Showing papers by "Rambam Health Care Campus published in 2019"
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State University of New York System1, Detroit Medical Center2, Universidade Federal do Rio Grande do Sul3, Rappaport Faculty of Medicine4, Rambam Health Care Campus5, National and Kapodistrian University of Athens6, University of North Carolina at Chapel Hill7, University of Genoa8, Drexel University9, Erasmus University Rotterdam10, University of Houston11, Mahidol University12, Northwestern University13, Monash University, Clayton campus14, Monash University15, University of Michigan16
TL;DR: In this paper, the authors report consensus therapeutic guidelines for agent selection and dosing of colistin and polymyxin antibiotics for optimal use in adult patients, as endorsed by the American College of Clinical Pharmacy (ACCP), Infectious Diseases Society of America (IDSA), International Society of Anti-Infective Pharmacology (ISAP), Society for Critical Care Medicine (SCCM), and Society of Infectious diseases Pharmacists (SIDP).
Abstract: The polymyxin antibiotics colistin (polymyxin E) and polymyxin B became available in the 1950s and thus did not undergo contemporary drug development procedures. Their clinical use has recently resurged, assuming an important role as salvage therapy for otherwise untreatable gram-negative infections. Since their reintroduction into the clinic, significant confusion remains due to the existence of several different conventions used to describe doses of the polymyxins, differences in their formulations, outdated product information, and uncertainties about susceptibility testing that has led to lack of clarity on how to optimally utilize and dose colistin and polymyxin B. We report consensus therapeutic guidelines for agent selection and dosing of the polymyxin antibiotics for optimal use in adult patients, as endorsed by the American College of Clinical Pharmacy (ACCP), Infectious Diseases Society of America (IDSA), International Society of Anti-Infective Pharmacology (ISAP), Society for Critical Care Medicine (SCCM), and Society of Infectious Diseases Pharmacists (SIDP). The European Society for Clinical Microbiology and Infectious Diseases (ESCMID) endorses this document as a consensus statement. The overall conclusions in the document are endorsed by the European Committee on Antimicrobial Susceptibility Testing (EUCAST). We established a diverse international expert panel to make therapeutic recommendations regarding the pharmacokinetic and pharmacodynamic properties of the drugs and pharmacokinetic targets, polymyxin agent selection, dosing, dosage adjustment and monitoring of colistin and polymyxin B, use of polymyxin-based combination therapy, intrathecal therapy, inhalation therapy, toxicity, and prevention of renal failure. The treatment guidelines provide the first ever consensus recommendations for colistin and polymyxin B therapy that are intended to guide optimal clinical use.
446 citations
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University of Paris1, McGill University2, Brigham and Women's Hospital3, Medical University of Vienna4, Case Western Reserve University5, Hospital General Universitario Gregorio Marañón6, Rambam Health Care Campus7, University College London8, Universidad Católica San Antonio de Murcia9, University of Geneva10, McMaster University11
TL;DR: The 2019 International Initiative on Thrombosis and Cancer clinical practice guidelines, which are based on a systematic review of the literature published up to December, 2018, are presented along with a Grading of Recommendations Assessment Development and Evaluation scale methods.
Abstract: Venous thromboembolism (VTE) is the second leading cause of death in patients with cancer. These patients are at a high risk of VTE recurrence and bleeding during anticoagulant therapy. The International Initiative on Thrombosis and Cancer is an independent academic working group aimed at establishing a global consensus for the treatment and prophylaxis of VTE in patients with cancer. The International Initiative on Thrombosis and Cancer last updated its evidence-based clinical practice guidelines in 2016 with a free, web-based mobile phone application, which was subsequently endorsed by the International Society on Thrombosis and Haemostasis. The 2019 International Initiative on Thrombosis and Cancer clinical practice guidelines, which are based on a systematic review of the literature published up to December, 2018, are presented along with a Grading of Recommendations Assessment Development and Evaluation scale methods, with the support of the French National Cancer Institute. These guidelines were reviewed by an expanded international advisory committee and endorsed by the International Society on Thrombosis and Haemostasis. Results from head-to-head clinical trials that compared direct oral anticoagulant with low-molecular-weight heparin are also summarised, along with new evidence for the treatment and prophylaxis of VTE in patients with cancer.
429 citations
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TL;DR: These guidelines present evidence-based international consensus statements on the management of severe acute pancreatitis from collaboration of a panel of experts meeting during the World Congress of Emergency Surgery in June 27–30, 2018 in Bertinoro, Italy.
Abstract: Although most patients with acute pancreatitis have the mild form of the disease, about 20–30% develops a severe form, often associated with single or multiple organ dysfunction requiring intensive care. Identifying the severe form early is one of the major challenges in managing severe acute pancreatitis. Infection of the pancreatic and peripancreatic necrosis occurs in about 20–40% of patients with severe acute pancreatitis, and is associated with worsening organ dysfunctions. While most patients with sterile necrosis can be managed nonoperatively, patients with infected necrosis usually require an intervention that can be percutaneous, endoscopic, or open surgical. These guidelines present evidence-based international consensus statements on the management of severe acute pancreatitis from collaboration of a panel of experts meeting during the World Congress of Emergency Surgery in June 27–30, 2018 in Bertinoro, Italy. The main topics of these guidelines fall under the following topics: Diagnosis, Antibiotic treatment, Management in the Intensive Care Unit, Surgical and operative management, and Open abdomen.
386 citations
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TL;DR: An integrated high-dimensional measurement of immune age describes a person’s immune status better than chronological age and predicts all-cause mortality beyond well-established risk factors in the Framingham Heart Study.
Abstract: Immune responses generally decline with age. However, the dynamics of this process at the individual level have not been characterized, hindering quantification of an individual's immune age. Here, we use multiple 'omics' technologies to capture population- and individual-level changes in the human immune system of 135 healthy adult individuals of different ages sampled longitudinally over a nine-year period. We observed high inter-individual variability in the rates of change of cellular frequencies that was dictated by their baseline values, allowing identification of steady-state levels toward which a cell subset converged and the ordered convergence of multiple cell subsets toward an older adult homeostasis. These data form a high-dimensional trajectory of immune aging (IMM-AGE) that describes a person's immune status better than chronological age. We show that the IMM-AGE score predicted all-cause mortality beyond well-established risk factors in the Framingham Heart Study, establishing its potential use in clinics for identification of patients at risk.
269 citations
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TL;DR: A label-free proteomic workflow is developed to analyse as few as 5,000 formalin-fixed, paraffin-embedded cells microdissected from each compartment and finds that stromal methyltransferase nicotinamide N-methyltransferase (NNMT) regulates the transition of normal fibroblasts to cancer-associated fibro Blasts through histone methylation and promotes ovarian cancer growth and metastasis.
Abstract: High-grade serous carcinoma has a poor prognosis, owing primarily to its early dissemination throughout the abdominal cavity. Genomic and proteomic approaches have provided snapshots of the proteogenomics of ovarian cancer1,2, but a systematic examination of both the tumour and stromal compartments is critical in understanding ovarian cancer metastasis. Here we develop a label-free proteomic workflow to analyse as few as 5,000 formalin-fixed, paraffin-embedded cells microdissected from each compartment. The tumour proteome was stable during progression from in situ lesions to metastatic disease; however, the metastasis-associated stroma was characterized by a highly conserved proteomic signature, prominently including the methyltransferase nicotinamide N-methyltransferase (NNMT) and several of the proteins that it regulates. Stromal NNMT expression was necessary and sufficient for functional aspects of the cancer-associated fibroblast (CAF) phenotype, including the expression of CAF markers and the secretion of cytokines and oncogenic extracellular matrix. Stromal NNMT expression supported ovarian cancer migration, proliferation and in vivo growth and metastasis. Expression of NNMT in CAFs led to depletion of S-adenosyl methionine and reduction in histone methylation associated with widespread gene expression changes in the tumour stroma. This work supports the use of ultra-low-input proteomics to identify candidate drivers of disease phenotypes. NNMT is a central, metabolic regulator of CAF differentiation and cancer progression in the stroma that may be therapeutically targeted. The authors find that stromal methyltransferase nicotinamide N-methyltransferase (NNMT) regulates the transition of normal fibroblasts to cancer-associated fibroblasts through histone methylation and promotes ovarian cancer growth and metastasis.
269 citations
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TL;DR: In patients hospitalized with Gram-negative bacteremia achieving clinical stability before day 7, an antibiotic course of 7 days was non-inferior to 14 days, an important antibiotic stewardship intervention.
Abstract: Background Gram-negative bacteremia is a major cause of morbidity and mortality in hospitalized patients. Data to guide the duration of antibiotic therapy are limited. Methods This was a randomized, multicenter, open-label, noninferiority trial. Inpatients with gram-negative bacteremia, who were afebrile and hemodynamically stable for at least 48 hours, were randomized to receive 7 days (intervention) or 14 days (control) of covering antibiotic therapy. Patients with uncontrolled focus of infection were excluded. The primary outcome at 90 days was a composite of all-cause mortality; relapse, suppurative, or distant complications; and readmission or extended hospitalization (>14 days). The noninferiority margin was set at 10%. Results We included 604 patients (306 intervention, 298 control) between January 2013 and August 2017 in 3 centers in Israel and Italy. The source of the infection was urinary in 411 of 604 patients (68%); causative pathogens were mainly Enterobacteriaceae (543/604 [90%]). A 7-day difference in the median duration of covering antibiotics was achieved. The primary outcome occurred in 140 of 306 patients (45.8%) in the 7-day group vs 144 of 298 (48.3%) in the 14-day group (risk difference, -2.6% [95% confidence interval, -10.5% to 5.3%]). No significant differences were observed in all other outcomes and adverse events, except for a shorter time to return to baseline functional status in the short-course therapy arm. Conclusions In patients hospitalized with gram-negative bacteremia achieving clinical stability before day 7, an antibiotic course of 7 days was noninferior to 14 days. Reducing antibiotic treatment for uncomplicated gram-negative bacteremia to 7 days is an important antibiotic stewardship intervention. Clinical trials registration NCT01737320.
229 citations
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European Institute of Oncology1, Auckland City Hospital2, Greenslopes Private Hospital3, Aarhus University Hospital4, Sheba Medical Center5, University of Sydney6, University of Copenhagen7, Rambam Health Care Campus8, Laval University9, Novartis10, Merck & Co.11, University of California, Los Angeles12
TL;DR: A randomized phase 2 trial testing triple combination of BRAF, MEK and PD-1 inhibition as first-line therapy in patients with BRAF-mutant melanoma shows durable responses and encouraging progression-free survival.
Abstract: Blocking programmed death 1 (PD-1) may enhance the durability of anti-tumor responses that are induced by the combined inhibition of BRAF and MEK1. Here we performed a randomized phase 2 trial (
NCT02130466
), in which patients with treatment-naive BRAFV600E/K-mutant, advanced melanoma received the BRAF inhibitor dabrafenib and the MEK inhibitor trametinib together with the PD-1-blocking antibody pembrolizumab (triplet; n = 60) or placebo (doublet; n = 60). The primary end point of progression-free survival was numerically improved in the triplet group—16.0 months—compared with 10.3 months in the doublet group (hazard ratio, 0.66; P = 0.043); however, the trial did not reach the planned benefit for a statistically significant improvement. Median duration of response was 18.7 months (95% confidence interval, 10.1–22.1) and 12.5 months (95% confidence interval, 6.0–14.1); 59.8 and 27.8% of responses were estimated to have lasted for more than 18 months for triplet and doublet treatment, respectively. Grade 3–5 treatment-related adverse events occurred in 58.3 and 26.7% of patients treated with triplet and doublet therapies, respectively, which were most commonly fever, increased transaminase levels and rash. One patient who received triplet therapy died of pneumonitis. In summary, triplet therapy with dabrafenib, trametinib and pembrolizumab conferred numerically longer progression-free survival and duration of response with a higher rate of grade 3/4 adverse events compared with the doublet therapy of dabrafenib, trametinib and placebo. A randomized phase 2 trial testing triple combination of BRAF, MEK and PD-1 inhibition as first-line therapy in patients with BRAF-mutant melanoma shows durable responses and encouraging progression-free survival.
226 citations
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TL;DR: In children and adolescents with type 2 diabetes, liraglutide, at a dose of up to 1.8 mg per day (added to metformin, with or without basal insulin), was efficacious in improving glycemic control over 52 weeks but came at the cost of an increased frequency of gastrointestinal adverse events.
Abstract: Background Metformin is the regulatory-approved treatment of choice for most youth with type 2 diabetes early in the disease. However, early loss of glycemic control has been observed with...
163 citations
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Middlemore Hospital1, Oslo University Hospital2, North Shore Hospital3, Wellington Management Company4, University Hospital Heidelberg5, University of Turin6, Mayo Clinic7, University of Colorado Boulder8, Rambam Health Care Campus9, Nagoya City University10, Institut Gustave Roussy11, Mount Sinai Hospital12, University of Cantabria13, University of Navarra14, Merck & Co.15, Emory University16
TL;DR: The FDA established that risks associated with the triple combination outweighed benefits and halted the study and presented an unplanned, ad-hoc interim analysis.
150 citations
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TL;DR: This study proposes two clinically feasible assays, one in biopsy and one in blood, for predicting non-response to anti-TNFα therapy prior to initiation of treatment and suggests that mechanism-driven novel drugs for non-responders should be developed.
Abstract: Objective Although anti-tumour necrosis factor alpha (anti-TNFα) therapies represent a major breakthrough in IBD therapy, their cost–benefit ratio is hampered by an overall 30% non-response rate, adverse side effects and high costs. Thus, finding predictive biomarkers of non-response prior to commencing anti-TNFα therapy is of high value. Design We analysed publicly available whole-genome expression profiles of colon biopsies obtained from multiple cohorts of patients with IBD using a combined computational deconvolution—meta-analysis paradigm which allows to estimate immune cell contribution to the measured expression and capture differential regulatory programmes otherwise masked due to variation in cellular composition. Insights from this in silico approach were experimentally validated in biopsies and blood samples of three independent test cohorts. Results We found the proportion of plasma cells as a robust pretreatment biomarker of non-response to therapy, which we validated in two independent cohorts of immune-stained colon biopsies, where a plasma cellular score from inflamed biopsies was predictive of non-response with an area under the curve (AUC) of 82%. Meta-analysis of the cell proportion-adjusted gene expression data suggested that an increase in inflammatory macrophages in anti-TNFα non-responding individuals is associated with the upregulation of the triggering receptor expressed on myeloid cells 1 (TREM-1) and chemokine receptor type 2 (CCR2)-chemokine ligand 7 (CCL7) –axes. Blood gene expression analysis of an independent cohort, identified TREM-1 downregulation in non-responders at baseline, which was predictive of response with an AUC of 94%. Conclusions Our study proposes two clinically feasible assays, one in biopsy and one in blood, for predicting non-response to anti-TNFα therapy prior to initiation of treatment. Moreover, it suggests that mechanism-driven novel drugs for non-responders should be developed.
141 citations
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TL;DR: New antibacterial drugs without pre-existing cross-resistance are under-represented and are urgently needed, especially for geographical regions with high resistance rates among Gram-negative bacteria and M tuberculosis.
Abstract: This analysis of the global clinical antibacterial pipeline was done in support of the Global Action Plan on Antimicrobial Resistance. The study analysed to what extent antibacterial and antimycobacterial drugs for systemic human use as well as oral non-systemic antibacterial drugs for Clostridium difficile infections were active against pathogens included in the WHO priority pathogen list and their innovativeness measured by their absence of cross-resistance (new class, target, mode of action). As of July 1, 2018, 30 new chemical entity (NCE) antibacterial drugs, ten biologics, ten NCEs against Mycobacterium tuberculosis, and four NCEs against C difficile were identified. Of the 30 NCEs, 11 are expected to have some activity against at least one critical priority pathogen expressing carbapenem resistance. The clinical pipeline is dominated by derivatives of established classes and most development candidates display limited innovation. New antibacterial drugs without pre-existing cross-resistance are under-represented and are urgently needed, especially for geographical regions with high resistance rates among Gram-negative bacteria and M tuberculosis.
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Paris Descartes University1, Ghent University Hospital2, University of Florence3, Rambam Health Care Campus4, University of Bari5, I.M. Sechenov First Moscow State Medical University6, Seconda Università degli Studi di Napoli7, Katholieke Universiteit Leuven8, university of lille9, Dresden University of Technology10, Russian Academy11, Hospital General Universitario Gregorio Marañón12, University of Erlangen-Nuremberg13, University of Cologne14, Sapienza University of Rome15, Rutgers University16, Carol Davila University of Medicine and Pharmacy17, Nippon Medical School18, Tulane University19, Lund University20, University of Verona21
TL;DR: Rituximab use was associated with a good safety profile in this large SSc-cohort and significant change was observed on skin fibrosis, but not on lung, but the limitation is the observational design.
Abstract: Objective To assess the safety and efficacy of rituximab in systemic sclerosis (SSc) in clinical practice. Methods We performed a prospective study including patients with SSc from the European Scleroderma Trials and Research (EUSTAR) network treated with rituximab and matched with untreated patients with SSc. The main outcomes measures were adverse events, skin fibrosis improvement, lung fibrosis worsening and steroids use among propensity score-matched patients treated or not with rituximab. Results 254 patients were treated with rituximab, in 58% for lung and in 32% for skin involvement. After a median follow-up of 2 years, about 70% of the patients had no side effect. Comparison of treated patients with 9575 propensity-score matched patients showed that patients treated with rituximab were more likely to have skin fibrosis improvement (22.7 vs 14.03 events per 100 person-years; OR: 2.79 [1.47–5.32]; p=0.002). Treated patients did not have significantly different rates of decrease in forced vital capacity (FVC)>10% (OR: 1.03 [0.55–1.94]; p=0.93) nor in carbon monoxide diffusing capacity (DLCO) decrease. Patients having received rituximab were more prone to stop or decrease steroids (OR: 2.34 [1.56–3.53], p Conclusion Rituximab use was associated with a good safety profile in this large SSc-cohort. Significant change was observed on skin fibrosis, but not on lung. However, the limitation is the observational design. The potential stabilisation of lung fibrosis by rituximab has to be addressed by a randomised trial.
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Centre Hospitalier Universitaire de Grenoble1, University of Milan2, Radboud University Nijmegen3, Rambam Health Care Campus4, State University of Campinas5, University of Pavia6, University of Cambridge7, Royal Perth Hospital8, Scripps Health9, Sher-I-Kashmir Institute of Medical Sciences10, University of Brescia11
TL;DR: The esophagus traverses three body compartments (neck, thorax, and abdomen) and is surrounded at each level by vital organs and can be life-threatening either by digestive contamination of surrounding structures in case of esophageal wall breach or concomitant damage of surrounding organs.
Abstract: The esophagus traverses three body compartments (neck, thorax, and abdomen) and is surrounded at each level by vital organs. Injuries to the esophagus may be classified as foreign body ingestion, caustic ingestion, esophageal perforation, and esophageal trauma. These lesions can be life-threatening either by digestive contamination of surrounding structures in case of esophageal wall breach or concomitant damage of surrounding organs. Early diagnosis and timely therapeutic intervention are the keys of successful management.
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Memorial Sloan Kettering Cancer Center1, Icahn School of Medicine at Mount Sinai2, Hebrew University of Jerusalem3, Koç University4, Ankara University5, Tel Aviv Sourasky Medical Center6, Gdańsk Medical University7, Flinders Medical Centre8, St. Vincent's Health System9, Dokuz Eylül University10, Gazi University11, Rambam Health Care Campus12, Princess Alexandra Hospital13, Wrocław Medical University14, Bristol-Myers Squibb15, Janssen Pharmaceutica16, Jagiellonian University17
TL;DR: The combination of ibrutinib and nivolumab led to overall responses in 22 (61%) of 36 patients with high-risk chronic lymphocytic leukaemia or small lymphocytics lymphoma, and 13 (65%) of 20 patients with Richter's transformation, which indicated an acceptable safety profile.
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GlaxoSmithKline1, Ege University2, Charles University in Prague3, Rambam Health Care Campus4, Brigham and Women's Hospital5, University of Eastern Piedmont6, Chonnam National University7, University of Kansas8, University of Valencia9, CEU San Pablo University10, Cornell University11, Charité12, Manchester Royal Infirmary13, University of Manchester14, Catholic University of Korea15, Royal Hobart Hospital16, Fred Hutchinson Cancer Research Center17, Halozyme Therapeutics18, University of Pennsylvania19, Duke University20
TL;DR: Among adults who had undergone autologous HSCT, a 2-dose course of recombinant zoster vaccine compared with placebo significantly reduced the incidence of herpes zoster over a median follow-up of 21 months.
Abstract: Importance Herpes zoster, a frequent complication following autologous hematopoietic stem cell transplantation (HSCT), is associated with significant morbidity. A nonlive adjuvanted recombinant zoster vaccine has been developed to prevent posttransplantation zoster. Objective To assess the efficacy and adverse event profile of the recombinant zoster vaccine in immunocompromised autologous HSCT recipients. Design, Setting, and Participants Phase 3, randomized, observer-blinded study conducted in 167 centers in 28 countries between July 13, 2012, and February 1, 2017, among 1846 patients aged 18 years or older who had undergone recent autologous HSCT. Interventions Participants were randomized to receive 2 doses of either recombinant zoster vaccine (n = 922) or placebo (n = 924) administered into the deltoid muscle; the first dose was given 50 to 70 days after transplantation and the second dose 1 to 2 months thereafter. Main Outcomes and Measures The primary end point was occurrence of confirmed herpes zoster cases. Results Among 1846 autologous HSCT recipients (mean age, 55 years; 688 [37%] women) who received 1 vaccine or placebo dose, 1735 (94%) received a second dose and 1366 (74%) completed the study. During the 21-month median follow-up, at least 1 herpes zoster episode was confirmed in 49 vaccine and 135 placebo recipients (incidence, 30 and 94 per 1000 person-years, respectively), an incidence rate ratio (IRR) of 0.32 (95% CI, 0.22-0.44;P Conclusions and Relevance Among adults who had undergone autologous HSCT, a 2-dose course of recombinant zoster vaccine compared with placebo significantly reduced the incidence of herpes zoster over a median follow-up of 21 months. Trial Registration ClinicalTrials.gov Identifier:NCT01610414
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TL;DR: A novel ECM-EHT model was established, which can be subjected to high-resolution long-term serial functional phenotyping, with important implications for cardiac disease modeling, drug testing and precision medicine.
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Discovery Institute1, University of California, Irvine2, University of Nebraska–Lincoln3, University of Maryland, College Park4, Tel Aviv University5, National Institutes of Health6, Technion – Israel Institute of Technology7, Harvard University8, University of Central Florida9, Rambam Health Care Campus10, Yale University11, Ludwig Institute for Cancer Research12, University of Zurich13
TL;DR: It is shown that altered intestinal microbiota contributes to anti-tumor immunity, limiting tumor expansion, and Rnf5 deficiency potentiates immune response against melanoma via altered microbiota, and isolate bacterial strains that confer the same phenotype to wild type mice.
Abstract: Accumulating evidence points to an important role for the gut microbiome in anti-tumor immunity. Here, we show that altered intestinal microbiota contributes to anti-tumor immunity, limiting tumor expansion. Mice lacking the ubiquitin ligase RNF5 exhibit attenuated activation of the unfolded protein response (UPR) components, which coincides with increased expression of inflammasome components, recruitment and activation of dendritic cells and reduced expression of antimicrobial peptides in intestinal epithelial cells. Reduced UPR expression is also seen in murine and human melanoma tumor specimens that responded to immune checkpoint therapy. Co-housing of Rnf5-/- and WT mice abolishes the anti-tumor immunity and tumor inhibition phenotype, whereas transfer of 11 bacterial strains, including B. rodentium, enriched in Rnf5-/- mice, establishes anti-tumor immunity and restricts melanoma growth in germ-free WT mice. Altered UPR signaling, exemplified in Rnf5-/- mice, coincides with altered gut microbiota composition and anti-tumor immunity to control melanoma growth.
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University of Washington1, Mayo Clinic2, Australian National University3, Omdurman Islamic University4, United Arab Emirates University5, University of Zagreb6, Hebrew University of Jerusalem7, Rambam Health Care Campus8, Scripps Health9, VA Boston Healthcare System10, University of Santiago de Compostela11, University of Michigan12, West Virginia University13, Transilvania University of Brașov14, Riverside University Health System - Medical Center15, Tianjin Medical University16, Jagiellonian University Medical College17, Tbilisi State Medical University18, University of Catania19, Cambridge University Hospitals NHS Foundation Trust20, Ovidius University21, Stanford University22, State University of Campinas23, Geneva College24, Northwestern University25, University of New Mexico26, University of A Coruña27, Mansoura University28, Universidade Federal de Juiz de Fora29, Queen Elizabeth Hospital Birmingham30, Ruhr University Bochum31, Inje University32, University of Pittsburgh33, Harvard University34, Universiti Sains Malaysia35, St. Louis College of Pharmacy36, University of Belgrade37, Albert Einstein College of Medicine38, University of Helsinki39, Mahidol University40, Universidad Nacional de Asunción41, University of Health Sciences Antigua42, Washington University in St. Louis43, Hacettepe University44, University of Colorado Denver45, University of Florida46, University of Valle47, University of Coimbra48, Medical University Plovdiv49, Tan Tock Seng Hospital50, Istituto Superiore di Sanità51, University of Rennes52, Masaryk University53, First Faculty of Medicine, Charles University in Prague54, University of Brescia55
TL;DR: An international multidisciplinary panel of experts from the World Society of Emergency Surgery updated its guidelines for management of CDI in surgical patients according to the most recent available literature, including recent changes introduced in the management of this infection.
Abstract: In the last three decades, Clostridium difficile infection (CDI) has increased in incidence and severity in many countries worldwide. The increase in CDI incidence has been particularly apparent among surgical patients. Therefore, prevention of CDI and optimization of management in the surgical patient are paramount. An international multidisciplinary panel of experts from the World Society of Emergency Surgery (WSES) updated its guidelines for management of CDI in surgical patients according to the most recent available literature. The update includes recent changes introduced in the management of this infection.
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Rambam Health Care Campus1, Scripps Health2, Chiba University3, University of Colorado Denver4, University of Pittsburgh5, State University of Campinas6, University of Zagreb7, Foothills Medical Centre8, United Arab Emirates University9, Royal Perth Hospital10, National and Kapodistrian University of Athens11, University of Grenoble12, Military Academy13, Riverside University Health System - Medical Center14, University of Buea15, University of Catania16
TL;DR: The aim of this paper is to present the World Society of Emergency Surgery and the American Association for the Surgery of Trauma (AAST) kidney and urogenital trauma management guidelines.
Abstract: Renal and urogenital injuries occur in approximately 10-20% of abdominal trauma in adults and children. Optimal management should take into consideration the anatomic injury, the hemodynamic status, and the associated injuries. The management of urogenital trauma aims to restore homeostasis and normal physiology especially in pediatric patients where non-operative management is considered the gold standard. As with all traumatic conditions, the management of urogenital trauma should be multidisciplinary including urologists, interventional radiologists, and trauma surgeons, as well as emergency and ICU physicians. The aim of this paper is to present the World Society of Emergency Surgery (WSES) and the American Association for the Surgery of Trauma (AAST) kidney and urogenital trauma management guidelines.
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TL;DR: To assess the efficacy and safety of a remote electrical neuromodulation (REN) device for the acute treatment of migraine, a large number of patients were referred for treatment with a single device.
Abstract: OBJECTIVE To assess the efficacy and safety of a remote electrical neuromodulation (REN) device for the acute treatment of migraine. BACKGROUND There is a significant unmet need for novel effective well-tolerated acute migraine treatments. REN is a novel acute migraine treatment that stimulates upper arm peripheral nerves to induce conditioned pain modulation - an endogenous analgesic mechanism in which conditioning stimulation inhibits pain in remote body regions. A recent pilot study showed that REN can significantly reduce headache. We have conducted a randomized, double-blind, sham-controlled study to further evaluate the efficacy and safety of REN for the acute treatment of migraine. METHODS This was a randomized, double-blind, sham-controlled, multicenter study conducted at 7 sites in the United States and 5 sites in Israel. Two hundred and fifty-two adults meeting the International Classification of Headache Disorders criteria for migraine with 2-8 migraine headaches per month were randomized in a 1:1 ratio to active or sham stimulation. A smartphone-controlled wireless device was applied for 30-45 minutes on the upper arm within 1 hour of attack onset; electrical stimulation was at a perceptible but non-painful intensity level. Migraine pain levels were recorded at baseline, 2, and 48 hours post-treatment. Most bothersome symptoms (MBS) were also recorded. The primary efficacy endpoint was the proportion of participants achieving pain relief at 2 hours post-treatment (improvement from severe or moderate pain to mild or none, or from mild pain to none). Relief of MBS and pain-free at 2 hours were key secondary endpoints. RESULTS Active stimulation was more effective than sham stimulation in achieving pain relief (66.7% [66/99] vs 38.8% [40/103]; therapeutic gain of 27.9% [CI95% , 15.6-40.2]; P < .0001), pain-free (37.4% vs 18.4%, P = .003), and MBS relief (46.3% vs 22.2%, P = .0008) at 2 hours post-treatment. The pain relief and pain-free superiority of the active treatment was sustained 48 hours post-treatment. The incidence of device-related adverse events was low and similar between treatment groups (4.8% [6/126] vs 2.4% [3/126], P = .499). CONCLUSIONS REN provides superior clinically meaningful relief of migraine pain and MBS compared to placebo, offering a safe and effective non-pharmacological alternative for acute migraine treatment.
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Walton Centre1, University of Liverpool2, University of Mainz3, University of Zurich4, Ghent University5, University of Bath6, Rambam Health Care Campus7, University of the West of England8, University of South Australia9, VU University Medical Center10, Paris Descartes University11, Aarhus University Hospital12, Pomeranian Medical University13
TL;DR: This work sought to establish standards for the diagnosis and management of CRPS, and found that in Europe, progress is hampered by significant heterogeneity in clinical practice.
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TL;DR: Analysis of the fecal microbiota of patients with pancreatic adenocarcinoma and patients with pre-cancerous pancreatic lesions found only a small part of the PC-associated microbial signals were observed, implying that microbiome-based early detection of such lesions will be challenging.
Abstract: Pancreatic cancer (PC) is a leading cause of cancer-related death in developed countries, and since most patients have incurable disease at the time of diagnosis, developing a screening method for early detection is of high priority. Due to its metabolic importance, alterations in pancreatic functions may affect the composition of the gut microbiota, potentially yielding biomarkers for PC. However, the usefulness of these biomarkers may be limited if they are specific for advanced stages of disease, which may involve comorbidities such as biliary obstruction or diabetes. In this study we analyzed the fecal microbiota of 30 patients with pancreatic adenocarcinoma, 6 patients with pre-cancerous lesions, 13 healthy subjects and 16 with non-alcoholic fatty liver disease, using amplicon sequencing of the bacterial 16S rRNA gene. Fourteen bacterial features discriminated between PC and controls, and several were shared with findings from a recent Chinese cohort. A Random Forest model based on the microbiota classified PC and control samples with an AUC of 82.5%. However, inter-subject variability was high, and only a small part of the PC-associated microbial signals were also observed in patients with pre-cancerous pancreatic lesions, implying that microbiome-based early detection of such lesions will be challenging.
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TL;DR: The new policy of labor management successfully decreased primary cesarean deliveries, with a small rise in instrumental deliveries, however, it also increased the other immediate maternal and neonatal complications.
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TL;DR: In this article, a neomorphic seed region mutation in the chondrocyte-specific, super-enhancer-associated MIR140 gene encoding microRNA-140 (miR-140) in a novel autosomal dominant human skeletal dysplasia was reported.
Abstract: MicroRNAs (miRNAs) are post-transcriptional regulators of gene expression. Heterozygous loss-of-function point mutations of miRNA genes are associated with several human congenital disorders1-5, but neomorphic (gain-of-new-function) mutations in miRNAs due to nucleotide substitutions have not been reported. Here we describe a neomorphic seed region mutation in the chondrocyte-specific, super-enhancer-associated MIR140 gene encoding microRNA-140 (miR-140) in a novel autosomal dominant human skeletal dysplasia. Mice with the corresponding single nucleotide substitution show skeletal abnormalities similar to those of the patients but distinct from those of miR-140-null mice6. This mutant miRNA gene yields abundant mutant miR-140-5p expression without miRNA-processing defects. In chondrocytes, the mutation causes widespread derepression of wild-type miR-140-5p targets and repression of mutant miR-140-5p targets, indicating that the mutation produces both loss-of-function and gain-of-function effects. Furthermore, the mutant miR-140-5p seed competes with the conserved RNA-binding protein Ybx1 for overlapping binding sites. This finding may explain the potent target repression and robust in vivo effect by this mutant miRNA even in the absence of evolutionary selection of miRNA-target RNA interactions, which contributes to the strong regulatory effects of conserved miRNAs7,8. Our study presents the first case of a pathogenic gain-of-function miRNA mutation and provides molecular insight into neomorphic actions of emerging and/or mutant miRNAs.
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TL;DR: Colistin resistance as determined by BMD was associated with significantly lower mortality among patients with severe CRAB infections and colistin monotherapy wasassociated with a better outcome compared to colist in-meropenem combination therapy.
Abstract: Background We evaluated the association between mortality and colistin resistance in Acinetobacter baumannii infections and the interaction with antibiotic therapy. Methods This is a secondary anal ...
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University of California, San Diego1, Rambam Health Care Campus2, Scripps Health3, University of Zagreb4, Military Academy5, Foothills Medical Centre6, United Arab Emirates University7, State University of Campinas8, National and Kapodistrian University of Athens9, Chiba University10, Harvard University11, University of Buea12, Virginia Commonwealth University13, University of Grenoble14, Riverside University Health System - Medical Center15
TL;DR: The aim of this paper is to present the World Society of Emergency Surgery (WSES) and American Association for the Surgery of Trauma (AAST) duodenal, pancreatic, and extrahepatic biliary tree trauma management guidelines.
Abstract: Duodeno-pancreatic and extrahepatic biliary tree injuries are rare in both adult and pediatric trauma patients, and due to their anatomical location, associated injuries are very common. Mortality is primarily related to associated injuries, but morbidity remains high even in isolated injuries. Optimal management of duodeno-bilio-pancreatic injuries is dictated primarily by hemodynamic stability, clinical presentation, and grade of injury. Endoscopic and percutaneous interventions have increased the ability to non-operatively manage these injuries. Late diagnosis and treatment are both associated to increased morbidity and mortality. Sequelae of late presentations of pancreatic injury and complications of severe pancreatic trauma are also increasingly addressed endoscopically and with interventional radiology procedures. However, for moderate and severe extrahepatic biliary and severe duodeno-pancreatic injuries, immediate operative intervention is preferred as associated injuries are frequent and commonly present with hemodynamic instability or peritonitis. The aim of this paper is to present the World Society of Emergency Surgery (WSES) and American Association for the Surgery of Trauma (AAST) duodenal, pancreatic, and extrahepatic biliary tree trauma management guidelines.
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03 Jul 2019
TL;DR: The results of this diagnostic study of tissue microarray hematoxylin-eosin–stained images from 5356 patients with breast cancer suggest that deep learning models may assist pathologists in molecular profiling of cancer with practically no added cost and time.
Abstract: Importance Immunohistochemistry (IHC) is the most widely used assay for identification of molecular biomarkers. However, IHC is time consuming and costly, depends on tissue-handling protocols, and relies on pathologists’ subjective interpretation. Image analysis by machine learning is gaining ground for various applications in pathology but has not been proposed to replace chemical-based assays for molecular detection. Objective To assess the prediction feasibility of molecular expression of biomarkers in cancer tissues, relying only on tissue architecture as seen in digitized hematoxylin-eosin (HE NPV, 51%-78%; and accuracy, 81%-90%). Diagnostic accuracy improved given more data. Morphological analysis of patients with ER-negative/PR-positive status by IHC revealed resemblance to patients with ER-positive status (Bhattacharyya distance, 0.03) and not those with ER-negative/PR-negative status (Bhattacharyya distance, 0.25). This suggests a false-negative IHC finding and warrants antihormonal therapy for these patients. Conclusions and Relevance For at least half of the patients in this study, MBMP appeared to predict biomarker expression with noninferiority to IHC. Results suggest that prediction accuracy is likely to improve as data used for training expand. Morphological-based molecular profiling could be used as a general approach for mass-scale molecular profiling based on digitized H&E-stained images, allowing quick, accurate, and inexpensive methods for simultaneous profiling of multiple biomarkers in cancer tissues.
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TL;DR: Over the last decades, the age-related decline of muscle mass and strength has been a focus of gerontologic research as a means for exploring the aging process and its consequences and has been recognized as a major public health issue.
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TL;DR: The synthesis of the literature shows that patients with sarcopenia have more severe chemotherapy toxicity as well as shorter OS and TTP, and that low muscle density is prognostic of OS for women with metastatic breast cancer.
Abstract: Breast cancer is the most common cancer and leading cause of cancer death in women. Body composition parameters, especially those related to muscle, have become a growing focus of cancer research. In this review, we summarize the literature on breast cancer and muscle parameters as well as combine their outcomes for overall survival (OS), time to tumor progression (TTP), and chemotherapy toxicity in a meta-analysis. A systematic search of the literature for randomized controlled trials and observational studies was conducted on MEDLINE, Cochrane CENTRAL, and EMBASE through May 1, 2019. Two reviewers independently searched and selected. Meta-analysis was conducted using a random-effects model. The risk of bias was evaluated using the Newcastle–Ottawa quality assessment for cohorts and GRADE summary of findings tool from Cochrane. A total of 754 articles were screened from which 6 articles and one abstract were selected. Using skeletal muscle index (SMI), patients classified as sarcopenic had a 68% greater mortality risk compared to non-sarcopenic patients (HR 1.68 95% CI 1.09–2.59, 5 studies) (p = .02) (i2 = 70%). Low muscle density was not predictive of OS (HR 1.44 95% CI 0.77–2.68, 2 studies) (p = .25) (i2 = 87%). Patients with sarcopenia (56%) had more grade 3–5 toxicity compared to non-sarcopenic (25%) (RR 2.17 95% CI 1.4–3.34, 3 studies) (p = .0005) (i2 = 0%). TTP was nearly 71 days longer in advanced/metastatic patients classified as non-sarcopenic compared to patients with sarcopenia (MD − 70.75 95% CI − 122.32 to − 19.18) (p = .007) (i2 = 0%). Our synthesis of the literature shows that patients with sarcopenia have more severe chemotherapy toxicity as well as shorter OS and TTP, and that low muscle density is prognostic of OS for women with metastatic breast cancer. Our findings suggest that in clinical practice, body composition assessment is valuable as a prognostic parameter in breast cancer.
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TL;DR: Both obesity per se, via the adipocytokine profile it induces, and low insulin sensitivity, are independent determinants of the adverse metabolic phenotype characteristic of the metabolic syndrome.
Abstract: Obesity in childhood is the main determinant of whole body reduced insulin sensitivity. This association has been demonstrated in multiple adult and pediatric cohorts. The mechanistic link explaining this association is the pattern of lipid partitioning in the face of excess calories and energy surplus. A tight relation exists between typical lipid deposition patterns, specifically within the skeletal muscle and liver, as well as he intra-abdominal compartment and whole body insulin sensitivity. The impact of lipid deposition within insulin responsive tissues such as the liver and skeletal muscle relates to the ability of fatty acid derivates to inhibit elements of the insulin signal transduction pathway. Strengthening the relation of obesity and reduced insulin sensitivity are the observations that weight gain reduces insulin sensitivity while weight loss increases it. This manifests as the appearance of cardiovascular risk factor clustering with weight gain and its recovery in the face of weight loss. Both obesity per se, via the adipocytokine profile it induces, and low insulin sensitivity, are independent determinants of the adverse metabolic phenotype characteristic of the metabolic syndrome.