Unbiased Reconstruction of a Mammalian Transcriptional Network Mediating Pathogen Responses

Models of mammalian regulatory networks controlling gene expression have been inferred from genomic data but have largely not been validated. We present an unbiased strategy to systematically perturb candidate regulators and monitor cellular transcriptional responses. We applied this approach to derive regulatory networks that control the transcriptional response of mouse primary dendritic cells to pathogens. Our approach revealed the regulatory functions of 125 transcription factors, chromatin modifiers, and RNA binding proteins, which enabled the construction of a network model consisting of 24 core regulators and 76 fine-tuners that help to explain how pathogen-sensing pathways achieve specificity. This study establishes a broadly applicable, comprehensive, and unbiased approach to reveal the wiring and functions of a regulatory network controlling a major transcriptional response in primary mammalian cells

Five insights from the Global Burden of Disease Study 2019

The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019 provides a rules-based synthesis of the available evidence on levels and trends in health outcomes, a diverse set of risk factors, and health system responses. GBD 2019 covered 204 countries and territories, as well as first administrative level disaggregations for 22 countries, from 1990 to 2019. Because GBD is highly standardised and comprehensive, spanning both fatal and non-fatal outcomes, and uses a mutually exclusive and collectively exhaustive list of hierarchical disease and injury causes, the study provides a powerful basis for detailed and broad insights on global health trends and emerging challenges. GBD 2019 incorporates data from 281 586 sources and provides more than 3.5 billion estimates of health outcome and health system measures of interest for global, national, and subnational policy dialogue. All GBD estimates are publicly available and adhere to the Guidelines on Accurate and Transparent Health Estimate Reporting. From this vast amount of information, five key insights that are important for health, social, and economic development strategies have been distilled. These insights are subject to the many limitations outlined in each of the component GBD capstone papers.Peer reviewe

Protective intraoperative ventilation with higher versus lower levels of positive end-expiratory pressure in obese patients (PROBESE): study protocol for a randomized controlled trial

Background: Postoperative pulmonary complications (PPCs) increase the morbidity and mortality of surgery in obese patients. High levels of positive end-expiratory pressure (PEEP) with lung recruitment maneuvers may improve intraoperative respiratory function, but they can also compromise hemodynamics, and the effects on PPCs are uncertain. We hypothesized that intraoperative mechanical ventilation using high PEEP with periodic recruitment maneuvers, as compared with low PEEP without recruitment maneuvers, prevents PPCs in obese patients. Methods/design The PRotective Ventilation with Higher versus Lower PEEP during General Anesthesia for Surgery in OBESE Patients (PROBESE) study is a multicenter, two-arm, international randomized controlled trial. In total, 2013 obese patients with body mass index ≥35 kg/m2 scheduled for at least 2 h of surgery under general anesthesia and at intermediate to high risk for PPCs will be included. Patients are ventilated intraoperatively with a low tidal volume of 7 ml/kg (predicted body weight) and randomly assigned to PEEP of 12 cmH2O with lung recruitment maneuvers (high PEEP) or PEEP of 4 cmH2O without recruitment maneuvers (low PEEP). The occurrence of PPCs will be recorded as collapsed composite of single adverse pulmonary events and represents the primary endpoint. Discussion To our knowledge, the PROBESE trial is the first multicenter, international randomized controlled trial to compare the effects of two different levels of intraoperative PEEP during protective low tidal volume ventilation on PPCs in obese patients. The results of the PROBESE trial will support anesthesiologists in their decision to choose a certain PEEP level during general anesthesia for surgery in obese patients in an attempt to prevent PPCs. Trial registration ClinicalTrials.gov identifier: NCT02148692. Registered on 23 May 2014; last updated 7 June 2016. Electronic supplementary material The online version of this article (doi:10.1186/s13063-017-1929-0) contains supplementary material, which is available to authorized users

Assessment of Intra-Abdominal Pressure with a Novel Continuous Bladder Pressure Monitor—A Clinical Validation Study

Introduction: Intra-abdominal hypertension and the resulting abdominal compartment syndrome are serious complications of severely ill patients. Diagnosis requires an intra-abdominal pressure (IAP) measurement, which is currently cumbersome and underused. We aimed to test the accuracy of a novel continuous IAP monitor. Methods: Adults having laparoscopic surgery and requiring urinary catheter intra-operatively were recruited to this single-arm validation study. IAP measurements using the novel monitor and a gold-standard foley manometer were compared. After anesthesia induction, a pneumoperitoneum was induced through a laparoscopic insufflator, and five randomly pre-defined pressures (between 5 and 25 mmHg) were achieved and simultaneously measured via both methods in each participant. Measurements were compared using Bland–Altman analysis. Results: In total, 29 participants completed the study and provided 144 distinct pairs of pressure measurements that were analyzed. A positive correlation between the two methods was found (R2 = 0.93). There was good agreement between the methods, with a mean bias (95% CI) of −0.4 (−0.6, −0.1) mmHg and a standard deviation of 1.3 mmHg, which was statistically significant but of no clinical importance. The limits of agreement (where 95% of the differences are expected to fall) were −2.9 and 2.2 mmHg. The proportional error was statistically insignificant (p = 0.85), suggesting a constant agreement between the methods across the range of values tested. The percentage error was 10.7%. Conclusions: Continuous IAP measurements using the novel monitor performed well in the clinical setup of controlled intra-abdominal hypertension across the evaluated range of pressures. Further studies should expand the range to more pathological values

Revisional Surgery of One Anastomosis Gastric Bypass for Severe Protein–Energy Malnutrition

Background: One anastomosis gastric bypass (OAGB) is safe and effective. Its strong malabsorptive component might cause severe protein–energy malnutrition (PEM), necessitating revisional surgery. We aimed to evaluate the safety and outcomes of OAGB revision for severe PEM. Methods: This was a single-center retrospective analysis of OAGB patients undergoing revision for severe PEM (2015–2021). Perioperative data and outcomes were retrieved. Results: Ten patients underwent revision for severe PEM. Our center’s incidence is 0.63% (9/1425 OAGB). All patients were symptomatic. Median (interquartile range) EWL and lowest albumin were 103.7% (range 57.6, 114) and 24 g/dL (range 19, 27), respectively, and 8/10 patients had significant micronutrient deficiencies. Before revision, nutritional optimization was undertaken. Median OAGB to revision interval was 18.4 months (range 15.7, 27.8). Median BPL length was 200 cm (range 177, 227). Reversal (n = 5), BPL shortening (n = 3), and conversion to Roux-en-Y gastric bypass (RYGB) (n = 2) were performed. One patient had anastomotic leak after BPL shortening. No death occurred. Median BMI and albumin increased from 22.4 kg/m2 (range 20.6, 30.3) and 35.5 g/dL (range 29.2, 41), respectively, at revision to 27.5 (range 22.2, 32.4) kg/m2 and 39.5 g/dL (range 37.2, 41.7), respectively, at follow-up (median 25.4 months, range 3.1, 45). Complete resolution occurs after conversion to RYGB or reversal to normal anatomy, but not after BPL shortening. Conclusions: Revisional surgery of OAGB for severe PEM is feasible and safe after nutritional optimization. Our results suggest that the type of revision may be an important factor for PEM resolution. Comparative studies are needed to define the role of each revisional option

Unbiased Reconstruction of a Mammalian Transcriptional Network Mediating Pathogen Responses

Models of mammalian regulatory networks controlling gene expression have been inferred from genomic data but have largely not been validated. We present an unbiased strategy to systematically perturb candidate regulators and monitor cellular transcriptional responses. We applied this approach to derive regulatory networks that control the transcriptional response of mouse primary dendritic cells to pathogens. Our approach revealed the regulatory functions of 125 transcription factors, chromatin modifiers, and RNA binding proteins, which enabled the construction of a network model consisting of 24 core regulators and 76 fine-tuners that help to explain how pathogen-sensing pathways achieve specificity. This study establishes a broadly applicable, comprehensive, and unbiased approach to reveal the wiring and functions of a regulatory network controlling a major transcriptional response in primary mammalian cells.Burroughs Wellcome Fund (Career Award at the Scientific Interface)National Institutes of Health (U.S.) (Pioneer Award)Alfred P. Sloan Foundatio

Unbiased Reconstruction of a Mammalian Transcriptional Network Mediating Pathogen Responses

Models of mammalian regulatory networks controlling gene expression have been inferred from genomic data but have largely not been validated. We present an unbiased strategy to systematically perturb candidate regulators and monitor cellular transcriptional responses. We applied this approach to derive regulatory networks that control the transcriptional response of mouse primary dendritic cells to pathogens. Our approach revealed the regulatory functions of 125 transcription factors, chromatin modifiers, and RNA binding proteins, which enabled the construction of a network model consisting of 24 core regulators and 76 fine-tuners that help to explain how pathogen-sensing pathways achieve specificity. This study establishes a broadly applicable, comprehensive, and unbiased approach to reveal the wiring and functions of a regulatory network controlling a major transcriptional response in primary mammalian cells.Burroughs Wellcome Fund (Career Award at the Scientific Interface)National Institutes of Health (U.S.) (Pioneer Award)Alfred P. Sloan Foundatio