Soil dissipation and efficacy on itchgrass of soil-applied residual herbicides pendimethalin and clomazone in Louisiana sugarcane.

BACKGROUND: Sugarcane (Saccharum sp.) growers in Louisiana report that the widely used soil residual herbicide, pendimethalin, is less effective at controlling itchgrass (Rottboellia chochinchinensis), possibly through accelerated dissipation from repeated applications. Some growers have started to use another herbicide, clomazone, in place of pendimethalin for itchgrass control when pendimethalin does not provide the necessary control. Little is known about the dissipation of these two herbicides, especially when applied together, in diverse sugarcane soils in Louisiana. Thus, the objective of the research was to measure the dissipation of pendimethalin and clomazone in soils having high itchgrass pressure. Soil samples from five fields were fortified (4 µg g-1) with clomazone and pendimethalin and monitored over the course of 163 days under laboratory conditions. Herbicide levels were determined by extracting the herbicides from soil with acetonitrile and analyzing the extracts with high performance liquid chromatography (HPLC). RESULTS: The results indicate that clomazone is persistent in the soils studied, with a degradation half-life (DT50) of ≥79 days. Pendimethalin dissipates more rapidly in soil with a DT50 ranging from 7 to 59 days. All itchgrass plants showed injury to herbicide but many grew out of symptoms, and responses were not consistent between soil types. CONCLUSION: Pendimethalin dissipation varied greatly between soil types, yet clomazone was generally persistent in each soil tested. However, when these soils were seeded with itchgrass, pendimethalin was more effective at controlling itchgrass than clomazone. Although persistent in the soils tested, the leaching potential of clomazone may limit its long-term effectiveness. Published 2024. This article is a U.S. Government work and is in the public domain in the USA.

Evaluating the quality of multiple-choice question pilot database: A global educator-created tool for concept-based pharmacology learning.

The Core Concepts of Pharmacology (CCP) initiative is developing educational resources to transform pharmacology education into a concept-based approach. This study evaluated the quality of global educator-created MCQs in generating items for the pharmacology concept inventory (PCI) instrument and developed as a resource for learning pharmacology fundamental concepts. A panel of 22 global pharmacology experts recruited from the CCP initiative research team participated in the MCQ pilot database design and evaluation. The quality analysis framework of the MCQs in the pilot database included four assessment tools: item writing guidelines (IWGs), Bloom's taxonomy, the CCP, and the MCQ design format. A two-phase evaluation process was involved, including inter-rater agreement on item quality, followed by resolving conflicts that occurred in quality assessment. The chi-square (χ2) test of independence and Cramer's V correlation tests were utilized to measure the relationship among quality assessment attributes. About 200 MCQs were gathered and 98% underwent expert evaluation. Nearly 80% addressed one or more CCP, with 52% designed using a context-dependent format. However, only 40% addressed higher levels of Bloom's cognitive domain and 10% adhered to all IWGs. A strong positive correlation was observed between the context-based item format and its effectiveness in assessing the higher cognitive domain, the main CCP and improved IWGs adherence. Context-based item construction can assess the higher cognitive skills and fundamental pharmacology concepts, showing potential for rigorous PCI development. The pilot database will store items to create the PCI, aiding the development of a concept-based pharmacology curriculum.

The Lycra arm sleeve for treatment of glenohumeral subluxation in people with sub-acute stroke: a randomized controlled (RC) feasibility study.

BACKGROUND: A Lycra arm sleeve has the potential to reduce glenohumeral subluxation (GHS) in people with stroke (PwS). Aims were (1) to provide feasibility data to inform a future fully powered randomized controlled trial, (2) to understand whether patients would be willing to be randomized, (3) to measure changes in GHS at 3 months after wearing the sleeve when compared to not wearing the sleeve. METHOD: PwS ≥18 years with ≤3/5 shoulder abduction strength and able to give informed consent were recruited. The feasibility data on recruitment, screening, and retention rate at 12 weeks were collected. Participants were asked if they would be happy to be randomized into one of the two groups. The immediate group received the Lycra sleeve on recruitment and wore for up to 10 hours/day for 3 months. The delayed group received the sleeve after follow-up assessment at 3 months. GHS was assessed using diagnostic ultrasound method. RESULTS: Over one year, 257 patients were screened, 34 patients were eligible, and 31 (91%) were recruited. Retention at 3 months was 27 (87%). Of those eligible, all found randomization to be acceptable. In the immediate group, GHS showed reduction from 2.6 ± 0.7 cm (95% CI 2.0-3.1 cm) at baseline to 2.2 ± 0.4 cm (CI 2.0-2.5 cm) at 12 weeks. In the delayed group, mean GHS remained unchanged over 3 months period (2.3 ± 0.5 cm, CI 1.9-2.7 cm). CONCLUSION: Recruitment was harder than anticipated, but there was high retention demonstrating feasible methodology. There is some indication of a clinical effect of Lycra sleeve on GHS early after stroke.

Occupational Exposure of On-Shift Ottawa Firefighters to Flame Retardants and Polycyclic Aromatic Hydrocarbons.

Firefighters can be exposed to complex mixtures of airborne substances, including hazardous substances released during structural fires. This study employed silicone wristbands (SWBs) as passive samplers to investigate potential exposure to polycyclic aromatic hydrocarbons (PAHs) and flame retardants (FRs). SWBs were deployed at different areas of four fire stations, in four truck cabins, and at an office control location; they were also donned outside the jackets of 18 firefighters who responded to fire calls. Overall, office areas had significantly lower PAHs than fire station areas. Vehicle bays and truck cabins had significantly higher concentrations of low molecular weight (LMW) PAHs than sleeping and living room areas. For organophosphate ester flame retardants (OPFRs), tri-n-butyl phosphate (TnBP) and tris(1-chloro-2-propyl) phosphate (TCPP) were detected in all the samples; 2-ethylhexyl diphenyl phosphate (EHDPP) was more frequently detected in the fire station areas. Triphenyl phosphate (TPP) concentrations were highest in the truck cabin and office areas, and tris(1,3-dichloro-2-propyl)phosphate (TDCPP) was highest in truck cabins. Thirteen of 16 PAHs and nine of 36 OPFRs were detected in all the SWBs worn by firefighters, and tris (2-butoxyethyl) phosphate (TBEP) was the predominant OPFR. Levels of LMW PAHs were significantly lower when firefighters did not enter the fire. LMW PAHs, HMW (high molecular weight) PAHs, and EHDPP were significantly elevated when heavy smoke was reported. This work highlights the potential for occupational exposure to PAHs and flame retardants in some fire station areas; moreover, factors that may influence exposure during fire suppression. Whilst firefighters' occupational exposure to PAHs is likely related to fire suppression and exposure to contaminated gear and trucks, exposure to OPFRs may be more related to their presence in truck interiors and electronics.

Cross-condition risk and protective factors for psychosocial distress in parents and carers of children and young people with appearance-affecting conditions and injuries.

Alongside typical parenting challenges, initial condition-specific research suggests thadifferent experiences and support needs.t parents of children with different visible differences may experience similar psychosocial difficulties. Despite this, large-scale cross-condition research to identify risk and protective factors for parental distress and psychosocial adjustment has been lacking. Two hundred and nine parents and carers of children with a range of visible differences completed an online survey comprised of standardised outcome measures, study-specific measures, and open-ended questions. Multiple regression modelling identified possible risk and protective factors, and data collected via open-ended questions were analysed using content analysis. Findings support themes previously identified in small-scale cross-condition qualitative research with parents of children with visible differences. Risk factors for parental negative affect and stress included parental reports of the noticeability of their child's visible difference and teasing. Protective factors included good parent-child communication, self-compassion, knowledge of their child's condition and satisfaction with treatment. The risk and protective factors identified provide important insight into the experiences of this parent population and indicate possible avenues for psychosocial intervention.

Early Intravenous Beta-Blockade with Esmolol in Adults with Severe Traumatic Brain Injury: A Phase 2a Intervention Design Study.

BACKGROUND: Targeted beta-blockade after severe traumatic brain injury may reduce secondary brain injury by attenuating the sympathoadrenal response. The potential role and optimal dosage for esmolol, a selective, short-acting, titratable beta-1 beta-blocker, as a safe, putative early therapy after major traumatic brain injury has not been assessed. METHODS: We conducted a single-center, open-label dose-finding study using an adaptive model-based design. Adults (18 years or older) with severe traumatic brain injury and intracranial pressure monitoring received esmolol within 24 h of injury to reduce their heart rate by 15% from baseline of the preceding 4 h while ensuring cerebral perfusion pressure was maintained above 60 mm Hg. In cohorts of three, the starting dosage and dosage increments were escalated according to a prespecified plan in the absence of dose-limiting toxicity. Dose-limiting toxicity was defined as failure to maintain cerebral perfusion pressure, triggering cessation of esmolol infusion. The primary outcome was the maximum tolerated dosage schedule of esmolol, defined as that associated with less than 10% probability of dose-limiting toxicity. Secondary outcomes include 6-month mortality and 6-month extended Glasgow Outcome Scale score. RESULTS: Sixteen patients (6 [37.5%] female patients; mean age 36 years [standard deviation 13 years]) with a median Glasgow Coma Scale score of 6.5 (interquartile range 5-7) received esmolol. The optimal starting dosage of esmolol was 10 µg/kg/min, with increments every 30 min of 5 µg/kg/min, as it was the highest dosage with less than 10% estimated probability of dose-limiting toxicity (7%). All-cause mortality was 12.5% at 6 months (corresponding to a standardized mortality ratio of 0.63). One dose-limiting toxicity event and no serious adverse hemodynamic effects were seen. CONCLUSIONS: Esmolol administration, titrated to a heart rate reduction of 15%, is feasible within 24 h of severe traumatic brain injury. The probability of dose-limiting toxicity requiring withdrawal of esmolol when using the optimized schedule is low. Trial registrationI SRCTN, ISRCTN11038397, registered retrospectively January 7, 2021 ( https://www.isrctn.com/ISRCTN11038397 ).

Understanding decision-making for and against oncoplastic breast-conserving surgery as an alternative to a mastectomy in early breast cancer: UK ANTHEM qualitative study.

BACKGROUND: Oncoplastic breast-conserving surgery may allow women with early breast cancer to avoid a mastectomy, but many women undergo more extensive surgery, even when breast-conserving options are offered. The aim of the ANTHEM qualitative study was to explore factors influencing women's surgical decision-making for and against oncoplastic breast-conserving surgery. METHODS: Semi-structured interviews were conducted with a purposive sample of women who had received either oncoplastic breast-conserving surgery or a mastectomy with or without immediate breast reconstruction to explore their rationale for procedure choice. Interviews were transcribed verbatim and analysed thematically. Trial registration number: ISRCTN18238549. RESULTS: A total of 27 women from 12 centres were interviewed. Out of these, 12 had chosen oncoplastic breast-conserving surgery and 15 had chosen a mastectomy with or without immediate breast reconstruction. Overwhelmingly, women's decisions were guided by their surgical teams. Decision-making for and against oncoplastic breast-conserving surgery was influenced by three key inter-related factors: perceptions of oncological safety; the importance of maintaining/restoring femininity and body image; and practical issues. Oncological safety was paramount. Women who reported feeling reassured that oncoplastic breast-conserving surgery was oncologically safe were happy to choose this option. Those who were not reassured were more likely to opt for a mastectomy, as a perceived 'safer' option. Most women wished to maintain/restore femininity, with the offer of immediate breast reconstruction essential to make a mastectomy an acceptable option. Practical issues such as the perceived magnitude of the surgery were a lesser concern. CONCLUSION: Decision-making is complex and heavily influenced by the surgical team. High-quality, accurate information about surgical options, including appropriate reassurance about the short- and long-term oncological safety of oncoplastic breast-conserving surgery is vital if women are to make fully informed decisions.

Severity of effect considerations regarding the use of mutation as a toxicological endpoint for risk assessment: A report from the 8th International Workshop on Genotoxicity Testing (IWGT).

Exposure levels without appreciable human health risk may be determined by dividing a point of departure on a dose-response curve (e.g., benchmark dose) by a composite adjustment factor (AF). An "effect severity" AF (ESAF) is employed in some regulatory contexts. An ESAF of 10 may be incorporated in the derivation of a health-based guidance value (HBGV) when a "severe" toxicological endpoint, such as teratogenicity, irreversible reproductive effects, neurotoxicity, or cancer was observed in the reference study. Although mutation data have been used historically for hazard identification, this endpoint is suitable for quantitative dose-response modeling and risk assessment. As part of the 8th International Workshops on Genotoxicity Testing, a sub-group of the Quantitative Analysis Work Group (WG) explored how the concept of effect severity could be applied to mutation. To approach this question, the WG reviewed the prevailing regulatory guidance on how an ESAF is incorporated into risk assessments, evaluated current knowledge of associations between germline or somatic mutation and severe disease risk, and mined available data on the fraction of human germline mutations expected to cause severe disease. Based on this review and given that mutations are irreversible and some cause severe human disease, in regulatory settings where an ESAF is used, a majority of the WG recommends applying an ESAF value between 2 and 10 when deriving a HBGV from mutation data. This recommendation may need to be revisited in the future if direct measurement of disease-causing mutations by error-corrected next generation sequencing clarifies selection of ESAF values.

Changes in attitudes towards telemedicine in acute burn care following the Covid-19 pandemic.

BACKGROUND: Telemedical referrals after burn injury had been shown to be advantageous over telephone referrals for multiple reasons, however there were several key barriers towards complete implementation. The Covid-19 pandemic facilitated the adoption of telemedicine to ensure the safety of both clinicians and patients. Due to the circumstances, it was unclear whether the pre-pandemic barriers still existed despite the complete implementation of telemedicine. This study aims to evaluate clinicians' views about the barriers towards implementation of a specific telemedicine system for burns referrals, and their changing attitudes following the pandemic, to identify key domains for improvement in current and future telemedicine systems. METHODS: A questionnaire was created to evaluate the attitudes of referring clinicians towards telemedicine, following literature searches and administration of a pilot questionnaire. This was administered via telephone to staff working in EDs and MIUs which referred to the South-West United Kingdom Burns Network using the Medical Data Solutions and Services (MDSAS) system, in both 2019 and 2022. A statistical analysis was performed to compare the attitudes of clinicians towards telemedicine both pre- and post-pandemic. RESULTS: 100 respondents completed the survey in 2019 and 70 in 2022, with similar demographics of respondents. Out of the twelve barriers identified, the lack of reliable Wi-Fi and need to duplicate notes were identified as the main obstacles to implementation in both time periods. In both years, the single greatest barrier reported was poor access to reliable Wi-Fi (p = 0.944). Miscommunication between clinicians using the system, inadequate numbers of devices and financial constraints were identified less frequently as barriers in 2022 than 2019 (p = 0.005, p = 0.047 and p < 0.001 respectively). However, significantly more respondents reported time pressures when waiting for a response to their telemedicine referral in 2022 (p = 0.022). CONCLUSION: Overall, clinicians displayed a positive attitude towards the MDSAS system for acute burns, with clinicians identifying fewer concerns with the system following the Covid-19 pandemic. However, concerns over the time pressures that this telemedicine system places on the referring clinician and existing Wi-Fi infrastructure persist. Further streamlining of the system and investment in internet access is recommended, with continued input from all stakeholders.

Improving motion management in radiation therapy: findings from a workshop and survey in Australia and New Zealand.

Motion management has become an integral part of radiation therapy. Multiple approaches to motion management have been reported in the literature. To allow the sharing of experiences on current practice and emerging technology, the University of Sydney and the New South Wales/Australian Capital Territory branch of the Australasian College of Physical Scientists and Engineers in Medicine (ACPSEM) held a two-day motion management workshop. To inform the workshop program, participants were invited to complete a survey prior to the workshop on current use of motion management techniques and their opinion on the effectiveness of each approach. A post-workshop survey was also conducted, designed to capture changes in opinion as a result of workshop participation. The online workshop was the most well attended ever hosted by the ACPSEM, with over 300 participants and a response to the pre-workshop survey was received from at least 60% of the radiation therapy centres in Australia and New Zealand. Motion management is extensively used in the region with use of deep inspiration breath-hold (DIBH) reported by 98% of centres for left-sided breast treatments and 91% for at least some right-sided breast treatments. Surface guided radiation therapy (SGRT) was the most popular session at the workshop and survey results showed that the use of SGRT is likely to increase. The workshop provided an excellent opportunity for the exchange of knowledge and experience, with most survey respondents indicating that their participation would lead to improvements in the quality of delivery of treatments at their centres.

Toward quantitative super-resolution methods for cryo-CLEM.

Cryogenic ultrastructural imaging techniques such as cryo-electron tomography have produced a revolution in how the structure of biological systems is investigated by enabling the determination of structures of protein complexes immersed in a complex biological matrix within vitrified cell and model organisms. However, so far, the portfolio of successes has been mostly limited to highly abundant complexes or to structures that are relatively unambiguous and easy to identify through electron microscopy. In order to realize the full potential of this revolution, researchers would have to be able to pinpoint lower abundance species and obtain functional annotations on the state of objects of interest which would then be correlated to ultrastructural information to build a complete picture of the structure-function relationships underpinning biological processes. Fluorescence imaging at cryogenic conditions has the potential to be able to meet these demands. However, wide-field images acquired at low numeric aperture (NA) using air immersion objective have a low resolving power and cannot provide accurate enough three-dimensional (3D) localization to enable the assignment of functional annotations to individual objects of interest or target sample debulking to ensure the preservation of the structures of interest. It is therefore necessary to develop super-resolved cryo-fluorescence workflows capable of fulfilling this role and enabling new biological discoveries. In this chapter, we present the current state of development of two super-resolution cryogenic fluorescence techniques, superSIL-STORM and astigmatism-based 3D STORM, show their application to a variety of biological systems and discuss their advantages and limitations. We further discuss the future applicability to cryo-CLEM workflows though examples of practical application to the study of membrane protein complexes both in mammalian cells and in Escherichia coli.

Use of herbal medication in the perioperative period: Potential adverse drug interactions.

Use of herbal medications and supplements has experienced immense growth over the last two decades, with retail sales in the USA exceeding $13 billion in 2021. Since the Dietary Supplement Health and Education Act (DSHEA) of 1994 reduced FDA oversight, these products have become less regulated. Data from 2012 shows 18% of U.S. adults used non-vitamin, non-mineral natural products. Prevalence varies regionally, with higher use in Western states. Among preoperative patients, the most commonly used herbal medications included garlic, ginseng, ginkgo, St. John's wort, and echinacea. However, 50-70% of surgical patients fail to disclose their use of herbal medications to their physicians, and most fail to discontinue them preoperatively. Since herbal medications can interact with anesthetic medications administered during surgery, the American Society of Anesthesiologists (ASA) and the American Association of Nurse Anesthetists (AANA) recommend stopping herbal medications 1-2 weeks before elective surgical procedures. Potential adverse drug effects related to preoperative use of herbal medications involve the coagulation system (e.g., increasing the risk of perioperative bleeding), the cardiovascular system (e.g., arrhythmias, hypotension, hypertension), the central nervous system (e.g., sedation, confusion, seizures), pulmonary (e.g., coughing, bronchospasm), renal (e.g., diuresis) and endocrine-metabolic (e.g., hepatic dysfunction, altered metabolism of anesthetic drugs). During the preoperative evaluation, anesthesiologists should inquire about the use of herbal medications to anticipate potential adverse drug interactions during the perioperative period.

The OdonAssist inflatable device for assisted vaginal birth-the ASSIST II study (United Kingdom).

BACKGROUND: Decreasing rates of assisted vaginal birth have been paralleled with increasing rates of cesarean deliveries over the last 40 years. The OdonAssist is a novel device for assisted vaginal birth. Iterative changes to clinical parameters, device design, and technique have been made to improve device efficacy and usability. OBJECTIVE: This study aimed to determine if the feasibility, safety, and efficacy of the OdonAssist device were sufficient to justify conducting a future randomized controlled trial. STUDY DESIGN: An open-label nonrandomized study of 104 participants having a clinically indicated assisted vaginal birth using the OdonAssist was undertaken at Southmead Hospital, Bristol, United Kingdom. Data were also collected from participants who consented to participate in the study but for whom trained OdonAssist operators were not available, providing a nested cohort. The primary clinical outcome was the proportion of births successfully expedited with the OdonAssist. Secondary outcomes included clinical, patient-reported, operator-reported, device and health care utilization. Neonatal outcome data were reviewed at day 28, and maternal outcomes were investigated up to day 90. Given that the number of successful OdonAssist births was ≥61 out of 104, the hypothesis of a poor rate of 50% was rejected in favor of a good rate of ≥65%. RESULTS: Between August 2019 and June 2021, 941 (64%) of the 1471 approached, eligible participants consented to participate. Of these, 104 received the OdonAssist intervention. Birth was assisted in all cephalic vertex fetal positions, at all stations ≥1 cm below the ischial spines (with or without regional analgesia). The OdonAssist was effective in 69 of the 104 (66%) cases, consistent with the hypothesis of a good efficacy rate. There were no serious device-related maternal or neonatal adverse reactions, and there were no serious adverse device effects. Only 4% of neonatal soft tissue bruising in the successful OdonAssist group was considered device-related, as opposed to 20% and 23% in the unsuccessful OdonAssist group and the nested cohort, respectively. Participants reported high birth perception scores. All practitioners found the device use to be straightforward. CONCLUSION: Recruitment to an interventional study of a new device for assisted vaginal birth is feasible; 64% of eligible participants were willing to participate. The success rate of the OdonAssist was comparable to that of the Kiwi OmniCup when introduced in the same unit in 2002, meeting the threshold for a randomized controlled trial to compare the OdonAssist with current standard practice. There were no disadvantages of study participation in terms of maternal and neonatal outcomes. There were potential advantages of using the OdonAssist, particularly reduced neonatal soft tissue injury. The same application technique is used for all fetal positions, with all operators deeming the device straightforward to use. This study provides important data to inform future study design.

Characterization of elusive rhamnosyl dioxanium ions and their application in complex oligosaccharide synthesis.

Attaining complete anomeric control is still one of the biggest challenges in carbohydrate chemistry. Glycosyl cations such as oxocarbenium and dioxanium ions are key intermediates of glycosylation reactions. Characterizing these highly-reactive intermediates and understanding their glycosylation mechanisms are essential to the stereoselective synthesis of complex carbohydrates. Although C-2 acyl neighbouring-group participation has been well-studied, the reactive intermediates in more remote participation remain elusive and are challenging to study. Herein, we report a workflow that is utilized to characterize rhamnosyl 1,3-bridged dioxanium ions derived from C-3 p-anisoyl esterified donors. First, we use a combination of quantum-chemical calculations and infrared ion spectroscopy to determine the structure of the cationic glycosylation intermediate in the gas-phase. In addition, we establish the structure and exchange kinetics of highly-reactive, low-abundance species in the solution-phase using chemical exchange saturation transfer, exchange spectroscopy, correlation spectroscopy, heteronuclear single-quantum correlation, and heteronuclear multiple-bond correlation nuclear magnetic resonance spectroscopy. Finally, we apply C-3 acyl neighbouring-group participation to the synthesis of complex bacterial oligosaccharides. This combined approach of finding answers to fundamental physical-chemical questions and their application in organic synthesis provides a robust basis for elucidating highly-reactive intermediates in glycosylation reactions.

Assessing Appearance, Speech, and Hearing (dis)Satisfaction in Individuals with Cleft Lip and/or Palate: A Contribution to General Population Norms.

BACKGROUND: Individuals with cleft lip and/or palate (CL/P) may grow up with a visible facial difference, alongside speech and/or hearing challenges. Self-perceptions are stronger predictors of psychosocial adjustment than objective assessments, highlighting the importance of patient-reported outcome measures. Previously titled the Satisfaction with Appearance (SwA) questionnaire, the Cleft Hearing, Appearance and Speech Questionnaire (CHASQ) has been used in several countries to assess patient satisfaction, guide clinical decision-making, and conduct craniofacial research, but has lacked general population norms from which to draw comparisons. The aim of this study was to contribute to the development of norms by utilising existing data collected in the United Kingdom (UK) in 2004 using the original SwA. METHODS: SwA data collected from school pupils (n = 761) aged 10-16 years were analysed across age and gender. RESULTS: Hair, Eyes and Ears received the highest ratings, while Teeth received the lowest ratings. Those who were younger, and those who were male, generally rated their appearance more favourably. Thresholds are proposed to identify young people in need of clinical monitoring (10%) and intervention (5%). DISCUSSION: This study supports the potential of the CHASQ as a clinically useful outcome measure and research tool with the ability to identify appearance concerns in relation to specific facial features, as well as overall appearance satisfaction in young people with and without CL/P. Further validation of its use in the CL/P population and other patient groups, as well as countries outside the UK would add additional weight to the CHASQ's utility.

Early Intravenous Beta-Blockade with Esmolol in Adults with Severe Traumatic Brain Injury (EBB-TBI): Protocol for a Phase 2a Intervention Design Study.

Traumatic brain injury is a leading cause of death and disability worldwide. Interventions that mitigate secondary brain injury have the potential to improve outcomes for patients and reduce the impact on communities and society. Increased circulating catecholamines are associated with worse outcomes and there are supportive animal data and indications in human studies of benefit from beta-blockade after severe traumatic brain injury. Here, we present the protocol for a dose-finding study using esmolol in adults commenced within 24 h of severe traumatic brain injury. Esmolol has practical advantages and theoretical benefits as a neuroprotective agent in this setting, but these must be balanced against the known risk of secondary injury from hypotension. The aim of this study is to determine a dose schedule for esmolol, using the continual reassessment method, that combines a clinically significant reduction in heart rate as a surrogate for catecholamine drive with maintenance of cerebral perfusion pressure. The maximum tolerated dosing schedule for esmolol can then be tested for patient benefit in subsequent randomized controlled trials.Trial registration ISRCTN, ISRCTN11038397, registered retrospectively 07/01/2021 https://www.isrctn.com/ISRCTN11038397.

Defining and unpacking the core concepts of pharmacology: A global initiative.

BACKGROUND AND PURPOSE: Development of core concepts in disciplines such as biochemistry, microbiology and physiology have transformed teaching. They provide the foundation for the development of teaching resources for global educators, as well as valid and reliable approaches to assessment. An international research consensus recently identified 25 core concepts of pharmacology. The current study aimed to define and unpack these concepts. EXPERIMENTAL APPROACH: A two-phase, iterative approach, involving 60 international pharmacology education experts, was used. The first phase involved drafting definitions for core concepts and identifying key sub-concepts via a series of online meetings and asynchronous work. These were refined in the second phase, through a 2-day hybrid workshop followed by a further series of online meetings and asynchronous work. KEY RESULTS: The project produced consensus definitions for a final list of 24 core concepts and 103 sub-concepts of pharmacology. The iterative, discursive methodology resulted in modification of concepts from the original study, including change of 'drug-receptor interaction' to 'drug-target interaction' and the change of the core concept 'agonists and antagonists' to sub-concepts of drug-target interaction. CONCLUSIONS AND IMPLICATIONS: Definitions and sub-concepts of 24 core concepts provide an evidence-based foundation for pharmacology curricula development and evaluation. The next steps for this project include the development of a concept inventory to assess acquisition of concepts, as well as the development of case studies and educational resources to support teaching by the global pharmacology community, and student learning of the most critical and fundamental concepts of the discipline.