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The hasty adoption of remote teaching (RT) by educational institutes in response to the COVID-19 pandemic has drastically impacted teaching, learning, and assessment. With most institutes unprepared for sudden lockdowns, and many educators lacking online teaching and assessment experience, old methods of assessment continued to be used, at least initially. When concerns about academic integrity soon followed, new pedagogical concepts and modes were trialed in the hopes of addressing perceived inadequacies. This study, using a mixed-method design, investigates teacher-participants' perceptions of online assessment and academic integrity. It explores the challenges they believed had a detrimental effect on the latter -- technical difficulties, problems due to lack of physical presence, student behavioral issues, and concerns about assessment design and process. This study also discusses teacher-participants' suggested approaches to safeguarding against dishonesty, including modifications in design, conduct, and evaluation of quizzes and exams. Finally, it ends with teacher-participants' recommendations and suggestions for policy-level changes to help minimize the adverse effects of prolonged RT.

The quality of linkage techniques has a direct impact on the quality of statistics produced on the linked data, and as such, ensuring linkage algorithms are of the highest quality is a vital mission of the Office for National Statistics (ONS). Deterministic hierarchical matchkeys are a linkage technique that applies a list of conditions to classify links, where records can only be linked once. The aim of the hierarchy is to classify correct links by running higher precision matchkeys first, removing linked records from the matching pool, and then running lower quality keys so that they are less likely to make incorrect links. Currently, no optimal method for ordering match-keys exists. Here we present novel research on a generalisable algorithmic approach to finding optimal matchkey orderings. A deterministic loop over a consistent set of matchkeys was used to link ONS’s 2021 Census to the 2021 Census Coverage Survey (CCS). A range of experimental ordering methods were implemented. Gold standard linked data was used for quality determination to produce metrics such as precision and recall for grading and comparing the experimental ordering methods. The required expertise of the user and computational efficiency were considered when comparing and recommending ordering methods. Removing historically subjective matchkey ordering methods and replacing with a deterministic ordering algorithm, can lead to better data linkage outcomes with reductions in linkage error. This can provide greater confidence to users of official statistics that linked data underpinning them are more reliable, trustworthy, and meaningful.

The COVID-19 pandemic effected a sudden shift to online teaching, prompting teachers to implement many uncommon or even unusual teaching techniques in this unforeseen context. This precipitous move to online teaching has radically altered our teaching practices, where teachers have had to either completely do away with traditional practices or modify them in significant ways. One of the primary concerns of online teaching voiced by many teachers is to hold students' interest and keep them engaged in the virtual classroom. Another challenge has been to make students interact with each other and the teacher. The authors of this paper believe that Task-Based Language Teaching (TBLT) addresses these concerns head-on. There are two reasons for this: first, its emphasis on real-life language through meaningful tasks; and second, it is student-centered. This paper provides a brief background of TBLT and technology-mediated TBLT. It will show how some coursebook materials could be used in TBLT to help online learners improve their language skills. The paper also outlines with examples how technology-mediated tasks could be deployed to encourage learners to use language in productive ways. Finally, the authors discuss some of the anticipated challenges concerning the application of TBLT in online teaching and learning contexts.

ABSTRACT Contemporary antifungal therapies utilized to treat filamentous fungal infections are inhibited by intrinsic and emerging drug resistance. Consequently, there is an urgent need to develop novel antifungal compounds that are effective against drug-resistant filamentous fungi. Here, we utilized an Aspergillus fumigatus cell-based high-throughput screen to identify small molecules with antifungal activity that also potentiated triazole activity. The screen identified 16 hits with promising activity against A. fumigatus. A nonspirocyclic piperidine, herein named MBX-7591, exhibited synergy with triazole antifungal drugs and activity against pan-azole-resistant A. fumigatus isolates. MBX-7591 has additional potent activity against Rhizopus species and CO2-dependent activity against Cryptococcus neoformans. Chemical, genetic, and biochemical mode of action analyses revealed that MBX-7591 increases cell membrane saturation by decreasing oleic acid content. MBX-7591 has low toxicity in vivo and shows good efficacy in decreasing fungal burden in a murine model of invasive pulmonary aspergillosis. Taken together, our results suggest MBX-7591 is a promising hit with a novel mode of action for further antifungal drug development to combat the rising incidence of triazole-resistant filamentous fungal infections.IMPORTANCEThe incidence of infections caused by fungi continues to increase with advances in medical therapies. Unfortunately, antifungal drug development has not kept pace with the incidence and importance of fungal infections, with only three major classes of antifungal drugs currently available for use in the clinic. Filamentous fungi, also called molds, are particularly recalcitrant to contemporary antifungal therapies. Here, a recently developed Aspergillus fumigatus cell reporter strain was utilized to conduct a high-throughput screen to identify small molecules with antifungal activity. An emphasis was placed on small molecules that potentiated the activity of contemporary triazole antifungals and led to the discovery of MBX-7591. MBX-7591 potentiates triazole activity against drug-resistant molds such as A. fumigatus and has activity against Mucorales fungi. MBX-7591’s mode of action involves inhibiting the conversion of saturated to unsaturated fatty acids, thereby impacting fungal membrane integrity. MBX-7591 is a novel small molecule with antifungal activity poised for lead development.

OBJECTIVE: The objective of this clinical practice guideline is to provide updated and new evidence-based recommendations for the comprehensive care of persons with diabetes mellitus to clinicians, diabetes-care teams, other health care professionals and stakeholders, and individuals with diabetes and their caregivers. METHODS: The American Association of Clinical Endocrinology selected a task force of medical experts and staff who updated and assessed clinical questions and recommendations from the prior 2015 version of this guideline and conducted literature searches for relevant scientific papers published from January 1, 2015, through May 15, 2022. Selected studies from results of literature searches composed the evidence base to update 2015 recommendations as well as to develop new recommendations based on review of clinical evidence, current practice, expertise, and consensus, according to established American Association of Clinical Endocrinology protocol for guideline development. RESULTS: This guideline includes 170 updated and new evidence-based clinical practice recommendations for the comprehensive care of persons with diabetes. Recommendations are divided into four sections: (1) screening, diagnosis, glycemic targets, and glycemic monitoring; (2) comorbidities and complications, including obesity and management with lifestyle, nutrition, and bariatric surgery, hypertension, dyslipidemia, retinopathy, neuropathy, diabetic kidney disease, and cardiovascular disease; (3) management of prediabetes, type 2 diabetes with antihyperglycemic pharmacotherapy and glycemic targets, type 1 diabetes with insulin therapy, hypoglycemia, hospitalized persons, and women with diabetes in pregnancy; (4) education and new topics regarding diabetes and infertility, nutritional supplements, secondary diabetes, social determinants of health, and virtual care, as well as updated recommendations on cancer risk, nonpharmacologic components of pediatric care plans, depression, education and team approach, occupational risk, role of sleep medicine, and vaccinations in persons with diabetes. CONCLUSIONS: This updated clinical practice guideline provides evidence-based recommendations to assist with person-centered, team-based clinical decision-making to improve the care of persons with diabetes mellitus.

Introduction: The emergency department (ED) is an effective setting for initiating medication for opioid use disorder (MOUD); however, predicting who will remain in treatment remains a central challenge. We hypothesize that baseline stage-of-change (SOC) assessment is associated with short-term treatment retention outcomes.Methods: This is a longitudinal cohort study of all patients enrolled in an ED MOUD program over 12 months. Eligible and willing patients were treated with buprenorphine at baseline and had addiction medicine specialist follow-up arranged. Treatment retention at 30 and 90 days was determined by review of the Prescription Drug Monitoring Program. We used uni- and multivariate logistic regression to evaluate associations between patient variables and treatment retention at 30 and 90 days.Results: From June 2018–May 2019, 279 patients were enrolled in the ED MOUD program. Of those patients 151 (54.1%) and 120 (43.0%) remained engaged in MOUD treatment at 30 and 90 days, respectively. The odds of treatment adherence at 30 days were significantly higher for those with advanced SOC (preparation/action/maintenance) compared to those presenting with limited SOC (pre-contemplation/contemplation) (60.0% vs 40.8%; odds ratio 2.18; 95% confidence interval 1.15 to 4.1; P 40, having medical insurance, and being employed were significant predictors of continued treatment adherence. At 90 days, advanced SOC, non-White race, age > 40, and having insurance were all significantly associated with higher likelihood of treatment engagement.Conclusion: Greater stage-of-change was significantly associated with MOUD treatment retention at 30 and 90 days post index ED visit.

Utilizing Bagasse Fly Ash (BFA) as an adsorbent, a byproduct from the sugar industry, proved effective in removing a mixture of Malachite Green and Methylene Blue dyes from aqueous solutions. To enhance its efficacy, the fly ash underwent chemical modification and underwent detailed characterization using FTIR, XRD, SEM, and TGA analyses. Subsequently, adsorption studies were conducted to optimize critical parameters—initial dye concentration, contact time, and pH levels—employing a Mixed-Level Factorial design to pinpoint the most favorable conditions for efficient dye removal. The modified Bagasse Fly Ash (BFA) resulted in a maximum adsorption capacity of 18.75 mg/g (71.5 %) for Malachite Green and 15.5 mg/g (67.2 %) for Methylene Blue at initial dye concentration of 100 mg/L, pH of 9.6, and time of 51.5 min. Analysis of the sorption data involved rigorous application of both Langmuir and Freundlich isotherm models, revealing a strong fit of the linear representation to the data for both dyes. Specifically, R2 values of 0.97 and 0.93 were observed for Malachite Green, while notably higher values of 0.99 and 0.96 were obtained for Methylene Blue, affirming an excellent model-data agreement. Additionally, a kinetic study revealed that the dye adsorption process (MB and MG) followed the pseudo-second-order kinetic model (R2 > 0.99), indicating that chemisorption as dominant adsorption mechanism and providing valuable insights into the dynamic behavior of the process.

The purpose of this study was to analyze the narratives constructed by urban youth in a summer program for future educators of color. In particular, we asked, "In what ways do students use texts to create counternarratives of urban education?" Utilizing visual counternarratives and counterstorytelling as theoretical frames, and through thematic analysis and visual amalgamated findings, we examined how students' written, visual, and audio texts countered stereotypes. Findings revealed that students used texts to create counternarratives of self, schools, and society.

Summary: Background: Atherosclerotic cardiovascular disease (ASCVD) is the leading cause of death worldwide, driven primarily by coronary artery disease (CAD). ASCVD risk estimators such as the pooled cohort equations (PCE) facilitate risk stratification and primary prevention of ASCVD but their accuracy is still suboptimal. Methods: Using deep electronic health record data from 7,116,209 patients seen at 70+ hospitals and clinics across 5 states in the USA, we developed an artificial intelligence-based electrocardiogram analysis tool (ECG-AI) to detect CAD and assessed the additive value of ECG-AI-based ASCVD risk stratification to the PCE. We created independent ECG-AI models using separate neural networks including subjects without known history of ASCVD, to identify coronary artery calcium (CAC) score ≥300 Agatston units by computed tomography, obstructive CAD by angiography or procedural intervention, and regional left ventricular akinesis in ≥1 segment by echocardiogram, as a reflection of possible prior myocardial infarction (MI). These were used to assess the utility of ECG-AI-based ASCVD risk stratification in a retrospective observational study consisting of patients with PCE scores and no prior ASCVD. The study period covered all available digitized EHR data, with the first available ECG in 1987 and the last in February 2023. Findings: ECG-AI for identifying CAC ≥300, obstructive CAD, and regional akinesis achieved area under the receiver operating characteristic (AUROC) values of 0.88, 0.85, and 0.94, respectively. An ensembled ECG-AI identified 3, 5, and 10-year risk for acute coronary events and mortality independently and additively to PCE. Hazard ratios for acute coronary events over 3-years in patients without ASCVD that tested positive on 1, 2, or 3 versus 0 disease-specific ECG-AI models at cohort entry were 2.41 (2.14–2.71), 4.23 (3.74–4.78), and 11.75 (10.2–13.52), respectively. Similar stratification was observed in cohorts stratified by PCE or age. Interpretation: ECG-AI has potential to address unmet need for accessible risk stratification in patients in whom PCE under, over, or insufficiently estimates ASCVD risk, and in whom risk assessment over time periods shorter than 10 years is desired. Funding: Anumana.

ObjectivePoor diet quality contributes to metabolic dysfunction. This study aimed to gain a greater understanding of the relationship between dietary macronutrient quality and glucose homeostasis in adults with cystic fibrosis (CF).DesignThis was a cross-sectional study of N = 27 adults with CF with glucose tolerance ranging from normal (n = 9) to prediabetes (n = 6) to being classified as having cystic fibrosis-related diabetes (CFRD, n = 12). Fasted blood was collected for analysis of glucose, insulin, and C-peptide. Insulin resistance was assessed by Homeostatic Model Assessment for Insulin Resistance (HOMA2-IR). Subjects without known CFRD also underwent a 2-h oral glucose tolerance test. Three-day food records were used to assess macronutrient sources. Dietary variables were adjusted for energy intake. Statistical analyses included ANOVA, Spearman correlations, and multiple linear regression.ResultsIndividuals with CFRD consumed less total fat and monounsaturated fatty acids (MUFA) compared to those with normal glucose tolerance (p

Objectives The Integrated Data Service (IDS) is a new cross-government service that facilitates research for the public good. Key to its success are Integrated Data Assets (IDAs): de-identified, grouped datasets that are joinable on an artificial ID and themed on a given topic. The Demographic Index (DI) comprises five linked administrative datasets. We are developing a generalisable method that will link administrative and survey datasets to the DI via a customisable, reproducible pipeline, to produce IDAs. Methods The method focuses on the traditional methodologies of deterministic and probabilistic data linkage and uses the Splink implementation of the Fellegi-Sunter method for probabilistic matching. The pipeline will include a tool for quality-assurance (QA) via clerical review. We are researching a generalisable implementation of Splink, deriving the method’s control parameters using the results of the deterministic matching. Additionally, we are researching application of Locality Sensitive Hashing (LSH), a dimensionality-reduction method suggested to improve computational efficiency, for blocking. This is especially important due to the large size of the datasets involved. Results We plan to produce linked datasets with three quality levels – prioritising precision, balancing precision and recall and prioritising recall. As the datasets are always linked to the DI, the DI’s artificial ID can be used as a ‘spine’ to bring them together as assets (IDAs). Initially, the method will be used on the 2021 England and Wales Census. Despite not including clerical matching in the method (except for quality-assurance), we anticipate a high precision and recall due to the quality of the Census and the number of linkage variables available. Thereafter, we plan for user testing with other datasets, including the Labour Market Survey. Conclusion Our generalisable linkage pipeline for the DI will, through its IDA outputs, facilitate research for the public good. This research will directly impact government policy and responses to national health emergencies, including Covid-19, and support government priorities such as Levelling Up and the transition towards Net Zero.

This study aims to investigate the influence of chemical reaction on the flow characteristics of a magnetohydrodynamic (MHD) Casson nanofluid over a porous stretching sheet with suction/injection. The nanofluid (NF) is comprised of a base fluid with suspended nanoparticles (NPs), and the Casson fluid (CF) model is employed to capture the non-Newtonian behavior. The governing partial differential equations (PDEs) for momentum, energy, and NP concentration are derived, incorporating the effects of magnetic field, viscous dissipation, chemical reaction, and porous medium. The resulting system of nonlinear ordinary differential equations (ODEs) is solved numerically using the Runge-Kutta-Fehlberg method together with the shooting process. The effects of various physical parameters, such as magnetic field strength, porous medium, CF parameters, NP volume fraction, suction/injection parameter, and chemical reaction parameter, on the flow characteristics are examined in detail. The results reveal that faster movement is linked to higher Grashof numbers and porous mediums, but weaker magnetic fields slow it down. The suction/injection affect velocity inversely. The Prandtl and Eckert numbers have opposite effects on temperature fields. The thermophoresis and Brownian motion parameters affect the opposite trends of the concentration and temperature distributions. The concentration reduces with chemical reaction parameters and the Lewis number. Heat transfer (HT) is enhanced for higher Brownian and thermophoresis. The findings of this study can have potential applications in various engineering fields, such as microfluidics, chemical processing, and thermal management systems, where precise control of fluid flow and heat transfer is essential.

Introduction The prevalence, severity, and quality of life (QoL) impact of diabetic retinopathy (DR) among African–Americans (AAs) with end-stage kidney disease (ESKD) undergoing dialysis are unknown.Research design and methods A cross-sectional study was conducted on 93 AA adults with diabetes and ESKD. The diagnosis of DR was based on a review of medical records and/or a positive photograph with a portable hand-held device reviewed by both artificial intelligence software and a retinal specialist. QoL, physical disability social determinants of health (SDoHs) were assessed by standardized questionnaires.Results The prevalence of DR was 75%, with 33% of participants having mild, 9.6% moderate and 57.4% severe DR. A total of 43% had normal visual acuity; 45% had moderate visual impairment; and 12% had severe visual impairment. We found a high burden of disease, multiple SDoH challenges, and low QoL and general health among patients with ESKD. The presence of DR had no significant impact on physical health and QoL compared with participants without DR.Conclusions DR is present in 75% of AA patients with diabetes and ESKD on haemodialysis. ESKD has a significant burden on general health and QoL; however, DR has a minor additional impact on the overall physical health and QoL in people with ESKD.

Neuroendocrine prostate cancer (NEPC), a lethal form of the disease, is characterized by loss of androgen receptor (AR) signaling during neuroendocrine transdifferentiation, which results in resistance to AR-targeted therapy. Clinically, genomically and epigenetically, NEPC resembles other types of poorly differentiated neuroendocrine tumors (NETs). Through pan-NET analyses, we identified ONECUT2 as a candidate master transcriptional regulator of poorly differentiated NETs. ONECUT2 ectopic expression in prostate adenocarcinoma synergizes with hypoxia to suppress androgen signaling and induce neuroendocrine plasticity. ONEUCT2 drives tumor aggressiveness in NEPC, partially through regulating hypoxia signaling and tumor hypoxia. Specifically, ONECUT2 activates SMAD3, which regulates hypoxia signaling through modulating HIF1α chromatin-binding, leading NEPC to exhibit higher degrees of hypoxia compared to prostate adenocarcinomas. Treatment with hypoxia-activated prodrug TH-302 potently reduces NEPC tumor growth. Collectively, these results highlight the synergy between ONECUT2 and hypoxia in driving NEPC, and emphasize the potential of hypoxia-directed therapy for NEPC patients.

This article employs the comparative case study (CCS) approach to examine how four public pre-kindergarten (pre-K) teachers in Michigan enacted a state-mandated parent involvement policy. Using CCS, we trace policy enactment from the policy text, through mid-level administrators, and into the classroom context. We demonstrate how teachers used strategic knowledge to develop hybrid parent involvement practices that satisfied program requirements while prioritizing the needs of families in their classrooms.

The use of photography in social science research has always been fraught with tensions and has changed drastically over the years (Azoulay, 2016; Edwards, 2015). In recent decades, photovoice has gained prominence as a participatory methodology that uses photography to create opportunities for community engagement in research (Greene et al., 2018; Latz, 2017). Wang and Burris (1997) describe photovoice as a methodology that "entrusts cameras to the hands of people to enable them to act as recorders, and potential catalysts for change, in their own communities" (p. 369). Photovoice emerged in response to questions that qualitative researchers were asking themselves about the purposes of research, who gets to participate, what stories are told, and from whose perspective (Evans-Agnew & Rosemberg, 2016). In this paper, the authors offer a brief overview of photovoice as a methodology and trace its epistemological foundations. They interrogate its contemporary manifestations in educational research and practice by reviewing articles using and/or critiquing the methodology. Building on these critiques, they draw on arts-based research to consider "alternative" possibilities for visual research

In the era of precision oncology, use of circulating tumor DNA (ctDNA) is emerging as a minimally invasive approach for the diagnosis and management of patients with cancer and as an enrichment tool in clinical trials. In recent years, the US Food and Drug Administration has approved multiple ctDNA-based companion diagnostic assays for the safe and effective use of targeted therapies and ctDNA-based assays are also being developed for use with immuno-oncology-based therapies. For early-stage solid tumor cancers, ctDNA may be particularly important to detect molecular residual disease (MRD) to support early implementation of adjuvant or escalated therapy to prevent development of metastatic disease. Clinical trials are also increasingly using ctDNA MRD for patient selection and stratification, with an ultimate goal of improving trial efficiency through use of an enriched patient population. Standardization and harmonization of ctDNA assays and methodologies, along with further clinical validation of ctDNA as a prognostic and predictive biomarker, are necessary before ctDNA may be considered as an efficacy-response biomarker to support regulatory decision making.

ObjectiveTo determine the clinical manifestations, risk factors, treatment modalities and maternal outcomes in pregnant women with lab-confirmed COVID-19 and compare it with COVID-19 negative pregnant women in same age group.DesignMulticentric case-control study.Data sourcesAmbispective primary data collection through paper-based forms from 20 tertiary care centres across India between April and November 2020.Study populationAll pregnant women reporting to the centres with a lab-confirmed COVID-19 positive result matched with controls.Data qualityDedicated research officers extracted hospital records, using modified WHO Case Record Forms (CRF) and verified for completeness and accuracy.Statistical analysisData converted to excel files and statistical analyses done using STATA 16 (StataCorp, TX, USA). Odds ratios (ORs) with 95% confidence intervals (CI) estimated using unconditional logistic regression.ResultsA total of 76,264 women delivered across 20 centres during the study period. Data of 3723 COVID positive pregnant women and 3744 age-matched controls was analyzed. Of the positive cases 56·9% were asymptomatic. Antenatal complications like preeclampsia and abruptio placentae were seen more among the cases. Induction and caesarean delivery rates were also higher among Covid positive women. Pre-existing maternal co-morbidities increased need for supportive care. There were 34 maternal deaths out of the 3723(0.9%) positive mothers, while covid negative deaths reported from all the centres were 449 of 72,541 (0·6%).ConclusionCovid-19 infection predisposed to adverse maternal outcomes in a large cohort of Covid positive pregnant women as compared to the negative controls.

Objective: Calcium is an essential mineral involved in the functioning of nearly every human cell. Calcium levels are regulated by dietary absorption, vitamin D status, and parathyroid hormone (PTH). This report describes a patient in whom childhood bowel resection and partial gastrectomy resulted in malabsorptive hypocalcemia in adulthood. Case Report: A 21-year-old man presented with syncope and a fall resulting in a right femoral neck fracture. His medical history included small bowel obstructions at age 9 requiring bowel resection, and at age 12 with gastric perforation and partial gastrectomy. Laboratory values showed calcium level of 4.9 mg/dL (8.9-10.3 mg/dL). PTH level was 273 pg/mL (12.0-88.0 pg/mL), 25-hydroxy-vitamin D was 28 ng/dL (30-100 ng/mL), and 1,25-dihydroxy-vitamin D was 54 pg/dL (18-72 pg/mL). Furthermore, magnesium and phosphorus levels were 2.1 mg/dL (1.5-2.6 mg/dL) and 4.4 mg/dL (2.4-4.7 mg/dL), respectively. Calcium levels improved to 9.5 mg/dL on 10% calcium gluconate drip but could not be maintained above 7 mg/dL on oral calcium carbonate supplementation, despite doses as high as 3750 mg three times daily with calcitriol 0.75 mcg twice daily. After switching from calcium carbonate to calcium citrate 3500 mg three times daily, the calcium level improved and was maintained between 8.3 and 9.0 mg/dL. Discussion: High calcium needs, other nutrient deficiencies, and response to calcium citrate versus calcium carbonate suggest malabsorption from achlorhydria and small bowel resection. Conclusion: This case emphasizes the gastrointestinal physiology in calcium homeostasis and highlights the recognition of hypocalcemia as a complication of gastric and bowel resection.

Ex vivo lung perfusion (EVLP) has increased donor lung utilization through assessment of “marginal” lungs prior to transplantation. To develop it as a donor lung reconditioning platform, prolonged EVLP is necessary, and new perfusates are required to provide sufficient nutritional support. Human pulmonary microvascular endothelial cells and epithelial cells were used to test different formulas for basic cellular function. A selected formula was further tested on an EVLP cell culture model, and cell confluence, apoptosis, and GSH and HSP70 levels were measured. When a cell culture medium (DMEM) was mixed with a current EVLP perfusate—Steen solution, DMEM enhanced cell confluence and migration and reduced apoptosis in a dose-dependent manner. A new EVLP perfusate was designed and tested based on DMEM. The final formula contains 5 g/L Dextran-40 and 7% albumin and is named as D05D7A solution. It inhibited cold static storage and warm reperfusion-induced cell apoptosis, improved cell confluence, and enhanced GSH and HSP70 levels in human lung cells compared to Steen solution. DMEM-based nutrient-rich EVLP perfusate could be a promising formula to prolong EVLP and support donor lung repair, reconditioning and further improve donor lung quality and quantity for transplantation with better clinical outcome.

Introduction: The emergency department (ED) is an effective setting for initiating medication for opioid use disorder (MOUD); however, predicting who will remain in treatment remains a central challenge. We hypothesize that baseline stage-of-change (SOC) assessment is associated with short-term treatment retention outcomes. Methods: This is a longitudinal cohort study of all patients enrolled in an ED MOUD program over 12 months. Eligible and willing patients were treated with buprenorphine at baseline and had addiction medicine specialist follow-up arranged. Treatment retention at 30 and 90 days was determined by review of the Prescription Drug Monitoring Program. We used uni- and multivariate logistic regression to evaluate associations between patient variables and treatment retention at 30 and 90 days. Results: From June 2018–May 2019, 279 patients were enrolled in the ED MOUD program. Of those patients 151 (54.1%) and 120 (43.0%) remained engaged in MOUD treatment at 30 and 90 days, respectively. The odds of treatment adherence at 30 days were significantly higher for those with advanced SOC (preparation/action/maintenance) compared to those presenting with limited SOC (pre-contemplation/contemplation) (60.0% vs 40.8%; odds ratio 2.18; 95% confidence interval 1.15 to 4.1; P 40, having medical insurance, and being employed were significant predictors of continued treatment adherence. At 90 days, advanced SOC, non-White race, age > 40, and having insurance were all significantly associated with higher likelihood of treatment engagement. Conclusion: Greater stage-of-change was significantly associated with MOUD treatment retention at 30 and 90 days post index ED visit.

ObjectiveApproximately 50% of obese Black patients with unprovoked diabetic ketoacidosis (DKA) or severe hyperglycemia (SH) at new-onset diabetes achieve near-normoglycemia remission with intensive insulin treatment. Despite the initial near-normoglycemia remission, most DKA/SH individuals develop hyperglycemia relapse after insulin discontinuation. Traditional biomarkers such as normal glucose tolerance at the time of remission were not predictive of hyperglycemia relapse. We tested whether 1-h plasma glucose (1-h PG) at remission predicts hyperglycemia relapse in Black patients with DKA/SH.MethodsSecondary analysis was performed of two prospective randomized controlled trials in 73 patients with DKA/SH at the safety net hospital with a median follow-up of 408 days. Patients with DKA/SH underwent a 5-point, 2-h 75-g oral glucose tolerance test after hyperglycemia remission. Hyperglycemia relapse is defined by fasting blood glucose (FBG) > 130 mg/dl, random blood glucose (BG) >180 mg/dl, or HbA1c > 7%.ResultsDuring the median 408 (interquartile range: 110–602) days of follow-up, hyperglycemia relapse occurred in 28 (38.4%) participants. One-hour PG value ≥199 mg/dl discriminates hyperglycemia relapse (sensitivity: 64%; specificity: 71%). Elevated levels of 1-h PG (≥199 mg/dl) were independently associated with hyperglycemia relapse (adjusted hazard ratio: 2.40 [95% CI: 1.04, 5.56]). In a multivariable model with FBG, adding 1-h PG level enhanced the prediction of hyperglycemia relapse, with significant improvements in C-index (Δ: +0.05; p = 0.04), net reclassification improvement (NRI: 48.7%; p = 0.04), and integrated discrimination improvement (IDI: 7.8%; p = 0.02) as compared with the addition of 2-h PG (NRI: 20.2%; p = 0.42; IDI: 1.32%; p = 0.41) or HbA1c (NRI: 35.2%; p = 0.143; IDI: 5.8%; p = 0.04).ConclusionOne-hour PG at the time of remission is a better predictor of hyperglycemia relapse than traditional glycemic markers among obese Black patients presenting with DKA/SH. Testing 1-h PG at insulin discontinuation identifies individuals at high risk of developing hyperglycemia relapse.

Abstract Background Approximately 10% of non‐small cell lung cancers (NSCLCs) that harbor epidermal growth factor receptor (EGFR) gene mutations have in‐frame insertions in exon 20 of the EGFR gene. These tumors do not usually respond to currently available EGFR‐tyrosine kinase inhibitors (TKIs). Tarloxotinib is a novel hypoxia‐activated prodrug that releases a potent, irreversible pan‐ERBB TKI (tarloxotinib‐E) under solid tumor hypoxia. Methods We examined the efficacy of tarloxotinib‐E against several types of Ba/F3 cells with introduced EGFR exon 20 mutations (EGFR A763insFQEA, V769insASV, D770insSVD, H773insH and H773insNPH mutations). We assayed growth inhibition for tarloxotinib (prodrug), tarloxotinib‐E (active form), poziotinib, afatinib, and osimertinib in Ba/F3 cells with each EGFR exon 20 mutation. We also explored acquired resistance mechanisms to tarloxotinib‐E by establishing cells with resistance to tarloxotinib‐E via chronic drug exposure after N‐ethyl‐N‐nitrosourea mutagenesis treatment. Results Among all tested Ba/F3 cell lines, IC50 was ≥72.1 times higher for tarloxotinib than for tarloxotinib‐E, which implies a wide therapeutic window with this prodrug strategy. Tarloxotinib‐E was efficacious against all tested Ba/F3 cells except for H773insH, which was less sensitive to all tested EGFR‐TKIs. As acquired resistance mechanisms to tarloxotinib‐E, we identified either T790M or C797S secondary mutations, depending on the original EGFR exon 20 mutation. Conclusions These findings indicate that tarloxotinib‐E could be effective for NSCLC with EGFR exon 20 mutations. Our results also show that T790M or C797S mutations can confer acquired resistance to tarloxotinib‐E; and suggest that resistance mechanisms are influenced by the baseline EGFR exon 20 mutations.

Objective: Concurrent autoimmune disorders, including autoimmune hepatitis (AIH), with Graves disease have been reported. Glucocorticoids can simultaneously lower thyroid hormone levels and treat AIH. Recurrence of hyperthyroidism is associated with recurrence of hepatitis. We present a case of coexisting AIH and Graves thyrotoxicosis, which improved with prednisone, but the thyrotoxicosis recurred during a prednisone taper while the hepatitis stayed in remission. Methods: Evaluation included measurements of liver enzyme levels, thyroid function tests, and thyroid-stimulating antibodies as well as abdominal ultrasound, magnetic resonance imaging, and liver biopsy. Results: A 47-year-old woman presented with nausea and jaundice. Workup showed an aspartate aminotransferase level of 1956 (reference, 10-42) U/L and alanine aminotransferase level of 1634 (reference, 14-54) IU/L. The liver biopsy was consistent with AIH. Nine months later, she reported palpitations, heat intolerance, and weight loss and was diagnosed with Graves disease. The patient received prednisone at 60 mg daily, and the liver and thyroid functions normalized after 1 month. Prednisone was tapered to 5 mg daily. Seven months later, she presented with a thyroid-stimulating hormone level of 0.049 (reference, 0.340-5.6) μIU/mL) and free thyroxine level of 3.96 (reference, 0.58-1.64) ng/dL. Liver enzymes remained at normal levels. Prednisone was increased from 5 to 20 mg to treat hyperthyroidism. The patient was referred for thyroidectomy for a diagnosis of Graves disease with thyrotoxicosis. Conclusion: This case is an example of coexisting autoimmune diseases, Graves disease and AIH, with different clinical courses. Despite initial resolution with glucocorticoid therapy, Graves disease recurred, while AIH stayed in remission.

Triple negative breast cancer is a deadly form of breast cancer with limited therapeutic options. Here the authors show the efficacy of GLUT1 pharmacological inhibition against a subset of tumors expressing RB1, thereby identifying RB1 protein level as a biomarker of sensitivity to anti-GLUT1 therapy.

Objectives: To reduce childhood mortality from severe malaria by implementing the World Health Organization's standardized malarial treatment protocol. Design: Observational study comparing the mortality rate from malaria before and after the intervention. Setting: Inpatient pediatric ward in a district referral hospital of Sierra Leone. Participants: A total of 1298 pediatric patients (ages 0-13 years, male and female) received the intervention, representing 100% of the pediatric patients admitted with severe malaria during the dates of implementation (there were no exclusion criteria). Interventions: We implemented the World Health Organization's standardized malarial protocol on September 30, 2015. Based on monthly run reports of mortality and root cause analysis, we adapted the malaria protocol by adding sublingual glucose as a treatment to target hypoglycemia complications in March 2016. Main Outcome Measures: The primary outcome was a change in monthly percent mortality from severe malaria, and the secondary outcome was the percent of mortality attributed to hypoglycemia. Results: The monthly average percent mortality from severe malaria dropped from 9% to 3.6% after the intervention, which was borderline statistically significant (p 0.06, CI 95% 1.5 to 5.6). The secondary outcome, percent of malarial deaths attributable to hypoglycemia via chart reviews, dropped from 83% to 44% across the study period. There was an increase in the average number of admissions for severe malaria from 71 to 153 children per month in the second half of the year (range from 49-212 per month). Conclusion: Implementing the WHO malaria treatment protocol with bedside tracking of protocol steps reduced malaria mortality and improved our ward's efficiency without adding any human or medical resources.

Bayesian optimisation is a statistical method that efficiently models and optimises expensive “black-box” functions. This review considers the application of Bayesian optimisation to experimental design, in comparison to existing Design of Experiments (DOE) methods. Solutions are surveyed for a range of core issues in experimental design including: the incorporation of prior knowledge, high dimensional optimisation, constraints, batch evaluation, multiple objectives, multi-fidelity data, and mixed variable types.

Tomato is an important crop and has immense health benefits and medicinal value. Here, we described how salinity stress affects tomato plant growth and developmental processes and productivity. It causes ionic toxicity, oxidative damage, osmotic stress, and hormonal imbalance. In this review, we emphasized the crucial role of ethylene (ET) towards in vitro development of tomato crop by mediating stress response, particularly high salt. There are evidences that salinity stress modulates the expression of ACS and beta-CAS, which leads to ET and cyanide accumulation. We draw attention to how ET negatively or positively mediates salinity stress response by maintaining endogenous biomolecules, Na+/K+ ion balance and redox homeostasis. How ET inhibitors and polyamines as protectants reverse the negative effects of ET/salinity stress-induced cellular damage by cross talk with important physiological processes-photosynthesis and respiratory and salt overly sensitive (SOS). The literature appraised herein will contribute to a better understanding of the development of salinity stress tolerant tomato.

There are around 11000 different bird species in the globe. Rarely are certain bird species encountered. Bird identification is a challenging task that usually leads to unclear labelling. When presented a picture of a bird, even professional bird watchers differ on the species. Despite having the same basic components across all bird species, form and appearance can vary greatly. Intraclass variance is substantial due to variations in lighting and backdrop, as well as a wide range of instances. Additionally, visual recognition of birds by humans is more comprehensible than audible recognition of birds. Consequently, the convolutional neural networks(CNN) is utilized for an automated bird species identification system. CNNs are a powerful Deep Learning ensemble that have shown to be effective in image processing. The dataset is used for both training and testing of a CNN system that classifies bird species. This will lead to quick identification of the bird species using an automated process.

Global multicultural teacher education courses and programs have made claims to offer Prospective Teachers (PSTs) a global understanding of diversity and multiculturalism. However, there is very little research that has examined the classroom experiences of PSTs and teacher educators. Drawing on a collaborative autoethnography, this article explores the ways our transnational identities shaped our experiences (as a PST and a teacher educator) in a global teacher education course focused on diversity and multiculturalism. We were guided by the following research question: How do we, as South Asian transnational migrants, experience the curriculum of a global multicultural education course in the United States? We found that the curricular nationalism within multicultural education courses often negates any critical engagement with the influence of transnationalism on immigrants and their educational experiences. Transnational migrants are expected to translate their experiences, cultural practices, and life ways to fit into the container of the U.S. nation-state. Furthermore, there was a visible absence of narratives and research about transnational lives and identities in the course curriculum. As teacher education programs prepare PSTs to enter classrooms with growing immigrant populations, it is important that we attend to this glaring gap in both practice and research.

Bromodomains are conserved protein interaction modules that recognize acetyl-lysine modifications. Here the authors present a set of 25 selective small molecule inhibitors covering 29 human bromodomain targets and comprehensively evaluate the selectivity of this probe-set.

Neuroendocrine prostate cancer (NEPC) is characterized by loss of androgen receptor (AR) signaling during neuroendocrine transdifferentiation, resulting in resistance to AR-targeted therapy. Here they report ONECUT2 to drive NEPC tumorigenesis via regulation of hypoxia signaling and tumor hypoxia, and find hypoxia directed therapy to be effective in NEPC.

This pilot examines whether resistance training (RT) can induce changes in kynurenine (KYN) metabolism, which may contribute to improved physical function in breast cancer survivors (BCSs). Thirty-six BCSs (63.2 ± 1.1 years) underwent assessments of physical function and visual analog scale (100 cm) fatigue and quality of life before and after 12 weeks of RT (N = 22) or non-exercise control (CBCT©: Cognitively Based Compassion Training, N = 10). Blood was collected before and after interventions for assessment of KYN, kynurenic acid (KYNA), and peroxisome proliferator-activated receptor γ co-activator 1α (PGC-1α). At baseline, the women were moderately fatigued (mean score: 46 cm) and at risk of poor functional mobility. A group*time interaction was observed for all measures of strength with improvements (~25–35%) following RT (p’s < 0.01), but not CBCT. Time effects were observed for fatigue (−36%) and quality of life (5%) (p’s < 0.01), where both groups improved in a similar manner. A group*time interaction was observed for KYN (p = 0.02) and PGC-1α (p < 0.05), with KYN decreasing and PGC-1α increasing following RT and the opposite following CBCT. These changes resulted in KYN/KYNA decreasing 34% post-RT, but increasing 21% following CBCT. These data support RT as a therapeutic intervention to counteract the long-term side effect of fatigue and physical dysfunction in BCSs. Additionally, the results suggest that this effect may be mediated through the activation of PGC-1α leading to alterations in KYN metabolism.

Over the past few decades advances in modern medicine have resulted in a global increase in the prevalence of fungal infections. Particularly people undergoing organ transplants or cancer treatments with a compromised immune system are at an elevated risk for lethal fungal infections such as invasive candidiasis, aspergillosis, cryptococcosis, etc. The emergence of drug resistance in fungal pathogens poses a serious threat to mankind and it is critical to identify new targets for the development of antifungals. Calcineurin and TOR proteins are conserved across eukaryotes including pathogenic fungi. Two small molecules FK506 and rapamycin bind to FKBP12 immunophilin and the resulting complexes (FK506-FKBP12 and rapamycin-FKBP12) target calcineurin and TOR, respectively in both humans and fungi. However, due to their immunosuppressive nature these drugs in the current form cannot be used as an antifungal. To overcome this, it is important to identify key differences between human and fungal FKBP12, calcineurin, and TOR proteins which will facilitate the development of new small molecules with higher affinity toward fungal components. The current review highlights FK506/rapamycin-FKBP12 interactions with calcineurin/TOR kinase in human and fungi, and development of non-immunosuppressive analogs of FK506, rapamycin, and novel small molecules in inhibition of fungal calcineurin and TOR kinase.

ABSTRACT Mucormycosis is an emerging lethal fungal infection in immunocompromised patients. Mucor circinelloides is a causal agent of mucormycosis and serves as a model system to understand genetics in Mucorales. Calcineurin is a conserved virulence factor in many pathogenic fungi, and calcineurin inhibition or deletion of the calcineurin regulatory subunit (CnbR) in Mucor results in a shift from hyphal to yeast growth. We analyzed 36 calcineurin inhibitor-resistant or bypass mutants that exhibited hyphal growth in the presence of calcineurin inhibitors or in the yeast-locked cnbRΔ mutant background without carrying any mutations in known calcineurin components. We found that a majority of the mutants had altered sequence in a gene, named here bycA (bypass of calcineurin). bycA encodes an amino acid permease. We verified that both the bycAΔ single mutant and the bycAΔ cnbRΔ double mutant are resistant to calcineurin inhibitor FK506, thereby demonstrating a novel mechanism of resistance against calcineurin inhibitors. We also found that the level of expression of bycA was significantly higher in the wild-type strain treated with FK506 and in the cnbRΔ mutants but was significantly lower in the wild-type strain without FK506 treatment. These findings suggest that bycA is a negative regulator of hyphal growth and/or a positive regulator of yeast growth in Mucor and that calcineurin suppresses expression of the bycA gene at the mRNA level to promote hyphal growth. BycA is involved in the Mucor hypha-yeast transition as our data demonstrate positive correlations among bycA expression, protein kinase A activity, and Mucor yeast growth. Also, calcineurin, independently of its role in morphogenesis, contributes to virulence traits, including phagosome maturation blockade, host cell damages, and proangiogenic growth factor induction during interactions with hosts. IMPORTANCE Mucor is intrinsically resistant to most known antifungals, which makes mucormycosis treatment challenging. Calcineurin is a serine/threonine phosphatase that is widely conserved across eukaryotes. When calcineurin function is inhibited in Mucor, growth shifts to a less virulent yeast growth form, which makes calcineurin an attractive target for development of new antifungal drugs. Previously, we identified two distinct mechanisms through which Mucor can become resistant to calcineurin inhibitors involving Mendelian mutations in the gene for FKBP12, including mechanisms corresponding to calcineurin A or B subunits and epimutations silencing the FKBP12 gene. Here, we identified a third novel mechanism where loss-of-function mutations in the amino acid permease corresponding to the bycA gene contribute to resistance against calcineurin inhibitors. When calcineurin activity is absent, BycA can activate protein kinase A (PKA) to promote yeast growth via a cAMP-independent pathway. Our data also show that calcineurin activity contributes to host-pathogen interactions primarily in the pathogenesis of Mucor.

Abstract Background Junctional adhesion molecule-A (JAM-A) is an adhesion molecule whose overexpression on breast tumor tissue has been associated with aggressive cancer phenotypes, including human epidermal growth factor receptor-2 (HER2)-positive disease. Since JAM-A has been described to regulate HER2 expression in breast cancer cells, we hypothesized that JAM-dependent stabilization of HER2 could participate in resistance to HER2-targeted therapies. Methods Using breast cancer cell line models resistant to anti-HER2 drugs, we investigated JAM-A expression and the effect of JAM-A silencing on biochemical/functional parameters. We also tested whether altered JAM-A expression/processing underpinned differences between drug-sensitive and -resistant cells and acted as a biomarker of patients who developed resistance to HER2-targeted therapies. Results Silencing JAM-A enhanced the anti-proliferative effects of anti-HER2 treatments in trastuzumab- and lapatinib-resistant breast cancer cells and further reduced HER2 protein expression and Akt phosphorylation in drug-treated cells. Increased epidermal growth factor receptor expression observed in drug-resistant models was normalized upon JAM-A silencing. JAM-A was highly expressed in all of a small cohort of HER2-positive patients whose disease recurred following anti-HER2 therapy. High JAM-A expression also correlated with metastatic disease at the time of diagnosis in another patient cohort resistant to trastuzumab therapy. Importantly, cleavage of JAM-A was increased in drug-resistant cell lines in conjunction with increased expression of ADAM-10 and -17 metalloproteases. Pharmacological inhibition or genetic silencing studies suggested a particular role for ADAM-10 in reducing JAM-A cleavage and partially re-sensitizing drug-resistant cells to the anti-proliferative effects of HER2-targeted drugs. Functionally, recombinant cleaved JAM-A enhanced breast cancer cell invasion in vitro and both invasion and proliferation in a semi-in vivo model. Finally, cleaved JAM-A was detectable in the serum of a small cohort of HER2-positive patients and correlated significantly with resistance to HER2-targeted therapy. Conclusions Collectively, our data suggest a novel model whereby increased expression and cleavage of JAM-A drive tumorigenic behavior and act as a biomarker and potential therapeutic target for resistance to HER2-targeted therapies.