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Abstract Low-abundance members of microbial communities are difficult to study in their native habitats, including Escherichia coli, a minor but common inhabitant of the gastrointestinal tract, and key opportunistic pathogen of the urinary tract. While multi-omic analyses have detailed interactions between uropathogenic Escherichia coli (UPEC) and the bladder mediating urinary tract infection (UTI), little is known about UPEC in its pre-infection reservoir, the gastrointestinal tract, partly due to its low relative abundance (

Abstract Introduction Patients with psoriasis (PSO) and psoriatic arthritis (PsA) may frequently switch biologic therapies over the course of treatment because of symptom variability and individual responses. Real-world studies analyzing patient characteristics and clinical factors associated with biologic switching are limited. Methods This longitudinal cohort study used real-world data from the CorEvitas Psoriasis Registry to evaluate the relationship between associated disease factors and biologic switching among patients with PSO and PsA in the United States (US) and Canada following initiation of a biologic. Patients were evaluated between April 2015–August 2022. Combinations of disease severity (as measured by Psoriasis Area Severity Index [PASI]) and Dermatology Life Quality Index (DLQI) as a measure of health-related quality of life (HRQoL) were assessed, and the association with time to switching was calculated using Cox proportional hazards regression modeling. Results Among 2580 patient-initiations (instances of patients initiating a biologic), 504 (19.5%) switched biologics within 30 months of initiation. Switching was more frequent when either PASI > 10 or DLQI > 5 compared with PASI ≤ 10 or DLQI ≤ 5 at follow-up. Patients with higher skin involvement (PASI > 10) and impact on HRQoL (DLQI > 5) were 14 times more likely to switch (hazard ratio = 14.2, 95% confidence interval: 10.7, 18.9) than those with lower skin involvement (PASI ≤ 10) and HRQoL (DLQI ≤ 5). Conclusions Patients with PSO and PsA treated in a real-world dermatology setting with substantial disease factors following biologic initiation were more likely to switch therapies. Those with PASI > 10 and DLQI > 5 switched more frequently than those with PASI ≤ 10 and DLQI ≤ 5.

Abstract Factors such as obesity, alcohol consumption, and tobacco use are associated with both increased psoriasis severity and inadequate response to systemic and biologic therapies. Obesity is linked to chronic inflammation, which can contribute to psoriasis pathogenesis. Fixed-dose therapies may have reduced efficacy in patients with a higher body mass index, while weight-based dosing can increase the burden of drug-specific side effects. Alcohol and nicotine from tobacco have also been shown to stimulate keratinocyte and immune cell proliferation and production of proinflammatory cytokines. While these risk factors are prevalent among patients with moderate-to-severe psoriasis, their influence on treatment outcomes may be overlooked when evaluating therapeutic options. Brodalumab is a fully human interleukin-17 receptor A antagonist approved for the treatment of moderate-to-severe psoriasis. In this review, we describe the lifestyle-related risk factors associated with decreased response to treatment. We further summarize the post hoc analyses of brodalumab in participant subgroups with moderate-to-severe psoriasis and a history of prior biologic failure, obesity, and alcohol or tobacco use from two phase 3 clinical trials (AMAGINE-2 and AMAGINE-3; ClinicalTrials.gov identifiers: NCT01708603 and NCT01708629, respectively). Our review of clinical trial and real-world data suggests that brodalumab is an efficacious and safe treatment option for patients with lifestyle factors that increase the likelihood of treatment failure, allowing them to achieve skin clearance and improve quality of life.

The addition of methane-reducing compounds (MRCs) to livestock drinking water presents an alternative method for enteric methane mitigation in extensive systems where these compounds cannot be fed through the diet. This work evaluated several such compounds with the potential to be deployed in this manner. Methane-reducing compounds were selected based on the existing literature and likelihood of dissolution when combined with a commercially available water-based nutrient supplement (uPRO) (uPRO ORANGE®, DIT AgTech, QLD, Australia). This, in turn, would demonstrate the capacity for MRCs to be administered through animal drinking water when such supplements are in use. This technique requires the analysis of MRC solubility and stability in solution, which was completed via Fourier transform infrared-attenuated total reflectance spectroscopy. The uPRO supplement is comprised of urea, urea phosphate, and ammonium sulfate, providing nitrogen, phosphorus, and sulfur—limiting nutrients for ruminants grazing extensive systems during drier periods of the year. Accordingly, medium-quality Rhodes grass hay was used in fermentation runs to simulate a basal diet during the dry season. Methane-reducing compounds were assessed in accordance with each variable measured (gas/methane production, dry matter digestibility, stability under different environmental conditions) along with existing research in the field to determine the most suitable compound for co-administration. Whilst most compounds examined in this study appeared to retain their structure in solution with uPRO, fermentation results varied in terms of successful methane mitigation. The additive Agolin Ruminant L emerged as the most promising compound for further in vivo investigation.

Abstract Oral Janus kinase inhibitors (JAKi), a class of advanced targeted systemic therapy, have demonstrated efficacy and safety in the treatment of moderate-to-severe atopic dermatitis (AD). Like other small molecules, oral JAKi have the potential for off-target effects including laboratory-related adverse events (AEs). Product labels for oral JAKi recommend an initial laboratory assessment and follow-up 4–12 weeks later to monitor for potential changes, based on evidence from clinical trials across therapeutic indications for oral JAKi, which may not reflect a population of moderate-to-severe AD patients typically seen in routine clinical practice. To address this gap, a panel of eight dermatologists with clinical and research experience with oral JAKi for the management of AD conducted a targeted review of the literature focused on key laboratory-related AEs associated with oral JAKi in the moderate-to-severe AD population. Based on the synthesis of evidence and informed opinion, a set of best practice statements related to fundamental standards of care and consensus recommendations on laboratory monitoring were suggested, and level of agreement was ascertained using a Likert scale from 0 to 100. There was a high level of agreement on three of the four suggested recommendations related to assessment and monitoring of key laboratory parameters and to dose reduction or switching in response to laboratory changes; there was a lower level of agreement related to the frequency of ongoing laboratory monitoring. Appropriate patient selection and laboratory assessment is an important strategy to mitigate the potential risks associated with oral JAKi when treating AD.

Abstract Generalized pustular psoriasis (GPP) is a rare, chronic and potentially life-threatening autoinflammatory skin disease characterized by widespread eruption of sterile pustules, with or without systemic inflammation. GPP can significantly reduce patients’ quality of life (QoL). Several therapeutic approaches have been described in the literature, but there is no consensus on optimal treatment. In this review, we summarize published literature on efficacy, safety and QoL outcomes associated with current treatment of GPP with both approved and non-approved products. Embase and MEDLINE databases were searched (1980–September 2023). A search protocol was designed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and registered on the PROSPERO database (CRD42021215437). Details on publication, population, intervention, efficacy, safety and QoL were captured and checked by independent reviewers. In total, 118 publications were included, with only 19% of publications reporting on the results of clinical trials. Treatment modalities reported for GPP included non-biologic systemic therapies such as retinoids, cyclosporine and methotrexate, topical agents, biologics and small molecules, among others. Results were highly heterogeneous and methodological quality was very low, with only the interleukin-36R inhibitor spesolimab reporting results from placebo-controlled randomized trials; based on this, spesolimab is now approved for GPP treatment in regions including the USA, Japan, China, the EU and several other countries. Some other biologics are approved exclusively in Japan and Taiwan for the treatment of GPP based on open-label studies with small patient numbers in lieu of double-blind studies. Non-standardization of clinical outcomes across studies remains a major hurdle in reaching a consensus on optimal treatment. However, recently trials have been conducted using well-defined, disease-specific endpoints to evaluate GPP-targeted treatments, which will hopefully advance patient care. In conclusion, this review highlights the need for prospective randomized studies with GPP-specific endpoints to determine the optimal treatment strategy.

Abstract SARS-CoV-2 has the capacity to evolve mutations that escape vaccine- and infection-acquired immunity and antiviral drugs. A variant-agnostic therapeutic agent that protects against severe disease without putting selective pressure on the virus would thus be a valuable biomedical tool that would maintain its efficacy despite the ongoing emergence of new variants. Here, we challenge male rhesus macaques with SARS-CoV-2 Delta—the most pathogenic variant in a highly susceptible animal model. At the time of challenge, we also treat the macaques with aerosolized RBD-62, a protein developed through multiple rounds of in vitro evolution of SARS-CoV-2 RBD to acquire 1000-fold enhanced ACE2 binding affinity. RBD-62 treatment equivalently suppresses virus replication in both upper and lower airways, a phenomenon not previously observed with clinically approved vaccines. Importantly, RBD-62 does not block the development of virus-specific T- and B-cell responses and does not elicit anti-drug immunity. These data provide proof-of-concept that RBD-62 can prevent severe disease from a highly virulent variant.

Abstract Given the persistent challenge of differentiating idiopathic Normal Pressure Hydrocephalus (iNPH) from similar clinical entities, we conducted an in-depth proteomic study of cerebrospinal fluid (CSF) in 28 shunt-responsive iNPH patients, 38 Mild Cognitive Impairment (MCI) due to Alzheimer’s disease, and 49 healthy controls. Utilizing the Olink Explore 3072 panel, we identified distinct proteomic profiles in iNPH that highlight significant downregulation of synaptic markers and cell-cell adhesion proteins. Alongside vimentin and inflammatory markers upregulation, these results suggest ependymal layer and transependymal flow dysfunction. Moreover, downregulation of multiple proteins associated with congenital hydrocephalus (e.g., L1CAM, PCDH9, ISLR2, ADAMTSL2, and B4GAT1) points to a possible shared molecular foundation between congenital hydrocephalus and iNPH. Through orthogonal partial least squares discriminant analysis (OPLS-DA), a panel comprising 13 proteins has been identified as potential diagnostic biomarkers of iNPH, pending external validation. These findings offer novel insights into the pathophysiology of iNPH, with implications for improved diagnosis.

The behavior of Acerocephala hanuuanamu sp. nov. found parasitizing Cryphalus brasiliensis under the surface of wood in Ficus microcarpa trees on the island of O‘ahu in Hawai‘i is deduced from observations in naturally occuring branches, and from direct observation using specially designed “phloem sandwich” observation chambers which consist of tree bark peeled through the phloem layer from freshly cut branches and sandwiched between a sheet of aluminum and a sheet of plexiglass. Cryphalus brasiliensis beetles, found living in large numbers in the phloem tissues in F. microcarpa trees, were collected and placed into these chambers. They tunneled into the wood and reproduced, producing an active colony of all life stages. Acerocephala hanuuanamu wasps were then placed into the system and their behavior observed. Typical behavior, aspects of which were recorded in video and still images, was as follows. A female A. hanuuanamu enters the tunnels of the bark beetles. She digs through the debris in the tunnels in a search for larvae and pupae. Cryphalus brasiliensis prepupae construct a hard pupal chamber around themselves before they pupate, and upon encountering a larva in the tunnels or the exterior of a pupal chamber with a pupa inside, she adeptly turns around in the tunnel to sting it, either inserting her ovipositor directly into the larva or by laboriously pushing it through the hard shell of the pupal chamber. When finished stinging, she withdraws her ovipositor slowly and carefully, often extracting tissue from the beetle immature as a sheath around her ovipositor. This structure remains projecting from the larva or pupa, and then the wasp turns around and host feeds through this structure, in the case of a pupa at a substantial distance through the wall of the pupal chamber. Oviposition occurs on larval stages and pupal stages. The egg hatches and the larva develops as an ectoparasitoid on the beetle. When finished feeding, it detaches and pupates in the tunnel. Mating behavior is also described. In addition to C. brasiliensis in F. microcarpa, A. hanuuanamu was also observed attacking Cryphalus mangiferae in mango (Mangifera indica) branches. Acerocephala ihulena sp. nov. was also found on O‘ahu parasitizing Eidophelus pacificus in hau (Hibiscus tiliaceus) branches, and is described. The genus Acerocephala is revised given the perspective resulting from these two new species and aspects of functional morphology observed in the behavioral studies, Acerocephala indica comb. nov. is transferred to the genus, and a key to the genus is provided.

Abstract Background SARS-CoV-2-infected patients may develop new conditions in the period after the acute infection. These conditions, the post-acute sequelae of SARS-CoV-2 infection (PASC, or Long COVID), involve a diverse set of organ systems. Limited studies have investigated the predictability of Long COVID development and its associated risk factors. Methods In this retrospective cohort study, we used electronic healthcare records from two large-scale PCORnet clinical research networks, INSIGHT (~1.4 million patients from New York) and OneFlorida+ (~0.7 million patients from Florida), to identify factors associated with having Long COVID, and to develop machine learning-based models for predicting Long COVID development. Both SARS-CoV-2-infected and non-infected adults were analysed during the period of March 2020 to November 2021. Factors associated with Long COVID risk were identified by removing background associations and correcting for multiple tests. Results We observed complex association patterns between baseline factors and a variety of Long COVID conditions, and we highlight that severe acute SARS-CoV-2 infection, being underweight, and having baseline comorbidities (e.g., cancer and cirrhosis) are likely associated with increased risk of developing Long COVID. Several Long COVID conditions, e.g., dementia, malnutrition, chronic obstructive pulmonary disease, heart failure, PASC diagnosis U099, and acute kidney failure are well predicted (C-index > 0.8). Moderately predictable conditions include atelectasis, pulmonary embolism, diabetes, pulmonary fibrosis, and thromboembolic disease (C-index 0.7–0.8). Less predictable conditions include fatigue, anxiety, sleep disorders, and depression (C-index around 0.6). Conclusions This observational study suggests that association patterns between investigated factors and Long COVID are complex, and the predictability of different Long COVID conditions varies. However, machine learning-based predictive models can help in identifying patients who are at risk of developing a variety of Long COVID conditions.

Background. The relevance of the study is due to insufficient knowledge of the influence of the structures of consciousness on the self-regulation of cognitive states in various stressful situations. The author's concept of mental regulation of psychological states served as a theoretical basis for empirical research. Objective. To identify the features of the relationship between indicators of mental regulation and the frequency of experiencing cognitive states in four situations with different stress levels. Study Participants. The study sample consisted of 70 schoolchildren (31 boys and 29 girls, Mage = 17.7 years) from secondary education schools. Methods. The study implemented the author’s questionnaires “Assessment of the frequency of experiencing mental states” and “Methods of self-regulation of mental states” (M.E. Valiullina). In the instructions, the respondents were presented with four types of situations characterized by different stress levels — from the weak level with a neutral context to the strong level with a negative emotional background. Apart from that, the study participants were tested by means of well-known psychological questionnaires: “Method for Studying the System of Life Meanings” (V.Yu. Kotlyakov), “Self-attitude Questionnaire” (S.R. Pantileev), “Method for Diagnosing Reflexivity” (A.V. Karpov, V.V. Ponomareva). Statistical data processing was carried out using frequency analysis and nonlinear correlation analysis according to Spearman. Results. The data analysis demonstrated: as the tension in the situation increases, the frequency of experiencing productive cognitive states decreases, the probability of unproductive states increases, and the number of applied regulation methods increases as well. Besides, as the tension in the situation increases, the involvement of the consciousness components (those of semantic sphere, reflection, and self-attitude) in the mental regulation of cognitive states increases, the degree of relationships integration increases, and the structure-forming indicators are highlighted. Conclusions. The results obtained show that the level of stress in the situation significantly influences the qualitative composition of the characteristics involved in the systems “mental regulation — cognitive state — regulation method” and “mental regulation — regulation method — cognitive state”

Abstract Metal-implant associated bacterial infections are a major clinical problem due to antibiotic treatment failure. As an alternative, we determined the effects of bacteriophage ISP on clinical isolates of Staphylococcus aureus in various stages of its life cycle in relation to biofilm formation and maturation. ISP effectively eliminated all planktonic phase bacteria, whereas its efficacy was reduced against bacteria attached to the metal implant and bacteria embedded within biofilms. The biofilm architecture hampered the bactericidal effects of ISP, as mechanical disruption of biofilms improved the efficacy of ISP against the bacteria. Phages penetrated the biofilm and interacted with the bacteria throughout the biofilm. However, most of the biofilm-embedded bacteria were phage-tolerant. In agreement, bacteria dispersed from mature biofilms of all clinical isolates, except for LUH15394, tolerated the lytic activity of ISP. Lastly, persisters within mature biofilms tolerated ISP and proliferated in its presence. Based on these findings, we conclude that ISP eliminates planktonic phase Staphylococcus aureus while its efficacy is limited against bacteria attached to the metal implant, embedded within (persister-enriched) biofilms, and dispersed from biofilms.

Abstract Our brain adeptly navigates goals across time frames, distinguishing between urgent needs and those of the past or future. The hippocampus is a region known for supporting mental time travel and organizing information along its longitudinal axis, transitioning from detailed posterior representations to generalized anterior ones. This study investigates the role of the hippocampus in distinguishing goals over time: whether the hippocampus encodes time regardless of detail or abstraction, and whether the hippocampus preferentially activates its anterior region for temporally distant goals (past and future) and its posterior region for immediate goals. We use a space-themed experiment with 7T functional MRI on 31 participants to examine how the hippocampus encodes the temporal distance of goals. During a simulated Mars mission, we find that the hippocampus tracks goals solely by temporal proximity. We show that past and future goals activate the left anterior hippocampus, while current goals engage the left posterior hippocampus. This suggests that the hippocampus maps goals using timestamps, extending its long axis system to include temporal goal organization.

Objectives: To report trends in carbapenem resistance and difficult-to-treat resistance (DTR) among clinical isolates of Gram-negative priority pathogens collected by the ATLAS global surveillance program from 2018 to 2022. Methods: Reference broth microdilution testing was performed in a central laboratory for 79,214 Enterobacterales, 30,504 Pseudomonas aeruginosa, and 13,500 Acinetobacter baumannii-calcoaceticus complex isolates collected by a constant set of 157 medical centres in 49 countries in Asia Pacific (APAC), Europe (EUR), Latin America (LATAM), Middle East-Africa (MEA), and North America (NA) regions. MICs were interpreted by 2023 CLSI M100 breakpoints. β-lactamase genes were identified for meropenem-nonsusceptible (MIC ≥2 mg/L) Enterobacterales isolates. Results: Carbapenem-resistant Enterobacterales (CRE) detection increased (P < 0.05) in APAC, EUR, LATAM, and MEA regions and decreased in NA, while annual DTR percentages increased in all five regions. Carbapenem-resistant P. aeruginosa (CRPA; decreased in MEA region) and carbapenem-resistant A. baumannii-calcoaceticus complex (CRAB; decreased in MEA region and increased in EUR) remained relatively stable over time in all regions, although notably, annual percentages of CRAB and DTR A. baumannii-calcoaceticus complex isolates were consistently >25 percentage points lower in NA than in other regions. For all regions except NA, the majority of changes in CRE percentages could be attributed to hospital-acquired infections. Among meropenem-nonsusceptible Enterobacterales, KPC was the most frequent carbapenemase in NA and EUR each year. NDM was the most prevalent carbapenemase detected in 2022 in other global regions. Conclusion: CRE, CRPA, CRAB, and DTR rates vary among global regions over time highlighting the need for continuing surveillance to inform treatment strategies and antimicrobial stewardship.

Introduction A proportion of people develop Long Covid after acute COVID-19, but with most studies concentrated in high-income countries (HICs), the global burden is largely unknown. Our study aims to characterise long-term COVID-19 sequelae in populations globally and compare the prevalence of reported symptoms in HICs and low-income and middle-income countries (LMICs).Methods A prospective, observational study in 17 countries in Africa, Asia, Europe and South America, including adults with confirmed COVID-19 assessed at 2 to

We present a genome assembly from an individual male Platypus cylindrus (the oak pinhole borer; Arthropoda; Insecta; Coleoptera; Curculionidae). The genome sequence is 147.5 megabases in span. Most of the assembly is scaffolded into 8 chromosomal pseudomolecules, including the X and Y sex chromosomes. The mitochondrial genome has also been assembled and is 19.29 kilobases in length. Gene annotation of this assembly on Ensembl identified 13,468 protein coding genes.

We present a genome assembly from an individual female Agrilus cyanescens (metallic wood-boring beetle; Arthropoda; Insecta; Coleoptera; Buprestidae). The genome sequence is 292.3 megabases in span. Most of the assembly is scaffolded into 10 chromosomal pseudomolecules, including the X sex chromosome. The mitochondrial genome has also been assembled and is 15.91 kilobases in length.

We present a genome assembly from an individual female Entiminae weevil, Polydrusus pterygomalis (Arthropoda; Insecta; Coleoptera; Curculionidae). The genome sequence has a total length of 1,051.50 megabases. Most of the assembly is scaffolded into 11 chromosomal pseudomolecules, including the X sex chromosome. The mitochondrial genome has also been assembled and is 20.95 kilobases in length.

Summary: Matrix stiffening by lysyl oxidase-like 2 (LOXL2)-mediated collagen cross-linking is proposed as a core feedforward mechanism that promotes fibrogenesis. Failure in clinical trials of simtuzumab (the humanized version of AB0023, a monoclonal antibody against human LOXL2) suggested that targeting LOXL2 may not have disease relevance; however, target engagement was not directly evaluated. We compare the spatial transcriptome of active human lung fibrogenesis sites with different human cell culture models to identify a disease-relevant model. Within the selected model, we then evaluate AB0023, identifying that it does not inhibit collagen cross-linking or reduce tissue stiffness, nor does it inhibit LOXL2 catalytic activity. In contrast, it does potently inhibit angiogenesis consistent with an alternative, non-enzymatic mechanism of action. Thus, AB0023 is anti-angiogenic but does not inhibit LOXL2 catalytic activity, collagen cross-linking, or tissue stiffening. These findings have implications for the interpretation of the lack of efficacy of simtuzumab in clinical trials of fibrotic diseases.

This study investigates the impact of board attributes on sustainability reporting among listed firms in Nigeria from 2013 to 2022, using a correlational research design. The research population encompasses all Nigerian listed firms, with a stratified sampling technique deemed appropriate for the study. Secondary data were sourced from the audited annual reports and accounts of sampled firms available on the Nigerian Exchange Group (NGX) website. The analysis of the extracted panel data was conducted using multiple regression techniques with STATA version 13. The findings of the study reveal that board size, gender diversity, and independence positively influence sustainability reporting, while board commitment has a negative impact on sustainability reporting. Consequently, the study recommends that the management of Nigerian listed firms should view large and diverse boards as an asset for promoting sustainability reporting. Such boards, comprising experienced and knowledgeable members, are more likely to make effective decisions on sustainability-related issues. Additionally, the presence of women on boards should be considered a valuable factor in encouraging comprehensive financial reporting, which includes qualitative and quantitative information on the social, environmental, and economic activities of the business for stakeholders.

This study seeks to examine the effect of capital structure on financial performance of the listed information and communications technology firms in Nigeria. This study adopted correlation and ex-post facto research design. The population of this study consists of all listed information and communications technology firms in Nigeria. Census sampling technique was employed. Multiple regression model based on pooled ordinary lease square, robust test was adopted in analyzing the panel data obtained from audited financial statement of the listed sampled information and communications technology firms for the periods of 10 years between (2013- 2022). The study reveals that both long term debt financing ratio short term debt financing, and debt to equity financing ratio have positive and significant influence on return on assets of the listed information and communications technology firms in Nigeria. On the other hand, equity financing ratio has a positive but insignificant effect on performance of listed information and communications technology companies in Nigeria. Therefore, it is recommended that the management of the listed information and communications technology firms in Nigeria should initiate coherent and integrated financial policies towards encouraging long-and short-term debt financing and debt to equity financing to ultimately improve the financial performance of the list information and communications technology firms in Nigeria.

BACKGROUND: The application of videofixation technologies in embryology is developing significantly. These technologies permit the objective analysis of the process of early embryogenesis of each cultured embryo without the necessity of removing the culture cup from the incubator. Timelapse technologies in routine practice allow for the guaranteed detection of embryo developmental pathologies that are inaccessible to traditional developmental monitoring methods [1, 2]. Nevertheless, the annotation and manual evaluation of all frames captured during the cultivation process can be a time-consuming process. Furthermore, video fixation itself does not eliminate the issue of objectivizing the quality of interpretation of the obtained images [3]. Intelligent technologies, in particular, solutions developed with the use of machine learning, are successfully employed in the resolution of such problems. AIM: The aim of this study is to develop a system for the automated analysis of the morphokinetic state of the human embryo with the aim of assessing its capacity for implantation. MATERIALS AND METHODS: The data were collected at the Family Medical Center (Ufa, Russia) and the Clinical Hospital IDK of the Mother and Child Group of Companies (Samara, Russia). Digital images of the period of preimplantation development of human embryos up to the blastocyst stage (days 0–6 from insemination) were obtained using an incubator for in vitro fertilization laboratories, the EmbryoVisor, with a timelapse (hyperlapse) video fixation system. Embryos were cultured individually in special micro-well WOW dishes (Vitrolife, Sweden). The data set was labelled using Label Studio Community Edition software. A recurrent convolutional neural network was selected to analyse the data and trained using multiple images. RESULTS: The development of the automatic analysis system is based on the classification of the morphokinetic state of the embryo according to the stages of embryogenesis: fertilization, fragmentation, morula formation, and blastocyst formation. Segmentation of multiple objects, such as pronuclei and polar bodies at the fertilization stage or blastomeres at the fragmentation stage, will be performed depending on a certain stage of development. We plan to build a binary classification of the presence of additional features (multinucleation, heterogeneity of the endoplasmic network), classification/regression of additional features (so, fragmentation can be estimated as discrete ranges or absolute values). The result is a system for labeling the morphodynamic profile of an embryo using deep learning. This method automates and accelerates the analysis process, which previously required significant time and human resources. CONCLUSIONS: It is anticipated that the developed system of automatic analysis of morphokinetic state of embryos will simplify the process of evaluating the quality of human embryos in in vitro fertilization laboratories, reducing the time and resources spent on this process. Furthermore, it will enhance the accuracy and reliability of assessing the implantation ability of embryos and could potentially serve as the foundation for the development of a support system for medical decision-making in embryology.

Recommendations for endurance exercise prescription are often based on percentages of heart rate (HR) or the volume of oxygen consumption (V˙O2) maximum or reserve that is extrapolated to a power output (P) or velocity. Previous work has demonstrated dissociations of the expected responses to exercise anchored to the critical heart rate (CHR) compared with the P associated with CHR. However, it is unclear if similar dissociations due to reductions in P to maintain the designated intensity would be present during exercise anchored to the V˙O2 associated with CHR (V˙O2CHR). The purpose of this study was to examine the patterns in physiological (V˙O2, HR, P, respiration rate [RR], muscle oxygen saturation [%SmO2]), neuromuscular (electromyographic and mechanomyographic amplitude [EMG AMP, MMG AMP], mean power frequency [EMG MPF, MMG MPF]), and perceptual (rating of perceived exertion [RPE]) responses during exercise at V˙O2CHR (V˙O2-clamp). On separate days, ten participants (age: 25 ± 4 yr) performed a graded exercise test and four constant P trials at 85–100% of peak P (PP) to derive CHR and V˙O2CHR. Responses were recorded during a trial to exhaustion at V˙O2CHR (32.86 ± 7.12 mL·kg−1·min−1; TLim = 31.31 ± 21.37 min) and normalized in 10% intervals of TLim to their respective values at PP. The one-way repeated-measures ANOVA with post hoc, Bonferroni-corrected, pairwise comparisons indicated differences (p < 0.001) from baseline for HR (mean ± SD %change = 8 ± 3%), RR (43 ± 38%), P (−15 ± 5%), EMG MPF (10 ± 8%), and RPE (65 ± 38%), but no differences (p = 0.077–0.955) for %SmO2 (−17 ± 53%), EMG AMP (−3 ± 16%), MMG AMP (40 ± 61%), and MMG MPF (1 ± 7%). The loss in performance observed during V˙O2-Clamp exercise may provide a quantification of the inefficiency associated with the V˙O2 slow component phenomenon. The neuromuscular responses suggested constant muscle excitation despite the reductions in P, but the metabolic and perceptual responses suggested a combination of feedforward and feedback mechanisms regulating TLim. Future studies should further examine responses to the V˙O2-Clamp exercise at a uniform threshold.

Abstract Introduction Plaque psoriasis is a common, often debilitating, chronic autoimmune inflammatory skin disease. Moderate-to-severe forms of psoriasis can be treated with biologics such as anti-interleukin and anti-tumor necrosis factor antibodies. We aimed to investigate treatment discontinuation among patients with psoriasis who initiated biologic treatment. Methods We conducted a retrospective, non-interventional cohort study based on anonymized claims data from the German statutory health insurance which covered the years from 2016 to 2021. We included adult patients with psoriasis who initiated biologic treatment in drug-specific cohorts. Over a 365-day follow-up period, we assessed the frequencies and the time until treatment discontinuation for different biologics. Differences in discontinuation rates were compared using a multivariate Cox proportional hazards model. Results A total of 2565 patients with psoriasis who initiated treatment with secukinumab (n = 612), adalimumab (n = 454), guselkumab (n = 354), ixekizumab (n = 259), ustekinumab (n = 241), tildrakizumab (n = 205), brodalumab (n = 166), risankizumab (n = 145), etanercept (n = 91), certolizumab (n = 29), and infliximab (n = 9) were included. A total of 1290 patients (50.29%) discontinued treatment during the follow-up period, ranging from 30.34% (risankizumab) to 69.23% (etanercept). Median time until discontinuation of treatment ranged from 102 days (etanercept) to 208 days (risankizumab). Once the biologic treatment was discontinued, 45.05% of patients restarted the treatment with the same agent, 23.10% of patients switched to another biologic, and 31.86% received no further biologic agent. Compared to patients treated with risankizumab, the treatment discontinuation rate was significantly higher (p

Abstract Background Integrated care involves care provided by a team of professionals, often in non-traditional settings. A common example worldwide is integrated school-based mental health (SBMH), which involves externally employed clinicians providing care at schools. Integrated mental healthcare can improve the accessibility and efficiency of evidence-based practices (EBPs) for vulnerable populations suffering from fragmented traditional care. However, integration can complicate EBP implementation due to overlapping organizational contexts, diminishing the public health impact. Emerging literature suggests that EBP implementation may benefit from the similarities in the implementation context factors between the different organizations in integrated care, which we termed inter-organizational alignment (IOA). This study quantitatively explored whether and how IOA in general and implementation context factors are associated with implementation outcomes in integrated SBMH. Methods SBMH clinicians from community-based organizations (CBOs; n clinician = 27) and their proximal student-support school staff (n school = 99) rated their schools and CBOs (clinician only) regarding general (organizational culture and molar climate) and implementation context factors (Implementation Climate and Leadership), and nine common implementation outcomes (e.g., treatment integrity, service access, acceptability). The levels of IOA were estimated by intra-class correlations (ICCs). We fitted multilevel models to estimate the standalone effects of context factors from CBOs and schools on implementation outcomes. We also estimated the 2-way interaction effects between CBO and school context factors (i.e., between-setting interdependence) on implementation outcomes. Results The IOA in general context factors exceeded those of implementation context factors. The standalone effects of implementation context factors on most implementation outcomes were larger than those of general context factors. Similarly, implementation context factors between CBOs and schools showed larger 2-way interaction effects on implementation outcomes than general context factors. Conclusions This study preliminarily supported the importance of IOA in context factors for integrated SBMH. The findings shed light on how IOA in implementation and general context factors may be differentially associated with implementation outcomes across a broad array of integrated mental healthcare settings.

Abstract Introduction Brodalumab is a human interleukin-17 receptor A antagonist indicated for the treatment of moderate-to-severe plaque psoriasis in adult patients who are candidates for systemic therapy or phototherapy and have failed to respond or have lost response to other systemic therapies. Although the US prescribing information for brodalumab includes a boxed warning regarding suicidal ideation and behavior, no causal association has been demonstrated. Here, we summarize 5 years of pharmacovigilance data, from August 15, 2017, through August 14, 2022, reported to Ortho Dermatologics by US patients and healthcare providers. Methods Prevalence of the most common adverse events (AEs) listed in the brodalumab package insert (incidence ≥ 1%) and AEs of special interest are described. Brodalumab exposure was estimated as the time from the first to last prescription-dispensing authorization dates. Data were collected from 4744 patients in the USA, with an estimated exposure of 5815 patient-years. Results Over 5 years, 11 cases of adjudicated major adverse cardiovascular events were reported (0.23 events/100 patients), a rate lower than that experienced by patients in the international Psoriasis Longitudinal Assessment and Registry. There were 106 serious infections. No serious fungal infections were reported. There were 40 confirmed and 2 suspected COVID-19 cases, with no new COVID-19-related deaths. Of 49 reported malignancies among 42 patients, 3 were deemed possibly related to brodalumab. No completed suicides and no new suicidal attempts were reported. Conclusion Five-year pharmacovigilance data are consistent with the established safety profile reported in long-term clinical trials and previous pharmacovigilance reports, with no new safety signals.

Abstract Neoadjuvant cisplatin-based chemotherapy is standard of care for muscle-invasive bladder cancer (MIBC). Immune checkpoint inhibition (ICI) alone, and ICI in combination with chemotherapy, have demonstrated promising pathologic response (

Abstract Agricultural soils are increasingly undergoing inadvertent and purposeful exposures to engineered CeO2 nanoparticles (NPs), which can impact crops and root-associated microbial communities. However, interactions between NP concentration and exposure duration on plant-mediated responses of root-associated bacterial communities are not well understood. Soybeans seedlings were grown in soil with uncoated NPs added at concentrations of 0, 1 or 100 mg kg−1. Total soil exposure durations were either 190 days, starting 106 days before planting or 84 days with NP amendments coinciding with planting. We assessed plant development, bacterial diversity, differential abundance and inferred functional changes across rhizosphere, rhizoplane, and root tissue compartments. Plant non-monotonic dose responses were mirrored in bacterial communities. Most notably, effects were magnified in the rhizoplane under low-dose, short-exposures. Enriched metabolic pathways were primarily related to biosynthesis and degradation/utilization/assimilation, rather than responses to metals or oxidative stress. Our results indicate that plant-mediated bacterial responses were greater than direct NP impacts. Also, we identify needs for modeling non-monotonic legume stress responses that account for coinfection with mutualistic and parasitic bacteroids. Our findings provide new insights regarding effects of applications of soil amendments such as biosolids containing NPs or nano-enabled formulations used in cultivation of legumes and other crops.

Abstract In urban areas, diverse and complex habitats for biodiversity are often lacking. This lack of diversity not only compromises essential ecological processes, such as pollination and nutrient cycling, but also diminishes the resilience of urban ecosystems to pests and diseases. To enhance urban biodiversity, a possible solution is to integrate shrubs alongside trees, thereby increasing the overall amount of vegetation, structural complexity and the associated resource diversity. Here, using a common garden experiment involving a variety of trees and shrubs planted alone and in combination, we evaluate how canopy-associated invertebrate assemblages are influenced by vegetation type. In particular, we test whether the presence of shrubs, alone or with trees, results in increased abundance and taxonomic richness of invertebrates, compared to trees on their own. We found that the overall abundance of invertebrates, and that of specific functional groups (e.g., herbivores, pollinators, detritivores), was higher on shrubs, compared to trees, and when trees and shrubs were planted in combination (relative to trees on their own). Our results suggest that planting shrub and tree species with wide and dense crowns can increase the associated abundance and taxonomic and functional group richness of invertebrate communities. Overall, our findings indicate that urban planning would benefit from incorporating shrubs alongside urban trees to maximise invertebrate abundance, diversity and function in urban landscapes.

Abstract Background The diagnostic process is a key element of medicine but it is complex and prone to errors. Infectious diseases are one of the three categories of diseases in which diagnostic errors can be most harmful to patients. In this study we aimed to estimate the effect of initial misdiagnosis of the source of infection in patients with bacteraemia on 14 day mortality using propensity score methods to adjust for confounding. Methods Data from a previously described longitudinal cohort of patients diagnosed with monobacterial bloodstream infection (BSI) at the Leiden University Medical Centre (LUMC) between 2013 and 2015 were used. Propensity score matching and inversed probability of treatment weighting (IPTW) were applied to correct for confounding. The average treatment effect on the treated (ATT), which in this study was the average effect of initial misdiagnosis on the misdiagnosed (AEMM), was estimated. Methodological issues that were encountered when applying propensity score methods were addressed by performing additional sensitivity analyses. Sensitivity analyses consisted of varying caliper in propensity score matching and using different truncated weights in inversed probability of treatment weighting. Results Data of 887 patients were included in the study. Propensity scores ranged between 0.015 and 0.999 and 80 patients (9.9%) had a propensity score > 0.95. In the matched analyses, 35 of the 171 misdiagnosed patients died within 14 days (20.5%), versus 10 of the 171 correctly diagnosed patients (5.8%), yielding a difference of 14.6% (7.6%; 21.6%). In the total group of patients, the observed percentage of patients with an incorrect initial diagnosis that died within 14 days was 19.8% while propensity score reweighting estimated that their probability of dying would have been 6.5%, if they had been correctly diagnosed (difference 13.3% (95% CI 6.9%;19.6%)). After adjustment for all variables that showed disbalance in the propensity score a difference of 13.7% (7.4%; 19.9%) was estimated. Sensitivity analyses yielded similar results. However, performing weighted analyses without truncation yielded unstable results. Conclusion Thus, we observed a substantial increase of 14 day mortality in initially misdiagnosed patients. Furthermore, several patients received propensity scores extremely close to one and were almost sure to be initially misdiagnosed.

Abstract Background Theory and correlational research indicate organizational leadership and climate are important for successful implementation of evidence-based practices (EBPs) in healthcare settings; however, experimental evidence is lacking. We addressed this gap using data from the WISDOM (Working to Implement and Sustain Digital Outcome Measures) hybrid type III effectiveness-implementation trial. Primary outcomes from WISDOM indicated the Leadership and Organizational Change for Implementation (LOCI) strategy improved fidelity to measurement-based care (MBC) in youth mental health services. In this study, we tested LOCI’s hypothesized mechanisms of change, namely: (1) LOCI will improve implementation and transformational leadership, which in turn will (2) mediate LOCI’s effect on implementation climate, which in turn will (3) mediate LOCI’s effect on MBC fidelity. Methods Twenty-one outpatient mental health clinics serving youth were randomly assigned to LOCI plus MBC training and technical assistance or MBC training and technical assistance only. Clinicians rated their leaders’ implementation leadership, transformational leadership, and clinic implementation climate for MBC at five time points (baseline, 4-, 8-, 12-, and 18-months post-baseline). MBC fidelity was assessed using electronic metadata for youth outpatients who initiated treatment in the 12 months following MBC training. Hypotheses were tested using longitudinal mixed-effects models and multilevel mediation analyses. Results LOCI significantly improved implementation leadership and implementation climate from baseline to follow-up at 4-, 8-, 12-, and 18-month post-baseline (all ps .05). LOCI’s improvement of clinic implementation climate from baseline to 12 months was mediated by improvement in implementation leadership from baseline to 4 months (proportion mediated [p m ] = 0.82, p = .004). Transformational leadership did not mediate LOCI’s effect on implementation climate (p = 0.136). Improvement in clinic implementation climate from baseline to 12 months mediated LOCI’s effect on MBC fidelity during the same period (p m = 0.71, p = .045). Conclusions LOCI improved MBC fidelity in youth mental health services by improving clinic implementation climate, which was itself improved by increased implementation leadership. Fidelity to EBPs in healthcare settings can be improved by developing organizational leaders and strong implementation climates. Trial registration ClinicalTrials.gov identifier: NCT04096274. Registered September 18, 2019.

The advent of remote livestock monitoring systems provides numerous possibilities for improving on-farm productivity, efficiency, and welfare. One potential application for these systems is for the detection of calving events. This study describes the integration of data from multiple sensor sources, including accelerometers, global navigation satellite systems (GNSS), an accelerometer-derived rumination algorithm, a walk-over-weigh unit, and a weather station for parturition detection using a support vector machine approach. The best performing model utilised data from GNSS, the ruminating algorithm, and weather stations to achieve 98.6% accuracy, with 88.5% sensitivity and 100% specificity. The top-ranking features of this model were primarily GNSS derived. This study provides an overview as to how various sensor systems could be integrated on-farm to maximise calving detection for improved production and welfare outcomes.

A sensitive and specific bioanalytical method was required to measure the exposure of a LAGA-mutated surrogate mouse IgG2a monoclonal antibody in mouse plasma, but the lack of highly specific reagents for the LAGA mutant hindered the development of a ligand-binding assay. Equally problematic is that no sensitive unique tryptic peptides suitable for quantitative mass spectrometric analysis could be identified in the mIgG2a complementarity-determining regions. To overcome these challenges, a trypsin alternative pepsin, an aspartic protease, was systematically investigated for its use in digesting the mutated mIgG2a antibody to allow generation of signature peptides for the bioanalytical quantification purpose. After a series of evaluations, a rapid one-hour pepsin digestion protocol was established for the mutated Fc backbone. Consequently, a new pepsin digestion-based liquid chromatography-tandem mass spectrometry (LC/MS/MS) method was successfully developed to support the mouse pharmacokinetic (PK) sample analysis. In brief, robust and reproducible C-terminal cleavage of both leucine and phenylalanine near the double mutation site of the mutated mIgG2a was accomplished at pH ≤2 and 37°C. Combined with a commercially available rat anti-mIgG2a heavy-chain antibody, the established immunoaffinity LC/MS/MS assay achieved a limit of quantitation of 20 ng/mL in the dynamic range of interest with satisfactory assay precision and accuracy. The successful implementation of this novel approach in discovery PK studies eliminates the need for tedious and costly generation of specific immunocapturing reagents for the LAGA mutants. The approach should be widely applicable for developing popular LAGA mutant-based biological therapeutics.

ABSTRACTThe surge in the clinical use of therapeutic antibodies has reshaped the landscape of pharmaceutical therapy for many diseases, including rare and challenging conditions. However, the administration of exogenous biologics could potentially trigger unwanted immune responses such as generation of anti-drug antibodies (ADAs). Real-world experiences have illuminated the clear correlation between the ADA occurrence and unsatisfactory therapeutic outcomes as well as immune-related adverse events. By retrospectively examining research involving immunogenicity analysis, we noticed the growing emphasis on elucidating the immunogenic epitope profiles of antibody-based therapeutics aiming for mechanistic understanding the immunogenicity generation and, ideally, mitigating the risks. As such, we have comprehensively summarized here the progress in both experimental and computational methodologies for the characterization of T and B cell epitopes of therapeutics. Furthermore, the successful practice of epitope-driven deimmunization of biotherapeutics is exceptionally highlighted in this article.

Aeolianites and cemented beach deposits on South Africa’s Cape coast preserve evidence of events that transpired on them when they were composed of unconsolidated sand. Over the past decades, numerous Pleistocene vertebrate tracksites have been identified on aeolianite palaeosurfaces in the Garden Route National Park, West Coast National Park, and Addo Elephant National Park. In the Garden Route National Park alone, 57 Pleistocene vertebrate tracksites have been discovered. An equilibrium exists, whereby new sites become exposed through cliff-collapse events, while known sites slump into the ocean, are eroded through the action of wind and water, or are destroyed through wave action. Engraved graffiti poses a further threat. These sites complement the traditional body fossil record, and have significant palaeoenvironmental and palaeoanthropological implications. Hominin sites are of global importance: one contains the oldest tracks attributed to Homo sapiens, others contain patterns made in sand by ancestral humans and constitutes a form of early palaeoart. Collectively, these sites have substantial geoheritage value. The discoveries create management questions: which sites require active management, and how should they be ranked in importance? Factors which need to be considered in developing a management strategy include the scientific and heritage value of the sites, whether recovery or replication is preferable, the presence or absence of suitable repositories, the level of the threat to site integrity, the accessibility of the site, and the feasibility of recovery. Checklists containing appropriate criteria and questions can form tools in assessing the importance of these ichnosites.

IntroductionSex differences in vulnerability to opioid use disorder (OUD) have been reported in some clinical and preclinical studies, but findings are mixed and further research is needed in this area. The goal of this study was to compare elasticity of demand (reinforcement efficacy) in an i.v. morphine self-administration (SA) model in male and female rats using a translationally relevant behavioral economics approach. Rate of acquisition and predictors of individual differences in demand (e.g., cumulative morphine infusions during acquisition) were also evaluated in both sexes.Materials, methods, and resultsAcquisition of morphine SA (0.4 mg/kg/infusion) under a fixed ratio (FR) 1 schedule of reinforcement was slower and infusions earned were lower in females than in males (n = 30–31/sex), but infusions earned did not differ between sexes during the FR 2 and FR 3 phases of acquisition. Increases in the FR response requirement across sessions during demand testing (FR 1–FR 96) resulted in a progressive reduction in morphine infusions in both sexes. Morphine consumption was well-described by an exponential demand function in both sexes and was associated with considerable individual vulnerability. There were no sex differences in elasticity of demand (rate of decline in morphine consumption with increasing price) or intensity of demand (consumption at zero price). A higher number of infusions earned during the FR 2 and FR 3 phases of acquisition and greater maximum response rates during demand testing were associated with lower demand elasticity (i.e., greater reinforcing efficacy) in both males and females, whereas other relationships were sex-specific (e.g., higher intensity of demand was associated with lower elasticity of demand in males but not in females).ConclusionOur findings indicate similar elasticity of demand and predictors of individual differences in demand for morphine in male and female rats, although sex differences were observed in initial rate of acquisition and in some correlations between morphine SA measures. These data are consistent with findings of similar OUD vulnerability in males and females in some human and animal studies.

Abstract Voriconazole is the cornerstone of the treatment and prevention of fungal infections. While there is a good correlation between CYP2C19 genotype and voriconazole exposure during prophylactic treatment, no correlation was found in patients with invasive aspergillosis. Proinflammatory cytokines result in inhibition of CYP2C19 enzyme activity (and may result in phenoconversion). Here we investigated the relationship between inflammation, CYP2C19 genotype‐predicted‐phenotype, and CYP2C19 activity in patients receiving voriconazole. Data were obtained from two prospective studies investigating voriconazole treatment (NCT02074462 and NCT00893555). Dose‐corrected voriconazole plasma concentration and C‐reactive protein (CRP) were used as proxies for CYP2C19 activity and inflammation, respectively. After data extraction and synthesis, data from 39 patients with paired voriconazole and CRP measurements were available. The distribution of CYP2C19 genotype‐predicted metabolizer phenotypes was 31% intermediate (IM), 41% normal (NM), and 28% rapid metabolizer (RM). During inflammation, dose‐corrected voriconazole levels were increased by 245%, 278%, and 486% for CYP2C19 NMs IMs and RMs, respectively. Patients with moderate or high CRP levels (>50 mg/L) were phenoconverted to a lower metabolizer phenotype irrespective of their CYP2C19 genotype. In a subgroup analysis of eight patients with longitudinal data available with and without inflammation, the pattern of the dose‐corrected voriconazole and CRP measurements were similar, with CYP2C19 activity following decreasing or increasing CRP levels. In conclusion, voriconazole plasma concentrations increase during inflammation due to downregulation of CYP2C19 activity. While this effect appears largest for CYP2C19 RMs, no clinically relevant differences were observed between the CYP2C19 genotypes.

Introduction A substantial proportion of patients with inflammatory bowel disease (IBD) on intravenous infliximab require dose intensification. Accessing additional intravenous infliximab is labour-intensive and expensive, depending on insurance and pharmaceutical reimbursement. Observational data suggest that subcutaneous infliximab may offer a convenient and safe alternative to maintain disease remission in patients requiring dose-intensified infliximab. A prospective, controlled trial is required to confirm that subcutaneous infliximab is as effective as dose-intensified intravenous infliximab, to identify predictors of disease flare and to establish the role of subcutaneous infliximab therapeutic drug monitoring.Methods and analysis The DISCUS-IBD trial is an investigator-initiated, prospective, multicentre, randomised, open-label non-inferiority study comparing the rate of disease flares in participants randomised to continue dose-intensified intravenous infliximab to those switched to subcutaneous infliximab after 48 weeks. Participants are adult patients with IBD in sustained corticosteroid-free remission on any regimen of dose-intensified infliximab up to a maximum of 10 mg/kg 4-weekly intravenously. Participants allocated to intravenous infliximab will continue infliximab at the same dose-intensified regimen they were receiving at study enrolment. Subcutaneous infliximab dosing will be stratified by prior intravenous infliximab dosing. Clinical (Harvey-Bradshaw Index, partial Mayo score), biochemical (C reactive protein, faecal calprotectin), pharmacokinetic (drug-level±antidrug antibodies) and qualitative data are collected 12-weekly until study conclusion at week 48. 13 sites across Australia will participate in recruitment to reach a calculated sample size of 120 participants.Ethics and dissemination Multisite ethics approval was obtained from the Health District Human Research Ethics Committee (HREC) at The Alfred Hospital under a National Mutual Acceptance (NMA) agreement (HREC/90559/Alfred-2022; Local Reference: Project 618/22, version 1.6, 2 March 2023). Findings will be reported at national and international gastroenterology meetings and published in peer-reviewed journals. DISCUS-IBD was prospectively registered with the Australian and New Zealand Clinical Trials Registry (ANZCTR) prior to commencing recruitment.Trial registration number ACTRN12622001458729.

Abstract In 2006 following several years of preliminary study, the American Society of Clinical Oncology (ASCO) launched the Quality Oncology Practice Initiative (QOPI). This cancer‐focused quality initiative evolved considerably over the next decade‐and‐a‐half and is expanding globally. QOPI is undoubtedly the leading standard‐bearer for quality cancer care and contemporary medical oncology practice. The program garners attention and respect among federal programs, private insurers, and medical oncology practices across the nation. The MaineHealth Cancer Care Network (MHCCN) has undergone expansive growth since 2017. The network provides cancer care to more than 70% of the cases in Maine in a largely rural health system in Northern New England. In fall 2020, the MHCCN QOPI project leadership, following collaborative discussions with the ASCO‐QOPI team, elected to proceed with a health system–cancer network‐wide QOPI certification. Key themes emerged over the course of our two‐year journey including: (1) Developing a highly interprofessional team committed to the project; (2) Capitalizing on a single electronic medical record for data transmission to CancerLinQ; (3) Prior experience, especially policy development, in other cancer‐focused accreditation programs across the network; and (4) Building consensus through quarterly stakeholder meetings and awarding Continuing Medical Education (CME) and American Board of Medical Specialists (ABMS) Maintenance of Certification (MOC) credits to oncologists. All participants demonstrated a genuine spirit to work together to achieve certification. We report our successful journey seeking ASCO‐QOPI certification across our network, which to our knowledge is the first‐of‐its‐kind endeavor.

Summary: Background: Little is known about post-acute sequelae of SARS-CoV-2 infection (PASC) after acquiring SARS-CoV-2 infection during pregnancy. We aimed to evaluate the association between acquiring SARS-CoV-2 during pregnancy compared with acquiring SARS-CoV-2 outside of pregnancy and the development of PASC. Methods: This retrospective cohort study from the Researching COVID to Enhance Recovery (RECOVER) Initiative Patient-Centred Clinical Research Network (PCORnet) used electronic health record (EHR) data from 19 U.S. health systems. Females aged 18–49 years with lab-confirmed SARS-CoV-2 infection from March 2020 through June 2022 were included. Validated algorithms were used to identify pregnancies with a delivery at >20 weeks’ gestation. The primary outcome was PASC, as previously defined by computable phenotype in the adult non-pregnant PCORnet EHR dataset, identified 30–180 days post-SARS-CoV-2 infection. Secondary outcomes were the 24 component diagnoses contributing to the PASC phenotype definition. Univariable comparisons were made for baseline characteristics between individuals with SARS-CoV-2 infection acquired during pregnancy compared with outside of pregnancy. Using inverse probability of treatment weighting to adjust for baseline differences, the association between SARS-CoV-2 infection acquired during pregnancy and the selected outcomes was modelled. The incident risk is reported as the adjusted hazard ratio (aHR) with 95% confidence intervals. Findings: In total, 83,915 females with SARS-CoV-2 infection acquired outside of pregnancy and 5397 females with SARS-CoV-2 infection acquired during pregnancy were included in analysis. Non-pregnant females with SARS-CoV-2 infection were more likely to be older and have comorbid health conditions. SARS-CoV-2 infection acquired in pregnancy as compared with acquired outside of pregnancy was associated with a lower incidence of PASC (25.5% vs 33.9%; aHR 0.85, 95% CI 0.80–0.91). SARS-CoV-2 infection acquired in pregnant females was associated with increased risk for some PASC component diagnoses including abnormal heartbeat (aHR 1.67, 95% CI 1.43–1.94), abdominal pain (aHR 1.34, 95% CI 1.16–1.55), and thromboembolism (aHR 1.88, 95% CI 1.17–3.04), but decreased risk for other diagnoses including malaise (aHR 0.35, 95% CI 0.27–0.47), pharyngitis (aHR 0.36, 95% CI 0.26–0.48) and cognitive problems (aHR 0.39, 95% CI 0.27–0.56). Interpretation: SARS-CoV-2 infection acquired during pregnancy was associated with lower risk of development of PASC at 30–180 days after incident SARS-CoV-2 infection in this nationally representative sample. These findings may be used to counsel pregnant and pregnant capable individuals, and direct future prospective study. Funding: National Institutes of Health (NIH) Other Transaction Agreement (OTA) OT2HL16184.

We present a genome assembly from an individual female Crepidodera aurea (flea beetle; Arthropoda; Insecta; Coleoptera; Chrysomelidae). The genome sequence is 509.0 megabases in span. Most of the assembly is scaffolded into 10 chromosomal pseudomolecules, including the X sex chromosome. The mitochondrial genome has also been assembled and is 18.69 kilobases in length. Gene annotation of this assembly on Ensembl identified 19,944 protein coding genes.

We present a genome assembly from an individual male Platypus cylindrus (the oak pinhole borer; Arthropoda; Insecta; Coleoptera; Curculionidae). The genome sequence is 147.5 megabases in span. Most of the assembly is scaffolded into 8 chromosomal pseudomolecules, including the X and Y sex chromosomes. The mitochondrial genome has also been assembled and is 19.29 kilobases in length. Gene annotation of this assembly on Ensembl identified 13,468 protein coding genes.

High energy density, long cyclability, and enhanced stability in a small footprint achieved through microfabrication are crucial for micro lithium‐ion batteries. Herein, a 3D Si‐clad NiSn anode characterized by a dendritic NiSn network and silicon nanoparticles is proposed. The dendritic network facilitates fast ion/electron transfer and provides expansion space for the silicon, while the uniformly distributed silicon enhances capacity and stability. The anode, scalable to the hundred‐micron scale, is fabricated via one‐step electrodeposition incorporating the dynamic template technique. This technique generates interconnected pores extending from the inner to the outer surface of the anode, facilitating electrolyte penetration and ion transport. As a result, the anodes in the Swagelok cells exhibit an ultrahigh areal capacity of up to 28.2 mAh cm−2 and an enhanced stability of 91% capacity retention after 300 cycles. The dendritic Si‐clad NiSn anode, based on microfabrication, presents an excellent opportunity to advance micro energy systems.

Chronic kidney disease-associated pruritus leads to decreased quality of life and is an independent risk factor for mortality. There is limited evidence for treatment of chronic kidney disease-associated pruritus, with only one on-label treatment approved by the FDA and Health Canada. We present a case of a 69-year-old female with a history of chronic kidney disease, who presented to clinic with a several-year history of diffuse, intense pruritus. There were no primary lesions. She was started on dupilumab 600 mg loading dose, then 300 mg subcutaneously every 2 weeks. At her follow-up appointment 5 months after initiation of dupilumab, she reported her pruritus as 1/10, with no interruptions in her sleep. Her creatinine remained elevated and was stable throughout the follow-up period. This case demonstrates sustained improvement in chronic kidney disease-associated pruritus with dupilumab. Further research is required to quantify the efficacy of dupilumab for treatment of chronic kidney disease-associated pruritus.

Abstract Background An increasing number of studies have described new and persistent symptoms and conditions as potential post-acute sequelae of SARS-CoV-2 infection (PASC). However, it remains unclear whether certain symptoms or conditions occur more frequently among persons with SARS-CoV-2 infection compared with those never infected with SARS-CoV-2. We compared the occurrence of specific COVID-associated symptoms and conditions as potential PASC 31- to 150-day following a SARS-CoV-2 test among adults and children with positive and negative test results. Methods We conducted a retrospective cohort study using electronic health record (EHR) data from 43 PCORnet sites participating in a national COVID-19 surveillance program. This study included 3,091,580 adults (316,249 SARS-CoV-2 positive; 2,775,331 negative) and 675,643 children (62,131 positive; 613,512 negative) who had a SARS-CoV-2 laboratory test during March 1, 2020–May 31, 2021 documented in their EHR. We used logistic regression to calculate the odds of having a symptom and Cox models to calculate the risk of having a newly diagnosed condition associated with a SARS-CoV-2 positive test. Results After adjustment for baseline covariates, hospitalized adults and children with a positive test had increased odds of being diagnosed with ≥ 1 symptom (adults: adjusted odds ratio[aOR], 1.17[95% CI, 1.11–1.23]; children: aOR, 1.18[95% CI, 1.08–1.28]) or shortness of breath (adults: aOR, 1.50[95% CI, 1.38–1.63]; children: aOR, 1.40[95% CI, 1.15–1.70]) 31–150 days following a SARS-CoV-2 test compared with hospitalized individuals with a negative test. Hospitalized adults with a positive test also had increased odds of being diagnosed with ≥ 3 symptoms or fatigue compared with those testing negative. The risks of being newly diagnosed with type 1 or type 2 diabetes (adjusted hazard ratio[aHR], 1.25[95% CI, 1.17–1.33]), hematologic disorders (aHR, 1.19[95% CI, 1.11–1.28]), or respiratory disease (aHR, 1.44[95% CI, 1.30–1.60]) were higher among hospitalized adults with a positive test compared with those with a negative test. Non-hospitalized adults with a positive test also had higher odds or increased risk of being diagnosed with certain symptoms or conditions. Conclusions Patients with SARS-CoV-2 infection, especially those who were hospitalized, were at higher risk of being diagnosed with certain symptoms and conditions after acute infection.

Background and Aims: Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common cause of chronic liver disease worldwide. The current and projected cost of treating individuals with MASLD in Canada remains unknown. Our objective was to calculate the projected liver-specific and total health-care costs for people living with MASLD in Canada from 2020 to 2050. Methods: The health-care usage of a cohort of patients diagnosed with MASLD in Calgary, Alberta was calculated using administrative data. Liver-specific encounters were identified and the average costs per year per patient were calculated. Projected costs were calculated by multiplying the average cost per patient within each health state by the projected prevalence of each health state. Results: There were 6358 patients in the cohort. The annual average liver-specific cost per patient was $7.02 for F0/F1, $35.30 for F2, $60.46 for F3, and $72.55 for F4. The projected Canada-wide liver-specific cost was $85.5 million in 2020 and was expected to increase by $51 million by 2050. The average annual total health-care cost per patient was $397.90 for F0/F1, $781.53 for F2, $2881.84 for F3, and $1598.82 for F4. Thus, the projected Canada-wide total health-care cost was $3.76 billion in 2020 and was expected to increase by almost $2 billion by 2050. Conclusion: These estimates underscore the need for a MASLD framework that focuses on both prevention and innovative care models to change the predicted trajectory of health-care costs.

Abstract Human natural killer T cells (NKTs) are innate-like T lymphocytes increasingly used for cancer immunotherapy. Here we show that human NKTs expressing the pro-inflammatory cytokine interleukin-12 (IL-12) undergo extensive and sustained molecular and functional reprogramming. Specifically, IL-12 instructs and maintains a Th1-polarization program in NKTs in vivo without causing their functional exhaustion. Furthermore, using CD62L as a marker of memory cells in human NKTs, we observe that IL-12 maintains long-term CD62L-expressing memory NKTs in vivo. Notably, IL-12 initiates a de novo programming of memory NKTs in CD62L-negative NKTs indicating that human NKTs circulating in the peripheral blood possess an intrinsic differentiation hierarchy, and that IL-12 plays a role in promoting their differentiation to long-lived Th1-polarized memory cells. Human NKTs engineered to co-express a Chimeric Antigen Receptor (CAR) coupled with the expression of IL-12 show enhanced antitumor activity in leukemia and neuroblastoma tumor models, persist long-term in vivo and conserve the molecular signature driven by the IL-12 expression. Thus IL-12 reveals an intrinsic plasticity of peripheral human NKTs that may play a crucial role in the development of cell therapeutics.

Abstract Repeat vaccination with egg-based influenza vaccines could preferentially boost antibodies targeting the egg-adapted epitopes and reduce immunogenicity to circulating viruses. In this randomized trial (Clinicaltrials.gov: NCT03722589), sera pre- and post-vaccination with quadrivalent inactivated egg-based (IIV4), cell culture-based (ccIIV4), and recombinant (RIV4) influenza vaccines were collected from healthcare personnel (18-64 years) in 2018−19 (N = 723) and 2019−20 (N = 684) influenza seasons. We performed an exploratory analysis. Vaccine egg-adapted changes had the most impact on A(H3N2) immunogenicity. In year 1, RIV4 induced higher neutralizing and total HA head binding antibodies to cell- A(H3N2) virus than ccIIV4 and IIV4. In year 2, among the 7 repeat vaccination arms (IIV4-IIV4, IIV4-ccIIV4, IIV4-RIV4, RIV4-ccIIV4, RIV4-RIV4, ccIIV4-ccIIV4 and ccIIV4-RIV4), repeat vaccination with either RIV4 or ccIIV4 further improved antibody responses to circulating viruses with decreased neutralizing antibody egg/cell ratio. RIV4 also had higher post-vaccination A(H1N1)pdm09 and A(H3N2) HA stalk antibodies in year 1, but there was no significant difference in HA stalk antibody fold rise among vaccine groups in either year 1 or year 2. Multiple seasons of non-egg-based vaccination may be needed to redirect antibody responses from immune memory to egg-adapted epitopes and re-focus the immune responses towards epitopes on the circulating viruses to improve vaccine effectiveness.

Abstract Background The study of plant photosynthesis is essential for productivity and yield. Thanks to the development of high-throughput phenotyping (HTP) facilities, based on chlorophyll fluorescence imaging, photosynthetic traits can be measured in a reliable, reproducible and efficient manner. In most state-of-the-art HTP platforms, these traits are automatedly analyzed at individual plant level, but information at leaf level is often restricted by the use of manual annotation. Automated leaf tracking over time is therefore highly desired. Methods for tracking individual leaves are still uncommon, convoluted, or require large datasets. Hence, applications and libraries with different techniques are required. New phenotyping platforms are initiated now more frequently than ever; however, the application of advanced computer vision techniques, such as convolutional neural networks, is still growing at a slow pace. Here, we provide a method for leaf segmentation and tracking through the fine-tuning of Mask R-CNN and intersection over union as a solution for leaf tracking on top-down images of plants. We also provide datasets and code for training and testing on both detection and tracking of individual leaves, aiming to stimulate the community to expand the current methodologies on this topic. Results We tested the results for detection and segmentation on 523 Arabidopsis thaliana leaves at three different stages of development from which we obtained a mean F-score of 0.956 on detection and 0.844 on segmentation overlap through the intersection over union (IoU). On the tracking side, we tested nine different plants with 191 leaves. A total of 161 leaves were tracked without issues, accounting to a total of 84.29% correct tracking, and a Higher Order Tracking Accuracy (HOTA) of 0.846. In our case study, leaf age and leaf order influenced photosynthetic capacity and photosynthetic response to light treatments. Leaf-dependent photosynthesis varies according to the genetic background. Conclusion The method provided is robust for leaf tracking on top-down images. Although one of the strong components of the method is the low requirement in training data to achieve a good base result (based on fine-tuning), most of the tracking issues found could be solved by expanding the training dataset for the Mask R-CNN model.

Abstract Background Cardiac repair and remodeling following myocardial infarction (MI) is a multifactorial process involving pro-reparative inflammation, angiogenesis and fibrosis. Noninvasive imaging using a radiotracer targeting these processes could be used to elucidate cardiac wound healing mechanisms. The alpha7 nicotinic acetylcholine receptor (ɑ7nAChR) stimulates pro-reparative macrophage activity and angiogenesis, making it a potential imaging biomarker in this context. We investigated this by assessing in vitro cellular expression of ɑ7nAChR, and by using a tritiated version of the PET radiotracer [18F]NS14490 in tissue autoradiography studies. Results ɑ7nAChR expression in human monocyte-derived macrophages and vascular cells showed the highest relative expression was within macrophages, but only endothelial cells exhibited a proliferation and hypoxia-driven increase in expression. Using a mouse model of inflammatory angiogenesis following sponge implantation, specific binding of [3H]NS14490 increased from 3.6 ± 0.2 µCi/g at day 3 post-implantation to 4.9 ± 0.2 µCi/g at day 7 (n = 4, P