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Runzhe Chen,1 Jos L Campbell,2,3 Baoan Chen1 1Department of Hematology and Oncology (Key Department of Jiangsu Medicine), Zhongda Hospital, Medical School, Southeast University, Nanjing, People’s Republic of China; 2Stanford University Department of Radiology, Molecular Imaging Program at Stanford, Palo Alto, CA, USA; 3Royal Melbourne Institute of Technology, School of Applied Science, Melbourne, VIC, Australia Abstract: Relapse of acute lymphoblastic leukemia remains a major cause of death in patients following allogeneic hematopoietic stem cell transplantation. Several factors may affect the concurrence and outcome of relapse, which include graft-versus-host disease, minimal residual disease or intrinsic factors of the disease, and transplantation characteristics. The mainstay of relapse prevention and treatment is donor leukocyte infusions, targeted therapies, second transplantation, and other novel therapies. In this review, we mainly focus on addressing the impact of graft-versus-host disease on relapse and the prophylaxis and treatment of acute lymphoblastic leukemia relapse following allogeneic hematopoietic stem cell transplantation. We also make recommendations for critical strategies to prevent relapse after transplantation and challenges that must be addressed to ensure success. Keywords: acute lymphoblastic leukemia, relapse, allogeneic hematopoietic stem cell transplantation, prevention, therapy

Abstract: Clinicians claim that myofascial trigger points (MTrPs) are a primary cause of pain in whiplash injured patients. Pain from MTrPs is often treated by needling, with or without injection. We conducted a placebo controlled study to test the feasibility of a phase III randomised controlled trial investigating the efficacy of MTrP needling in patients with whiplash associated pain. Forty-one patients referred for physiotherapy with a recent whiplash injury, were recruited. Patients were randomised to receive standardised physiotherapy plus either acupuncture or a sham needle control. A trial was judged feasible if: i) the majority of eligible patients were willing to participate; ii) the majority of patients had MTrPs; iii) at least 75% of patients provided completed self-assessment data; iv) no serious adverse events were reported and v) the end of treatment attrition rate was less than 20%. 70% of those patients eligible to participate volunteered to do so; all participants had clinically identified MTrPs; a 100% completion rate was achieved for recorded self-assessment data; no serious adverse events were reported as a result of either intervention; and the end of treatment attrition rate was 17%. A phase III study is both feasible and clinically relevant. This study is currently being planned. [ABSTRACT FROM AUTHOR]

Background: Perchlorate (ClO4-) is an environmental contaminant known to disrupt the thyroid axis of many terrestrial and aquatic species. ClO4- competitively inhibits iodide uptake into the thyroid at the sodium/iodide symporter and disrupts hypothalamic-pituitary-thyroid (HPT) axis homeostasis in rodents. Objective: We evaluated the proposed mode of action for ClO4--induced rat HPT axis perturbations using a biologically based doseDSresponse (BBDR) model of the HPT axis coupled with a physiologically based pharmacokinetic model of ClO4-. Methods: We configured a BBDR-HPT/ClO4- model to describe competitive inhibition of thyroidal uptake of dietary iodide by ClO4- and used it to simulate published adult rat drinking water studies. We compared model-predicted serum thyroid-stimulating hormone (TSH) and total thyroxine (TT4) concentrations with experimental observations reported in these ClO4- drinking water studies. Results: The BBDR-HPT/ClO4- model failed to predict the ClO4--induced onset of disturbances in the HPT axis. Using ClO4- inhibition of dietary iodide uptake into the thyroid, the model underpredicted both the rapid decrease in serum TT4 concentrations and the rise in serum TSH concentrations. Conclusions: Assuming only competitive inhibition of thyroidal uptake of dietary iodide, BBDRHPT/ ClO4- model calculations were inconsistent with the rapid decrease in serum TT4 and the corresponding increase in serum TSH. Availability of bound iodide in the thyroid gland governed the rate of hormone secretion from the thyroid. ClO4- is translocated into the thyroid gland, where it may act directly or indirectly on thyroid hormone synthesis/secretion in the rat. The rate of decline in serum TT4 in these studies after 1 day of treatment with ClO4- appeared consistent with a reduction in thyroid hormone production/secretion. This research demonstrates the utility of a biologically based model to evaluate a proposed mode of action for ClO4- in a complex biological process. [ABSTRACT FROM AUTHOR]

There is both a clear need and a political will to improve self-care in long-term conditions: demand for self-care support interventions is rising. This article discusses current approaches to supporting self-care in primary care, evidence in favour of self-care support, and issues for GPs to consider in planning self-care support systems. In planning care pathways, important choices need to be made about whether to use individual or group-based approaches and what intensity of intervention is appropriate to match patient needs. Investment may also be needed in both health professional competences and practice systems to optimise their ability to support patient self-care. Self-care support is a key approach for the future of UK health care. Practices that are well trained and well organised to support self-care will respond better to the complex challenges of achieving improvements in the outcomes of long-term conditions. [ABSTRACT FROM AUTHOR]

Background: Consultation behaviour is recognized as having numerous determinants, but patients' perceptions of medical urgency have been neglected as a variable of potential importance.Objectives: We aimed to describe the variation in patients' perceptions of medical urgency, and to investigate the influence of socio-economic deprivation on such perceptions. We also aimed to investigate the association between patients' perceptions of urgency and their perception of doctor availability.Methods: We carried out a questionnaire survey (incorporating 10 clinical vignettes) of patients attending one of 17 participating practices during a 1-week study period. A medical urgency score was calculated for each patient, and compared for patients sharing similar characteristics. The setting was West Lothian, Scotland.Results: Patients' perceptions of medical urgency as measured by the urgency score were normally distributed amongst a sample of 4999 patients attending their GP. Whilst socio-economic deprivation was a significant determinant of perceptions of medical urgency, the effect was small and can probably be discounted as an important variable determining such perceptions. An association was observed between patients' perceptions of doctor availability following a non-urgent consultation request and a heightened sense of medical urgency.Conclusions: Further work is required to explain the differences in the population with regard to perceptions of medical urgency, and to examine the association between patients' perceptions of the seriousness of symptoms and the urgency of consultation requests. [ABSTRACT FROM AUTHOR]

Reported prevalence of myocardial infarction-related post-traumatic stress disorder (PTSD) varies from 0 to 25%. PTSD after myocardial infarction may affect quality of life, cardiovascular outcomes, and health service usage. Of 164 patients with previous myocardial infarction, 111 participated in the study and 36 had PTSD, giving a prevalence of 32%; the lowest possible estimate being 22%. PTSD was associated with significantly worse general health than that of individuals without PTSD. Prevalence of PTSD did not vary with time since myocardial infarction. PTSD was not associated with adverse risk factors for future myocardial infarction, such as smoking, high blood pressure, and poor compliance with medication. PTSD after myocardial infarction may be a common, persistent, and overlooked cause of psychological morbidity. [ABSTRACT FROM AUTHOR]

Background: The terminology of a do-not-resuscitate order (DNR) can be confusing and controversial for patients at the end of life. We examined whether changing the name to "Beneficial Care Only" (BCO) would increase patient acceptance., Research Question: Would individuals be more willing to forgo full code status and accept a no-CPR order if the order title was "Beneficial Care Only"?, Study Design and Methods: We conducted a cross-sectional survey of 599 adults residing in the United States, presenting participants with a hypothetical scenario of a terminal patient. Half were given a choice between "full code" (FC) and "DNR" status, and half were given a choice between FC and BCO status. The 20-item survey included multiple-choice responses and one free-response question., Results: In our nationally representative survey of U.S. participants who were 50% female and 26% nonwhite (99% response rate, n = 599/600), there was no difference in participant preference for BCO or DNR overall (p = 0.7616) and across participant sociodemographic characteristics. While themes of participant reasons for choosing against CPR were similar for both DNR and BCO preferences, including (1) harms imposed by CPR, (2) lack of quality of life, (3) trust in the medical team, (4) avoidance of suffering, two additional themes appeared only for BCO responses: (1) CPR would be useless, and (2) the patient would continue to receive beneficial care., Interpretation: We found no statistically significant difference in preference between BCO and DNR orders for a terminally ill patient. These findings suggest changing the terminology of DNR to BCO may not lead to changes in decisions to forgo CPR. The additional themes identified with the use of BCO support the concept that BCO terminology conveys to the recipient that all beneficial care will continue to be provided to the patient., (Copyright © 2024. Published by Elsevier Inc.)

Background: Health service policy in many jurisdictions is driving greater investment into digital primary care services. While some patients and practices may benefit, there are concerns that not all are able or wish to access primary care services online. "Digital facilitation" is the "range of processes, procedures, and personnel seeking to support patients in their uptake and use of online services" and may address such concerns., Objective: As part of a multimethod research program, we undertook surveys of practice staff and patients to gain insight into the support being offered by practices and explore patients' experiences of this support., Methods: General practices from 4 regions of England were sent a questionnaire exploring the modes of digital facilitation offered, the personnel involved in its delivery, and views on the motivations and drivers for providing support. Moreover, 12,822 patients registered with 62 general practices (predominantly those providing practice survey responses) were sent a questionnaire exploring their experiences of any support offered by their practice to use online services., Results: Almost one-third of practices (156/500, 31.2%) responded to the practice survey, with most reporting using passive modes of digital facilitation (eg, display, leaflets, and SMS text messages) and few using active modes (eg, offering tablets or computers or using practice champions). However, 90.9% (130/143) reported providing ad hoc support. Practices agreed that it was the responsibility of both the practice (105/144, 72.9%) and the wider National Health Service (118/143, 82.5%) to support patients in using online services and that providing such support benefited the practice (126/144, 87.5%) and their patients (132/144, 91.7%). Nearly a quarter of the patients (3051/12,822, 23.8%) responded to the patient survey, with few (522/3051, 17.11% or less) reporting awareness of any modes of digital facilitation apart from text messages and emails (1205/3051, 39.5%) and only 13.36% (392/2935) reporting receiving support to use online services. Adjusted logistic regression analyses showed that older patients had a lower likelihood of 4 outcomes: being aware of, or of using, digital facilitation efforts, or being told about or being helped to use online services (all P<.05), particularly with regard to being helped to use online services (adjusted odds ratio for patients aged 85 years versus those aged 55-64 years: 0.08, 95% CI 0.02-0.36). However, ethnic minority participants or those for whom their first language was not English had positive associations with these outcomes., Conclusions: General practices recognize that patients would benefit from support to access online services. However, the support provided is often passive or ad hoc, and patients were seldom aware of digital facilitation efforts that their practice provided. There is potential to increase engagement with online primary care services by providing more support for all patients, particularly to provide targeted support for older patients., (©Rachel Winder, John L Campbell, Nurunnahar Akter, Abodunrin Q Aminu, Jeffrey Lambert, Emma Cockcroft, Chloe Thomas, Christopher E Clark, Carol Bryce, Jon Sussex, Helen Atherton, Christine Marriott, Gary Abel. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 07.08.2024.)

Background: Reducing Emissions from Deforestation and forest Degradation (REDD+) is a program established under the United Nations Framework Convention on Climate Change (UNFCCC) to reduce carbon emissions from forests in developing countries. REDD+ uses an incentive-based approach whereby participating countries are paid to reduce forest carbon loss and increase carbon storage. Country-level carbon accounting is challenging, and estimates of uncertainty in emission reductions are increasingly required in REDD+ reports. This requirement is hard to meet if countries lack the necessary resources, tools, and capabilities. Some REDD+ programs adjust their payments for the uncertainty reported, which presents a perverse incentive because uncertainties are larger if more sources of uncertainty are reported. We surveyed people involved in REDD+ reporting to assess current capacities and barriers to improving estimates of uncertainty., Results: Representatives from 27 countries (44% of REDD+ countries at the time of survey implementation) responded to the survey. Nearly all respondents thought it important to include uncertainty in REDD+ reports, but most felt that the uncertainty reporting by their countries was inadequate. Our independent assessment of reports by these countries to the UNFCCC supported this opinion: Most countries reported uncertainty in activity data (91%) but not in emission factors (4-14%). Few countries use more advanced approaches to estimate uncertainty, such as Monte Carlo and Bayesian techniques, and many respondents indicated that they lack expertise, knowledge, or technical assistance. Other barriers include lack of financial resources and appropriate data. Despite these limitations, nearly all respondents indicated a strong desire to improve estimates of uncertainty in REDD+ reports., Conclusions: The survey indicated that people involved in REDD+ reporting think it highly important to improve estimates of uncertainty in forest carbon accounting. To meet this challenge, it is essential to understand the obstacles countries face in quantifying uncertainty so we can identify where best to allocate efforts and funds. Investments in training and resources are clearly needed to better quantify uncertainty and would likely have successful outcomes given the strong desire for improvement. Tracking the efficacy of programs implemented to improve estimates of uncertainty would be useful for making further refinements., (© 2024. The Author(s).)

Several code-based methods have been created for comparing the frontal sinus in skeletal identification scenarios. However, little is known regarding matched-pair accuracy rates of these methods or how varying image modalities may affect these rates. The goals of this study were to validate the exclusion rates and to establish matched-pair accuracy rates of two well-cited coding methods, Cameriere et al. [23] and Tatlisumak et al. [24]. Additionally, individual variables were assessed for consistency in scoring between image modalities. Using a sample of U.S. African American, Native American, and European American females and males (n = 225), we examined individual variable scoring and string codes between two different image modalities (radiographs and CT-based 3D models). Arcades showed poor scoring consistency between modalities (p < 0.001). Although exclusion rates were similar to those reported in the original studies (93%-96%), matched-pair accuracy rates were low (13%-18%). None of the demographics (collection, sex, age, ancestry, and orientation) had an effect on the odds of a match. Interobserver and intraobserver analyses showed moderate to near-perfect agreement for all variables except supraorbital cells, which had minimal to no agreement. Currently, we do not recommend the application of these frontal sinus coding methods independent of other supporting identification methods given low variable consistency and accuracy rates. Visual identification should still be used to include or exclude an identification when using the frontal sinus., (© 2024 American Academy of Forensic Sciences.)

Background: Rural primary care practices struggle to employ and retain staff, and existing literature regarding recruitment and retention is focused on doctors. Shortages of qualified staff affect practice functioning, quality of care, and patient experience. Dispensing of medications is a rural service valued by patients. However, little is known about how dispensing services are valued by practices or related to the recruitment and retention of staff., Aim: To understand barriers to, and facilitators of, joining and remaining in rural dispensing practice employment, and to explore how rural practices value dispensing services., Design & Setting: Qualitative inquiry in rural primary care practices across England., Method: Semi-structured interviews with rural dispensing staff were undertaken, audio-recorded, transcribed verbatim, and analysed using framework analysis., Results: In total, 17 staff from 12 practices across England were interviewed between June and November 2021. Reasons for taking up employment in rural dispensing practices included perceived career autonomy, development opportunities, and preference for working and living in a rural setting. Skills required for dispensers' roles balanced against low wages were a barrier to recruitment. For nurses, barriers included perceived lack of knowledge around their role in rural care. Revenue from dispensing, opportunities for staff development, job satisfaction, and positive work environments drove retention of staff. However, negative perceptions of rural practice, travel difficulties, lack of applicants, and insufficient remuneration for roles were barriers to retention., Conclusion: Barriers to, and facilitators of, rural primary care recruitment and retention vary by role, and include factors unique to the rural setting., (Copyright © 2024, The Authors.)

The Human Interference Scoring System (HISS) is a novel food-based diet-quality-classification system based on the existing NOVA method. HISS involves food and fluid allocation into categories from digital imagery based on food processing levels, followed by meal plan analysis using food-servings quantification. The primary purpose of this work was to evaluate the reliability of HISS. Trained nutrition professionals analyzed digital photographs from five hypothetical 24 h food recalls and categorized foods into one of four HISS categories. A secondary purpose was to assess the nutrient composition of the food recalls and other selected foods from the HISS categories. Participants effectively categorized foods into HISS categories, with only minor discrepancies noted. High inter-rater reliability was observed in the outer HISS categories: unprocessed and ultra-processed foods. Ultra-processed items consistently displayed elevated energy, carbohydrates, and sugar compared to unprocessed foods, while unprocessed foods exhibited notably higher dietary fiber. This study introduces the HISS as a potentially useful tool for quantifying a food-quality-based system using digital-photography-based assessments. Its high inter-rater reliability and ability to capture relationships between food processing levels and nutrient composition make it a promising method for assessing dietary habits and food quality.

FANCD2 protein, a key coordinator and effector of the interstrand crosslink repair pathway, is also required to prevent excessive nascent strand degradation at hydroxyurea-induced stalled forks. The RAD51 recombinase has also been implicated in regulation of resection at stalled replication forks. The mechanistic contributions of these proteins to fork protection are not well understood. Here, we used purified FANCD2 and RAD51 to study how each protein regulates DNA resection at stalled forks. We characterized three mechanisms of FANCD2-mediated fork protection: (1) The N-terminal domain of FANCD2 inhibits the essential DNA2 nuclease activity by directly binding to DNA2 accounting for over-resection in FANCD2 defective cells. (2) Independent of dimerization with FANCI, FANCD2 itself stabilizes RAD51 filaments to inhibit multiple nucleases, including DNA2, MRE11 and EXO1. (3) Unexpectedly, we uncovered a new FANCD2 function: by stabilizing RAD51 filaments, FANCD2 acts to stimulate the strand exchange activity of RAD51. Our work biochemically explains non-canonical mechanisms by which FANCD2 and RAD51 protect stalled forks. We propose a model in which the strand exchange activity of FANCD2 provides a simple molecular explanation for genetic interactions between FANCD2 and BRCA2 in the FA/BRCA fork protection pathway., (© The Author(s) 2023. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Introduction: ß-chloroprene (2-chloro-1,3-butadiene; CP) causes lung tumors after inhalation exposures in rats and mice. Mice develop these tumors at lower exposures than rats. In rats CP exposures cause depletion of lung glutathione (GSH). Methods: PBPK models developed to relate the appearance of mouse lung tumors with rates of CP metabolism to reactive metabolites or total amounts metabolized during exposures have been expanded to include production of reactive metabolites from CP. The extended PBPK model describes both the unstable oxirane metabolite, 2-CEO, and metabolism of the more stable oxirane, 1-CEO, to reactive metabolites via microsomal oxidation to a diepoxide, and linked production of these metabolites to a PK model predicting GSH depletion with increasing CP exposure. Key information required to develop the model were available from literature studies identifying: 1) microsomal metabolites of CP, and 2) in vitro rates of clearance of CP and 1-CEO from active microsomal preparations from mice, rats, hamsters and humans. Results: Model simulation of concentration dependence of disproportionate increases in reactive metabolite concentrations as exposures increases and decreases in tissue GSH are consistent with the dose-dependence of tumor formation. At the middle bioassay concentrations with a lung tumor incidence, the predicted tissue GSH is less than 50% background. These simulations of reduction in GSH are also consistent with the gene expression results showing the most sensitive pathways are Nrf2-regulation of oxidative stress and GSH metabolism. Discussion: The PBPK model is used to correlate predicted tissue exposure to reactive metabolites with toxicity and carcinogenicity of CP., Competing Interests: Four of the authors JC, HC, CV, and PG involved in the development of the current manuscript are employed by Ramboll US Consulting, Inc., a private consulting firm providing services to private and public organizations on toxicology and risk assessment issues. The authors did not receive any direct compensation from Denka Performance Elastomer, LLC. and were provided salary compensation as part of their employment as consultants. MA, an independent consultant, worked as a subcontractor to Ramboll US Consulting, Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Campbell, Clewell, Van Landingham, Gentry and Andersen.)

In both terrestrial and aquatic environments, a large number of animal behaviors rely on visual cues, with vision acting as the dominant sense for many fish. However, many other streams of information are available, and multiple cues may be incorporated simultaneously. Being free from the constraints of many of their terrestrial counterparts, fish have an expanded range of possible movements typified by a volume rather than an area. Cues such as hydrostatic pressure, which relates to navigation in a vertical plane, may provide more salient and reliable information to fish as they are not affected by poor light conditions or turbidity. Here, we tested banded tetra fish ( Astyanax fasciatus ) in a simple foraging task in order to determine whether visual cues would be prioritized over other salient information, most notably hydrostatic pressure gradients. We found that in both vertical and horizontal arrays there was no evidence for fish favoring one set of cues over the other, with subjects making choices at random once cues were placed into conflict. Visual cues remained as important in the vertical axis as they were in the horizontal axis.

Objectives: The National Clinical Excellence Awards (NCEAs) in England and Wales were designed, as a form of performance-related pay, to reward high-performing senior doctors and dentists. To inform future scoring of applications and subsequent schemes, we sought to understand how current assessors and other stakeholders would define excellence, differentiate between levels of excellence and ensure unbiased definitions and scoring., Design: Semistructured qualitative interview study., Participants: 25 key informants were identified from Advisory Committee on Clinical Excellence Awards subcommittees, and relevant professional organisations in England and Wales. Informants were purposively sampled to achieve variety in gender and ethnicity., Findings: Participants reported that NCEAs had a role in incentivising doctors to strive for excellence. They were consistent in identifying 'clinical excellence' as involving making an exceptional difference to patients and the National Health Service, and in going over and above the expectations associated with the doctor's job plan. Informants who were assessors reported: encountering challenges with the current scoring scheme when seeking to ensure a fair assessment; recognising tendencies to score more or less leniently; and the potential for conscious or unconscious bias in assessments. Particular groups of doctors, including women, doctors in some specialties and settings, doctors from minority ethnic groups, and doctors who work less than full time, were described as being less likely to self-nominate, lacking support in making applications or lacking motivation to apply on account of a perceived likelihood of not being successful. Practical suggestions were made for improving support and training for applicants and assessors., Conclusions: Participants in this qualitative study identified specific concerns in respect of the current approaches adopted in applying for and in assessing NCEAs, pointing to the importance of equity of opportunity to apply, the need for regular training for assessors, and to improved support for applicants and potential applicants., Competing Interests: Competing interests: BMT, GAA, JS, RF, LH and EP declare no completing interests. JLC holds a national clinical excellence award. JLC has previously been both a member and Chair of a Regional Subcommittee of ACCEA, although had no involvement with ACCEA administration at the time the research was commissioned and undertaken., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ.)

Introduction: The UK has worse cancer outcomes than most comparable countries, with a large contribution attributed to diagnostic delay. Electronic risk assessment tools (eRATs) have been developed to identify primary care patients with a ≥2% risk of cancer using features recorded in the electronic record., Methods and Analysis: This is a pragmatic cluster randomised controlled trial in English primary care. Individual general practices will be randomised in a 1:1 ratio to intervention (provision of eRATs for six common cancer sites) or to usual care. The primary outcome is cancer stage at diagnosis, dichotomised to stage 1 or 2 (early) or stage 3 or 4 (advanced) for these six cancers, assessed from National Cancer Registry data. Secondary outcomes include stage at diagnosis for a further six cancers without eRATs, use of urgent referral cancer pathways, total practice cancer diagnoses, routes to cancer diagnosis and 30-day and 1-year cancer survival. Economic and process evaluations will be performed along with service delivery modelling. The primary analysis explores the proportion of patients with early-stage cancer at diagnosis. The sample size calculation used an OR of 0.8 for a cancer being diagnosed at an advanced stage in the intervention arm compared with the control arm, equating to an absolute reduction of 4.8% as an incidence-weighted figure across the six cancers. This requires 530 practices overall, with the intervention active from April 2022 for 2 years., Ethics and Dissemination: The trial has approval from London City and East Research Ethics Committee, reference number 19/LO/0615; protocol version 5.0, 9 May 2022. It is sponsored by the University of Exeter. Dissemination will be by journal publication, conferences, use of appropriate social media and direct sharing with cancer policymakers., Trial Registration Number: ISRCTN22560297., Competing Interests: Competing interests: WH owns background IP for the eRATs but will not use this for personal finacial benefit from any NHS use. All other authors declare no competing interests., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ.)

Increasing fire severity and warmer, drier postfire conditions are making forests in the western United States (West) vulnerable to ecological transformation. Yet, the relative importance of and interactions between these drivers of forest change remain unresolved, particularly over upcoming decades. Here, we assess how the interactive impacts of changing climate and wildfire activity influenced conifer regeneration after 334 wildfires, using a dataset of postfire conifer regeneration from 10,230 field plots. Our findings highlight declining regeneration capacity across the West over the past four decades for the eight dominant conifer species studied. Postfire regeneration is sensitive to high-severity fire, which limits seed availability, and postfire climate, which influences seedling establishment. In the near-term, projected differences in recruitment probability between low- and high-severity fire scenarios were larger than projected climate change impacts for most species, suggesting that reductions in fire severity, and resultant impacts on seed availability, could partially offset expected climate-driven declines in postfire regeneration. Across 40 to 42% of the study area, we project postfire conifer regeneration to be likely following low-severity but not high-severity fire under future climate scenarios (2031 to 2050). However, increasingly warm, dry climate conditions are projected to eventually outweigh the influence of fire severity and seed availability. The percent of the study area considered unlikely to experience conifer regeneration, regardless of fire severity, increased from 5% in 1981 to 2000 to 26 to 31% by mid-century, highlighting a limited time window over which management actions that reduce fire severity may effectively support postfire conifer regeneration.

Introduction: A physiologically based pharmacokinetic (PBPK) model for 3-chloroallyl alcohol (3-CAA) was developed and used to evaluate the design of assays for the in vivo genotoxicity of 3-CAA. Methods: Model development was supported by read across from a published PBPK model for ethanol. Read across was motivated by the expectation that 3-CAA, which like ethanol is a primary alcohol, is metabolized largely by hepatic alcohol dehydrogenases. The PBPK model was used to evaluate how two metrics of tissue dosimetry, maximum blood concentration (Cmax; mg/L) and area under the curve (AUC; mg-hr/L) vary with dose of 3-CAA and with dose route (oral gavage, drinking water). Results: The model predicted that oral gavage results in a 6-fold higher Cmax than the same dose administered in drinking water, but in similar AUCs. Predicted Cmax provided the best correlation with severe toxicity (e.g., lethality) from 3-CAA, consistent with the production of a reactive metabolite. Therefore, drinking water administration can achieve higher sustained concentration without severe toxicity in vivo . Discussion: This evaluation is significant because cytotoxicity is a potential confounder of mutagenicity testing. The PBPK model can be used to ensure that studies meet OECD and USEPA test guidelines and that the highest dose used is not associated with severe toxicity. In addition, PBPK modeling provides assurance of target tissue (e.g., bone marrow) exposure even in the absence of laboratory data, by defining the relationship between applied dose and target tissue dose based on accepted principles of pharmacokinetics, relevant physiology and biochemistry of the dosed animals, and chemical-specific information., Competing Interests: Four of the authors RC, HC, JC, and RG involved in the development of the current manuscript are employed by Ramboll US Consulting, Inc., a private consulting firm providing services to private and public organizations on toxicology and risk assessment issues. They did not receive any direct compensation from Arysta Life Science S. A. S and were provided salary compensation as part of their employment as consultants. MM, an independent consultant, worked as a subcontractor to Ramboll US Consulting, Inc. on this manuscript. The remaining author WC is employed by UPL Limited, Inc., the parent company for Arysta Life Science S.A.S, and a company that manufactures clethodim. Author MM was employed by the company Martha M. Moore LLC., (Copyright © 2023 Conolly, Clewell, Moore, Campbell, Cheng and Gentry.)

In earlier physiologically based pharmacokinetic (PBPK) models for manganese (Mn), the kinetics of transport of Mn into and out of tissues were primarily driven by slow rates of association and dissociation of Mn with tissue binding sites. However, Mn is known to show rapidly reversible binding in tissues. An updated Mn model for primates, following similar work with rats, was developed that included rapid association/dissociation processes with tissue Mn-binding sites, accumulation of free Mn in tissues after saturation of these Mn-binding sites and rapid rates of entry into tissues. This alternative structure successfully described Mn kinetics in tissues in monkeys exposed to Mn via various routes including oral, inhalation, and intraperitoneal, subcutaneous, or intravenous injection and whole-body kinetics and tissue levels in humans. An important contribution of this effort is showing that the extension of the rate constants for binding and cellular uptake established in the monkey were also able to describe kinetic data from humans. With a consistent model structure for monkeys and humans, there is less need to rely on cadaver data and whole-body tracer studies alone to calibrate a human model. The increased biological relevance of the Mn model structure and parameters provides greater confidence in applying the Mn PBPK models to risk assessment. This model is also well-suited to explicitly incorporate emerging information on the role of transporters in tissue disposition, intestinal uptake, and hepatobiliary excretion of Mn., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Society of Toxicology.)

Background: Postextubation dysphagia is a known consequence of endotracheal intubation. Several risk factors for postextubation dysphagia have been identified that could be used to help determine which patients should undergo swallowing assessment by an appropriate professional., Local Problem: At the authors' institution, critical care nurses, health care providers, and speech-language pathology professionals lacked a clear process for referring patients for swallowing assessment after extubation, resulting in inefficiency and confusion. Information to guide their decision-making in this area was needed. To address this need, a multidisciplinary group convened and developed a guide with specific indicators., Methods: A review of the literature on postextubation dysphagia was conducted to determine the most appropriate indicators for the guide, which was piloted in the medical intensive care unit. The utilization rate was calculated. Referrals to speech-language pathology professionals were tabulated before and after the project., Results: During the 11 months before implementation of the project, there were 994 speech-language pathology consultations for postextubation evaluation of swallowing. During the 11 months after implementation, there were 831 consultations, representing a 16.4% reduction. The decline in consultations resulted in cost savings in addition to preventing unnecessary testing before patients' resumption of oral intake. The utilization rate for the guide during the project was 58%., Conclusion: The decision guide was an effective tool to help nurses and health care providers determine which patients should be referred to speech-language pathology professionals for swallowing assessment after extubation, facilitating the appropriate use of limited health care resources., (©2023 American Association of Critical-Care Nurses.)

Understanding the dose-response for formaldehyde-induced nasal cancer in rats is complicated by (1) the uneven distribution of inhaled formaldehyde across the interior surface of the nasal cavity and, (2) the presence of endogenous formaldehyde (endoF) in the nasal mucosa. In this work, we used computational fluid dynamics (CFD) modeling to predict flux of inhaled (exogenous) formaldehyde (exogF) from air into tissue at the specific locations where DNA adducts were measured. Experimental work has identified DNA-protein crosslink (DPX) adducts due to exogF and deoxyguanosine (DG) adducts due to both exogF and endoF. These adducts can be considered biomarkers of exposure for effects of endoF and exogF on DNA that may be part of the mechanism of tumor formation. We describe a computational model linking CFD-predicted flux of formaldehyde from air into tissue, and the intracellular production of endoF, with the formation of DPX and DG adducts. We assumed that, like exogF, endoF can produce DPX. The model accurately reproduces exogDPX, exogDG, and endoDG data after inhalation from 0.7 to 15 ppm. The dose-dependent concentrations of exogDPX and exogDG are predicted to exceed the concentrations of their endogenous counterparts at about 2 and 6 ppm exogF, respectively. At all concentrations examined, the concentrations of endoDPX and exogDPX were predicted to be at least 10-fold higher than that of their DG counterparts. The modeled dose-dependent concentrations of these adducts are suitable to be used together with data on the dose-dependence of cell proliferation to conduct quantitative modeling of formaldehyde-induced rat nasal carcinogenicity., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Society of Toxicology.)

Background: Electronic clinical decision support tools (eCDS) are increasingly available to assist General Practitioners (GP) with the diagnosis and management of a range of health conditions. It is unclear whether the use of eCDS tools has an impact on GP workload. This scoping review aimed to identify the available evidence on the use of eCDS tools by health professionals in general practice in relation to their impact on workload and workflow., Methods: A scoping review was carried out using the Arksey and O'Malley methodological framework. The search strategy was developed iteratively, with three main aspects: general practice/primary care contexts, risk assessment/decision support tools, and workload-related factors. Three databases were searched in 2019, and updated in 2021, covering articles published since 2009: Medline (Ovid), HMIC (Ovid) and Web of Science (TR). Double screening was completed by two reviewers, and data extracted from included articles were analysed., Results: The search resulted in 5,594 references, leading to 95 full articles, referring to 87 studies, after screening. Of these, 36 studies were based in the USA, 21 in the UK and 11 in Australia. A further 18 originated from Canada or Europe, with the remaining studies conducted in New Zealand, South Africa and Malaysia. Studies examined the use of eCDS tools and reported some findings related to their impact on workload, including on consultation duration. Most studies were qualitative and exploratory in nature, reporting health professionals' subjective perceptions of consultation duration as opposed to objectively-measured time spent using tools or consultation durations. Other workload-related findings included impacts on cognitive workload, "workflow" and dialogue with patients, and clinicians' experience of "alert fatigue"., Conclusions: The published literature on the impact of eCDS tools in general practice showed that limited efforts have focused on investigating the impact of such tools on workload and workflow. To gain an understanding of this area, further research, including quantitative measurement of consultation durations, would be useful to inform the future design and implementation of eCDS tools., (© 2023. The Author(s).)

We developed a structural identification method for eicosanoids with various ring structures using mass spectrometry. We discovered that an electron beam with a kinetic energy of 10 eV, which is in the Electron Impact Excitation of Ions from Organics (EIEIO) regime, cleaved the fatty acids enough to distinguish constitutional and cis/trans isomers. In addition to EIEIO, a comparison to authentic standards using differential mobility spectrometry (DMS) can identify diastereomers, which was difficult by EIEIO. The combination of EIEIO and DMS can provide a high-throughput method to identify complete structures of eicosanoids in mixed samples, which is not allowed with conventional analytical methods though eicosanoids are important signaling molecules in biosystems.

This review shows that relatively simple changes to diet and lifestyle can significantly, and rapidly, reduce the risks associated with coronavirus disease 2019 (COVID-19) in terms of infection risk, severity of disease, and even disease-related mortality. A wide range of interventions including regular exercise, adequate sleep, plant-based diets, maintenance of healthy weight, dietary supplementation, and time in nature have each been shown to have beneficial effects for supporting more positive health outcomes with COVID-19, in addition to promoting better overall health. This paper brings together literature from these areas and presents the argument that non-pharmaceutical approaches should not be overlooked in our response to COVID-19. It is noted that, in several cases, interventions discussed result in risk reductions equivalent to, or even greater than, those associated with currently available vaccines. Where the balance of evidence suggests benefits, and the risk is minimal to none, it is suggested that communicating the power of individual actions to the public becomes morally imperative. Further, many lives could be saved, and many harms from the vaccine mandates avoided, if we were willing to embrace this lifestyle-centred approach in our efforts to deal with COVID-19., (Copyright © 2022 Shanghai Changhai Hospital. Published by Elsevier B.V. All rights reserved.)

Background: Guidelines recommend measuring blood pressure (BP) in both arms, adopting the higher arm readings for diagnosis and management. Data to support this recommendation are lacking. We evaluated associations of higher and lower arm systolic BPs with diagnostic and treatment thresholds, and prognosis in hypertension, using data from the Inter-arm Blood Pressure Difference-Individual Participant Data Collaboration., Methods: One-stage multivariable Cox regression models, stratified by study, were used to examine associations of higher or lower reading arm BPs with cardiovascular mortality, all-cause mortality, and cardiovascular events, in individual participant data meta-analyses pooled from 23 cohorts. Cardiovascular events were modelled for Framingham and atherosclerotic cardiovascular disease risk scores. Model fit was compared throughout using Akaike information criteria. Proportions reclassified across guideline recommended intervention thresholds were also compared., Results: We analyzed 53 172 participants: mean age 60 years; 48% female. Higher arm BP, compared with lower arm, reclassified 12% of participants at either 130 or 140 mm Hg systolic BP thresholds (both P< 0.001). Higher arm BP models fitted better for all-cause mortality, cardiovascular mortality, and cardiovascular events (all P <0.001). Higher arm BP models better predicted cardiovascular events with Framingham and atherosclerotic cardiovascular disease risk scores (both P <0.001) and reclassified 4.6% and 3.5% of participants respectively to higher risk categories compared with lower arm BPs)., Conclusions: Using BP from higher instead of lower reading arms reclassified 12% of people over thresholds used to diagnose hypertension. All prediction models performed better when using the higher arm BP. Both arms should be measured for accurate diagnosis and management of hypertension., Registration: URL: https://www., Clinicaltrials: gov; Unique identifier: CRD42015031227.

Background: Systolic inter-arm differences (IAD) in blood pressure (BP) contribute independently to cardiovascular risk estimates. This can be used to refine predicted risk and guide personalised interventions., Aim: To model the effect of accounting for IAD in cardiovascular risk estimation in a primary care population free of pre-existing cardiovascular disease., Design & Setting: A cross-sectional analysis of people aged 40-75 years attending NHS Health Checks in one general practice in England., Method: Simultaneous bilateral BP measurements were made during health checks. QRISK2, atherosclerotic cardiovascular disease (ASCVD), and Framingham cardiovascular risk scores were calculated before and after adjustment for IAD using previously published hazard ratios. Reclassification across guideline-recommended intervention thresholds was analysed., Results: Data for 334 participants were analysed. Mean (standard deviation) QRISK2, ASCVD, and Framingham scores were 8.0 (6.9), 6.9 (6.5), and 10.7 (8.1), respectively, rising to 8.9 (7.7), 7.1 (6.7), and 11.2 (8.5) after adjustment for IAD. Thirteen (3.9%) participants were reclassified from below to above the 10% QRISK2 threshold, three (0.9%) for the ASCVD 10% threshold, and nine (2.7%) for the Framingham 15% threshold., Conclusion: Knowledge of IAD can be used to refine cardiovascular risk estimates in primary care. By accounting for IAD, recommendations of interventions for primary prevention of cardiovascular disease can be personalised and treatment offered to those at greater than average risk. When assessing elevated clinic BP readings, both arms should be measured to allow fuller estimation of cardiovascular risk., (Copyright © 2022, The Authors.)