A Risk Score Model for Locoregional Recurrence Following Upfront Surgery for Pancreatic Adenocarcinoma: Implications for Adjuvant Therapy.

AIMS: The aims of the study were to identify predictors of locoregional failure (LRF) following surgery for pancreatic adenocarcinoma, develop a prediction risk score model of LRF and evaluate the impact of postoperative radiation therapy (PORT) on LRF. MATERIALS AND METHODS: A retrospective review was conducted on patients with stages I-III pancreatic adenocarcinoma who underwent surgery at our institution (2005-2016). Univariable and then multivariable analyses were used to evaluate clinicopathological factors associated with LRF for patients who did not receive PORT. The risk score of LRF was calculated based on the sum of coefficients of the predictors of LRF. The model was applied to the entire cohort to evaluate the impact of PORT on the high- and low-risk groups for LRF. RESULTS: In total, 467 patients were identified (median follow-up 22 months). Among patients who did not receive PORT (n = 440), predictors of LRF were pN+, involved or close ≤1 mm margin(s), moderately and poorly differentiated tumour grade and lymphovascular invasion. After adding patients who received PORT, the 2-year LRF in the high-risk group was 57% for patients who did not receive PORT (n = 242) and 32% among patients who received PORT (n = 22), with an absolute benefit to LRF of 25% (95% confidence interval 5-52%, P = 0.07). The 2-year overall survival for the high-versus the low-risk group was 36% versus 67% (P < 0.001). CONCLUSION: This risk group classification could be used to identify pancreatic adenocarcinoma patients with higher risk of LRF who may benefit from PORT. However, validation and prospective evaluation are warranted.

Depression and change in occupational functioning in type 2 diabetes.

BACKGROUND: The effect of depression on both employment and productivity in type 2 diabetes (T2D) is poorly understood. AIMS: We tested whether depressive symptoms at diagnosis of T2D are associated with change in employment status and productivity over 2-year follow-up. METHODS: In a prospective analysis of working-age (18-63 years) people with newly diagnosed T2D recruited from primary care, we tested the association between depressive symptoms at diagnosis of T2D (baseline) and employment rates over 2 years. Using the Patient Health Questionnaire-9, depressive symptoms were measured categorically (depression caseness score ≥10) and continuously. In those employed, we measured changes in presenteeism and absenteeism using the World Health Organization (WHO) Health and Work Performance Questionnaire in univariate and multivariate models, respectively, including and excluding part-time workers. RESULTS: Of 1202 people aged 18-63 at baseline, 982 (82%) provided employment information; the mean age was 50.3 (SD 8.1) years, 44% were female, 59% of non-white ethnicity and 16% had depression. After adjustment for age, sex, ethnicity, socio-economic status, diabetes control and depression treatment, depression caseness was associated with worsening unemployment over 2 years only in full-time workers (odds ratio 0.43 (95% CI 0.20, 0.96), P < 0.05). In those employed full-time or part-time, total depressive symptoms were associated with worsening presenteeism over 2 years after full adjustment (ß = -2.63 (95% CI -4.81, -0.45), P < 0.05), despite no association with worsening absenteeism. CONCLUSIONS: In newly diagnosed T2D, depressive symptoms demonstrate an association with worsening employment rate and decline in work productivity over 2-year follow-up.

Depressive symptoms in inflammatory bowel disease: an extraintestinal manifestation of inflammation?

Depressive symptoms are reported by more than 20% of people with inflammatory bowel disease (IBD), while sleep difficulties and fatigue are even more common. Co-morbid depressive symptoms predict a poor IBD course, including increased risk of relapse and surgery, which is inconsistently improved by psychological treatments. Rather than being distinct systems, there is compelling evidence for bidirectional communication between gut and brain, driven by neural, metabolic, endocrine and inflammatory mediators. An emerging concept is that depressive symptoms may be mechanistically linked to excess inflammation and dysregulation of the gut-brain axis. Given the close link between the intestinal microbiota and host immune responses, patients prone to shifts in their intestinal microbiome, including smokers, those with poor diet and early life stress, may be exposed to exaggerated immune responses. Excess inflammation is associated with brain changes (depressive symptoms, fatigue, sleep difficulties) and worsening gastrointestinal symptoms, which are exacerbated by psychological distress. Equally, treatments both for depressive symptoms and IBD provide opportunities to break this cycle by reducing the causes and effects of inflammation. As well as addressing potential risk factors such as smoking and diet, treatments to alter the microbiome may reduce depressive symptoms. Observational evidence suggests that anti-inflammatory treatments for IBD may improve co-morbid depressive symptoms correlating with reduction in inflammation. With a growing range of treatments targeting inflammation centrally, peripherally and in the gut, IBD provides a unique model to understand the interplay between brain and gut in the pathogenesis of depressive symptoms, both in IBD and in the whole population.

Investigating incretin-based therapies as a novel treatment for depression in type 2 diabetes: Findings from the South London Diabetes (SOUL-D) Study.

We aimed to investigate the association between incretin-based therapies and 1-year change in depressive symptoms in a cohort of 1735 patients with newly diagnosed type 2 diabetes. The incretin group experienced significant reduction in depressive symptoms compared to controls. This was independent of HbA1c and may be mediated by an anti-inflammatory mechanism.

Planned versus unplanned portal vein resections during pancreaticoduodenectomy for adenocarcinoma.

BACKGROUND: The management of portal vein (PV) involvement by pancreatic adenocarcinoma during pancreaticoduodenectomy (PD) is controversial. The aim of this study was to compare the outcomes of unplanned and planned PV resections as part of PD. METHODS: An analysis of PD over 11 years was performed. Patients who had undergone PV resection (PV-PD) were identified, and categorized into those who had undergone planned or unplanned resection. Postoperative and oncological outcomes were compared. RESULTS: Of 249 patients who underwent PD for pancreatic adenocarcinoma, 66 (26·5 per cent) had PV-PD, including 27 (41 per cent) planned and 39 (59 per cent) unplanned PV resections. Twenty-five of 27 planned PV resections were circumferential PV-PD, whereas 25 of 39 unplanned PV resections were partial PV-PD. Planned PV resections were performed in slightly younger patients (mean(s.d.) 60(9) versus 65(10) years; P = 0·031), and associated with longer operating times (mean(s.d.) 602(131) versus 458(83) min; P < 0·001) and more major complications (26 versus 5 per cent; P = 0·026). Planned PV resections were associated with a lower rate of positive margins (4 versus 44 per cent; P < 0·001) despite being carried out for larger tumours (mean(s.d.) 3·9(1·4) versus 2·9(1·0) cm; P = 0·002). There was no difference in survival between the two groups (P = 0·998). On multivariable analysis, margin status was a significant predictor of survival. CONCLUSION: Although planned PV resections for pancreatic adenocarcinoma were associated with higher rates of postoperative morbidity than unplanned resections, R0 resection rates were better.

A percolation-like model for simulating inter-cellular diffusion in the context of bystander signalling in tumour.

Despite ongoing active research, the role of the radiation bystander effect in modifying local tissue response to an ionising radiation dose remains unclear. The present study aims to provide new insight by simulating the diffusion-mediated inter-cellular communication processes in 2D and 3D cell-like structures to calculate likely signal ranges in the diffusion limited case. Random walks of individual signalling molecules were tracked between cells with inclusion of molecule-receptor interactions. The resulting diffusion anomaly is a function of cell density, signal uptake probability and the spatial arrangement of cells local to the signal origin. Uptake probability effects dominate percolation effects in disordered media. Diffusion through 2D structures is more conducive to anomalous diffusion than diffusion through 3D structures. Values for time-dependent diffusion constants and permeability are derived for typical simulation parameters. Even at low signal uptake probabilities the communication range is restricted to a mean value of less than 100 µm owing to complete signal uptake by 600 s. This should be considered in light of the potential influence of signal relaying, flow-dynamics or vasculature-mediated signalling.

Hydrogelation and self-assembly of Fmoc-tripeptides: unexpected influence of sequence on self-assembled fibril structure, and hydrogel modulus and anisotropy.

The self-assembly and hydrogelation properties of two Fmoc-tripeptides [Fmoc = N-(fluorenyl-9-methoxycarbonyl)] are investigated, in borate buffer and other basic solutions. A remarkable difference in self-assembly properties is observed comparing Fmoc-VLK(Boc) with Fmoc-K(Boc)LV, both containing K protected by N(epsilon)-tert-butyloxycarbonate (Boc). In borate buffer, the former peptide forms highly anisotropic fibrils which show local alignment, and the hydrogels show flow-aligning properties. In contrast, Fmoc-K(Boc)LV forms highly branched fibrils that produce isotropic hydrogels with a much higher modulus (G' > 10(4) Pa), and lower concentration for hydrogel formation. The distinct self-assembled structures are ascribed to conformational differences, as revealed by secondary structure probes (CD, FTIR, Raman spectroscopy) and X-ray diffraction. Fmoc-VLK(Boc) forms well-defined beta-sheets with a cross-beta X-ray diffraction pattern, whereas Fmoc-KLV(Boc) forms unoriented assemblies with multiple stacked sheets. Interchange of the K and V residues when inverting the tripeptide sequence thus leads to substantial differences in self-assembled structures, suggesting a promising approach to control hydrogel properties.

Emergency intubation for acutely ill and injured patients.

BACKGROUND: Emergency intubation has been widely advocated as a life saving procedure in severe acute illness and injury associated with real or potential compromises to the patient's airway and ventilation. However, some initial data have suggested a lack of observed benefit. OBJECTIVES: To determine in acutely ill and injured patients who have real or anticipated problems in maintaining an adequate airway whether emergency endotracheal intubation, as opposed to other airway management techniques, improves the outcome in terms of survival, degree of disability at discharge or length of stay and complications occurring in hospital. SEARCH STRATEGY: We searched the Cochrane Injuries Group Specialised Register (December 2006), Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2006, Issue 4), MEDLINE (1950 to November 2006), EMBASE (1980 to week 50, December 2006), National Research Register (Issue 4, 2006), CINAHL (1980 to December 2006), BIDS (to December 2006) and ICNARC (to December 2006). We also examined reference lists of articles for relevant material and contacted experts in the field. Non-English language publications were searched for and examined. SELECTION CRITERIA: All randomised (RCTs) or controlled clinical trials involving the emergency use of endotracheal intubation in the injured or acutely ill patient were examined. DATA COLLECTION AND ANALYSIS: The full texts of 452 studies were reviewed independently by two authors using a standard form. Where the review authors felt a study may be relevant for inclusion in the final review or disagreed, the authors examined the study and a collective decision was made regarding its inclusion or exclusion from the review. The results were not combined in a meta-analysis due to the heterogeneity of patients, practitioners and alternatives to intubation that were used. MAIN RESULTS: We identified three eligible RCTs carried out in urban environments. Two trials involved adults with non-traumatic out-of-hospital cardiac arrest. One of these trials found a non-significant survival disadvantage in patients randomised to receive a physician-operated intubation versus a combi-tube (RR 0.44, 95% CI 0.09 to 1.99). The second trial detected a non-significant survival disadvantage in patients randomised to paramedic intubation versus an oesophageal gastric airway (RR 0.86, 95% CI 0.39 to 1.90). The third included study was a trial of children requiring airway intervention in the prehospital environment. The results indicated no difference in survival (OR 0.82, 95% CI 0.61 to 1.11) or neurologic outcome (OR 0.87, 95% CI 0.62 to 1.22) between paramedic intubation versus bag-valve-mask ventilation and later hospital intubation by emergency physicians; however, only 42% of the children randomised to paramedic endotracheal intubation actually received it. AUTHORS' CONCLUSIONS: The efficacy of emergency intubation as currently practised has not been rigorously studied. The skill level of the operator may be key in determining efficacy. In non-traumatic cardiac arrest, it is unlikely that intubation carries the same life saving benefit as early defibrillation and bystander cardiopulmonary resuscitation (CPR). In trauma and paediatric patients, the current evidence base provides no imperative to extend the practice of prehospital intubation in urban systems. It would be ethical and pertinent to initiate a large, high quality randomised trial comparing the efficacy of competently practised emergency intubation with basic bag-valve-mask manoeuvres (BVM) in urban adult out-of-hospital non-traumatic cardiac arrest.

Assessing procedural skills in context: Exploring the feasibility of an Integrated Procedural Performance Instrument (IPPI).

BACKGROUND: The assessment of clinical procedural skills has traditionally focused on technical elements alone. However, in real practice, clinicians are expected to be able to integrate technical with communication and other professional skills. We describe an integrated procedural performance instrument (IPPI), where clinicians are assessed on 12 clinical procedures in a simulated clinical setting which combines simulated patients (SPs) with inanimate models or items of medical equipment. Candidates are observed remotely by assessors whose data are fed back to the clinician within 24 hours of the assessment. This paper describes the feasibility of IPPI. RESULTS: A full-scale IPPI and 2 pilot studies with trainee and qualified health care professionals has yielded an extensive data set including 585 scenario evaluations from candidates, 60 from clinical assessors and 31 from simulated patients (SPs). Interview and questionnaire data showed that for the majority of candidates IPPI provided a powerful and valuable learning experience. Realism was rated highly. Remote and real-time assessment worked effectively, although for some procedures limited camera resolution affected observation of fine details. DISCUSSION: IPPI offers an innovative approach to assessing clinical procedural skills. Although resource-intensive, it has the potential to provide insight into individual's performance over a spectrum of clinical scenarios and at no risk to the safety of patients. Additional benefits of IPPI include assessment in real time from experts (allowing remote rating by external examiners) as well as provision of feedback from simulated patients.

Transcript initiation, polyadenylation, and functional promoter mapping for the dihydrofolate reductase-thymidylate synthase gene of Toxoplasma gondii.

The fused dihydrofolate reductase/thymidylate synthase gene of Toxoplasma gondii contains ten exons spanning approximately 8 kb of genomic DNA. We have examined the ends of DHFR-TS transcripts within this gene, and find a complex pattern including two discrete 5' termini and multiple polyadenylation sites. No TATAA box or other classical promoter motif is evident in 1.4 kb of genomic DNA upstream of the coding region, but transcript mapping by RNase protection and primer extension reveals two prominent 5' ends at positions -369 and -341 nt relative to the ATG initiation codon. Upstream genomic sequences include GC-rich regions and the (opposite strand) WGAGACG motif previously identified in other T. gondii promoters. Mutagenesis of recombinant reporter plasmids demonstrates that this region is essential for efficient transgene expression. Sequencing the 3' ends from multiple independent mRNA clones demonstrates numerous polyadenylation sites, distributed over >650 nt of genomic sequence beginning approximately 250 nt downstream of the stop codon. Within this region, certain sites seem to be preferred: 14 different positions were found among the 32 polyadenylated transcripts examined, but approximately 40% of the transcripts map to two loci. The 3' noncoding region is rich in A and T nucleotides, and contains an imperfect 50 nt direct repeat, but no obvious poly(A) addition signal was identified.

The PEP respiratory monitor: a validation study.

The search for a reliable and accurate respiratory rate monitor for use in non-intubated patients has proved to be a long and fruitless one. A new device fulfilling the criteria for such a monitor has recently been described. The pyroelectric polymer (PEP) device is safe, non-invasive, and cheap. In this study the PEP device, transthoracic impedance, and standard observer counting were all compared with the existing gold standard of capnography in 12 healthy adult volunteers. Using a standard statistical technique it was shown that the PEP device performed as well as a capnograph and was more accurate than the other currently available methods of monitoring respiratory rate.

Does patient position during liver surgery influence the risk of venous air embolism?

BACKGROUND: It is generally believed that positioning of the patient in a head-down tilt (Trendelenberg position) decreases the likelihood of a venous air embolism during liver resection. METHODS: The physiological effect of variation in horizontal attitude on central and hepatic venous pressure was measured in 10 patients during liver surgery. Hemodynamic indices were recorded with the operating table in the horizontal, 20 degrees head-up and 20 degrees head-down positions. RESULTS: There was no demonstrable pressure gradient between the hepatic and central venous levels in any of the positions. The absolute pressures did, however, vary in a predictable way, being highest in the head-down and lowest during head-up tilt. However, on no occasion was a negative intraluminal pressure recorded. CONCLUSION: The effect on venous pressures caused by the change in patient positioning alone during liver surgery does not affect the risk of venous air embolism.

Placement of electrodes for defibrillation--a review of the evidence.

Defibrillation is the only reliable treatment for ventricular fibrillation. Its success depends on the passage of an adequate current through the chest rather than on the administration of a preset energy. The final determinant of both efficacy and cellular damage is myocardial current density. Therefore, the current should be evenly distributed with an average value that exceeds the defibrillation threshold throughout a critical mass of myocardium but does not cause further local dysfunction. The distribution of current is altered by the relative positions of the two electrodes. European guidelines for electrode (paddle) placement during defibrillation are based on empirical studies and traditional practice. However, there is increasing evidence to suggest that bi-axillary electrode placement may be superior to traditional antero-apical and antero-posterior positions.

The PEP transducer: a new way of measuring respiratory rate in the non-intubated patient.

OBJECTIVES: To explore the use of a pyroelectric polymer (PEP) film as a transducer for a simple respiratory rate monitor and to evaluate the transducer in a laboratory situation. METHODS: Laboratory evaluation of a new pyroelectric transducer for measurement of respiratory rate. RESULTS: The amplified output from the pyroelectric film produced an excellent respiratory trace when used on a normal spontaneously breathing subject. The transducer is cheap, robust, and reliable. CONCLUSIONS: PEP films have the potential to be used as cheap and effective transducers in respiratory rate monitors for non-intubated patients. In the laboratory, they have many desirable characteristics which should now be evaluated in a clinical setting.

Emergency intubation of infants: does laryngoscope blade design make any difference?

OBJECTIVE: To compare intubation times and ease of use for a range of infant laryngoscope blades in the hands of accident and emergency (A&E) personnel. METHODS: Seven different blades were compared in terms of intubation times and ease of use scores in the hands of 30 A&E senior house officers (SHOs) and nurses using a standard infant manikin. RESULTS: There was a significant difference in intubation times between the seven blades (p < 0.001). Intubation with two blade designs (Seward and Soper) took almost twice as long as for the other blades (p < 0.05). Subjective ease of use scoring also identified the Seward and Soper blades as being the most difficult to use (p < 0.05). There were no significant differences between SHO and nurse intubation times or ease of use scoring. Successful intubation was achieved within 30 seconds in 90% of attempts. All but two of the subjects used an incorrect levering technique for intubation despite all having previously received training in infant intubation. CONCLUSIONS: No current standard exists regarding the utilisation of infant laryngoscope blades in the A&E department. The first line blade available should be a C shaped blade (Miller, Oxford, Robert-shaw, or Wisconsin). Other blade designs should be kept for use only by more experienced personnel or in difficult intubation situations. Intubation training must focus on correct technique and regular assessment is essential.

Use of an electric ear syringe in the emergency department.

OBJECTIVES: To introduce an electric ear syringe into an emergency department and evaluate its use in the removal of foreign bodies from the external auditory canal. METHODS: Report of the use of a new device (the Propulse electric ear syringe) in an emergency department with a retrospective audit of the management of all cases of aural foreign bodies during one year. RESULTS: Almost 60% of the 84 patients who presented with foreign bodies in the auditory canal were children. Staff chose to treat over half of all patients with aural foreign bodies with the electric ear syringe. The overall success rates for the removal of the foreign bodies were: electric syringe, 93% in adults and 88% in children and instrumentation, 68% in adults and 50% in children. CONCLUSIONS: Irrigation with an electric ear syringe is an effective method of removing foreign bodies from the external auditory canal. The device tested was safe, inexpensive, easy to use, and readily acceptable to both adults and children. The availability of an electric ear syringe in an emergency department can avoid the need for specialist referral and the subsequent removal of foreign bodies under general anaesthesia.