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A tumour grows when the total division (birth) rate of its cells exceeds their total mortality (death) rate. The capability for uncontrolled growth within the host tissue is acquired via the accumulation of driver mutations which enable the tumour to progress through various hallmarks of cancer. We present a mathematical model of the penultimate stage in such a progression. We assume the tumour has reached the limit of its present growth potential due to cell competition that either results in total birth rate reduction or death rate increase. The tumour can then progress to the final stage by either seeding a metastasis or acquiring a driver mutation. We influence the ensuing evolutionary dynamics by cytotoxic (increasing death rate) or cytostatic (decreasing birth rate) therapy while keeping the effect of the therapy on net growth reduction constant. Comparing the treatments head to head we derive conditions for choosing optimal therapy. We quantify how the choice and the related gain of optimal therapy depends on driver mutation, metastasis, intrinsic cell birth and death rates, and the details of cell competition. We show that detailed understanding of the cell population dynamics could be exploited in choosing the right mode of treatment with substantial therapy gains.

Abstract BackgroundPrevious reports have objectively demonstrated the efficacy of botulinum toxin for brow elevation. No previous clinical trial has reported a combined approach to botulinum toxin A injection with hyaluronic acid (HA) injection in the upper face for periorbital region beautification focusing on eyebrow reshaping. ObjectivesTo evaluate the effect of IncobotulinumtoxinA injection using the ONE21 technique combined with HA injection (CPM technology) to redefine brow shape and position. MethodsA prospective pilot study was designed to evaluate the effect of IncobotulinumtoxinA injection using the ONE21 technique—with a preestablished scheme of doses and injection-site distribution—combined with HA injection (CPM technology) periosteally into the palpebromalar groove and subdermally in the anterior temporal region, to redefine brow shape and position. Objective eyebrow measurements were taken by an independent investigator using the Merz Aesthetic Scale (MAS) for brow positioning. Patient satisfaction was also evaluated. Some patients were also assessed using the Vectra System (Canfield Scientific, Parsippany, NJ). ResultsEleven females, aged 29 to 55 years, were included in this prospective pilot study. The totality of patients (11/100%) had at least ≥1-point improvement in the MAS brow positioning. All patients (100%) reported significant aesthetic improvement of their periorbital region and appearance, with 82% of the patients much improved. Mild side effects, such as ecchymosis and transient temporal edema, were reported. ConclusionsThe combined technique improved the appearance of the orbital area by uplifting the lateral eyebrow and creating an almond-shaped eye effect, which characterizes the trending marketing term Foxy eyes. Further studies, including more cases, are needed to obtain a statistically significant outcome. Level of Evidence: 4

Abstract Background In the absence of clinical trials, data on the safety of medicine exposures in pregnancy are dependent on observational studies conducted after the agent has been licensed for use. This requires an accurate history of antenatal medicine use to determine potential risks. Medication use is commonly determined by self-report, clinician records, and electronic pharmacy data; different data sources may be more informative for different types of medication and resources may differ by setting. We compared three methods to determine antenatal medicine use (self-report, clinician records and electronic pharmacy dispensing records [EDR]) in women attending antenatal care at a primary care facility in Cape Town, South Africa in a setting with high HIV prevalence. Methods Structured, interview-administered questionnaires recorded self-reported medicine use. Data were collected from clinician records and EDR on the same participants. We determined agreement between these data sources using Cohen’s kappa and, lacking a gold standard, used Latent Class Analysis to estimate sensitivity, specificity and positive predictive value (PPV) for each data source. Results Between 55% and 89% of 967 women had any medicine use documented depending on the data source (median number of medicines/participant = 5 [IQR 3–6]). Agreement between the datasets was poor regardless of class except for antiretroviral therapy (ART; kappa 0.6–0.71). Overall, agreement was better between the EDR and self-report than with either dataset and the clinician records. Sensitivity and PPV were higher for self-report and the EDR and were similar for the two. Self-report was the best source for over-the-counter, traditional and complementary medicines; clinician records for vaccines and supplements; and EDR for chronic medicines. Conclusions Medicine use in pregnancy was common and no single data source included all the medicines used. ART was the most consistently reported across all three datasets but otherwise agreement between them was poor and dependent on class. Using a single data collection method will under-estimate medicine use in pregnancy and the choice of data source should be guided by the class of the agents being investigated.

Air entrained concrete is used for outdoor structures in cold climate to enhance freeze-thaw resistance. A well dispersed air void system is incorporated in the fresh concrete, consisting of spherical air voids that provide expansion space for freezing water and thus act as pressure-relief. The amount of air entrainment (AE), which results from adding an air entrainment agent to the fresh concrete during mixing, needs to be controlled so as not to significantly reduce the strength of the hardened concrete. Excessive AE has been reported in some bridge concretes in Finland, triggering a comprehensive inspection of 96 bridges. The paper describes the testing methodologies used in this case-study of comprehensive national bridge-inventory level inspection, assess the main findings (compressive strength and porosity), and concludes on the lessons learned concerning the effectiveness of inspection methods. The large dataset of concretes, presented here, was treated statistically. The amount of AE in hardened concrete had been steadily increasing in recent years Salparanta et al. [1]. The study shows the importance of a representative number of samples when conducting inspections and found that the use of rebound hammer and core testing correlation to establish additional in situ strength measurements led to overly conservative results. It was verified that the immediate safety of the inspected bridges was not in question, and that a re-evaluation of the safety margins and special maintenance protocols may be required to assure adequate long-term service life for some of the bridges that exhibited exceptionally high AE.

Abstract 5G mobile network technology together with edge computing will create new opportunities for developing novel road safety services in order to better support connected and automated driving in challenging situations. This paper studies the feasibility and benefits of localized mobile network edge applications for supporting vehicles in diverse conditions. We study a particular scenario, where vehicle sensor data processing, required by road safety services, is installed into the mobile network edge in order to extend the electronic horizon of the sensors carried by other vehicles. Specifically, we focus on a LiDAR data-based obstacle warning case where vehicles receive obstacle warnings from the mobile network edge. The proposed solution is based on a generic system architecture. In this paper, we first evaluate different connectivity and computing options associated with such a system using ns-3 simulations. Then, we introduce a proof-of-concept implementation of the LiDAR-based obstacle warning scenario together with first results from an experimental evaluation, conducted both in a real vehicle testbed environment and in a laboratory setting. As a result, we obtain first insights on the feasibility of the overall solution and further enhancements needed.

Abstract Background and Aims Atypical wounds comprise about 20% of all chronic wounds. Their diagnosis and treatment are challenging and require multidisciplinary cooperation. More knowledge is needed about the clinical characteristics and comorbidities of atypical wounds to enhance the treatment of these wounds. Methods We studied clinical characteristics and comorbidities of the atypical wounds by using the patient data retrieved from the Oulu University Hospital patient database from the year 1996 to the end of 2019 with the following International Classification of Diseases codes: L88, L95.0, L95.8, L95.9, and L98.1. Results In our data, there were 135 patients with atypical wound, more commonly seen in females (N = 84, 62.2%) than in males (N = 51, 37.8%) (p

Abstract BackgroundRelaxation of depressor muscles in the lower face with botulinum toxin A (BoNT-A) can create a lifting effect and dramatically improve jawline contour and resting facial expression. Even with the recent increase in interest in lower face rejuvenation, BoNT-A is a relatively under-recognized tool for treatment of this area. When treating the lower face, an understanding of anatomy and the relationship between the facial muscles is especially important, as injection patterns must be customized for consistently positive outcomes. ObjectivesThis study was aimed to provide basic knowledge of the activities of the muscles in the lower face and neck and to describe the basis for injecting BoNT-A to create lift in this area. Expert guidance for injection is also provided. MethodsAs part of a continuing medical education course on differentiating botulinum toxin products, a panel of 4 expert physician injectors participated in a live webinar to discuss the implications of increasing toxin use. ResultsThe practical guidance in this manuscript is based on the most frequently requested information by audience members and the information considered critical for success by the authors. The authors outline the functional anatomy of the lower face most relevant for BoNT-A treatment and case studies as well as methods for patient evaluation and injection technique are also provided. Videos showing treatment planning and injection technique for the lower face and neck are included. ConclusionsBoNT-A is an important nonsurgical tool for creating lift in the lower face. Level of Evidence: 5

Proposing and elaborating upon the concept of onomastic capital as a multidisciplinary lens for socio-onomastic research, this article considers some of the historical underpinnings that contribute to onomastic capital, before focusing specifically on the recent dramatic growth in the phenomenon of selling naming rights to (semi-)public spaces. This marketization of names has been especially visible in sports and entertainment venues. To examine emerging naming patterns and practices resulting from such name sponsorship activity, the article explores a database of onomastic material from a variety of European contexts: England and Wales, Finland, Germany, Italy, Norway and Scotland.

We use an analytic solver for the single-impurity Anderson model based on simplified parquet equations to describe the Kondo asymptotics. This scheme uses a two-particle self-consistency to control the strong-coupling Kondo critical behavior of this model at half filling. The equations can be written in the real-frequency representation, which gives us direct access to spectral functions unlike numerical schemes in the Matsubara formalism. We compare our results to those obtained by second-order perturbation theory, numerical renormalization group, and continuous-time quantum Monte Carlo in order to assess the reliability of this approximation. [ABSTRACT FROM AUTHOR]

This study examined weight loss during an extensive 1-year lifestyle programme in primary care in Finland in overweight subjects (n = 134, age 18–69 years; BMI > 30, or BMI > 25 with a comorbidity that would benefit from weight loss) between 2009 and 2013 in a single arm design. The programme included four medical doctor visits, five sessions by a dietitian (advice on diet and on-location shopping behaviour), cooking classes, exercise supervised by personal trainer, and group discussions. A motivational interview method was applied.Of the 134 participants, 92 (69%) completed the 1-year programme. Among the participants 44% lost ≥ 5%, while 21% lost ≥ 10% of their initial body weight. In intention-to-treat-analyses, the mean weight loss during one year was 4.8 kg (p

In this paper, we address the introduction of Virtual Reality (VR) tools to the education of industrial design (ID) university students. We present three cases of how we have introduced VR technology in different courses of the industrial design curriculum at the University of [REMOVED FOR REVIEW]. As the first example (Case I), we introduced a VR simulation as an empathetic design tool to simulate visual disabilities. The second example (Case II) is reported from a course where students created concepts for a head mounted display (HMD) AR application in smart buildings, and tried out interaction with a HMD VR application. In the third example (Case III), VR was used as a display environment to exhibit students’ 3D industrial design concept models. We report our experiences and lessons learnt, as well as recorded student feedback from the trials. As salient findings, we report the general positive feedback, successful integration with the taught themes especially when connected to physical 3D models, as well as suggested improvements. Hindering the adoption of the technology from the teaching point of view, we report on the lack of infrastructure for multi-user groups in classrooms, the additional effort required to set up the technical system, and limited features supporting multimodality.

Accurate identification of insect species is an indispensable and challenging requirement for every entomologist, particularly if the species is involved in disease outbreaks. The European MediLabSecure project designed an identification (ID) exercise available to any willing participant with the aim of assessing and improving knowledge in mosquito taxonomy. The exercise was based on high-definition photomicrographs of mosquitoes (26 adult females and 12 larvae) collected from the western Palaearctic. Sixty-five responses from Europe, North Africa and the Middle East were usable. The study demonstrated that the responders were better at identifying females (82% correct responses) than larvae (63%). When the responders reported that they were sure of the accuracy of their ID, the success rate of ID increased (92% for females and 88% for larvae). The top three tools used for ID were MosKeyTool (72% of responders), the ID key following Becker et al. [2010. Mosquitoes and their control, 2nd edn. Berlin: Springer] (38%), and the CD-ROM of Schaffner et al. [2001. Les moustiques d’Europe: logiciel d’identification et d’enseignement – The mosquitoes of Europe: an identification and training programme. Montpellier: IRD; EID] (32%), while other tools were used by less than 10% of responders. Responders reporting the identification of mosquitoes using the MosKeyTool were significantly better (80% correct responses) than non-MosKeyTool users (69%). Most responders (63%) used more than one ID tool. The feedback from responders in this study was positive, with the exercise being perceived as halfway between educational training and a fun quiz. It raised the importance of further expanding training in mosquito ID for better preparedness of mosquito surveillance and control programmes.

In this reflection, we seek to develop some of Professor Gill’s inspiring ideas on the notion of (un)welcome further. We do this, in particular, by problematizing his largely dualistic conception of the emotionally-invested, inter-personal forms of welcome contra a bureaucratic tendency to abstract welcome, to hollow it out emotionally. We argue that if applied too rigidly, this dichotomy can be unwieldy for making sense of the actual socio-spatial and emotional dynamics of (un)welcome. To elaborate this criticism, we expand on the notion of welcome from three interrelated perspectives. First, we argue that besides the opposite poles of people who welcome refugees, and forces that attempt to exclude them, great many actors convey more ambiguous and contextually varying attitudes to (un)welcoming immigrants. In the light of Lefebvre’s conceptual triad of social space, we next point out that Gill’s conceptualization pays inadequate heed to the practiced and societally recompensing aspects of everyday spatiality and welcoming. Finally, we take a cue from Gill’s suggestion to analyze welcome from the emotional geographies perspective, and reflect on exclusionary and inclusionary socio-spatial processes related to refugees’ emotions (lived space) and coping tactics (practiced space).

Artikkelissa vertailemme Berliinin olympialaisia (1936) ja Saksan jalkapallon MM-kisoja (2006) Guy Debordin ajatuksia soveltaen keskitetyn (media) spektaakkelin erilaisina ja eri aikakausiin sijoittuvina muotoina. Lähestymme ensin mainittua propagandan, jälkimmäistä brändin käsitteen avulla. Tarkastelemme ihmisten toimintaa kaupunkitilassa urheiluspektaakkelien tuottamiseen kytkeytyvien poliittisten ja taloudellisten valtaintressien kautta. Kohdistamme huomiomme erityisesti propaganda- ja brändikoneistojen tapoihin suostutella kaupungeissa liikkuvia ihmisiä odotetun yleisöyden ja esiintyjyyden ideaalirooleihin suunnitelmallisesti organisoidun ja tunteisiin vetoavan urbaanin ympäristön tuottamisen avulla. Esimerkkitapauksemme ovat historiallisesti merkittäviä hetkiä kehityksessä, jossa joukkoviestintä on ohjannut urheilutapahtumien organisointia, esillepanoa ja niihin liittyvää ihmisten tilallista ja affektiivista (joukko)liikuttamista. Argumenttimme perustuvat tutkimuskirjallisuuteen, dokumentaarisiin elokuviin ja havaintoihin Saksan jalkapallon MM-kisojen kisakaupungeista.

Therapeutic targeting of the adenosine deaminase ADAR has great potential in cancer and other indications; however, it remains unclear what approach can enable effective and selective therapeutic inhibition. Herein, we conduct multi-staged guide RNA screening and identify high efficiency Cas9 guide RNAs to enable a CRISPR/Cas-based approach for ADAR knockout. Through characterization in human primary immune cell systems we observe similar activity with two-part guide RNA and single guide RNA, dose responsive activity, similar guide activity rank order across different cell types, and favorable computational off-target profiles of candidate guide RNAs. We determine that knockout of ADAR using these guide RNAs induces pharmacodynamic responses primarily consisting of immunological responses such as a type I interferon response, consistent with the known function of ADAR as a key regulator of dsRNA sensing. We observe similar biological effects with targeting only the p150 isoform or both p110 and p150 isoforms of ADAR, indicating that at least in the contexts evaluated, loss of p150 ADAR mediates the primary response. These findings provide a resource of well-characterized, high efficiency ADAR-targeting Cas9 guide RNAs suitable for genomic medicines utilizing different delivery modalities and addressing different therapeutic areas., Competing Interests: All authors are employees of Spotlight Therapeutics, Inc., or were employees at the time the research took place. KM, AT, SCW, BGG, AJC and MJJ are inventors on patent applications related to this work including patent applications related to in vivo and in vitro delivery of Cas9 ribonucleoproteins and patent applications related to guide RNA sequences. SCW is a prior consultant for BioEntre, consultant for Actym Therapeutics, an inventor on a patent for a mouse model of autoimmune adverse events, and employee of Inversion Therapeutics. Benjamin Gowen is an employee of Editpep, Inc. KM, AT, SCW, BGG, AJC and MJJ are inventors on patent applications related to this work including patent applications related to in vivo and in vitro delivery of Cas9 ribonucleoproteins and patent applications related to guide RNA sequences. The patent numbers are US20240209355A1; CA3214548A1; WO2023196844A2; WO2024077184A3; WO2021062201A1; WO2024077184A2; WO2024226822A2. This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2025 Gowen et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Genetic medicines, including CRISPR/Cas technologies, extend tremendous promise for addressing unmet medical need in inherited retinal disorders and other indications; however, there remain challenges for the development of therapeutics. Herein, we evaluate genome editing by engineered Cas9 ribonucleoproteins (eRNP) in vivo via subretinal administration using mouse and pig animal models. Subretinal administration of adenine base editor and double strand break-inducing Cas9 nuclease eRNPs mediate genome editing in both species. Editing occurs in retinal pigmented epithelium (RPE) and photoreceptor cells, with favorable tolerability in both species. Using transgenic reporter strains, we determine that editing primarily occurs close to the site of administration, within the bleb region associated with subretinal injection. Our results show that subretinal administration of eRNPs in mice mediates base editing of up to 12% of the total neural retina, with an average rate of 7% observed at the highest dose tested. In contrast, a substantially lower editing efficiency was observed in minipigs; even with direct quantification of only the treated region, a maximum base editing rate of 1.5%, with an average rate of <1%, was observed. Our data highlight the importance of species consideration in translational studies for genetic medicines targeting the eye and provide an example of a lack of translation between small and larger animal models in the context of subretinal administration of Cas9 eRNPs., Competing Interests: Declaration of interests: All authors except PKS, BRP, DG, and KS are employees of Spotlight Therapeutics, Inc., or were employees at the time the research took place. KM, SCW, BGG, AJC and MJJ are inventors on patent applications related to in vivo and in vitro delivery of Cas9 ribonucleoproteins and patent applications related to guide RNA sequences. SCW is a prior consultant for BioEntre, consultant for Actym Therapeutics, an inventor on a patent for a mouse model of autoimmune adverse events, and employee of Inversion Therapeutics. Benjamin Gowen is an employee of Editpep, Inc. KS is a member of the scientific advisory boards of Andson Biotech, Bharat Biotech, and Notch Therapeutics.

KRAS protein is known to be frequently mutated in various cancers. The most common mutations being at position 12, 13 and 61. The positions 12 and 13 form part of the phosphate binding region (P-loop) of KRAS. Owing to mutation, the protein remains in continuous active state and affects the normal cellular process. Understanding the structural changes owing to mutations in GDP-bound (inactive state) and GTP-bound (active state) may help in the design of better therapeutics. To understand the structural flexibility due to the mutations specifically located at P-loop regions (G12D, G12V and G13D), extensive molecular dynamics simulations (24 μs) have been carried for both inactive (GDP-bound) and active (GTP-bound) structures for the wild type and these mutants. The study revealed that the local structural changes at the site of mutations allosterically guide changes in distant regions of the protein through hydrogen bond and hydrophobic signalling network. The dynamic cross correlation analysis and the comparison of the correlated motions among different systems manifested that changes in SW-I, SW-II, α3 and the loop preceding α3 affects the interactions of GDP/GTP with different regions of the protein thereby affecting its hydrolysis. Further, the Markov state modelling analysis confirmed that the mutations, especially G13D imparts rigidity to structure compared to wild type and thus limiting its conformational state in either intermediate state or active state. The study suggests that along with SW-I and SW-II regions, the loop region preceding the α3 helix and α3 helix are also involved in affecting the hydrolysis of nucleotides and may be considered while designing therapeutics against KRAS., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors. Published by Elsevier Ltd.)

Background: Transthyretin amyloid cardiomyopathy (ATTR-CM) is associated with significant mortality. The Val122Ile variant, highly prevalent in Black patients, portends poorer survival compared with other ATTR-CM subtypes. Although Val122Ile is biologically more aggressive, the contribution of race and socioeconomic status (SES) to disease outcomes in patients with ATTR-CM is undefined., Objectives: The aim of this study was to evaluate the impact of race and SES on clinical outcomes in patients with ATTR-CM., Methods: Patients with ATTR-CM who received care at Johns Hopkins Hospital between 2006 and 2022 were included. SES was assessed using area deprivation index (ADI). Associations of race and ADI with heart failure (HF) hospitalization and/or death were measured using multivariable logistic or Cox proportional hazards models., Results: Of 282 patients, 225 (80%) were men, and 129 (46%) were Black. Black vs White patients disproportionately constituted the highest ADI (most deprived) category (66% vs 28%; P  = 0.004), and Black patients were more likely to have HF hospitalization or death over 5 years compared with White patients (log-rank P  < 0.001). Among those with ADI >25, Black patients had a significantly greater hazard of HF hospitalization or death compared with White patients, independent of disease stage at diagnosis (HR: 2.77; 95% CI: 1.45-5.32; P  = 0.002)., Conclusions: Black patients with low SES may be at greater risk for underdiagnosis and adverse outcomes compared with White patients. Ongoing efforts are needed to improve outcomes in this subset of patients with ATTR-CM., Competing Interests: The authors have reported that they have no relationships relevant to the contents of this paper to disclose.PerspectivesCOMPETENCY IN MEDICAL KNOWLEDGE: Hereditary ATTR-CM related to the Val122Ile genetic variant is a highly morbid cause of HF in Black individuals and leads to worse outcomes compared with wild-type ATTR-CM disease. Black patients from the most socioeconomically deprived areas had the poorest event-free survival compared with other groups. Among patients with ADI > 25, the hazard of HF hospitalization or mortality was significantly higher in Black compared with White patients, even when adjusting for disease severity at diagnosis. TRANSLATIONAL OUTLOOK: Black patients are underrepresented in contemporary ATTR-CM clinical trials. Future trial designs need to focus on increasing representation of Black patients as well as those with Val122Ile disease to identify effective therapies for patients at risk for worse outcomes to patients with wild-type disease. Moreover, a greater understanding of the more aggressive pathobiology of Val122Ile is needed in this vulnerable patient subset., (© 2024 The Authors.)

Background: The diagnosis of heart failure with preserved ejection fraction (HFpEF) in the clinical setting remains challenging, especially in patients with obesity., Objectives: This study aimed to identify novel predictors of HFpEF well suited for patients with obesity., Methods: We performed a retrospective analysis of a well-characterized cohort of patients with obesity with HFpEF (n = 404; mean body mass index [BMI] 36.6 kg/m 2 ) and controls (n = 67). We used the machine learning algorithm Gradient Boosting Machine to analyze the association of various parameters with the diagnosis of HFpEF and subsequently created a multivariate logistic model for the diagnosis., Results: Gradient Boosting Machine identified BMI, estimated glomerular filtration rate, left ventricular mass index, and left atrial to left ventricular volume ratio as the strongest predictors of HFpEF. These variables were used to build a model that identified HFpEF with a sensitivity of 0.83, a specificity of 0.82, and an area under the curve (AUC) of 0.88. Internal validation of the model with optimism-adjusted AUC showed an AUC of 0.87. Within the studied cohort, the novel score outperformed the H2FPEF score (AUC: 0.88 vs 0.74; P  < 0.001)., Conclusions: In a HFpEF cohort with obesity, BMI, estimated glomerular filtration rate, left ventricular mass index, and left atrial to left ventricular volume ratio most correlated with the identification of HFpEF, and a score based on these variables (HFpEF-JH score) outperformed the currently used H2PEF score. Further validation of this novel score is warranted, as it may facilitate improved diagnostic accuracy of HFpEF, particularly in patients with obesity., Competing Interests: This work was performed by Northwestern University and Johns Hopkins University HFpEF Clinic and supported by 10.13039/100000050NHLBI grants 5K08HLO145108-03 and 1R01HL160716-01 to Dr Adamo and T32-HL007227 to Dr Lovell, institutional funds from the Johns Hopkins Division of Cardiology awarded to Drs Adamo and Sharma and 10.13039/100000968American Heart Association Strategically Focused Research Network grant (#16SFRN28780016) to Dr Shah. Dr Shah has received research grants from the 10.13039/100000002National Institutes of Health (U54 HL160273, R01 HL107577, R01 HL127028, R01 HL140731, and R01 HL149423), 10.13039/100004325AstraZeneca, Corvia, and 10.13039/100004319Pfizer; and consulting fees from Abbott, AstraZeneca, Amgen, Aria CV, Axon Therapies, Bayer, Boehringer-Ingelheim, Boston Scientific, Bristol Myers Squibb, Cyclerion, Cytokinetics, Edwards Lifesciences, Eidos, Imara, Impulse Dynamics, Intellia, Ionis, Lilly, Merck, Metabolic Flux, MyoKardia, N.G.M. Biopharmaceuticals, Novartis, Novo Nordisk, Pfizer, Prothena, Regeneron, Rivus, Sardocor, Shifamed, Tenax, and Tenaya. Dr Adamo has received consultant fees from Kiniksa Pharmaceuticals and being cofounder of i-Cordis L.L.C. Dr Sharma has served as an advisory board member and consultant to Alleviant, AstraZeneca, Bayer, Boehringer Ingelheim, Edwards Lifesciences, Imbria, Novartis, Novo Nordisk, RIVUS, and ViCardia and has received grant funding from 10.13039/100002429Amgen, 10.13039/100000009FNIH, and the 10.13039/100000968American Heart Association. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2024 The Authors.)

The COVID-19 pandemic in the later phase showed the presence of the B.1.1.529 variant of the SARS-CoV-2 designated as Omicron. AYUSH-64 a poly herbal drug developed by Central Council for Research in Ayurvedic Sciences (CCRAS) has been recommended by Ministry of Ayush in asymptomatic, mild to moderate COVID-19 patients. One of the earlier, in-silico study has shown the binding of the constituents of AYUSH-64 to the main protease (M pro ) of the SARS-CoV-2. This study enlisted four phytochemicals of AYUSH-64, which were found to have significant binding with the M pro . In continuation to the same, the current study proposes to understand the binding of these four phytochemicals to main protease (M pro) and receptor binding domain (RBD) of spike protein of the Omicron variant. An enhanced molecular docking methodology, namely, ensemble docking has been used to find the most efficiently binding phytochemical. Using molecular dynamics (MD) simulations and clustering approach it was observed that the M pro and RBD Spike of Omicron variant of SARS-CoV-2 in complex with human ACE2 tends to attain 4 and 8 conformational respectively. Based on the docking studies, the best binding phytochemical of the AYUSH-64, akummicine N-oxide was selected for MD simulations. MD simulations of akummicine N-oxide bound to omicron variant of M pro and RBD Spike-ACE complex was performed. The conformational, interaction and binding energy analysis suggested that the akummicine N-oxide binds well with M pro and RBD Spike-ACE2 complex. The interaction between RBD Spike and ACE2 was observed to weaken in the presence of akummicine N-oxide. Hence, it can be inferred that, these phytochemicals from AYUSH-64 formulation may have the potential to act against the Omicron variant of SARS-CoV-2., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors. Published by Elsevier B.V.)

Background: Shyonaka (Oroxylum indicum Vent) is widely used in Ayurveda and in ethnomedical practice for the treatment of inflammation, pain, diarrhea, non-healing ulcers, and cancer. Owing to the high prevalence of Epstein-Barr virus (EBV) infection in Nasopharyngeal carcinoma (NPC) patients, simultaneous targeting of proteins involved in both EBV replication and NPC proliferation might help to manage the disease effectively., Objectives: This study is designed to identify potential dual targeting inhibitors from Oroxylum indicum having the potential to inhibit both EBV and NPC. This study also attempted quantitative analysis of Shyonaka Bark Decoction (SBD) to confirm the presence of Baicalein and Chrysin which are predominant marker compounds of Shyonaka., Methodology: The HPLC analysis of stem bark and root bark of Oroxylum indicum was done to estimate the presence of marker compounds Baicalein and Chrysalin. The in-silico analysis included ADMET analysis followed by molecular docking of known compounds from Oroxylum indicum (retrieved from IMPPAT database) onto the target proteins of EBV (BHRF1, NEC1, dUTPase, Uracil DNA glycosylase) and NPC (COX-2, EGFR, and MDM2) using DOCK6 tool. Further validations were done using the molecular dynamics simulations of top screened molecules onto the selected target proteins using AMBER20 package and their corresponding MMGBSA binding free-energy values were calculated., Results: The molecular docking revealed that the key molecules from the plant, scutellarein 7-rutinoside (S7R), scutellarin (SCU) and 6-hydroxyluteolin, Baicalein and 5,7-Dihydroxy-2-phenyl-6-[3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxychromen-4-one (57D) are effectively intervening with the target proteins of EBV, one of the key causative factors of NPC and the NPC specific targets which have the potential to reduce tumor size and other consequences of NPC. The molecular dynamics simulations of S7R, Baicalein and 57D, Baicalein with MDM-2 protein and dUTPase protein, respectively, showed stable interactions between them which were further assessed by the binding energy calculations., Conclusion: Overall, the in-silico evaluation of these phytochemicals with target proteins indicates their potential to inhibit both EBV and NPC which needs further in-vitro and in-vivo validations., Competing Interests: Conflict of Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: The decision to perform biventricular repair (BVR) in neonates and infants presenting with either single or multiple left ventricle outflow obstructions (LVOTOs) and a borderline left ventricle (BLV) is subject to extensive discussion, and limited information is known regarding the long-term outcomes. As a result, the objective of this study is to critically assess and summarize the available data regarding the prognosis of neonates and infants with LVOTO and BLV who underwent BVR., Methods: In February 2023, we conducted a review study with three different medical search engines (the National Library of Medicine, Science Direct, and Cochrane Library) for Medical Subject Headings and free text terms including "congenital heart disease", "outcome", and "borderline left ventricle". The search was refined by adding keywords for "Shone's complex", "complex LVOT obstruction", "hypoplastic left heart syndrome/complex", and "critical aortic stenosis"., Results: Out of a total of 51 studies, 15 studies were included in the final analysis. The authors utilized heterogeneous definitions to characterize BLV, resulting in considerable variation in inclusion criteria among studies. Three distinct categories of studies were identified, encompassing those specifically designed to evaluate BLV, those focused on Shone's complex, and finally those on aortic stenosis. Despite the challenges associated with comparing data originating from slightly different cardiac defects and from different eras, our results indicate a favorable survival rate and clinical outcome following BVR. However, the incidence of reintervention remains high, and concerns persist regarding residual pulmonary hypertension, which has been inadequately investigated., Conclusions: The available data concerning neonates and infants with LVOTO and BLV who undergo BVR are inadequate and fragmented. Consequently, large-scale studies are necessary to fully ascertain the long-term outcome of these complex defects.

Different types of chemicals and products may exhibit various health risks when administered into the human body. For toxicity reasons, the number of new drugs entering the market through the conventional drug development process has been reduced over the years. However, with the advent of big data and artificial intelligence, machine learning techniques have emerged as a potential solution for predicting toxicity and ensuring efficient drug development and chemical safety. An ML model for toxicity prediction can reduce experimental costs and time while addressing ethical concerns by drastically reducing the need for animals and clinical trials. Herein, MolToxPred, an ML-based tool, has been developed using a stacked model approach to predict the potential toxicity of small molecules and metabolites. The stacked model consists of random forest, multi-layer perceptron, and LightGBM as base classifiers and Logistic Regression as the meta classifier. For training and validation purposes, a comprehensive set of toxic and non-toxic molecules is curated. Different structural and physicochemical-based features in the form of molecular descriptors and fingerprints were employed. MolToxPred utilizes a comprehensive feature selection process and optimizes its hyperparameters through Bayesian optimization with stratified 5-fold cross-validation. In the evaluation phase, MolToxPred achieved an AUROC of 87.76% on the test set and 88.84% on an external validation set. The McNemar test was used as the post-hoc test to determine if the stacked models' performance was significantly different compared to the base learners. The developed stacked model outperformed its base classifiers and an existing tool in the literature, reaffirming its better performance. The hypothesis is that the incorporation of a diverse set of data, the subsequent feature selection, and a stacked ensemble approach give MolToxPred the edge over other methods. In addition to this, an attempt has been made to identify structural alerts responsible for endpoints of the Tox21 data to determine the association of a molecule with a plausible downstream pathway of action. MolToxPred may be helpful for drug discovery and regulatory pipelines in pharmaceutical and other industries for in silico toxicity prediction of small molecule candidates., Competing Interests: There are no conflicts of interest to declare., (This journal is © The Royal Society of Chemistry.)

KRAS activation is known to be modulated by a guanine nucleotide exchange factor (GEF), namely, Son of Sevenless1 (SOS1). SOS1 facilitates the exchange of GDP to GTP thereby leading to activation of KRAS. The binding of GDP/GTP to KRAS at the REM/allosteric site of SOS1 regulates the activation of KRAS at CDC25/catalytic site by facilitating its exchange. Different aspects of the allosteric activation of KRAS through SOS1 are still being explored. To understand the SOS1 mediated activation of KRAS, molecular dynamics simulations for a total of nine SOS1 complexes (KRAS-SOS1-KRAS) were performed. These nine systems comprised different combinations of KRAS-bound nucleotides (GTP/GDP) at REM and CDC25 sites of SOS1. Various conformational and thermodynamic parameters were analyzed for these simulation systems. MMPBSA free energy analysis revealed that binding at CDC25 site of SOS1 was significantly low for GDP-bound KRAS as compared to that of GTP-bound KRAS. It was observed that presence of either GDP/GTP bound KRAS at the REM site of SOS1 affected the activation related changes in the KRAS present at CDC25 site. The conformational changes at the catalytic site of SOS1 resulting from GDP/GTP-bound KRAS at the allosteric changes may hint at KRAS activation through different pathways (slow/fast/rare). The allosteric effect on activation of KRAS at CDC25 site may be due to conformations adopted by switch-I, switch-II, beta2 regions of KRAS at REM site. The effect of structural rearrangements occurring at allosteric KRAS may have led to increased interactions between SOS1 and KRAS at both the sites. The SOS1 residues involved in these important interactions with KRAS at the REM site were R694, S732 and K735. Whereas the ones interacting with KRAS at CDC25 site were S807, W809 and K814. This may suggest the crucial role of these residues in guiding the allosteric activation of KRAS at CDC25 site. The conformational shifts observed in the switch-I, switch-II and alpha3 regions of KRAS at CDC25 site may be attributed to be a part of allosteric activation. The binding affinities, interacting residues and conformational dynamics may provide an insight into development of inhibitors targeting the SOS1 mediated KRAS activation., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors.)

Vaccination with the primary two-dose series of SARS-CoV-2 mRNA protects against infection with the ancestral strain, and limits the presentation of severe disease after re-infection by multiple variants of concern (VOC), including Omicron, despite the lack of a strong neutralizing response to these variants. We compared antibody responses in serum samples collected from mRNA-1273 (Moderna) vaccinated subjects to identify mechanisms of immune escape and cross-protection. Using pseudovirus constructs containing domain-specific amino acid changes representative of Omicron BA.1, combined with domain competition and RBD-antibody depletion, we showed that RBD antibodies were primarily responsible for virus neutralization and variant escape. Antibodies to NTD played a less significant role in antibody neutralization but acted along with RBD to enhance neutralization. S2 of Omicron BA.1 had no impact on neutralization escape, suggesting it is a less critical domain for antibody neutralization; however, it was as capable as S1 at eliciting IgG3 responses and NK-cell mediated, antibody-dependent cell cytotoxicity (ADCC). Antibody neutralization and ADCC activities to RBD, NTD, and S1 were all prone to BA.1 escape. In contrast, ADCC activities to S2 resisted BA.1 escape. In conclusion, S2 antibodies showed potent ADCC function and resisted Omicron BA.1 escape, suggesting that S2 contributes to cross-protection against Omicron BA.1. In line with its conserved nature, S2 may hold promise as a vaccine target against future variants of SARS-CoV-2., Competing Interests: Author YC was employed by the company Leidos. Author TL was employed by company Vysnova Partners, Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Balinsky, Jiang, Jani, Cheng, Zhang, Belinskaya, Qiu, Long, Schilling, Jenkins, Corson, Martin, Letizia, Hontz and Sun.)

Anomalies of the tricuspid valve (TV) are associated with worsened prognosis in congenital heart disease (CHD). Here, we present a descriptive study examining changes in TV morphology in two CHD conditions-repaired tetralogy of Fallot (rTOF) and hypoplastic left heart syndrome (HLSH), using three-dimensional echocardiography. Full volume acquisitions of the TV and right ventricle (RV) were performed from an RV-focused apical view using ECG gating over 2-5 consecutive cardiac cycles using 3D echocardiography, from which TV annulus and leaflet parameters were quantified. A total of 40 rTOF patients (age 14 ± 9.8 years), 40 HLHS patients (age1.0 ± 1.5 years) and 80 age and gender matched controls were included. Among leaflet parameters, antero-posterior and posterior-septal TV coaptation heights were smaller in rTOF (p < 0.001) vs. control. Conversely, only the short-axis TV height was different in HLHS vs. controls (HLHS 1.6 ± 0.4 cm vs. control 1.4 ± 0.3 cm). TV leaflet parameters tended to be larger in HLHS, while leaflet coaptation distances were similar between groups. We demonstrate that 3D echocardiography for assessment of the TV is feasible in rTOF and HLHS patients and identifies unique differences in TV morphology. Future studies should clarify the clinical significance of TV morphology in these patient populations., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Background: Right ventricular (RV) contractile dysfunction commonly occurs and worsens outcomes in patients with heart failure with reduced ejection fraction and pulmonary hypertension (HFrEF-PH). However, such dysfunction often goes undetected by standard clinical RV indices, raising concerns that they may not reflect aspects of underlying myocyte dysfunction. We thus sought to characterize RV myocyte contractile depression in HFrEF-PH, identify those components reflected by clinical RV indices, and uncover underlying biophysical mechanisms., Methods: Resting, calcium-, and load-dependent mechanics were prospectively studied in permeabilized RV cardiomyocytes isolated from explanted hearts from 23 patients with HFrEF-PH undergoing cardiac transplantation and 9 organ donor controls., Results: Unsupervised machine learning using myocyte mechanical data with the highest variance yielded 2 HFrEF-PH subgroups that in turn mapped to patients with decompensated or compensated clinical RV function. This correspondence was driven by reduced calcium-activated isometric tension in decompensated clinical RV function, whereas surprisingly, many other major myocyte contractile measures including peak power and myocyte active stiffness were similarly depressed in both groups. Similar results were obtained when subgroups were first defined by clinical indices, and then myocyte mechanical properties in each group compared. To test the role of thick filament defects, myofibrillar structure was assessed by x-ray diffraction of muscle fibers. This revealed more myosin heads associated with the thick filament backbone in decompensated clinical RV function, but not compensated clinical RV function, as compared with controls. This corresponded to reduced myosin ATP turnover in decompensated clinical RV function myocytes, indicating less myosin in a crossbridge-ready disordered-relaxed (DRX) state. Altering DRX proportion (%DRX) affected peak calcium-activated tension in the patient groups differently, depending on their basal %DRX, highlighting potential roles for precision-guided therapeutics. Last, increasing myocyte preload (sarcomere length) increased %DRX 1.5-fold in controls but only 1.2-fold in both HFrEF-PH groups, revealing a novel mechanism for reduced myocyte active stiffness and by extension Frank-Starling reserve in human heart failure., Conclusions: Although there are many RV myocyte contractile deficits in HFrEF-PH, commonly used clinical indices only detect reduced isometric calcium-stimulated force, which is related to deficits in basal and recruitable %DRX myosin. Our results support use of therapies to increase %DRX and enhance length-dependent recruitment of DRX myosin heads in such patients., Competing Interests: Disclosures T.C.I. provides consulting services to Edgewise Therapeutics Inc and receives collaborative research funding from Bristol Myers Squibb Inc, but such work is unrelated to the content of this article. The other authors report no conflicts.

Background Blood speckle tracking echocardiography allows for direct quantification of interventricular and aortic flow profiles, principally in children. Here, we sought to demonstrate the feasibility and reproducibility of blood speckle tracking echocardiography in the aortas of healthy children. Methods and Results One hundred healthy White children evaluated for the screening of congenital heart disease were prospectively enrolled. Echocardiographic examinations were performed using a Vivid E 95 ultrasound system, with blood speckle tracking from a focused and zoomed view of the aortic root and the ascending aorta. Vortex position, height (mm), width (mm), sphericity index, and area (cm 2 ) were measured and indexed by body surface area. Median (interquartile range) age was 8.2 (5.6-11.0) years, median (interquartile range) weight was 28 (19-35) kg, and median (interquartile range) body surface area was 1.01 (0.79-1.16) m 2 . Vortices were visualized in only a single phase of the cardiac cycle in 25 subjects-14 (56.0%) were evident in early diastole and 11 (44.0%) in late systole. Vortices visualized in diastole had a mean area of 0.27±0.1 cm 2 /m 2 , while those in systole had a mean area of 0.34±0.12 cm 2 /m 2 . In a subset of 20 patients, inter- and intraobserver coefficient of variation and intraclass correlation coefficients were determined and showed good reproducibility. Conclusions We demonstrate feasibility and reproducibility of blood speckle tracking and identified vortical flow patterns in the aortic root and ascending aorta in healthy children. These data may serve as a baseline for evaluating aortic flow patterns in children with congenital and acquired heart disease.

We investigated the temporal profile of multiple components of the serological response after asymptomatic or mildly symptomatic SARS-CoV-2 infection, in a cohort of 67 previously SARS-CoV-2 naive young adults, up to 8.5 months after infection. We found a significant decrease of spike IgG and neutralization antibody titers from early (11 to 56 days) to late (4 to 8.5 months) time points postinfection. Over the study period, S1-specific IgG levels declined significantly faster than that of the S2-specific IgG. Further, serum antibodies from PCR-confirmed participants cross-recognized S2, but not S1, of the betacoronaviruses HKU1 and OC43, suggesting a greater degree of cross-reactivity of S2 among betacoronaviruses. Antibody-Dependent Natural Killer cell Activation (ADNKA) was detected at the early time point but significantly decreased at the late time point. Induction of serum Antibody-Dependent Monocyte Phagocytosis (ADMP) was detected in all the infected participants, and its levels remained stable over time. Additionally, a reduced percentage of participants had detectable neutralizing activity against the Beta (50%), Gamma (61 to 67%), and Delta (90 to 94%) variants, both early and late postinfection, compared to the ancestral strain (100%). Antibody binding to S1 and RBD of Beta, Gamma, Delta (1.7 to 2.3-fold decrease), and Omicron (10 to 16-fold decrease) variants was also significantly reduced compared to the ancestral SARS-CoV-2 strain. Overall, we found variable temporal profiles of specific components and functionality of the serological response to SARS-CoV-2 in young adults, which is characterized by lasting, but decreased, neutralizing activity and antibody binding to S1, stable ADMP activity, and relatively stable S2-specific IgG levels. IMPORTANCE Adaptive immunity mediated by antibodies is important for controlling SARS-CoV-2 infection. While vaccines against COVID-19 are currently widely distributed, a high proportion of the global population is still unvaccinated. Therefore, understanding the dynamics and maintenance of the naive humoral immune response to SARS-CoV-2 is of great importance. In addition, long-term responses after asymptomatic infection are not well-characterized, given the challenges in identifying such cases. Here, we investigated the longitudinal humoral profile in a well-characterized cohort of young adults with documented asymptomatic or mildly symptomatic SARS-CoV-2 infection. By analyzing samples collected preinfection, early after infection and during late convalescence, we found that, while neutralizing activity decreased over time, high levels of serum S2 IgG and Antibody-Dependent Monocyte Phagocytosis (ADMP) activity were maintained up to 8.5 months after infection. This suggests that a subset of antibodies with specific functions could contribute to long-term protection against SARS-CoV-2 in convalescent unvaccinated individuals.

β-thalassemia is a genetic hemoglobin (Hb) disorder that affects millions of people world-wide. It is characterized by ineffective erythropoiesis and anemia. The resultant chronic anemia can require life-long blood transfusion regimens, leading to secondary hemochromatosis. Moreover, the abnormal red blood cells (RBCs) from β-thalassemia patients are prone to hemolytic events that release cell-free Hb and heme causing a series of events that result in oxidative organ and tissue damage. In this study, β-thalassemic mice were treated with a protein scavenger for six weeks, apohemoglobin-haptoglobin (apoHb-Hp), this protein scavenges cell free Hb and heme. We hypothesize that scavenging cell-free Hb and heme will lead to a positive therapeutic event. After the apoHb-hp treatment it was observed to reduce the weight of the liver and spleen and show an improvement in liver function by a drop in ALT, AST, and ALP markers. ApoHb-hp treatment also hints at an improved RBC half-life as the number of reticulocytes decreased, the mean corpuscular volume (MCV) increased, mean corpuscular hemoglobin increase and the RBC distribution width decreased. Furthermore, apoHb-Hp treatment reduced circulating serum iron concentration and transferrin saturation concentration. Based on these outcomes, introducing a scavenger protein can benefit β-thalassemic mice. This study demonstrated that apoHb-Hp treatment may be a viable strategy to mitigate toxicities associated with cell free Hb and heme, a driver of β-thalassemic issues., Competing Interests: Conflict of interest statement ISP and AFP are inventors on a pending patent application outlining methods related to the production of proteins such as apohemoglobin and haptoglobin (PCT/US2020/016267). Furthermore, ISP, AFP and PC are inventors on a pending patent application outlining biomedical applications of the apohemoglobin-haptoglobin complex (PCT/US2020/033836)., (Copyright © 2022 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Sufficient cardiac contractility is necessary to ensure the sufficient cardiac output to provide an adequate end-organ perfusion. Inadequate cardiac output and the diminished perfusion of vital organs from depressed myocardium contractility is a hallmark end-stage of heart failure. There are no available therapeutics that directly target contractile proteins to improve the myocardium contractility and reduce mortality. The purpose of this study is to present a proof of concept to aid in the development of muscle activators (myotropes) for augmenting the contractility in clinical heart failure. Here we use a combination of cardiomyocyte mechanics, the biochemical quantification of the ATP turnover, and small angle X-ray diffraction on a permeabilized porcine myocardium to study the mechanisms of EMD-57033 (EMD) for activating myosin. We show that EMD increases the contractility in a porcine myocardium at submaximal and systolic calcium concentrations. Biochemical assays show that EMD decreases the proportion of myosin heads in the energy sparing super-relaxed (SRX) state under relaxing conditions, which are less likely to interact with actin during contraction. Structural assays show that EMD moves the myosin heads in relaxed muscles from a structurally ordered state close to the thick filament backbone, to a disordered state closer to the actin filament, while simultaneously inducing structural changes in the troponin complex on the actin filament. The dual effects of EMD on activating myosin heads and the troponin complex provides a proof of concept for the use of small molecule muscle activators for augmenting the contractility in heart failure.

The ongoing evolution of SARS-CoV-2 requires monitoring the capability of immune responses to cross-recognize Variants of Concern (VOC). In this cross-sectional study, we examined serological and cell-mediated immune memory to SARS-CoV-2 variants, including Omicron, among a cohort of 18-21-year-old Marines with a history of either asymptomatic or mild SARS-CoV-2 infection 6 to 14 months earlier. Among the 210 participants in the study, 169 were unvaccinated while 41 received 2 doses of mRNA-based COVID-19 vaccines. Vaccination of previously infected participants strongly boosted neutralizing and binding activity and memory B and T cell responses including the recognition of Omicron, compared to infected but unvaccinated participants. Additionally, no measurable differences were observed in immune memory in healthy young adults with previous symptomatic or asymptomatic infections, for ancestral or variant strains. These results provide mechanistic immunological insights into population-based differences observed in immunity against Omicron and other variants among individuals with different clinical histories., Competing Interests: The views expressed in this article are those of the authors and do not necessarily reflect the official policy or position of the Department of the Navy, Department of Defense, or the US Government. PS, EC, CWG, JM, AM, EN, LW, CP, VS, MS, CGB, and AGL are military Service members or employees of the US Government. This work was prepared as part of their official duties. Title 17, U.S.C., §105 provides that copyright protection under this title is not available for any work of the US Government. Title 17, U.S.C., §101 defines the US Government work as a work prepared by a military Service member or employee of the US Government as part of that person’s official duties. SC has consulted for GSK, JP Morgan, Citi, Morgan Stanley, Avalia NZ, Nutcracker Therapeutics, University of California, California State Universities, United Airlines, Adagio, and Roche. AS is a consultant for Gritstone Bio, Flow Pharma, Arcturus Therapeutics, ImmunoScape, CellCarta, Avalia, Moderna, Fortress, and Repertoire. LJI has filed for patent protection for various aspects of T cell epitope and vaccine design work. PS, IR, CHC, AG, CAB, SV, AT, NIB, VJ, SJJ, DAB, EC, CWG, JM, AM, EN, LW, CKP, VAS, MS, ASM, CB, SCS, and AGL have no competing interests to declare.

The pathogen transmitting Aedes albopictus mosquito is spreading rapidly in Europe, putting millions of humans and animals at risk. This species is well-established in Albania since its first detection in 1979. The sterile insect technique (SIT) is increasingly gaining momentum worldwide as a component of area-wide-integrated pest management. However, estimating how the sterile males will perform in the field and the size of target populations is crucial for better decision-making, designing and elaborating appropriate SIT pilot trials, and subsequent large-scale release strategies. A mark-release-recapture (MRR) experiment was carried out in Albania within a highly urbanized area in the city of Tirana. The radio-sterilized adults of Ae. albopictus Albania strain males were transported by plane from Centro Agricoltura Ambiente (CAA) mass-production facility (Bologna, Italy), where they were reared. In Albania, sterile males were sugar-fed, marked with fluorescent powder, and released. The aim of this study was to estimate, under field conditions, their dispersal capacity, probability of daily survival and competitiveness, and the size of the target population. In addition, two adult mosquito collection methods were also evaluated: BG-Sentinel traps baited with BG-Lure and CO 2, (BGS) versus human landing catch (HLC). The overall recapture rates did not differ significantly between the two methods (2.36% and 1.57% of the total male released were recaptured respectively by BGS and HLC), suggesting a similar trapping efficiency under these conditions . Sterile males traveled a mean distance of 93.85 ± 42.58 m and dispersed up to 258 m. Moreover, they were observed living in the field up to 15 days after release with an average life expectancy of 4.26 ± 0.80 days. Whether mosquitoes were marked with green, blue, yellow, or pink, released at 3.00 p.m. or 6.00 p.m., there was no significant difference in the recapture, dispersal, and survival rates in the field. The Fried competitiveness index was estimated at 0.28. This mark-release-recapture study provided important data for better decision-making and planning before moving to pilot SIT trials in Albania. Moreover, it also showed that both BG-traps and HLC were successful in monitoring adult mosquitoes and provided similar estimations of the main entomological parameters needed., Competing Interests: Author FS is employed by F S Consultancy. Authors AB and MA were employed by Invent Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Velo, Balestrino, Kadriaj, Carvalho, Dicko, Bellini, Puggioli, Petrić, Michaelakis, Schaffner, Almenar, Pajovic, Beqirllari, Ali, Sino, Rogozi, Jani, Nikolla, Porja, Goga, Fălcuă, Kavran, Pudar, Mikov, Ivanova-Aleksandrova, Cvetkovikj, Akıner, Mikovic, Tafaj, Bino, Bouyer and Mamai.)

Human and animal vector-borne diseases, particularly mosquito-borne diseases, are emerging or re-emerging worldwide. Six Aedes invasive mosquito (AIM) species were introduced to Europe since the 1970s: Aedes aegypti , Ae. albopictus , Ae. japonicus , Ae. koreicus , Ae. atropalpus and Ae. triseriatus . Here, we report the results of AIMSurv2020, the first pan-European surveillance effort for AIMs. Implemented by 42 volunteer teams from 24 countries. And presented in the form of a dataset named "AIMSurv Aedes Invasive Mosquito species harmonized surveillance in Europe. AIM-COST Action. Project ID: CA17108". AIMSurv2020 harmonizes field surveillance methodologies for sampling different AIMs life stages, frequency and minimum length of sampling period, and data reporting. Data include minimum requirements for sample types and recommended requirements for those teams with more resources. Data are published as a Darwin Core archive in the Global Biodiversity Information Facility- Spain, comprising a core file with 19,130 records (EventID) and an occurrences file with 19,743 records (OccurrenceID). AIM species recorded in AIMSurv2020 were Ae. albopictus , Ae. japonicus and Ae. koreicus , as well as native mosquito species., Competing Interests: The authors declare that they have no competing interests., (© The Author(s) 2022.)

Dengue fever, caused by any of four dengue viruses (DENV1-4), is a major global burden. Currently, there is no effective vaccine that prevents infection in dengue naïve populations. We tested the ability of two novel adjuvants (Advax-PEI and Advax-2), using aluminum hydroxide (alum) as control, to enhance the immunogenicity of formalin- or psoralen-inactivated (PIV or PsIV) DENV2 vaccines in mice. Mice were vaccinated on days 0 and 30, and serum samples were collected on days 30, 60, 90, and 101. Neutralizing antibodies were determined by microneutralization (MN) assays, and the geometric mean 50% MN (MN 50 ) titers were calculated. For the PIV groups, after one dose MN 50 titers were higher in the novel adjuvant groups compared to the alum control, while MN 50 titers were comparable between the adjuvant groups after the second dose. For the PsIV groups, both novel adjuvants induced higher MN 50 titers than the alum control after the second dose. Spleen cells were collected on days 45 and 101 for enzyme-linked immunospot (ELISPOT) for IFNγ and IL4. Both PIV and PsIV groups elicited different degrees of IFNγ and IL4 responses. Overall, Advax-2 gave the best responses just ahead of Advax-PEI. Given Advax-2's extensive human experience in other vaccine applications, it will be pursued for further development.

Background: Applications of atrial speckle tracking echocardiography (STE) strain (ε) analysis in pediatric cardiac surgery have been limited. This study aims to evaluate the feasibility of atrial STE ε analysis and the progression of atrial ε values as a function of post-operative time in children after pediatric cardiac surgery. Methods: 131 children (mean 1.69 ± 2.98; range 0.01−15.16 years) undergoing cardiac surgery were prospectively enrolled. Echocardiographic examinations were performed pre-operatively and at 3 different post-operative intervals: Time 1 (24−36 h), Time 2 (3−5 days), Time 3 (>5 days, before discharging). The right and left atrium longitudinal systolic contractile (Ct), Conduit (Cd), and Reservoir (R) ε were evaluated with a novel atrial specific software with both P- and R-Gating methods. One hundred and thirty-one age-matched normal subjects (mean 1.7 ± 3.2 years) were included as controls. Results: In all, 309 examinations were performed over the post-operative times. For each post-operative interval, all STE atrial ε parameters assessed were significantly lower compared to controls (all p < 0.0001). The lowest atrial ε values were found at Time 1, with only partial recovery thereafter (p from 0.02 to 0.04). All atrial ε values at discharge were decreased compared to the controls (all p < 0.0001). Significant correlations of the atrial ε values with cardio-pulmonary-bypass time, left and right ventricular ε values (p < 0.05), and ejection fraction (p < 0.05) were demonstrated. Conclusions: Atrial ε is highly reduced after surgery with only partial post-operative recovery in the near term. Our study additionally demonstrates that post-surgical atrial and ventricular ε responses correlated with each other.

SARS-CoV-2 T cell responses are associated with COVID-19 recovery, and Class I- and Class II-restricted epitopes have been identified in the spike (S), nucleocapsid (N) and membrane (M) proteins and others. This prospective COVID-19 Health Action Response for Marines (CHARM) study enabled assessment of T cell responses against S, N and M proteins in symptomatic and asymptomatic SARS-CoV-2 infected participants. At enrollment all participants were negative by qPCR; follow-up occurred biweekly and bimonthly for the next 6 weeks. Study participants who tested positive by qPCR SARS-CoV-2 test were enrolled in an immune response sub-study. FluoroSpot interferon-gamma (IFN-γ) and IL2 responses following qPCR-confirmed infection at enrollment (day 0), day 7 and 14 and more than 28 days later were measured using pools of 17mer peptides covering S, N, and M proteins, or CD4+CD8 peptide pools containing predicted epitopes from multiple SARS-CoV-2 antigens. Among 124 asymptomatic and 105 symptomatic participants, SARS-CoV-2 infection generated IFN-γ responses to the S, N and M proteins that persisted longer in asymptomatic cases. IFN-γ responses were significantly (p = 0.001) more frequent to the N pool (51.4%) than the M pool (18.9%) among asymptomatic but not symptomatic subjects. Asymptomatic IFN-γ responders to the CD4+CD8 pool responded more frequently to the S pool (55.6%) and N pool (57.1%), than the M pool (7.1%), but not symptomatic participants. The frequencies of IFN-γ responses to the S and N+M pools peaked 7 days after the positive qPCR test among asymptomatic (S pool: 22.2%; N+M pool: 28.7%) and symptomatic (S pool: 15.3%; N+M pool 21.9%) participants and dropped by >28 days. Magnitudes of post-infection IFN-γ and IL2 responses to the N+M pool were significantly correlated with IFN-γ and IL2 responses to the N and M pools. These data further support the central role of Th1-biased cell mediated immunity IFN-γ and IL2 responses, particularly to the N protein, in controlling COVID-19 symptoms, and justify T cell-based COVID-19 vaccines that include the N and S proteins., Competing Interests: The authors have declared that no competing interests exist.

Background: Ventricular interdependence may account for altered ventricular mechanics in congenital heart disease. The present study aimed to identify differences in load-dependent right ventricular (RV)-left ventricular (LV) interactions in porcine models of pulmonary stenosis (PS) and pulmonary insufficiency (PI) by invasive admittance-derived hemodynamics in conjunction with noninvasive cardiovascular magnetic resonance (CMR)., Methods: Seventeen pigs were used in the study (7 with PS, 7 with PI, and 3 controls). Progressive PS was created by tightening a Teflon tape around the pulmonary artery, and PI was created by excising 2 leaflets of the pulmonary valve. Admittance catheterization data were obtained for the RV and LV at 10 to 12 weeks after model creation, with the animal ventilated under temporary diaphragm paralysis. CMR was performed in all animals immediately prior to pressure-volume catheterization., Results: In the PS group, RV contractility was increased, manifested by increased end-systolic elastance (mean difference, 1.29 mm Hg/mL; 95% confidence interval [CI], 0.57-2.00 mm Hg/mL). However, in the PI group, no significant changes were observed in RV systolic function despite significant changes in RV diastolic function. In the PS group, LV end-systolic volume was significantly lower compared with controls (mean difference, 25.1 mL; 95% CI, -40.5 to -90.7 mL), whereas in the PI group, the LV showed diastolic dysfunction, demonstrated by an elevated isovolumic relaxation constant and ventricular stiffness (mean difference, 0.03 mL -1 ; 95% CI, -0.02 to 0.09 mL -1 )., Conclusions: The LV exhibits systolic dysfunction and noncompliance with PI. PS is associated with preserved LV systolic function and evidence of some LV diastolic dysfunction. Interventricular interactions influence LV filling and likely account for differential effects of RV pressure and volume overload on LV function., (Copyright © 2021 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)