Showing papers by "Rappaport Faculty of Medicine published in 2020"
TL;DR: An overview of various cutaneous manifestations in patients with COVID-19 through three case reports and a literature review is provided to aid in the timely diagnosis of this infection.
260 citations
244 citations
TL;DR: It is found that neurons in thalamus and deep cortical layers are most sensitive to changes in consciousness level, consistent across different anesthetic agents and sleep and inform how targeted deep brain stimulation can alleviate disorders of consciousness.
178 citations
TL;DR: There is a continued need for innovation and new-class antibacterial agents in order to provide effective therapeutic options against infections specifically caused by XDR and PDR Gram-negative bacteria.
Abstract: The antibacterial agents currently in clinical development are predominantly derivatives of well-established antibiotic classes and were selected to address the class-specific resistance mechanisms and determinants that were known at the time of their discovery. Many of these agents aim to target the antibiotic-resistant priority pathogens listed by the WHO, including Gram-negative bacteria in the critical priority category, such as carbapenem-resistant Acinetobacter, Pseudomonas and Enterobacterales. Although some current compounds in the pipeline have exhibited increased susceptibility rates in surveillance studies that depend on geography, pre-existing cross-resistance both within and across antibacterial classes limits the activity of many of the new agents against the most extensively drug-resistant (XDR) and pan-drug-resistant (PDR) Gram-negative pathogens. In particular, cross-resistance to unrelated classes may occur by co-selection of resistant strains, thus leading to the rapid emergence and subsequent spread of resistance. There is a continued need for innovation and new-class antibacterial agents in order to provide effective therapeutic options against infections specifically caused by XDR and PDR Gram-negative bacteria. New antibacterial agents are urgently needed to address the global increase in resistance. In this Review, Theuretzbacher and colleagues critically review the current published literature and publicly available information on antibacterial agents in all phases of clinical development.
171 citations
University of Rouen1, University Medical Center Groningen2, Akdeniz University3, Aarhus University Hospital4, Dresden University of Technology5, Rappaport Faculty of Medicine6, University of Reims Champagne-Ardenne7, University Hospital of Bern8, University of Florence9, Tehran University of Medical Sciences10, Post Graduate Institute of Medical Education and Research11, Poznan University of Medical Sciences12, Sofia Medical University13, University of Münster14, University of Parma15, University of Würzburg16, St. John's University17, Medical University of Warsaw18, National Skin Centre19, University of Zagreb20, University of Milan21, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico22, University of Barcelona23, Rabin Medical Center24, St George's Hospital25, University of Modena and Reggio Emilia26, Semmelweis University27, Guy's and St Thomas' NHS Foundation Trust28, Tel Aviv Sourasky Medical Center29, Tel Aviv University30, Karadeniz Technical University31, Boston Children's Hospital32, University of Lübeck33, University of Marburg34
TL;DR: Pemphigus encompasses a group of life‐threatening autoimmune bullous diseases characterized by blisters and erosions of the mucous membranes and skin that was almost always fatal before the era of immunosuppressive treatment.
Abstract: BACKGROUND
Pemphigus encompasses a group of life-threatening autoimmune bullous diseases characterized by blisters and erosions of the mucous membranes and skin. Before the era of immunosuppressive treatment, pemphigus was almost always fatal. Due to its rarity, only few randomized controlled therapeutic trials are available. Recently, rituximab has been approved as first-line treatment for moderate and severe pemphigus vulgaris in Europe and the United States.
OBJECTIVES
The Autoimmune blistering diseases Task Force of the European Academy of Dermatology and Venereology (EADV) has initiated a throughout update of the guideline for the management of patients with pemphigus.
RESULTS
The guidelines for the management of pemphigus were updated, and the degree of consent among all task force members was included. The final version of the guideline was consented by the European Dermatology Forum (EDF) and several patient organizations.
135 citations
TL;DR: It is found that LMWH can improve the coagulation dysfunction of CO VID-19 patients, and has anti-inflammatory effects of reducing IL-6 and increasing lymphocyte%, which can be used as a potential therapeutic drug for the treatment of COVID-19 and provide guidance for subsequent clinical treatment.
Abstract: Summary Background On March 11, 2020, the World Health Organization declared its assessment of COVID-19 as a global pandemic. However, specific antiviral drugs are still unavailable, and pateints are managed by multiple complementary treatments. Methods The electronic medical records of COVID-19 patients where basic information, complete blood count, coagulation profile, inflammatory cytokines and serum biochemical indicators in 42 patients with COVID-19 (21 of whom were treated with low molecular weight heparin (LMWH), and 21 without LMWH) that were retrospectively analyzed to compare and evaluate the effect of LMWH treatment on disease progression. Findings 42 patients with COVID-19 treated at the hospital between February 1 and March 15, 2020, were selected for the study, of which 21 underwent LMWH treatment (LMWH group), and 21 did not (Control), during hospitalization. Changes in the percentage of lymphocytes in the LMWH group before and after LMWH treatment were significantly different from those in the control group (11·10±9·50 vs. 3·08±9·66, p=0·011, respectively). Changes in the levels of D-dimer and fibrinogen degradation products (FDP) in the LMWH group before and after LMWH treatment were significantly different from those in the control group (-2·85±3·90, -0·05±0.85, p=0·002; -9·05±13·14, -1·78±3·15, p=0·035). Strikingly, in the LMWH group, IL-6 levels were significantly reduced after LMWH treatment (47·47±58·86, 15·76±25·71, p=0·006). Besides, the changes in IL-6 levels in the LMWH group before and after LMWH treatment were significantly different from those in the control group (-32·46±65·97, 14·96±151·09, p=0·031). Interpretation LMWH improves the coagulation dysfunction of COVID-19 patients and exerts anti-inflammatory effects by reducing IL-6 and increasing lymphocyte %. It appears that LMWH can be used as a potential therapeutic drug for the treatment of COVID-19, paving the way for a subsequent well-controlled clinical trial. Funding National Natural Science Foundation of China (No. 81603037 to SC) and the National Key Research and Development Plan of China(2017YFC0909900).
130 citations
TL;DR: The results support the use of LMWH as a potential therapeutic drug for the treatment of COVID‐19, paving the way for a subsequent well‐controlled clinical study.
Abstract: On March 11, 2020, the World Health Organization declared its assessment of coronavirus disease 2019 (COVID-19) as a global pandemic. However, specific anti-severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) drugs are still under development, and patients are managed by multiple complementary treatments. We performed a retrospective analysis to compare and evaluate the effect of low molecular weight heparin (LMWH) treatment on disease progression. For this purpose, the clinical records and laboratory indicators were extracted from electronic medical records of 42 patients with COVID-19 (21 of whom were treated with LMWH, and 21 without LMWH) hospitalized (Union Hospital of Huazhong University of Science and Technology) from February 1 to March 15, 2020. Changes in the percentage of lymphocytes before and after LMWH treatment were significantly different from those in the control group (P = 0.011). Likewise, changes in the levels of D-dimer and fibrinogen degradation products in the LMWH group before and after treatment were significantly different from those in the control group (P = 0.035). Remarkably, IL-6 levels were significantly reduced after LMWH treatment (P = 0.006), indicating that, besides other beneficial properties, LMWH may exert an anti-inflammatory effect and attenuate in part the "cytokine storm" induced by the virus. Our results support the use of LMWH as a potential therapeutic drug for the treatment of COVID-19, paving the way for a subsequent well-controlled clinical study.
120 citations
104 citations
TL;DR: Glycine-based treatment attenuates experimental NAFLD by stimulating hepatic FAO and glutathione synthesis and modulated the gut microbiome through a potentially indirect effect, indicating the potential of the approach as a treatment.
Abstract: Nonalcoholic fatty liver disease (NAFLD) including nonalcoholic steatohepatitis (NASH) has reached epidemic proportions with no pharmacological therapy approved. Lower circulating glycine is consistently reported in patients with NAFLD, but the causes for reduced glycine, its role as a causative factor, and its therapeutic potential remain unclear. We performed transcriptomics in livers from humans and mice with NAFLD and found suppression of glycine biosynthetic genes, primarily alanine-glyoxylate aminotransferase 1 (AGXT1). Genetic (Agxt1−/− mice) and dietary approaches to limit glycine availability resulted in exacerbated diet-induced hyperlipidemia and steatohepatitis, with suppressed mitochondrial/peroxisomal fatty acid β-oxidation (FAO) and enhanced inflammation as the underlying pathways. We explored glycine-based compounds with dual lipid/glucose-lowering properties as potential therapies for NAFLD and identified a tripeptide (Gly-Gly-L-Leu, DT-109) that improved body composition and lowered circulating glucose, lipids, transaminases, proinflammatory cytokines, and steatohepatitis in mice with established NASH induced by a high-fat, cholesterol, and fructose diet. We applied metagenomics, transcriptomics, and metabolomics to explore the underlying mechanisms. The bacterial genus Clostridium sensu stricto was markedly increased in mice with NASH and decreased after DT-109 treatment. DT-109 induced hepatic FAO pathways, lowered lipotoxicity, and stimulated de novo glutathione synthesis. In turn, inflammatory infiltration and hepatic fibrosis were attenuated via suppression of NF-κB target genes and TGFβ/SMAD signaling. Unlike its effects on the gut microbiome, DT-109 stimulated FAO and glutathione synthesis independent of NASH. In conclusion, impaired glycine metabolism may play a causative role in NAFLD. Glycine-based treatment attenuates experimental NAFLD by stimulating hepatic FAO and glutathione synthesis, thus warranting clinical evaluation.
97 citations
International Agency for Research on Cancer1, Imperial College London2, University of Ioannina3, Fred Hutchinson Cancer Research Center4, University Hospitals Bristol NHS Foundation Trust5, University of Bristol6, National Institutes of Health7, University of Leeds8, German Cancer Research Center9, Royal Melbourne Hospital10, University of Melbourne11, American Cancer Society12, University of Barcelona13, Harvard University14, University of Hamburg15, University of Southern California16, Cedars-Sinai Medical Center17, University of Toronto18, Cancer Council Victoria19, Dresden University of Technology20, Ohio State University21, Umeå University22, Seoul National University23, University of Washington24, University of North Carolina at Chapel Hill25, University of Milan26, University of Virginia27, Karolinska Institutet28, Karolinska University Hospital29, Mayo Clinic30, The Heart Research Institute31, Case Western Reserve University32, Prevention Institute33, Utrecht University34, Memorial Sloan Kettering Cancer Center35, Cornell University36, Institut Gustave Roussy37, Université Paris-Saclay38, Paris Descartes University39, University of Cambridge40, Johns Hopkins University41, Rappaport Faculty of Medicine42, Andalusian School of Public Health43, University of South Florida44, University of Pittsburgh45, University of Utah46, University of Oxford47, Huntsman Cancer Institute48, Wageningen University and Research Centre49, Charles University in Prague50, Academy of Sciences of the Czech Republic51, First Faculty of Medicine, Charles University in Prague52, Memorial University of Newfoundland53
TL;DR: Two-sample Mendelian randomisation analyses using summary genetic data from the UK Biobank and GWA consortia found that a one standard deviation increment in average acceleration was associated with lower risks of breast cancer and colorectal cancer.
Abstract: Physical activity has been associated with lower risks of breast and colorectal cancer in epidemiological studies; however, it is unknown if these associations are causal or confounded. In two-sample Mendelian randomisation analyses, using summary genetic data from the UK Biobank and GWA consortia, we found that a one standard deviation increment in average acceleration was associated with lower risks of breast cancer (odds ratio [OR]: 0.51, 95% confidence interval [CI]: 0.27 to 0.98, P-value = 0.04) and colorectal cancer (OR: 0.66, 95% CI: 0.48 to 0.90, P-value = 0.01). We found similar magnitude inverse associations for estrogen positive (ER+ve) breast cancer and for colon cancer. Our results support a potentially causal relationship between higher physical activity levels and lower risks of breast cancer and colorectal cancer. Based on these data, the promotion of physical activity is probably an effective strategy in the primary prevention of these commonly diagnosed cancers.
92 citations
Radboud University Nijmegen1, Trinity College, Dublin2, St John of Jerusalem Eye Hospital Group3, Ghent University Hospital4, Seconda Università degli Studi di Napoli5, Hebrew University of Jerusalem6, Rappaport Faculty of Medicine7, University of Amsterdam8, Leiden University Medical Center9, university of lille10, First Faculty of Medicine, Charles University in Prague11, Ljubljana University Medical Centre12, Federal University of São Paulo13, University of Ljubljana14, University of California, Los Angeles15, University of Cape Town16, Jikei University School of Medicine17, Hannover Medical School18, University Hospital Regensburg19, Erasmus University Rotterdam20, University of Western Australia21, Sir Charles Gairdner Hospital22, University of Alberta23, Fundación Instituto Leloir24, University of Montpellier25, Tel Aviv Sourasky Medical Center26, Tel Aviv University27, Medical University of Warsaw28, University of Auckland29, University of Regensburg30
TL;DR: Deep sequencing of ABCA4 and midigene-based splice assays allowed the identification of SVs and causal deep-intronic variants in 25% of biallelic STGD1 cases, which represents a model study that can be applied to other inherited diseases.
TL;DR: Current evidence concurs that hospital wastewater is an important source for antibiotic resistance in aquatic environments, mainly multidrug-resistant Gram-negative bacteria.
TL;DR: In this article, the authors reviewed phase 3 clinical trials utilizing immunotherapy in the first line for treatment of non-small cell lung cancer (NSCLC) including Pembrolizumab in KeyNOTE-024, KEYNOTE-042, KEYnote-189 and KEYNote-407; Nivolumab and Ipilimumab in CHECKMATE-227 and CHECKmATE 9LA; and Atezolizumabs in IMpower110, IMpower130 and IMpower150.
Abstract: Immunotherapy for non-small cell lung cancer (NSCLC) is incorporated increasingly in first line treatments protocols. Multiple phase 3 studies have tested different medications targeting programmed death receptor 1 (PD-1), programmed death-ligand 1 (PD-L1), cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), with or without chemotherapy. The inclusion criteria differ between the various clinical trials, including the cut-off levels of PD-L1 expression on tumor cells, and the tumor histology (squamous or non-squamous). Patients with tumor expression levels of PD-L1 ≥ 50% are candidates for treatment with single agent Pembrolizumab or Atezolizumab. Patients with PD-L1 1%; immunotherapy doublet, Nivolumab and Ipilimumab, or single agent immunotherapy combined with chemotherapy. Here we review phase 3 clinical trials utilizing immunotherapy in the first line for treatment of NSCLC, including Pembrolizumab in KEYNOTE-024, KEYNOTE-042, KEYNOTE-189 and KEYNOTE-407; Nivolumab and Ipilimumab in CHECKMATE-227 and CHECKMATE 9LA; and Atezolizumab in IMpower110, IMpower130 and IMpower150.
TL;DR: In an analysis of associations with CRC per standard deviation of PRS, the cumulative burden of CRC-associated common genetic variants to associate with early-onset cancer, and to be more strongly associated with early toonset than late-ONSet cancer-particularly in the absence of CRC family history is found.
International Agency for Research on Cancer1, Brigham and Women's Hospital2, Harvard University3, University of Bristol4, University Hospitals Bristol NHS Foundation Trust5, University of Ioannina6, Imperial College London7, Fred Hutchinson Cancer Research Center8, National Institutes of Health9, Cancer Epidemiology Unit10, University of Leeds11, German Cancer Research Center12, University of Melbourne13, Royal Melbourne Hospital14, Utrecht University15, Kaiser Permanente16, American Cancer Society17, University of Virginia18, University of Barcelona19, Ohio State University20, Cancer Council Victoria21, Cedars-Sinai Medical Center22, Lunenfeld-Tanenbaum Research Institute23, Monash University, Clayton campus24, University of Southern California25, Dresden University of Technology26, University of Washington27, University of North Carolina at Chapel Hill28, Chonnam National University29, University of Hawaii30, Karolinska University Hospital31, Karolinska Institutet32, University of León33, Memorial Sloan Kettering Cancer Center34, Cornell University35, Huntsman Cancer Institute36, Institut Gustave Roussy37, Université Paris-Saclay38, Paris Descartes University39, Johns Hopkins University40, Massey University41, Rappaport Faculty of Medicine42, University of Pittsburgh43, University of Utah44, Wageningen University and Research Centre45, Umeå University46, Charles University in Prague47, First Faculty of Medicine, Charles University in Prague48, Academy of Sciences of the Czech Republic49, Memorial University of Newfoundland50, Vanderbilt University51
TL;DR: In an analysis of blood samples from almost 400,000 participants in the UK Biobank, a higher level of IGF1, determined by genetic factors, was associated with colorectal cancer.
TL;DR: The use of synthetic structured data provides a close estimate to real data results and is thus a powerful tool in shaping research hypotheses and accessing estimated analyses, without risking patient privacy.
Abstract: Background: Privacy restrictions limit access to protected patient-derived health information for research purposes. Consequently, data anonymization is required to allow researchers data access for initial analysis before granting institutional review board approval. A system installed and activated at our institution enables synthetic data generation that mimics data from real electronic medical records, wherein only fictitious patients are listed.
Objective: This paper aimed to validate the results obtained when analyzing synthetic structured data for medical research. A comprehensive validation process concerning meaningful clinical questions and various types of data was conducted to assess the accuracy and precision of statistical estimates derived from synthetic patient data.
Methods: A cross-hospital project was conducted to validate results obtained from synthetic data produced for five contemporary studies on various topics. For each study, results derived from synthetic data were compared with those based on real data. In addition, repeatedly generated synthetic datasets were used to estimate the bias and stability of results obtained from synthetic data.
Results: This study demonstrated that results derived from synthetic data were predictive of results from real data. When the number of patients was large relative to the number of variables used, highly accurate and strongly consistent results were observed between synthetic and real data. For studies based on smaller populations that accounted for confounders and modifiers by multivariate models, predictions were of moderate accuracy, yet clear trends were correctly observed.
Conclusions: The use of synthetic structured data provides a close estimate to real data results and is thus a powerful tool in shaping research hypotheses and accessing estimated analyses, without risking patient privacy. Synthetic data enable broad access to data (eg, for out-of-organization researchers), and rapid, safe, and repeatable analysis of data in hospitals or other health organizations where patient privacy is a primary value.
Medical University of Vienna1, Rappaport Faculty of Medicine2, University Hospital of Basel3, Semmelweis University4, University of Belgrade5, University of Zagreb6, Josip Juraj Strossmayer University of Osijek7, Carol Davila University of Medicine and Pharmacy8, Charles University in Prague9, Sofia Medical University10, Vilnius University11
TL;DR: A manifesto for change is proposed, in order to increase uptake of SGLT2i and GLP-1 RA in appropriate patients as a matter of urgency, especially those who could be readily switched from an agent without proven cardiorenal benefit.
Abstract: The disclosure of proven cardiorenal benefits with certain antidiabetic agents was supposed to herald a new era in the management of type 2 diabetes (T2D), especially for the many patients with T2D who are at high risk for cardiovascular and renal events. However, as the evidence in favour of various sodium–glucose transporter-2 inhibitor (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1 RA) accumulates, prescriptions of these agents continue to stagnate, even among eligible, at-risk patients. By contrast, dipeptidyl peptidase-4 inhibitors (DPP-4i) DPP-4i remain more widely used than SGLT2i and GLP-1 RA in these patients, despite a similar cost to SGLT2i and a large body of evidence showing no clear benefit on cardiorenal outcomes. We are a group of diabetologists united by a shared concern that clinical inertia is preventing these patients from receiving life-saving treatments, as well as placing them at greater risk of hospitalisation for heart failure and progression of renal disease. We propose a manifesto for change, in order to increase uptake of SGLT2i and GLP-1 RA in appropriate patients as a matter of urgency, especially those who could be readily switched from an agent without proven cardiorenal benefit. Central to our manifesto is a shift from linear treatment algorithms based on HbA1c target setting to parallel, independent considerations of atherosclerotic cardiovascular disease, heart failure and renal risks, in accordance with newly updated guidelines. Finally, we call upon all colleagues to play their part in implementing our manifesto at a local level, ensuring that patients do not pay a heavy price for continued clinical inertia in T2D.
TL;DR: It is reported here that cancer cells from different tissues can be toggled between transformed and rigidity-dependent growth states by the absence or presence of mechanosensory modules, respectively.
Abstract: A common feature of cancer cells is the alteration of kinases and biochemical signalling pathways enabling transformed growth on soft matrices, whereas cytoskeletal protein alterations are thought to be a secondary issue. However, we report here that cancer cells from different tissues can be toggled between transformed and rigidity-dependent growth states by the absence or presence of mechanosensory modules, respectively. In various cancer lines from different tissues, cells had over tenfold fewer rigidity-sensing contractions compared with normal cells from the same tissues. Restoring normal levels of cytoskeletal proteins, including tropomyosins, restored rigidity sensing and rigidity-dependent growth. Further depletion of other rigidity sensor proteins, including myosin IIA, restored transformed growth and blocked sensing. In addition, restoration of rigidity sensing to cancer cells inhibited tumour formation and changed expression patterns. Thus, the depletion of rigidity-sensing modules through alterations in cytoskeletal protein levels enables cancer cell growth on soft surfaces, which is an enabling factor for cancer progression. A range of cancer cell types are shown to lack rigidity-sensing due to alteration in specific cytoskeletal sensor proteins and this sensing ability can be reversed from a transformed to a rigidity-dependent growth state by the sensor proteins, resulting in restoration of contractility and adhesion.
TL;DR: The aim is to review the latest technological and methodical advances in teleophthalmology and highlight their implementation in screening and managing various ocular conditions as well as potential diagnostic and treatment applications in view of the recent SARS-CoV-2 virus outbreak.
Abstract: Technological advances in recent years have resulted in the development and implementation of various modalities and techniques enabling medical professionals to remotely diagnose and treat numerous medical conditions in diverse medical fields, including ophthalmology. Patients who require prolonged isolation until recovery, such as those who suffer from COVID-19, present multiple therapeutic dilemmas to their caregivers. Therefore, utilizing remote care in the daily workflow would be a valuable tool for the diagnosis and treatment of acute and chronic ocular conditions in this challenging clinical setting. Our aim is to review the latest technological and methodical advances in teleophthalmology and highlight their implementation in screening and managing various ocular conditions. We present them as well as potential diagnostic and treatment applications in view of the recent SARS-CoV-2 virus outbreak. A computerized search from January 2017 up to March 2020 of the online electronic database PubMed was performed, using the following search strings: “telemedicine,” “telehealth,” and “ophthalmology.” More generalized complementary contemporary research data regarding the COVID-19 pandemic was also obtained from the PubMed database. A total of 312 records, including COVID-19-focused studies, were initially identified. After exclusion of non-relevant, non-English, and duplicate studies, a total of 138 records were found eligible. Ninety records were included in the final qualitative analysis. Teleophthalmology is an effective screening and management tool for a range of adult and pediatric acute and chronic ocular conditions. It is mostly utilized in screening of retinal conditions such as retinopathy of prematurity, diabetic retinopathy, and age-related macular degeneration; in diagnosing anterior segment condition; and in managing glaucoma. With improvements in image processing, and better integration of the patient’s medical record, teleophthalmology should become a more accepted modality, all the more so in circumstances where social distancing is inflicted upon us.
TL;DR: In light of the importance of the glycocalyx in preserving endothelial cell integrity and its involvement in pathological conditions, several promising therapeutic strategies have been suggested to restore the damaged glycocalyX and to attenuate its deleterious consequences.
Abstract: The glycocalyx is a layer coating the luminal surface of vascular endothelial cells. It is vital for endothelial function as it participates in microvascular reactivity, endothelium interaction with blood constituents, and vascular permeability. Structural and functional damage to glycocalyx occurs in various disease states. A prominent clinical situation characterized by glycocalyx derangement is ischemia-reperfusion (I/R) of the whole body as well as during selective I/R to organs such as the kidney, heart, lung, or liver. Degradation of the glycocalyx is now considered a cornerstone in I/R-related endothelial dysfunction, which further impairs local microcirculation with a feed-forward loop of organ damage, due to vasoconstriction, leukocyte adherence, and activation of the immune response. Glycocalyx damage during I/R is evidenced by rising plasma levels of its principal constituents, heparan sulfate and syndecan-1. By contrast, the concentrations of these compounds in the circulation decrease after successful protective interventions in I/R, suggesting their use as surrogate biomarkers of endothelial integrity. In light of the importance of the glycocalyx in preserving endothelial cell integrity and its involvement in pathologic conditions, several promising therapeutic strategies to restore the damaged glycocalyx and to attenuate its deleterious consequences have been suggested. This review focuses on alterations of glycocalyx during I/R injury in general (to vital organs in particular), and on maneuvers aimed at glycocalyx recovery during I/R injury.
TL;DR: It is the impression that the adoption of these guidelines would help reduce the burden of RSV andPalivizumab guidelines should reflect the latest evidence.
University of Bristol1, International Agency for Research on Cancer2, Fred Hutchinson Cancer Research Center3, National Institutes of Health4, University of Leeds5, German Cancer Research Center6, University of Melbourne7, Royal Melbourne Hospital8, Kaiser Permanente9, University of Virginia10, University of Barcelona11, University of Hamburg12, Imperial College London13, Ohio State University14, Cedars-Sinai Medical Center15, University of Southern California16, Lunenfeld-Tanenbaum Research Institute17, American Cancer Society18, Cancer Council Victoria19, Monash University, Clayton campus20, Dresden University of Technology21, University of Washington22, Johns Hopkins University23, University of North Carolina at Chapel Hill24, Chonnam National University25, University of Hawaii26, Karolinska Institutet27, Karolinska University Hospital28, University of León29, Utrecht University30, Memorial Sloan Kettering Cancer Center31, Cornell University32, Rappaport Faculty of Medicine33, University of Pittsburgh34, University of Utah35, University of Ioannina36, Huntsman Cancer Institute37, Wageningen University and Research Centre38, Umeå University39, Charles University in Prague40, First Faculty of Medicine, Charles University in Prague41, Academy of Sciences of the Czech Republic42, Memorial University of Newfoundland43, Vanderbilt University44
TL;DR: Adiposity was associated with numerous metabolic alterations, but none of these explained associations between adiposity and CRC, and it is suggested that higher BMI more greatly raises CRC risk among men, whereas higher WHR more greatly rises CRCrisk among women.
Abstract: Higher adiposity increases the risk of colorectal cancer (CRC), but whether this relationship varies by anatomical sub-site or by sex is unclear. Further, the metabolic alterations mediating the effects of adiposity on CRC are not fully understood. We examined sex- and site-specific associations of adiposity with CRC risk and whether adiposity-associated metabolites explain the associations of adiposity with CRC. Genetic variants from genome-wide association studies of body mass index (BMI) and waist-to-hip ratio (WHR, unadjusted for BMI; N = 806,810), and 123 metabolites from targeted nuclear magnetic resonance metabolomics (N = 24,925), were used as instruments. Sex-combined and sex-specific Mendelian randomization (MR) was conducted for BMI and WHR with CRC risk (58,221 cases and 67,694 controls in the Genetics and Epidemiology of Colorectal Cancer Consortium, Colorectal Cancer Transdisciplinary Study, and Colon Cancer Family Registry). Sex-combined MR was conducted for BMI and WHR with metabolites, for metabolites with CRC, and for BMI and WHR with CRC adjusted for metabolite classes in multivariable models. In sex-specific MR analyses, higher BMI (per 4.2 kg/m2) was associated with 1.23 (95% confidence interval (CI) = 1.08, 1.38) times higher CRC odds among men (inverse-variance-weighted (IVW) model); among women, higher BMI (per 5.2 kg/m2) was associated with 1.09 (95% CI = 0.97, 1.22) times higher CRC odds. WHR (per 0.07 higher) was more strongly associated with CRC risk among women (IVW OR = 1.25, 95% CI = 1.08, 1.43) than men (IVW OR = 1.05, 95% CI = 0.81, 1.36). BMI or WHR was associated with 104/123 metabolites at false discovery rate-corrected P ≤ 0.05; several metabolites were associated with CRC, but not in directions that were consistent with the mediation of positive adiposity-CRC relations. In multivariable MR analyses, associations of BMI and WHR with CRC were not attenuated following adjustment for representative metabolite classes, e.g., the univariable IVW OR for BMI with CRC was 1.12 (95% CI = 1.00, 1.26), and this became 1.11 (95% CI = 0.99, 1.26) when adjusting for cholesterol in low-density lipoprotein particles. Our results suggest that higher BMI more greatly raises CRC risk among men, whereas higher WHR more greatly raises CRC risk among women. Adiposity was associated with numerous metabolic alterations, but none of these explained associations between adiposity and CRC. More detailed metabolomic measures are likely needed to clarify the mechanistic pathways.
TL;DR: The risk of infection by COVID-19 appears to be reduced by half among current smokers, which may reveal unique infection mechanisms present for CO VID-19 which may be targeted to combat the disease and reduce its infection rate.
Abstract: BACKGROUND Smokers are generally more susceptible to infectious respiratory diseases and are at higher risk of developing severe complications from these infections. Conflicting reports exist regarding the impact of smoking on the risk of Coronavirus disease 2019 (COVID-19). METHODS We carried out a population-based study among over 3,000,000 adult members of Clalit Health Services, the largest health provider in Israel. Since the beginning of the disease outbreak, and until May 16, 2020, over 145,000 adults underwent RT-PCR testing for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), and 3.3% had positive results. We performed a case-control study among patients who underwent SARS-CoV-2 testing, to assess the impact of smoking on infection incidence and severity. Individuals with positive tests were matched in a 1:5 ratio to individuals tested negative, of the same sex, age, and ethnicity/religion. Conditional logistic regressions were performed to evaluate odds ratios for current and previous smoking on the risk of testing positive. Multivariable logistic regressions were performed among patients infected with COVID-19 to estimate the association between smoking and fatal or severe disease requiring ventilation. Regressions were performed with and without adjustment for preexisting medical conditions. RESULTS Current smokers (9.8%) were significantly less prevalent among members tested positive compared to the general population (19.4%, P CONCLUSION The risk of infection by COVID-19 appears to be reduced by half among current smokers. This intriguing finding may reveal unique infection mechanisms present for COVID-19 which may be targeted to combat the disease and reduce its infection rate.
TL;DR: The photoplethysmography-based device was found similar to the gold-standard sphygmomanometer- based device with high agreement and reliability levels, which might enable a reliable, more convenient method for repeated BP monitoring.
Abstract: Repeated blood pressure (BP) measurements allow better control of hypertension. Current measurements rely on cuff-based devices. The aim of the present study was to compare BP measurements using a novel cuff-less photoplethysmography-based device to a standard sphygmomanometer device. Males and females were recruited from within the general population who arrived at a public BP screening station. One to two measurements were taken from each using a sphygmomanometer-based and the photoplethysmography-based devices. Devices were considered equal if the mean difference between paired measurements was below 5 mmHg and the Standard Deviation (SD) was no greater than 8 mmHg. Agreement and reliability analyses were also performed. 1057 subjects were included in the study analysis. There were no adverse events during the study. The mean (± SD) difference between paired measurements for all subjects was -0.1 ± 3.6 mmHg for the systolic and 0.0 ± 3.5 mmHg for the diastolic readings. We found 96.31% agreement in identifying hypertension and an Interclass Correlation Coefficient of 0.99 and 0.97 for systolic and diastolic measurements, respectively. The photoplethysmography-based device was found similar to the gold-standard sphygmomanometer-based device with high agreement and reliability levels. The device might enable a reliable, more convenient method for repeated BP monitoring.
TL;DR: It is essential to commence with targeted studies to learn from the current pandemic, with the possibility of preemptive intervention, depending on the findings and time course of the continuing pandemic.
Abstract: The viral pandemic of the coronavirus disease 2019 (COVID-19), generated by a novel mutated severe acute respiratory syndrome coronavirus (SARS-CoV-2), has become a serious worldwide public health emergency, evolving exponentially. While the main organ targeted in this disease is the lungs, other vital organs, such as the heart and kidney, may be implicated. The main host receptor of the SARS-CoV-2 is angiotensin converting enzyme 2 (ACE2), a major component of the renin-angiotensin-aldosterone system (RAAS). The ACE2 is also involved in testicular male regulation of steroidogenesis and spermatogenesis. As the SARS-CoV-2 may have the potential to infect the testis via ACE2 and adversely affect male reproductive system, it is essential to commence with targeted studies to learn from the current pandemic, with the possibility of preemptive intervention, depending on the findings and time course of the continuing pandemic.
04 May 2020
TL;DR: Two techniques are presented that enable continuous and noninvasive cuff-less BP estimation using photoplethysmography (PPG) signals with Convolutional Neural Networks (CNNs) and are as accurate as the values estimated by many home BP measuring devices.
Abstract: Blood pressure (BP) is a vital sign of the human body and an important parameter for early detection of cardiovascular diseases. It is usually measured using cuff-based devices or monitored invasively in critically-ill patients. This paper presents two techniques that enable continuous and noninvasive cuff-less BP estimation using photoplethysmography (PPG) signals with Convolutional Neural Networks (CNNs). The first technique is calibration-free. The second technique achieves a more accurate measurement by estimating BP changes with respect to a patient's PPG and ground truth BP values at calibration time. For this purpose, it uses Siamese network architecture. When trained and tested on the MIMIC-II database, it achieves mean absolute difference in the systolic and diastolic BP of 5.95 mmHg and 3.41 mmHg respectively. These results almost comply with the AAMI recommendation and are as accurate as the values estimated by many home BP measuring devices.
TL;DR: Critical pieces of the FAO machinery have been identified that have the potential to be targeted for improved treatment of patients with TNBC, especially the claudin-low molecular subtype.
Abstract: Recent studies have suggested that fatty acid oxidation (FAO) is a key metabolic pathway for the growth of triple negative breast cancers (TNBCs), particularly those that have high expression of MYC. However, the underlying mechanism by which MYC promotes FAO remains poorly understood. We used a combination of metabolomics, transcriptomics, bioinformatics, and microscopy to elucidate a potential mechanism by which MYC regulates FAO in TNBC. We propose that MYC induces a multigenic program that involves changes in intracellular calcium signalling and fatty acid metabolism. We determined key roles for fatty acid transporters (CD36), lipases (LPL), and kinases (PDGFRB, CAMKK2, and AMPK) that each contribute to promoting FAO in human mammary epithelial cells that express oncogenic levels of MYC. Bioinformatic analysis further showed that this multigenic program is highly expressed and predicts poor survival in the claudin-low molecular subtype of TNBC, but not other subtypes of TNBCs, suggesting that efforts to target FAO in the clinic may best serve claudin-low TNBC patients. We identified critical pieces of the FAO machinery that have the potential to be targeted for improved treatment of patients with TNBC, especially the claudin-low molecular subtype.
TL;DR: This is the first study to show that early cardiac remodeling nurtures tumor growth and metastasis and therefore promotes cancer progression, and highlights the importance of early diagnosis and treatment of cardiac remodelling because it may attenuate cancer progression and improve cancer outcome.
Abstract: Background: Recent evidence suggests that cancer and cardiovascular diseases are associated. Chemotherapy drugs are known to result in cardiotoxicity, and studies have shown that heart failure and ...
TL;DR: Three consecutive patients with advanced post-allo-SCT relapse, whose residual disease was eradicated following administration of daratumumab, provided on a compassionate basis are described.
Abstract: Prognosis of patients with advanced relapse of T-cell acute lymphoblastic leukemia (T-ALL) or CD19/CD22-negative ALL relapsing following allogeneic stem cell transplantation (allo-SCT) is poor. Currently available therapy for relapsed T or CD19/CD22-negative ALL is based on intensive chemotherapy and may lead to complete remission (CR). Among the general ALL population, patients experiencing multiple relapses, central nervous system (CNS) involvement or early relapse after transplant are at a particularly high risk [1, 2]. Moreover, in such patients, detection of minimal residual disease (MRD) following intensive therapy may be predictive of an ultimate disease relapse, if no further effective therapy is prescribed [2]. Given that leukemic blasts commonly express CD38, daratumumab, a recombinant monoclonal antihuman CD38 antibody approved for myeloma therapy, has been suggested to be also potent in acute leukemia. Evidence of daratumumab efficacy in T-ALL has been demonstrated in preclinical studies on the mouse model [3, 4]. To the best of knowledge, there is only one previously reported case of successful remission induction with daratumumab in a patient with Philadelphia chromosome positive refractory B-ALL [5] and one report of MRD eradication in a patient who developed advanced relapse following allo-SCT [6]. We herein describe three consecutive patients with advanced post-allo-SCT relapse, whose residual disease was eradicated following administration of daratumumab, provided on a compassionate basis. The patients received intensive chemotherapy for a third or fourth early relapse, achieved remission but remained MRD. At that point, all of them were treated with daratumumab at doses and schedules identical to the myeloma protocol and achieved MRD remission after 3–4 doses of induction. All the patients are currently alive and in MRD remission for 44, 43, and 5 weeks, respectively. Multiparameter flow cytometry was employed for MRD monitoring, using the antibody panels based on patient-specific leukemia-associated aberrant immunophenotypes, with surface CD3, cytoplasmatic CD3, and CD45 being the backbone. Patient 1 is a 24-year-old male who presented in May 2016 with T-cell lymphoblastic lymphoma involving the mediastinum, while neither the bone marrow (BM) nor the CNS was affected. Following ECOG 2993-based induction therapy, his PET became negative. At that point, additional three cycles of high-dose methotrexate and consolidation were prescribed followed by the maintenance therapy. In August 2017, a relapse involving BM and CNS was diagnosed, and a second remission was achieved after therapy with mitoxantrone+ high-dose cytarabine (HiDAC). During CR2, following total body irradiation conditioning, the patient underwent allo-SCT from his matched brother. Three and a half months post transplant he experienced a third relapse affecting the BM and extramedullary sites (skin and lymph nodes). He was treated with two cycles of nelarabine 1.5 g/m per day on days 1, 3, and 5 and following that BM examination demonstrated remission, while flow cytometry identified 0.09% of CD38+ residual disease cells. Daratumumab was then administered as per a * Yishai Ofran y_ofran@rambam.health.gov.il