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Sulindac (sulfoxide) is a prodrug in reversible metabolic equilibrium with its pharmacologically active metabolite, the corresponding sulfide. Following simultaneous parenteral injection of sulfoxide-14C and sulfide-3H at equivalent dosage, all labeled species in the plasma of rats and guinea pigs and in representative tissues were determined at various times. Rate constants for sulfoxide in equilibrium or formed from sulfide, calculated from the rates of interchange of the two labels in plasma, are still higher than those approximated from earlier, single-label studies, and indicate turnovers of total body pools every 45 and 8.5 min in rat and guinea pig, respectively. From the time-course of tissue/plasma ratios of endogenous labeled species, it can be concluded that kidney and liver are major sites of bioactivation of the prodrug, with significant sulfoxide leads to sulfide activity present in all tissues examined. At steady state, tissue concentrations of each redox form are determined by the ratio of the metabolic rate constants for the two opposing biotransformations and by unique tissue/plasma distributive constants for each redox form, resulting in all tissues, except lung, and at all times examined, in a sulfide/sulfoxide ratio greater than one.

AbstractContinuously, cost overruns in construction projects, as a leading cause of project failure, have been attracting more and more attention among construction stakeholders. Notably, cost overrun prediction model development can help identify factors that lead to cost overruns, thereby substantially improving cost estimates. Meanwhile, a machine learning application on archival data to estimate construction cost overrun is still in development. Motivated by this, we applied an Extreme Gradient Boosting (XGBoost) machine to analyze historical data of construction projects in Ghana completed between 2016 and 2018. The comparison between the actual and predicted cost yielded a good model prediction. The RMSE, MSE, MAE, and MAPE values are 0.202, 0.041, 0.069, and 0.306, respectively. To visually explain the importance of each feature for cost overrun prediction, we used SHAP values to illustrate the effect of each feature for model interpretability. According to SHAP ranking, we discover that the initial contract amount, the number of storeys, scope changes, and the initial duration are the variables that most accurately predict project completion costs and cost overruns. This research explores an innovative way to understand and evaluate essential variables that can help develop a prediction model of cost overruns that could aid the construction industry’s cost estimation.

Camellia oleiferais an important edible oil woody plant in China. Anthracnose is a serious disease of C. oleifera, causing severe economic losses and posing a huge threat to the C. oleiferaindustry. The fungi Colletotrichum siamenseis one of the main pathogens causing anthracnose of C. oleifera. In this study, antifungal activity of microorganisms isolated from garbage enzyme against C. siamensewere investigated for the first time. 8 strains were isolated and purified from garbage enzyme. By morphological observation, gene sequence analysis, among the strains, 4 isolates were identified as Trichoderma harzianumand 4 isolates were identified as Bacillus subtilis. The result showed that 8 isolates displayed a relatively good potential on inhibiting the mycelial growth in C. siamense, but T. harzianumwas more effective than B. subtilisas a biocontrol agent, with the best efficiency of 76.5%. In the vitro treatments, the combination of T. harzianumand B. subtiliswere the most effective treatments in reducing the incidence and severity of anthracnose in C.oleifera, with the highest control efficiency of 77.56%. It can be concluded that T. harzianumand B. subtilisare promising biocontrol agents to manage anthracnose. These promising results provided valuable information on using garbage enzyme of wastes as a new source of antagonists to control fungi disease.

Post-artesunate delayed hemolysis (PADH) occurred in 6 of 24 children treated with artesunate for severe malaria in the United States; however, severe hemolysis requiring hospitalization or transfusion was rare. In children in the United States treated with artesunate, counseling, and symptom monitoring may be preferred to weekly laboratory surveillance for PADH.We find that delayed hemolysis is common in children treated with artesunate for severe malaria in the United States. However, severe hemolysis appears rare. Counseling and symptom monitoring may be preferable to weekly laboratory surveillance for PADH in this population.

Purpose: To analyze the functions of the stomatognathic system in children with or without molar-incisor hypomineralization (MIH). Methods: For this cross-sectional study, 72 children aged 6–12 years were recruited and divided in two groups: with MIH (G1) and without MIH (G2). T-SCAN was used to verify the distribution of occlusal contacts, gnathodynamometer to measure maximum molar bite force, and Iowa Oral Pressure Instrument (IOPI) to assess the strength of facial expression muscles. The ttest and paired t test (p≤ 0.05) were used for statistical comparisons. Results: The molars affected by MIH exhibited lower distribution of occlusal forces (p< 0.001) and lower maximum molar bite force (p< 0.05) compared to the molars in the control group. However, there was no difference between the MIH-affected sides compared to the unaffected side, nor between the molars affected by MIH and their antagonists (p> 0.05). There were no differences in the forces of the facial expression muscles between the groups. Conclusions: These findings suggest that MIH significantly impacts occlusal force distribution and bite force, but not facial expression musculature.

There is a lack of peer-reviewed research on occupational therapy using Zones of Regulation™ concepts for autistic youth. The purpose of this article is to describe the feasibility of a newly-developed occupational therapy intervention using Zones of Regulation™ concepts (OT-ZOR) for autistic youth. Specifically, we aimed to evaluate: (a) participant recruitment, retention, and attendance; (b) intervention fidelity, safety, and assessment completion; (c) intervention acceptability; and (d) preliminary participant outcomes. A single-arm feasibility study was completed with outcome measures before and after 10 weeks of OT-ZOR. Fourteen autistic youth ages 6 to 13 completed the study. Youth attended 94% of OT-ZOR sessions. Providers achieved 97% fidelity to the intervention. Occupational therapists and caregivers expressed overall satisfaction with the OT-ZOR intervention. Youth demonstrated significant decreases in irritability, hyperactivity, emotional reactivity, and dysphoria. OT-ZOR is feasible to implement, acceptable to providers and caregivers, and may improve self-regulation in autistic youth.

IMPORTANCE: Patient-reported outcome measures (PROMs) are increasingly recognized for their ability to promote patient-centered care, but concerted health information technology (HIT)–enabled PROM implementations have yet to be achieved for national surgical quality improvement. OBJECTIVE: To evaluate the feasibility of collecting PROMs within a national surgical quality improvement program. DESIGN, SETTING, AND PARTICIPANTS: This was a pragmatic implementation cohort study conducted from February 2020 to March 2023. Hospitals in the US participating in the American College of Surgeons National Surgical Quality Improvement Program and their patients were included in this analysis. EXPOSURES: Strategies to increase PROM collection rates were identified using the Institute for Healthcare Improvement (IHI) Framework for Spread and the Consolidated Framework for Implementation Research and operationalized with the IHI Model for Improvement’s Plan-Do-Study-Act (PDSA) cycles. MAIN OUTCOMES AND MEASURES: The primary goal was to accrue more than 30 hospitals and achieve collection rates of 30% or greater in the first 3 years. Logistic regression was used to identify hospital-level factors associated with achieving collection rates of 30% or greater and to identify patient-level factors associated with response to PROMs. RESULTS: At project close, 65 hospitals administered PROMs to 130 365 patients (median [IQR] age, 60.1 [46.2-70.0] years; 77 369 female [59.4%]). Fifteen PDSA cycles were conducted to facilitate implementation, primarily targeting the Consolidated Framework for Implementation Research domains of Inner Setting (ie, HIT platform) and Individuals (ie, patients). The target collection rate was exceeded in quarter 3 (2022). Fifty-eight hospitals (89.2%) achieved collection rates of 30% or greater, and 9 (13.8%) achieved collection rates of 50% or greater. The median (IQR) maximum hospital-level collection rate was 40.7% (34.6%-46.7%). The greatest increases in collection rates occurred when both email and short-message service text messaging were used, communications to patients were personalized with their surgeon’s and hospital’s information, and the number of reminders increased from 2 to 5. No identifiable hospital characteristic was associated with achieving the target collection rate. Patient age and insurance status contributed to nonresponse. CONCLUSIONS AND RELEVANCE: Results of this cohort study suggest that the large-scale electronic collection of PROMs into a national multispecialty surgical registry was feasible. Findings suggest that HIT platform functionality and earning patient trust were the keys to success; although, iterative opportunities to increase collection rates and address nonresponse remain. Future work to drive continuous surgical quality improvement with PROMs are ongoing.

In lactating mothers, the high calcium (Ca2+) demand for milk production triggers significant bone loss1. Although oestrogen normally counteracts excessive bone resorption by promoting bone formation, this sex steroid drops precipitously during this postpartum period. Here we report that brain-derived cellular communication network factor 3 (CCN3) secreted from KISS1 neurons of the arcuate nucleus (ARCKISS1) fills this void and functions as a potent osteoanabolic factor to build bone in lactating females. We began by showing that our previously reported female-specific, dense bone phenotype2originates from a humoral factor that promotes bone mass and acts on skeletal stem cells to increase their frequency and osteochondrogenic potential. This circulatory factor was then identified as CCN3, a brain-derived hormone from ARCKISS1neurons that is able to stimulate mouse and human skeletal stem cell activity, increase bone remodelling and accelerate fracture repair in young and old mice of both sexes. The role of CCN3 in normal female physiology was revealed after detecting a burst of CCN3 expression in ARCKISS1neurons coincident with lactation. After reducing CCN3 in ARCKISS1neurons, lactating mothers lost bone and failed to sustain their progeny when challenged with a low-calcium diet. Our findings establish CCN3 as a potentially new therapeutic osteoanabolic hormone for both sexes and define a new maternal brain hormone for ensuring species survival in mammals.

The beam diagnosis system, used to assess beam quality, plays a crucial role in the overall commissioning and operation of accelerator-based injectors. Among various diagnostic methods, magnet-based approaches stand out due to their simplicity and ease of implementation, notably the dipole (D) magnet-based energy analysis system and the quadrupole (Q) magnet-based emittance measurement system. To cater to the specific needs of typical injectors operating within the energy range of 3∼15 MeV, a universal beam diagnosis platform based on magnets is planned for development. This platform will facilitate the measurement of fundamental beam parameters such as energy, energy spread, emittance, current, and transverse size. Thus, in addition to Q and D magnets, the transport line will also incorporate essential insertion components such as Fluorscreen and a fast current transformer. In this context, the physical design of the magnet-based diagnosis system has been conducted, and comprehensive investigations have been performed to evaluate the impacts of engineering factors, such as fringe fields and magnetic field instability, on measurement accuracy. The system's compatibility and potential for future upgrades have also been considered in the design process.

AbstractStudents’ perceived competencies may reflect dispositions to trigger and enhance engagement acts and promote engagement benefits. Although perceived competencies and engagement acts are significant resources in STEM learning, their relationships remain unclear. Accordingly, we applied the transactional model of engagement (TME) to examine these associations, focusing on how emotional and cognitive engagement affect the mediating effect of perceived digital inquiry on perceived creativity. The participants were 305 secondary school STEM learners in Hong Kong. Mediation analyses showed that emotional engagement mediated the positive relationship between perceived digital inquiry and creativity, whereas cognitive engagement had no such mediating effect.

IMPORTANCE: Treatment of erythema and flushing in rosacea is challenging. Calcitonin gene-related peptide (CGRP) has been associated with the pathogenesis of rosacea, raising the possibility that inhibition of the CGRP pathway might improve certain features of the disease. OBJECTIVE: To examine the effectiveness, tolerability, and safety of erenumab, an anti–CGRP-receptor monoclonal antibody, for the treatment of rosacea-associated erythema and flushing. DESIGN, SETTING, AND PARTICIPANTS: This single-center, open-label, single-group, nonrandomized controlled trial was conducted between June 9, 2020, and May 11, 2021. Eligible participants included adults with rosacea with at least 15 days of either moderate to severe erythema and/or moderate to extreme flushing. No concomitant rosacea treatment was allowed throughout the study period. Visits took place at the Danish Headache Center, Copenhagen University Hospital, Rigshospitalet in Copenhagen, Denmark. Participants received 140 mg of erenumab subcutaneously every 4 weeks for 12 weeks. A safety follow-up visit was performed at week 20. Data analysis occurred from January 2023 to January 2024. INTERVENTION: 140 mg of erenumab every 4 weeks for 12 weeks. MAIN OUTCOMES AND MEASURES: The primary outcome was mean change in the number of days with moderate to extreme flushing during weeks 9 through 12, compared with the 4-week run-in period (baseline). The mean change in number of days with moderate to severe erythema was a secondary outcome. Adverse events were recorded for participants who received at least 1 dose of erenumab. Differences in means were calculated with a paired t test. RESULTS: A total of 30 participants (mean [SD] age, 38.8 [13.1] years; 23 female [77%]; 7 male [23%]) were included, of whom 27 completed the 12-week study. The mean (SD) number of days with moderate to extreme flushing was reduced by −6.9 days (95% CI, −10.4 to −3.4 days; P < .001) from 23.6 (5.8) days at baseline. The mean (SD) number of days with moderate to severe erythema was reduced by −8.1 days (95% CI, −12.5 to −3.7 days; P < .001) from 15.2 (9.1) days at baseline. Adverse events included transient mild to moderate constipation (10 participants [33%]), transient worsening of flushing (4 participants [13%]), bloating (3 participants [10%]), and upper respiratory tract infections (3 participants [10%]), consistent with previous data. One participant discontinued the study due to a serious adverse event (hospital admission due to gallstones deemed unrelated to the study), and 2 participants withdrew consent due to lack of time. CONCLUSIONS AND RELEVANCE: These findings suggest that erenumab might be effective in reducing rosacea-associated flushing and chronic erythema (participants generally tolerated the treatment well, which was consistent with previous data), and that CGRP-receptor inhibition holds potential in the treatment of erythema and flushing associated with rosacea. Larger randomized clinical trials are needed to confirm this finding. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04419259

ABSTRACTThis paper describes a numerical analysis to predict the deformation and time to rupture of the small punch creep test for 316 L(N) austenitic steel. The constitutive model incorporates elasto-plastic nonlinear kinematic hardening and creep with primary, secondary and tertiary creep calibrated to the RCC-MRx code data. The computations are assessed by comparing with experimental data for a 500 µm thick sample clamped with a diameter of 5 mm loaded with a force 300,400 and 500N at 700°C. The model predicts the experimental observations quite well with respect to minimum deflection rate and time to rupture and its location using a local critical strain criterion. A very important feature is that the deformation and total effective strain distribution at rupture are almost identical for all loads as function of the time divided by the time to rupture.

Macrocycles and medium-sized rings are important in many scientific fields and technologies but are hard to make using current methods, especially on a large scale. Outlined herein is a strategy by which functionalized macrocycles and medium-sized rings can be prepared using cyclization/ring expansion (CRE) cascade reactions, without resorting to high dilution conditions. CRE cascade reactions are designed to operate exclusively via kinetically favorable 5–7-membered ring cyclization steps; this means that the problems typically associated with classical end-to-end macrocyclization reactions are avoided. A modular synthetic approach has been developed to facilitate the simple assembly of the requisite linear precursors, which can then be converted into an extremely broad range of functionalized macrocycles and medium-sized rings using one of nine CRE protocols.

ABSTRACTA uniaxial creep model that describes creep over a wide stress range was developed for P91 steel using an artificial neural network (ANN). The training dataset was based on measurements from uniaxial creep tests and information derived from a combination of the logistic creep strain prediction and the Wilshire models. The ANN model reproduces the training dataset with high accuracy (R2 = 0.975; RMSE (Root Mean Square Error) = 0.19). The model can be easily implemented in finite element analysis (FEA) codes since it provides an analytical expression of the true creep rate as a function of temperature, true stress and true creep strain. In FEA simulations under the same conditions as the training dataset, the model provides times to rupture and minimum creep rates very close to those in the training dataset. The model can be adapted for heats with different properties from the average behaviour of the training dataset by means of a stress-scaling factor.

We demonstrate the measurement of W-band radio-frequency (RF) electric fields using a sensor integrated on an electrically-passive fiber-coupled thin-film lithium niobate platform. The sensor consists of three cascaded bow-tie antennas that directly phase-modulate the optical signal. By using a two-tone optical probe, the high-frequency RF signal is down-converted to a much lower intermediate frequency. The measured intermediate frequency of the photonic down-conversion system can be tuned by changing the separation of the two optical tones. In our case, the two optical tones are generated by driving an external phase modulator with a frequency approximately half of the RF signal to be measured, allowing the measurement of RF E-fields from 78–89 GHz while driving the phase modulator at < 44 GHz and keeping the resulting intermediate frequencies < 2 GHz. The E-field measured sensitivity of 6 mV/m/√Hz is limited in practice by the low (−19 dBm) optical power exiting the sensor, which is largely due to the high (32 dB) optical insertion loss of the device. This loss is technical in nature and not due to a fundamental limitation. The experimental results are consistent with derived expressions for the E-field sensitivity.

This paper discusses traversable wormholes in a dark-energy setting by starting with a model due to Sung-Won Kim. This model, based on the Friedmann–Lemaître–Robertson–Walker model, is combined with a generalized Kaluza–Klein model. It is well known that phantom dark energy can in principle support traversable wormholes due to the violation of the null energy condition (NEC), a necessary condition for holding a wormhole open. Since the phantom divide constitutes a serious barrier, we retain the dark-energy assumption a′′(t)>0but stay below the phantom divide. To show that the violation of the NEC can only come from the fifth dimension requires a careful analysis of the scale factor a(t). While needed in the overall model, certain 1-forms lack this scale factor since the extra dimension, often assumed to be compactified, would not be affected by the cosmological expansion. The result is a viable wormhole model of the Sung-Won-Kim type. Our main conclusion involves Morris–Thorne wormholes: due to the Kaluza–Klein gravity, we obtain a valid wormhole solution without crossing the phantom divide.

Purpose: This paper introduces a novel analysis model for a sound energy harvester that goes beyond the traditional methods based on piezoelectric or electromagnetic effects. The proposed model utilizes both piezoelectric and flexoelectric effects and consists of a flexoelectric vibrating plate and a phononic crystal with defect points to enhance the power of sound energy harvesting. Methods: Using plane wave expansion and supercell methods, this paper obtains the defect band frequencies and corresponding acoustic pressure distribution of the defective state phononic crystal. By applying the Hamiltonian principle, the electromechanical control equations for the double-layer flexoelectric plate are derived. The Galerkin method is employed to solve these equations, providing an approximate closed-form solution for voltage output. Finite-element simulations validate the theoretical results. Conclusion: The study reveals a significant enhancement (3.66 times) in voltage output for the sound energy harvester at the micro-nano-scale through the combined effects of flexoelectricity and piezoelectricity. The presence of defect state phononic crystal results in 4.24-fold, 11.60-fold, and 2.55-fold increases in voltage output, power output, and energy conversion efficiency, respectively, for the flexoelectric sound energy harvester. Additionally, optimal laying schemes and load resistance for the flexoelectric layer are provided.

This paper proposes and describes a context- and subject-specific professional digital competence (PDC) framework for beginning English language teachers in Hong Kong. Taking a localised approach, the framework was developed through a four-stage data collection process, (1) Literature review of empirical studies conducted in Hong Kong of English language teachers’ technology use, (2) Review of local government curriculum documents; (3) An online survey of English language teachers’ technology use (n= 83); (4) follow-up individual interviews (n= 22). The study revealed that the local subject-specific PDC of teachers includes five aspects; Technological proficiency; Pedagogical compatibility; Preparing students for the digital world; Risk, well-being and ethical awareness and Professional work. Each aspect includes ability statements. The framework can be used to evaluate existing teacher education programmes, support the development of pre-service English-language teachers and facilitate self-, peer- and teacher assessment. The elements of PDC can be converted into programme- and course-level learning outcomes or incorporated into assessment rubrics. In addition, the methods used to develop the framework can be used by scholars in other contexts and subject areas to develop localised subject-specific PDC frameworks.

Purpose: Degenerative mitral stenosis (DMS) is associated with a poor prognosis. Although mean transmitral gradient (TMG) has shown a good correlation with outcome, little is known about the association between other echocardiographic parameters and prognosis in patients with DMS. The current study aimed to evaluate the prognostic value of left atrial volume index (LAVI) in patients with DMS. Methods: A total of 155 patients with DMS (72[63–80] years, 67% female) were included. The population was divided according to LAVI: normal-sized LAVI (LAVI ≤ 34 ml/m2); and enlarged LAVI (> 34 ml/m2). Results: Patients with enlarged LAVI had a higher left ventricular mass index (120[96–146] vs. 91[70–112] g/m2 p < 0.001), as well as a higher prevalence of significant mitral regurgitation and severe aortic stenosis (23% vs. 10% p = 0.046 and 38% vs. 15% p=0.001, respectively) compared to patients with normal-sized LAVI. During a median follow-up of 25 months, 56 (36%) patients died. Patients with enlarged LAVI had worse prognosis compared to patients with normal-sized LAVI (p = 0.026). In multivariable Cox regression model, an enlarged LAVI was independently associated with all-cause mortality (HR 2.009, 95% CI 1.040 to 3.880, P = 0.038). Conclusion: An enlarged LAVI (> 34 ml/m2) is significantly associated with excess mortality in patients with DMS. After adjusting for potential confounders, an enlarged LAVI was the only parameter that remained independently associated with prognosis.

Aging primarily affects memory and executive functions, a relationship that may be underpinned by the fact that almost all adults over 60 years old develop small vessel disease (SVD). The fact that a wide range of neuropathologies could only explain up to 43% of the variation in age-related cognitive impairment suggests that other factors, such as cognitive reserve, may play a role in the brain’s resilience against aging-related cognitive decline. This study aims to examine the relationship between structural–functional-connectivity coupling (SFC), and aging, cognitive abilities and reserve, and SVD-related neuropathologies using a cohort of n= 176 healthy elders from the Harvard Aging Brain Study. The SFC is a recently proposed biomarker that reflects the extent to which anatomical brain connections can predict coordinated neural activity. After controlling for the effect of age, sex, and years of education, global SFC, as well as the intra-network SFC of the dorsolateral somatomotor and dorsal attention networks, and the inter-network SFC between dorsolateral somatomotor and frontoparietal networks decreased with age. The global SFC decreased with total cognitive score. There were significant interaction effects between years of education versus white matter hyperintensities and between years of education versus cerebral microbleeds on inter-network SFC. Enlarged perivascular space in basal ganglia was associated with higher inter-network SFC. Our results suggest that cognitive ability is associated with brain coupling at the global level and cognitive reserve with brain coupling at the inter-functional-brain-cluster level with interaction effect from white matter hyperintensities and cerebral microbleed in a cohort of healthy elderlies.

Graphical Abstract

In this editorial, we discuss the affordances and challenges of emerging technologies in designing and implementing STEM education as a planned theme of this special issue. We view that emerging technologies, such as artificial intelligence (AI) and virtual reality, have a double-edged sword effect on STEM learning and teaching. Exploring the effect will help provide a balanced view that simultaneously recognizes the benefits and pitfalls of the technologies and avoids overstating either one. This themed issue highlights how immersive and AI-driven learning environments advance and transform STEM education in different contexts. It consists of this editorial, three research reviews, and two empirical research articles contributed by scholars from five different regions, including Australia, Hong Kong, mainland China, Singapore, and the USA. They discussed the educational, social, and technological effects of emerging technologies. Each article discusses to various extent about the current research status, what and how the technologies can afford, and what concerns the technologies may bring to STEM education.

The SS18-SSX fusion drives oncogenic transformation in synovial sarcoma by bridging SS18, a member of the mSWI/SNF (BAF) complex, to Polycomb repressive complex 1 (PRC1) target genes. Here we show that the ability of SS18-SSX to occupy H2AK119ub1-rich regions is an intrinsic property of its SSX C terminus, which can be exploited by fusion to transcriptional regulators beyond SS18. Accordingly, SS18-SSX recruitment occurs in a manner that is independent of the core components and catalytic activity of BAF. Alternative SSX fusions are also recruited to H2AK119ub1-rich chromatin and reproduce the expression signatures of SS18-SSX by engaging with transcriptional activators. Variant Polycomb repressive complex 1.1 (PRC1.1) acts as the main depositor of H2AK119ub1 and is therefore required for SS18-SSX occupancy. Importantly, the SSX C terminus not only depends on H2AK119ub1 for localization, but also further increases it by promoting PRC1.1 complex stability. Consequently, high H2AK119ub1 levels are a feature of murine and human synovial sarcomas. These results uncover a critical role for SSX-C in mediating gene deregulation in synovial sarcoma by providing specificity to chromatin and further enabling oncofusion binding by enhancing PRC1.1 stability and H2AK119ub1 deposition.