Non-randomised patients in a cholecystectomy trial: characteristics, procedures, and outcomes

BACKGROUND: Laparoscopic cholecystectomy is now considered the first option for gallbladder surgery. However, 20% to 30% of cholecystectomies are completed as open operations often on elderly and fragile patients. The external validity of randomised trials comparing mini-laparotomy cholecystectomy and laparoscopic cholecystectomy has not been studied. The aim of this study is to analyse characteristics, procedures, and outcomes for all patients who underwent cholecystectomy without being included in such a trial. METHODS: Characteristics (age, sex, co-morbidity, and ASA-score), operation time, hospital stay, and mortality were compared for patients who underwent cholecystectomy outside and within a randomised controlled trial comparing mini-laparotomy and laparoscopic cholecystectomy. RESULTS: During the inclusion period 1719 patients underwent cholecystectomy. 726 patients were randomised and 724 of them completed the trial; 993 patients underwent cholecystectomy outside the trial. The non-randomised patients were older – and had more complications from gallstone disease, higher co-morbidity, and higher ASA – score when compared with trial patients. They were also more likely to undergo acute surgery and they had a longer postoperative hospital stay, with a median 3 versus 2 days (p < 0.001 for all comparisons). Standardised mortality ratio within 90 days of operation was 3.42 (mean) (95% CI 2.17 to 5.13) for non-randomised patients and 1.61 (mean) (95%CI 0.02 to 3.46) for trial patients. For non-randomised patients, operation time did not differ significantly between mini-laparotomy and open cholecystectomy in multivariate analysis. However, the operation for laparoscopic cholecystectomy lasted 20 minutes longer than open cholecystectomy. Hospital stay was significantly shorter for both mini-laparotomy and laparoscopic cholecystectomy compared to open cholecystectomy. CONCLUSION: Non-randomised patients were older and more sick than trial patients. The assignment of healthier patients to trials comparing mini-laparotomy cholecystectomy and laparoscopic cholecystectomy limits the external validity of conclusions reached in such trials

On reliable discovery of molecular signatures

<p>Abstract</p> <p>Background</p> <p>Molecular signatures are sets of genes, proteins, genetic variants or other variables that can be used as markers for a particular phenotype. Reliable signature discovery methods could yield valuable insight into cell biology and mechanisms of human disease. However, it is currently not clear how to control error rates such as the false discovery rate (FDR) in signature discovery. Moreover, signatures for cancer gene expression have been shown to be unstable, that is, difficult to replicate in independent studies, casting doubts on their reliability.</p> <p>Results</p> <p>We demonstrate that with modern prediction methods, signatures that yield accurate predictions may still have a high FDR. Further, we show that even signatures with low FDR may fail to replicate in independent studies due to limited statistical power. Thus, neither stability nor predictive accuracy are relevant when FDR control is the primary goal. We therefore develop a general statistical hypothesis testing framework that for the first time provides FDR control for signature discovery. Our method is demonstrated to be correct in simulation studies. When applied to five cancer data sets, the method was able to discover molecular signatures with 5% FDR in three cases, while two data sets yielded no significant findings.</p> <p>Conclusion</p> <p>Our approach enables reliable discovery of molecular signatures from genome-wide data with current sample sizes. The statistical framework developed herein is potentially applicable to a wide range of prediction problems in bioinformatics.</p

Dissociable effects of 5-HT2C receptor antagonism and genetic inactivation on perseverance and learned non-reward in an egocentric spatial reversal task

Cognitive flexibility can be assessed in reversal learning tests, which are sensitive to modulation of 5-HT2C receptor (5-HT2CR) function. Successful performance in these tests depends on at least two dissociable cognitive mechanisms which may separately dissipate associations of previous positive and negative valence. The first is opposed by perseverance and the second by learned non-reward. The current experiments explored the effect of reducing function of the 5-HT2CR on the cognitive mechanisms underlying egocentric reversal learning in the mouse. Experiment 1 used the 5-HT2CR antagonist SB242084 (0.5 mg/kg) in a between-groups serial design and Experiment 2 used 5-HT2CR KO mice in a repeated measures design. Animals initially learned to discriminate between two egocentric turning directions, only one of which was food rewarded (denoted CS+, CS−), in a T- or Y-maze configuration. This was followed by three conditions; (1) Full reversal, where contingencies reversed; (2) Perseverance, where the previous CS+ became CS− and the previous CS− was replaced by a novel CS+; (3) Learned non-reward, where the previous CS− became CS+ and the previous CS+ was replaced by a novel CS-. SB242084 reduced perseverance, observed as a decrease in trials and incorrect responses to criterion, but increased learned non-reward, observed as an increase in trials to criterion. In contrast, 5-HT2CR KO mice showed increased perseverance. 5-HT2CR KO mice also showed retarded egocentric discrimination learning. Neither manipulation of 5-HT2CR function affected performance in the full reversal test. These results are unlikely to be accounted for by increased novelty attraction, as SB242084 failed to affect performance in an unrewarded novelty task. In conclusion, acute 5-HT2CR antagonism and constitutive loss of the 5-HT2CR have opposing effects on perseverance in egocentric reversal learning in mice. It is likely that this difference reflects the broader impact of 5HT2CR loss on the development and maintenance of cognitive function

Energy expenditure during egg laying is equal for early and late breeding free-living female great tits

In many bird populations, variation in the timing of reproduction exists but it is not obvious how this variation is maintained as timing has substantial fitness consequences. Daily energy expenditure (DEE) during the egg laying period increases with decreasing temperatures and thus perhaps only females that can produce eggs at low energetic cost will lay early in the season, at low temperatures. We tested whether late laying females have a higher daily energy expenditure during egg laying than early laying females in 43 great tits (Parus major), by comparing on the same day the DEE of early females late in their laying sequence with DEE of late females early in their egg laying sequence. We also validated the assumption that there are no within female differences in DEE within the egg laying sequence. We found a negative effect of temperature and a positive effect of female body mass on DEE but no evidence for differences in DEE between early and late laying females. However, costs incurred during egg laying may have carry-over effects later in the breeding cycle and if such carry-over effects differ for early and late laying females this could contribute to the maintenance of phenotypic variation in laying dates

Effects of a training program after surgically treated ankle fracture: a prospective randomised controlled trial

<p>Abstract</p> <p>Background</p> <p>Despite conflicting results after surgically treated ankle fractures few studies have evaluated the effects of different types of training programs performed after plaster removal. The aim of this study was to evaluate the effects of a 12-week standardised but individually suited training program (training group) versus usual care (control group) after plaster removal in adults with surgically treated ankle fractures.</p> <p>Methods</p> <p>In total, 110 men and women, 18-64 years of age, with surgically treated ankle fracture were included and randomised to either a 12-week training program or to a control group. Six and twelve months after the injury the subjects were examined by the same physiotherapist who was blinded to the treatment group. The main outcome measure was the Olerud-Molander Ankle Score (OMAS) which rates symptoms and subjectively scored function. Secondary outcome measures were: quality of life (SF-36), timed walking tests, ankle mobility tests, muscle strength tests and radiological status.</p> <p>Results</p> <p>52 patients were randomised to the training group and 58 to the control group. Five patients dropped out before the six-month follow-up resulting in 50 patients in the training group and 55 in the control group. Nine patients dropped out between the six- and twelve-month follow-up resulting in 48 patients in both groups. When analysing the results in a mixed model analysis on repeated measures including interaction between age-group and treatment effect the training group demonstrated significantly improved results compared to the control group in subjects younger than 40 years of age regarding OMAS (p = 0.028), muscle strength in the plantar flexors (p = 0.029) and dorsiflexors (p = 0.030).</p> <p>Conclusion</p> <p>The results of this study suggest that when adjusting for interaction between age-group and treatment effect the training model employed in this study was superior to usual care in patients under the age of 40. However, as only three out of nine outcome measures showed a difference, the beneficial effect from an additional standardised individually suited training program can be expected to be limited. There is need for further studies to elucidate how a training program should be designed to increase and optimise function in patients middle-aged or older.</p> <p>Trial Registration</p> <p>Current Controlled Trials ACTRN12609000327280</p

The gray matter volume of the amygdala is correlated with the perception of melodic intervals: a voxel-based morphometry study

Music is not simply a series of organized pitches, rhythms, and timbres, it is capable of evoking emotions. In the present study, voxel-based morphometry (VBM) was employed to explore the neural basis that may link music to emotion. To do this, we identified the neuroanatomical correlates of the ability to extract pitch interval size in a music segment (i.e., interval perception) in a large population of healthy young adults (N = 264). Behaviorally, we found that interval perception was correlated with daily emotional experiences, indicating the intrinsic link between music and emotion. Neurally, and as expected, we found that interval perception was positively correlated with the gray matter volume (GMV) of the bilateral temporal cortex. More important, a larger GMV of the bilateral amygdala was associated with better interval perception, suggesting that the amygdala, which is the neural substrate of emotional processing, is also involved in music processing. In sum, our study provides one of first neuroanatomical evidence on the association between the amygdala and music, which contributes to our understanding of exactly how music evokes emotional responses

Mesenchymal Stromal Cells Engage Complement and Complement Receptor Bearing Innate Effector Cells to Modulate Immune Responses

Infusion of human third-party mesenchymal stromal cells (MSCs) appears to be a promising therapy for acute graft-versus-host disease (aGvHD). To date, little is known about how MSCs interact with the body's innate immune system after clinical infusion. This study shows, that exposure of MSCs to blood type ABO-matched human blood activates the complement system, which triggers complement-mediated lymphoid and myeloid effector cell activation in blood. We found deposition of complement component C3-derived fragments iC3b and C3dg on MSCs and fluid-phase generation of the chemotactic anaphylatoxins C3a and C5a. MSCs bound low amounts of immunoglobulins and lacked expression of complement regulatory proteins MCP (CD46) and DAF (CD55), but were protected from complement lysis via expression of protectin (CD59). Cell-surface-opsonization and anaphylatoxin-formation triggered complement receptor 3 (CD11b/CD18)-mediated effector cell activation in blood. The complement-activating properties of individual MSCs were furthermore correlated with their potency to inhibit PBMC-proliferation in vitro, and both effector cell activation and the immunosuppressive effect could be blocked either by using complement inhibitor Compstatin or by depletion of CD14/CD11b-high myeloid effector cells from mixed lymphocyte reactions. Our study demonstrates for the first time a major role of the complement system in governing the immunomodulatory activity of MSCs and elucidates how complement activation mediates the interaction with other immune cells

Outcome and quality of life after surgically treated ankle fractures in patients 65 years or older

<p>Abstract</p> <p>Background</p> <p>Despite high incidence of ankle fractures in the elderly, studies evaluating outcome and impact of quality of life in this age group specifically are sparse. The aim of this study was to evaluate outcome and quality of life 6 and 12 months after injury in patients 65 years or older who had been operated on due to an ankle fracture.</p> <p>Methods</p> <p>Sixty patients 65 years or older were invited to participate in the study. 6 and 12 months after the injury a questionnaire including inquiry to participate, the Olerud-Molander Ankle Score (OMAS), Short-Form 36 (SF-36), Linear Analogue Scale (LAS), Self-rated Ankle Function and some supplementary questions was sent home to the patients. The supplementary questions concerned subjective experience of ankle instability, sporting and physical activity level before injury and recaptured activity level at follow-ups, need of walking aid before injury, state of living before injury and at follow-ups and co-morbidities. After the 12-month follow-up the patients were also called for a radiological examination.</p> <p>Results</p> <p>Fifty patients (83%) answered the questionnaire at 6-month and 46 (77%) at the 12-month follow-up. Although, 45 (90%) fractures were low-energy trauma 44 (88%) were bi- or trimalleolar and post-operative reduction results were complete in 23 (46%) ankles. The median OMAS improved from 60 (Interquartile range (IQR) 36) at 6-month to 70 (IQR 35) at 12-month (p = 0.002), but at 12-month still sixty percent or more of the patients reported pain, swelling, problems when stair-climbing and reduced activities of daily life. Twenty (40%) rated their ankle function as 'good' or 'very good' at 6-month and 30 (60%) at 12-month. Forty-one (82%) were physically active before injury but still one year after only 18/41 had returned to their pre-injury physical activity level. According to SF-36 four dimensions differed from the age- and gender matched normative data of the Swedish population, 'physical function', 'role physical' and 'role emotional' were below norms at 6-month for women (p = 0.010, p = 0.024 and 0.031) and 'general health' was above norms at 12-month for men (p = 0.044).</p> <p>Conclusion</p> <p>One year after surgically treated ankle fractures a majority of patients continue to have symptoms and reported functional limitations. However, SF-36 scores indicate that only females had functional status below the age- and gender matched normative data of the Swedish population.</p

The HDAC Inhibitor FK228 Enhances Adenoviral Transgene Expression by a Transduction-Independent Mechanism but Does Not Increase Adenovirus Replication

The histone deacetylase inhibitor FK228 has previously been shown to enhance adenoviral transgene expression when cells are pre-incubated with the drug. Upregulation of the coxsackie adenovirus receptor (CAR), leading to increased viral transduction, has been proposed as the main mechanism. In the present study, we found that the highest increase in transgene expression was achieved when non-toxic concentrations of FK228 were added immediately after transduction, demonstrating that the main effect by which FK228 enhances transgene expression is transduction-independent. FK228 had positive effects both on Ad5 and Ad5/f35 vectors with a variety of transgenes and promoters, indicating that FK228 works mainly by increasing transgene expression at the transcriptional level. In some cases, the effects were dramatic, as demonstrated by an increase in CD40L expression by FK228 from 0.3% to 62% when the murine prostate cancer cell line TRAMP-C2 was transduced with Ad[CD40L]. One unexpected finding was that FK228 decreased the transgene expression of an adenoviral vector with the prostate cell-specific PPT promoter in the human prostate adenocarcinoma cell lines LNCaP and PC-346C. This is probably a consequence of alteration of the adenocarcinoma cell lines towards a neuroendocrine differentiation after FK228 treatment. The observations in this study indicate that FK228 enhances adenoviral therapy by a transduction-independent mechanism. Furthermore, since histone deacetylase inhibitors may affect the differentiation of cells, it is important to keep in mind that the activity and specificity of tissue- and tumor-specific promoters may also be affected