Enhanced recovery protocols for major upper gastrointestinal, liver and pancreatic surgery

BACKGROUND: 'Fast-track surgery' or 'enhanced recovery protocol' or 'fast-track rehabilitation', incorporating one or more elements of preoperative education, pain relief, early mobilisation, enteral nutrition and growth factors, may improve health-related quality of life and reduce length of hospital stay and costs. The role of enhanced recovery protocols in major upper gastrointestinal, liver and pancreatic surgery is unclear. OBJECTIVES: To assess the benefits and harms of enhanced recovery protocols compared with standard care (or usual practice) in major upper gastrointestinal, liver and pancreatic surgery. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL; Cochrane Library; 2015, Issue 3), MEDLINE, EMBASE and Science Citation Index Expanded until March 2015 to identify randomised trials. We also searched the references of included trials to identify further trials. SELECTION CRITERIA: We considered only randomised controlled trials (RCTs) performed in people undergoing major upper gastrointestinal, liver and pancreatic surgery, irrespective of language, blinding or publication status for inclusion in the review. DATA COLLECTION AND ANALYSIS: Two review authors independently identified trials and independently extracted data. We calculated the risk ratio (RR), mean difference (MD), or standardised mean difference (SMD) with 95% confidence intervals (CIs) using both fixed-effect and random-effects models using Review Manager 5, based on available case analysis. MAIN RESULTS: Ten studies met the inclusion criteria for the review, and nine studies provided information on one or more outcomes for the review. A total of 1014 participants were randomly assigned to the enhanced recovery protocol (499 participants) or standard care (515 participants) in the nine RCTs. Most of the trials included low anaesthetic risk participants with high performance status undergoing different upper gastrointestinal, liver and pancreatic surgeries. Eight trials incorporated more than one element of the enhanced recovery protocol. All of the trials were at high risk of bias. The overall quality of evidence was low or very low.None of the trials reported long-term mortality, medium-term health-related quality of life(three months to one year), time to return to normal activity, or time to return to work. The difference between the enhanced recovery protocol and standard care were imprecise for short-term mortality (enhanced recovery protocol: 4/425 (adjusted proportion = 0.6%); standard care: 1/443 (0.2%); seven trials; 868 participants; RR 2.79; 95% CI 0.44 to 17.73; very low quality evidence), proportion of people with serious adverse events (enhanced recovery protocol: 4/157 (adjusted proportion = 0.6%); standard care: 0/184 (0.0%); two trials; 341 participants; RR 5.57; 95% CI 0.68 to 45.89; very low quality evidence), number of serious adverse events (enhanced recovery protocol: 34/421 (8 per 100 participants); standard care: 46/438 (11 per 100 participants); seven trials; 859 participants; rate ratio 0.72; 95% CI 0.45 to 1.13; very low quality evidence), health-related quality of life (four trials; 373 participants; SMD 0.29; 95% CI -0.04 to 0.62; very low quality evidence) and hospital readmissions (enhanced recovery protocol: 14/355 (adjusted proportion = 3.3%); standard care: 9/378 (2.4%); seven trials; 733 participants; RR 1.4; 95% CI 0.69 to 2.87; very low quality evidence). The enhanced recovery protocol group had a lower proportion of people with mild adverse events (enhanced recovery protocol: 31/254 (adjusted proportion = 10.9%); standard care: 51/271 (18.8%); four trials; 525 participants; RR 0.58; 95% CI 0.39 to 0.85; low quality evidence), fewer number of mild adverse events (enhanced recovery protocol: 69/499 (13 per 100 participants); standard care: 128/515 (25 per 100 participants); nine trials; 1014 participants; rate ratio 0.52; 95% CI 0.39 to 0.70; low quality evidence), shorter length of hospital stay (nine trials; 1014 participants; MD -2.19 days; 95% CI -2.53 to -1.85; low quality evidence) and lower costs (four trials; 282 participants; MD USD -6300; 95% CI -8400 to -4200; low quality evidence) than standard care group. AUTHORS' CONCLUSIONS: Based on low quality evidence, enhanced recovery protocols may reduce length of hospital stay and costs (primarily because of reduction in hospital stay) in people undergoing major upper gastrointestinal, liver and pancreatic surgeries. However, the validity of the results is uncertain because of the risk of bias in the trials and the way the outcomes were measured. Future RCTs should be conducted with low risk of bias, and measure clinically important outcomes for including the three months to one year period

Transmembrane helix dynamics of bacterial chemoreceptors supports a piston model of signalling.

Transmembrane α-helices play a key role in many receptors, transmitting a signal from one side to the other of the lipid bilayer membrane. Bacterial chemoreceptors are one of the best studied such systems, with a wealth of biophysical and mutational data indicating a key role for the TM2 helix in signalling. In particular, aromatic (Trp and Tyr) and basic (Arg) residues help to lock α-helices into a membrane. Mutants in TM2 of E. coli Tar and related chemoreceptors involving these residues implicate changes in helix location and/or orientation in signalling. We have investigated the detailed structural basis of this via high throughput coarse-grained molecular dynamics (CG-MD) of Tar TM2 and its mutants in lipid bilayers. We focus on the position (shift) and orientation (tilt, rotation) of TM2 relative to the bilayer and how these are perturbed in mutants relative to the wildtype. The simulations reveal a clear correlation between small (ca. 1.5 Å) shift in position of TM2 along the bilayer normal and downstream changes in signalling activity. Weaker correlations are seen with helix tilt, and little/none between signalling and helix twist. This analysis of relatively subtle changes was only possible because the high throughput simulation method allowed us to run large (n = 100) ensembles for substantial numbers of different helix sequences, amounting to ca. 2000 simulations in total. Overall, this analysis supports a swinging-piston model of transmembrane signalling by Tar and related chemoreceptors

Impaired phonemic discrimination in logopenic variant primary progressive aphasia

Logopenic variant primary progressive aphasia (lvPPA) is the least well defined of the major primary progressive aphasia (PPA) syndromes. We assessed phoneme discrimination in patients with PPA (semantic, nonfluent/agrammatic, and logopenic variants) and typical Alzheimer’s disease, relative to healthy age‐matched participants. The lvPPA group performed significantly worse than all other groups apart from tAD, after adjusting for auditory verbal working memory. In the combined PPA cohort, voxel‐based morphometry correlated phonemic discrimination score with grey matter in left angular gyrus. Our findings suggest that impaired phonemic discrimination may help differentiate lvPPA from other PPA subtypes, with important diagnostic and management implications

Previously described sequence variant in CDK5RAP2 gene in a Pakistani family with autosomal recessive primary microcephaly

<p>Abstract</p> <p>Background</p> <p>Autosomal Recessive Primary Microcephaly (MCPH) is a disorder of neurogenic mitosis. MCPH leads to reduced cerebral cortical volume and hence, reduced head circumference associated with mental retardation of variable degree. Genetic heterogeneity is well documented in patients with MCPH with six loci known, while pathogenic sequence variants in four respective genes have been identified so far. Mutations in <it>CDK5RAP2 </it>gene at MCPH3 locus have been least involved in causing MCPH phenotype.</p> <p>Methods</p> <p>All coding exons and exon/intron splice junctions of <it>CDK5RAP2 </it>gene were sequenced in affected and normal individuals of Pakistani MCPH family of Kashmiri origin, which showed linkage to MCPH3 locus on chromosome 9q33.2.</p> <p>Results</p> <p>A previously described nonsense mutation [243 T>A (S81X)] in exon 4 of <it>CDK5RAP2 </it>gene has been identified in the Pakistani family, presented here, with MCPH Phenotype. Genomic and cDNA sequence comparison revealed that the exact nomenclature for this mutation is 246 T>A (Y82X).</p> <p>Conclusion</p> <p>Recurrent observation of Y82X mutation in <it>CDK5RAP2 </it>gene in this Pakistani family may be a sign of confinement of a rare ancestral haplotype carrying this pathogenic variant within Northern Pakistani population, as this has not been reported in any other population.</p

ASPM and microcephalin expression in epithelial ovarian cancer correlates with tumour grade and survival

BACKGROUND: The clinico-pathological and molecular heterogeneity of epithelial ovarian cancer (EOC) complicates its early diagnosis and successful treatment. Highly aneuploid tumours and the presence of ascitic fluids are hallmarks of EOC. Two microcephalyassociated proteins, abnormal spindle-like microcephaly-associated protein (ASPM) and microcephalin, are involved in mitosis and DNA damage repair. Their expression is deregulated at the RNA level in EOC. Here, ASPM and microcephalin protein expression in primary cultures established from the ascites of patients with EOC was determined and correlated with clinical data to assess their suitability as biomarkers. METHODS: Five established ovarian cancer cell lines, cells derived from two benign ovarian ascites samples and 40 primary cultures of EOC derived from ovarian ascites samples were analysed by protein slot blotting and/or immunofluorescence to determine ASPM and microcephalin protein levels and their cellular localisation. Results were correlated with clinico-pathological data. RESULTS: A statistically significant correlation was identified for ASPM localisation and tumour grade, with high levels of cytoplasmic ASPM correlating with grade 1 tumours. Conversely, cytoplasmic microcephalin was only identified in high-grade tumours. Furthermore, low levels of nuclear microcephalin correlated with reduced patient survival. CONCLUSION: Our results suggest that ASPM and microcephalin have the potential to be biomarkers in ovarian cance

Angelman Syndrome Protein UBE3A Interacts with Primary Microcephaly Protein ASPM, Localizes to Centrosomes and Regulates Chromosome Segregation

Many proteins associated with the phenotype microcephaly have been localized to the centrosome or linked to it functionally. All the seven autosomal recessive primary microcephaly (MCPH) proteins localize at the centrosome. Microcephalic osteodysplastic primordial dwarfism type II protein PCNT and Seckel syndrome (also characterized by severe microcephaly) protein ATR are also centrosomal proteins. All of the above findings show the importance of centrosomal proteins as the key players in neurogenesis and brain development. However, the exact mechanism as to how the loss-of-function of these proteins leads to microcephaly remains to be elucidated. To gain insight into the function of the most commonly mutated MCPH gene ASPM, we used the yeast two-hybrid technique to screen a human fetal brain cDNA library with an ASPM bait. The analysis identified Angelman syndrome gene product UBE3A as an ASPM interactor. Like ASPM, UBE3A also localizes to the centrosome. The identification of UBE3A as an ASPM interactor is not surprising as more than 80% of Angelman syndrome patients have microcephaly. However, unlike in MCPH, microcephaly is postnatal in Angelman syndrome patients. Our results show that UBE3A is a cell cycle regulated protein and its level peaks in mitosis. The shRNA knockdown of UBE3A in HEK293 cells led to many mitotic abnormalities including chromosome missegregation, abnormal cytokinesis and apoptosis. Thus our study links Angelman syndrome protein UBE3A to ASPM, centrosome and mitosis for the first time. We suggest that a defective chromosome segregation mechanism is responsible for the development of microcephaly in Angelman syndrome

Flammable biomes dominated by eucalypts originated at the Cretaceous-Palaeogene boundary

Fire is a major modifier of communities, but the evolutionary origins of its prevalent role in shaping current biomes are uncertain. Australia is among the most fire-prone continents, with most of the landmass occupied by the fire-dependent sclerophyll and savanna biomes. In contrast to biomes with similar climates in other continents, Australia has a tree flora dominated by a single genus, Eucalyptus, and related Myrtaceae. A unique mechanism in Myrtaceae for enduring and recovering from fire damage likely resulted in this dominance. Here, we find a conserved phylogenetic relationship between post-fire resprouting (epicormic) anatomy and biome evolution, dating from 60 to 62 Ma, in the earliest Palaeogene. Thus, fire-dependent communities likely existed 50 million years earlier than previously thought. We predict that epicormic resprouting could make eucalypt forests and woodlands an excellent long-term carbon bank for reducing atmospheric CO2 compared with biomes with similar fire regimes in other continents

Reconstructing grassland fire history using sedimentary charcoal: Considering count, size and shape

Citation: Leys, B. A., Commerford, J. L., & McLauchlan, K. K. (2017). Reconstructing grassland fire history using sedimentary charcoal: Considering count, size and shape. Plos One, 12(4), 15. doi:10.1371/journal.pone.0176445Fire is a key Earth system process, with 80% of annual fire activity taking place in grassland areas. However, past fire regimes in grassland systems have been difficult to quantify due to challenges in interpreting the charcoal signal in depositional environments. To improve reconstructions of grassland fire regimes, it is essential to assess two key traits: (1) charcoal count, and (2) charcoal shape. In this study, we quantified the number of charcoal pieces in 51 sediment samples of ponds in the Great Plains and tested its relevance as a proxy for the fire regime by examining 13 potential factors influencing charcoal count, including various fire regime components (e.g. the fire frequency, the area burned, and the fire season), vegetation cover and pollen assemblages, and climate variables. We also quantified the width to length (W: L) ratio of charcoal particles, to assess its utility as a proxy of fuel types in grassland environments by direct comparison with vegetation cover and pollen assemblages. Our first conclusion is that charcoal particles produced by grassland fires are smaller than those produced by forest fires. Thus, a mesh size of 120 mu m as used in forested environments is too large for grassland ecosystems. We recommend counting all charcoal particles over 60 mu m in grasslands and mixed grass-forest environments to increase the number of samples with useful data. Second, a W: L ratio of 0.5 or smaller appears to be an indicator for fuel types, when vegetation surrounding the site is before composed of at least 40% grassland vegetation. Third, the area burned within 1060m of the depositional environments explained both the count and the area of charcoal particles. Therefore, changes in charcoal count or charcoal area through time indicate a change in area burned. The fire regimes of grassland systems, including both human and climatic influences on fire behavior, can be characterized by long-term charcoal records