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Abstract Up to 40% of patients with estrogen receptor (ER)-positive breast cancer will develop resistance against the majority of current ER-directed therapies. Resistance can arise through various mechanisms such as increased expression levels of coregulators, and key mutations acquired in the receptor’s ligand binding domain rendering it constitutively active. To overcome these resistance mechanisms, we explored targeting the ER Activation Function 2 (AF2) site, which is essential for coactivator binding and activation. Using artificial intelligence and the deep docking methodology, we virtually screened > 1 billion small molecules and identified 290 potential AF2 binders that were then characterized and validated through an iterative screening pipeline of cell-based and cell-free assays. We ranked the compounds based on their ability to reduce the transcriptional activity of the estrogen receptor and the viability of ER-positive breast cancer cells. We identified a lead compound, VPC-260724, which inhibits ER activity at low micromolar range. We confirmed its direct binding to the ER-AF2 site through a PGC1α peptide displacement experiment. Using proximity ligation assays, we showed that VPC-260724 disrupts the interaction between ER-AF2 and the coactivator SRC-3 and reduces the expression of ER target genes in various breast cancer models including the tamoxifen resistant cell line TamR3. In conclusion, we developed a novel ER-AF2 binder, VPC-260724, which shows antiproliferative activity in ER-positive breast cancer models. The use of an ER-AF2 inhibitor in combination with current treatments may provide a novel complementary therapeutic approach to target treatment resistance in ER-positive breast cancer.

The consensus tracking problem of leader-follower multi-agent systems (MASs) with singular structures on jointly connected topology is studied in this paper. To achieve the objective of consensus tracking, a distributed adaptive control protocol is formulated to adjust the coupling weights among the agents using the adaptive rate, where the adaptive protocol can be implemented by each agent in a fully distributed manner without using any global information. A fuzzy logic system method is used to deal with the nonlinear terms in response to the limitations of nonlinear system analysis. The consensus tracking problem is transformed into an error system stability analysis, and two sufficient conditions are provided to guarantee the control objective based on Lyapunov stability theory and singular system theory. Finally, the effectiveness of this method is verified through a simulation example.

The post-total laryngectomy airway poses perioperative challenges to anesthesia management. While endobronchial intubation is a cited complication, a low-lying stoma may increase this risk. Furthermore, the stoma’s proximity to a median sternotomy increases surgical and airway management complexity. This report highlights a case of endobronchial intubation in a patient with a low-lying stoma who presented for coronary artery bypass graft. With a stoma at the upper border of the sternum, intraoperative innovation was required to prevent endobronchial intubation while remaining out of the surgical field. This innovation may be useful in urgent surgical situations.

Diffuse optical spectroscopy (DOS) techniques characterize scattering media by examining their optical response to laser illumination. Time-domain DOS methods involve illuminating the medium with a laser pulse and using a fast photodetector to measure the time-dependent intensity of light that exits the medium after multiple scattering events. While DOS research traditionally focused on characterizing biological tissues, we demonstrate that time-domain diffuse optical measurements can also be used to characterize snow. We introduce a model that predicts the time-dependent reflectance of a dry snowpack as a function of its density, grain size, and black carbon content. We develop an algorithm that retrieves these properties from measurements at two wavelengths. To validate our approach, we assembled a two-wavelength lidar system to measure the time-dependent reflectance of snow samples with varying properties. Rather than measuring direct surface returns, our system captures photons that enter and exit the snow at different points, separated by a small distance (4–10 cm). We observe clear, linear correlations between our retrievals of density and black carbon concentration, and ground truth. For black carbon concentration the correlation is nearly one-to-one. We also find that our method is capable of distinguishing between small and large grain sizes.

Background 3D printed implant surgical guides are designed to improve implant placement accuracy. However, they are a potential source of contamination during implant surgery and therefore require sterilization to prevent post-surgical infection. This study evaluated the effect that steam sterilizing 3D printed implant surgical guides has on the accuracy of fully guided implant placement.Methods 3D printed models were prepared with an edentulous site at the right maxillary central incisor. A surgical guide was designed and fabricated to place a bone level implant at this edentulous site. Ten implants were placed with surgical guides, followed by ten placed with the same guides after autoclave sterilization at 134°C for 6 minutes. Implants were scanned and analyzed using three-dimensional analysis software. The implant platform position, apex position, and angulation were evaluated before and after sterilization of the surgical guides.Results There were statistically significant deviations of implant platform and apex in the x-axis (bucco-lingual), y-axis (mesio-distal), and implant angulation (Wilcoxon signed-rank test, p

The objective of this study was to determine the effect of increasing hot carcass weight (HCW) on pork ham and belly processing characteristics. Pigs (n = 85) were slaughtered and divided into 3 HCW categories: Average (99 to 109 kg), Heavy (116 to 126 kg), and Very Heavy (134 to 144 kg). Fresh hams were fabricated and further processed as 3-piece (inside, outside, and knuckle) boneless cured hams. Fresh belly quality measurements were taken before bacon processing. Data were analyzed using the MIXED procedure in SAS including the main effect of weight class, with sex and sire line as random blocking effects. Means were considered significant at P ≤ 0.05. There were no differences (P = 0.08) in ham processing characteristics including pump uptake, retention, and cook yield. However, cured hams from heavier car- casses were less red and less yellow (P < 0.01). Heavier carcasses produced longer, thicker, and wider bellies (P < 0.01), but bellies did not differ in firmness (P = 0.16). Despite reduced pump uptake (P < 0.01), bellies from heavier carcasses had greater cooked yield than those from lighter carcasses (P < 0.01). Total area of sliced bacon increased with increasing carcass weight. Bacon slice lean area percentage decreased (P < 0.01) in bacon from Very Heavy carcasses compared to lighter carcasses. Iodine value was decreased (P = 0.04) approximately 2.5 units from 68.6 in fresh bellies from Average carcasses to 66.2 in bellies from Very Heavy carcasses. Overall, processing characteristics of hams and bellies were not impaired at heavier carcass weights, though the consumer acceptability of larger slices of bacon from heavier carcasses should be determined.

Piper crassinervium Kunth (Piperaceae) essential oil (EO) was evaluated for its toxicity and repellency against red imported fire ants (RIFA), Solenopsis invicta Buren, and a hybrid (HIFA) of red (S. invicta) and black (S. richteri Forel) imported fire ants. Through bioactivity-guided fractionation, two major components, elemicin and myristicin, were isolated from the EO. Removal of treated sand in a digging bioassay was used as the criterion for repellency. The EO showed significantly higher repellency at concentrations of 7.8 µg/g against RIFA and HIFA workers, as compared to the DEET (N,N-diethyl-meta-toluamide) or ethanol control. Elemicin exhibited repellency at 3.9 and 7.8 µg/g against RIFA and HIFA workers, respectively, whereas myristicin was active at 7.8 µg/g against both species. DEET failed at 31.25 µg/g against RIFA and 15.6 µg/g against HIFA. The EO showed LC50 values of 97.9 and 73.7 µg/g against RIFA and HIFA workers, respectively. Myristicin was more toxic against RIFA and HIFA with LC50 values of 54.3 and 35.3 µg/g, respectively. Elemicin showed 20–40% mortality at the highest screening dose of 125 µg/g. Fipronil exhibited the highest toxicity against RIFA and HIFA, with LC50 of 0.43 and 0.51 µg/g, respectively. Different formulations of these natural products should be evaluated to explore their use potential under natural field conditions.

The objective was to characterize the effects of increasing carcass weight on pork carcass characteristics and yields from traditional and alternative fabrication methods, as well as evaluate the size of novel retail cuts. Pigs (n = 85) were slaughtered and divided into 3 hot carcass weight (HCW) categories: Average (99 to 109 kg), Heavy (116 to 126 kg), and Very Heavy (134 to 144 kg). Loin muscle area (LMA) and back fat depth were measured on all carcasses. Paired right and left sides were fabricated traditionally and alternatively (shoulder separation at the 4th/5th rib), respectively. From the alternative side, the serratus ventralis (SV) was removed from the cellar-trimmed butt, and the triceps brachii (TB) was removed from the picnic shoulder. All individual primals and subprimals were weighed for yield calculations. Data were analyzed using the MIXED procedure in SAS including the main effect of weight class, with sex and sire line as fixed blocking effects. Differences were considered significant at P ≤ 0.05. Regardless of fabrication method, whole primal and subprimal weights increased (P < 0.01) in heavier carcass weight classes compared with lighter classes, but when expressed as a percentage of chilled side weight, these increases did not often translate into meaningful differences in distribution of carcass weight. While the alternative shoulder-loin separation reduced loin and belly length, loins and bellies from heavier carcasses weighed more than those from carcasses typically produced in the U.S. pork industry today. Serratus ventralis weight was increased (P < 0.01) approximately 0.28 kg from Average to Very Heavy, while the TB weight was increased (P < 0.01) approximately 0.24 kg from Average to Very Heavy. At heavier weights, alternative fabrication of carcasses yielded novel cuts from the shoulder including the SV and TB that were of size to warrant further exploration as retail offerings.

Background: The consequences for children born with birth defects and developmental disabilities encompassed by foetal alcohol spectrum disorder (FASD) are profound, affecting all areas of social, behavioural and cognitive functioning. Given the strong evidence for a core deficit in executive functioning, underpinned by impaired self-regulation skills, there has been a growing focus on the development of interventions that enhance or support the development of executive functions (EFs). Objectives: The primary objective of this review is to synthesise the evidence for structured psychological interventions that explicitly aim to improve EF in children. The review also sought to ascertain if the effectiveness of interventions were influenced by characteristics of the intervention, participants or type of EF targeted by the intervention. Search Methods: Sixteen databases, 18 grey literature search locations and 9 trial registries were systematically searched to locate eligible studies (up to December 2020). These searches were supplemented with reference harvesting, forward citation searching, hand searches of topic-relevant journals and contact with experts. Selection Criteria: Studies were included in the review if they reported on an impact evaluation of a psychological intervention aiming to improve EF in children 3-16 years who either had confirmed prenatal alcohol exposure or a formal diagnosis falling under the umbrella term of FASDs. Eligible study designs included randomised controlled trials (RCTs) and quasi-experimental designs with either no treatment, wait list control or an alternative treatment as a comparison condition. Single-group pre-post designs were also included. Data Collection and Analysis: Standard methodological procedures expected by the Campbell Collaboration were used at all stages of this review. Standardised mean differences (SMDs) were used to estimate intervention effects, which were combined with random effects meta-analysis (data permitting). Risk of bias was assessed using the Cochrane Risk of Bias Tool (RoB2) and Cochrane Risk of Bias in Non-Randomised Studies-Interventions tool (ROBINS-I). Main Results: The systematic search identified 3820 unique records. After title/abstract and full-text screening, 11 eligible studies (reported in 21 eligible documents) were deemed eligible, with a combined 253 participants. Of the 11 studies, 6 were RCTs, 1 was a quasi-experiment and 4 were single-group pre-post intervention designs. All studies were rated as having an overall high or serious risk of bias, with some variation across domains for RCTs. For RCT and quasi-experimental studies, the overall effect of EF interventions on direct and indirect measures of EF generally favoured the experimental condition, but was not statistically significant. There was no difference between intervention and comparison groups on direct measures of auditory attention (k = 3; SMD = 0.06, 95% confidence interval [CI] = -1.06, 1.18), visual attention (k = 2; SMD = 0.90, 95% CI = -1.41, 3.21), cognitive flexibility (k = 2; SMD = 0.23, 95% CI = -0.40, 0.86), attentional inhibition (k = 2; SMD = 0.04, 95% CI = -0.58, 0.65), response inhibition (k = 3; SMD = 0.47, 95% CI = -0.04, 0.99), or verbal working memory (k = 1; d = 0.6827; 95% CI = -0.0196, 1.385). Significant heterogeneity was found across studies on measures of auditory attention and visual attention, but not for measures of cognitive flexibility, attentional inhibition or response inhibition. Available data prohibited further exploration of heterogeneity. There was no statistical difference between intervention and comparison groups on indirect measures of global executive functioning (k = 2; SMD = 0.21, 95% CI = -0.40, 0.82), behavioural regulation (k = 2; SMD = 0.18, 95% CI = -0.43, 0.79), or emotional control (k = 3; SMD = 0.01, 95% CI = -0.33, 0.36). Effect sizes were positive and not significant for meta-cognition (k = 1; SMD = 0.23, 95% CI = -0.72, 1.19), shifting (k = 2; SMD = 0.04, 95% CI = -0.35, 0.43), initiation (k = 1; SMD = 0.04, 95% CI = -0.40, 0.49), monitoring (k = 1; SMD = 0.25, 95% CI = -0.20, 0.70) and organisation of materials (k = 1; SMD = 0.25, 95% CI = -0.19, 0.70). Effect sizes were negative and not statistically different for effortful control (k = 1; SMD = -0.53, 95% CI = -1.50, 0.45), inhibition (k = 2; SMD = -0.08, 95% CI = -0.47, 0.31), working memory (k = 1; SMD = 0.00, 95% CI = -0.45, 0.44), and planning and organisation (k = 1; SMD = -0.10, 95% CI = -0.55, 0.34). No statistically significant heterogeneity was found for any of the syntheses of indirect measures of EF. Based on pre-post single-group designs, there was evidence for small to medium sized improvements in EF based on direct measures (cognitive flexibility, verbal working memory and visual working memory) and indirect measures (behavioural regulation, shifting, inhibition and meta-cognition). However, these results must be interpreted with caution due to high risk of bias. Authors' Conclusions: This review found limited and uncertain evidence for the effectiveness of interventions for improving executive functioning in children with FASD across 8 direct and 13 indirect measures of EF. The findings are limited by the small number of high-quality studies that could be synthesised by meta-analysis and the very small sample sizes for the included studies.

Abstract Background Recent progress in cancer immunotherapy encourages the expansion of chimeric antigen receptor (CAR) T cell therapy in solid tumors including hepatocellular carcinoma (HCC). Overexpression of MET receptor tyrosine kinase is common in HCC; however, MET inhibitors are effective only when MET is in an active form, making patient stratification difficult. Specific MET-targeting CAR-T cells hold the promise of targeting HCC with MET overexpression regardless of signaling pathway activity. Methods MET-specific CARs with CD28ζ or 4-1BBζ as co-stimulation domains were constructed. MET-CAR-T cells derived from healthy subjects (HS) and HCC patients were evaluated for their killing activity and cytokine release against HCC cells with various MET activations in vitro, and for their tumor growth inhibition in orthotopic xenograft models in vivo. Results MET-CAR.CD28ζ and MET-CAR.4-1BBζ T cells derived from both HS and HCC patients specifically killed MET-positive HCC cells. When stimulated with MET-positive HCC cells in vitro, MET-CAR.CD28ζ T cells demonstrated a higher level of cytokine release and expression of programmed cell death protein 1 (PD-1) than MET-CAR.4-1BBζ T cells. When analyzed in vivo, MET-CAR.CD28ζ T cells more effectively inhibited HCC orthotopic tumor growth in mice when compared to MET-CAR.4-1BBζ T cells. Conclusion We generated and characterized MET-specific CAR-T cells for targeting HCC with MET overexpression regardless of MET activation. Compared with MET-CAR.4-1BBζ, MET-CAR.CD28ζ T cells showed a higher anti-HCC potency but also a higher level of T cell exhaustion. While MET-CAR.CD28ζ is preferred for further development, overcoming the exhaustion of MET-CAR-T cells is necessary to improve their therapeutic efficacy in vivo.

People who consume high quantities of seafood are at a heightened risk for marine biotoxin exposure. Coastal Indigenous peoples may experience higher levels of risk than the general population due to their reliance on traditional marine foods. Most evidence on the health risks associated with biotoxins focus on a single exposure at one point in time. There is limited research on other types of exposures that may occur among those who regularly consume large quantities of seafood. The objective of this review is to assess what is known about the unique biotoxin exposure risks associated with the consumption patterns of many coastal Indigenous populations. These risks include [1]: repeated exposure to low doses of a single or multiple biotoxins [2]; repeated exposures to high doses of a single or multiple biotoxins; and [3] exposure to multiple biotoxins at a single point in time. We performed a literature search and collected 23 recent review articles on the human health effects of different biotoxins. Using a narrative framework synthesis approach, we collated what is known about the health effects of the exposure risks associated with the putative consumption patterns of coastal Indigenous populations. We found that the health effects of repeated low- or high-dose exposures and the chronic health effects of marine biotoxins are rarely studied or documented. There are gaps in our understanding of how risks differ by seafood species and preparation, cooking, and consumption practices. Together, these gaps contribute to a relatively poor understanding of how biotoxins impact the health of those who regularly consume large quantities of seafood. In the context of this uncertainty, we explore how known and potential risks associated with biotoxins can be mitigated, with special attention to coastal Indigenous populations routinely consuming seafood. Overall, we conclude that there is a need to move beyond the single-dose single-outcome model of exposure to better serve Indigenous communities and others who consume high quantities of seafood.

Soybean is one of the most economically important crops worldwide. However, soybean yield can be substantially decreased by many diseases. Soybean genotypes could have different reactions to pathogen infection. As a first step toward investigating the biochemical basis of soybean resistance and susceptibility to disease, phytochemicals in the seeds of 52 soybean genotypes previously reported to have different reactions to diseases of soybean rust (SBR), Phomopsis seed decay (PSD), and purple seed stain (PSS) were analyzed. Using GC-MS, a total of 46 compounds were tentatively identified which included 11 chemical groups. Among those, the major group was esters, followed by carboxylic acid, ketone, and sugar moieties. Compounds having reported antioxidant, anti-microbial, and anti-inflammatory activities were also identified. UHPLC-DAD/MS analysis indicated that there were five major isoflavone components presented in the samples, including daidzin, glycitin, genistin, malonyldaidzin, and malonylglycitin. Isoflavones have been reported to play an important role in defense from plant pathogens. Although there was variance in the isoflavone content among soybean genotypes, those with the SBR resistance Rpp6 gene (PI 567102B, PI 567104B, PI 567129) consistently exhibited the highest concentrations of daidzin, glycitin, genistin, and malonyldaidzin. The SBR resistant genotype, PI 230970 (Rpp2) had the greatest amount of genistin. The SBR resistant genotype, PI 200456 (Rpp5) resistant genotype uniquely contained glycitein, a compound that was absent in the other 51 genotypes examined. A PSD-resistant genotype PI 424324B had nearly four times the amount of stigmasterol as PI 556625, which was susceptible to SBR, PSD, and PSS in our previous tests. Results of this study provide useful information for further investigation of the biochemical basis of soybean resistance to diseases. The results may also aid in selection of soybean lines for breeding for resistance to soybean rust and other diseases.

Study Design Retrospective cohort. Purpose To determine (1) the effects of serotonin reuptake inhibitors in pseudarthrosis rates after anterior cervical decompression and fusion (ACDF) and (2) to identify patient-reported outcome measures in patients taking serotonin reuptake inhibitors. Overview of Literature Recent literature suggests that selective serotonin reuptake inhibitors (SSRIs) may inhibit fracture healing via downregulation of osteoblast differentiation. Spinal fusion supplementation with osteoblast-rich substances enhances spinal fusion, thus SSRIs may be detrimental. Methods Patients with 1-year postoperative dynamic cervical spine radiographs following ACDF were grouped into serotonin reuptake inhibitor prescriptions (SSRI, serotonin-norepinephrine reuptake inhibitor [SNRI], or tricyclic antidepressant [TCA]) and no prescription (atypical antidepressant or no antidepressant). Pseudarthrosis was defined as ≥1 mm interspinous process motion on dynamic radiographs. Logistic regression models were controlled for confounding to analyze pseudarthrosis rates. Alpha was set at p-values of

Abstract Background Due to relatively low malaria parasitaemia in pregnancy, an appropriate field test that can adequately detect infections in pregnant women presenting with illness or for malaria screening during antenatal care is crucially important. The objective was to evaluate the diagnostic accuracy of loop-mediated isothermal amplification (LAMP) for the detection of uncomplicated malaria in pregnancy. Methods This was a meta-analysis of diagnostic accuracy. Relevant studies that assessed the diagnostic performance of LAMP for the detection of malaria in pregnancy were searched in health-related electronic databases including PubMed, Ovid, and Google Scholar. The methodological quality of the studies included was evaluated using the QUADAS-2 tool. Results Of the 372 studies identified, eight studies involving 2999 pregnant women in five endemic countries that assessed the accuracy of LAMP were identified. With three types of PCR as reference tests, the pooled sensitivity of LAMP was 91% (95%CI 67–98%) and pooled specificity was 99% (95%CI 83–100%, 4 studies), and the negative likelihood ratio was 9% (2–40%). Caution is needed in the interpretation as there was substantial between-study heterogeneity (I 2: 80%), and a low probability that a person without infection is tested negative. With microscopy as a reference, the pooled sensitivity of LAMP was 95% (95%CI 26–100%) and pooled specificity was 100% (95%CI 94–100%, 4 studies). There was a wide range of sensitivity and substantial between-study heterogeneity (I 2 : 83.5–98.4%). To investigate the source of heterogeneity, a meta-regression analysis was performed with covariates. Of these potential confounding factors, reference test (p: 0.03) and study design (p:0.03) had affected the diagnostic accuracy of LAMP in malaria in pregnancy. Overall, there was a low certainty of the evidence in accuracy estimates. Conclusion The findings suggest that LAMP is more sensitive than traditional tests used at facilities, but the utility of detecting and treating these low-density infections is not well understood. Due to the limited number of studies with bias in their methodological quality, variation in the study design, and different types of reference tests further research is likely to change the estimate. Well-conceived large prospective studies with blinding of the index test results are recommenced.

Background : The year 2022 marks the 30th anniversary of heart transplant service in Hong Kong (HK). In this study, we describe prevailing trends and outcomes of advanced heart failure (AHF), including heart transplantations (HTx), in HK over the past 30 years. Methods : Trends in heart failure prevalence in HK from 1993 to 2021 were analyzed based on data from the Hospital Authority Clinical Data and Reporting System. All AHF patients referred for HTx consideration between 1992 and 2021 were reviewed. The bridge-to-transplant (BTT) utilization of short-term mechanical circulatory support (ST-MCS) devices, including venoarterial extracorporeal membrane oxygenation (VA-ECMO) and durable left ventricular assist devices (LVADs), from 2010 to 2021 was reviewed. Results : Overall, 237 heart transplants were performed in HK, with 10-year posttransplant and median survival of 68.1% and 18.7 years, respectively. An increase in AHF clinic referrals was correlated with increasing heart failure prevalence (R2=0.635, P

Abstract Commercially cultivated Limnospira (species formerly classified to genus Arthrospira) is a popular food/supplement consumed by millions of people worldwide for health benefits. The objective of the current research was to advance the standardization technology for Limnospira. Quantitative methods were established to detect fatty acids as potential chemical markers and immune-enhancing activity. Analysis of 20 different batches of biomass obtained from one commercial grower demonstrated that there was a statistically significant relationship between the sum of two fatty acids (linoleic and γ-linolenic) and Toll-like receptor (TLR)2/TLR1-dependent activation (R 2 = 0.48, p = 0.0007). Investigation of 12 biomass samples sourced from growers in 10 different countries demonstrated that fatty acid content was again significantly correlated with biological activity (R 2 = 0.72, p = 0.0005) and the content of fatty acids varied by twofold and activity by 12.5-fold. This large variation between different samples confirms the need to use the present standardization methods to ensure consistent and properly characterized biomass for consumers and for future scientific research.

Key Clinical Message Serotonin syndrome can be a life‐threatening condition that occurs from the overactivity of serotonin in the central nervous system. This report describes the use of cyproheptadine for the management of serotonin syndrome in a patient taking fluoxetine and bupropion, who received methylene blue for vasoplegia syndrome. A 61‐year‐old female taking fluoxetine and bupropion preoperatively was given a total of three doses of methylene blue 100 mg IV within a brief time frame during and after a planned coronary artery bypass graft surgery. Postoperatively, the patient was not following commands, was agitated and confused, febrile with diaphoresis, tachycardic, had muscle rigidity, and horizontal ocular clonus. The patient's presentation was most consistent with serotonin syndrome due to a drug–drug interaction. Cyproheptadine and supportive care were used successfully to treat serotonin syndrome, and the patient was discharged home 14 days postoperatively. Based on the literature, there is no standardized method of weaning cyproheptadine when used for serotonin syndrome. The patient in our case received a total of 188 mg of cyproheptadine over the course of 10 days and did not experience any side effects. This case highlights a potential dosing regimen that can be used for other patients.

Abstract In this paper, we find the optimal transmission of messages in computer networks. This problem has been formulated as a nondelayed optimal control problem in several recent papers on TCP (transmission control protocol). Since the actual transmission of messages from origins to destinations should consist of both forward transmission delays of the buffers and latency of the links, we remodel the problem as a time-delayed optimal control problem consisting of both control-dependent time-delayed arguments and discrete time-delayed arguments. We then develop a modified control parameterization method for solving this time-delayed optimal control problem. The gradients of the new objective function and constraint functions generated by this modified control parametrization method are derived. A numerical example is solved by using the time-delayed version of the problem that we formulate, as well as the nondelayed version of the problem in the literature. Numerical results clearly illustrate the efficiency of the modified control parameterization method for solving both versions of this optimal transmission problem. Comparison of results of the two versions concerning the optimal transmission rates at the origins, the optimal output flow rates at the destination, and the queue sizes at the buffers are obtained. These comparison results clearly reflect how the optimal transmission of messages in computer networks in real life can be affected by both the forward transmission delays of the buffers and the latency of the links.

Catholic entities are being sued for personal injury compensation arising from sexual abuse perpetrated by church personnel. In some jurisdictions, the situation has deteriorated because of changes to the statute of limitations, the naming of an entity to sue, the setting aside of previous settlements, and abuse compensation law firms. Oftentimes there are overstated, doubtful or apparently false claims, and disturbing decisions. There is a feeling of being cornered with minimal prospects for change. How and what does the Church communicate when its predicament is frequently not ‘right and just?’ This article scrutinizes such powerlessness using the Magisterium of the Catholic Church on the truth of social communications. The Church insists on a proper understanding of truth and its uses. Despite the new adverse realities, the Church’s responses should communicate the truth in love. The article begins an analysis of various factors and recent changes causing the Church to find itself in a no-win situation. Next, several significant yet alternative perspectives are presented. Finally, there is an investigation of the magisterial teachings of the Catholic Church on the truth of social communications which offer a theological context to rethink the Church’s current circumstances.

Oxidosqualene cyclases (OSCs) are the key enzymes accountable for the cyclization of 2,3-oxidosqualene to varied triterpenoids and phytosterols. Hoodia gordonii (from the family Apocynaceae), a native of the Kalahari deserts of South Africa, Namibia, and Botswana, is being sold as a prevalent herbal supplement for weight loss. The appetite suppressant properties are attributed to P57AS3, an oxypregnane steroidal glycoside. At the molecular level, the enzymes involved in the biosynthesis of triterpenes and phytosterols from H. gordonii have not been previously reported. In the current study, predicted transcripts potentially encoding oxidosqualene cyclases were recognized first by searching publicly available H. gordonii RNA-seq datasets. Two OSC-like sequences were selected for functional analysis. A monofunctional OSC, designated HgOSC1 which encodes lupeol synthase, and HgOSC2, a multifunctional cycloartenol synthase forming cycloartenol and other products, were observed through recombinant enzyme studies. These studies revealed that distinct OSCs exist for triterpene formation in H. gordonii and provided opportunities for the metabolic engineering of specific precursors in producing phytosterols in this plant species.

The health risks associated with wildfires are expected to increase due to climate change. Children are susceptible to wildfire smoke, but little is known about indoor smoke exposure at childcare facilities. The objective of this analysis was to estimate the effects of outdoor PM _2.5 and wildfire smoke episodes on indoor PM _2.5 at childcare facilities across British Columbia, Canada. We installed low-cost air-quality sensors inside and outside 45 childcare facilities and focused our analysis on operational hours (Monday–Friday, 08:00–18:00) during the 2022 wildfire season (01 August–31 October). Using random-slope random-intercept linear mixed effects regression, we estimated the overall and facility-specific effects of outdoor PM _2.5 on indoor PM _2.5 , while accounting for covariates. We examined how wildfire smoke affected this relationship by separately analyzing days with and without wildfire smoke. Average indoor PM _2.5 increased by 235% on wildfire days across facilities. There was a positive relationship between outdoor and indoor PM _2.5 that was not strongly influenced by linear adjustment for meteorological and area-based socio-economic factors. A 1.0 μ g m ^−3 increase in outdoor PM _2.5 was associated with a 0.55 μ g m ^−3 [95% CI: 0.47, 0.63] increase indoors on non-wildfire smoke days and 0.51 μ g m ^−3 [95% CI: 0.44, 0.58] on wildfire-smoke days. Facility-specific regression coefficients of the effect of outdoor PM _2.5 on indoor PM _2.5 was variable between facilities on wildfire (0.18–0.79 μ g m ^−3 ) and non-wildfire days (0.11–1.03 μ g m ^−3 ). Indoor PM _2.5 responded almost immediately to increased outdoor PM _2.5 concentrations. Across facilities, 89% and 93% of the total PM _2.5 infiltration over 60 min occurred within the first 10 min following an increase in outdoor PM _2.5 on non-wildfire and wildfire days, respectively. We found that indoor PM _2.5 in childcare facilities increased with outdoor PM _2.5 . This effect varied between facilities and between wildfire-smoke and non-wildfire smoke days. These findings highlight the importance of air quality monitoring at childcare facilities for informed decision-making.

Abstract Western North America experienced an unprecedented extreme heat event (EHE) in 2021, characterized by high temperatures and reduced air quality. There were approximately 740 excess deaths during the EHE in the province of British Columbia, making it one of the deadliest weather events in Canadian history. It is important to understand who is at risk of death during EHEs so that appropriate public health interventions can be developed. This study compares 1,614 deaths from 25 June to 02 July 2021 with 6,524 deaths on the same dates from 2012 to 2020 to examine differences in the prevalence of 26 chronic diseases between the two groups. Conditional logistic regression was used to estimate the odds ratio (OR) for each chronic disease, adjusted for age, sex, and all other diseases, and conditioned on geographic area. The OR [95% confidence interval] for schizophrenia among all EHE deaths was 3.07 [2.39, 3.94], and was larger than the ORs for other conditions. Chronic kidney disease and ischemic heart disease were also significantly increased among all EHE deaths, with ORs of 1.36 [1.18, 1.56] and 1.18 [1.00, 1.38], respectively. Chronic diseases associated with EHE mortality were somewhat different for deaths attributed to extreme heat, deaths with an unknown/pending cause, and non‐heat‐related deaths. Schizophrenia was the only condition associated with significantly increased odds of EHE mortality in all three subgroups. These results confirm the role of mental illness in EHE risk and provide further impetus for interventions that target specific groups of high‐risk individuals based on underlying chronic conditions.

Aims:: The terminology of obstetric pelvic floor disorders should be defined and reported as part of a wider clinically oriented consensus. Methods:: This Report combines the input of members of two International Organizations, the International Continence Society (ICS) and the International Urogynecological Association (IUGA). The process was supported by external referees. Appropriate clinical categories and a sub-classification were developed to give coding to definitions. An extensive process of 12 main rounds of internal and 2 rounds of external review was involved to exhaustively examine each definition, with decision-making by consensus. Results:: A terminology report for obstetric pelvic floor disorders, encompassing 357 separate definitions, has been developed. It is clinically-based with the most common diagnoses defined. Clarity and user-friendliness have been key aims to make it usable by different specialty groups and disciplines involved in the study and management of pregnancy, childbirth and female pelvic floor disorders. Clinical assessment, investigations, diagnosis, conservative and surgical treatments are major components. Illustrations have been included to supplement and clarify the text. Emerging concepts, in use in the literature and offering further research potential but requiring further validation, have been included as an appendix. As with similar reports, interval (5–10 year) review is anticipated to maintain relevance of the document and ensure it remains as widely applicable as possible. Conclusion:: A consensus-based Terminology Report for obstetric pelvic floor disorders has been produced to support clinical practice and research.

The parable of the Prodigal Son in Luke 15 elicits profound responses and emotions in various times, places, and cultures. Why has it stood the test of time as one of Jesus’ most famous parables? One possible answer is that the story carries enduring appeal because of the underlying structure of the parable, a recurring pattern in literature called the monomyth. Peeling back the layers of the parable, one may uncover the foundational archetypes of the parable that make it timeless. Hidden significance of the parable may be illuminated by comparing its narrative to the hero quest of Joseph Campbell and the monomyth archetypes of Northrop Frye and Leland Ryken, both of which emphasize a cyclical movement that unifies all of literature. Also important are the specific archetypes within the general monomyth archetype, such as father and mother, bread and water. The parable also contains the four elements (mythoi) of the circular monomyth: romance, tragedy, anti-romance, and comedy. Using archetypal and myth criticism, this article demonstrates that the parable has enduring attraction because its underlying archetypes appeal to a deep layer of the human psyche and to what is elemental to the human experience.

Background: The coronavirus disease-2019 (COVID-19) pandemic significantly affected management of cardiovascular disease around the world. The effect of the pandemic on volume of cardiovascular diagnostic procedures is not known. Objectives: This study sought to evaluate the effects of the early phase of the COVID-19 pandemic on cardiovascular diagnostic procedures and safety practices in Asia. Methods: The International Atomic Energy Agency conducted a worldwide survey to assess changes in cardiovascular procedure volume and safety practices caused by COVID-19. Testing volumes were reported for March 2020 and April 2020 and were compared to those from March 2019. Data from 180 centers across 33 Asian countries were grouped into 4 subregions for comparison. Results: Procedure volumes decreased by 47% from March 2019 to March 2020, showing recovery from March 2020 to April 2020 in Eastern Asia, particularly in China. The majority of centers cancelled outpatient activities and increased time per study. Practice changes included implementing physical distancing and restricting visitors. Although COVID testing was not commonly performed, it was conducted in one-third of facilities in Eastern Asia. The most severe reductions in procedure volumes were observed in lower-income countries, where volumes decreased 81% from March 2019 to April 2020. Conclusions: The COVID-19 pandemic in Asia caused significant reductions in cardiovascular diagnostic procedures, particularly in low-income countries. Further studies on effects of COVID-19 on cardiovascular outcomes and changes in care delivery are warranted.

Background This study aimed to evaluate the effects of hypercarbia on arterial oxygenation during one-lung ventilation (OLV). Methods Fifty adult patients undergoing elective video-assisted thoracoscopic lobectomy or pneumonectomy were enrolled. Group I patients (n = 25) were first maintained at normocarbia (PaCO2: 38–42 mmHg) for 30 min and then at hypercarbia (45–50 mmHg). In Group II patients (n = 25), PaCO2 was maintained in the reverse order. Arterial oxygen partial pressure (PaO2), respiratory variables, hemodynamic variables, and hemoglobin concentration were compared during normocarbia and hypercarbia. Arterial O2 content and O2 delivery were calculated. Results PaO2 values during normocarbia and hypercarbia were 66.5 ± 10.6 and 79.7 ± 17.3 mmHg, respectively (mean difference: 13.2 mmHg, 95% CI for difference of means: 17.0 to 9.3, P < 0.001). SaO2 values during normocarbia and hypercarbia were 92.5 ± 4.8% and 94.3 ± 3.1% (P = 0.009), respectively. Static compliance of the lung (33.0 ± 5.4 vs. 30.4 ± 5.3 ml/cmH2O, P < 0.001), arterial O2 content (15.4 ± 1.4 vs. 14.9 ± 1.5 ml/dl, P < 0.001) and O2 delivery (69.9 ± 18.4 vs. 65.1 ± 18.1 ml/min, P < 0.001) were significantly higher during hypercarbia than during normocarbia. Conclusions Hypercarbia increases PaO2 and O2 carrying capacity and improves pulmonary mechanics during OLV, suggesting that it may help manage oxygenation during OLV. Therefore, permissive hypercarbia may be a simple and valuable modality to manage arterial oxygenation during OLV.

Abstract Aims Heart failure (HF) and type 2 diabetes (T2D), common co‐morbidities, translate into worse patient prognoses and higher direct costs than for either condition alone. Empagliflozin has been shown to markedly reduce cardiovascular (CV) deaths and HF hospitalizations (HHF) in HF patients with T2D. This study evaluated the lifetime cost‐effectiveness of supplementing standard of care (SoC) with empagliflozin, relative to SoC alone, in HF patients with T2D from the UK payer perspective. Methods and results An existing discrete‐event simulation model was adapted for the economic evaluation. Risk equations developed from time‐dependent parametric survival analyses using patient‐level HF subpopulation data from the EMPA‐REG OUTCOME trial were employed to predict CV and renal events. Non‐CV death, utility weights, and costs were drawn from UK sources. Quality‐adjusted life years (QALYs) and costs were discounted at 3.5% per annum. Relative to SoC, empagliflozin with SoC yielded fewer first HHF, recurrent HHF, CV death, and non‐fatal myocardial infarction but more non‐fatal stroke events. Empagliflozin with SoC vs. SoC alone was associated with increased average life expectancy (10.80 vs. 9.59 LYs) and quality of life (6.27 vs. 5.62 QALYs), though at higher lifetime cost (£18 197 vs. £16 829) per person, resulting in an incremental cost‐effectiveness ratio of £2093 per QALY. The probability of empagliflozin being cost‐effective in the HF subpopulation at a £20 000 per QALY willingness‐to‐pay threshold was 91%. Conclusions This analysis suggests that adding empagliflozin to SoC in HF patients with T2D constitutes a cost‐effective use of UK healthcare resources and may provide long‐term health benefits to patients.

In recent years, the popularity of copaiba oil-resin has increased worldwide due to its medicinal value and wide applications in industry. Despite its popularity, the oil has not been standardized by industry or regulatory agencies. Product adulteration in order to maximize profits has become a problem. To address these issues, the current study describes the chemical and chemometric characterization of forty copaiba oil-resin samples by GC/MS. The results demonstrated, with the exception of commercial samples, that all sample groups contained six characteristic compounds (β-caryophyllene, α-copaene, trans-α-bergamotene, α-humulene, γ-muurolene, and β-bisabolene) in varying concentrations. Furthermore, compositional patterns were observed in individual groups which corresponded to sample origin. Within the commercial group, two samples did not contain or contained only one of the characteristic compounds. Principal component analysis (PCA) revealed distinct groups which largely corresponded to sample origin. Moreover, commercial samples were detected by PCA as outliers, and formed a group far removed from the other samples. These samples were further subjected to analysis using a SFC/MS method. Product adulteration with soybean oil was clearly detected, with each individual triglyceride in soybean oil being unambiguously identified. By combining these analytical techniques, the overall quality of copaiba oil-resin can be assessed.

Sample preparation remains both a challenging and time-consuming process in the field of bioanalytical chemistry. Many traditional techniques often require multi-step processes, which can introduce additional errors to the analytical method. Given the complexity of many biological matrices, thorough analyte extraction presents a major challenge to researchers. In the present study, a headspace solid-phase microextraction (HS-SPME) coupled with a GC/Q-ToF-MS method, was developed to quantify in vitro metabolism of β-caryophyllene by both human liver microsome (HLM) and S9 liver fractions. Validation of the method was demonstrated both in terms of linearity (R2 = 0.9948) and sensitivity with a limit of detection of 3 ng/mL and a limit of quantitation of 10 ng/mL. In addition, the method also demonstrated both inter- and intra-day precision with the relative standard deviation (RSD) being less than 10% with four concentrations ranging from 50–500 ng/mL. Since this method requires no solvents and minimal sample preparation, it provides a rapid and economical alternative to traditional extraction techniques. The method also eliminates the need to remove salts or buffers, which are commonly present in biological matrices. Although this method was developed to quantify in vitro metabolism of one analyte, it could easily be adapted to detect or quantify numerous volatiles and/or semi-volatiles found in biological matrices.

This paper presents the application of machine vision and learning techniques to detect and identify the number of flower clusters on apple trees leading to the ability to predict the potential yield of apples. A new field robot was designed and built to collect and build a dataset of 1500 images of apples trees. The trained model produced a cluster precision of 0.88 or 88% and a percentage error of 14% over 106 trees running the mobile vehicle on both sides of the trees. The detection model was predicting less than the actual amount but the fruit flower count is still significant in that it can give the researcher information on the estimated growth and production of each tree with respect to the actions applied to each fruit tree. A bias could be included to compensate for the average undercount. The resulting F1-Score of the object detection model was 80%, which is similar to other research methods ranging from an F1-Score of 77.3% to 84.1%. This paper helps lay the foundation for future application of machine vision and learning techniques within apple orchards or other fruit tree settings.

Bacteria with multiple drug resistance (MDR) have become a global issue worldwide, and hundreds of thousands of people’s lives are threatened every year. The emergence of novel MDR strains and insufficient development of new antimicrobial agents are the major reasons that limit the choice of antibiotics for the treatment of bacterial infection. Thus, preserving the clinical value of current antibiotics could be one of the effective approaches to resolve this problem. Here we identified numerous novel small RNAs that were downregulated in the MDR clinical isolates of Pseudomonas aeruginosa (P. aeru), and we demonstrated that overexpression of one of these small RNAs (sRNAs), AS1974, was able to transform the MDR clinical strain to drug hypersusceptibility. AS1974 is the master regulator to moderate the expression of several drug resistance pathways, including membrane transporters and biofilm-associated antibiotic-resistant genes, and its expression is regulated by the methylation sites located at the 5′ UTR of the gene. Our findings unravel the sRNA that regulates the MDR pathways in clinical isolates of P. aeru. Moreover, transforming bacterial drug resistance to hypersusceptibility using sRNA could be the potential approach for tackling MDR bacteria in the future.

Academic scholarship has steadily reported unfavourable clinical findings on the sport of boxing, and national medical bodies have issued calls for restrictions on the sport. Yet, the positions taken on boxing by medical bodies have been subject to serious discussions. Beyond the medical and legal writings, there is also literature referring to the social and cultural features of boxing as ethically significant. However, what is missing in the bioethical literature is an understanding of the boxers themselves. This is apart from their brain injuries, the debates about the degenerative brain disease known as chronic traumatic encephalopathy (CTE), and related issues about the disease. This article argues that the lives of boxers, their relationships, their careers, and their futures, also requires its own research, particularly in telling stories about their lives, and those lives and futures which boxing affects. The article uses two approaches. First, to imagine a more enduring “whole of life viewpoint” by using an extended future timeframe. Second, to consider perspectives of a person’s significant others. After reviewing the boxing literature, the article discusses social settings and then explores the hidden social relationships in life after boxing. With these longer time and close relationship viewpoints, three important themes emerge: family and kinship; age, stage and career; and the effects of boxing fatalities. These analyses are used in conjunction with relevant clinical findings. which complement the telling of stories to improve medical information, and engages professional and public empathy for people’s experience of illness and difficulties in coping.

Poison inhibitors of DNA topoisomerase II (TOP2) are clinically used drugs that cause cancer cell death by inducing DNA damage, which mechanism of action is also associated with serious side effects such as secondary malignancy and cardiotoxicity. In contrast, TOP2 catalytic inhibitors induce limited DNA damage, have low cytotoxicity, and are effective in suppressing cancer cell proliferation. They have been sought after to be prospective anticancer therapies. Herein the discovery of new TOP2 catalytic inhibitors is described. A new druggable pocket of TOP2 protein at its DNA binding domain was used as a docking site to virtually screen ~6 million molecules from the ZINC15 library. The lead compound, T60, was characterized to be a catalytic TOP2 inhibitor that binds TOP2 protein and disrupts TOP2 from interacting with DNA, resulting in no DNA cleavage. It has low cytotoxicity, but strongly inhibits cancer cell proliferation and xenograft growth. T60 also inhibits androgen receptor activity and prostate cancer cell growth. These results indicate that T60 is a promising candidate compound that can be further developed into new anticancer drugs.

Members of the genus Salvia are used as culinary herbs and are prized for their purported medicinal attributes. Since physiological effects can vary widely between species of Salvia, it is of great importance to accurately identify botanical material to ensure safety for consumers. In the present study, an in-depth chemical investigation is performed utilizing GC/Q-ToF combined with chemometrics. Twenty-four authentic plant samples representing five commonly used Salvia species, viz. S. apiana, S. divinorum, S. mellifera, S. miltiorrhiza, and S. officinalis, are analyzed using a GC/Q-ToF technique. High-resolution spectral data are employed to construct a sample class prediction (SCP) model followed by principal component analysis (PCA) and partial least square discriminant analysis (PLS-DA). This model demonstrates 100% accuracy for both prediction and recognition abilities. Additionally, the marker compounds present in each species are identified. Furthermore, to reduce the time required and increase the confidence level for compound identification and the classification of different Salvia species, a personal compound database and library (PCDL) containing marker and characteristic compounds is constructed. By combining GC/Q-ToF, chemometrics, and PCDL, the unambiguous identification of Salvia botanicals is achieved. This high-throughput method can be utilized for species specificity and to probe the overall quality of various Salvia-based products.

Objective: To gather consumer perspectives of a mental health screening protocol and to identify the incidence of previously unrecognized mental health concerns (case finding). Design: Pilot study using mixed methods: quantitative (survey) and qualitative (interviews). Setting: Primary care health team in Kitchener, Ontario, Canada. Participants: Patients (N=15) with spinal cord injury living in the community. Participants ranged in age from 21 to 81 years of age (mean=46); 12 were men, 8 had tetraplegia and 5 paraplegia. The number of years since injury ranged from 1 to 32 (mean=13). Intervention: Implementation of a mental health screening protocol consisting of standardized screening tools for depression, anxiety, substance abuse, social isolation, somatoform disorder, functional status, chronic pain, and cognitive impairment. Main Outcome Measures: Positive results on screening tool, acceptability of the screening process, perceptions of the value of screening, and intentions to follow resulting treatment recommendations. Results: Screening identified 11 of 15 individuals with a chronic pain condition; 1 individual screened positive for depression, 1 for anxiety, 3 for potential substance abuse, and 1 for social isolation. Most of the participants (12/13) rated the screening protocol as very acceptable. All but 1 individual intended to follow resulting treatment recommendations. Interview analyses generated themes related to disclosure of experiences that were incomplete that concealed important information and perceptions that the screening protocol failed to assess resiliency. Although perceived as valuable, participants felt screening tools alone did not capture information important to them. Conclusions: Screening tools alone may not identify mental health issues. Interviews in addition to screening tools are needed to accurately identify mental health issues in this population. Identification of mental health issues is critical to ensuring access to effective interventions and improving health outcomes and quality of life for individuals with SCI. Keywords: Mental health, Rehabilitation, Screening, Spinal cord injuries