Predictions of tissue concentrations of myclobutanil, oxyfluorfen, and pronamide in rat and human after oral exposures via GastroPlusTM physiologically based pharmacokinetic modelling.

Heritage agrochemicals like myclobutanil, oxyfluorfen, and pronamide, are extensively used in agriculture, with well-established studies on their animal toxicity. Yet, human toxicity assessment relies on conventional human risk assessment approaches including the utilization of animal-based ADME (Absorption, Distribution, Metabolism, and Excretion) data. In recent years, Physiologically Based Pharmacokinetic (PBPK) modelling approaches have played an increasing role in human risk assessment of many chemicals including agrochemicals. This study addresses the absence of PBPK-type data for myclobutanil, oxyfluorfen, and pronamide by generating in vitro data for key input PBPK parameters (Caco-2 permeability, rat plasma binding, rat blood to plasma ratio, and rat liver microsomal half-life), followed by generation of PBPK models for these three chemicals via the GastroPlusTM software. Incorporating these experimental input parameters into PBPK models, the prediction accuracy of plasma AUC (area under curve) was significantly improved. Validation against rat oral administration data demonstrated substantial enhancement. Steady-state plasma concentrations (Css) of pronamide aligned well with published data using measured PBPK parameters. Following validation, parent-based tissue concentrations for these agrochemicals were predicted in humans and rats after single or 30-day repeat exposure of 10 mg/kg/day. These predicted concentrations contribute valuable information for future human toxicity risk assessments of these agrochemicals.

'One Is Too Many' preventing self-harm and suicide in military veterans: a quantitative evaluation.

INTRODUCTION: In 2021, the Armed Forces Covenant Fund Trust allocated over £2 million to programmes designed to have a clear and demonstrable impact on suicide prevention. Four grant holders delivered a combination of psychotherapeutic interventions, group activities, social prescribing, peer support mentoring, life skills coaching, educational courses and practical help with housing and employment. The evaluation was completed between August 2021 and July 2023. METHODS: A survey was completed by 503 participants at entry and 423 at exit. It captured data regarding demographic and military-specific details, health status, situational stressors, predisposing symptoms, help-seeking behaviour, social engagement, housing, living arrangements and employment status. The questionnaire included a number of validated psychometric questionnaires. RESULTS: This evaluation revealed reductions in situational stressors, symptoms and mental health illnesses. Seventy-six per cent of participants had completed an Operational Tour, and 77% were exposed to a traumatic event during service. It was the negative impact of unresolved traumatic effects that influenced service-users to require support. Forty-nine per cent delayed seeking help, and 36% self-referred to the One Is Too Many programme which demonstrates the importance of this option. There were improvements in the participants' social networking, social activities, club membership and having people to rely on. Only 4% of participants were women which reinforces the requirement to explore initiatives to engage with female veterans. CONCLUSIONS: Timely therapeutic and social prescribing interventions in a safe environment lowered depression, anxiety and the associated situational stressors leading to self-harming and may have reduced suicide. It presented another option to veterans and their families regarding where they can obtain support, care and therapeutic interventions. The programme provided a strong foundation for delivery organisations to forge lasting collaborative partnerships that can be extended to working with other authorities and institutes. The results highlight pathways for prevention and intervention strategies to inform policymakers, healthcare professionals and third-sector organisations.

Evaluation of the NHS England 'Op COURAGE' High Intensity Service for military veterans with significant mental health problems.

INTRODUCTION: In November 2020, The NHS for England launched a pilot High Intensity Service (HIS) programme for treating military veterans complex mental health problems. Seven regional grants were awarded to manage the HIS, including NHS Solent, in South East England. This paper details an evaluation of the HIS, which was conducted from February 2021 to August 2022. METHODS: This mixed-methods study gained quantitative data from a specifically designed questionnaire that included a number of validated psychometric questionnaires. These were completed by either HIS staff or beneficiaries at entry and exit from the HIS, and qualitative data were gained from semi-structured interviews with the HIS staff. RESULTS: Data were sourced from 45 pre-questionnaires, 25 post programme questionnaires and 11 interviews. This evaluation identified reductions in situational stressors, symptoms and reported illnesses for veterans in crisis. There were reductions in depression, anxiety and post-traumatic stress disorder following programme exit. Staff reported that there was no notable changes in stress levels which appeared to remain high at programme exit. Staff interviews highlighted the importance of simultaneously understanding the social and psychological needs of veterans in mental health crisis. The benefits of integrating veteran staff members into military veteran health services were identified, demonstrating improvements in education around military culture in civilian services. CONCLUSIONS: The importance of collaboration between clinical and veteran staff members in veteran health services was noted, demonstrating the positive impact social care provision has on veteran's overall health and well-being. Veteran engagement with the service was advocated as a result of veterans accessing the service feeling understood. This first independent evaluation of the HIS provides a positive reflection, and adds to the limited empirical evidence exploring veteran engagement in health services.

Team Effort: A Call for Mental Health Clinicians to Support Sports Access for Transgender and Gender Diverse Youth.

There has been an increase in the number of youth in the United States who identify as transgender and/or as nonbinary, which generally refers to people whose gender identity does not align with the one associated with their assigned sex at birth. Unfortunately, transgender and gender diverse (TGD) youth have higher rates of depression, suicidality, self-harm, and disordered eating compared to cisgender peers.1 It is critical to emphasize, however, that such health disparities are reflective of TGD people having to simultaneously navigate transphobic, homophobic, and racist social contexts; manage gender dysphoria, which is the distress resulting from an incongruence between gender identity and assigned sex at birth; and endure an onslaught of anti-transgender legislation that attacks the rights and bodies of TGD people. Given that TGD youth have had alarmingly high rates of suicide for the past decade, it is imperative that health care providers identify and increase access to opportunities and activities that promote positive socioemotional development to mitigate such risk. One resource that has the potential to boost mental health outcomes for this community is physical activity and sports (PA/S).

Virtual Communication Across Differences: Development of a Workshop on Managing Patient Bias.

PROBLEM: Despite the prevalence and detrimental effects of racial discrimination in American society and its health care systems, few medical schools have designed and implemented curricula to prepare medical students to respond to patient bias and racism. APPROACH: During the summer of 2020, a virtual communication class was designed that focused on training medical students in how to respond to patient bias and racism. Following brief didactics at the start of the session, students practiced scenarios with actors in small groups and received direct feedback from faculty. For each scenario, students were instructed to briefly gather a patient's history and schedule an appointment with the attending whose name triggered the patient to request an "American" provider. In one scenario, the patient's request was motivated by untreated hearing loss and difficulty understanding accents. In another, it was motivated by racist views toward foreign physicians. Students were to use motivational interviewing (MI) to uncover the reasoning behind the request and respond appropriately. Students assessed their presession and postsession confidence on 5 learning objectives that reflect successful communication modeled after MI techniques. OUTCOMES: Following the session, student skills confidence increased in exploring intentions and beliefs ( P = .026), navigating a conversation with a patient exhibiting bias ( P = .019) and using nonverbal skills to demonstrate empathy ( P = .031). Several students noted that this was their first exposure to the topic in a medical school course and first opportunity to practice these skills under supervision. NEXT STEPS: The experience designing and implementing this module preparing students in responding to patient bias and racism suggests that such an effort is feasible, affordable, and effective. With the clear need for such a program and positive impact on student confidence navigating these discussions, including such training in medical school programs appears feasible and is strongly encouraged.

Identifying protective factors for gender diverse adolescents' mental health.

Few studies have disentangled differences in victimization exposures and mental health symptoms among gender diverse subgroups, nor considered the role of potential protective factors in ameliorating the impact of victimization on gender diverse youths' mental health. Here we report findings from a secondary data analysis, in which we address this gap by analyzing cross-sectional survey data (N = 11,264 in the final analytic sample) from a population-based survey of youth in participating school districts in a large Midwestern U.S. county. Relative to cisgender youth with gender conforming expression, transgender youth and cisgender youth with nonconforming gender expression are more likely to experience victimization and severe mental health concerns. Additionally, school-connectedness moderates the association between bias-based harassment and depression for cisgender youth with gender nonconforming expression, and family support/monitoring buffers the association of peer victimization with suicide attempts among transgender youth. Findings highlight the need to better understand factors which may confer protection among gender diverse adolescents, so that in turn appropriate supports across key contexts can be implemented.

Evaluating the performance characteristics of five lateral flow assays for the detection of the SARS-CoV-2 nucleocapsid antigen.

In response to the COVID-19 pandemic, lateral flow assays (LFAs) for the detection of SARS-CoV-2 antigen have been proposed as a complementary option to the more costly and time consuming reverse-transcriptase polymerase chain reaction (RT-PCR). We assessed five commercially available SARS-CoV-2 antigen detecting LFAs (ASSUT EUROPE (Rome, Italy), Besthree (Taizhou, China), Encode (Zhuhai, China), Fortress (Antrim UK), and Hughes Medical (Buckinghamshire, UK), using samples collected from hospitalised individuals with COVID-19 and compared these results against established RT-PCR assays with the aim of estimating test performance characteristics. We performed a diagnostic accuracy study of the five LFAs on 110 inpatients with confirmed COVID-19 and 75 COVID-19 negative control participants. Assay evaluation was performed using a modified version of each manufacturer's protocol allowing for parallel testing of a single sample on multiple assays. Additional variables were studied including infection acquisition, oxygenation requirements at time of swabbing, and patient outcomes. The 110 patients were 48% (53) female, with mean age 67 years (range 26-100 years), and 77% (85) cases were community onset SARS-CoV-2. Across the five assays, sensitivity ranged from 64 (95% CI 53-73) to 76% (95% CI 65-85); Fortress performed best with sensitivity of 76% (95% CI 65-85). Specificity was high across all assays with 4/5 LFAs achieving 100%. LFA sensitivity was not dependant on RT-PCR cycle thresholds. SARS-CoV-2 antigen detecting LFAs may complement RT-PCR testing to facilitate early diagnosis and provide community testing strategies for identification of patients with COVID-19, however we find suboptimal test performance characteristics across a range of commercially available manufacturers, below WHO and MHRA pre-set sensitivity performance thresholds. With such variation in sensitivity between LFAs and PCR testing and between assay brands, we advise caution in the deployment of LFAs outside of environments with clinical oversight.

Strategies aimed at preventing long-term opioid use in trauma and orthopaedic surgery: a scoping review.

BACKGROUND: Long-term opioid use, which may have significant individual and societal impacts, has been documented in up to 20% of patients after trauma or orthopaedic surgery. The objectives of this scoping review were to systematically map the research on strategies aiming to prevent chronic opioid use in these populations and to identify knowledge gaps in this area. METHODS: This scoping review is reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) Checklist. We searched seven databases and websites of relevant organizations. Selected studies and guidelines were published between January 2008 and September 2021. Preventive strategies were categorized as: system-based, pharmacological, educational, multimodal, and others. We summarized findings using measures of central tendency and frequency along with p-values. We also reported the level of evidence and the strength of recommendations presented in clinical guidelines. RESULTS: A total of 391 studies met the inclusion criteria after initial screening from which 66 studies and 20 guidelines were selected. Studies mainly focused on orthopaedic surgery (62,1%), trauma (30.3%) and spine surgery (7.6%). Among system-based strategies, hospital-based individualized opioid tapering protocols, and regulation initiatives limiting the prescription of opioids were associated with statistically significant decreases in morphine equivalent doses (MEDs) at 1 to 3 months following trauma and orthopaedic surgery. Among pharmacological strategies, only the use of non-steroidal anti-inflammatory drugs and beta blockers led to a significant reduction in MEDs up to 12 months after orthopaedic surgery. Most studies on educational strategies, multimodal strategies and psychological strategies were associated with significant reductions in MEDs beyond 1 month. The majority of recommendations from clinical practice guidelines were of low level of evidence. CONCLUSIONS: This scoping review advances knowledge on existing strategies to prevent long-term opioid use in trauma and orthopaedic surgery patients. We observed that system-based, educational, multimodal and psychological strategies are the most promising. Future research should focus on determining which strategies should be implemented particularly in trauma patients at high risk for long-term use, testing those that can promote a judicious prescription of opioids while preventing an illicit use, and evaluating their effects on relevant patient-reported and social outcomes.

Nanopore sequencing of clonal IGH rearrangements in cell-free DNA as a biomarker for acute lymphoblastic leukemia.

Background: Acute Lymphoblastic Leukemia (ALL) is the most common pediatric cancer, and patients with relapsed ALL have a poor prognosis. Detection of ALL blasts remaining at the end of treatment, or minimal residual disease (MRD), and spread of ALL into the central nervous system (CNS) have prognostic importance in ALL. Current methods to detect MRD and CNS disease in ALL rely on the presence of ALL blasts in patient samples. Cell-free DNA, or small fragments of DNA released by cancer cells into patient biofluids, has emerged as a robust and sensitive biomarker to assess cancer burden, although cfDNA analysis has not previously been applied to ALL. Methods: We present a simple and rapid workflow based on NanoporeMinION sequencing of PCR amplified B cell-specific rearrangement of the (IGH) locus in cfDNA from B-ALL patient samples. A cohort of 5 pediatric B-ALL patient samples was chosen for the study based on the MRD and CNS disease status. Results: Quantitation of IGH-variable sequences in cfDNA allowed us to detect clonal heterogeneity and track the response of individual B-ALL clones throughout treatment. cfDNA was detected in patient biofluids with clinical diagnoses of MRD and CNS disease, and leukemic clones could be detected even when diagnostic cell-count thresholds for MRD were not met. These data suggest that cfDNA assays may be useful in detecting the presence of ALL in the patient, even when blasts are not physically present in the biofluid sample. Conclusions: The Nanopore IGH detection workflow to monitor cell-free DNA is a simple, rapid, and inexpensive assay that may ultimately serve as a valuable complement to traditional clinical diagnostic approaches for ALL.

Case Report: Syndrome of Remitting Seronegative Symmetrical Synovitis with Pitting Edema-A Rare but Treatable Condition in Palliative Medicine.

The syndrome of remitting seronegative symmetrical synovitis with pitting edema (RS3PE) is a rare diagnosis that is often missed due to lack of both definitive diagnostic criteria and awareness of the disease. This case report describes a patient with chronic lymphocytic leukemia whose diagnosis of RS3PE was possibly delayed due to concomitant treatment-related arthralgias. The pathophysiology, presentation, and treatment of RS3PE are discussed. Greater awareness of malignancy-related RS3PE is crucial from a palliative care perspective as typical opioid pain management will prove ineffective and delay appropriate treatment.

Biological Investigations of Ru(II) Complexes With Diverse ß-diketone Ligands.

The ß-diketone scaffold is a commonly used synthetic intermediate, and is a functional group found in natural products such as curcuminoids. This core structure can also act as a chelating ligand for a variety of metals. In order to assess the potential of this scaffold for medicinal inorganic chemistry, seven different κ2-O,O'-chelating ligands were used to construct Ru(II) complexes with polypyridyl co-ligands, and their biological activity was evaluated. The complexes demonstrated promising structure-dependent cytotoxicity. Three complexes maintained high activity in a tumor spheroid model, and all complexes demonstrated low in vivo toxicity in a zebrafish model. From this series, the best compound exhibited a ~ 30-fold window between cytotoxicity in a 3-D tumor spheroid model and potential in vivo toxicity. These results suggest that κ2-O,O'-ligands can be incorporated into Ru(II)-polypyridyl complexes to create favorable candidates for future drug development.

Global upper-atmospheric heating on Jupiter by the polar aurorae.

Jupiter's upper atmosphere is considerably hotter than expected from the amount of sunlight that it receives1-3. Processes that couple the magnetosphere to the atmosphere give rise to intense auroral emissions and enormous deposition of energy in the magnetic polar regions, so it has been presumed that redistribution of this energy could heat the rest of the planet4-6. Instead, most thermospheric global circulation models demonstrate that auroral energy is trapped at high latitudes by the strong winds on this rapidly rotating planet3,5,7-10. Consequently, other possible heat sources have continued to be studied, such as heating by gravity waves and acoustic waves emanating from the lower atmosphere2,11-13. Each mechanism would imprint a unique signature on the global Jovian temperature gradients, thus revealing the dominant heat source, but a lack of planet-wide, high-resolution data has meant that these gradients have not been determined. Here we report infrared spectroscopy of Jupiter with a spatial resolution of 2 degrees in longitude and latitude, extending from pole to equator. We find that temperatures decrease steadily from the auroral polar regions to the equator. Furthermore, during a period of enhanced activity possibly driven by a solar wind compression, a high-temperature planetary-scale structure was observed that may be propagating from the aurora. These observations indicate that Jupiter's upper atmosphere is predominantly heated by the redistribution of auroral energy.

Influence of concomitant injuries on post-concussion symptoms after a mild traumatic brain injury - a prospective multicentre cohort study.

Objectives: To compare post-concussion symptoms (PCS) and return to normal activities between mild Traumatic Brain Injury (mTBI) patients with or without concomitant injuries at 7-and 90 days post-mTBI.Methods: Design: Sub-analysis of a multicentre prospective cohort study. PARTICIPANTS AND SETTING: patients with mTBI from 7 Canadian Emergency Departments. PROCEDURE: Research assistants conducted telephone follow-ups using the Rivermead Postconcussion Symptoms Questionnaire (RPQ) at 7-, 30- and 90 days post-mTBI. MAIN OUTCOME: Presence of PCS (RPQ: ≥3 symptoms) at 90 days. SECONDARY OUTCOMES: RPQ score ≥21, prevalence of individual RPQ symptoms and patients' return to normal activities, at 7- and 90-days. Adjusted risk ratios (RR) were calculated.Results: 1725 mTBI patients were included and 1055 (61.1%) had concomitant injuries. Patients with concomitant injuries were at higher risk of having ≥3 symptoms on the RPQ (RR:1.26 [95% CI 1.01-1.58]) at 90 days. They were also at higher risk of experiencing specific symptoms (dizziness, fatigue, headaches and taking longer to think) and of non-return to their normal activities (RR:2.11 [95% CI 1.30-3.45]).Conclusion: Patients with concomitant injuries have slightly more PCS and seemed to be at higher risk of non-return to their normal activities 90 days, compared to patients without concomitant injuries.

Point-of-care SARS-CoV-2 serological assays for enhanced case finding in a UK inpatient population.

Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2) has become a global pandemic. Case identification is currently made by real-time polymerase chain reaction (PCR) during the acute phase and largely restricted to healthcare laboratories. Serological assays are emerging but independent validation is urgently required to assess their utility. We evaluated five different point-of-care (POC) SARS-CoV-2 antibody test kits against PCR, finding concordance across the assays (n = 15). We subsequently tested 200 patients using the OrientGene COVID-19 IgG/IgM Rapid Test Cassette and find a sensitivity of 74% in the early infection period (day 5-9 post symptom onset), with 100% sensitivity not seen until day 13, demonstrating inferiority to PCR testing in the infectious period. Negative rate was 96%, but in validating the serological tests uncovered potential false-negatives from PCR testing late-presenting cases. A positive predictive value (PPV) of 37% in the general population precludes any use for general screening. Where a case definition is applied however, the PPV is substantially improved (95.4%), supporting use of serology testing in carefully targeted, high-risk populations. Larger studies in specific patient cohorts, including those with mild infection are urgently required to inform on the applicability of POC serological assays to help control the spread of SARS-CoV-2 and improve case finding of patients that may experience late complications.

The effect of ego depletion on challenge and threat evaluations during a potentially stressful public speaking task.

It has been well established that challenge and threat evaluations affect the performance of potentially stressful tasks. However, the factors that influence these evaluations have rarely been examined. Objective: This study examined the effects of ego depletion on challenge and threat evaluations during a public speaking task. Method: 262 participants (150 males, 112 females; Mage = 20.5, SD = 4.3) were randomly assigned to either an ego depletion or control group. Participants then completed self-report measures of trait self-control. The ego depletion group performed a written transcription task requiring self-control, while the control group transcribed the text normally. Before the public speaking task, participant's challenge and threat evaluations and subjective ratings of performance were assessed via self-report items. Results: The results of independent t-tests supported the effectiveness of the self-control manipulation. There were no significant differences between the ego depletion and control groups in terms of challenge and threat evaluations or subjective performance. Additional correlation analyses revealed that trait measures of self-control were significantly and negatively related to challenge and threat evaluations and subjective performance. Conclusion: Findings suggest that ego depletion might not influence appraisals of potentially stressful tasks, and thus add to recent evidence questioning the ego-depletion phenomenon.

Atmospheric implications of the lack of H3+ detection at Neptune.

H3+ has been detected at all of the solar system giant planets aside from Neptune. Current observational upper limits imply that there is far less H3+ emission at Neptune than rudimentary modelling would suggest. Here, we explore via modelling a range of atmospheric conditions in order to find some that could be consistent with observational constraints. In particular, we consider that the upper atmosphere might be much cooler than it was during the 1989 Voyager 2 encounter, and we examine the impact of an enhanced influx of external material that could act to reduce H3+ density. Resulting ionosphere models that are consistent with existing H3+ observational constraints have an exospheric temperature of 450 K or less, 300 K lower than the Voyager 2 value. Alternatively, if a topside CO influx of 2 × 108 cm-2 s-1 is imposed, the upper atmospheric temperature can be higher, up to 550 K. The potential cooling of Neptune's atmosphere is relevant for poorly understood giant planet thermospheric energetics, and would also impact aerobreaking manoeuvers for any future spacecraft. Such a large CO influx, if present, could imply Triton is a very active moon with prominent atmospheric escape, and/or that Neptune's rings significantly modify its upper atmosphere, and the introduction of so much exogenic material would complicate interpretation of the origin of species observed in Neptune's lower atmosphere. This article is part a discussion meeting issue 'Future exploration of ice giant systems'.

Parental ancestry and risk of early pregnancy loss at high altitude.

High altitude pregnancy is associated with increased frequency of low birth weight infants and neonatal complications, the risks of which are higher in women of low-altitude ancestry. Does ancestry also influence the risk of miscarriage (pregnancy loss <20 weeks) in high-altitude pregnancy? To answer this, 5386 women from La Paz, Bolivia (3300-4150 m) with ≥1 live-born infant were identified. Data were extracted from medical records including maternal and paternal ancestry, demographic factors, and reproductive history. The risk of miscarriage by ancestry was assessed using multivariate logistic regression, adjusting for parity, and maternal age. Andean women experienced first live-births younger than Mestizo or European women (21.7 ± 4.6 vs 23.4 ± 8.0 vs 24.1 ± 5.1, P < .001). Andeans experienced more pregnancies per year of reproductive life (P < .001) and had significantly higher ratios of live-births to miscarriages than women of Mestizo or European ancestry (P < .001). Andean women were 24% less likely to have ever experienced a miscarriage compared to European women (OR:0.76; CI:0.62-0.90, P < .001). The woman's partner's ancestry wasn't a significant independent predictor of miscarriage. In conclusion, the risk of miscarriage at high altitude is lower in Andean women. The lack of a paternal ancestry effect suggests underlying mechanisms relate more to differential maternal adaptation in early pregnancy than fetal genetics.

Avobenzone incorporation in a diverse range of Ru(II) scaffolds produces potent potential antineoplastic agents.

Four structurally distinct classes of polypyridyl ruthenium complexes containing avobenzone exhibited low micromolar and submicromolar potencies in cancer cells, and were up to 273-fold more active than the parent ligand. Visible light irradiation enhanced the cytotoxicity of some complexes, making them promising candidates for combined chemo-photodynamic therapy.