The endoscopically placed duodenal-jejunal bypass sleeve or EndoBarrier Gastrointestinal Liner has been designed to achieve weight loss in morbidly obese patients. We report on the first European ...experience with this device.
A multicenter, randomized clinical trial was performed. Forty-one patients were included and 30 underwent sleeve implantation. Eleven patients served as a diet control group. All patients followed the same low-calorie diet during the study period. The purpose of the study was to determine the safety and efficacy of the device.
Twenty-six devices were successfully implanted. In 4 patients, implantation could not be achieved. Four devices were explanted prior to the initial protocol end point because of migration (1), dislocation of the anchor (1), sleeve obstruction (1), and continuous epigastric pain (1). The remaining patients all completed the study. Mean procedure time was 35 minutes (range: 12-102 minutes) for a successful implantation and 17 minutes (range: 5-99 minutes) for explantation. There were no procedure related adverse events. During the study period the 26 duodenal-jejunal bypass sleeve patients (100%) had at least one adverse event, mainly abdominal pain and nausea during the first week after implantation. Initial mean body mass index (BMI, kg/m2) was 48.9 and 47.4 kg/m2 for the device and control patients, respectively. Mean excess weight loss after 3 months was 19.0% for device patients versus 6.9% for control patients (P < 0.002). Absolute change in BMI at 3 months was 5.5 and 1.9 kg/m2, respectively. Type 2 diabetes mellitus was present at baseline in 8 patients of the device group and improved in 7 patients during the study period (lower glucose levels, HbA1c, and medication requirements).
The EndoBarrier Gastrointestinal Liner is a feasible and safe noninvasive device with excellent short-term weight loss results. The device also has a significant positive effect on type 2 diabetes mellitus. Long-term randomized and sham studies for weight loss and treatment of diabetes are necessary to determine the role of the device in the treatment of morbid obesity.This study was registered at www.clinicaltrials.gov (registration number: NCT00830440).
Transcription activator-like effector nucleases (TALENs) and RNA-guided nucleases derived from clustered, regularly interspaced, short palindromic repeats (CRISPR)-Cas9 systems have become ubiquitous ...genome editing tools. Despite this, the impact that distinct high-order chromatin conformations have on these sequence-specific designer nucleases is, presently, ill-defined. The same applies to the relative performance of TALENs and CRISPR/Cas9 nucleases at isogenic target sequences subjected to different epigenetic modifications. Here, to address these gaps in our knowledge, we have implemented quantitative cellular systems based on genetic reporters in which the euchromatic and heterochromatic statuses of designer nuclease target sites are stringently controlled by small-molecule drug availability. By using these systems, we demonstrate that TALENs and CRISPR/Cas9 nucleases are both significantly affected by the high-order epigenetic context of their target sequences. In addition, this outcome could also be ascertained for S. pyogenes CRISPR/Cas9 complexes harbouring Cas9 variants whose DNA cleaving specificities are superior to that of the wild-type Cas9 protein. Thus, the herein investigated cellular models will serve as valuable functional readouts for screening and assessing the role of chromatin on designer nucleases based on different platforms or with different architectures or compositions.
Introduction
Best–worst scaling (BWS) is becoming increasingly popular to elicit preferences in health care. However, little is known about current practice and trends in the use of BWS in health ...care. This study aimed to identify, review and critically appraise BWS in health care, and to identify trends over time in key aspects of BWS.
Methods
A systematic review was conducted, using Medline (via Pubmed) and EMBASE to identify all English-language BWS studies published up until April 2016. Using a predefined extraction form, two reviewers independently selected articles and critically appraised the study quality, using the Purpose, Respondents, Explanation, Findings, Significance (PREFS) checklist. Trends over time periods (≤2010, 2011, 2012, 2013, 2014 and 2015) were assessed further.
Results
A total of 62 BWS studies were identified, of which 26 were BWS object case studies, 29 were BWS profile case studies and seven were BWS multi-profile case studies. About two thirds of the studies were performed in the last 2 years. Decreasing sample sizes and decreasing numbers of factors in BWS object case studies, as well as use of less complicated analytical methods, were observed in recent studies. The quality of the BWS studies was generally acceptable according to the PREFS checklist, except that most studies did not indicate whether the responders were similar to the non-responders.
Conclusion
Use of BWS object case and BWS profile case has drastically increased in health care, especially in the last 2 years. In contrast with previous discrete-choice experiment reviews, there is increasing use of less sophisticated analytical methods.
Unreliable predictions can occur when an artificial intelligence (AI) system is presented with data it has not been exposed to during training. We demonstrate the use of conformal prediction to ...detect unreliable predictions, using histopathological diagnosis and grading of prostate biopsies as example. We digitized 7788 prostate biopsies from 1192 men in the STHLM3 diagnostic study, used for training, and 3059 biopsies from 676 men used for testing. With conformal prediction, 1 in 794 (0.1%) predictions is incorrect for cancer diagnosis (compared to 14 errors 2% without conformal prediction) while 175 (22%) of the predictions are flagged as unreliable when the AI-system is presented with new data from the same lab and scanner that it was trained on. Conformal prediction could with small samples (N = 49 for external scanner, N = 10 for external lab and scanner, and N = 12 for external lab, scanner and pathology assessment) detect systematic differences in external data leading to worse predictive performance. The AI-system with conformal prediction commits 3 (2%) errors for cancer detection in cases of atypical prostate tissue compared to 44 (25%) without conformal prediction, while the system flags 143 (80%) unreliable predictions. We conclude that conformal prediction can increase patient safety of AI-systems.
DNA-based control of protein activity Engelen, W; Janssen, B M G; Merkx, M
Chemical communications (Cambridge, England),
01/2016, Volume:
52, Issue:
18
Journal Article
Peer reviewed
Open access
DNA has emerged as a highly versatile construction material for nanometer-sized structures and sophisticated molecular machines and circuits. The successful application of nucleic acid based systems ...greatly relies on their ability to autonomously sense and act on their environment. In this feature article, the development of DNA-based strategies to dynamically control protein activity via oligonucleotide triggers is discussed. Depending on the desired application, protein activity can be controlled by directly conjugating them to an oligonucleotide handle, or expressing them as a fusion protein with DNA binding motifs. To control proteins without modifying them chemically or genetically, multivalent ligands and aptamers that reversibly inhibit their function provide valuable tools to regulate proteins in a noncovalent manner. The goal of this feature article is to give an overview of strategies developed to control protein activity via oligonucleotide-based triggers, as well as hurdles yet to be taken to obtain fully autonomous systems that interrogate, process and act on their environments by means of DNA-based protein control.
The emergence of glassy dynamics and the glass transition in dense disordered systems is still not fully understood theoretically. Mode-coupling theory (MCT) has shown to be effective in describing ...some of the non-trivial features of glass formation, but it cannot explain the full glassy phenomenology due to the strong approximations on which it is based. Generalized mode-coupling theory (GMCT) is a hierarchical extension of the theory, which is able to outclass MCT by carefully describing the dynamics of higher-order correlations in its generalized framework. Unfortunately, the theory has so far only been developed for single-component systems and as a result works poorly for highly polydisperse materials. In this paper, we solve this problem by developing GMCT for multi-component systems. We use it to predict the glassy dynamics of the binary Kob–Andersen Lennard-Jones mixture, as well as its purely repulsive Weeks–Chandler–Andersen analogue. Our results show that each additional level of the GMCT hierarchy gradually improves the predictive power of GMCT beyond its previous limit. This implies that our theory is able to harvest more information from the static correlations, thus being able to better understand the role of attraction in supercooled liquids from a first-principles perspective.
Graphic abstract
Summary
Postbariatric loss of muscle tissue could negatively affect long‐term health due to its role in various bodily processes, such as metabolism and functional capacity. This meta‐analysis aimed ...to unravel time‐dependent changes in the magnitude and progress of lean body mass (LBM), fat‐free mass (FFM), and skeletal muscle mass (SMM) loss following bariatric surgery. A systematic literature search was conducted in Pubmed, Embase, and Web of Science. Fifty‐nine studies assessed LBM (n = 37), FFM (n = 20), or SMM (n = 3) preoperatively and ≥1 time points postsurgery. Random‐effects meta‐analyses were performed to determine pooled loss per outcome parameter and follow‐up time point. At 12‐month postsurgery, pooled LBM loss was −8.13 kg 95%CI −9.01; −7.26. FFM loss and SMM loss were −8.23 kg 95%CI −10.74; −5.73 and −3.18 kg 95%CI −5.64; −0.71, respectively. About 55% of 12‐month LBM loss occurred within 3‐month postsurgery, followed by a more gradual decrease up to 12 months. Similar patterns were seen for FFM and SMM. In conclusion, >8 kg of LBM and FFM loss was observed within 1‐year postsurgery. LBM, FFM, and SMM were predominantly lost within 3‐month postsurgery, highlighting that interventions to mitigate such losses should be implemented perioperatively.
This report investigated the impact of graft-versus-host disease (GVHD) on transplantation outcomes in 1859 acute myeloid leukemia patients given allogeneic peripheral blood stem cells after ...reduced-intensity conditioning (RIC allo-SCT). Grade I acute GVHD was associated with a lower risk of relapse (hazards ratio (HR)=0.7, P=0.02) translating into a trend for better overall survival (OS; HR=1.3; P=0.07). Grade II acute GVHD had no net impact on OS, while grade III-IV acute GVHD was associated with a worse OS (HR=0.4, P<0.0.001) owing to high risk of nonrelapse mortality (NRM; HR=5.2, P<0.0001). In time-dependent multivariate Cox analyses, limited chronic GVHD tended to be associated with a lower risk of relapse (HR=0.72; P=0.07) translating into a better OS (HR=1.8; P<0.001), while extensive chronic GVHD was associated with a lower risk of relapse (HR=0.65; P=0.02) but also with higher NRM (HR=3.5; P<0.001) and thus had no net impact on OS. In-vivo T-cell depletion with antithymocyte globulin (ATG) or alemtuzumab was successful at preventing extensive chronic GVHD (P<0.001), but without improving OS for ATG and even with worsening OS for alemtuzumab (HR=0.65; P=0.001). These results highlight the role of the immune-mediated graft-versus-leukemia effect in the RIC allo-SCT setting, but also the need for improving the prevention and treatment of severe GVHD.
The metabolic syndrome is a cluster of overlapping conditions resulting in an increased incidence of type 2 diabetes, cardiovascular disease, and cancer. In the last few decades, prevalence of the ...metabolic syndrome in the Western world has reached epidemic proportions and this is likely due to alterations in diet and the environment as well as decreased physical activity. This review discusses how the Western diet and lifestyle (Westernization) has played an important etiological role in the pathogenesis of the metabolic syndrome and its consequences by exerting negative effects on activity of the insulin-insulin-like growth factor-I (insulin-IGF-I) system. It is further proposed that interventions that normalize/reduce activity of the insulin-IGF-I system may play a key role in the prevention and treatment of the metabolic syndrome. For successful prevention, limitation, and treatment of the metabolic syndrome, the focus should be primarily on changing our diets and lifestyle in accordance with our genetic make-up, formed in adaptation to Paleolithic diets and lifestyles during a period of several million years of human evolution. Translating this insight into clinical practice, however, requires not only individual changes in our food and lifestyle, starting in pediatric populations at a very young age, but also requires fundamental changes in our current health systems and food industry. Change is needed: primary prevention of the metabolic syndrome should be made a political priority. New strategies and policies should be developed to stimulate and implement behaviors encouraging the sustainable use of healthy diets and lifestyles to prevent the metabolic syndrome before it develops.
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