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Computational cell segmentation is a vital area of research, particularly in the analysis of images of cancer cells. The use of cell lines, such as the widely utilized HeLa cell line, is crucial for studying cancer. While deep learning algorithms have been commonly employed for cell segmentation, their resource and data requirements can be impractical for many laboratories. In contrast, image processing algorithms provide a promising alternative due to their effectiveness and minimal resource demands. This article presents the development of an algorithm utilizing digital image processing to segment the nucleus and shape of HeLa cells. The research aims to segment the cell shape in the image center and accurately identify the nucleus. The study uses and processes 300 images obtained from Serial Block-Face Scanning Electron Microscopy (SBF-SEM). For cell segmentation, the morphological operation of erosion was used to separate the cells, and through distance calculation, the cell located at the center of the image was selected. Subsequently, the eroded shape was employed to restore the original cell shape. The nucleus segmentation uses parameters such as distances and sizes, along with the implementation of verification stages to ensure accurate detection. The accuracy of the algorithm is demonstrated by comparing it with another algorithm meeting the same conditions, using four segmentation similarity metrics. The evaluation results rank the proposed algorithm as the superior choice, highlighting significant outcomes. The algorithm developed represents a crucial initial step towards more accurate disease analysis. In addition, it enables the measurement of shapes and the identification of morphological alterations, damages, and changes in organelles within the cell, which can be vital for diagnostic purposes.

Knowledge representation (KR) is vital in designing symbolic notations to represent real-world facts and facilitate automated decision-making tasks. Knowledge graphs (KGs) have emerged so far as a popular form of KR, offering a contextual and human-like representation of knowledge. In international economics, KGs have proven valuable in capturing complex interactions between commodities, companies, and countries. By putting the gravity model, which is a common economic framework, into the process of building KGs, important factors that affect trade relationships can be taken into account, making it possible to predict international trade patterns. This paper proposes an approach that leverages Knowledge Graph embeddings for modeling international trade, focusing on link prediction using embeddings. Thus, valuable insights are offered to policymakers, businesses, and economists, enabling them to anticipate the effects of changes in the international trade system. Moreover, the integration of traditional machine learning methods with KG embeddings, such as decision trees and graph neural networks are also explored. The research findings demonstrate the potential for improving prediction accuracy and provide insights into embedding explainability in knowledge representation. The paper also presents a comprehensive analysis of the influence of embedding methods on other intelligent algorithms.

Animal production intensification puts pressure on resources, leads to environmental impacts, animal welfare and biodiversity issues. Livestock products provide key components of the human diet and contribute to rural territories through ecosystem services such as nutrient and biomass recycling. Life cycle assessment (LCA) is key to assess environmental impacts in livestock systems and products. A harmonization of LCA methods is necessary to improve evaluations in these areas as LCA still lacks accuracy and robustness in addressing sustainability across livestock systems and products. Here, a participatory harmonization approach was applied to provide a framework to evaluate LCAs of current and future livestock systems. A total of 29 workshops with targeted discussions among 21 LCA experts were organised, together with two anonymous surveys to harmonise evaluation criteria. First, key research topics for improving LCAs of livestock systems were identified as follows: i) Food, feed, fuel and biomaterial competition, crop-livestock interaction and the circular economy; ii) Biodiversity; iii) Animal welfare; iv) Nutrition; v) GHG emissions. Next, general evaluation criteria were identified for livestock focussed LCA methods, considering livestock systems characteristics: Transparency and Reproducibility, Completeness, Fairness and Acceptance, Robustness and Accuracy. Evaluation criteria specific to each key topic were also identified. This participatory method was successful in narrowing down general and specific evaluation criteria through targeted discussion. Moreover, this study provided a holistic participatory framework for the evaluation of LCA methods addressing the impacts of livestock systems across a range of key topics which can be further used for other sectors.

Intro: Antimicrobial resistance has been considered a global health problem, being one of the 10 most important public health problems worldwide. During the COVID-19 pandemic, a large number of antibiotics were used without any control, both on an outpatient basis and in hospitalization, which can have serious consequences. Methods: Prior informed consent, a cross-sectional descriptive study was conducted with a sample of 322 physicians. A survey was carried out in Google forms, and it was shared by telephone messages and social networks. Findings: 322 physicians, 60.9% women and 39.1% men, mean age 33.4 years, 85.9% general practitioners, 11.5% specialist physicians. 47.2% work in private institutions, 36% in public centers. Antibiotic policies in institutions: 50.3% do not have regulations for the use of antibiotics in COVID-19, only 29.5% work with policies to control the use of antibiotics and control measures against antibiotic resistance, 73.9% lack a committee for infection control and prevention of antibiotic resistance. Use of antibiotics: only 20.8% never used antibiotics in COVID-19, 45.6% used antibiotics in severe COVID-19, 40.4% hospitalized patients, and 33.5% outpatients. The most used antibiotics were azithromycin (67.1%), levofloxacin (53.4%), ceftriaxone (53.4%), and amoxicillin plus clavulanic acid (34.8%). 43.2% consider that using antibiotics can reduce mortality in moderate and severe COVID-19, 50.3% believe antibiotics should be suspended if there is clinical improvement, 96.3% believe there is an increase in self-medication of antibiotics, 59.8% consider that they used antibiotics inconrrectly at some point, 58.1% consider antibiotic resistance to be a problem in their workplace. 86.3% currently make less use of antibiotics in patients with COVID-19. Conclusion: In Honduras, there are deficiencies in policies for the use of antibiotics and control of antimicrobial resistance. Most doctors consider that they have used antibiotics incorrectly, including antibiotics that can generate resistance.

Some antimethanogenic feed additives for ruminants promote rumen dihydrogen (H2) accumulation potentially affecting the optimal fermentation of diets. We hypothesised that combining an H2 acceptor with a methanogenesis inhibitor can decrease rumen H2 build-up and improve the production of metabolites that can be useful for the host ruminant. We performed three in vitro incubation experiments using rumen fluid from lactating Holstein cows: Experiment 1 examined the effect of phenolic compounds (phenol, catechol, resorcinol, hydroquinone, pyrogallol, phloroglucinol, and gallic acid) at 0, 2, 4, and 6 mM on ruminal fermentation for 24 h; Experiment 2 examined the combined effect of each phenolic compound from Experiment 1 at 6 mM with two different methanogenesis inhibitors (Asparagopsis taxiformis or 2-bromoethanesulfonate (BES)) for 24 h incubation; Experiment 3 examined the effect of a selected phenolic compound, phloroglucinol, with or without BES over a longer term using sequential incubations for seven days. Results from Experiment 1 showed that phenolic compounds, independently of the dose, did not negatively affect rumen fermentation, whereas results from Experiment 2 showed that phenolic compounds did not decrease H2 accumulation or modify CH4 production when methanogenesis was decreased by up to 75% by inhibitors. In Experiment 3, after three sequential incubations, phloroglucinol combined with BES decreased H2 accumulation by 72% and further inhibited CH4 production, compared to BES alone. Interestingly, supplementation with phloroglucinol (alone or in combination with the CH4 inhibitor) decreased CH4 production by 99% and the abundance of methanogenic archaea, with just a nominal increase in H2 accumulation. Supplementation of phloroglucinol also increased total volatile fatty acid (VFA), acetate, butyrate, and total gas production, and decreased ammonia concentration. This study indicates that some phenolic compounds, particularly phloroglucinol, which are naturally found in plants, could improve VFA production, decrease H2 accumulation and synergistically decrease CH4 production in the presence of antimethanogenic compounds.

The lack of data on disaster-related loss and damage, especially in developing countries, obstructs the implementation of the Sendai Framework for Disaster Risk Reduction (SFDRR). This weakens the accuracy, timeliness, and quality of the SFDRR monitoring process at the national level. This is the case for the country of Ecuador, who has not reported on the progress of SFDRR Target B, indicator B-5a, the number of workers in agriculture with crops damaged or destroyed. Consequently, this research developed a geospatial model approach to model indicator B-5a in the context of flooding. The model uses Sentinel-1 synthetic aperture radar and other spatial data to quantify indicator B-5a at a cantonal spatial level across three ecological regions in Ecuador. The results of the model were validated against country provided in-situ measured loss and damage reference data by combining elements of flood exposure and vulnerability. A statistical analysis was used to assess the agreement of the models with reference data and the models' ability to reproduce the reference data. The validation procedure produced models that had high agreement with the reference data, but the models were sensitive to the different ecological regions. This validated geospatial model approach is, to the best of the authors' knowledge, the first attempt to validate geospatially measured Sendai indicators against reference data, and provides an opportunity to support countries without information on disaster-related loss and damage in monitoring indicator B-5a of the SFDRR.

Background: Trastuzumab-dkst is a biosimilar of trastuzumab. The phase 3 HERITAGE trial demonstrated equivalent overall response rate (ORR) with trastuzumab-dkst or originator trastuzumab at 24 weeks in patients with HER2-positive metastatic breast cancer receiving chemotherapy. We now present the correlation of ORR with progression-free survival (PFS) for maintenance monotherapy with trastuzumab-dkst vs trastuzumab at 48 weeks of treatment, and the safety, tolerability, and immunogenicity. Methods: HERITAGE is a multicenter, double-blind, randomized, parallel-group, phase 3 study. Patients were randomized 1:1 to receive trastuzumab-dkst or trastuzumab in combination with taxane followed by continued monotherapy until disease progression. The analysis included PFS at 48 weeks to support the primary efficacy endpoint of ORR and safety, tolerability, and immunogenicity of trastuzumab-dkst vs trastuzumab as maintenance monotherapy. Results: Of 500 randomized patients, 342 entered the monotherapy phase; 214 patients received ≥48 weeks of treatment. There were no statistically significant differences between PFS, ORR, or interim overall survival at week 48 between trastuzumab-dkst and trastuzumab. Week 24 ORR was highly correlated with week 48 PFS (rb = 0.75). Cumulative treatment-emergent adverse events (TEAEs) and serious AEs were similar in both groups, with few grade ≥3 TEAEs. Immunogenicity was low and similar in both groups at 48 weeks. Conclusion: The correlation between ORR and PFS supports the design of first-line metastatic trials assessing biosimilar trastuzumab. Overall, trastuzumab-dkst and trastuzumab were well tolerated with similar efficacy, including ORR and PFS, in combination with a taxane followed by monotherapy.

Lipid nanoparticles (LNPs) are the most clinically advanced delivery system for RNA-based drugs but have predominantly been investigated for intravenous and intramuscular administration. Subcutaneous administration opens the possibility of patient self-administration and hence long-term chronic treatment that could enable messenger RNA (mRNA) to be used as a novel modality for protein replacement or regenerative therapies. In this study, we show that subcutaneous administration of mRNA formulated within LNPs can result in measurable plasma exposure of a secreted protein. However, subcutaneous administration of mRNA formulated within LNPs was observed to be associated with dose-limiting inflammatory responses. To overcome this limitation, we investigated the concept of incorporating aliphatic ester prodrugs of anti-inflammatory steroids within LNPs, i.e., functionalized LNPs to suppress the inflammatory response. We show that the effectiveness of this approach depends on the alkyl chain length of the ester prodrug, which determines its retention at the site of administration. An unexpected additional benefit to this approach is the prolongation observed in the duration of protein expression. Our results demonstrate that subcutaneous administration of mRNA formulated in functionalized LNPs is a viable approach to achieving systemic levels of therapeutic proteins, which has the added benefits of being amenable to self-administration when chronic treatment is required.

Changes in the distribution of a species can be used to as a metric of conservation status and to identify the loss or gain of isolated populations. This mapping process is a primary tool of the IUCN SSC Red List assessment. Most distribution maps are based on expert opinion or species distribution models based on a combination of species detection records and known habitat and landscape affiliations for that species. However, modeling the distribution for some species is difficult due to low levels of sampling, low detectability, and loose or uncertain associations with landscape attributes. These issues may be particularly prevalent for Asian bears that have generalist habitat requirements and are heavily poached across their range. Presently the range of all bear species in Asia is delineated primarily using expert opinion. Members of the IUCN SSC Bear Specialist Group attempted to create a rule set to combine current detections with known habitat and home range preferences to improve distribution maps for the purpose of conservation metrics and monitoring. The results of applying this rule set for giant pandas (Ailuropoda melanoleuca) closely matched the current IUCN mapped range, but the results for Asiatic black bears (Ursus thibetanus) did not corroborate the IUCN map based solely on expert opinion. We present a list of recommended actions for improving distribution mapping for bears in Asia and possibly any species whose current distribution is heavily influenced by poorly measured metrics such as poaching.

Objective: To describe the clinical characteristics, outcomes, and risk factors for death of patients with coronavirus disease 2019 (COVID-19) in a community hospital setting. Patients and Methods: This single-center retrospective cohort study included 313 adult patients with laboratory-confirmed COVID-19 admitted to a community hospital in Cook County, Illinois, from March 1, 2020, to May 25, 2020. Demographics, medical history, underlying comorbidities, symptoms, signs, laboratory findings, imaging studies, management, and progression to discharge or death data were collected and analyzed. Results: Of 313 patients, the median age was 68 years (interquartile range, 59.0-78.5 years; range, 19-98 years), 182 (58.1%) were male, 119 (38%) were white, and 194 (62%) were admitted from a long-term care facility (LTCF). As of May 25, 2020, there were 212 (67.7%) survivors identified, whereas 101 (32.3%) nonsurvivors were identified. Multivariable Cox regression analysis showed increasing hazards of inpatient death associated with older age (hazard ratio [HR] 1.02; 95% CI, 1.01-1.04), LTCF residence (HR, 3.23; 95% CI, 1.68-6.20), and quick Sequential Organ Failure Assessment scores (HR, 2.59; 95% CI, 1.78-3.76). Conclusion: In this single-center retrospective cohort study of 313 adult patients hospitalized with COVID-19 illness in a community hospital in Cook County, Illinois, older patients, LTCF residents, and patients with high quick Sequential Organ Failure Assessment scores were found to have worse clinical outcomes and increased risk of death.

Objective: To evaluate the performance of the Quick COVID-19 Severity Index (qCSI) and the Brescia-COVID Respiratory Severity Scale (BCRSS) in predicting intensive care unit (ICU) admissions and in-hospital mortality in patients with coronavirus disease 2019 (COVID-19) pneumonia. Methods: This was a retrospective cohort study of 313 consecutive hospitalized adult patients (18 years or older) with confirmed COVID-19. The area under the receiver operating characteristic curve (AUC) was used to assess the discriminatory power of the qCSI score and BCRSS prediction rule compared to the CURB-65 score for predicting mortality and intensive care unit admission. Results: The overall in-hospital fatality rate was 32.3%, and the ICU admission rate was 31.3%. The CURB-65 score had the highest numerical AUC to predict in-hospital mortality (AUC 0.781) compared to the qCSI score (AUC 0.711) and the BCRSS prediction rule (AUC 0.663). For ICU admission, the qCSI score had the highest numerical AUC (AUC 0.761) compared to the BCRSS prediction rule (AUC 0.735) and the CURB-65 score (AUC 0.629). Conclusions: The CURB-65 and qCSI scoring systems showed a good performance for predicting in-hospital mortality. The qCSI score and the BCRSS prediction rule showed a good performance for predicting ICU admission.

Summary: 3D cardiac engineered constructs have yielded not only the next generation of cardiac regenerative medicine but also have allowed for more accurate modeling of both healthy and diseased cardiac tissues. This is critical as current cardiac treatments are rudimentary and often default to eventual heart transplants. This review serves to highlight the various cell types found in cardiac tissues and how they correspond with current advanced fabrication methods for creating cardiac engineered constructs capable of shedding light on various pathologies and providing the therapeutic potential for damaged myocardium. In addition, insight is given toward the future direction of the field with an emphasis on the creation of specialized and personalized constructs that model the region-specific microtopography and function of native cardiac tissues.

Background: Approximately 80% of breast cancer survivors are prescribed oral endocrine therapy (ET) medication for 5–10 years following primary treatment, making adherence to ET a critical aspect of cancer survivorship care. Despite the benefits of ET, non-adherence is problematic, and up to half of breast cancer survivors ave been documented to discontinue ET early. Our team developed My Journey, an online, mindfulness-based program designed to improve adherence to ET. This manuscript describes the usability testing of My Journey and the protocol development for the My Journey randomized feasibility trial. Methods: Usability participants were women (N = 15) with a diagnosis of hormone receptor-positive non-metastatic breast cancer who had initiated ET. Participant impressions and feedback were collected qualitatively and quantitatively using items on usefulness, satisfaction, and ease of use. Participants in the 8-week feasibility trial (N = 80) will be randomized to receive the web-based My Journey intervention or a health education comparison condition. Results: Quantitative feedback on the usability trial was favorable, with a mean overall usability score of 106.3 (SD = 7.7; Range: 83–115) indicating above average usability. Qualitative data showed that participants found several strengths in the initial design of the My Journey online tool and that participants liked the layout of My Journey. Conclusions: Findings indicate that the My Journey online tool is useable. The program's feasibility is being evaluated in a randomized trial.

In this paper, we present hardware accelerators created with high-level synthesis techniques for sparse and dense matrix multiplication operations. The cores can operate with different precisions and are designed to be integrated in a heterogeneous CPU-FPGA system for Edge AI applications. The methodology involves quantization-sparsity aware training and it is applied to a case study consisting of human activity classification. We initially investigate the effects of quantization and sparsity on the accuracy of neural networks with convolution, dense and recurrent layers observing better tolerance to pruning when recurrent layers are present. Then, we propose the hardware accelerators that can switch precision at run-time and work with any matrix size up to a maximum configured at compile time. We compare the performance of these accelerators at different levels of precision and sparsity levels and create a performance model to enable workload balancing. The results show that the proposed sparse matrix multipliers can outperform dense multipliers when sparsity levels are higher than 70% and the improvements are more evident when higher precision arithmetic or structural pruning is used. Additionally, sparsity levels as high as 99% can maintain the level of accuracy required in the network especially when recurrent layers are deployed. Overall, the balance between sparse and dense performance depends on matrix shape, precision, structural pruning and sparsity levels and performance modelling can be used to balance concurrent execution in a heterogeneous configuration.

Purpose: Heating of gradient coils and passive shim components is a common cause of instability in the B0 field, especially when gradient intensive sequences are used. The aim of the study was to set a benchmark for typical drift encountered during MR spectroscopy (MRS) to assess the need for real-time field-frequency locking on MRI scanners by comparing field drift data from a large number of sites. Method: A standardized protocol was developed for 80 participating sites using 99 3T MR scanners from 3 major vendors. Phantom water signals were acquired before and after an EPI sequence. The protocol consisted of: minimal preparatory imaging; a short pre-fMRI PRESS; a ten-minute fMRI acquisition; and a long post-fMRI PRESS acquisition. Both pre- and post-fMRI PRESS were non-water suppressed. Real-time frequency stabilization/adjustment was switched off when appropriate. Sixty scanners repeated the protocol for a second dataset. In addition, a three-hour post-fMRI MRS acquisition was performed at one site to observe change of gradient temperature and drift rate. Spectral analysis was performed using MATLAB. Frequency drift in pre-fMRI PRESS data were compared with the first 5:20 minutes and the full 30:00 minutes of data after fMRI. Median (interquartile range) drifts were measured and showed in violin plot. Paired t-tests were performed to compare frequency drift pre- and post-fMRI. A simulated in vivo spectrum was generated using FID-A to visualize the effect of the observed frequency drifts. The simulated spectrum was convolved with the frequency trace for the most extreme cases. Impacts of frequency drifts on NAA and GABA were also simulated as a function of linear drift. Data from the repeated protocol were compared with the corresponding first dataset using Pearson's and intraclass correlation coefficients (ICC). Results: Of the data collected from 99 scanners, 4 were excluded due to various reasons. Thus, data from 95 scanners were ultimately analyzed. For the first 5:20 min (64 transients), median (interquartile range) drift was 0.44 (1.29) Hz before fMRI and 0.83 (1.29) Hz after. This increased to 3.15 (4.02) Hz for the full 30 min (360 transients) run. Average drift rates were 0.29 Hz/min before fMRI and 0.43 Hz/min after. Paired t-tests indicated that drift increased after fMRI, as expected (p < 0.05). Simulated spectra convolved with the frequency drift showed that the intensity of the NAA singlet was reduced by up to 26%, 44 % and 18% for GE, Philips and Siemens scanners after fMRI, respectively. ICCs indicated good agreement between datasets acquired on separate days. The single site long acquisition showed drift rate was reduced to 0.03 Hz/min approximately three hours after fMRI. Discussion: This study analyzed frequency drift data from 95 3T MRI scanners. Median levels of drift were relatively low (5-min average under 1 Hz), but the most extreme cases suffered from higher levels of drift. The extent of drift varied across scanners which both linear and nonlinear drifts were observed.

Balance between inhibitory and excitatory neurotransmitter systems and the protective role of the major antioxidant glutathione (GSH) are central to early healthy brain development. Disruption has been implicated in the early life pathophysiology of psychiatric disorders and neurodevelopmental conditions including Autism Spectrum Disorder.Edited magnetic resonance spectroscopy (MRS) methods such as HERMES have great potential for providing important new non-invasive insights into these crucial processes in human infancy. In this work, we describe a systematic approach to minimise the impact of specific technical challenges inherent to acquiring MRS data in a neonatal population, including automatic segmentation, full tissue-correction and optimised GABA+ fitting and consider the minimum requirements for a robust edited-MRS acquisition. With this approach we report for the first time simultaneous GABA+, Glx (glutamate + glutamine) and GSH concentrations in the neonatal brain (n = 18) in two distinct regions (thalamus and anterior cingulate cortex (ACC)) using edited MRS at 3T.The improved sensitivity provided by our method allows specific regional neurochemical differences to be identified including: significantly lower Glx and GSH ratios to total creatine in the thalamus compared to the ACC (p < 0.001 for both), and significantly higher GSH levels in the ACC following tissue-correction (p < 0.01). Furthermore, in contrast to adult GABA+ which can typically be accurately fitted with a single peak, all neonate spectra displayed a characteristic doublet GABA+ peak at 3 ppm, indicating a lower macromolecule (MM) contribution to the 3 ppm signal in neonates. Relatively high group-level variance shows the need to maximise voxel size/acquisition time in edited neonatal MRS acquisitions for robust estimation of metabolites.Application of this method to study how these levels and balance are altered by early-life brain injury or genetic risk can provide important new knowledge about the pathophysiology underlying neurodevelopmental disorders.

Summary: The etiology of peripartum cardiomyopathy remains unknown. One hypothesis is that an increase in the 16-kDa form of prolactin is pathogenic and suggests that breastfeeding may worsen peripartum cardiomyopathy by increasing prolactin, while bromocriptine, which blocks prolactin release, may be therapeutic. An autoimmune etiology has also been proposed. The authors investigated the impact of breastfeeding on cellular immunity and myocardial recovery for women with peripartum cardiomyopathy in the IPAC (Investigations in Pregnancy Associated Cardiomyopathy) study. Women who breastfed had elevated prolactin, and prolactin levels correlated with elevations in CD8+ T cells. However, despite elevated prolactin and cytotoxic T cell subsets, myocardial recovery was not impaired in breastfeeding women. Key Words: breastfeeding, immune activation, peripartum cardiomyopathy

Summary: During somatic cell reprogramming to induced pluripotent stem cells (iPSCs), fibroblasts undergo dynamic molecular changes, including a mesenchymal-to-epithelial transition (MET) and gain of pluripotency; processes that are influenced by Yamanaka factor stoichiometry. For example, in early reprogramming, high KLF4 levels are correlated with the induction of functionally undefined, transiently expressed MET genes. Here, we identified the cell-surface protein TROP2 as a marker for cells with transient MET induction in the high-KLF4 condition. We observed the emergence of cells expressing the pluripotency marker SSEA-1+ mainly from within the TROP2+ fraction. Using TROP2 as a marker in CRISPR/Cas9-mediated candidate screening of MET genes, we identified the transcription factor OVOL1 as a potential regulator of an alternative epithelial cell fate characterized by the expression of non-iPSC MET genes and low cell proliferation. Our study sheds light on how reprogramming factor stoichiometry alters the spectrum of intermediate cell fates, ultimately influencing reprogramming outcomes. : Woltjen and colleagues identified the transcription factor OVOL1 as a potential regulator of transient MET induction in high-KLF4 reprogramming. Transient MET induction inhibits the expansion of intermediate partially reprogrammed cells. Their study provides insight into how reprogramming factor stoichiometry affects intermediate cell fates and reprogramming outcomes. Keywords: iPSC, reprogramming, stoichiometry, Klf4, mesenchymal-to-epithelial transition, Tacstd2, TROP2, Ovol1, SSEA-1, CRISPR/Cas9

Staphylococcal Toxic Shock Syndrome (TSS) is characterized by rapid onset of fever, rash, hypotension, and multiorgan system involvement. Clinical manifestations of staphylococcal TSS include fever, chills, hypotension, and a diffuse macular erythroderma followed by desquamation one to two weeks later. The disease came to public attention in the 1980s with the occurrence of a series of menstrual-associated cases. However, the relative incidence of staphylococcal TSS not associated with menstruation has increased, and still, it remains an overlooked cause of septic shock. We present the case of a healthy 19-year-old male that presented with fever, chills, malaise, near-syncope, and a non-fluctuant, mobile nodule in the left armpit. The patient developed septic shock requiring critical care. He underwent extensive investigations resulting negative except for PCR for the detection of MRSA, raising the suspicion for STSS. For that reason, antibiotics for staphylococcal coverage were started, after which he started to improve. Ultimately, the mobile nodule evolved to fluctuant access. Incision and drainage was performed, and cultures confirmed the presence of Staphylococcus aureus.

Over the past years there has been a considerable increase in the use of aortic bioprostheses for treating aortic valve disease. With the increasing use of implanted medical devices, the incidence of prosthetic valve endocarditis has also increased. This is accompanied by a shift in the microbiology of infectious endocarditis. Micrococcus species are usually regarded as contaminants from skin and mucous membranes that rarely cause infectious diseases, however, they have the capacity to create biofilms from prosthetic materials and hence, to cause disease. We report the case of a 54-year-old woman who developed native valve infective endocarditis due to Micrococcus luteus. To our knowledge, only 18 cases of M. luteus prosthetic valve endocarditis have been described, none in the English literature.

Diffuse alveolar hemorrhage is a condition with high morbidity and mortality. The majority of cases are caused by pulmonary capillaritis associated with systemic vasculitis. Infection disease has also been associated with this condition. A 62-year-old woman with a history of chronic alcohol abuse presented with shortness of breath, hemoptysis, constipation, and icterus. Chest x-rays on admission showed diffuse patchy opacities concerning for diffuse alveolar hemorrhage. The patient quickly developed acute respiratory failure requiring intubation. PCR identified human metapneumovirus and bronchoalveolar lavage confirmed alveolar hemorrhage. Despite all efforts, the patient ultimately developed multi-organ failure and died. Human metapneumovirus is usually associated with mild upper and lower respiratory tract infections in young children. Nevertheless, clinicians should recognize that this virus has recently emerged as a significant pathogen, particularly in adult patients with underlying conditions and the elderly population.

This article provides a description of an agricultural household survey data of rice growers collected in Ecuador between October 2014 and March 2015. The household survey was implemented using a structured questionnaire administered among 1028 households in the main rice production areas of Ecuador (i.e. Guayas, Los Rios, Manabi, and El Oro provinces). Information collected was provided by household heads (male or female) and included household and plot level data. The survey information includes household socio-demographic characteristics (e.g. age, education, gender, main economic activity, etc.), farm characteristics (e.g. farm land size, assets ownership, other crops planted, etc.), rice management practices (e.g. variety and input use, production costs, etc.), and rice production and utilization (e.g. yields, prices, sales, etc.). Additional socio-economic context variables were also recorded such as government subsidies to rice production, participation in rural organizations, and food security related questions. The dataset contains a total of 6288 variables among numeric, categorical and string variables. The dataset is shared publicly on the Harvard dataverse site and provide access to questionnaires, the complete data and a brief report.

Cancer is the second leading cause of death worldwide, and it is estimated that Human papillomavirus (HPV) related cancers account for 5% of all human cancers. Current HPV vaccines are extremely effective at preventing infection and neoplastic disease; however, they are prophylactic and do not clear established infections. Therapeutic vaccines which trigger cell-mediated immune responses for the treatment of established infections and malignancies are therefore required. The E6 and E7 early genes are ideal targets for vaccine therapy due to their role in disruption of the cell cycle and their constitutive expression in premalignant and malignant tissues. Several strategies have been investigated for the development of therapeutic vaccines, including live-vector, nucleic acid, peptide, protein-based and cell-based vaccines as well as combinatorial approaches, with several vaccine candidates progressing to clinical trials. With the current understanding of the HPV life cycle, molecular mechanisms of infection, carcinogenesis, tumour biology, the tumour microenvironment and immune response mechanisms, an approved HPV therapeutic vaccine seems to be a goal not far from being achieved. In this article, the status of therapeutic HPV vaccines in clinical trials are reviewed, and the potential for plant-based vaccine production platforms described. Keywords: Therapeutic vaccine, HPV, E6 and E7, Cervical cancer, Plant-based production

Symmetric collisions of massive nuclei, such as 238U + 248Cm, have been proposed as ways to make new n-rich heavy nuclei via multi-nucleon transfer (MNT) reactions. We have measured the yields of several projectile-like and target-like fragments from the reaction of 1360 MeV 204Hg + 198Pt. We find that current models for this symmetric collision (GRAZING, DNS, ImQMD) significantly underestimate the yields of these transfer products, even for small transfers. Keywords: Multi-nucleon transfer, GRAZING predictions, DNS model, Improved Quantum Molecular Dynamics model, 204Hg + 198Pt

Hendra virus is a paramyxovirus of Australian flying fox bats. It was first detected in August 1994, after the death of 20 horses and one human. Since then it has occurred regularly within a portion of the geographical distribution of all Australian flying fox (fruit bat) species. There is, however, little understanding about which species are most likely responsible for spillover, or why spillover does not occur in other areas occupied by reservoir and spillover hosts. Using ecological niche models of the four flying fox species we were able to identify which species are most likely linked to spillover events using the concept of distance to the niche centroid of each species. With this novel approach we found that 20 out of 27 events occur disproportionately closer to the niche centroid of two species (P. alecto and P. conspicillatus). With linear regressions we found a negative relationship between distance to the niche centroid and abundance of these two species. Thus, we suggest that the bioclimatic niche of these two species is likely driving the spatial pattern of spillover of Hendra virus into horses and ultimately humans.

Cutaneous squamous cell carcinomas (SCCs) and basal cell carcinomas (BCCs) have different clinical behaviors, despite both being keratinocyte carcinomas mainly caused by ultraviolet radiation. Whether these distinct features are associated with tumor-associated macrophages (TAMs) is largely unknown. The main goal of this study was to conduct a comprehensive analysis of density and polarization states of TAMs in SCCs versus BCCs. The role of lactic acid in TAM polarization in SCC versus BCC was examined. We found that SCCs have a higher density of CD68 + TAMs compared to BCCs. TAMs in SCCs express higher levels of TAM-associated markers (arginase-1, MMP9, CD40 and CD127) than those in BCCs. Interestingly, differential expression of TAM-associated markers between SCCs and BCCs was reproduced in human monocytic THP-1 cells stimulated with SCC- or BCC-conditioned media. Analysis of soluble factor(s) in these tumors further revealed that SCCs have a significantly higher concentration of lactic acid than BCCs, and lactic acid was sufficient to upregulate TAM markers. Our results demonstrate that TAMs in SCCs versus BCCs differ in density and polarization states, which can be determined by soluble factors including tumor-derived lactic acid. These differences in TAMs may contribute to the distinct clinical behaviors of SCCs versus BCCs. This work was supported by grants from the National Institutes of Health and the Doris Duke Charitable Foundation. Research in context: Few studies have studied tumor-associated macrophages in the context of SCC versus BCC. It has been demonstrated that macrophages mobilize to the epidermis after being exposed to ultraviolet-B radiation and produce interleukin-10 (IL-10). It has also been shown that the production of IL-10 results in the evasion of T cell-mediated immunity in BCCs and SCCs. However, the relationship between TAMs and the clinical behaviors of SCCs and BCCs remains largely unclear. Our study shows that despite their similar origins, human cutaneous SCCs and BCCs are considerably different in their TAMs. To our knowledge, these results provide the first evidence of differential TAM density and polarization in SCCs versus BCCs, which may contribute to their characteristic clinical behaviors. Future studies are necessary to elucidate the mechanisms by which TAMs influence these cancers with the goal of developing therapies tailored to each type of malignancy.

Abstract Evidence that enables us to identify, assess, and access the small airways in asthma and chronic obstructive pulmonary disease (COPD) has led INTERASMA (Global Asthma Association) and WAO to take a position on the role of the small airways in these diseases. Starting from an extensive literature review, both organizations developed, discussed, and approved the manifesto, which was subsequently approved and endorsed by the chairs of ARIA and GA2LEN. The manifesto describes the evidence gathered to date and defines and proposes issues on small airway involvement and management in asthma and COPD with the aim of challenging assumptions, fostering commitment, and bringing about change. The small airways (defined as those with an internal diameter

As the quintessential reprogramming model, OCT3/4, SOX2, KLF4, and c-MYC re-wire somatic cells to achieve induced pluripotency. Yet, subtle differences in methodology confound comparative studies of reprogramming mechanisms. Employing transposons, we systematically assessed cellular and molecular hallmarks of mouse somatic cell reprogramming by various polycistronic cassettes. Reprogramming responses varied in the extent of initiation and stabilization of transgene-independent pluripotency. Notably, the cassettes employed one of two KLF4 variants, differing only by nine N-terminal amino acids, which generated dissimilar protein stoichiometry. Extending the shorter variant by nine N-terminal amino acids or augmenting stoichiometry by KLF4 supplementation rescued both protein levels and phenotypic disparities, implicating a threshold in determining reprogramming outcomes. Strikingly, global gene expression patterns elicited by published polycistronic cassettes diverged according to each KLF4 variant. Our data expose a Klf4 reference cDNA variation that alters polycistronic factor stoichiometry, predicts reprogramming hallmarks, and guides comparison of compatible public data sets.

This study reports the synthesis of porous nano alumina employing carboxylato-alumoxanes [Al(O)x(OH)y(O2CR)z]n as precursors for controlling the pore size, pore size distribution and porosity of the alumina, using a new process ecofriendly. The carboxylato-alumoxanes was prepared by the reaction of boehmite with carboxylic acids. The boehmite was obtained by the hydrolysis of aluminum alkoxide in an aqueous solution. The colophony extract is employed as a source of carboxylic acids. The materials were characterized, using XRD, TGA, N2 physical adsorption, SEM, TEM, NMR and FTIR. A mechanism was proposed for the formation of the synthesized structures. TEM measurements confirmed particle size ranged from 5 to 8 nm.

Objective To study the diagnostic and treatment modalities used in drug allergy/hypersensitivity among members of the World Allergy Organization (WAO).Methods A questionnaire comprising 39 questions was circulated electronically to member societies, associate member societies, and regional and affiliate organizations of WAO between June 29, 2009, and August 9, 2009.Results Eighty-two responses were received. Skin testing was used by 74.7%, with only 71.4% having access to penicillin skin test reagents. In vitro-specific IgE tests were used by 67.4%, and basophil activation test was used by 54.4%. Lymphocyte transformation tests were used by 36.8% and patch tests by 54.7%. Drug provocation tests were used by 68.4%, the most common indication being to exclude hypersensitivity where history/symptoms were not suggestive of drug hypersensitivity/allergy (76.9%). Rapid desensitization for chemotherapy, antibiotics, or biologic agents was used by 69.6%. Systemic corticosteroid was used in the treatment of Stevens-Johnson syndrome by 72.3%, and high-dose intravenous immunoglobulins in toxic epidermal necrolysis by 50.8%. Human leukocyte antigen screening before prescription of abacavir was used by 92.9% and before prescription of carbamazepine by 21.4%.Conclusions Results of this survey form a useful framework for developing educational and training needs and for improving access to drug allergy diagnostic and treatment modalities across WAO member societies. Keywords: desensitization, drug allergy, hypersensitivity, skin tests

Background: Evidence for the efficacy of combined PD-1 and HER2 blockade with chemotherapy on progression-free and overall survival in HER2-positive gastro-oesophageal cancer is scarce. The first interim analysis of the randomised, phase 3 KEYNOTE-811 study showed a superior objective response with pembrolizumab compared with placebo when added to trastuzumab plus fluoropyrimidine and platinum-based chemotherapy. Here, we report results from protocol-specified subsequent interim analyses of KEYNOTE-811., Methods: The randomised, phase 3 KEYNOTE-811 trial involved 168 medical centres in 20 countries worldwide. Patients aged 18 years or older with locally advanced or metastatic HER2-positive gastro-oesophageal junction adenocarcinoma, without previous first-line treatment, were randomly assigned (1:1) by an integrated interactive voice-response and web-response system to intravenous pembrolizumab 200 mg or placebo, both to be combined with standard chemotherapy (fluoropyrimidine and platinum-based therapy) plus trastuzumab every 3 weeks for up to 35 cycles or until disease progression, unacceptable toxic effects, or investigator or participant-initiated withdrawal. Randomisation used a block size of four and was stratified by region, PD-L1 status, and chemotherapy. Dual primary endpoints were progression-free and overall survival, analysed by intention to treat. Safety was assessed in all randomly assigned patients who received at least one dose of study treatment according to the treatment received. KEYNOTE-811 is registered with ClinicalTrials.gov (NCT03615326) and is active but not recruiting., Findings: Between Oct 5, 2018, and Aug 6, 2021, 698 patients were assigned to pembrolizumab (n=350) or placebo (n=348). 564 (81%) were male and 134 (19%) were female. At the third interim analysis, 286 (82%) of 350 patients in the pembrolizumab group and 304 (88%) of 346 in the placebo group who received treatment had discontinued treatment, mostly due to disease progression. At the second interim analysis (median follow-up 28·3 months [IQR 19·4-34·3] in the pembrolizumab group and 28·5 months [20·1-34·3] in the placebo group), median progression-free survival was 10·0 months (95% CI 8·6-11·7) in the pembrolizumab group versus 8·1 months (7·0-8·5) in the placebo group (hazard ratio [HR] 0·72, 95% CI 0·60-0·87; p=0·0002). Median overall survival was 20·0 months (17·8-23·2) versus 16·9 months (15·0-19·8; HR 0·87 [0·72-1·06]; p=0·084). At the third interim analysis (median follow-up 38·4 months [IQR 29·5-44·4] in the pembrolizumab group and 38·6 months [30·2-44·4] in the placebo group), median progression-free survival was 10·0 months (8·6-12·2) versus 8·1 months (7·1-8·6; HR 0·73 [0·61-0·87]), and median overall survival was 20·0 months (17·8-22·1) versus 16·8 months (15·0-18·7; HR 0·84 [0·70-1·01]), but did not meet prespecified criteria for significance and will continue to final analysis. Grade 3 or worse treatment-related adverse events occurred in 204 (58%) of 350 patients in the pembrolizumab group versus 176 (51%) of 346 patients in the placebo group. Treatment-related adverse events that led to death occurred in four (1%) patients in the pembrolizumab group and three (1%) in the placebo group. The most common treatment-related adverse events of any grade were diarrhoea (165 [47%] in the pembrolizumab group vs 145 [42%] in the placebo group), nausea (154 [44%] vs 152 [44%]), and anaemia (109 [31%] vs 113 [33%])., Interpretation: Compared with placebo, pembrolizumab significantly improved progression-free survival when combined with first-line trastuzumab and chemotherapy for metastatic HER2-positive gastro-oesophageal cancer, specifically in patients with tumours with a PD-L1 combined positive score of 1 or more. Overall survival follow-up is ongoing and will be reported at the final analysis., Funding: Merck Sharp & Dohme., Competing Interests: Declaration of interests YYJ reports research funding to their institution from MSD, the US National Cancer Institute, the US Department of Defense, Cycle of Survival, Fred's Team, Rgenix, Bayer, Genentech/Roche, Bristol-Myers Squibb, and Eli Lilly; fees for advisory board participation from Inspira, Merck Serono, Bristol-Myers Squibb, Eli Lilly, Pfizer, Bayer, Imugene, Merck Sharp & Dohme, Daiichi Sankyo, Zymeworks, SeaGen, Basilea Pharmaceutical, and AstraZeneca; and equity in Inspira. AK reports research funding to their institution from AstraZeneca, Ono Pharmaceutical, Daiichi Sankyo, and MSD; consulting fees from Zymeworks, MSD, and Astellas Pharma; and honoraria from Bristol-Myers Squibb, Daiichi Sankyo, Ono Pharmaceutical, Eli Lilly, and Taiho Pharmaceutical. YB, JX, PY, LSW, YO, MB, HCC, and S-KQ report research funding to their institutions from Merck Sharp & Dohme, a subsidiary of Merck & Co (MSD). SL reports research funding to their institution from Amgen, Astellas, AstraZeneca, Bayer, Bristol-Myers Squibb, Daichii Sankyo, Hutchinson, Incyte, Merck Serono, Mirati, MSD, Pfizer, Roche, and Servier; consulting fees from Amgen, AstraZeneca, Bristol-Myers Squibb, Daichii Sankyo, Incyte, Lilly, Merck Serono, MSD, Servier, and Astellas; and honoraria from Amgen, Bristol-Myers Squibb, Incyte, GSK, Lilly, Merck Serono, MSD, Pierre Fabre, Roche, and Servier. JPM reports grants from MSD, Bristol-Myers Squibb, Zymeworks, Astellas, Bayer, and Diachii; honoraria from MSD, Astellas, Bayer, and Bristol-Myers Squibb; and reimbursement for travel from MSD, Daichii, and BMS. LS reports research funding to their institution from MSD, Beijing Xiantong Biomedical Technology, Qiku Pharmaceutical Co, Zaiding Pharmaceutical (Shanghai) Co, Jacobio Pharmaceuticals Co, Beihai Kangcheng (Beijing) Medical Technology Co, Boehringer Ingelheim, Harbour, and Merck; and consulting fees from Harbour and Merck. KS reports research funding to their institution from Astellas Pharma, Ono Pharmaceutical, Daiichi Sankyo, Taiho Pharmaceutical, Chugai Pharma, MSD, Amgen, and Eisai; consulting fees from Eli Lilly and Company, Bristol-Myers Squibb, Takeda Pharmaceutical, Novatis, AbbVie, Daiichi Sankyo, Taiho Pharmaceutical, GSK, Amgen, Boehringer Ingelheim, MSD, Astellas, Guardant Health Japan, and Janssen; and honoraria from Bristol-Myers Squibb, Takeda Pharmaceuticals, and Janssen. EVC reports research funding to their institution from Bayer, Boehringer Ingelheim, Celgene, Ipsen, Lilly, Merck Sharp & Dohme, Merck KGaA, Novartis, Rocher, and Servier; and fees for advisory board consulting for Array, AstraZeneca, Bayer, Biocartis, Bristol-Myers Squibb, Celgene, Daiichi, Halozyme, GSK, Incyte, Ipsen, Lilly, Merck Sharp & Dohme, Merck KGaA, Novartis, Pierre Fabre, Roche, Servier, Sirtex, and Taiho. JT reports consulting fees from Array Biopharma, AstraZeneca, Bayer, Boehringer Ingelheim, Cardiff Oncology, Chugai, Daiichi Sankyo, F Hoffman-La Roche, Genentech, HalioDx SAS, Hutchison MediPharma International, Ikena Oncology, Inspira, IQVIA, Lilly, Menarini, Merck Serono, Merus, MSD, Mirati, Neophore, Novartis, Ona Therapeutics, Orion Biotechnology, Peptomyc, Pfizer, Pierre Fabre, Samsung Bioepis, Sanofi, Scandion Oncology, Scorpion Therapeutics, Seattle Genetics, Servier, Sotio Biotech, Taiho, Tessa Therapeutics, TheraMyc, and Tolremo Therapeutics; honoraria from Imedex/HMP, Medscape Education, MJH Life Sciences, PeerView Institute for Medical Education, and Physicians Education Resource; and stock options in Oniria Therapeutics. KL, C-SS, and PB are employees of and own stock options in MSD. SYR reports research funding to their institution from Amgen, Astellas, Daiichi Sankyo, Eisai, Merck, Roche, Zymework, Indivumed, MSD, Ono, Bristol-Myers Squibb, and AstraZeneca; consultancy fees from Amgen, Astellas, Daiichi Sankyo, Eisai, LG Biochem, Indivumed, MSD, Ono, Bristol-Myers Squibb, and AstraZeneca; and fees for speakers bureaus from Lilly, Eisai, Daiichi Sankyo, MSD, Ono, and Bristol-Myers Squibb., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: First-line chemotherapy for advanced or metastatic human epidermal growth factor receptor 2 (HER2)-negative gastric or gastro-oesophageal junction adenocarcinoma has a median overall survival (OS) of less than 1 year. We aimed to evaluate first-line programmed cell death (PD)-1 inhibitor-based therapies in gastric, gastro-oesophageal junction, and oesophageal adenocarcinoma. We report the first results for nivolumab plus chemotherapy versus chemotherapy alone., Methods: In this multicentre, randomised, open-label, phase 3 trial (CheckMate 649), we enrolled adults (≥18 years) with previously untreated, unresectable, non-HER2-positive gastric, gastro-oesophageal junction, or oesophageal adenocarcinoma, regardless of PD-ligand 1 (PD-L1) expression from 175 hospitals and cancer centres in 29 countries. Patients were randomly assigned (1:1:1 while all three groups were open) via interactive web response technology (block sizes of six) to nivolumab (360 mg every 3 weeks or 240 mg every 2 weeks) plus chemotherapy (capecitabine and oxaliplatin every 3 weeks or leucovorin, fluorouracil, and oxaliplatin every 2 weeks), nivolumab plus ipilimumab, or chemotherapy alone. Primary endpoints for nivolumab plus chemotherapy versus chemotherapy alone were OS or progression-free survival (PFS) by blinded independent central review, in patients whose tumours had a PD-L1 combined positive score (CPS) of five or more. Safety was assessed in all patients who received at least one dose of the assigned treatment. This study is registered with ClinicalTrials.gov, NCT02872116., Findings: From March 27, 2017, to April 24, 2019, of 2687 patients assessed for eligibility, we concurrently randomly assigned 1581 patients to treatment (nivolumab plus chemotherapy [n=789, 50%] or chemotherapy alone [n=792, 50%]). The median follow-up for OS was 13·1 months (IQR 6·7-19·1) for nivolumab plus chemotherapy and 11·1 months (5·8-16·1) for chemotherapy alone. Nivolumab plus chemotherapy resulted in significant improvements in OS (hazard ratio [HR] 0·71 [98·4% CI 0·59-0·86]; p<0·0001) and PFS (HR 0·68 [98 % CI 0·56-0·81]; p<0·0001) versus chemotherapy alone in patients with a PD-L1 CPS of five or more (minimum follow-up 12·1 months). Additional results showed significant improvement in OS, along with PFS benefit, in patients with a PD-L1 CPS of one or more and all randomly assigned patients. Among all treated patients, 462 (59%) of 782 patients in the nivolumab plus chemotherapy group and 341 (44%) of 767 patients in the chemotherapy alone group had grade 3-4 treatment-related adverse events. The most common any-grade treatment-related adverse events (≥25%) were nausea, diarrhoea, and peripheral neuropathy across both groups. 16 (2%) deaths in the nivolumab plus chemotherapy group and four (1%) deaths in the chemotherapy alone group were considered to be treatment-related. No new safety signals were identified., Interpretation: Nivolumab is the first PD-1 inhibitor to show superior OS, along with PFS benefit and an acceptable safety profile, in combination with chemotherapy versus chemotherapy alone in previously untreated patients with advanced gastric, gastro-oesophageal junction, or oesophageal adenocarcinoma. Nivolumab plus chemotherapy represents a new standard first-line treatment for these patients., Funding: Bristol Myers Squibb, in collaboration with Ono Pharmaceutical., Competing Interests: Declaration of interests YYJ reports receiving consulting or advisory board fees from AstraZeneca, Daiichi Sankyo, Imugene, Jounce Therapeutics, Merck Serono, Michael J Hennessy Associates, Paradigm Medical Communications, Pfizer, Seattle, Genetics, and Zymeworks; receiving consulting or advisory and research funding from Eli Lilly, Bristol Myers Squibb, and Merck & Co; receiving research funding from Bayer, Boehringer Ingelheim, Genentech/Roche, MSK Cancer Center Support Grant/Core Grant (P30 CA008748), and Ono Pharmaceutical; receiving speaker's bureau fees from the American Society of Clinical Oncology; and receiving stock options from Rgenix, outside the submitted work. KS reports receiving personal fees for advisory roles from AbbVie, Bristol Myers Squibb, GlaxoSmithKline, Novartis, Ono Pharmaceutical Company, Pfizer, and Takeda; receiving advisory role or research funding from Astellas Pharma, Eli Lilly, Merck Pharmaceutical, and Taiho Pharmaceutical; receiving honoraria (lecture fees) from AbbVie, Novartis, and Yakult Honsha; and receiving research funding from Chugai Pharma, Daiichi Sankyo, Dainippon Sumitomo Pharma, and Medi Science, outside the submitted work. MM reports receiving research grants from AIO, Amgen, German Federal Ministry of Education and Research, Bristol Myers Squibb, European Organisation for Research and Treatment of Cancer, German Cancer Aid, Merck Serono, Merck Sharp & Dohme, and Pfizer; receiving personal fees from Bristol Myers Squibb, Falk Foundation, Lilly, MCI Group, Merck Serono, Merck Sharp & Dohme, Pfizer, and Roche; and receiving non-financial support from AIO, Amgen, Bristol Myers Squibb, German Federal Ministry of Education and Research, European Organisation for Research and Treatment of Cancer, and German Cancer Aid, outside the submitted work. MG reports receiving grants and personal fees from Bristol Myers Squibb and Novartis; and receiving personal fees from Merck Sharp & Dohme and Roche, outside the submitted work. KY reports receiving grants and personal fees from Daiichi-Sankyo, Ono Pharmaceutical Company, Taiho Pharmaceutical, and Yakult Honsha; receiving personal fees from Chugai, Lilly, and Takeda; receiving grants from Sanofi; and receiving personal fees from Bristol Myers Squibb, Merck Serono, and Takeda, outside the submitted work. MS reports receiving personal fees for clinical research from Bristol Myers Squibb, during the conduct of the study; and receiving personal fees for clinical research from Astellas, AstraZeneca, Eli Lilly, GlaxoSmithKline, Merck Serono, Merck Sharp & Dohme, Novartis, Pfizer, Regeneron, and Roche, outside the submitted work. MT reports receiving research funding from Bristol Myers Squibb, during the conduct of the study. RK reports receiving grants from Amgen, AstraZeneca, Athenex, Eli Lilly, Nektar, and Sanofi; receiving grants and non-financial support from Roche; grants and personal fees from Astellas and Novartis; grants, personal fees, and non-financial support from Bristol Myers Squibb, Merck Sharp & Dohme, and Pfizer; and personal fees from Gador, outside the submitted work. MVK reports serving in an advisory role for Bristol Myers Squibb, Merck Sharp & Dohme, Ipsen, Roche, Sandoz, Sanofi, and Servier, outside the submitted work. RB reports serving as a medical adviser for Merck Serono and Novartis; receiving clinical research funding from Novartis; serving as a medical adviser and speaker for AstraZeneca, Bristol Myers Squibb, and Pfizer; receiving clinical research funding from Bristol Myers Squibb, Merck Sharp & Dohme, and Roche; and serving as a speaker for Merck, during the conduct of the study. TZ reports receiving personal advisory board fees from AstraZeneca, Bristol Myers Squibb, Lilly, Merck Sharp & Dohme, Novartis, Roche, and Sanofi, outside the submitted work. JMC reports personal fees and consulting and travel support from Bristol Myers Squibb; and research funding from AstraZeneca, Esperas Pharma, Merck, and Tesaro, outside the submitted work. VP, DC, MLe, HX, KK, and MLi report employment with Bristol Myers Squibb and ownership of stock in Bristol Myers Squibb. JAA reports receiving clinical research grants and receiving personal advisory board fees from Bristol Myers Squibb, during the conduct of the study. All other authors declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Safety pharmacology is an essential part of drug development aiming to identify, evaluate and investigate undesirable pharmacodynamic properties of a drug primarily prior to clinical trials. In particular, cardiovascular adverse drug reactions (ADR) have halted many drug development programs. Safety pharmacology has successfully implemented a screening strategy to detect cardiovascular liabilities, but there is room for further refinement. In this setting, we present the INSPIRE project, a European Training Network in safety pharmacology for Early Stage Researchers (ESRs), funded by the European Commission's H2020-MSCA-ITN programme. INSPIRE has recruited 15 ESR fellows that will conduct an individual PhD-research project for a period of 36 months. INSPIRE aims to be complementary to ongoing research initiatives. With this as a goal, an inventory of collaborative research initiatives in safety pharmacology was created and the ESR projects have been designed to be complementary to this roadmap. Overall, INSPIRE aims to improve cardiovascular safety evaluation, either by investigating technological innovations or by adding mechanistic insight in emerging safety concerns, as observed in the field of cardio-oncology. Finally, in addition to its hands-on research pillar, INSPIRE will organize a number of summer schools and workshops that will be open to the wider community as well. In summary, INSPIRE aims to foster both research and training in safety pharmacology and hopes to inspire the future generation of safety scientists., Competing Interests: Declaration of Competing Interest The views expressed in this publication are those of the authors and do not necessarily represent the decisions, policy or views of their respective institutions., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)