Five-year outcome after laparoscopic anterior partial versus Nissen fundoplication: four randomized trials

Author version made available in accordance with the publisher's policy.Objective: To compare longer term (5-year) outcomes for reflux control and post-surgery side effects following laparoscopic anterior (90˚ and 180˚) partial vs. Nissen fundoplication for gastroesophageal reflux. Summary Background Data: Laparoscopic Nissen fundoplication is the most frequently performed surgical procedure for gastroesophageal reflux. It achieves excellent control of reflux, but in some patients is followed by troublesome side effects. To reduce the risk of side effects laparoscopic anterior partial fundoplication variants have been advocated, although some studies suggest poorer reflux control. Methods: From 1995 to 2003, 461 patients with gastroesophageal reflux were enrolled in 4 randomized controlled trials comparing anterior partial vs. Nissen fundoplication. Two trials evaluated anterior 180˚, and 2 anterior 90˚ partial fundoplication. The original trial data were combined and a re-analysis from original data was undertaken to determine outcomes at 5-years follow-up. Reflux symptom control and side effects were evaluated in a blinded fashion using standardized questionnaires, including 0-10 analog scores (0=no symptoms, 10=severe symptoms). Results: At 5 years, patients who underwent an anterior 90˚ or 180˚ partial fundoplication had less side effects compared with Nissen fundoplication and were equally satisfied with the overall outcome. Reflux control, measured by heartburn scores and antisecretory medication use, was similar for anterior 180˚ partial vs. Nissen fundoplication, but inferior after anterior 90˚ partial vs. Nissen fundoplication. Conclusions: Anterior 180˚ partial fundoplication achieves durable control of reflux symptoms and less side effects compared with Nissen fundoplication. Although reflux control following anterior 90˚ partial fundoplication appears less effective than after Nissen fundoplication. This data supports the use of anterior 180˚ partial fundoplication for the surgical treatment of gastroesophageal reflux

Randomized controlled trial of laparoscopic anterior 180° partial versus posterior 270° partial fundoplication.

Article first published online: 28 NOV 2013. This item is under embargo for a period of 12 months from the date of publication, in accordance with the publisher's policy.BACKGROUND: Previous trials show good outcomes following anterior and posterior partial versus Nissen fundoplication for gastro-oesophageal reflux. However, it is unclear which partial fundoplication performs best. This study compared anterior 180° versus posterior 270° fundoplication. METHODS: At three hospitals, patients were randomized to anterior 180° versus posterior 270° partial fundoplication, and clinical outcomes were determined using a structured questionnaire at 3, 6 and 12 months. Heartburn, dysphagia and satisfaction were assessed using 0-10 analoue scales, and adverse outcomes and side effects were determined. Endoscopy, manometry and pH monitoring were performed 6 months after surgery. RESULTS: Forty-seven patients were randomized to anterior (n = 23) versus posterior (n = 24) fundoplication. Clinical outcomes for 93-98% of patients were available at each follow-up point. At 12 months, the mean heartburn score was higher following anterior fundoplication (2.7 versus 0.8, P = 0.045), although differences were not significant at earlier follow-up. Conversely, following posterior fundoplication, patients were less able to belch at 3 (56% versus 16%, P = 0.013) and 6 months (43% versus 9%, P = 0.017). No significant differences were demonstrated for dysphagia. Both groups had high rates of satisfaction with the outcome - 85% versus 86% satisfied at 12 months follow-up. CONCLUSION: Both partial fundoplications are effective treatments for gastro-oesophageal reflux. Posterior partial fundoplication is associated with less reflux symptoms offset by more side effects.Australian National Health & Medical Research Council

Limitations of student-driven formative assessment in a clinical clerkship. A randomised controlled trial

Background Teachers strive to motivate their students to be self-directed learners. One of the methods used is to provide online formative assessment material. The concept of formative assessment and use of these processes is heavily promoted, despite limited evidence as to their efficacy.Methods Fourth year medical students, in their first year of clinical work were divided into four groups. In addition to the usual clinical material, three of the groups were provided with some form of supplementary learning material. For two groups, this was provided as online formative assessment. The amount of time students spent on the supplementary material was measured, their opinion on learning methods was surveyed, and their performance in summative exams at the end of their surgical attachments was measured.Results The performance of students was independent of any educational intervention imposed by this study. Despite its ready availability and promotion, student use of the online formative tools was poor.Conclusion Formative learning is an ideal not necessarily embraced by students. If formative assessment is to work students need to be encouraged to participate, probably by implementing some form of summative assessment.Edward J Palmer and Peter G Devit

Laparoscopic repair of very large hiatus hernia with sutures versus absorbable mesh versus nonabsorbable mesh a randomized controlled trial

Author version made available in accordance with pubilsher policy. 12 month embargo applies from the date of publication (1 Feb 2015).Objective: Determine whether absorbable or non-absorbable mesh in repair of large hiatus hernias reduces the risk of recurrence, compared to suture repair. Summary Background Data: Repair of large hiatus hernia is associated with radiological recurrence rates of up to 30%, and to improve outcomes mesh repair has been recommended. Previous trials have shown less short term recurrence with mesh, but adverse outcomes limit mesh use. Methods: Multicentre prospective double blind randomized controlled trial of 3 methods of repair; sutures vs. absorbable mesh vs. non-absorbable mesh. Primary outcome - hernia recurrence assessed by barium meal X-ray and endoscopy at 6 months. Secondary outcomes - clinical symptom scores at 1, 3, 6 and 12 months. Results: 126 patients enrolled - 43 sutures, 41 absorbable mesh and 42 non-absorbable mesh. 96.0% were followed to 12 months, with objective follow-up data in 92.9%. A recurrent hernia (any size) was identified in 23.1% following suture repair, 30.8% - absorbable mesh, and 12.8% - non-absorbable mesh (p=0.161). Clinical outcomes were similar, except less heartburn at 3 & 6 months and less bloating at 12 months with non-absorbable mesh, and more heartburn at 3 months, odynophagia at 1 month, nausea at 3 & 12 months, wheezing at 6 months, and inability to belch at 12 months following absorbable mesh. The magnitude of the clinical differences were small. Conclusions: No significant differences were seen for recurrent hiatus hernia, and the clinical differences were unlikely to be clinically significant. Overall outcomes following sutured repair were similar to mesh repair

Simulating chemistry efficiently on fault-tolerant quantum computers

Quantum computers can in principle simulate quantum physics exponentially faster than their classical counterparts, but some technical hurdles remain. Here we consider methods to make proposed chemical simulation algorithms computationally fast on fault-tolerant quantum computers in the circuit model. Fault tolerance constrains the choice of available gates, so that arbitrary gates required for a simulation algorithm must be constructed from sequences of fundamental operations. We examine techniques for constructing arbitrary gates which perform substantially faster than circuits based on the conventional Solovay-Kitaev algorithm [C.M. Dawson and M.A. Nielsen, \emph{Quantum Inf. Comput.}, \textbf{6}:81, 2006]. For a given approximation error $\epsilon$, arbitrary single-qubit gates can be produced fault-tolerantly and using a limited set of gates in time which is $O(\log \epsilon)$ or $O(\log \log \epsilon)$; with sufficient parallel preparation of ancillas, constant average depth is possible using a method we call programmable ancilla rotations. Moreover, we construct and analyze efficient implementations of first- and second-quantized simulation algorithms using the fault-tolerant arbitrary gates and other techniques, such as implementing various subroutines in constant time. A specific example we analyze is the ground-state energy calculation for Lithium hydride.Comment: 33 pages, 18 figure

Similarity of aberrant DNA methylation in Barrett's esophagus and esophageal adenocarcinoma

Background Barrett's esophagus (BE) is the metaplastic replacement of squamous with columnar epithelium in the esophagus, as a result of reflux. It is the major risk factor for the development of esophageal adenocarcinoma (EAC). Methylation of CpG dinucleotides of normally unmethylated genes is associated with silencing of their expression, and is common in EAC. This study was designed to determine at what stage, in the progression from BE to EAC, methylation of key genes occurs. Results We examined nine genes (APC, CDKN2A, ID4, MGMT, RBP1, RUNX3, SFRP1, TIMP3, and TMEFF2), frequently methylated in multiple cancer types, in a panel of squamous (19 biopsies from patients without BE or EAC, 16 from patients with BE, 21 from patients with EAC), BE (40 metaplastic, seven high grade dysplastic) and 37 EAC tissues. The methylation frequency, the percentage of samples that had any extent of methylation, for each of the nine genes in the EAC (95%, 59%, 76%, 57%, 70%, 73%, 95%, 74% and 83% respectively) was significantly higher than in any of the squamous groups. The methylation frequency for each of the nine genes in the metaplastic BE (95%, 28%, 78%, 48%, 58%, 48%, 93%, 88% and 75% respectively) was significantly higher than in the squamous samples except for CDKN2A and RBP1. The methylation frequency did not differ between BE and EAC samples, except for CDKN2A and RUNX3 which were significantly higher in EAC. The methylation extent was an estimate of both the number of methylated alleles and the density of methylation on these alleles. This was significantly greater in EAC than in metaplastic BE for all genes except APC, MGMT and TIMP3. There was no significant difference in methylation extent for any gene between high grade dysplastic BE and EAC. Conclusion We found significant methylation in metaplastic BE, which for seven of the nine genes studied did not differ in frequency from that found in EAC. This is also the first report of gene silencing by methylation of ID4 in BE or EAC. This study suggests that metaplastic BE is a highly abnormal tissue, more similar to cancer tissue than to normal epithelium.Eric Smith, Neville J De Young, Sandra J Pavey, Nicholas K Hayward, Derek J Nancarrow, David C Whiteman, B Mark Smithers, Andrew R Ruszkiewicz, Andrew D Clouston, David C Gotley, Peter G Devitt, Glyn G Jamieson and Paul A Dre

Quality of Life Following Repair of Large Hiatal Hernia is Improved but not Influenced by Use of Mesh: Results From a Randomized Controlled Trial

Author version made available following 12 month embargo from date of publication (5 Feb 2015) in accordance with Publisher copyright policy.Introduction Laparoscopic surgery is the treatment of choice for repair of large hiatus hernia, but can be followed by recurrence. Repair with prosthetic mesh has been recommended to prevent recurrence, although complications following mesh repair have generated disagreement about whether or not mesh should be used. The early objective and clinical results of a randomized trial of repair with mesh vs. sutures have been reported, and revealed few differences. In the current study we evaluated quality of life outcomes within this trial at follow-up to 2 years. Methods In a multicenter prospective double-blind randomized trial three methods for repair of large hiatus hernia were compared: sutures vs. repair with absorbable mesh (Surgisis) vs. nonabsorbable (Timesh). Quality of life assessment using the Short-Form 36 (SF-36) questionnaire was undertaken at 3, 6, 12 and 24 months after surgery. SF-36 outcomes (8 individual scales and 2 composite scales) were determined for each group, and compared between groups, and across different follow-up points. Results 126 patients were enrolled - 43 sutures, 41 absorbable mesh and 42 non-absorbable mesh. 115 (91.3%) completed a preoperative questionnaire, and 113 (89.7%) completed the postoperative questionnaire at 3 months, 116 (92.1%) at 6 months, 114 (90.5%) at 12 months, and 91 (72.2%) at 24 months. The SF-36 Physical and Mental Component scores (PCS & MCS) improved significantly following surgery, and this improvement was sustained across 24 months follow-up (p<0.001 for PCS and MCS at each follow-up point). There were no significant differences between the groups for the component scores or the eight SF-36 subscale scores at each follow-up time. 29 individuals had a recurrence at 6 months follow-up, of which 9 were symptomatic. The PCS were higher in patients with recurrence vs. without (p<0.01), and in patients with a symptomatic recurrence vs. asymptomatic recurrence vs. no recurrence (p=0.001). Conclusion SF-36 measured quality of life improved significantly after repair of large hiatal hernia at up to 2 years follow-up, and there were no differences in outcome for the different repair techniques. The use of mesh vs. no mesh in repair of large hiatal hernia did not influence quality of life

Assessment of higher order cognitive skills in undergraduate education: modified essay or multiple choice questions? Research paper

Background: Reliable and valid written tests of higher cognitive function are difficult to produce, particularly for the assessment of clinical problem solving. Modified Essay Questions (MEQs) are often used to assess these higher order abilities in preference to other forms of assessment, including multiple-choice questions (MCQs). MEQs often form a vital component of end-of-course assessments in higher education. It is not clear how effectively these questions assess higher order cognitive skills. This study was designed to assess the effectiveness of the MEQ to measure higher-order cognitive skills in an undergraduate institution. Methods: An analysis of multiple-choice questions and modified essay questions (MEQs) used for summative assessment in a clinical undergraduate curriculum was undertaken. A total of 50 MCQs and 139 stages of MEQs were examined, which came from three exams run over two years. The effectiveness of the questions was determined by two assessors and was defined by the questions ability to measure higher cognitive skills, as determined by a modification of Bloom's taxonomy, and its quality as determined by the presence of item writing flaws. Results: Over 50% of all of the MEQs tested factual recall. This was similar to the percentage of MCQs testing factual recall. The modified essay question failed in its role of consistently assessing higher cognitive skills whereas the MCQ frequently tested more than mere recall of knowledge. Conclusion: Construction of MEQs, which will assess higher order cognitive skills cannot be assumed to be a simple task. Well-constructed MCQs should be considered a satisfactory replacement for MEQs if the MEQs cannot be designed to adequately test higher order skills. Such MCQs are capable of withstanding the intellectual and statistical scrutiny imposed by a high stakes exit examination.Edward J Palmer, Peter G Devit

Silencing Dkk1 expression rescues dexamethasone-induced suppression of primary human osteoblast differentiation

<p>Abstract</p> <p>Background</p> <p>The Wnt/β-catenin pathway is a major signaling cascade in bone biology, playing a key role in bone development and remodeling. The objectives of this study were firstly, to determine the effects of dexamethasone exposure on Wnt/β-catenin signaling at an intracellular and transcriptional level, and secondly, to assess the phenotypic effects of silencing the Wnt antagonist, Dickkopf-1 (Dkk1) in the setting of dexamethasone exposure.</p> <p>Methods</p> <p>Primary human osteoblasts were exposed in vitro to 10^-8M dexamethasone over a 72 h time course. The phenotypic marker of osteoblast differentiation was analyzed was alkaline phosphatase activity. Intracellular β-catenin trafficking was assessed using immunoflourescence staining and TCF/LEF mediated transcription was analyzed using a Wnt luciferase reporter assay. Dkk1 expression was silenced using small interfering RNA (siRNA).</p> <p>Results</p> <p>Primary human osteoblasts exposed to dexamethasone displayed a significant reductions in alkaline phosphatase activity over a 72 h time course. Immunoflourescence analaysis of β-catenin localization demonstrated a significant reduction in intracytosolic and intranuclear β-catenin in response to dexamethasone exposure. These changes were associated with a reduction of TCF/LEF mediated transcription. Silencing Dkk1 expression in primary human osteoblasts exposed to dexamethasone resulted in an increase in alkaline phosphatase activity when compared to scrambled control.</p> <p>Conclusions</p> <p>Wnt/β-catenin signaling plays a key role in regulating glucocorticoid-induced osteoporosis <it>in vitro</it>. Silencing Dkk1 expression rescues dexamethasone-induced suppression of primary human osteoblast differentiation. Targeting of the Wnt/β-catenin signaling pathway offers an exciting opportunity to develop novel anabolic bone agents to treat osteoporosis and disorders of bone mass.</p

Ontogeny of Toll-Like and NOD-Like Receptor-Mediated Innate Immune Responses in Papua New Guinean Infants

Studies addressing the ontogeny of the innate immune system in early life have reported mainly on Toll-like receptor (TLR) responses in infants living in high-income countries, with little or even no information on other pattern recognition receptors or on early life innate immune responses in children living under very different environmental conditions in less-developed parts of the world. In this study, we describe whole blood innate immune responses to both Toll-like and nucleotide-binding oligomerization domain (NOD)-like receptor agonists including the widely used vaccine adjuvant ‘alum’ in a group of Papua New Guinean infants aged 1–3 (n = 18), 4–6 (n = 18), 7–12 (n = 21) and 13–18 (n = 10) months old. Depending on the ligands and cytokines studied, different age-related patterns were found: alum-induced IL-1β and CXCL8 responses were found to significantly decline with increasing age; inflammatory (IL-6, IL-1β, IFN-γ) responses to TLR2 and TLR3 agonists increased; and IL-10 responses remained constant or increased during infancy, while TNF-α responses either declined or remained the same. We report for the first time that whole blood innate immune responses to the vaccine adjuvant alum decrease with age in infancy; a finding that may imply that the adjuvant effect of alum in pediatric vaccines could be age-related. Our findings further suggest that patterns of innate immune development may vary between geographically diverse populations, which in line with the ‘hygiene hypothesis’ particularly involves persistence of innate IL-10 responses in populations experiencing higher infectious pressure