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Abstract Heat pumps (HPs) have emerged as a key technology for reducing energy use and greenhouse gas emissions. This study evaluates the potential switch to air-to-air HPs (AAHPs) in Toulouse, France, where conventional space heating is split between electric and gas sources. In this context, we find that AAHPs reduce heating energy consumption by 57% to 76%, with electric heating energy consumption decreasing by 6% to 47%, resulting in virtually no local heating-related CO2 emissions. We observe a slight reduction in near-surface air temperature of up to 0.5 °C during cold spells, attributable to a reduction in sensible heat flux, which is unlikely to compromise AAHPs operational efficiency. While Toulouse’s heating energy mix facilitates large energy savings, electric energy consumption may increase in cities where gas or other fossil fuel sources prevail. Furthermore, as AAHPs efficiency varies with internal and external conditions, their impact on the electrical grid is more complex than conventional heating systems. The results underscore the importance of matching heating system transitions with sustainable electricity generation to maximize environmental benefits. The study highlights the intricate balance between technological advancements in heating and their broader environmental and policy implications, offering key insights for urban energy policy and sustainability efforts.

Schülerlabore haben unter anderem zum Ziel, die Motivation, insbesondere das Interesse – i.S. einer gegenstandsbezogenen Motivation – von Schüler*innen an MINT-Themen und -Arbeitsweisen zu fördern. Darüber hinaus konnten sie sich schneller und produktiver als die formalen Bildungsorte den Herausforderungen der digitalen Transformation stellen. Das Potenzial, Schülerlabore auch als innovative Orte der Lehrkräftefortbildung (LFB) zu nutzen und digitalisierungsbezogene Kompetenzen bei Lehrkräften aufzubauen, wurde bisher nicht ausgeschöpft. Im Verbundprojekt mit insgesamt acht Standorten werden Schülerlabore zu LFB-Labs-digital ausgebaut und die Frage nach Implementierungsvoraussetzungen gelingender Fortbildungen in der digitalen Welt im MINT-Bereich bearbeitet. In diesem Artikel werden die theoretische Fundierung, Ziele und anvisierten Forschungsarbeiten des Verbunds LFB-Labs-digital dargelegt. Zur Unterstützung der mit der forschungsbasierten Qualitätsentwicklung der MINT-bezogenen Aus-, Fort- und Weiterbildung von Lehrkräften betrauten Einrichtungen in den Ländern sollen in Kooperation mit dem Kompetenzzentrum MINT des Bundes die Lernorte „Schülerlabore“ für die digitale LFB erschlossen werden, um vermittelt hierüber die Motivation von Schüler*innen für die MINT-Fächer zu fördern. Die in den Schülerlaboren evaluierten und vom fächerübergreifenden adaptiven Qualitätsmanagement für die LFB wissenschaftlich begleiteten Good-Practice-Beispiele werden zur Grundlage für den „Referenzrahmen LFB-Labs-digital“. Dieser wird – vor dem Hintergrund einer Ergebnistriangulation aus der Begleitforschung sowie den damit parallelisierten Studien zur Evidenzbasierung der Lehrkräftequalifizierung in der digitalen Welt und dem Musterqualitätshandbuch LFB – entwickelt und von einem Implementierungsbeirat mit ausgewiesenen Expert*innen in diesem Bereich auf Transferoptionen hin geprüft. Die digitale Infrastruktur für die LFB-Labs-digital-Veranstaltungsformate wird hierzu prozessbegleitend ausgebaut.

Abstract A case of delayed-onset post-cataract-surgery keratitis and endophthalmitis, caused by the melanin-producing fungus Exophiala oligosperma, is presented. The patient presented with an infection at the corneal side-port wound 5 months after an uneventful phacoemulsification surgery. Despite pars plana vitrectomy and combination antifungal treatment, the patient required an evisceration of the globe. Limited clinical information is available about the treatment of eye infections caused by this organism.

Purpose – The US Government is challenged to maintain pace as the world’s de facto provider of space object cataloging data. Augmenting capabilities with nontraditional sensors present an expeditious and low-cost improvement. However, the large tradespace and unexplored system of systems performance requirements pose a challenge to successful capitalization. This paper aims to better define and assess the utility of augmentation via a multi-disiplinary study. Design/methodology/approach – Hypothetical telescope architectures are modeled and simulated on two separate days, then evaluated against performance measures and constraints using multi-objective optimization in a heuristic algorithm. Decision analysis and Pareto optimality identifies a set of high-performing architectures while preserving decision-maker design flexibility. Findings – Capacity, coverage and maximum time unobserved are recommended as key performance measures. A total of 187 out of 1017 architectures were identified as top performers. A total of 29% of the sensors considered are found in over 80% of the top architectures. Additional considerations further reduce the tradespace to 19 best choices which collect an average of 49–51 observations per space object with a 595–630 min average maximum time unobserved, providing redundant coverage of the Geosynchronous Orbit belt. This represents a three-fold increase in capacity and coverage and a 2 h (16%) decrease in the maximum time unobserved compared to the baseline government-only architecture as-modeled. Originality/value – This study validates the utility of an augmented network concept using a physics-based model and modern analytical techniques. It objectively responds to policy mandating cataloging improvements without relying solely on expert-derived point solutions.

Abstract Background and Aims Frail older adults are more than twice as likely to experience postoperative complications. Preoperative exercise may better prepare these patients through improved stamina and mobility experienced in the days following surgery. We measured the impact of a walking intervention using an activity tracker and coaching on postoperative stamina, and mobility in older adults with frailty traits. Methods We included patients aged 60+ and scoring 4+ on the Edmonton Frailty Scale. We then randomized patients to intervention versus control stratified by anticipated hospital stay (1 night vs. 2+ night) and baseline stamina (i.e., 6‐min walk distance [6MWD]). Intervention patients received an activity tracker and linked smart phone. An athletic trainer (AT) prescribed a daily step count goal and titrated this up after checking in with patients during weekly telephone calls. Controls received general walking recommendations. We then measured postoperative 6MWD 1–3 days after surgery. We also assessed postoperative mobility by measuring steps walked the day after surgery using a thigh‐worn monitor. Because many patients could not walk postoperatively, we compared intervention‐control difference in both 6MWD and steps using Wilcoxon rank testing and Tobit and ordinal logistic regression adjusting for several patient characteristics. Results We randomized 104 eligible patients; 80 patients remained for final analysis. There was no difference in intervention versus control postoperative 6MWD (median 72 vs. 74 m Wilcoxon p = 0.54) or postoperative steps taken (median 128 vs. 51 steps Wilcoxon p = 0.76). Analysis adjusting for patient characteristics was consistent with these findings. Conclusion Our intervention consisting of goal setting with an activity tracker and telephonic coaching by an AT did not appear to improve stamina or mobility measured in the days after surgery. Small sample size limited our ability to examine this impact in subsets defined by surgical specialty or baseline stamina.

Dynamic magnetic resonance imaging has emerged as a powerful modality for investigating upper-airway function during speech production. Analyzing the changes in the vocal tract airspace, including the position of soft-tissue articulators (e.g., the tongue and velum), enhances our understanding of speech production. The advent of various fast speech MRI protocols based on sparse sampling and constrained reconstruction has led to the creation of dynamic speech MRI datasets on the order of 80–100 image frames/second. In this paper, we propose a stacked transfer learning U-NET model to segment the deforming vocal tract in 2D mid-sagittal slices of dynamic speech MRI. Our approach leverages (a) low- and mid-level features and (b) high-level features. The low- and mid-level features are derived from models pre-trained on labeled open-source brain tumor MR and lung CT datasets, and an in-house airway labeled dataset. The high-level features are derived from labeled protocol-specific MR images. The applicability of our approach to segmenting dynamic datasets is demonstrated in data acquired from three fast speech MRI protocols: Protocol 1: 3 T-based radial acquisition scheme coupled with a non-linear temporal regularizer, where speakers were producing French speech tokens; Protocol 2: 1.5 T-based uniform density spiral acquisition scheme coupled with a temporal finite difference (FD) sparsity regularization, where speakers were producing fluent speech tokens in English, and Protocol 3: 3 T-based variable density spiral acquisition scheme coupled with manifold regularization, where speakers were producing various speech tokens from the International Phonetic Alphabetic (IPA). Segments from our approach were compared to those from an expert human user (a vocologist), and the conventional U-NET model without transfer learning. Segmentations from a second expert human user (a radiologist) were used as ground truth. Evaluations were performed using the quantitative DICE similarity metric, the Hausdorff distance metric, and segmentation count metric. This approach was successfully adapted to different speech MRI protocols with only a handful of protocol-specific images (e.g., of the order of 20 images), and provided accurate segmentations similar to those of an expert human.

Abstract Can we improve the modeling of urban land surface processes with machine learning (ML)? A prior comparison of urban land surface models (ULSMs) found that no single model is “best” at predicting all common surface fluxes. Here, we develop an urban neural network (UNN) trained on the mean predicted fluxes from 22 ULSMs at one site. The UNN emulates the mean output of ULSMs accurately. When compared to a reference ULSM (Town Energy Balance; TEB), the UNN has greater accuracy relative to flux observations, less computational cost, and requires fewer input parameters. When coupled to the Weather Research Forecasting (WRF) model using TensorFlow bindings, WRF‐UNN is stable and more accurate than the reference WRF‐TEB. Although the application is currently constrained by the training data (1 site), we show a novel approach to improve the modeling of surface fluxes by combining the strengths of several ULSMs into one using ML.

Abstract The treatment of cloud structure in numerical weather and climate models is often greatly simplified to make them computationally affordable. Here we propose to correct the European Centre for Medium‐Range Weather Forecasts 1D radiation scheme ecRad for 3D cloud effects using computationally cheap neural networks. 3D cloud effects are learned as the difference between ecRad's fast 1D Tripleclouds solver that neglects them and its 3D SPARTACUS (SPeedy Algorithm for Radiative TrAnsfer through CloUd Sides) solver that includes them but is about five times more computationally expensive. With typical errors between 20% and 30% of the 3D signal, neural networks improve Tripleclouds' accuracy for about 1% increase in runtime. Thus, rather than emulating the whole of SPARTACUS, we keep Tripleclouds unchanged for cloud‐free parts of the atmosphere and 3D‐correct it elsewhere. The focus on the comparably small 3D correction instead of the entire signal allows us to improve predictions significantly if we assume a similar signal‐to‐noise ratio for both.

Abstract There is limited guidance on the use of helicopter medical personnel to facilitate care of critically ill COVID‐19 patients. This manuscript describes the emergence of this novel virus, its mode of transmission, and the potential impacts on patient care in the unique environment of rotor wing aircraft. It details the development of clinical and operational guidelines for flight crew members. This allows other out‐of‐hospital clinicians to utilize our framework to augment or supplement their own for the current response effort to COVID‐19. It further serves as a road map for future response to the care of high consequence infectious disease patients.

Chronic Kidney Disease (CKD), a global health burden, is strongly associated with age-related renal function decline, hypertension, and diabetes, which are all frequent consequences of obesity. Despite extensive studies, the mechanisms determining susceptibility to CKD remain insufficiently understood. Clinical evidence together with prior studies from our group showed that perinatal metabolic disorders after intrauterine growth restriction or maternal obesity adversely affect kidney structure and function throughout life. Since obesity and aging processes converge in similar pathways we tested if perinatal obesity caused by high-fat diet (HFD)-fed dams sensitizes aging-associated mechanisms in kidneys of newborn mice. The results showed a marked increase of γH2AX-positive cells with elevated 8-Oxo-dG (RNA/DNA damage), both indicative of DNA damage response and oxidative stress. Using unbiased comprehensive transcriptomics we identified compartment-specific differentially-regulated signaling pathways in kidneys after perinatal obesity. Comparison of these data to transcriptomic data of naturally aged kidneys and prematurely aged kidneys of genetic modified mice with a hypomorphic allele of Ercc1, revealed similar signatures, e.g., inflammatory signaling. In a biochemical approach we validated pathways of inflammaging in the kidneys after perinatal obesity. Collectively, our initial findings demonstrate premature aging-associated processes as a consequence of perinatal obesity that could determine the susceptibility for CKD early in life.

Abstract Within the planetary boundary layer (PBL), surface forcing response, drag, turbulence, and vertical mixing are important processes and play a more critical role here than in the overlying “free atmosphere.” The PBL height (PBLH) is an important parameter in climate models, weather forecasts, and air quality prediction. The NASA Goddard Earth Sciences Data and Information Services Center (GES DISC) provides data processing, archiving, and distribution services for numerous Earth science products. PBLH is a parameter in three products served by GES DISC, which are from the atmospheric infrared sounder (AIRS), the global positioning system (GPS) radio occultation (RO) experiment, and the NASA reanalysis product Modern‐Era Retrospective analysis for Research and Applications‐2 (MERRA‐2). These products have different spatial and temporal resolutions and coverages, and their PBLH definitions are also different. To better serve the PBL research community, we have summarized the specifications of these products. A 10‐year seasonal mean intercomparison is also conducted to provide further guidance to users. The intercomparison results show that MERRA‐2 has a much shallower PBL than AIRS and GPS RO. An experimental study indicates that the different PBLH definition in MERRA‐2 caused smaller values of PBLH. The improvement of the water vapor retrieval in AIRS version 7 over version 6 results in the version 7 PBLH agreeing better with GPS RO and MERRA‐2 than version 6, especially near the equator and low latitudes.

Background Non-compressible truncal hemorrhage (NCTH) is the leading cause of preventable death after trauma. Resuscitative endovascular balloon occlusion of the aorta (REBOA) achieves temporary hemorrhage control, supporting cardiac and cerebral perfusion prior to definitive hemostasis. Aortic zone selection algorithms vary among institutions. We evaluated the efficacy of an algorithm for REBOA use.Methods A multicenter prospective, observational study conducted at six level 1 trauma centers over 12 months. Inclusion criteria were age >15 years with evidence of infradiaphragmatic NCTH needing emergent hemorrhage control within 60 min of ED arrival. An algorithm characterized by the results of focused assessment with sonography in trauma and pelvic X-ray was assessed post hoc for efficacy in a cohort of patients receiving REBOA.Results Of the 8166 patients screened, 78 patients had a REBOA placed. 21 patients were excluded, leaving 57 patients for analysis. The algorithm ensures REBOA deployment proximal to hemorrhage source to control bleeding in 98.2% of cases and accurately predicts the optimal REBOA zone in 78.9% of cases. If the algorithm was violated, bleeding was optimally controlled in only 43.8% (p=0.01). Three (75.0%) of the patients that received an inappropriate zone 1 REBOA died, two from multiple organ failure (MOF). All three patients that died with an inappropriate zone 3 REBOA died from exsanguination.Discussion This algorithm ensures proximal hemorrhage control and accurately predicts the primary source of hemorrhage. We propose a new algorithm that will be more inclusive. A zone 3 REBOA should not be performed when a zone 1 is indicated by the algorithm as 100% of these patients exsanguinated. MOF, perhaps from visceral ischemia in patients with an inappropriate zone 1 REBOA, may have been prevented with zone 3 placement or limited zone 1 occlusion time.Level of evidence Level III.

Satellite remote sensing and model data play an important role in research and applications of tropical meteorology and climatology over vast, data-sparse oceans and remote continents. Since the first weather satellite was launched by NASA in 1960, a large collection of NASA’s Earth science data is freely available to the research and application communities around the world, significantly improving our overall understanding of the Earth system and environment. Established in the mid-1980s, the NASA Goddard Earth Sciences Data and Information Services Center (GES DISC), located in Maryland, USA, is a data archive center for multidisciplinary, satellite and model assimilation data products. As one of the 12 NASA data centers in Earth sciences, GES DISC hosts several important NASA satellite missions for tropical meteorology and climatology such as the Tropical Rainfall Measuring Mission (TRMM), the Global Precipitation Measurement (GPM) Mission and the Modern-Era Retrospective analysis for Research and Applications (MERRA). Over the years, GES DISC has developed data services to facilitate data discovery, access, distribution, analysis and visualization, including Giovanni, an online analysis and visualization tool without the need to download data and software. Despite many efforts for improving data access, a significant number of challenges remain, such as finding datasets and services for a specific research topic or project, especially for inexperienced users or users outside the remote sensing community. In this article, we list and describe major NASA satellite remote sensing and model datasets and services for tropical meteorology and climatology along with examples of using the data and services, so this may help users better utilize the information in their research and applications.

Evaluating the health status of marine ecosystems becomes ever increasingly important especially against the backdrop of rising pressures from human activities. This is true especially for coastal seas such as the Baltic Sea that is surrounded by highly industrialized countries. Nutrients and pollutants such as nitrate and hydrogen sulfide, which have a major impact on ecosystem functioning, are two of several key environmental indicators for assessing the status of natural waters, and therefore of considerable interest. The frequency and the spatial coverage of the nitrate and hydrogen sulfide measurements are currently limited by the cost of the laboratory analysis and personnel. Optical in situ sensors can help to overcome this challenge by allowing reagentless and fast detection of dissolved chemical species. A chemical-free optical sensor has been used for direct and simultaneous measurements of both key parameters, and the results were compared with traditional methods. The data were collected during an observational program conducted in the Baltic Sea in February 2018. We used the OPUS UV spectral sensor, which was deployed for the first time in coastal waters, in combination with a deep-sea telemetry system to enable near-real time measurements during CTD profiling. Data processing was carried out using a multiple linear regression procedure. Measurements from both OPUS and on-board analysis were in good agreement. The results showed, that in situ UV-VIS spectrophotometry provides the capability to determine the concentration distributions of nitrate and hydrogen sulfide in the brackish waters of the Baltic Sea.

Background: The systemic and ocular manifestations of diabetes are an increasing burden on both private and public healthcare systems. The ability to accurately predict patient susceptibility and prognostic implications of the disease is essential to its optimal management and planning. Aim: The purpose of this paper was to review alternative biomarkers to those currently in use regarding the diagnosis and prognosis of diabetes and the ocular effects of the disease. Current biomarkers include Fasting Plasma Glucose (FPG), Oral Glucose Tolerance Test (OGTT) and Glycolated Haemoglobin (HbA1c). Methods: The research strategy comprised of a comprehensive literature review of articles from Mendeley, Cochrane and Elsevier with additional input from experts in the field serving as co-authors. Results: The review found that there are alternative biomarkers to those currently utilised. These include adiponectin, apolipoprotein B, C-reactive protein and ferritin. Fructosamine, while useful where whole blood is available, is unreliable as a diagnostic biomarker resulting in a 10% variation coefficient. Post-prandial glucose (PPG) measurement most closely predicted HbA1c. Conclusion: With prediction of risk for diabetes in individuals, a value combination, expressed as either a numerical score or a percentage, consisting of adiponectin, apolipoprotein B, C-reactive protein and ferritin, almost doubled the relative risk of contracting the disease. Eye care practitioners need to question diabetic patients about their FPG and HbA1c levels and encourage them to have the relevant tests regularly, including PPG. The importance of biomarkers should be emphasised and used as an educational tool to facilitate better diabetes management and treatment adherence.

The deep basins of the Baltic Sea, including the Gotland and Landsort Deeps, are well-known for the exceptional occurrence of sedimentary Mn carbonate. Although the details of the mechanisms of Mn carbonate formation are still under debate, a close relationship with episodic major Baltic inflows (MBIs) is generally assumed, at least for the Gotland Basin. However, the few studies on Mn cycling during MBIs suffer from a limited temporal resolution. Here we report on Mn dynamics in the water column and sediments of the Gotland Deep following an MBI that entered the Baltic Sea in December 2014. Water column profiles of dissolved Mn were obtained at a monthly to bi-monthly resolution between February 2015 and March 2017 and revealed an impact of the MBI on the Gotland Deep bottom waters beginning in March 2015. Water column profiles and budget estimates provided evidence for remarkable losses of dissolved Mn associated with the enhanced deposition of Mn oxide particles, as documented in sediment trap samples and surface sediments. In July 2015, subsequent to the nearly full oxygenation of the water column, clear signals of the re-establishment of bottom water anoxia appeared, interrupted by a second inflow pulse around February 2016. However, dissolved Mn concentrations of up to 40 μM in the bottom waters in June 2016 again indicated a pronounced reduction of Mn oxide and the escape of dissolved Mn back into the open water column. The absence of substantial amounts of Mn carbonate in the surface sediments at the end of the observation period suggested that the duration of bottom water oxygenation plays an important role in the formation of this mineral. Data from both an instrumental time series and a dated sediment core from the Gotland Deep supported this conclusion. Enhanced Mn carbonate formation occurred especially between the 1960s and mid-1970s, when several MBIs caused a long-lasting oxygenation of the water column. By contrast, Mn carbonate layers were much less pronounced or even missing after single MBIs in 1993, 2003, and 2014, each of which provided a comparatively short-term supply of O2 to the deeper water column.

This paper describes the "strucplot" framework for the visualization of multi-way contingency tables. Strucplot displays include hierarchical conditional plots such as mosaic, association, and sieve plots, and can be combined into more complex, specialized plots for visualizing conditional independence, GLMs, and the results of independence tests. The framework's modular design allows flexible customization of the plots' graphical appearance, including shading, labeling, spacing, and legend, by means of "graphical appearance control" functions. The framework is provided by the R package vcd.

Being among the most popular and efficient classification and regression methods currently available, implementations of support vector machines exist in almost every popular programming language. Currently four R packages contain SVM related software. The purpose of this paper is to present and compare these implementations.

Periocular infantile capillary hemangiomas do not always respond well to conventional treatment modalities such as systemic or intralesional corticosteroids, radiotherapy or debulking surgery. The authors describe the use of intralesional bleomycin injections (IBIs) to treat potentially amblyogenic lesions in two cases where other modalities have failed. In both cases monthly IBIs successfully cleared the visual axis of the affected eye before the age of 1 year thus preventing permanent sensory deprivation amblyopia. A total of five and nine injections, respectively, were used and no significant side effects were noted. IBI appears to be a useful alternative in the treatment of periocular capillary hemangiomas refractory to more conventional modalities.

This article was prompted by the response to the results of an earlier publication (Meyer 1995) which sought to establish actual practice regarding medium of instruction at matric level in formerly DET black secondary schools in what was then the Transvaal. The results of that investigation showed that the actual position regarding medium of instruction, primarily in the Northern Province, was that two-thirds of teachers and students followed a policy of using only English, while most of the remaining one-third pursued a policy of simultaneous use of English and a vernacular language. Fewer than five per cent of teachers and stitdents claimed to use only their first language as medium. This article reports on a series of chi;zllenges to the claim that English-only is the predominant medium, suggesting instead that the phenomenon of codeswitching or the simultaneous use of two languages is most common. The possible implications for medium of instruction policy formulation and implementation are briefly considered Die respons op die resultate van 'n vroeer publikasie (Meyer 1995) het tot hierdie artikel aanleiding gegee. Die vorige artikel het gepoog om vas te stel wat in werklikheid plaasvind ten opsigte van medium van onderrig op matriekvlak in voormalige ''DET' swart sekondere skole in die eertydse Transvaal. Die resultate van daardie ondersoek het getoon dat die werklike toestand ten opsigte van medium van onde"ig, vera/ in die Noordelike Provinsie, was dat twee derdes van die onderwysers en studente 'n beleid gevolg het van alleenlik Engels te gebruik, terwyl die meeste van die oorblywende een derde 'n beleid van die gelyktydige gebruik van Engels en die moedertaal gevolg het. Minder as vyf per sent van onderwysers en studente het beweer dat hulle net hulle moedertaal as medium gebruik het. Hierdie artikel berig oor 'n reeks uitdagings wat die bewering bevraagteken dat die alleen gebruik van Engels die oorwegende medium is. Daar word aangevoer dat die verskynsel van kodewisseling of die gelyktydige gebruik van twee tale eerder die algemene gebruik is. Die moontlike implikasies wat dit vir die medium van onde"igbeleidformulering en -implementering inhou word kortliks in oenskou ge,neem.

A METals In Situ analyzer (METIS) has been used to determine dissolved manganese (II) concentrations in the subhalocline waters of the Gotland Deep (central Baltic Sea). High-resolution in situ measurements of total dissolved Mn were obtained in near real-time by spectrophotometry using 1-(2-pyridylazo)-2-naphthol (PAN). PAN is a complexing agent of dissolved Mn and forms a wine-red complex with a maximum absorbance at a wavelength of 562 nm. Results are presented together with ancillary temperature, salinity, and dissolved O 2 data. Lab calibration of the analyzer was performed in a pressure testing tank. A detection limit of 77 nM was obtained. For validation purposes, discrete water samples were taken by using a pump-CTD system. Dissolved Mn in these samples was determined by an independent laboratory based method (inductively coupled plasma–optical emission spectrometry, ICP-OES). Mn measurements from both METIS and ICP-OES analysis were in good agreement. The results showed that the in situ analysis of dissolved Mn is a powerful technique reducing dependencies on heavy and expensive equipment (pump-CTD system, ICP-OES) and is also cost and time effective.

We present data structures and algorithms for sets and some generalizations thereof (fuzzy sets, multisets, and fuzzy multisets) available for R through the sets package. Fuzzy (multi-)sets are based on dynamically bound fuzzy logic families. Further extensions include user-definable iterators and matching functions.

During the last decade text mining has become a widely used discipline utilizing statistical and machine learning methods. We present the tm package which provides a framework for text mining applications within R. We give a survey on text mining facilities in R and explain how typical application tasks can be carried out using our framework. We present techniques for count-based analysis methods, text clustering, text classification and string kernels.

Organoids are 3-dimensional (3D) self-assembled structures capable of replicating the microanatomy and physiology of the epithelial components of their organ of origin. Adult stem cell (ASC) derived organoids from the liver have previously been shown to differentiate into primarily mature cholangiocytes, and their partial differentiation into functional hepatocytes can be promoted using specific media compositions. While full morphological differentiation of mature hepatocytes from ASCs has not yet been reported for any species, the functional differentiation can be approximated using various media compositions.Six differentiation media formulations from published studies on hepatic organoids were used for the differentiation protocol. Target species for these protocols were humans, mice, cats, and dogs, and encompassed various combinations and concentrations of four major hepatocyte media components: Bone morphogenetic protein 7 (BMP7), Fibroblast Growth Factor 19 (FGF19), Dexamethasone (Dex), and Gamma-Secretase Inhibitor IX (DAPT). Additionally, removing R-spondin from basic organoid media has previously been shown to drive the differentiation of ASC into mature hepatocytes. Differentiation media (N = 20) were designed to encompass combinations of the four major hepatocyte media components. The preferred differentiation of ASC-derived organoids from liver tissue into mature hepatocytes over cholangiocytes was confirmed by albumin production in the culture supernatant.Out of the twenty media compositions tested, six media resulted in the production of the highest amounts of albumin in the supernatant of the organoids. The cell lines cultured using these six media were further characterized via histological staining, transmission electron microscopy, RNA in situ hybridization, analysis of gene expression patterns, immunofluorescence, and label-free proteomics. The results indicate that preferential hepatocyte maturation from canine ADC-derived organoids from liver tissue is mainly driven by Dexamethasone and DAPT components. FGF19 did not enhance organoid differentiation but improved cell culture survival. Furthermore, we confirm that removing R-spondin from the media is crucial for establishing mature hepatic organoid cultures.

Preclinical biomedical research is limited by the predictiveness of in vivo and in vitro models. While in vivo models offer the most complex system for experimentation, they are also limited by ethical, financial, and experimental constraints. In vitro models are simplified models that do not offer the same complexity as living animals but do offer financial affordability and more experimental freedom; therefore, they are commonly used. Traditional 2D cell lines cannot fully simulate the complexity of the epithelium of healthy organs and limit scientific progress. The One Health Initiative was established to consolidate human, animal, and environmental health while also tackling complex and multifactorial medical problems. Reverse translational research allows for the sharing of knowledge between clinical research in veterinary and human medicine. Recently, organoid technology has been developed to mimic the original organ’s epithelial microstructure and function more reliably. While human and murine organoids are available, numerous other organoids have been derived from traditional veterinary animals and exotic species in the last decade. With these additional organoid models, species previously excluded from in vitro research are becoming accessible, therefore unlocking potential translational and reverse translational applications of animals with unique adaptations that overcome common problems in veterinary and human medicine.

Long-acting injectable (LAI) formulations promise to deliver patient benefits by overcoming issues associated with non-adherence. A preclinical assessment of semi-solid prodrug nanoparticle (SSPN) LAI formulations of emtricitabine (FTC) is reported here. Pharmacokinetics over 28 days were assessed in Wistar rats, New Zealand white rabbits, and Balb/C mice following intramuscular injection. Two lead formulations were assessed for the prevention of an HIV infection in NSG-cmah−/− humanised mice to ensure antiviral activities were as anticipated according to the pharmacokinetics. Cmax was reached by 12, 48, and 24 h in rats, rabbits, and mice, respectively. Plasma concentrations were below the limit of detection (2 ng/mL) by 21 days in rats and rabbits, and 28 days in mice. Mice treated with SSPN formulations demonstrated undetectable viral loads (700 copies/mL detection limit), and HIV RNA remained undetectable 28 days post-infection in plasma, spleen, lung, and liver. The in vivo data presented here demonstrate that the combined prodrug/SSPN approach can provide a dramatically extended pharmacokinetic half-life across multiple preclinical species. Species differences in renal clearance of FTC mean that longer exposures are likely to be achievable in humans than in preclinical models.

Abstract Background Frail older surgical patients face more than a two-fold increase in postoperative complications, including myocardial infarction, deep vein thrombosis, pulmonary embolism, pneumonia, ileus, and others. Many of these complications occur because of postoperative loss of stamina and poor mobility. Preoperative exercise may better prepare these vulnerable patients for surgery. We present the protocol for our ongoing randomized trial to assess the impact of a preoperative walking intervention with remote coaching and pedometer on outcomes of stamina (six-minute walk distance- 6MWD) and mobility (postoperative steps) in older adults with frailty traits. Methods We will be conducting a randomized clinical trial with a total of 120 patients permitting up to a 33% rate of attrition, to reach a final sample size of 80 (with 40 patients for each study arm). We will include patients who are age 60 or higher, score 4 or greater on the Edmonton Frailty Scale assessment, and will be undergoing a surgical operation that requires a 2 or more night hospital stay to be eligible for our trial. Using block randomization stratified on baseline 6MWD, we will assign patients to wear a pedometer. At the end of three baseline days, an athletic trainer (AT) will provide a daily step count goal reflecting a 10–20% increase from baseline. Subsequently, the AT will call weekly to further titrate the goal or calls more frequently if the patient is not meeting the prescribed goal. Controls will receive general walking advice. Our main outcome is change in 6MWD on postoperative day (POD) 2/3 vs. baseline. We will also collect 6MWD approximately 4 weeks after surgery and daily in-hospital steps. Conclusion If changes in a 6MWD and step counts are significantly higher for the intervention group, we believe this will confirm our hypothesis that the intervention leads to decreased loss of stamina and mobility. Once confirmed, we anticipate expanding to multiple centers to assess the interventional impact on clinical endpoints. Trial registration The randomized clinical trial was registered on clinicaltrials.gov under the identifier NCT03892187 on March 27, 2019.

Abstract Background Large animal models, such as the dog, are increasingly being used for studying diseases including gastrointestinal (GI) disorders. Dogs share similar environmental, genomic, anatomical, and intestinal physiologic features with humans. To bridge the gap between commonly used animal models, such as rodents, and humans, and expand the translational potential of the dog model, we developed a three-dimensional (3D) canine GI organoid (enteroid and colonoid) system. Organoids have recently gained interest in translational research as this model system better recapitulates the physiological and molecular features of the tissue environment in comparison with two-dimensional cultures. Results Organoids were derived from tissue of more than 40 healthy dogs and dogs with GI conditions, including inflammatory bowel disease (IBD) and intestinal carcinomas. Adult intestinal stem cells (ISC) were isolated from whole jejunal tissue as well as endoscopically obtained duodenal, ileal, and colonic biopsy samples using an optimized culture protocol. Intestinal organoids were comprehensively characterized using histology, immunohistochemistry, RNA in situ hybridization, and transmission electron microscopy, to determine the extent to which they recapitulated the in vivo tissue characteristics. Physiological relevance of the enteroid system was defined using functional assays such as optical metabolic imaging (OMI), the cystic fibrosis transmembrane conductance regulator (CFTR) function assay, and Exosome-Like Vesicles (EV) uptake assay, as a basis for wider applications of this technology in basic, preclinical and translational GI research. We have furthermore created a collection of cryopreserved organoids to facilitate future research. Conclusions We establish the canine GI organoid systems as a model to study naturally occurring intestinal diseases in dogs and humans, and that can be used for toxicology studies, for analysis of host-pathogen interactions, and for other translational applications.

Non-adherence to daily drug regimens is responsible for many negative clinical effects including drug resistance in life-long treatments for HIV. Here, the authors report on a HIV prodrug nanoparticle platform for long-acting sustained release of water-soluble drug compounds following injection.

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Abstract  We used whole genome scan association mapping to identify loci with major effect on oleic acid content in maize kernels. Single nucleotide polymorphism haplotypes at 8,590 loci were tested for association with oleic acid content in 553 maize inbreds. A single locus with major effect on oleic acid was mapped between 380 and 384 cM in the IBM2 neighbors genetic map on chromosome 4 and confirmed in a biparental population. A fatty acid desaturase, fad2, identified ∼2 kb from the associated genetic marker, is the most likely candidate gene responsible for the differences in the phenotype. The fad2 alleles with high- and low-oleic acid content were sequenced and allelic differences in fad2 RNA level in developing embryos was investigated. We propose that a non-conservative amino acid polymorphism near the active site of fad2 contributes to the effect on oleic acid content. This is the first report of the use of a high resolution whole genome scan association mapping where a putative gene responsible for a quantitative trait was identified in plants. [ABSTRACT FROM AUTHOR]

OBJECTIVESTo show that the slow arylamine N-acetyltransferase type 2 (NAT2) catalysed acetylator function is associated with the development of age-related cataracts.METHODSBoth the acetylator phenotype and genotype of 139 patients with age-related cataracts were determined, and the distribution of the acetylator subtypes in the cased population was compared with the distribution in the general (control) population. The genotype was determined by restriction-enzyme analysis of DNA, and the phenotype was determined using the elimination characteristics of isoniazid as discriminant.RESULTSThe frequency of alleles coding for slow acetylator characteristics was higher in the patients than in the controls, and the difference was significant (P = 0.013).CONCLUSIONSSlow acetylators are at higher risk of developing age-related cataracts than fast acetylators and we suggest that exogenous factors, which can be detoxified by acetylation, are aetiological agents for cataract formation. Identification of and avoidance of such (environmental) agents should reduce the incidence of age-related cataracts. [ABSTRACT FROM AUTHOR]

Disruption of lipid and carbohydrate homeostasis is an important factor in the development of prevalent metabolic diseases such as diabetes, obesity, and atherosclerosis. Therefore, small molecules that could reduce insulin dependence and regulate dyslipidemia could have a dramatic effect on public health. The grapefruit flavonoid naringenin has been shown to normalize lipids in diabetes and hypercholesterolemia, as well as inhibit the production of HCV. Here, we demonstrate that naringenin regulates the activity of nuclear receptors PPARα, PPARγ, and LXRα. We show it activates the ligand-binding domain of both PPARα and PPARγ, while inhibiting LXRα in GAL4-fusion reporters. Using TR-FRET, we show that naringenin is a partial agonist of LXRα, inhibiting its association with Trap220 co-activator in the presence of TO901317. In addition, naringenin induces the expression of PPARα co-activator, PGC1α. The flavonoid activates PPAR response element (PPRE) while suppressing LXRα response element (LXRE) in human hepatocytes, translating into the induction of PPAR-regulated fatty acid oxidation genes such as CYP4A11, ACOX, UCP1 and ApoAI, and inhibition of LXRα-regulated lipogenesis genes, such as FAS, ABCA1, ABCG1, and HMGR. This effect results in the induction of a fasted-like state in primary rat hepatocytes in which fatty acid oxidation increases, while cholesterol and bile acid production decreases. Our findings explain the myriad effects of naringenin and support its continued clinical development. Of note, this is the first description of a non-toxic, naturally occurring LXRα inhibitor.

In his work _Christus Victor_, Gustaf Aulén argued that Anselm of Canterbury’s account of the atonement was foreign to ancient Christian belief. In particular, Aulén argued that Anselm diverged from the original understanding of the doctrine as presented by the church fathers. Aulén argued that the Eastern church rightly endorsed a model of the atonement that he called the ‘classic view’, while Anselm in the West later wrongly developed a theory of satisfaction that Aulén called the ‘Latin’ view. This critique, by extension, applies to other ‘Anselmic’ theories of atonement such as penal substitution that, like Anselm’s, also affirm that Christ’s death in some way satisfied God’s requirements in response to human sin. Patristic literature shows, however, that Aulén’s conclusion is more imposition than exposition. Fathers from both East and West commonly advanced theories that comport well with what Aulén called the Latin view alongside _Christus Victor_.