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BACKGROUND: Patients with chronic gastrointestinal disease such as inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), celiac disease, gastroesophageal reflux disease (GERD), pancreatitis, and chronic liver disease (CLD) often suffer from obesity because of coincidence (IBD, IBS, celiac disease) or related pathophysiology (GERD, pancreatitis and CLD). It is unclear if such patients need a particular diagnostic and treatment that differs from the needs of lean gastrointestinal patients. The present guideline addresses this question according to current knowledge and evidence.OBJECTIVE: The present practical guideline is intended for clinicians and practitioners in general medicine, gastroenterology, surgery and other obesity management, including dietitians and focuses on obesity care in patients with chronic gastrointestinal diseases.METHODS: The present practical guideline is the shortened version of a previously published scientific guideline developed according to the standard operating procedure for ESPEN guidelines. The content has been re-structured and transformed into flow-charts that allow a quick navigation through the text.RESULTS: In 100 recommendations (3× A, 33× B, 24 × 0, 40× GPP, all with a consensus grade of 90% or more) care of gastrointestinal patients with obesity - including sarcopenic obesity - is addressed in a multidisciplinary way. A particular emphasis is on CLD, especially metabolic associated liver disease, since such diseases are closely related to obesity, whereas liver cirrhosis is rather associated with sarcopenic obesity. A special chapter is dedicated to obesity care in patients undergoing bariatric surgery. The guideline focuses on adults, not on children, for whom data are scarce. Whether some of the recommendations apply to children must be left to the judgment of the experienced pediatrician.CONCLUSION: The present practical guideline offers in a condensed way evidence-based advice how to care for patients with chronic gastrointestinal diseases and concomitant obesity, an increasingly frequent constellation in clinical practice.

Contains fulltext : 290886.pdf (Publisher’s version ) (Closed access) This guideline will inform physicians, nurses, dieticians, pharmacists, caregivers and other home parenteral nutrition (HPN) providers, as well as healthcare administrators and policy makers, about appropriate and safe HPN provision. This guideline will also inform patients requiring HPN. The guideline is based on previous published guidelines and provides an update of current evidence and expert opinion; it consists of 71 recommendations that address the indications for HPN, central venous access device (CVAD) and infusion pump, infusion catheter and CVAD site care, nutritional admixtures, program monitoring and management. Meta-analyses, systematic reviews and single clinical trials based on clinical questions were searched according to the PICO format. The evidence was evaluated and used to develop clinical recommendations implementing Scottish Intercollegiate Guidelines Network methodology. The guideline was commissioned and financially supported by ESPEN and members of the guideline group were selected by ESPEN.

The present guideline is an update and extension of the ESPEN scientific guideline on Clinical Nutrition in Inflammatory Bowel Disease published first in 2017. The guideline has been rearranged according to the ESPEN practical guideline on Clinical Nutrition in Inflammatory Bowel Disease published in 2020. All recommendations have been checked and, if needed, revised based on new literature, before they underwent the ESPEN consensus procedure. Moreover, a new chapter on microbiota modulation as a new option in IBD treatment has been added. The number of recommendations has been increased to 71 recommendations in the guideline update. The guideline is aimed at professionals working in clinical practice, either in hospitals or in outpatient medicine, and treating patients with IBD. General aspects of care in patients with IBD, and specific aspects during active disease and in remission are addressed. All recommendations are equipped with evidence grades, consensus rates, short commentaries and links to cited literature.

Comparison ofS-adenosyl-l-methionine (SAM) analogue generation by halide methyltransferase (HMT) and methionine adenosyltransferase (MAT) for methyltransferase catalysed alkylation., Methyltransferases provide excellent specificity in late-stage alkylation of biomolecules. Their dependence onS-adenosyl-l-methionine (SAM) mandates efficient access to SAM analogues for biocatalytic applications. We directly compared halide methyltransferase (HMT) and methionine adenosyltransferase (MAT) to access SAM analogues and explored their utility in cascade reactions with NovO for regioselective, late-stage Friedel-Crafts alkylation of a coumarin. The HMT cascade efficiently provided SAM for methylation, while the MAT cascade also supplied high levels of SAM analogues for alkylation reactions.

Tidal stream currents change in magnitude and direction during flood and ebb tides. Setting the most appropriate yaw angles for a tidal turbine is not only important to account for the performance of a single turbine, but can also be significant for the interactions between the turbines within an array. In this paper, a partial differentiation equation (PDE) constrained optimisation approach is established based on the Thetis coastal ocean modelling framework. The PDE constraint takes the form here of the two-dimensional, depth-averaged shallow water equations which are used to simulate tidal elevations and currents in the presence of tidal stream turbine arrays. The Sequential Least Squares Programming (SLSQP) algorithm is applied with a gradient obtained via the adjoint method in order to perform array design optimisation. An idealised rectangular channel test case is studied to demonstrate this optimisation framework. Located in the centre of the computational domain, arrays comprised of 12 turbines are tested in aligned and staggered layouts. The setups are initially optimised based on their yaw angles alone. In turn, turbine coordinates and yaw angles are also optimized simultaneously. Results indicate that for an aligned turbine array case under steady state conditions, the energy output can be increased by approximately 80\% when considering yaw angle optimisation alone. For the staggered turbine array, the increase is approximately 30\%. The yaw optimised staggered array is able to outperform the yaw optimised aligned array by approximately 8\%. If both layout and the yaw angles of the turbines are considered within the optimisation then the increase is more significant compared with optimising yaw angle alone.

A novel single-use bioreactor was recently introduced to the market that is agitated by impellers suspended on flexible ropes rather than a rigid shaft. Computational fluid dynamics (CFD) models were created and validated by particle image velocimetry (PIV) to predict the bioreactor’s fluid flow and mixing. The data were then used to scale-up a Spodoptera frugiperda, subclone 9 (Sf9) insect cell-based production of recombinant adeno-associated virus (AAV) from a benchtop glass bioreactor to the single-use system with 30 L working volume. This viral vector is one of the most commonly used in gene therapies. The volumetric power input was kept constant while maintaining reasonable mixing times and shear stresses between the scales. Peak cell densities of up to 7.2·10^6 cells/mL and maximum virus titers of 1.7·10^11vg/mL were achieved. Similar cell growth and metabolite profiles further proved the successful process transfer between the two geometrically non-similar bioreactor systems. The pilot bioreactor yielded between 3.3 and 4.8·10^15 vg that, depending on the therapy, can be sufficient for the treatment of a single patient.

Background: In patients with coronary artery disease and concomitant asymptomatic severe carotid stenosis, combined simultaneous coronary artery bypass grafting (CABG) and carotid endarterectomy (CEA) has been widely performed despite lack of evidence from randomized trials. We recently showed that the risk of stroke or death within 30 days was higher following CABG+CEA compared with CABG alone. Here, we report long-term outcomes following CABG with versus without CEA. Methods: The CABACS (Coronary Artery Bypass Graft Surgery in Patients With Asymptomatic Carotid Stenosis Study) is a randomized, controlled, multicenter, open trial. Patients with asymptomatic severe (≥70%) carotid stenosis undergoing CABG were allocated either CABG+CEA or CABG alone, and follow-up was 5 years. Major secondary end points included nonfatal stroke or death, any death and any nonfatal stroke. Due to low recruitment, the study was stopped prematurely after randomization of 127 patients in 17 centers. Results: By 5 years, the rate of stroke or death did not significantly differ between groups (CABG+CEA 40.6% [95% CI, 0.285–0.536], CABG alone 35.0% [95% CI, 0.231–0.484]; P =0.58). Higher albeit statistically nonsignificant rates of nonfatal strokes occurred at any time following CABG+CEA versus CABG alone (1 year: 19.3% versus 7.1%, P =0.09; 5 years: 29.4% versus 18.8%, P =0.25). All-cause mortality up to 5 years was similar in both groups (CABG+CEA: 25.4% versus CABG alone: 23.3%, hazard ratio, 1.148 [95% CI, 0.560–2.353]; P =0.71). Subgroup analyses did not reveal any significant effect of age, sex, preoperative modified Rankin Scale and center on outcome events. Conclusions: During 5-years follow-up, combined simultaneous CABG+CEA was associated with a higher albeit statistically nonsignificant rate of stroke or death compared with CABG alone. This was mainly due to a nonsignificantly higher perioperative risk following CABG+CEA. Since the power of our study was not sufficient, no significant effect of either procedure could be observed at any time during follow-up. Registration: URL: http://www.controlled-trials.com ; Unique identifier: ISRCTN13486906.

Zusammenfassung Hintergrund Die mediterrane Ernährung (MedE) zeigte in mehreren Studien einen präventiven Effekt hinsichtlich Typ 2 Diabetes, kardiovaskulären Erkrankungen und Tumorerkrankungen. Zur MedE wird in der Regel ein mäßiger Konsum von Wein, speziell Rotwein, empfohlen, dem selbst ein kardioprotektiver Effekt zugesprochen wird. Jedoch zeigen zahlreiche Studien, dass schon kleine Mengen Alkohol das Krebsrisiko erhöhen können. In der vorliegenden Arbeit soll eine Übersicht zur aktuellen Datenlage zum Zusammenhang zwischen dem Alkoholkonsum im Rahmen einer MedE, dem Krebsrisiko sowie dem Risiko für kardiovaskuläre Erkrankungen erstellt werden. Methoden Im Rahmen einer systematischen Literaturrecherche in den Datenbanken PubMed und Scopus wurde nach den Schlagwörtern „diet, mediterranean“ und „alcohol drinking“ gesucht. Voraussetzung war, dass Angaben zur Art und Menge des konsumierten Alkohols im Rahmen der MedE vorlagen. Ergebnisse Die Umsetzung der MedE kann sowohl das Risiko kardiometabolischer Erkrankungen als auch das Krebsrisiko u. a. für Brustkrebs senken. Moderater Alkoholkonsum zeigt protektive Effekte auf das Herz-Kreislauf-System, ist jedoch mit einem erhöhten Risiko für diverse Krebserkrankungen assoziiert. Mehrere Studien beschreiben eine Assoziation zwischen Alkoholkonsum und Brustkrebsinzidenz, wobei die Ergebnisse zwischen den Studien nicht einheitlich waren. Dabei kommt dem täglichen Glas Rotwein mit ca. 10–15 g Ethanol als vorherrschendem alkoholischen Getränk der Mittelmeerregion eine risikosenkende Wirkung zu. Schlussfolgerung Moderater Konsum von Rotwein hat nach der vorliegenden systematischen Literaturanalyse, anders als andere alkoholische Getränke, einen protektiven Effekt auf kardiometabolische Erkrankungen und möglicherweise auch auf genetisch bedingten Brustkrebs, während der Konsum von anderen Alkoholgetränken die schützende Wirkung einer MedE möglicherweise reduziert.

Background: Patients with chronic gastrointestinal (GI) disease such as inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), celiac disease, gastroesophageal reflux disease (GERD), pancrea-titis, and chronic liver disease (CLD) often suffer from obesity because of coincidence (IBD, IBS, celiac disease) or related pathophysiology (GERD, pancreatitis and CLD). It is unclear if such patients need a particular diagnostic and treatment that differs from the needs of lean GI patients. The present guideline addresses this question according to current knowledge and evidence.Objective: The objective of the guideline is to give advice to all professionals working in the field of gastroenterology care including physicians, surgeons, dietitians and others how to handle patients with GI disease and obesity.Methods: The present guideline was developed according to the standard operating procedure for ESPEN guidelines, following the Scottish Intercollegiate Guidelines Network (SIGN) grading system (A, B, 0, and good practice point (GPP)). The procedure included an online voting (Delphi) and a final consensus conference.Results: In 100 recommendations (3x A, 33x B, 24x 0, 40x GPP, all with a consensus grade of 90% or more) care of GI patients with obesity -including sarcopenic obesity -is addressed in a multidisciplinary way. A particular emphasis is on CLD, especially fatty liver disease, since such diseases are closely related to obesity, whereas liver cirrhosis is rather associated with sarcopenic obesity. A special chapter is dedi-cated to obesity care in patients undergoing bariatric surgery. The guideline focuses on adults, not on children, for whom data are scarce. Whether some of the recommendations apply to children must be left to the judgment of the experienced pediatrician.Conclusion: The present guideline offers for the first time evidence-based advice how to care for patients with chronic GI diseases and concomitant obesity, an increasingly frequent constellation in clinical practice.(c) 2022 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Omega-6 and omega-3 polyunsaturated fatty acids (PUFAs) are precursors of pro- and anti-inflammatory lipid mediators. Serum PUFA levels could influence the severity of inflammatory oral diseases, such as gingivitis.The study analyzed serum PUFA levels in a six-week randomized controlled trial in individuals on the Mediterranean diet (MedD), associations with the intake of specific foods, and possible correlations with oral inflammatory parameters.Data from 37 study participants on either a MedD (MedDG; n = 18) or a "Western diet" in the control group (CG, n = 19) were analyzed. Dental examinations and serum analyses were performed at two time points, T1 (baseline) and T2 (week 6). Serum PUFA status, adherence to the MedD, and data from a Food Frequency Questionnaire were analyzed.Within the MedDG omega-6 fatty acid levels decreased significantly. In the overall sample, the proportional decrease in sites with bleeding on probing correlated weakly to moderately with the decrease in total omega-6 fatty acid level (Spearman's ρ = 0.274) and the decrease in gingival index correlated moderately with the decrease in linoleic acid level (Spearman's ρ = 0.351). Meat and fast-food consumption correlated positively with levels of various omega-6 fatty acids, whereas nut, fish, and dairy product consumption correlated positively with omega-3 levels.Adherence to a MedD was associated with a decrease in serum omega-6 levels, which positively affected the omega-6/omega-3 ratio. The MedD associated reduction in serum omega-6 levels may be a mechanism that favorably affects gingival inflammatory parameters.

The Upper Silurian Salina Group of eastern North America is well known for its thick evaporite successions and hydrocarbon resources. These strata have been assigned to numerous chronostratigraphic schemes within Ohio and Michigan and are currently identified by varying subsurface and outcrop nomenclatural schemes. These chronostratigraphic challenges have persisted for over 50 yr and dramatically inhibit the correlation of events recorded in the Silurian section of eastern North America with the global record of Silurian biogeochemical events. To help resolve the chronostratigraphic correlation of these units, we provide new high-resolution δ13Ccarb chemostratigraphic analyses of a core located in central Ohio for strata assigned to the Greenfield and Tymochtee Formations and integrate existing biostratigraphic, chemostratigraphic, and subsurface geophysical data in western, southern, and eastern Ohio. The new data presented here, integrated for the first time with basinwide subsurface geophysical data, demonstrate a mid-late Homerian Stage global sea-level lowstand, suggest a short interval of tectonic stability within the study area at the beginning of “Salina B–G” deposition, during which accommodation was occupied by the Greenfield Formation and laterally equivalent strata, and provide chronostratigraphic constraints for basin flexure and potential forebulge migration associated with renewed tectonic activity. The new chronostratigraphic correlation of these strata provides a broader picture of Silurian environmental change across the eastern half of the Laurentian paleocontinent.

Background Patients with chronic gastrointestinal (GI) disease such as inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), celiac disease, gastroesophageal reflux disease (GERD), pancreatitis, and chronic liver disease (CLD) often suffer from obesity because of coincidence (IBD, IBS, celiac disease) or related pathophysiology (GERD, pancreatitis and CLD). It is unclear if such patients need a particular diagnostic and treatment that differs from the needs of lean GI patients. The present guideline addresses this question according to current knowledge and evidence. Objective The objective of the guideline is to give advice to all professionals working in the field of gastroenterology care including physicians, surgeons, dietitians and others how to handle patients with GI disease and obesity. Methods The present guideline was developed according to the standard operating procedure for European Society for Clinical Nutrition and Metabolism guidelines, following the Scottish Intercollegiate Guidelines Network grading system (A, B, 0, and good practice point [GPP]). The procedure included an online voting (Delphi) and a final consensus conference. Results In 100 recommendations (3x A, 33x B, 24x 0, 40x GPP, all with a consensus grade of 90% or more) care of GI patients with obesity - including sarcopenic obesity - is addressed in a multidisciplinary way. A particular emphasis is on CLD, especially fatty liver disease, since such diseases are closely related to obesity, whereas liver cirrhosis is rather associated with sarcopenic obesity. A special chapter is dedicated to obesity care in patients undergoing bariatric surgery. The guideline focuses on adults, not on children, for whom data are scarce. Whether some of the recommendations apply to children must be left to the judgment of the experienced pediatrician. Conclusion The present guideline offers for the first time evidence-based advice how to care for patients with chronic GI diseases and concomitant obesity, an increasingly frequent constellation in clinical practice.

Wastewater, which contains everything from pathogens to pollutants, is a geospatially-and temporally-linked microbial fingerprint of a given population. As a result, it can be leveraged for monitoring multiple dimensions of public health across locales and time. Here, we integrate targeted and bulk RNA sequencing (n=1,419 samples) to track the viral, bacterial, and functional content over geospatially distinct areas within Miami Dade County from 2020-2022. First, we used targeted amplicon sequencing (n=966) to track diverse SARS-CoV-2 variants across space and time, and we found a tight correspondence with clinical caseloads from University students (N = 1,503) and Miami-Dade County hospital patients (N = 3,939 patients), as well as an 8-day earlier detection of the Delta variant in wastewater vs. in patients. Additionally, in 453 metatranscriptomic samples, we demonstrate that different wastewater sampling locations have clinically and public-health-relevant microbiota that vary as a function of the size of the human population they represent. Through assembly, alignment-based, and phylogenetic approaches, we also detect multiple clinically important viruses (e.g., norovirus ) and describe geospatial and temporal variation in microbial functional genes that indicate the presence of pollutants. Moreover, we found distinct profiles of antimicrobial resistance (AMR) genes and virulence factors across campus buildings, dorms, and hospitals, with hospital wastewater containing a significant increase in AMR abundance. Overall, this effort lays the groundwork for systematic characterization of wastewater to improve public health decision making and a broad platform to detect emerging pathogens.

ZusammenfassungDie Durchführung der parenteralen Ernährung im ambulanten Bereich wird durch zahlreiche Verunsicherungen behindert. Der niedergelassene Arzt ist nicht selten unzureichend vertraut mit der komplexen Materie und wendet sich an die Verordnungsberatung der Kassenärztlichen Vereinigung. Typische Fragen zur parenteralen Ernährung betreffen die Indikation, die wirtschaftliche Verordnungsweise von Ernährungsprodukten, von Hilfsmitteln und Verbandstoffen und auch von häuslicher Krankenpflege. Somit geht es um Evidenz, aber auch um Transparenz und Rechtsicherheit bei der Anwendung von Dreikammerbeuteln (60-70 % der Anwendungen) und durch compounding individuell zubereitete Ernährungsbeutel (30-40 % der Anwendungen). Antworten auf diese Fragen sollen im folgenden Leitfaden gegeben werden, der im Auftrag der Kassenärztlichen Vereinigung Baden-Württemberg basierend auf aktuellen S3-Leitlinien zum Thema erstellt wurde. Auf die Risiken eines Ökonomie-basierten Steuerungsmodel für heimparenterale Ernährung wird eingegangen, da eine solche Therapievorgabe eine mögliche Einschränkung von Patientenkomfort und Patientensicherheit bedeuten kann. Der Leitfaden bietet dem niedergelassenen Arzt nicht nur in Baden-Württemberg eine alternative Orientierung zur praktischen Durchführung der heimparenteralen Ernährung. Infusionstherapien, die den in diesem Leitfaden genannten Behandlungskriterien entsprechen und deren Indikationsstellung, Kontrolle und notwendige Dauer patientenbezogen durch ausreichende Dokumentation nachgewiesen werden kann, gelten in der Regel als wirtschaftlich, sagt die Kassenärztlichen Vereinigung Baden-Württemberg.

Background Cardiovascular disease (CVD) is an important cause of morbidity and mortality in breast cancer survivors. Effective screening modalities to identify CVD risk are lacking in this population. Adrenomedullin (ADM) has been suggested as a biomarker for subclinical cardiac dysfunction in the general population. Levels of ADM have been proven to be responsive to lifestyle changes that lead to improved cardiovascular health. As BRCA1/2 mutation carriers are deemed to be at an increased risk for CVD, the aim of this study was to examine plasma ADM levels in a cohort of BRCA mutation carriers and to assess their association with cardiovascular risk factors.Methods Plasma ADM concentrations were measured in 292 female BRCA1/2 mutation carriers with and without a history of breast cancer. Subjects were classified into high versus low ADM levels based on the median ADM level in the entire cohort (13.8 pg/mL). Logistic regression models were used to estimate the odds ratios (OR) of having elevated ADM levels by several cardiovascular risk factors.Results Of all women (median age: 43 years), 57.5% had a previous diagnosis of breast cancer. The median time between diagnosis and study entry was three years (range: 0 – 32 years). Women presenting with metabolic syndrome had 22-fold increased odds of having elevated ADM levels (p Conclusions This is the first study in BRCA mutation carriers that has linked circulating ADM levels to traditional cardiovascular risk factors. The long-term clinical implications of these findings are yet to be determined.

Objective: the switch between nonseizure and seizure states involves profound alterations in network excitability and synchrony. In this study, we aimed to identify and compare features of neural excitability and dynamics across multiple zebrafish seizure and epilepsy models. Methods: inspired by video-electroencephalographic recordings in patients, we developed a framework to study spontaneous and photically evoked neural and locomotor activity in zebrafish larvae, by combining high-throughput behavioral tracking and whole-brain in vivo two-photon calcium imaging. Results: our setup allowed us to dissect behavioral and physiological features that are divergent or convergent across multiple models. We observed that spontaneous locomotor and neural activity exhibit great diversity across models. Nonetheless, during photic stimulation, hyperexcitability and rapid response dynamics were well conserved across multiple models, highlighting the reliability of photically evoked activity for high-throughput assays. Intriguingly, in several models, we observed that the initial elevated photic response is often followed by rapid decay of neural activity and a prominent depressed state. Elevated photic response and following depressed state in seizure-prone networks are significantly reduced by the antiseizure medication valproic acid. Finally, rapid decay and depression of neural activity following photic stimulation temporally overlap with slow recruitment of astroglial calcium signals that are enhanced in seizure-prone networks. Significance We argue that fast decay of neural activity and depressed states following photic response are likely due to homeostatic mechanisms triggered by excessive neural activity. An improved understanding of the interplay between elevated and depressed excitability states might suggest tailored epilepsy therapies., European Research Council (ERC); European Union (EU); Horizon 2020; Helse Midt--Norge; Norges Forskningsrad

International audience; CHARGE syndrome is a rare congenital disorder frequently caused by mutations in the chromodomain helicase DNA-binding protein-7 CHD7. Here, we developed and systematically characterized two genetic mouse models with identical, heterozygous loss-of-function mutation of the Chd7 gene engineered on inbred and outbred genetic backgrounds. We found that both models showed consistent phenotypes with the core clinical manifestations seen in CHARGE syndrome, but the phenotypes in the inbred Chd7 model were more severe, sometimes having reduced penetrance and included dysgenesis of the corpus callosum, hypoplasia of the hippocampus, abnormal retrosplenial granular cortex, ventriculomegaly, hyperactivity, growth delays, impaired grip strength and repetitive behaviors. Interestingly, we also identified previously unreported features including reduced levels of basal insulin and reduced blood lipids. We suggest that the phenotypic variation reported in individuals diagnosed with CHARGE syndrome is likely due to the genetic background and modifiers. Finally, our study provides a valuable resource, making it possible for mouse biologists interested in Chd7 to make informed choices on which mouse model they should use to study phenotypes of interest and investigate in more depth the underlying cellular and molecular mechanisms.

Background Clinical complexity is increasingly prevalent among patients with atrial fibrillation (AF). The ‘Atrial fibrillation Better Care’ (ABC) pathway approach has been proposed to streamline a more holistic and integrated approach to AF care; however, there are limited data on its usefulness among clinically complex patients. We aim to determine the impact of ABC pathway in a contemporary cohort of clinically complex AF patients. Methods From the ESC-EHRA EORP-AF General Long-Term Registry, we analysed clinically complex AF patients, defined as the presence of frailty, multimorbidity and/or polypharmacy. A K-medoids cluster analysis was performed to identify different groups of clinical complexity. The impact of an ABC-adherent approach on major outcomes was analysed through Cox-regression analyses and delay of event (DoE) analyses. Results Among 9966 AF patients included, 8289 (83.1%) were clinically complex. Adherence to the ABC pathway in the clinically complex group reduced the risk of all-cause death (adjusted HR [aHR]: 0.72, 95%CI 0.58–0.91), major adverse cardiovascular events (MACEs; aHR: 0.68, 95%CI 0.52–0.87) and composite outcome (aHR: 0.70, 95%CI: 0.58–0.85). Adherence to the ABC pathway was associated with a significant reduction in the risk of death (aHR: 0.74, 95%CI 0.56–0.98) and composite outcome (aHR: 0.76, 95%CI 0.60–0.96) also in the high-complexity cluster; similar trends were observed for MACEs. In DoE analyses, an ABC-adherent approach resulted in significant gains in event-free survival for all the outcomes investigated in clinically complex patients. Based on absolute risk reduction at 1 year of follow-up, the number needed to treat for ABC pathway adherence was 24 for all-cause death, 31 for MACEs and 20 for the composite outcome. Conclusions An ABC-adherent approach reduces the risk of major outcomes in clinically complex AF patients. Ensuring adherence to the ABC pathway is essential to improve clinical outcomes among clinically complex AF patients.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) in wastewater has been used to track community infections of coronavirus disease-2019 (COVID-19), providing critical information for public health interventions. Since levels in wastewater are dependent upon human inputs, we hypothesize that tracking infections can be improved by normalizing wastewater concentrations against indicators of human waste [Pepper Mild Mottle Virus (PMMoV), β-2 Microglobulin (B2M), and fecal coliform]. In this study, we analyzed SARS-CoV-2 and indicators of human waste in wastewater from two sewersheds of different scales: a University campus and a wastewater treatment plant. Wastewater data were combined with complementary COVID-19 case tracking to evaluate the efficiency of wastewater surveillance for forecasting new COVID-19 cases and, for the larger scale, hospitalizations. Results show that the normalization of SARS-CoV-2 levels by PMMoV and B2M resulted in improved correlations with COVID-19 cases for campus data using volcano second generation (V2G)-qPCR chemistry (

Millions of transcriptome samples were generated by the Library of Integrated Network-based Cellular Signatures (LINCS) program. When these data are processed into searchable signatures along with signatures extracted from Genotype-Tissue Expression (GTEx) and Gene Expression Omnibus (GEO), connections between drugs, genes, pathways and diseases can be illuminated. SigCom LINCS is a webserver that serves over a million gene expression signatures processed, analyzed, and visualized from LINCS, GTEx, and GEO. SigCom LINCS is built with Signature Commons, a cloud-agnostic skeleton Data Commons with a focus on serving searchable signatures. SigCom LINCS provides a rapid signature similarity search for mimickers and reversers given sets of up and down genes, a gene set, a single gene, or any search term. Additionally, users of SigCom LINCS can perform a metadata search to find and analyze subsets of signatures and find information about genes and drugs. SigCom LINCS is findable, accessible, interoperable, and reusable (FAIR) with metadata linked to standard ontologies and vocabularies. In addition, all the data and signatures within SigCom LINCS are available via a well-documented API. In summary, SigCom LINCS, available at https://maayanlab.cloud/sigcom-lincs, is a rich webserver resource for accelerating drug and target discovery in systems pharmacology.

The Global Leadership Initiative on Malnutrition (GLIM) provides consensus criteria for the diagnosis of malnutrition that can be widely applied. The GLIM approach is based on the assessment of three phenotypic (weight loss, low body mass index, and low skeletal muscle mass) and two etiologic (low food intake and presence of disease with systemic inflammation) criteria, with diagnosis confirmed by any combination of one phenotypic and one etiologic criterion fulfilled. Assessment of muscle mass is less commonly performed than other phenotypic malnutrition criteria, and its interpretation may be less straightforward, particularly in settings that lack access to skilled clinical nutrition practitioners and/or to body composition methodologies. In order to promote the widespread assessment of skeletal muscle mass as an integral part of the GLIM diagnosis of malnutrition, the GLIM consortium appointed a working group to provide consensus-based guidance on assessment of skeletal muscle mass. When such methods and skills are available, quantitative assessment of muscle mass should be measured or estimated using dual-energy x-ray absorptiometry, computerized tomography, or bioelectrical impedance analysis. For settings where these resources are not available, then the use of anthropometric measures and physical examination are also endorsed. Validated ethnic- and sex-specific cutoff values for each measurement and tool are recommended when available. Measurement of skeletal muscle function is not advised as surrogate measurement of muscle mass. However, once malnutrition is diagnosed, skeletal muscle function should be investigated as a relevant component of sarcopenia and for complete nutrition assessment of persons with malnutrition.

ZusammenfassungZahlreiche Studien haben gezeigt, dass die mediterrane Ernährung vor ernährungsmitbedingten Erkrankungen wie Übergewicht, Diabetes mellitus Typ 2, Herz-Kreislauf-Erkrankungen und verschiedenen Krebsentitäten, einschließlich Brustkrebs, schützen kann. Die zugrunde liegenden Mechanismen sind jedoch weitgehend unklar. Bislang wurde vor allem die Rolle antiinflammatorischer Fettsäuren diskutiert. In der vorliegenden Übersichtsarbeit soll am Beispiel des genetisch determinierten sowie des sporadischen Brustkrebses der Frage nachgegangen werden, welche Rolle das Darmmikrobiom spielen könnte, dessen Zusammensetzung und Funktion durch die mediterrane Ernährung verändert wird.

Submesoscale eddies, fronts, and filaments are ubiquitous in the upper ocean and play an important role in biogeochemical and mixing processes as well as in the energy budget. To capture the high spatial variability of submesoscale processes, it is desirable to simultaneously resolve the vertical and horizontal gradients of hydrographic properties on scales of 10 m to 10 km. We present a revised towed CTD chain, for rapid quasi-synoptic in situ measurements of submesoscale oceanographic features, that is lighter, more robust and scientifically more useful than previous towed CTD chains. This new instrument provides a horizontal resolution of O(1 m) and can be towed at speeds of up to 5 ms-1 for measurements of the upper 100 m of the water column while providing a reasonable vertical resolution of O(1 m – 10 m). Individual CTD probes are equipped with temperature, conductivity, pressure and either rapid response dissolved oxygen or fluorescence sensors at multiple depths, enabling both hydrographic and biogeochemical studies at high resolution. A flexible probe hardware allows either real-time data collection or internal data logging for offline post-processing. Finally, we outline the necessary post-processing steps and provide data examples. With the presented data examples we show and conclude that the advanced towed CTD chain is a flexible and lightweight take on the towed CTD chain concept. It can easily be adapted to scientific needs and provides high quality very high resolution oceanographic data.

The Swarm data products are well-suited to address a number of crucial topics for space weather science and monitoring, such as investigating spatial and temporal characteristics of ionospheric irregularities or improving topside approaches in ionospheric models for monitoring and forecasting the dynamics of the geo-plasma environment. Precision and safety of life applications using trans-ionospheric signals require key information on space weather conditions in particular on the perturbation degree of the ionosphere. Such applications are particularly vulnerable against severe spatial gradients and rapid changes of the electron density (Ne) as well as the total electron content (TEC) measured along different satellite‐receiver links. Here, we propose two new Swarm products 1) the TEC Gradient Ionosphere indeX (TEGIX) and 2) the Ne Gradient Ionosphere indeX (NEGIX). The TEGIX estimates spatial TEC gradients in the topside ionosphere (Swarm up to GNSS orbit) using GNSS Precise Orbit Determination (POD) measurements whereas the NEGIX estimates spatial Ne gradients using Swarm onboard Langmuir probe (LP) measurements (2 Hz sampled). The approach takes benefit from the coordinated flight of satellites A and C at an orbit height of about 460 km. We will present a first version of both products and will explore their potential impact, utility, and use through case studies.Acknowledgement:The work is funded by the MIGRAS (Monitoring of Ionospheric Gradients At SWARM) project under the Swarm DISC Subcontract Doc. no: SW‐CO‐DTU‐GS‐133, Rev: 1.

The ESA Swarm satellites have since year 2014 provided measurements of electron density at a frequency of 2 Hz and at times also 16 Hz corresponding to about 500 m along the satellite paths. Spectral indices, structure functions and scaling exponents of these 16 Hz density estimates were analyzed to study the F-region ionospheric irregularities at altitudes between about 425 and 510 km. The data were obtained during the period from October 2014 to October 2022.The Power Spectral Densities (PSDs) observed followed to a very good approximation a power law. The values of spectral indices p obtained showed a peak centered at around -2.5, located at the Equatorial Ionization Anomaly (EIA) belts. The largest contribution to the spectra came from in the South American-Antlantic-African longitudes and it was generally low in the Asian-Pacific region. The angle between the Swarm satellite orbital path and the magnetic field (∠(B, v)) was examined. The highest percentage of occurrence of ionospheric irregularities and the peak in spectral index was obtained for ∠(B, v) between 0° and about 40°. Over this range of angles PSD spectra steepened with increasing ∠(B, v) (p becomes increasingly negative), consistent with local anisotropic turbulence at scales of a few km. The probability distributions of density differences (structure functions) are non-Gaussian at all orders, similar to many other observations in space plasma. The scaling exponent function is non-linearly concave, which is usually taken as a sign of intermittency.

Obesity is characterized by low-grade inflammation and increased gut permeability. Here, we aim to evaluate the effect of a nutritional supplement on these parameters in subjects with overweight and obesity. A double-blinded, randomized clinical trial was conducted in 76 adults with overweight or obesity (BMI 28 to 40) and low-grade inflammation (high-sensitivity C-reactive protein (hs-CRP) between 2 and 10 mg/L). The intervention consisted of a daily intake of a multi-strain probiotic of Lactobacillus and Bifidobacterium, 640 mg of omega-3 fatty acids (n-3 FAs), and 200 IU of vitamin D (n = 37) or placebo (n = 39), administered for 8 weeks. hs-CRP levels did not change post-intervention, other than an unexpected slight increase observed in the treatment group. Interleukin (IL)-6 levels decreased in the treatment group (p = 0.018). The plasma fatty acid (FA) levels of the arachidonic acid (AA)/eicosapentaenoic acid (EPA) ratio and n-6/n-3 ratio (p < 0.001) decreased, and physical function and mobility improved in the treatment group (p = 0.006). The results suggest that hs-CRP may not be the most useful inflammatory marker, but probiotics, n-3 FAs, and vitamin D, as non-pharmaceutical supplements, may exert modest effects on inflammation, plasma FA levels, and physical function in patients with overweight and obesity and associated low-grade inflammation.

The British Association for Psychopharmacology developed an evidence-based consensus guideline on the management of catatonia. A group of international experts from a wide range of disciplines was assembled. Evidence was gathered from existing systematic reviews and the primary literature. Recommendations were made on the basis of this evidence and were graded in terms of their strength. The guideline initially covers the diagnosis, aetiology, clinical features and descriptive epidemiology of catatonia. Clinical assessments, including history, physical examination and investigations are then considered. Treatment with benzodiazepines, electroconvulsive therapy and other pharmacological and neuromodulatory therapies is covered. Special regard is given to periodic catatonia, malignant catatonia, neuroleptic malignant syndrome and antipsychotic-induced catatonia. There is attention to the needs of particular groups, namely children and adolescents, older adults, women in the perinatal period, people with autism spectrum disorder and those with certain medical conditions. Clinical trials were uncommon, and the recommendations in this guideline are mainly informed by small observational studies, case series and case reports, which highlights the need for randomised controlled trials and prospective cohort studies in this area.

S1: LSD1 inhibition reduces cell viability and migration capacities. S2: Multivariate analysis shows no significant expression differences for the studied genes in between untreated A549 and cisplatin treated A549 cells. S3: IHC staining shows colocalization of LSD1 and PLK1 in LUAD. Table S1: Cell line information Table S2: Primer sequences used for qPCR Table S3: Antibodies used for western blotting and IF

PDF file - 456K, Table S1: Growth inhibition of NCI-60 panel of cancer cell lines by L002 (NSC764414); Supplemental Figure 1: Distribution of hits in the primary potentiator screen ; Supplemental Figure 2: Hit distribution in the primary and counterscreen assays ; Supplemental Figure 3: Fluorescence-based in vitro p300 inhibition assay ; Supplemental Figure 4: Summary of the HTS campaign ; Supplemental Figure 5: L002 does not inhibit HDACs ; Supplemental Figure 6: L002 does not inhibit HMTs ; Supplemental Figure 7: Impacts of L002 and other hits on histone modifications

Lysine-specific demethylase 1 (LSD1) is a histone modifier that is highly overexpressed in lung adenocarcinoma, which results in aggressive tumor biology. Tumor cell proliferation and migration analysis after LSD1 inhibition in the lung adenocarcinoma cell line PC9, using the LSD1 inhibitor HCI-2509 and siRNA, demonstrated that LSD1 activity was essential for proliferation and migration capacities of tumor cells. Moreover, reduced proliferation rates after LSD1 inhibition were shown to be associated with a cell-cycle arrest of the tumor cells in the G2–M-phase. Expression profiling followed by functional classification and pathway analysis indicated prominent repression of the polo-like kinase 1 (PLK1) pathway upon LSD1 inhibition. In contrast, transient overexpression of exogenous PLK1 plasmid rescued the LSD1 inhibition–mediated downregulation of PLK1 pathway genes. Mechanistically, LSD1 directly regulates expression of PLK1 by binding to its promoter region that subsequently affects expression of its downstream target genes. Notably, using lung adenocarcinoma TCGA datasets a significant correlation between LSD1 and PLK1 along with its downstream targets was observed. Furthermore, the LSD1/PLK1 linkage was confirmed by IHC analysis in a clinical lung adenocarcinoma cohort (n = 43). Conclusively, this is the first study showing a direct transcriptional link between LSD1 and PLK1.Implications:These findings point to a role of LSD1 in regulating PLK1 and thus efficient G2–M-transition–mediating proliferation of tumor cells and suggest targeting the LSD1/PLK1 axis as a novel therapeutic approach for lung adenocarcinoma treatment.

Acetyltransferase p300 (KAT3B) plays key roles in signaling cascades that support cancer cell survival and sustained proliferation. Thus, p300 represents a potential anticancer therapeutic target. To discover novel anticancer agents that target p300, we conducted a high-throughput screening campaign. A library of 622,079 compounds was assayed for cytotoxicity to the triple-negative breast cancer (TNBC) cell line MDA-MB-231 but not to the human mammary epithelial cells. The resulting compounds were tested in a biochemical assay for inhibiting the enzymatic activity of p300. One compound (L002, NSC764414) displayed an IC50 of 1.98 μmol/L against p300 in vitro, inhibited acetylation of histones and p53, and suppressed STAT3 activation in cell-based assays. L002 could be docked to the active site of the p300 catalytic domain. Biochemical tests of a series of related compounds revealed functional groups that may impact inhibitory potency of L002 against p300. Interestingly, these analogs showed inhibitory activities against the cellular paralog of p300 (CBP), p300/CBP-associated factor, and GCN5, but not to other acetyltransferases (KAT5, KAT6B, and KAT7), histone deacetylases, and histone methyltransferases. Among the NCI-60 panel of cancer cell lines, leukemia and lymphoma cell lines were extremely sensitive to L002, whereas it is toxic to only a limited number of cell lines derived from solid tumors. Notably, breast cancer cell lines, especially those derived from TNBC, were highly susceptible to L002. In vivo, it potently suppressed tumor growth and histone acetylation of MDA-MB-468 xenografts. Thus, these new acetyltransferase inhibitors are potential anticancer therapeutics. Mol Cancer Ther; 12(5); 610–20. ©2013 AACR.

Numerical studies of ice flow have consistently identified the grounding zone of outlet glaciers and ice streams (the region where ice starts to float) as crucial for predicting the rate of grounded ice loss to the ocean. Owing to the extreme environments and difficulty of access to ocean cavities beneath ice shelves, field observations are rare. Estimates of melt rates derived from satellites are also difficult to make near grounding zones with confidence. Therefore, numerical ocean models are important tools to investigate these critical and remote regions. The relative inflexibility of structured grid models means, however, that they can struggle to resolve these processes in irregular cavity geometries near grounding zones. To help solve this issue, we present a new nonhydrostatic unstructured mesh model for flow under ice shelves built using the Firedrake finite element framework. We demonstrate our ability to simulate full ice shelf cavity domains using the community standard ISOMIP+ Ocean0 test case and compare our results against those obtained with the popular MITgcm model. Good agreement is found between the two models, despite their use of different discretisation schemes and the sensitivity of the melt rate parameterisation to grid resolution. Verification tests based on the Method of Manufactured Solutions (MMS) show that the new model discretisation is sound and second-order accurate. A main driver behind using Firedrake is the availability of an automatically generated adjoint model. Our first adjoint calculations, of sensitivities of melt rate with respect to different inputs in an idealised grounding zone domain, are promising and point to the ability to address a number of important questions on ocean influence on ice shelf vulnerability in the future.

PI3K-targeting therapy represents one of the most sought-after therapies for glioblastoma (GBM). Several small-molecule inhibitors have been evaluated in clinical trials, however, the emergence of resistance limits treatment potential. Here, we generated a patient-derived glioma sphere–forming cell (GSC) xenograft model resistant to the PI3K-specific inhibitor BKM-120. Integrated RNA sequencing and high-throughput drug screening revealed that the Aurora A kinase (Aurora A)/Polo-like kinase 1 (PLK1)/cyclin-dependent kinase 1 (CDK1) signaling pathway was the main driver of PI3K inhibitor resistance in the resistant xenografts. Aurora kinase was upregulated and pCDK1 was downregulated in resistant tumors from both xenografts and tumor tissues from patients treated with the PI3K inhibitor. Mechanistically, the tyrosine kinase receptor Tie2 physically interacted with FGFR1, promoting STAT3 phosphorylation and binding to the AURKA promoter, which increased Aurora A expression in resistant GSCs. Concurrent inhibition of Aurora A and PI3K signaling overcame PI3K inhibitor–induced resistance. This study offers a proof of concept to target PI3K and the collateral-activated pathway to improve GBM therapy.Significance:These findings provide novel insights into the mechanisms of PI3K inhibitor resistance in glioblastoma.

Compounds map of high-throughput drug screening

This file contains supplementary Figure S1 to S6, and Table S3 and S4.

RPPA antibody list

Full drug names and the abbreviations

Supplementary Fig. 1: Ectopic PIK3CAH1047R expression induces a modest activation of the EGFR downstream signaling pathway in BEAS-2B clones. Supplementary Fig. 2: the steady state level of miR-29b and the relative copy number of the miR-29b2 locus are significantly correlated in KRAS/EGFR wildtype tumors. Supplementary Fig. 3: miR-138 expression is not induced by mutant KRAS or mutant EGFR in adenocarcinoma tissues. Supplementary Fig. 4: Inhibitors of the EGFR signaling pathway downregulate expression of key downstream effectors. Supplementary Fig. 5: miR-29b confers resistance to TNFalpha+ActD-induced apoptosis. Supplementary Fig. 6: TNFAIP3 is a target of miR-29b. Supplementary Fig. 7: miR-29b sensitizes A549 cells to cisplatin-induced apoptosis.

Patient characteristics.

A global understanding of miRNA function in EGFR signaling pathways may provide insights into improving the management of KRAS-mutant lung cancers, which remain relatively recalcitrant to treatment. To identify miRNAs implicated in EGFR signaling, we transduced bronchial epithelial BEAS-2B cells with retroviral vectors expressing KRASG12V and monitored miRNA expression patterns by microarray analysis. Through this approach, we defined miR-29b as an important target for upregulation by mutant KRAS in non–small cell lung cancers. Cell biologic analyses showed that pharmacologic inhibition of EGFR or MEK was sufficient to reduce levels of miR-29b, while PI3K inhibition had no effect. In KRASG12V-transduced BEAS-2B cells, introduction of anti-miR-29b constructs increased the sensitivity to apoptosis, arguing that miR-29b mediated apoptotic resistance conferred by mutant KRAS. Mechanistic investigations traced this effect to the ability of miR-29b to target TNFAIP3/A20, a negative regulator of NF-κB signaling. Accordingly, overexpression of an miR-29b–refractory isoform of TNFAIP3 restored NF-κB and extrinsic apoptosis, confirming that TNFAIP3 is a functionally relevant target of miR-29b. We also noted that miR-29b could confer sensitivity to intrinsic apoptosis triggered by exposure to cisplatin, a drug used widely in lung cancer treatment. Thus, miR-29b expression may tilt cells from extrinsic to intrinsic mechanisms of apoptosis. Overall, our results reveal a complexity in cancer for miR-29b, which can act as either an oncogene or tumor suppressor gene depending on signaling context. Cancer Res; 76(14); 4160–9. ©2016 AACR.