural OR 0.59 CI 0.38–0.93; spinal OR 0.55 CI 0.37–0.83; combined spinal/epidural OR 0.56 CI 0.40–0.80), those given intraoperative ketamine (OR 1.27 CI 1.01–1.59), opioids (OR 1.25 CI 1.09–1.44), postoperative benzodiazepines (OR 2.47 CI 2.04–2.97), and ketamine infusion (OR 10.59 CI 5.26–19.91) were at a higher risk.
In this cohort of hip and knee arthroplasty patients, anaesthesia type and perioperative medications were associated with increased odds for postoperative delirium. Our results support the notion that modifiable risk factors may exacerbate or attenuate risk for postoperative delirium.
•Depression and anxiety among psychiatric inpatients were negatively associated with richness, alpha diversity, and specific bacterial taxa.•Microbiota richness, alpha diversity, and bacterial taxa ...early in the hospitalization were associated with depression remission at discharge.•Coprococcus catus may be a significant contributor to the association between the gut microbiota and psychiatric functioning.•A large psychiatric sample from a controlled environment and accounting for confounding variables are clear strengths of the current study.
Emerging evidence implicates the gut microbiota in central nervous system functioning via its effects on inflammation, the hypothalamic-pituitary axis, and/or neurotransmission. Our understanding of the cellular underpinnings of the brain-gut relationship is based almost exclusively on animal models with some small-scale human studies. This study examined the relationship between the gut microbiota and psychiatric symptom severity and treatment response among inpatients with serious mental illness.
We collected data from adult inpatients (N = 111). Measures of diagnoses, suicide severity, trauma, depression, and anxiety were collected shortly after admission, while self-collected fecal swabs were collected early in the course of hospitalization and processed using 16S rRNA gene sequencing and whole genome shotgun sequencing methods.
Results indicate that depression and anxiety severity shortly after admission were negatively associated with bacterial richness and alpha diversity. Additional analyses revealed a number of bacterial taxa associated with depression and anxiety severity. Gut microbiota richness and alpha diversity early in the course of hospitalization was a significant predictor of depression remission at discharge.
This study is among the first to demonstrate a gut microbiota relationship with symptom severity among psychiatric inpatients as well as a relationship to remission of depression post-treatment. These findings are consistent with animal models and limited human studies as well as with the broader literature implicating inflammation in the pathophysiology of depression. These findings offer the foundation for further studies of novel therapeutic approaches to the treatment, prevention of, or recurrence of serious mental illness.
A catalogue of molecular aberrations that cause ovarian cancer is critical for developing and deploying therapies that will improve patients' lives. The Cancer Genome Atlas project has analysed ...messenger RNA expression, microRNA expression, promoter methylation and DNA copy number in 489 high-grade serous ovarian adenocarcinomas and the DNA sequences of exons from coding genes in 316 of these tumours. Here we report that high-grade serous ovarian cancer is characterized by TP53 mutations in almost all tumours (96%); low prevalence but statistically recurrent somatic mutations in nine further genes including NF1, BRCA1, BRCA2, RB1 and CDK12; 113 significant focal DNA copy number aberrations; and promoter methylation events involving 168 genes. Analyses delineated four ovarian cancer transcriptional subtypes, three microRNA subtypes, four promoter methylation subtypes and a transcriptional signature associated with survival duration, and shed new light on the impact that tumours with BRCA1/2 (BRCA1 or BRCA2) and CCNE1 aberrations have on survival. Pathway analyses suggested that homologous recombination is defective in about half of the tumours analysed, and that NOTCH and FOXM1 signalling are involved in serous ovarian cancer pathophysiology.
Because most potential molecular markers and targets are proteins, proteomic profiling is expected to yield more direct answers to functional and pharmacological questions than does transcriptional ...profiling. To aid in such studies, we have developed a protocol for making reverse-phase protein lysate microarrays with larger numbers of spots than previously feasible. Our first application of these arrays was to profiling of the 60 human cancer cell lines (NCI-60) used by the National Cancer Institute to screen compounds for anticancer activity. Each glass slide microarray included 648 lysate spots representing the NCI-60 cell lines plus controls, each at 10 two-fold serial dilutions to provide a wide dynamic range. Mouse monoclonal antibodies and the catalyzed signal amplification system were used for immunoquantitation. The signal levels from the >30,000 data points for our first 52 antibodies were analyzed by using P-Scan and a quantitative dose interpolation method. Clustered image maps revealed biologically interpretable patterns of protein expression. Among the principal early findings from these arrays were two promising pathological markers for distinguishing colon from ovarian adenocarcinomas. When we compared the patterns of protein expression with those we had obtained for the same genes at the mRNA level by using both cDNA and oligonucleotide arrays, a striking regularity appeared: cell-structure-related proteins almost invariably showed a high correlation between mRNA and protein levels across the NCI-60 cell lines, whereas non-cell-structure-related proteins showed poor correlation.
A prospective, observational study.
To identify outcome predictors of surgery for degenerative lumbar spinal stenosis.
Degenerative lumbar spinal stenosis is the most frequent indication for spine ...surgery in the elderly. More than 25% of surgical patients have a poor outcome, yet little is known about factors that predict the outcome of surgery.
Surgery was performed on 199 patients with degenerative lumbar spinal stenosis, and they were observed for 2 years after surgery in four referral centers. Surgery consisted of decompressive laminectomy with or without arthrodesis. Outcomes included validated measures of symptom severity, walking capacity, and satisfaction with the results of surgery. Potential predictors of outcome included sociodemographic factors and physical examination, as well as radiographic, psychological, social, and clinical history variables.
The proportion of patients with severe pain decreased from 81% before surgery to 31% by 2 years afterward. The most powerful preoperation predictor of greater walking capacity, milder symptoms, and greater satisfaction was the patient's report of good or excellent health before surgery. Low cardiovascular comorbidity also predicted a favorable outcome.
Patient's assessments of their own health and comorbidity are the most cogent outcome predictors of surgery for spinal stenosis.
For analysis of multidrug resistance, a major barrier to effective cancer chemotherapy, we profiled mRNA expression of the 48 known human ABC transporters in 60 diverse cancer cell lines (the NCI-60) ...used by the National Cancer Institute to screen for anticancer activity. The use of real-time RT-PCR avoided artifacts commonly encountered with microarray technologies. By correlating the results with the growth inhibitory profiles of 1,429 candidate anticancer drugs tested against the cells, we identified which transporters are more likely than others to confer resistance to which agents. Unexpectedly, we also found and validated compounds whose activity is potentiated, rather than antagonized, by the MDR1 multidrug transporter. Such compounds may serve as leads for development.
The Spine Patient Outcomes Research Trial showed an overall advantage for operative compared with nonoperative treatment of lumbar disc herniations. Because a recent randomized trial showed no ...benefit for operative treatment of a disc at the lumbosacral junction (L5-S1), we reviewed subgroups within the Spine Patient Outcomes Research Trial to assess the effect of herniation level on outcomes of operative and nonoperative care.
The combined randomized and observation cohorts of the Spine Patient Outcomes Research Trial were analyzed by actual treatment received stratified by level of disc herniation. Overall, 646 L5-S1 herniations, 456 L4-L5 herniations, and eighty-eight upper lumbar (L2-L3 or L3-L4) herniations were evaluated. Primary outcome measures were the Short Form-36 bodily pain and physical functioning scales and the modified Oswestry Disability Index assessed at six weeks, three months, six months, one year, and two years. Treatment effects (the improvement in the operative group minus the improvement in the nonoperative group) were estimated with use of longitudinal regression models, adjusting for important covariates.
At two years, patients with upper lumbar herniations (L2-L3 or L3-L4) showed a significantly greater treatment effect from surgery than did patients with L5-S1 herniations for all outcome measures: 24.6 and 7.1, respectively, for bodily pain (p = 0.002); 23.4 and 9.9 for Short Form-36 physical functioning (p = 0.014); and -19 and -10.3 for Oswestry Disability Index (p = 0.033). There was a trend toward greater treatment effect for surgery at L4-L5 compared with L5-S1, but this was significant only for the Short Form-36 physical functioning subscale (p = 0.006). Differences in treatment effects between the upper lumbar levels and L4-L5 were significant for Short Form-36 bodily pain only (p = 0.018).
The advantage of operative compared with nonoperative treatment varied by herniation level, with the smallest treatment effects at L5-S1, intermediate effects at L4-L5, and the largest effects at L2-L3 and L3-L4. This difference in effect was mainly a result of less improvement in patients with upper lumbar herniations after nonoperative treatment.
The TP53 tumor suppressor gene is frequently mutated in human cancers. An analysis of five data platforms in 10,225 patient samples from 32 cancers reported by The Cancer Genome Atlas (TCGA) enables ...comprehensive assessment of p53 pathway involvement in these cancers. More than 91% of TP53-mutant cancers exhibit second allele loss by mutation, chromosomal deletion, or copy-neutral loss of heterozygosity. TP53 mutations are associated with enhanced chromosomal instability, including increased amplification of oncogenes and deep deletion of tumor suppressor genes. Tumors with TP53 mutations differ from their non-mutated counterparts in RNA, miRNA, and protein expression patterns, with mutant TP53 tumors displaying enhanced expression of cell cycle progression genes and proteins. A mutant TP53 RNA expression signature shows significant correlation with reduced survival in 11 cancer types. Thus, TP53 mutation has profound effects on tumor cell genomic structure, expression, and clinical outlook.
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•TP53 mutation effects analyzed by five data platforms in 32 cancers/10,225 patients•More than 91% of cancers with TP53 mutations show loss of both functional TP53 alleles•TP53 mutation affects genomic stability, global RNA, miRNA, and protein expression•Mutant p53 RNA expression signature helps prognostic predictions in 11 cancer types
Donehower et al. performed a comprehensive analysis of the effects of TP53 gene mutation in 32 cancer types and 10,225 patients from The Cancer Genome Atlas (TCGA). Data synthesized from five different analysis platforms show how mutant TP53 increases genomic instability and induces major pathway signaling changes in cancer cells.
We used cDNA microarrays to explore the variation in expression of approximately 8,000 unique genes among the 60 cell lines used in the National Cancer Institute's screen for anti-cancer drugs. ...Classification of the cell lines based solely on the observed patterns of gene expression revealed a correspondence to the ostensible origins of the tumours from which the cell lines were derived. The consistent relationship between the gene expression patterns and the tissue of origin allowed us to recognize outliers whose previous classification appeared incorrect. Specific features of the gene expression patterns appeared to be related to physiological properties of the cell lines, such as their doubling time in culture, drug metabolism or the interferon response. Comparison of gene expression patterns in the cell lines to those observed in normal breast tissue or in breast tumour specimens revealed features of the expression patterns in the tumours that had recognizable counterparts in specific cell lines, reflecting the tumour, stromal and inflammatory components of the tumour tissue. These results provided a novel molecular characterization of this important group of human cell lines and their relationships to tumours in vivo.
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