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Objective Determine the pharmacokinetics (PK) and exposure–response of hydroxychloroquine (HCQ) and desethylhydroxychloroquine (DHCQ) in paediatric SLE (pSLE).Methods We conducted an exploratory phase 2, direct-to-family trial. Children enrolled in the Childhood Arthritis and Rheumatology Research Alliance (CARRA) Registry with a diagnosis of pSLE were eligible if they were receiving HCQ as standard of care for ≥3 months. Biological samples were collected at up to four visits over a 6-month period. At each visit, plasma was obtained to measure the concentrations of HCQ and DHCQ, as well as cytokines. HCQ and DHCQ plasma PK data were analysed using a population PK modelling approach.Results Twenty-five subjects provided a total of 88 plasma concentrations for PK analysis. There was a poor linear fit between HCQ concentrations and total body weight (R2=0.03). There was a decline in both interferon (IFN)-alpha and IFN-gamma with higher concentrations of HCQ and DHCQ. Volume of distribution for HCQ in plasma was higher in children compared with published values in adults (73 000 L vs 44 000 L), but clearance values in children were similar to adults.Conclusions We report the first population PK model for HCQ and DHCQ in children using data from a novel direct-to-family clinical trial. We observed high interindividual variability in HCQ PK and found that weight-based dosing for HCQ is poorly correlated with drug concentrations, suggesting the need to use therapeutic drug monitoring to individualise dosing. Furthermore, our results suggest that the current weight-based dosing paradigm for HCQ may result in suboptimal drug exposures, particularly for children with obesity. Accordingly, additional studies of HCQ are needed in pSLE to determine the optimal drug concentration and dosing to reduce disease activity and improve outcomes.Trial registration number NCT04358302.

Introduction Direct-to-family clinical trials efficiently provide data while reducing the participation burden for children and their families. Although these trials can offer significant advantages over traditional clinical trials, the process of designing and implementing direct-to-family studies is poorly defined, especially in children with rheumatic disease. This paper provides lessons learnt from the design and implementation of a self-controlled, direct-to-family pilot trial aimed to evaluate the effects of a medication management device on adherence to hydroxychloroquine in paediatric SLE.Methods Several design features accommodate a direct-to-family approach. Participants meeting eligibility criteria from across the USA were identified a priori through a disease registry, and all outcome data are collected remotely. The primary outcome (medication adherence) is evaluated using electronic medication event-monitoring, plasma drug levels, patient questionnaires and pill counts. Secondary and exploratory endpoints include (1) lupus disease activity measured by a remote SLE Disease Activity Index examination and the Systemic Lupus Activity Questionnaire; and (2) hydroxychloroquine pharmacokinetics and pharmacodynamics. Recruitment of the initial target of 20 participants was achieved within 10 days. Due to initial recruitment success, enrolment was increased to 26 participants. Additional participants who were interested were placed on a waiting list in case of dropouts during the study.Discussion and dissemination Direct-to-family trials offer several advantages but present unique challenges. Lessons learnt from the protocol development, design, and implementation of this trial will inform future direct-to-family trials for children and adults with rheumatic diseases. Additionally, the data collected remotely in this trial will provide critical information regarding the accuracy of teleresearch in lupus, the impact of adherence to hydroxychloroquine on disease activity and a pharmacokinetic analysis to inform paediatric-specific dosing of hydroxychloroquine.Trial registration number ClinicalTrials.gov Registry (NCT04358302).

Many engineering courses rely on in-person lectures and textbooks for content delivery, with homework sets and exams for evaluating and reinforcing student progress. Yet some research studies have shown that exams--high-pressure, time-limited assessments--are detrimental to the learning process and unnecessarily increase students' stress. We describe a new student centered teaching approach based on four pedagogical domains: scaffolded, universally-designed, mastery-based, and gameful learning. The approach was implemented in an engineering course by first chunking the content into small, easily digestible topics. Next, multiple modalities were used to deliver this content, including textbook references, virtual lectures, condensed presentation slides, summary sheets, and two-minute videos. Finally, the typical grading system was replaced by a point system using multiple 10- and 20-point quizzes, all of which could be attempted multiple times through unique versions for each student. Several findings emerged from our examination of this overall instructional strategy. The flexibility in learning and assessment enhanced students' mastery of content and maximized their sense of ownership in the learning process. The multiple attempts on quizzes provided the students with more freedom to fail and resulted in a more supportive learning environment. Last, the multimodal delivery and self-controlled assessment process promoted inclusive and equitable learning. This course structure can be translated to many other engineering courses, with spreadsheets and a web-based quiz making program developed to assist in the process.

Abstract The Society for Cardiovascular Magnetic Resonance (SCMR) is an international society focused on the research, education, and clinical application of cardiovascular magnetic resonance (CMR). “Cases of SCMR” is a case series hosted on the SCMR website ( https://www.scmr.org ) that demonstrates the utility and importance of CMR in the clinical diagnosis and management of cardiovascular disease. The COVID-19 Case Collection highlights the impact of coronavirus disease 2019 (COVID-19) on the heart as demonstrated on CMR. Each case in series consists of the clinical presentation and the role of CMR in diagnosis and guiding clinical management. The cases are all instructive and helpful in the approach to patient management. We present a digital archive of the 2021 Cases of SCMR and the 2020 and 2021 COVID-19 Case Collection series of nine cases as a means of further enhancing the education of those interested in CMR and as a means of more readily identifying these cases using a PubMed or similar literature search engine.

Abstract Pediatric physiologically‐based pharmacokinetic (P‐PBPK) models have been used to predict age related changes in the pharmacokinetics (PKs) of renally cleared drugs mainly in relation to changes in glomerular filtration rate. With emerging data on ontogeny of renal transporters, mechanistic models of renal clearance accounting for the role of active and passive secretion should be developed and evaluated. Data on age‐related physiological changes and ontogeny of renal transporters were applied into a mechanistic kidney within a P‐PBPK model. Plasma concentration–time profile and PK parameters of cimetidine, ciprofloxacin, metformin, tenofovir, and zidovudine were predicted in subjects aged 1 day to 18 years. The predicted and observed plasma concentration–time profiles and PK parameters were compared. The predicted concentration–time profile means and 5th and 95th percent intervals generally captured the observed data and variability in various studies. Overall, based on drugs and age bands, predicted to observed clearance were all within two‐fold and in 11 of 16 cases within 1.5‐fold. Predicted to observed area under the curve (AUC) and maximum plasma concentration (Cmax) were within two‐fold in 12 of 14 and 12 of 15 cases, respectively. Predictions in neonates and early infants (up to 14 weeks postnatal age) were reasonable with 15–20 predicted PK parameters within two‐fold of the observed. ciprofloxacin but not zidovudine PK predictions were sensitive to basal kidney uptake transporter ontogeny. The results indicate that a mechanistic kidney model accounting for physiology and ontogeny of renal processes and transporters can predict the PK of renally excreted drugs in children. Further data especially in neonates are required to verify the model and ontogeny profiles.

Abstract Clinical trials during public health emergencies of novel medical products such as therapeutics and vaccines in resource-limited settings are daunting due to the limited capacity for regulatory assessment. Regulating clinical trials during the Ebola outbreak in Sierra Leone required expedited evaluation to identify medical products that could be promptly introduced to combat the epidemic in the absence of approved treatment or prevention. This article explored the decisions taken by the Pharmacy Board of Sierra Leone through its Expert Committee on Medicine Safety and Clinical Trials regarding clinical trials oversight during the Ebola epidemic and the lessons learned. This independent expert committee assessed and provided scientific opinions to the Pharmacy Board of Sierra Leone to inform approval of all clinical trials within 10–15 working days. We also requested for assisted review from the African Vaccine Regulatory Forum and support from the US Food and Drug Administration through a unilateral recognition and reliance memorandum of understanding. In addition, the Agency-ensured structures and systems were in place for reporting and reviewing adverse events and serious adverse events, management of biological samples, submission and review of progress reports, and good clinical practice inspections. Unfortunately, the Ebola epidemic revealed many weaknesses in the country’s clinical trials regulatory structure and processes. Government and partners should further offer more resources to build the clinical trial structures and systems so that the Agency will be better poised to handle future public health emergencies.

Abstract Natural Killer T (NKT) cells and Mucosal-Associated Invariant T (MAIT) cells are innate-like T cells that express semi-invariant αβ T cell receptors (TCRs) through which they recognise CD1d and MR1 molecules, respectively, in complex with specific ligands. These cells play important roles in health and disease in many organs, but their precise intra-organ location is not well established. Here, using CD1d and MR1 tetramer staining techniques, we describe the precise location of NKT and MAIT cells in lymphoid and peripheral organs. Within the thymus, NKT cells were concentrated in the medullary side of the corticomedullary junction. In spleen and lymph nodes, NKT cells were mainly localised within T cell zones, although following in vivo activation with the potent NKT-cell ligand α-GalCer, they expanded throughout the spleen. MAIT cells were clearly detectable in Vα19 TCR transgenic mice and were rare but detectable in lymphoid tissue of non-transgenic mice. In contrast to NKT cells, MAIT cells were more closely associated with the B cell zone and red pulp of the spleen. Accordingly, we have provided an extensive analysis of the in situ localisation of NKT and MAIT cells and suggest differences between the intra-organ location of these two cell types.

Abstract There has been a significant increase in the use of physiologically based pharmacokinetic (PBPK) models during the past 20 years, especially for pediatrics. The aim of this study was to give a detailed overview of the growth and areas of application of pediatric PBPK (P‐PBPK) models. A total of 181 publications and publicly available regulatory reviews were identified and categorized according to year, author affiliation, platform, and primary application of the P‐PBPK model (in clinical settings, drug development or to advance pediatric model development in general). Secondary application areas, including dose selection, biologics, and drug interactions, were also assessed. The growth rate for P‐PBPK modeling increased 33‐fold between 2005 and 2020; this was mainly attributed to growth in clinical and drug development applications. For primary applications, 50% of articles were classified under clinical, 18% under drug development, and 33% under model development. The most common secondary applications were dose selection (75% drug development), pharmacokinetic prediction and covariate identification (47% clinical), and model parameter identification (68% model development), respectively. Although population PK modeling remains the mainstay of approaches supporting pediatric drug development, the data presented here demonstrate the widespread application of P‐PBPK models in both drug development and clinical settings. Although applications for pharmacokinetic and drug–drug interaction predictions in pediatrics is advocated, this approach remains underused in areas such as assessment of pediatric formulations, toxicology, and trial design. The increasing number of publications supporting the development and refinement of the pediatric model parameters can only serve to enhance optimal use of P‐PBPK models.

The mechanisms regulating mitosis and differentiation during development are thought to be distinct. Here they show that in Drosophila the mitotic kinase Polo regulates cellular morphogenesis after cell cycle exit.

Increasing growth in land-based wind turbine blades to enable higher machine capacities and capacity factors is creating challenges in design, manufacturing, logistics, and operation. Enabling further blade growth will require technology innovation. An emerging solution to overcome logistics constraints is to segment the blades spanwise and chordwise, which is effective, but the additional field-assembled joints result in added mass and loads, as well as increased reliability concerns in operation. An alternative to this methodology is to design slender flexible blades that can be shipped on rail lines by flexing during transport. However, the increased flexibility is challenging to accommodate with a typical glass-fiber, upwind design. In a two-part paper series, several design options are evaluated to enable slender flexible blades: downwind machines, optimized carbon fiber, and active aerodynamic controls. Part 1 presents the system-level optimization of the rotor variants as compared to conventional and segmented baselines, with a low-fidelity representation of the blades. The present work, Part 2, supplements the system-level optimization in Part 1 with high-fidelity blade structural optimization to ensure that the designs are at feasible optima with respect to material strength and fatigue limits, as well as global stability and structural dynamics constraints. To accommodate the requirements of the design process, a new version of the Numerical Manufacturing And Design (NuMAD) code has been developed and released. The code now supports laminate-level blade optimization and an interface to the International Energy Agency Wind Task 37 blade ontology. Transporting long, flexible blades via controlled flapwise bending is found to be a viable approach for blades of up to 100 m. The results confirm that blade mass can be substantially reduced by going either to a downwind design or to a highly coned and tilted upwind design. A discussion of active and inactive constraints consisting of material rupture, fatigue damage, buckling, deflection, and resonant frequencies is presented. An analysis of driving load cases revealed that the downwind designs are dominated by loads from sudden, abrupt events like gusts rather than fatigue. Finally, an analysis of carbon fiber spar caps for downwind machines finds that, compared to typical carbon fibers, the use of a new heavy-tow carbon fiber in the spar caps is found to yield between 9 % and 13 % cost savings.

OBJECTIVE: Proper blood flow is essential for the maintenance of homeostasis for the human cerebrum. The dural venous sinuses comprise the dominant cerebral venous outflow path. Understanding the spatial configuration of the dural venous sinuses can provide valuable insight into several pathological conditions. Previously, only two-dimensional or cadaveric data have been used to understand cerebral outflow. For the first time, we applied three-dimensional rotational venography (3D-RV) to study and provide detailed quantitative morphological measurements of the terminal cerebral venous sinus system in several pathological states. SUBJECTS ANDMETHODS: Patients who underwent a 3D-RV procedure were identified by reviewing our local institution's endovascular database. Patients with high-quality angiographic images were selected. Eighteen patients were included (37.1 ± 3.8 years). Sinuses were divided into four segments, starting at the torcula and ending at the internal jugular vein. Segment length, 3D displacement, and cross-sectional area were measured. RESULTS: The transverse sinus (60.2 mm) was the longest segment, followed by the sigmoid sinus (55.1 mm). Cross-sectional areas were smallest at the middle of the transverse sinus (21.3 mm2) but increased at the sigmoid sinus (33.5 mm2) and at the jugular bulb (49.7 mm2). The only variation in displacements of venous flow was at the sigmoid-jugular junction, where 55% of cases had lateral displacements versus 45% medial, and 78% superior versus 22% inferior. CONCLUSIONS: We describe the terminal venous sinus system of patients with a variety of diagnoses, detailing segment length, cross-sectional area, and 3D path.

INTRODUCTION: We studied the relationship of acute ischemic stroke (AIS) large-vessel occlusion clot composition with vessel recanalization and preprocedure imaging. SUBJECTS AND METHODS: Individual clots from AIS patients who underwent mechanical thrombectomy (MT) between September 2016 and September 2018 were examined. Clot composition was analyzed histologically through a trichrome staining and image segmentation, and the area occupied by red blood cells (RBCs), fibrin, or mixed composition was quantified. RESULTS: Forty-three patients (65.4 ± 12.7 years, 39% of females) who underwent 92 retrieval passes (mean 2.14, range 1–6) were included in this study. Fibrin (44%) occupied the greatest area, followed by mixed composition (34%) and RBCs (22%). A stent retriever was deployed in 81% of cases, 20 patients (47%) achieved first-pass efficacy (FPE) (thrombolysis in cerebral infarction [TICI] 2b-3 after first pass), 41 (95%) achieved successful revascularization (TICI 2b-3), and 21 (49%) had good outcome (modified Rankin Scale [mRS] ≤2) at 90 days. Hyperdense artery sign (HAS) on initial computed tomography was correlated with mixed clot composition (P = 0.01) and lack of fibrin content (P = 0.03). In the univariate analysis, FPE was associated with RBC clot area, atrial fibrillation, and occlusion location but not with fibrin clot area, mixed clot area, stroke etiology, thrombectomy technique, distal emboli, or 90-day mRS. In the multivariate analysis, FPE was significantly correlated with low RBC clot area (odd ratio = 0.96, confidence interval [0.92.99], P = 0.034) but not with atrial fibrillation or location. CONCLUSION: Our results suggest that HAS is correlated with mixed clot composition and lower fibrin content and that lower RBC clot composition is associated with FPE in patients undergoing MT.

The tribological enhancement of base lubricant under different concentration of formulated Eichhornia Crassipes carbon nanotubes (EC-CNTs) was conducted in this research. Cyclic heating approach was adopted in the formulation of EC-CNT and scientifically characterized. The characterization results confirmed the sample EC-CNTs. The effect of EC-CNT in base rapeseed oil terms of concentration, coefficient of friction (COF) and surface roughness (Ra), load carrying capacity, lubrication film stability and film mechanism were evaluated using high frequency reciprocating rig machine. The results showed that inclusion of EC-CNTs into base rapeseed oil, enhanced the tribological properties. The resultant values of COF were 0.064, 0.051 and 0.087 for rapeseed blended 1 mass%, 2.5 mass%, 4 mass% EC-CNT respectively. This is 38.5% COF reduction from 2.5 mass% EC-CNT against base oil. Under wear scar diameter, 2.5 mass% showed 47.9% reduction compared to base oil. The Ra was reduced with addition of nanoparticles, especially with 2.5 mass%. The tribological enhancement by EC-CNT is attributed from tribo-chemical reaction between the particles and the interfaces leading to formation of active protective tribo-film. The mechanism exhibited by the nanoparticles were healing and rolling from which the tribo-enhancement were achieved.

Objective: To describe a case of acute invasive fungal sinusitis (AIFS), unique in its presentation with limited superficial invasion, underlying a fungal crust, in a patient on antifungal prophylaxis. To present accompanying images and pathology results that capture the very early stages of fungal invasion and depict the ongoing battle between fungal organisms and the immune system. Methods: Case report with literature review. Results: We present the case of a 74-year-old immunocompromised male on prophylactic voriconazole who was admitted with neutropenic fever and was found to have superficially invasive fungal sinusitis. Pathology from the initial surgical debridement showed superficial invasion of the middle turbinate mucosa, but no angioinvasion. Biopsies from a second surgical debridement were negative for fungal organisms, but fungal cultures were positive. The patient was treated with amphotericin B and posaconazole and discharged with plans for likely lifelong posaconazole. Conclusion: This case augments the existing AIFS literature in that the histopathology uniquely demonstrates limited superficial invasion, underlying a fungal crust, likely portraying the early stages of AIFS. Additionally, this case highlights new and ongoing clinical questions surrounding AIFS prevention and diagnosis, particularly in immunocompromised patients.

Abstract Increasing amounts of genetic data have led to the development of polygenic risk scores (PRSs) for a variety of diseases. These scores, built from the summary statistics of genome-wide association studies (GWASs), are able to stratify individuals based on their genetic risk of developing various common diseases and could potentially be used to optimize the use of screening and preventative treatments and improve personalized care for patients. Many challenges are yet to be overcome, including PRS validation, healthcare professional and patient education, and healthcare systems integration. Ethical challenges are also present in how this information is used and the current lack of diverse populations with PRSs available. In this review, we discuss the topics above and cover the nature of PRSs, visualization schemes, and how PRSs can be improved. With these tools on the horizon for multiple diseases, scientists, clinicians, health systems, regulatory bodies, and the public should discuss the uses, benefits, and potential risks of PRSs.

Abstract We show that malicious COVID-19 content, including racism, disinformation, and misinformation, exploits the multiverse of online hate to spread quickly beyond the control of any individual social media platform. We provide a first mapping of the online hate network across six major social media platforms. We demonstrate how malicious content can travel across this network in ways that subvert platform moderation efforts. Machine learning topic analysis shows quantitatively how online hate communities are sharpening COVID-19 as a weapon, with topics evolving rapidly and content becoming increasingly coherent. Based on mathematical modeling, we provide predictions of how changes to content moderation policies can slow the spread of malicious content.

Abstract Disrupting the emergence and evolution of potentially violent online extremist movements is a crucial challenge. Extremism research has analyzed such movements in detail, focusing on individual- and movement-level characteristics. But are there system-level commonalities in the ways these movements emerge and grow? Here we compare the growth of the Boogaloos, a new and increasingly prominent U.S. extremist movement, to the growth of online support for ISIS, a militant, terrorist organization based in the Middle East that follows a radical version of Islam. We show that the early dynamics of these two online movements follow the same mathematical order despite their stark ideological, geographical, and cultural differences. The evolution of both movements, across scales, follows a single shockwave equation that accounts for heterogeneity in online interactions. These scientific properties suggest specific policies to address online extremism and radicalization. We show how actions by social media platforms could disrupt the onset and ‘flatten the curve’ of such online extremism by nudging its collective chemistry. Our results provide a system-level understanding of the emergence of extremist movements that yields fresh insight into their evolution and possible interventions to limit their growth.

INTRODUCTION: Acute ischemic stroke (AIS) complicating cardiac interventions (CI) is well described. The use of mechanical thrombectomy (MT) for treatment of emergent large vessel occlusion (ELVO) in this setting, however, is not widely reported. METHODS: Cases of patients undergoing MT for AIS with ELVO at a single institution were reviewed. Cases preceded by recent CI were investigated retrospectively. Data was collected for patient demographics, type of cardiac intervention, stroke characteristics, neurovascular intervention, and patient outcomes. RESULTS: Between 2008 and 2017, registry analysis identified nine patients treated with MT for AIS complicating recent CI. Patients were more commonly male with a mean age of 67 years. A large majority had a known cardiac arrhythmia. Coronary artery bypass graft surgery (CABG) was the most identified CI, followed by valve repair, and cardiac ablations. Mean presenting NIHSS was 18. Most presented with hemiplegia. Seven cases were found to have MCA occlusions. Stent-retrievers were used in 6 cases with excellent recanalization in five MCA cases (TICI 2c or 3) and in two basilar cases. Despite immediate improvements in NIHSS scores in most cases, functional outcomes were poor in 7 cases (mRS of 4-6). Three cases were complicated by hemorrhage and three cases ended in mortality. CONCLUSION: AIS with ELVO following recent CI is associated with high rates of mortality and poor functional outcomes despite MT. Further work is needed to understand the key drivers to poor outcomes in this ELVO subgroup.

ABSTRACT: Significant changes in growth potential and feed conversion have been bred into the modern broiler chicken for well over 60 yr. These metabolic changes have had significant effects on the immune performance as well. To better understand these genetic differences in immunometabolism we studied the immune response of the modern broiler and the Athens Canadian Random Bred (ACRB) heritage broiler strain. We injected newly hatched modern broiler and ACRB chicks intraabdominally with CpG oligonucleotide, an immunostimulatory synthetic oligonucleotide. We conducted species-specific kinome array analysis and gene expression analysis on jejunum and cecal tonsil tissue. We also performed metabolic analysis of blood cells. In the modern birds, there is an initial inflammatory response to the injection at d 3 post-hatch with activation of PI3K-Akt, JAK-STAT, and NF-κB signaling, and IL-1β and IL-6 mRNA expression. By d 15 post-hatch this response changed to deactivation and downregulation of these immune responses in modern but not heritage broilers. Metabolic analysis showed an increase in glycolysis in peripheral blood mononuclear cells from modern birds given CpG, but no difference in ACRB. These results show that the ACRB birds may have a less inflammatory and more stable immune profile in response to immune stimulation than the modern broilers, possibly resulting in a more disease resistant phenotype overall.

Poetry evokes emotions. It does so, according to the theory we present, from three sorts of simulation. They each can prompt emotions, which are communications both within the brain and among people. First, models of a poem's semantic contents can evoke emotions as do models that occur in depictions of all kinds, from novels to perceptions. Second, mimetic simulations of prosodic cues, such as meter, rhythm, and rhyme, yield particular emotional states. Third, people's simulations of themselves enable them to know that they are engaged with a poem, and an aesthetic emotion can occur as a result. The three simulations predict certain sorts of emotion, e.g., prosodic cues can evoke basic emotions of happiness, sadness, anger, and anxiety. Empirical evidence corroborates the theory, which we relate to other accounts of poetic emotions.

ABSTRACT: Necrotic enteritis (NE) is a devastating disease that has seen a resurgence of cases following the removal of antibiotics from feed resulting in financial loss and significant animal health concerns across the poultry industry. The objective was to evaluate the efficacy of a microencapsulated blend of organic (25% citric and 16.7% sorbic) acids and botanicals (1.7% thymol and 1% vanillin [AviPlusP]) to reduce clinical NE and determine the signaling pathways associated with any changes. Day-of-hatch by-product broiler breeder chicks were randomly assigned to a control (0) or supplemented (500 g/MT) diet (n = 23–26) and evaluated in a NE challenge model (n = 3). Birds were administered 2X cocci vaccine on d 14 and challenged with a cocktail of Clostridium perfringens strains (107) on d 17 to 19. On d 20 to 21 birds were weighed, euthanized, and scored for NE lesions. Jejunal tissue was collected for kinome analysis using an immuno-metabolism peptide array (n = 5; 15/treatment) to compare tissue from supplement-fed birds to controls. Mortality and weight were analyzed using Student's t test and lesion scores analyzed using F-test two-sample for variances (P < 0.05). The kinome data was analyzed using PIIKA2 peptide array analysis software and fold-change between control and treated groups determined. Mortality in the supplemented group was 47.4% and 70.7% in controls (P = 0.004). Lesions scores were lower (P = 0.006) in supplemented birds (2.47) compared to controls (3.3). Supplement-fed birds tended (P = 0.19) to be heavier (848.6 g) than controls (796.2 g). Kinome analysis showed T cell receptor, TNF and NF-kB signaling pathways contributed to the improvements seen in the supplement-fed birds. The following peptides were significant (P < 0.05) in all 3 pathways: CHUK, MAP3K14, MAP3K7, and NFKB1 indicating their importance. Additionally, there were changes to IL6, IL10, and IFN- γ mRNA expression in tissue between control- and supplement-fed chickens. In conclusion, the addition of a microencapsulated blend of organic acids and botanicals to a broiler diet reduced the clinical signs of NE that was mediated by specific immune-related pathways.

Purpose: To describe an atypical case of necrotizing herpetic retinitis (NHR) that presented initially with mild anterior uveitis, optic disc swelling, and peripapillary serous retinal detachment (SRD). Observations: A 48-year-old Asian Indian man presented with blurred central vision and pain in his left eye. Examination revealed mild anterior chamber inflammation, optic disc swelling, and a peripapillary SRD in the affected eye. Multimodal imaging, including widefield fluorescein angiography, showed optic disc leakage and confirmed the presence of a peripapillary SRD, but was otherwise unremarkable with no evidence of retinitis. The patient was diagnosed with presumed Vogt-Koyanagi-Harada disease and was treated with systemic corticosteroids. While there was objective visual improvement initially, the patient subsequently noted peripheral vision loss and was found to have peripheral necrotizing retinitis and occlusive retinal vasculitis in affected eye. Polymerase chain reaction-based testing of aqueous humor detected varicella zoster virus DNA, confirming the diagnosis of NHR. Conclusion and importance: Optic disc edema and peripapillary SRD may precede the development of overt retinitis in some patients with NHR.

ObjectivesMagnesium sulfate is a second-tier therapy for asthma exacerbations in children; guidelines recommend a single-dose to improve pulmonary function and decrease the odds of admission to the in-patient setting. However, many clinicians utilize prolonged magnesium sulfate infusions for children with refractory asthma. The purpose of this review is to describe the efficacy and safety of magnesium sulfate infusions administered over ≥ 1 h in children with status asthmaticus.MethodsMedline was searched using the keywords “magnesium sulfate” and “children.” Articles evaluating the use of magnesium sulfate infusions for ≥1 h published between 1946 and August 2021 were included. Published abstracts were not included because of lack of essential details. All articles were screened by two reviewers.ResultsEight reports including 447 children were included. The magnesium regimens evaluated included magnesium delivered over 1 h (n = 148; 33.1%), over 4–5 h (n = 105; 23.5%), and over >24 h (n = 194; 43.4%). Majority of patients received a bolus dose of 25–75 mg/kg/dose prior to initiation of a prolonged infusion (n = 299; 66.9%). For the patients receiving magnesium infusions over 4–5 h, the dosing regimen varied between 40 and 50 mg/kg/h. For those receiving magnesium infusions >24 h, the dosing varied between 18.4 and 25 mg/kg/h for a duration between 53.4 and 177.5 h. Only three reports including 186 patients (41.6%) included an evaluation of clinical outcomes including evaluation of lung function parameters, reduction in PICU transfers, and/or decrease in emergency department length of stay. Five reports including 261 patients (58.4%) evaluated magnesium serum concentrations. In most reports, the goal concentrations were between 4 and 6 mg/dL. Only 3 (1.1%) out of the 261 patients had supratherapeutic magnesium concentrations. The only reports finding adverse events attributed to magnesium were noted in those receiving infusions for >24 h. Clinically significant adverse events included hypotension (n = 74; 16.6%), nausea/vomiting (n = 35; 7.8%), mild muscle weakness (n = 22; 4.9%), flushing (n = 10; 2.2%), and sedation (n = 2; 0.4%).ConclusionSignificant variability was noted in magnesium dosing regimens, with most children receiving magnesium infusions over >4 h. Most reports did not assess clinical outcomes. Until future research is conducted, the use of prolonged magnesium sulfate infusions should be reserved for refractory asthma therapy.

The brain maintains cardiovascular homeostasis, in part, via the arterial baroreflex which senses changes in blood pressure (BP) at the level of the aortic arch. Sensory afferents innervating the aortic arch employ baroreceptors to convert stretch exerted on the arterial wall into action potentials carried by the vagus nerve to second order neurons residing within the nucleus of the solitary tract (NTS). Although the baroreflex was described more than 80 years ago, the specific molecular, structural, and functional phenotype of the baroreceptors remain uncharacterized. This is due to the lack of tools that provide the genetic and target organ specificity that is required to selectively characterize baroreceptor afferents. Here, we use a novel approach to selectively target baroreceptors. Male mice on a C57BL/6J background were anesthetized with isoflurane, intubated, and artificially ventilated. Following sternotomy, the aortic arch was exposed, and a retrograde adeno-associated virus was applied to the aortic arch to direct the expression of channelrhoropsin-2 (ChR2) and/or tdTomato (tdTom) to sensory afferents presumably functioning as baroreceptors. Consistent with the structural characteristics of arterial baroreceptors, robust tdTom expression was observed in nerve endings surrounding the aortic arch, within the fibers of the aortic depressor and vagus nerves, cell bodies of the nodose ganglia (NDG), and neural projections to the caudal NTS (cNTS). Additionally, the tdTom labeled cell bodies within the NDG also expressed mRNAs coding for the mechanically gated ion channels, PIEZO-1 and PIEZO-2. In vitro electrophysiology revealed that pulses of blue light evoked excitatory post-synaptic currents in a subset of neurons within the cNTS, suggesting a functional connection between the labeled aortic arch sensory afferents and second order neurons. Finally, the in vivo optogenetic stimulation of the cell bodies of the baroreceptor expressing afferents in the NDG produced robust depressor responses. Together, these results establish a novel approach for selectively targeting sensory neurons innervating the aortic arch. This approach may be used to investigate arterial baroreceptors structurally and functionally, and to assess their role in the etiology or reversal of cardiovascular disease.

The 2019 novel coronavirus pneumonia (COVID-19) is an ongoing global pandemic with a worldwide death toll of over 416,000 as of June 10, 2020. Although the first documented cases in Wuhan, China were patients with severe respiratory symptoms including cough, fever, fatigue, and shortness of breath, the disease process can also be asymptomatic. In this case report, an asymptomatic 63-year-old male with Lynch syndrome undergoing a routine staging fluorodeoxyglucose positron-emission tomography/computed tomography was found to have typical radiologic features of COVID-19 with marked pulmonary FDG uptake and was subsequently diagnosed via reverse-transcription polymerase chain reaction. Many studies have described the appearance of COVID-19 on chest radiography and CT with the most common imaging features being bilateral, peripheral, and basilar predominant ground glass opacities and consolidation. Although these findings are typically nonspecific for an atypical lung infection, early recognition of COVID-19 in the setting of a global pandemic (even in the asymptomatic patient) is critical in order to limit the spread of disease.

The illegal pet trade facilitates the global dispersal of invasive alien species (IAS), providing opportunities for new pests to establish in novel recipient environments. Despite the increasing threat of IAS to the environment and economy, biosecurity efforts often lack suitable, scientifically-based methods to make effective management decisions, such as identifying an established IAS population from a single incursion event. We present a proof-of-concept for a new application of a stable isotope technique to identify wild and captive histories of an invasive pet species. Twelve red-eared slider turtles (Trachemys scripta elegans) from historic Australian incursions with putative wild, captive and unknown origins were analysed to: (1) present best-practice methods for stable isotope sampling of T. s. elegans incursions; (2) effectively discriminate between wild and captive groups using stable isotope ratios; and (3) present a framework to expand the methodology for use on other IAS species. A sampling method was developed to obtain carbon (δ13C) and nitrogen (δ15N) stable isotope ratios from the keratin layer of the carapace (shells), which are predominantly influenced by dietary material and trophic level respectively. Both δ13C and δ15N exhibited the potential to distinguish between the wild and captive origins of the samples. Power simulations demonstrated that isotope ratios were consistent across the carapace and a minimum of eight individuals were required to effectively discriminate wild and captive groups, reducing overall sampling costs. Statistical classification effectively separated captive and wild groups by δ15N (captive: δ15N‰ ≥ 9.7‰, minimum of 96% accuracy). This study outlines a practical and accessible method for detecting IAS incursions, to potentially provide biosecurity staff and decision-makers with the tools to quickly identify and manage future IAS incursions.

Necrotic enteritis (NE) is one of the most common and costly diseases in the modern broiler industry, having an estimated economic impact of $6 billion dollars annually. Increasing incidents of NE have resulted from restrictions on the use of antibiotic feed additives throughout the broiler industry. As such, finding effective antibiotic alternatives has become a priority. In this study, an experimental model of NE was used, comprising a commercial infectious bursal disease virus vaccine and Clostridium perfringens (C. perfringens) inoculation. Yeast cells wall (YCW) components, β-glucan (BG), and mannoproteins (MPTs) were evaluated for their effects on disease development. Chicken-specific immunometabolic kinome peptide arrays were used to measure differential phosphorylation between control (uninfected), challenged (infected), and challenged and treated birds in duodenal, jejunal, and ileal tissues. Treatment groups included crude YCW preparation, BG, MPT, or BG+MPT as feed additives. Data analysis revealed kinome profiles cluster predominantly by tissue, with duodenum showing the greatest relative signaling and jejunum showing the greatest response to treatment. BG, MPT, and BG+MPT cluster together, separate from controls and challenge birds in each tissue. Changes in signaling resulting from the treatments were observed in cell growth and survival responses as well as immune responses. None of the treatments of disease challenge returned the profiles to control-like. This is attributable to immune modulation and metabolic effects of the treatments generating distinct profiles from control. Importantly, all the treatments are distinct from the challenge group despite being challenged themselves. Only BG+MPT treatment had a significant effect on bird weight gain compared with the NE challenge group, and this treatment had the greatest impact on gut tissue signaling in all segments. The signaling changes elicited by BG+MPT during an NE challenge were increased cell growth and survival signaling, reducing cell death, apoptosis and innate inflammatory responses, and generating compensatory signaling to reduce disease severity.

Aging induces cardiovascular disease, but which RNA molecules control cardiac aging is poorly understood. Here the authors identified the aging-regulated non-coding RNA Sarrah, which controls cardiomyocyte survival and cardiac function by inducing cardioprotective genes.

Abstract Background Environmental organic dust exposures enriched in Toll-like receptor (TLR) agonists can reduce allergic asthma development but are associated with occupational asthma and chronic bronchitis. The TLR adaptor protein myeloid differentiation factor88 (MyD88) is fundamental in regulating acute inflammatory responses to organic dust extract (ODE), yet its role in repetitive exposures is unknown and could inform future strategies. Methods Wild-type (WT) and MyD88 knockout (KO) mice were exposed intranasally to ODE or saline daily for 3 weeks (repetitive exposure). Repetitively exposed animals were also subsequently rested with no treatments for 4 weeks followed by single rechallenge with saline/ODE. Results Repetitive ODE exposure induced neutrophil influx and release of pro-inflammatory cytokines and chemokines were profoundly reduced in MyD88 KO mice. In comparison, ODE-induced cellular aggregates, B cells, mast cell infiltrates and serum IgE levels remained elevated in KO mice and mucous cell metaplasia was increased. Expression of ODE-induced tight junction protein(s) was also MyD88-dependent. Following recovery and then rechallenge with ODE, inflammatory mediators, but not neutrophil influx, was reduced in WT mice pretreated with ODE coincident with increased expression of IL-33 and IL-10, suggesting an adaptation response. Repetitively exposed MyD88 KO mice lacked inflammatory responsiveness upon ODE rechallenge. Conclusions MyD88 is essential in mediating the classic airway inflammatory response to repetitive ODE, but targeting MyD88 does not reduce mucous cell metaplasia, lymphocyte influx, or IgE responsiveness. TLR-enriched dust exposures induce a prolonged adaptation response that is largely MyD88-independent. These findings demonstrate the complex role of MyD88-dependent signaling during acute vs. chronic organic dust exposures.

Lysine fatty acylation is an important protein posttranslational modification but mammalian lysine fatty acyl transferases have remained unknown so far. Here the authors report that the human N-terminal glycine myristoyltransferases 1 and 2 catalyze the addition of myristoyl chains to specific lysine residues and show that they myristoylate ARF6 lysine 3, which explains the unusual membrane binding properties of ARF6.

Purpose: To report two cases of vitreoretinal lymphoma that developed following primary testicular lymphoma and review the literature. Observations: Two men, one age 66 and the other age 77, both with a history of diffuse large B-cell testicular lymphoma, diagnosed one and three years previously, respectively, presented with vitritis and yellow-white subretinal infiltrates. Diagnostic vitrectomy in both cases revealed diffuse large B-cell lymphoma. Systemic work up in both cases showed no evidence of disease relapse elsewhere. Each were treated with intravitreal methotrexate injections. Conclusions: Vitreoretinal lymphoma can occur following primary testicular lymphoma, and may mimic primary vitreoretinal lymphoma. Monitoring of patients with a history of testicular lymphoma with regular dilated fundus examinations should be considered.

Abstract Over the last several decades, the study of Earth surface processes has progressed from a descriptive science to an increasingly quantitative one due to advances in theoretical, experimental, and computational geosciences. The importance of geomorphic forecasts has never been greater, as technological development and global climate change threaten to reshape the landscapes that support human societies and natural ecosystems. Here we explore best practices for developing socially relevant forecasts of Earth surface change, a goal we are calling “earthcasting”. We suggest that earthcasts have the following features: they focus on temporal (∼1–∼100 years) and spatial (∼1 m–∼10 km) scales relevant to planning; they are designed with direct involvement of stakeholders and public beneficiaries through the evaluation of the socioeconomic impacts of geomorphic processes; and they generate forecasts that are clearly stated, testable, and include quantitative uncertainties. Earthcasts bridge the gap between Earth surface researchers and decision‐makers, stakeholders, researchers from other disciplines, and the general public. We investigate the defining features of earthcasts and evaluate some specific examples. This paper builds on previous studies of prediction in geomorphology by recommending a roadmap for (a) generating earthcasts, especially those based on modeling; (b) transforming a subset of geomorphic research into earthcasts; and (c) communicating earthcasts beyond the geomorphology research community. Earthcasting exemplifies the social benefit of geomorphology research, and it calls for renewed research efforts toward further understanding the limits of predictability of Earth surface systems and processes, and the uncertainties associated with modeling geomorphic processes and their impacts.

Rift Valley fever virus (RVFV) is a mosquito-borne bunyavirus with a wide host range including ruminants and humans. RVFV outbreaks have had devastating effects on public health and the livestock industry in African countries. However, there is no approved RVFV vaccine for human use in non-endemic countries and no FDA-approved antiviral drug for RVFV treatment. The RVFV 78kDa protein (P78), which is a membrane glycoprotein, plays a role in virus dissemination in the mosquito host, but its biological role in mammalian hosts remains unknown. We generated an attenuated RVFV MP-12 strain-derived P78-High virus and a virulent ZH501 strain-derived ZH501-P78-High virus, both of which expressed a higher level of P78 and carried higher levels of P78 in the virion compared to their parental viruses. We also generated another MP-12-derived mutant virus (P78-KO virus) that does not express P78. MP-12 and P78-KO virus replicated to similar levels in fibroblast cell lines and Huh7 cells, while P78-High virus replicated better than MP-12 in Vero E6 cells, fibroblast cell lines, and Huh7 cells. Notably, P78-High virus and P78-KO virus replicated less efficiently and more efficiently, respectively, than MP-12 in macrophage cell lines. ZH501-P78-High virus also replicated poorly in macrophage cell lines. Our data further suggest that inefficient binding of P78-High virus to the cells led to inefficient virus internalization, low virus infectivity and reduced virus replication in a macrophage cell line. P78-High virus and P78-KO virus showed lower and higher virulence than MP-12, respectively, in young mice. ZH501-P78-High virus also exhibited lower virulence than ZH501 in mice. These data suggest that high levels of P78 expression attenuate RVFV virulence by preventing efficient virus replication in macrophages. Genetic alteration leading to increased P78 expression may serve as a novel strategy for the attenuation of RVFV virulence and generation of safe RVFV vaccines.

The Interior of Alaska is one of the few remaining places in the world with intact ecosystems. Protected areas in this region, particularly Denali National Park and Preserve and Denali State Park, are high-profile tourism destinations situated in a rural landscape that is inhabited by a diverse array of stakeholders. Public land management agencies are faced with the challenging task of engaging these rural residents in discussions about their relationships with a rapidly changing landscape to understand change and growth. This study evaluated residents’ perceptions of social and ecological dynamics of protected areas in Interior Alaska using data from fuzzy cognitive mapping exercises that were part of focus groups and interviews across six local communities. Guided by an exploratory resilience framework, we established a baseline understanding of features that characterized social and ecological conditions at a regional scale. Results showed how residents valued a variety of socio-cultural, socioeconomic, and ecological features of the landscape. The region was predominantly characterized by tourism, sense of community, subsistence, and wilderness. Climate change and large-scale development were the primary drivers of change. Our findings also showed that although the characterization of the region was shared in many ways, there were nuanced differences articulated by residents in each community that warrant attention. These findings provide a structured platform for building resilience and interpreting variability in visions for the future.

Quantum tomographic techniques enable the complete characterisation of continuous variable quantum states. Here the authors demonstrate a broadband tomography protocol for single electrons that goes beyond the bandwidth restrictions of existing methods.

Physiologically‐based pharmacokinetic (PBPK) modeling allows assessment of the covariates contributing to the large pharmacokinetic (PK) variability of tacrolimus; these include multiple physiological and biochemical differences among patients. A PBPK model of tacrolimus was developed, including a virtual population with physiological parameter distributions reflecting renal transplant patients. The ratios of predicted to observed dose‐normalized maximum plasma concentration (Cmax), 0–12‐hour area under the concentration–time curve (AUC0–12 hour), and trough plasma concentration (Ctrough) ranged from 0.92‐fold to 1.15‐fold, indicating good predictive performance. The model quantitatively indicated the impact of cytochrome P450 (CYP)3A4 abundance, hematocrit, and serum albumin levels, in addition to CYP3A5 genotype status, on tacrolimus PK and associated variability. Age‐dependent change in tacrolimus trough concentration in pediatric patients was mainly attributed to the CYP3A ontogeny profile. This study demonstrates the utility of PBPK modeling as a tool for mechanistic and quantitative assessment of the impact of patient physiological differences on observed large PK variability.