Abstract Introduction Data on enhanced recovery programmes after pancreatoduodenectomy (ERP-PD) is limited. The aim of this pilot study was to evaluate the feasibility, safety and clinical outcomes ...of ERP-PD when implemented at a high-volume UK university referral centre. Methods This was an observational single-surgeon case-control study (before-and-after pathway). A total of 20 consecutive patients were prospectively enrolled for the ERP-PD and compared with 24 consecutive patients previously treated during an equal time frame. Results Patients in the ERP-PD group had a significant shorter time to remove naso-gastric tube (median of 5 vs. 7 days, p = 0.0001), start liquid diet (median of 2 vs. 5 days, p < 0.0001), start solid food (median of 4 vs. 9 days, p < 0.0001), pass stools (median of 6 vs. 7 days, p = 0.002), and had shorter length of stay (median of 8.5 days vs. 13 days, p = 0.015) compared to the pre-pathway group. Postoperative complications were overall less frequent but not significantly different in the ERP-PD group ( p = 0.077). No difference in mortality and readmission rates was found. Conclusions Our findings support the feasibility and safety of ERP-PD. Improved patients' outcomes, significant bed day savings and increase National Health Service productivity are anticipated with implementation of ERP-PD on a larger scale.
There is a high coincidence between obesity and psychiatric disorders including depression. Depressive disorders are commonly treated with antidepressants, including the selective serotonin reuptake ...inhibitor Lexapro (escitalopram). Although candidates for elective Roux-en-Y gastric bypass (RYGB) surgery may be treated with escitalopram, drug dosing strategies are typically not adjusted postoperatively. Therefore, studies are needed to better characterize escitalopram drug concentrations in a postsurgical setting.
Turbulent flow-liquid chromatographic-tandem mass spectrometric methods were used to quantify escitalopram concentrations in serum in study participants approved for RYGB. Blood was collected from study subjects 2 weeks before surgery, and 2 and 6 weeks postoperatively, to assess the impact of RYGB on systemic drug concentrations.
Twelve samples from 4 study participants were collected and analyzed for serum escitalopram concentrations. Two weeks post-RYGB, although there were minimal changes in each participant's body mass index (<5%), drug concentrations were 33% (4%-71%) decreased as compared with presurgical serum concentrations. There were further decreases in drug concentrations 6 weeks postsurgery. All clinical laboratory values were within normal reference intervals.
RYGB significantly alters the gastrointestinal tract and impacts escitalopram drug concentrations, even shortly after surgery.
Theta burst pattern repetitive transcranial magnetic stimulation (TBS) is increasingly applied to treat depression. TBS's brevity is well-suited to application in accelerated schedules. Sizeable ...trials of accelerated TBS are lacking; and optimal TBS parameters such as stimulation intensity are not established.
We conducted a three arm, single blind, randomised, controlled, multi-site trial comparing accelerated bilateral TBS applied at 80 % or 120 % of the resting motor threshold and left unilateral 10 Hz rTMS. 300 patients with treatment-resistant depression (TRD) were recruited. TBS arms applied 20 bilateral prefrontal TBS sessions over 10 days, while the rTMS arm applied 20 daily sessions of 10 Hz rTMS to the left prefrontal cortex over 4 weeks. Primary outcome was depression treatment response at week 4.
The overall treatment response rate was 43.7 % and the remission rate was 28.2 %. There were no significant differences for response (p = 0.180) or remission (p = 0.316) across the three groups. Response rates between accelerated bilateral TBS applied at sub- and supra-threshold intensities were not significantly different (p = 0.319). Linear mixed model analysis showed a significant effect of time (p < 0.01), but not rTMS type (p = 0.680).
This is the largest accelerated bilateral TBS study to date and provides evidence that it is effective and safe in treating TRD. The accelerated application of TBS was not associated with more rapid antidepressant effects. Bilateral sequential TBS did not have superior antidepressant effect to unilateral 10 Hz rTMS. There was no significant difference in antidepressant efficacy between sub- and supra-threshold accelerated bilateral TBS.
•Accelerated bilateral theta burst stimulation (TBS) is effective and safe in depression.•Accelerated bilateral TBS at 80 % RMT and 120 % RMT were equally effective.•Accelerated TBS scheduling did not result in a faster antidepressant effect.
Background: The predominant species in clinical
Enterobacter isolates is
E. hormaechei. Many articles, clinicians, and GenBank submissions misname these strains as
E. cloacae. The lack of sequenced ...type strains or named species/subspecies for some clades in the
E. cloacae complex complicate the issue.
Methods: The genomes of the type strains for
Enterobacter hormaechei subsp.
oharae,
E.
hormaechei subsp.
steigerwaltii, and
E. xiangfangensis, and two strains from Hoffmann clusters III and IV of the
E. cloacae complex were sequenced. These genomes, the
E.
hormaechei subsp.
hormaechei type strain, and other available
Enterobacter type strains were analysed in conjunction with all extant
Enterobacter genomes in NCBI's RefSeq using Average Nucleotide Identity (ANI).
Results: There were five recognizable subspecies of
E. hormaechei:
E. hormaechei subsp.
hoffmannii subsp. nov.,
E. hormaechei subsp.
xiangfangensis comb. nov., and the three previously known subspecies. One of the strains sequenced from the
E. cloacae complex was not a novel
E. hormaechei subspecies but rather a member of a clade of a novel species:
E. roggenkampii sp. nov..
E. muelleri was determined to be a later heterotypic synonym of
E. asburiae which should take precedence.
Conclusion: The phylogeny of the
Enterobacter genus, particularly the
cloacae complex, was re-evaluated based on the type strain genome sequences and all other available
Enterobacter genomes in RefSeq.
Progress towards the total synthesis of the macrolide natural product anthracimycin is described. This new approach utilises an intermolecular Diels-Alder strategy followed by epimeirsation to form ...the key
-decalin framework. The route culminates in the stereoselective synthesis of an advanced tricyclic lactone intermediate, containing five contiguous sterogenic centres with the correct relative and absolute stereochemistry required for the anthracimycin core motif.
BACKGROUND AND PURPOSE—Despite moderate heritability, the phenotypic heterogeneity of ischemic stroke has hampered gene discovery, motivating analyses of diagnostic subtypes with reduced sample ...sizes. We assessed evidence for a shared genetic basis among the 3 major subtypeslarge artery atherosclerosis (LAA), cardioembolism, and small vessel disease (SVD), to inform potential cross-subtype analyses.
METHODS—Analyses used genome-wide summary data for 12 389 ischemic stroke cases (including 2167 LAA, 2405 cardioembolism, and 1854 SVD) and 62 004 controls from the Metastroke consortium. For 4561 cases and 7094 controls, individual-level genotype data were also available. Genetic correlations between subtypes were estimated using linear mixed models and polygenic profile scores. Meta-analysis of a combined LAA–SVD phenotype (4021 cases and 51 976 controls) was performed to identify shared risk alleles.
RESULTS—High genetic correlation was identified between LAA and SVD using linear mixed models (rg=0.96, SE=0.47, P=9×10) and profile scores (rg=0.72; 95% confidence interval, 0.52–0.93). Between LAA and cardioembolism and SVD and cardioembolism, correlation was moderate using linear mixed models but not significantly different from zero for profile scoring. Joint meta-analysis of LAA and SVD identified strong association (P=1×10) for single nucleotide polymorphisms near the opioid receptor μ1 (OPRM1) gene.
CONCLUSIONS—Our results suggest that LAA and SVD, which have been hitherto treated as genetically distinct, may share a substantial genetic component. Combined analyses of LAA and SVD may increase power to identify small-effect alleles influencing shared pathophysiological processes.
Colloid-matrix assemblies in regenerative medicine Clarke, Kimberly C.; Douglas, Alison M.; Brown, Ashley C. ...
Current opinion in colloid & interface science,
10/2013, Volume:
18, Issue:
5
Journal Article
Peer reviewed
The development of tissue engineering scaffolds has focused on mimicking the natural biochemical and biophysical environment of the extracellular matrix (ECM). In this review, we describe a variety ...of strategies aimed at reproducing and also simplifying the ECM. Despite the progress that has been made, the degree of complexity that needs to be incorporated into these scaffolds is still not known. We begin by describing the ECM and its biological functions followed by outlining current efforts to engineer ECMs with both natural and synthetic polymers. We then focus on colloidal particles as potential artificial ECM components that could increase the complexity as modular building blocks. Drawing from examples from the literature we present the broad utility of colloids and describe how these applications could be useful in the development of ECM mimetic systems.
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•The structural, compositional and functional features of the extracellular matrix are presented.•Recent efforts at recapitulating some or all of these features are discussed.•Colloids offer routes to introduce new properties and functions into materials.•We discuss the wide range of opportunities for colloids as functional modifiers of extracellular matrix components.
Paracetamol overdose is common but patient stratification is suboptimal. We investigated the usefulness of new biomarkers that have either enhanced liver specificity (microRNA-122 miR-122) or provide ...mechanistic insights (keratin-18 K18, high mobility group box-1 HMGB1, and glutamate dehydrogenase GLDH). The use of these biomarkers could help stratify patients for their risk of liver injury at hospital presentation.
Using data from two prospective cohort studies, we assessed the potential for biomarkers to stratify patients who overdose with paracetamol. We completed two independent prospective studies: a derivation study (MAPP) in eight UK hospitals and a validation study (BIOPAR) in ten UK hospitals. Patients in both cohorts were adults (≥18 years in England, ≥16 years in Scotland), were diagnosed with paracetamol overdose, and gave written informed consent. Patients who needed intravenous acetylcysteine treatment for paracetamol overdose had circulating biomarkers measured at hospital presentation. The primary endpoint was acute liver injury indicating need for continued acetylcysteine treatment beyond the standard course (alanine aminotransferase ALT activity >100 U/L). Receiver operating characteristic (ROC) curves, category-free net reclassification index (cfNRI), and integrated discrimination index (IDI) were applied to assess endpoint prediction.
Between June 2, 2010, and May 29, 2014, 1187 patients who required acetylcysteine treatment for paracetamol overdose were recruited (985 in the MAPP cohort; 202 in the BIOPAR cohort). In the derivation and validation cohorts, acute liver injury was predicted at hospital presentation by miR-122 (derivation cohort ROC–area under the curve AUC 0·97 95% CI 0·95–0·98), HMGB1 (0·95 0·93–0·98), and full-length K18 (0·95 0·92–0·97). Results were similar in the validation cohort (miR-122 AUC 0·97 95% CI 0·95–0·99, HMGB1 0·98 0·96–0·99, and full-length K18 0·93 0·86–0·99). A combined model of miR-122, HMGB1, and K18 predicted acute liver injury better than ALT alone (cfNRI 1·95 95% CI 1·87–2·03, p<0·0001 in the MAPP cohort; 1·54 1·08–2·00, p<0·0001 in the BIOPAR cohort).
Personalised treatment pathways could be developed by use of miR-122, HMGB1, and full-length K18 at hospital presentation for patient stratification. This prospective study supports their use for hepatic safety assessment of new medicines.
Edinburgh and Lothians Health Foundation, UK Medical Research Council.
Due to rising resistance, new antibacterial strategies are needed, including methods for targeted antibiotic release. As targeting vectors, chelating molecules called siderophores that are released ...by bacteria to acquire iron have been investigated for conjugation to antibacterials, leading to the clinically approved drug cefiderocol. The use of small‐molecule catalysts for prodrug activation within cells has shown promise in recent years, and here we investigate siderophore‐linked ruthenium catalysts for the activation of antibacterial prodrugs within cells. Moxifloxacin‐based prodrugs were synthesised, and their catalyst‐mediated activation was demonstrated under anaerobic, biologically relevant conditions. In the absence of catalyst, decreased antibacterial activities were observed compared to moxifloxacin versus Escherichia coli K12 (BW25113). A series of siderophore‐linked ruthenium catalysts were investigated for prodrug activation, all of which displayed a combinative antibacterial effect with the prodrug, whereas a representative example displayed little toxicity against mammalian cell lines. By employing complementary bacterial growth assays, conjugates containing siderophore units based on catechol and azotochelin were found to be most promising for intracellular prodrug activation.
Ganging up on bacteria: Siderophore‐linked ruthenium catalysts were investigated for the activation of an antibacterial prodrug within cells. A fluoroquinolone prodrug was developed and shown to be compatible with the catalysts under micro‐aerobic, biologically relevant conditions. The co‐addition of the catalysts and prodrug to E. coli showed a combinative effect, with the dihydroxybenzoic acid‐ and azotochelin‐linked catalysts showing most promise for cellular uptake and thus intracellular prodrug activation.
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