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The apolipoprotein (APOE) ɛ4 allele is a risk factor for Alzheimer's disease (AD), whereas the ɛ2 allele is thought to be protective against AD. Few studies have examined the relationship between brain pathologies, atrophy, white matter hyperintensities (WMHs) and APOE status in those with the ɛ2ɛ4 genotype and results are inconsistent for those with an ɛ2 allele. Alzheimer's disease neuroimaging participants were divided into 1 of 4 APOE allele profiles (E4 = ɛ4ɛ4 or ɛ3ɛ4; E2 = ɛ2ɛ2 or ɛ2ɛ3; E3 = ɛ3ɛ3; or E24 = ɛ2ɛ4). Linear mixed models examined the relationship between APOE profiles and brain changes (i.e. regional WMHs, ventricle size, hippocampal and entorhinal cortex volume, amyloid level, and phosphorylated tau measures), while controlling for age, sex, education, and diagnostic status at baseline and over time. APOE ɛ4 was associated with increased pathology, whereas ɛ2 positivity is associated with reduced baseline and lower accumulation of pathologies and neurodegeneration. APOE ɛ2ɛ4 was similar to ɛ4 (increased neurodegeneration) but with a slower rate of change. The strong associations observed between APOE and pathology show the importance of how genetic factors influence structural brain changes. These findings suggest that ɛ2ɛ4 genotype is related to increased declines associated with the ɛ4 as opposed to the protective effects of the ɛ2. These findings have important implications for initiating treatments and interventions. Given that people with the ɛ2ɛ4 genotype can expect to have increased atrophy, they should be considered (alongside those with an ɛ4) in targeted interventions to reduce brain changes that occur with AD. [ABSTRACT FROM AUTHOR]

Introduction: Antipsychotic use for adolescents (defined here as under 25 year olds) must be done with caution, giving due thought to advantages and potential side effects. Antipsychotics are extremely useful and effective drugs, but have side effects and many of these are problematic. It has been noted that Risperidone is often used for this age group, despite the UK guidance being cautious about its use. Objectives: To assess the extent of Risperidone prescribing in Norfolk/Suffolk for this patient group and to consider the monitoring of this. Given that bone mass density is set down in teens – mid 20's, this is a particularly concerning issue when given to this age group. Additionally, distressing side effects and issues with fertility shoudl be considered. If risperidone is used, Maudsley is very clear that this must be monitored: baseline/annual prolactin levels done, and action should be taken if these are elevated and/or the patient symptomatic. Methods: 1) Evaluate numbers of adolescents, under 2ndry care Mental health service who have been prescribed Risperidone 2) Consider who prescibed it and the indication 3) to consider if routine monitoring had been completed (specifically, baseline prolactin and then annual prolactin levels) 4) to consider if these patients had developed side effects Results: Almost 20% of 18-25 years olds, due to be seen in Youth Community Service had been prescribed Risperidone. Of these, only 44% had had prolactin levels done, despite the guidance. This equates to the over half not having prolactin checked. 60% of patients reveiwed had symptoms of hyperprolactinemia. Indications for use included emotional dysregulation/EUPD, psychosis, ADHD, OCD/ASD and depression Conclusions: Risperidone should be used with extreme caution in this patient group. Medication can be very useful for some young people experiencing distressing symptoms but, as Hippocrates advises, "do no harm" and seek not to cause iatrogenic harm. Given that many of the young people seen by mental health services are experiencing emotional dysregulation (not necessarily an abnormal state in adolescent, when much is in flux), it is tempting to consider medication as one means of trying to alleviate distress. There is no clear treatment for dysregulated feelings, and most would accept that psychological support is more appropriate. Disclosure of Interest: None Declared [ABSTRACT FROM AUTHOR]

Mental health has become increasingly important for the applied sport psychologist, a factor which may include screening, promoting literacy, individual support, and educational programs. However, despite of this importance, few checks have been made on the perceived preparedness of sport psychologists to undertake this work and whether differences may exist between those recently qualified compared to experienced practitioners. Underpinned by the theoretical domains framework, 62 Health and Care Professions Council registered practitioner sport and exercise psychologists (30 females: age: M = 46.13 years and SD = 10.44 years and 32 males: age: M = 43.25 years and SD = 10.47 years) completed an online survey to assess whether they felt equipped to address the mental health dimension of their work. The survey comprised three sections: Demographic and background information, a series of statements (n = 31) adapted from the determinants of implementation behavior questionnaire, and three questions with space for free text comments, inviting participants to explain their level of preparedness to incorporate and deliver mental health interventions. A 6 × 12 analyses of variance yielded significant differences between domain ratings but not across levels of experience or interactions. Data from free text comments were analyzed thematically and categorized into the following three themes: (a) complementing the performance role, (b) awareness of professional boundaries, and (c) importance of further continued professional development. Combined, although practitioners emphasized importance, preparedness ratings ranged from neutral to somewhat agree, calling for further specific sport psychology-based mental health training., (© 2024 The Author(s). European Journal of Sport Science published by Wiley‐VCH GmbH on behalf of European College of Sport Science.)

Many patients cannot tolerate low-dose weekly methotrexate (MTX) therapy for inflammatory arthritis treatment due to life-threatening toxicity. Although biologics offer a target-specific therapy, it raises the risk of serious infections and even cancer due to immune system suppression. We introduce an anti-inflammatory arthritis MTX ester prodrug using a long-circulating biocompatible polymeric macromolecule: folic acid (FA) functionalized hyperbranched polyglycerol (HPG). In vitro the drug MTX is incrementally released through pH and enzymatic degradation over 2 weeks. The role of matrix metalloproteinases (MMPs) in site-specific prodrug activation was verified using synovial fluid (SF) of 26 rheumatology patients and 4 healthy controls. Elevated levels of specific MMPs-markers of joint inflammation-positively correlated with enhanced prodrug release explained by acid-catalyzed hydrolysis of esters by proteases. Intravenously administered 111 In-radiolabeled prodrug confirmed by SPECT/CT imaging that it accumulated preferentially in inflamed joints while reducing off-target side-effects in a mouse model of rheumatoid arthritis (RA). Added FA as a targeting vector prolonged prodrug action; prodrug with 4x less MTX applied every 2 weeks was as effective as weekly MTX therapy. The preclinical results suggest a prodrug-based strategy for the treatment of inflammatory joint diseases, with potential for other chronic inflammatory diseases and cancer., (© 2024 The Author(s). Advanced Healthcare Materials published by Wiley‐VCH GmbH.)

Though conceptually attractive, the use of water-soluble prodrug technology to enhance oral bioavailability of highly insoluble small molecule therapeutics has not been widely adopted. In large part, this is due to the rapid enzymatic or chemical hydrolysis of prodrugs within the gastrointestinal tract, resulting in drug precipitation and no overall improvement in oral bioavailability relative to standard formulation strategies. We reasoned that an optimal water-soluble prodrug could be attained if the rate of prodrug hydrolysis were reduced to favor drug absorption rather than drug precipitation. In doing so, the rate of hydrolysis provides a pharmacokinetic control point for drug delivery. Herein, we report the discovery of a water-soluble promoiety (Sol-moiety) technology to optimize the oral bioavailability of highly insoluble small molecule therapeutics, possessing various functional groups, without the need for sophisticated, often toxic, lipid or organic solvent-based formulations. The power of the technology is demonstrated with marked pharmacokinetic improvement of the commercial drugs enzalutamide, vemurafenib, and paclitaxel. This led to a successful efficacy study of a water-soluble orally administered prodrug of paclitaxel in a mouse pancreatic tumor model., (© 2024. The Author(s).)

Objectives: With high disease and disability burden in rural and remote regions, student-assisted clinics can be an effective workforce development tool to meet community health needs and workforce shortages. This research sought to identify the conditions under which student-assisted clinics can be successfully utilised as a workforce development strategy, with specific application to remote Queensland, Australia., Methods: A rapid review of the international literature in English was conducted. This was the most appropriate type of review because the results of the review were time-sensitive, with the student-assisted clinic model being trialled in Queensland soon. A mixed methods design was applied, with the search strategy piloted with one database., Results: Eleven studies met the inclusion criteria. Seven reported data on participant experiences, including consumers, students, services/clinics, and educators/supervisors/health professionals. Each of the studies operationalised student-assisted clinics through practice models (university-driven learning need), service delivery models (service driven need addressed through a student workforce), community need models (student delivered services primarily addressing a community health need), and blended models (practice need and community need). Some studies reported concerns about fragmentation of services, referral pathways and issues with follow-up, while others reported concerns about sustainable funding. All models reported successful outcomes when focused on service or consumer health outcomes, or student learning outcomes., Conclusions: Student-assisted clinics make an important contribution to the development of the rural and remote health workforce. Student-assisted clinics can complement and extend existing services, supporting workforce development in an overstretched health system impacted by an ongoing pandemic., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Parkinson's disease (PD) is marked by the death of neuromelanin-rich dopaminergic and noradrenergic cells in the substantia nigra (SN) and the locus coeruleus (LC), respectively, resulting in motor and cognitive impairments. While SN dopamine dysfunction has clear neurophysiological effects, the association of reduced LC norepinephrine signaling with brain activity in PD remains to be established. We used neuromelanin-sensitive T1-weighted MRI (NPD = 58; NHC = 27) and task-free magnetoencephalography (NPD = 58; NHC = 65) to identify neuropathophysiological factors related to the degeneration of the LC and SN in patients with PD. We found pathological increases in rhythmic alpha (8-12 Hz) activity in patients with decreased LC neuromelanin, with a stronger association in patients with worse attentional impairments. This negative alpha-LC neuromelanin relationship is strongest in fronto-motor cortices, where alpha activity is inversely related to attention scores. Using neurochemical colocalization analyses with normative atlases of neurotransmitter transporters, we also show that this effect is more pronounced in regions with high densities of norepinephrine transporters. These observations support a noradrenergic association between LC integrity and alpha band activity. Our data also show that rhythmic beta (15-29 Hz) activity in the left somato-motor cortex decreases with lower levels of SN neuromelanin; the same regions where beta activity reflects axial motor symptoms. Together, our findings clarify the association of well-documented alterations of rhythmic neurophysiology in PD with cortical and subcortical neurochemical systems. Specifically, attention-related alpha activity is related to dysfunction of the noradrenergic system, and beta activity with relevance to motor impairments reflects dopaminergic dysfunction., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Importance: Central centrifugal cicatricial alopecia (CCCA) is a scarring alopecia predominantly affecting Black female individuals. Current conventional treatments target inflammation but not the underlying fibrotic processes, often leading to permanent hair loss., Objective: To investigate the associations of low-dose oral metformin, an antidiabetic medication with antifibrotic properties, with clinical symptoms and scalp gene expression patterns in patients with CCCA., Design, Setting, and Participants: This retrospective clinical case series and transcriptomic analysis included patients treated at a single tertiary academic medical center between January 2023 and March 2024. All patients had biopsy-confirmed CCCA refractory to standard treatments. Transcriptomic analysis was performed on patients with previously banked, paired scalp biopsies before and after treatment with adjuvant metformin for at least 6 weeks., Exposure: Extended-release metformin, 500 mg, once daily was added to participants' baseline CCCA treatment regimens., Main Outcomes and Measures: Clinical assessments included pruritus, inflammation, scalp resistance, and hair regrowth. Gene expression profiling via bulk RNA sequencing analysis evaluated differential gene expression and pathway enrichment., Results: A total of 12 Black female participants were included in the study, and transcriptomic analysis was performed in 4 participants. After at least 6 months of metformin treatment, 9 participants experienced improvement in disease, including scalp pain, inflammation, and/or pruritus, and 6 demonstrated clinical evidence of hair regrowth. The addition of metformin led to reversal of many prominent gene pathways previously identified in CCCA. Transcriptomic analysis revealed upregulation of pathways and genes (keratin-associated proteins [KRTAPs]) involved in keratinization, epidermis development, and the hair cycle (absolute log2-fold change > 4), with concomitant downregulation of fibrosis-related pathways and genes (eg, MMP7, COL6A1) (fold change >1.5; all false discovery rate <.05). Gene set analysis showed reduced expression of helper T cell 17 and epithelial-mesenchymal transition pathways and elevated adenosine monophosphate kinase signaling and KRTAPs after metformin treatment., Conclusions and Relevance: In this case series of patients with treatment-refractory CCCA, low-dose oral metformin was associated with symptomatic improvement and dual modulation of gene expression, stimulating hair growth pathways while suppressing fibrosis and inflammation markers. These findings provide a rationale for future clinical trials studying metformin as a targeted therapy for CCCA and other cicatricial alopecias.

Importance: There are reported benefits from vitrectomy for diabetic macular edema (DME); however, data precede anti-vascular endothelial growth therapy (VEGF) therapy, supporting a need to assess the current role of vitrectomy., Objective: To determine rates of recruitment and efficacy outcomes of vitrectomy plus internal limiting membrane (ILM) peeling adjunctive to treat-and-extend (T&E) anti-VEGF injections for diabetic macular edema (DME)., Design, Setting, and Participants: This was a single-masked, multicenter randomized clinical trial at 21 sites in the United Kingdom from June 2018 to January 2021, evaluating single eyes of treatment-naive patients with symptomatic vision loss from DME for less than 1 year. Inclusion criteria were best-corrected visual acuity (BCVA) Early Treatment Diabetic Retinopathy Study letter score greater than 35 (approximate Snellen equivalent, 20/200 or better) and central subfield thickness (CST) greater than 350 μm after 3 monthly intravitreal injections of ranibizumab or aflibercept. Data analysis was performed in July 2023., Interventions: Patients were randomized 1:1 into vitrectomy plus standard care or standard care alone and further stratified into groups with vs without vitreomacular interface abnormality. Both groups received a T&E anti-VEGF injection regimen with aflibercept, 2 mg, or ranibizumab, 0.5 mg. The vitrectomy group additionally underwent pars plana vitrectomy with epiretinal membrane or ILM peel within 1 month of randomization., Main Outcomes and Measures: Rate of recruitment and distance BCVA. Secondary outcome measures were CST, change in BCVA and CST, number of injections, rate of completed follow-up, and withdrawal rate., Results: Over 32 months, 47 of a planned 100 patients were enrolled; 42 (89%; mean [SD] age, 63 [11] years; 26 [62%] male) completed 12-month follow-up visits. Baseline characteristics appeared comparable between the control (n = 23; mean [SD] age, 66 [10] years) and vitrectomy (n = 24; mean [SD] age, 62 [12] years) groups. No difference in 12-month BCVA was noted between groups, with a 12-month median (IQR) BCVA letter score of 73 (65-77) letters (Snellen equivalent, 20/40) in the control group vs 77 (67-81) letters (Snellen equivalent, 20/32) in the vitrectomy group (difference, 4 letters; 95% CI, -8 to 2; P = .24). There was no difference in BCVA change from baseline (median [IQR], -1 [-3 to 2] letters for the control group vs -2 [-8 to 2] letters for the vitrectomy group; difference, 1 letter; 95% CI, -5 to 7; P = .85). No difference was found in CST changes (median [IQR], -94 [-122 to 9] μm for the control group vs -32 [-48 to 25] μm for the vitrectomy group; difference, 62 μm; 95% CI, -110 to 11; P = .11)., Conclusions and Relevance: Enrollment goals could not be attained. However, with 47 participants, evidence did not support a clinical benefit of vitrectomy plus ILM peeling as an adjunct to a T&E regimen of anti-VEGF therapy for DME., Trial Registration: isrctn.org Identifier: ISRCTN59902040.

Background: The logistics of timely processing of blood specimens remains a barrier in population health studies to the generation of micronutrient status data., Objectives: To test a blood specimen processing protocol that includes overnight postage with cooling and its effect on nutritional biomarker concentrations., Methods: This study was embedded within the United Kingdom National Diet and Nutrition Survey. Paired specimens were collected from 64 participants (16 y+). One set of specimens were processed within 2 h of collection ["field"] and paired samples were mailed in an insulated box with cold packs using an overnight postal service to a central laboratory ["postal"]. Specimen processing protocols were aligned across field sites and the central laboratory. Specimens were frozen and later analyzed using established methods for vitamins, minerals, lipids, ferritin, and C-reactive protein (CRP). Percent difference was calculated between protocols and compared with quality specifications determined from intra- and interindividual variation., Results: In the postal protocol, ferritin [geometric mean percent difference (95% confidence interval)] [6% (3, 8)] (P = 0.002) and zinc [4% (1, 6)] (P = 0.004) were higher compared with the field protocol. Retinol [-3% (-4, -1)] (P < 0.0001) and selenium [-3% (-5, -1)] (P = 0.003) concentrations were lower in the postal protocol, whereas total [2% (1, 3)] and HDL [4% (2, 5)] cholesterol were higher (P < 0.0001) than in the field protocol. Percent differences were within the optimum quality specification for the majority of biomarkers, but ferritin, zinc, and selenium fell outside of the optimum limits. Higher ferritin concentration in the postal protocol led to a decrease in the proportion of specimens with ferritin concentration <15 μg/L from 13% to 9%., Conclusions: The majority of micronutrient biomarkers, serum lipids, and CRP were minimally affected by delayed processing when cooled. The study suggests acceptable stability of nutritional biomarkers within the described protocol, which can provide accurate data for nutritional biomarkers commonly measured in studies and surveys., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

The Multi-Action Plan model offers an idiosyncratic, sport-specific, and applied framework categorising two peak (Type 1 & 2) and two non-peak performance types (Type 3 & 4). The purpose of the present study was to examine the transitions between these Performance Types across three competition-simulating training judo fights. After videoing three judo fights per participant, we interviewed six high-level judo practitioners (Md age  = 19 years) using video-stimulated recall. While watching their fights, participants indicated which Performance Types they experienced during each fight and, subsequently, discussed their experience with the lead researcher. Findings indicated that participants spent most time in effortful mental states (Type 2 & 3). Additionally, they identified currently not defined states 'between' current typologies, e.g., T2.5. Overall, participants reported more down- than upregulations. Specifically, they described downregulations as mostly uncontrolled and related to fatigue, technical-tactical, or cognitive-emotional transition cues. In contrast, they characterised upregulations as deliberate and proactive mental resets, utilising strategies such as self-talk. Lastly, we discussed our findings in relation to existing literature and offered implications for research and practice., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Data are limited on the impact of commencing antiplatelet therapy on von Willebrand Factor Antigen (VWF:Ag) or von Willebrand Factor propeptide (VWFpp) levels and ADAMTS13 activity, and their relationship with platelet reactivity following TIA/ischaemic stroke. In this pilot, observational study, VWF:Ag and VWFpp levels and ADAMTS13 activity were quantified in 48 patients ≤4 weeks of TIA/ischaemic stroke (baseline), and 14 days (14d) and 90 days (90d) after commencing aspirin, clopidogrel or aspirin+dipyridamole. Platelet reactivity was assessed at moderately-high shear stress (PFA-100® Collagen-Epinephrine / Collagen-ADP / INNOVANCE PFA P2Y assays), and low shear stress (VerifyNow® Aspirin / P2Y12, and Multiplate® Aspirin / ADP assays). VWF:Ag levels decreased and VWFpp/VWF:Ag ratio increased between baseline and 14d and 90d in the overall population (P ≤ 0.03). In the clopidogrel subgroup, VWF:Ag levels decreased and VWFpp/VWF:Ag ratio increased between baseline and 14d and 90d (P ≤ 0.01), with an increase in ADAMTS13 activity between baseline vs. 90d (P ≤ 0.03). In the aspirin+dipyridamole subgroup, there was an inverse relationship between VWF:Ag and VWFpp levels with both PFA-100 C-ADP and INNOVANCE PFA P2Y closure times (CTs) at baseline (P ≤ 0.02), with PFA-100 C-ADP, INNOVANCE PFA P2Y and C-EPI CTs at 14d (P ≤ 0.05), and between VWF:Ag levels and PFA-100 INNOVANCE PFA P2Y CTs at 90d (P = 0.03). There was a positive relationship between ADAMTS13 activity and PFA-100 C-ADP CTs at baseline (R 2  = 0.254; P = 0.04). Commencing/altering antiplatelet therapy, mainly attributed to commencing clopidogrel in this study, was associated with decreasing endothelial activation following TIA/ischaemic stroke. These data enhance our understanding of the impact of VWF:Ag and VWFpp especially on ex-vivo platelet reactivity status at high shear stress after TIA/ischaemic stroke., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Aims: Next generation sequencing (NGS) on tumour tissue is integral to the delivery of personalised medicine and targeted therapy. NGS on liquid biopsy, a much less invasive technology, is an emerging clinical tool that has rapidly expanded clinical utility. Gene mutations in cell-free total nucleic acids (cfTNA) circulating in the blood are representative of whole tumour biology and can reveal different mutations from different tumour sites, thus addressing tumour heterogeneity challenges., Methods: The novel Ion Torrent Genexus NGS system with automated sample preparation, onboard library preparation, templating, sequencing, data analysis and Oncomine Reporter software was used. cfTNA extracted from plasma was verified with the targeted pan-cancer (~50 genes) Oncomine Precision Assay (OPA). Assessment criteria included analytical sensitivity, specificity, limits of detection (LOD), accuracy, repeatability, reproducibility and the establishment of performance metrics., Results: An ISO 15189 accredited, minimally invasive cfTNA NGS diagnostic service has been implemented. High sensitivity (>83%) and specificity between plasma and tissue were observed. A sequencing LOD of 1.2% was achieved when the depth of coverage was >22 000×. A reduction (>68%) in turnaround time (TAT) of liquid biopsy results was achieved: 5 days TAT for in-house analysis from sample receipt to a final report issued to oncologists as compared with >15 days from reference laboratories., Conclusion: Tumour-derived somatic variants can now be reliably assessed from plasma to provide minimally invasive tumour profiling. Successful implementation of this accredited service resulted in:Appropriate molecular profiling of patients where tumour tissue is unavailable or inaccessible.Rapid TAT of plasma NGS results., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

Little is known about eukaryotic chemorepulsion. The enzymes phosphatase and tensin homolog (PTEN) and CnrN dephosphorylate phosphatidylinositol 3,4,5-trisphosphate [PI(3,4,5)P3] to phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2]. Dictyostelium discoideum cells require both PTEN and CnrN to induce chemorepulsion of cells away from the secreted chemorepellent protein AprA. How D. discoideum cells utilize two proteins with redundant phosphatase activities in response to AprA is unclear. Here, we show that D. discoideum cells require both PTEN and CnrN to locally inhibit Ras activation, decrease basal levels of PI(3,4,5)P3 and increase basal numbers of macropinosomes, and AprA prevents this increase. AprA requires both PTEN and CnrN to increase PI(4,5)P2 levels, decrease PI(3,4,5)P3 levels, inhibit proliferation, decrease myosin II phosphorylation and increase filopod sizes. PTEN, but not CnrN, decreases basal levels of PI(4,5)P2, and AprA requires PTEN, but not CnrN, to induce cell roundness. Together, our results suggest that CnrN and PTEN play unique roles in AprA-induced chemorepulsion., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2024. Published by The Company of Biologists Ltd.)

A combination of improvements in patient survival, increasing treatment duration, and the development of more expensive agents has led to a doubling of per-capita spending on cancer medicines in Ireland (2008-2018). Despite this, access to new drugs is poor in comparison to other EU countries. We examine methods to optimise oncology drug spending to facilitate access to newer anticancer agents. Key targets for spending optimisation (biosimilar use, clinical trials and expanded access programs, waste reduction, avoidance of futile treatment, and altered drug scheduling) were identified through an exploratory analysis. A structured literature search was performed, with a focus on articles relevant to the Irish Healthcare system, supplemented by reports from statutory bodies. At the present time, EMA-approved agents are available once approved by the NCPE. Optimising drug costs occurs through guideline-based practice and biosimilar integration, the latter provides €80 million in cost savings annually. Access to novel therapies can occur via over 50 clinical trials and 28 currently available expanded access programmes. Additional strategies include reversion to weight-based immunotherapy dosing, potentially saving €400,000 per year in our centre alone, vial sharing, and optimisation of treatment schedules. A variety of techniques are being employed by oncologists to optimise costs and increase access to innovation for patients. Use of biosimilars, drug wastage, and prescribing at end of life should be audited as key performance indicators, which may lead to reflective practice on treatment planning. Such measures could further optimise oncology drug expenditure nationally facilitating approval of new agents., (© 2024. The Author(s).)

Introduction: Although substantial research indicates that challenge plays a big role in the development of talent, little is known of the experiences of young performers as they negotiate and learn from these challenges., Methods: As such, to better understand the nature and impact of challenge on the Talent Development (TD) pathway, we longitudinally tracked nine young footballers from progressive age-bands (five aged 11 years and four aged 14) as they experienced challenge over a 15-month period using a mixed-methods design. Five semi-structured interviews separated by three months were conducted, and data were analysed via thematic analysis., Results: Our findings suggested that participants encountered recurrent challenging events, categorised into common/uncommon, planned/unplanned, individual-focused/group-focused challenges. Support for the benefits of challenges was pervasive throughout the data with participants progressing through stages with each challenge (drop, rebound and growth). However, the magnitude and rate at which participants experienced these stages was highly idiosyncratic. Indeed, the perceived impact, scale, and, ultimately, consequential developmental impact of these challenges appeared to vary greatly with participants displaying different responses to similar events. Such differences were underpinned by several individual factors (such as prior experiences and perceived coping skills), contextual characteristics of the challenge (such as type and timing) and support around the challenge (such as priming and reflection opportunities)., Conclusion: Implications include the need for coaches and psychologists to systematically assess and carefully monitor the individual circumstances, needs and skillset of young performers and use this information as a platform for deploying individualised, timely and developmentally appropriate challenges along with relative support to ensure optimal learning and growth from them., Competing Interests: RC, DC were employed by Grey Matters Performance Ltd. 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. The author DC declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (© 2024 Papastaikoudis, Collins and Collins.)

The Multi-Action Plan (MAP) model presents an idiosyncratic framework for human performance. MAP research has categorised four Performance Types (PTs; T1-T4) using self-paced activities. Specifically, T1-4 present four distinct mental states experienced by athletes during performance, differing, among other aspects, in the level of effort and perceived control. However, transitions between PTs are yet to be empirically investigated. This study aimed to examine MAP in the hyperdynamic open-skill combat context of judo. We explored how judoka experienced PTs and the transition processes between these mental states. Six British, high-level judoka (n = 6; Mdn age  = 19) were interviewed using a retrospective semi-structured interview schedule. Interpretative phenomenological analysis indicated that judo presents a hyperdynamic difficult-to-predict performance context due to the opponent and fighting rhythm. Second, participants strongly related to T2 and T3 and less to T1 and T4. They also reported experiences 'between' T2 and T3. Lastly, participants reported common transition pathways (e.g., T2-T3), typical transition cues, and specific trainable strategies to optimise performance. Findings are discussed in relation to existing literature. Lastly, we present limitations, applied, and research considerations., (© 2024 The Authors. European Journal of Sport Science published by Wiley‐VCH GmbH on behalf of European College of Sport Science.)

Objectives: This project used a systematic and integrated knowledge translation (IKT) approach to co-create theory- and evidence-based best practices for physical activity counseling for adults with spinal cord injury (SCI)., Methods: Guided by the IKT Guiding Principles, we meaningfully engaged research users throughout this project. A systematic approach was used. An international, multidisciplinary expert panel ( n  = 15), including SCI researchers, counselors, and people with SCI, was established. Panel members participated in two online meetings to discuss the best practices by drawing upon new knowledge regarding counselor-client interactions, current evidence, and members' own experiences. We used concepts from key literature on SCI-specific physical activity counseling and health behavior change theories. An external group of experts completed an online survey to test the clarity, usability and appropriateness of the best practices., Results: The best practices document includes an introduction, the best practices, things to keep in mind, and a glossary. Best practices focused on how to deliver a conversation and what to discuss during a conversation. Examples include: build rapport, use a client-centred approach following the spirit of motivational interviewing, understand your client's physical activity barriers, and share the SCI physical activity guidelines. External experts ( n  = 25) rated the best practices on average as clear, useful, and appropriate., Conclusion: We present the first systematically co-developed theory- and evidence-based best practices for SCI physical activity counseling. The implementation of the best practices will be supported by developing training modules. These new best practices can contribute to optimizing SCI physical activity counseling services across settings.

This study utilizes a controlled experimental design to investigate the influence of a virtual reality experience on empathy, compassion, moral reasoning, and moral foundations. With continued debate and mixed results from previous studies attempting to show relationships between virtual reality and empathy, this study takes advantage of the technology for its ability to provide a consistent, repeatable experience, broadening the scope of analysis beyond empathy. A systematic literature review identified the most widely used and validated moral psychology assessments for the constructs, and these assessments were administered before and after the virtual reality experience. The study is comprised of two pre-post experiments with student participants from a university in the United States. The first experiment investigated change in empathy and moral foundations among 44 participants, and the second investigated change in compassion and moral reasoning among 69 participants. The results showed no significant change in empathy nor compassion, but significant change in moral reasoning from personal interest to post-conventional stages, and significant increase in the Care/harm factor of moral foundations. By testing four of the primary constructs of moral psychology with the most widely used and validated assessments in controlled experiments, this study attempts to advance our understanding of virtual reality and its potential to influence human morality. It also raises questions about our self-reported assessment tools and provides possible new insights for the constructs examined., Competing Interests: The 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 © 2024 Dunivan, Mann, Collins and Wittmer.)

Prevention of sports injury and illness and protection of athlete health are key mandates of the IOC. Methodological limitations in Olympic Games surveillance and retired Olympian studies mean there are gaps in the available evidence on Olympian health and the varied challenges occurring at different stages throughout an athlete's career. This (protocol) paper describes the methods for implementation of the IOC Olympian Health Cohort. The study aims to establish a longitudinal cohort of current Olympians and follow them prospectively (around 15 years) throughout their Olympic careers and retirement. The study will use participants who have completed self-report questionnaires. Olympians will be recruited after each Summer and Winter Olympic Games, and all National Olympic Committee (NOC) athletes aged 16 years or older are eligible. The first phase included the Tokyo 2020/2021 and Beijing 2022 Olympians, with the study promoted via IOC platforms, Athlete365 and NOCs. Questionnaires include baseline demographics, sports exposure and history of injuries and illnesses impacting the athlete's ability to continue to train and/or compete for at least 2 weeks. Questions also address retirement from sports, musculoskeletal, mental and general health, and quality of life measures. This protocol describes the methods for the 15-year global IOC Olympian Health Cohort Study, from participant recruitment to the development and distribution of the study questionnaire. This protocol will be updated to report future changes in the study's conduct or questionnaire content. These data will help identify risk factors and inform risk-reduction strategies. The ultimate goal is to protect the health of all athletes during their careers and retirement., Competing Interests: Competing interests: TS works as a scientific manager in the Medical and Scientific Department of the IOC. LE is head of scientific activities in the Medical and Scientific Department of the IOC, editor of the British Journal of Sports Medicine and associate editor of the Journal of Bone and Joint Surgery. DP received funding from the IOC to undertake the IOC Cohort Study., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

SNAPSHOT USA is a multicontributor, long-term camera trap survey designed to survey mammals across the United States. Participants are recruited through community networks and directly through a website application (https://www.snapshot-usa.org/). The growing Snapshot dataset is useful, for example, for tracking wildlife population responses to land use, land cover, and climate changes across spatial and temporal scales. Here we present the SNAPSHOT USA 2021 dataset, the third national camera trap survey across the US. Data were collected across 109 camera trap arrays and included 1711 camera sites. The total effort equaled 71,519 camera trap nights and resulted in 172,507 sequences of animal observations. Sampling effort varied among camera trap arrays, with a minimum of 126 camera trap nights, a maximum of 3355 nights, a median 546 nights, and a mean 656 ± 431 nights. This third dataset comprises 51 camera trap arrays that were surveyed during 2019, 2020, and 2021, along with 71 camera trap arrays that were surveyed in 2020 and 2021. All raw data and accompanying metadata are stored on Wildlife Insights (https://www.wildlifeinsights.org/), and are publicly available upon acceptance of the data papers. SNAPSHOT USA aims to sample multiple ecoregions in the United States with adequate representation of each ecoregion according to its relative size. Currently, the relative density of camera trap arrays varies by an order of magnitude for the various ecoregions (0.22-5.9 arrays per 100,000 km 2 ), emphasizing the need to increase sampling effort by further recruiting and retaining contributors. There are no copyright restrictions on these data. We request that authors cite this paper when using these data, or a subset of these data, for publication. Any use of trade, firm, or product names is for descriptive purposes only and does not imply endorsement by the US Government., (© 2024 The Ecological Society of America.)

Informal caregivers often provide transfer assistance to individuals with disabilities; however, repeated transfers are associated with a high risk of musculoskeletal pain and injury, and training and education around transfers is minimal. The purpose of this study was to develop and assess the content validity of a new tool, the Caregiver Assisted Transfer Technique Instrument (CATT), which could be used to provide an objective indicator of transfer performance. Item importance, clarity, and appropriateness of responses were rated on a five-point Likert scale by clinicians ( n  = 15), informal caregivers ( n  = 10), and individuals with spinal cord injury ( n  = 5). The content validity index and modified Kappa of each item was calculated. Participants also provided qualitative feedback on item content. In general, items were rated favorably for their importance (4.47 to 5.00), clarity (4.33 to 4.90), and appropriateness of responses (4.38 to 4.90), and most items had excellent content validity (k* ≥ 0.75). Feedback from participants led to the creation of two versions of the CATT: one for manual lifting techniques (CATT-M) and one for transfers performed via lift-based technologies (CATT-L). Future work will focus on establishing the reliability and validity of the CATT as well as developing training and education interventions surrounding assisted transfers.

The COVID-19 pandemic had a devastating impact on unemployment, which-compounded by the additional stressors associated with the pandemic-had considerable mental health impact. The current study examined the trajectory of mental health amongst those experiencing pandemic-related job loss, alongside the impact of risk and protective factors. Data were obtained from 374 Australian participants who were allocated to a waitlist control arm of a randomised control trial. The outcome variables assessed at baseline and six-month follow-up consisted of depression, anxiety, and suicidality. The assessed risk and protective factors were age, gender, relationship status, education, exercise frequency, COVID-related stress, dispositional resilience, and coping self-efficacy. Re-employment by follow-up was used as a covariate. Overall, there were decreases in depression and anxiety symptoms, and partial evidence of decreased suicidality, demonstrating an apparent capacity for individuals to better cope with their circumstances over time. Demographics and exercise had no effect on changes in mental health. Those with high COVID-related stress, low resilience, and low coping self-efficacy had worse mental health at baseline, although exhibited significantly greater improvements in mental health over time. Obtaining re-employment by follow-up did not predict changes in mental health. The present results offer an optimistic picture of recovery for those experiencing pandemic-related job loss, even for those with the most substantial risk and severity. The likely protective role played by Australian social welfare policies over the course of the study is explored. Stress around one's broader sociocultural or economic circumstances, perceived resilience, and coping self-efficacy are valuable targets for intervention., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Traffic emissions are a dominant source of secondary organic aerosol (SOA) in urban environments. Though tailpipe exhaust has drawn extensive attention, the impact of non-tailpipe emissions on atmospheric SOA has not been well studied. Here, a closure study was performed combining urban tunnel experiments and dynamometer tests using an oxidation flow reactor in situ photo-oxidation. Results show a significant gap between field and laboratory research; the average SOA formation potential from real-world fleet is 639 ± 156 mg kg fuel -1 , higher than the reconstructed result (188 mg kg fuel -1 ) based on dynamometer tests coupled with fleet composition inside the tunnel. Considering the minimal variation of SOA/CO in emission standards, we also reconstruct CO and find the critical role of high-emitting events in the real-world SOA burden. Different profiles of organic gases are detected inside the tunnel than tailpipe exhaust, such as more abundant C 6 -C 9 aromatics, C 11 -C 16 species, and benzothiazoles, denoting contributions from non-tailpipe emissions to SOA formation. Using these surrogate chemical compounds, we roughly estimate that high-emitting, evaporative emission, and asphalt-related and tire sublimation share 14, 20, and 10% of the SOA budget, respectively, partially explaining the gap between field and laboratory research. These experimental results highlight the importance of non-tailpipe emissions to atmospheric SOA.

Competing Interests: Competing interests: none.

Background: Health, fitness and lifestyle professionals can play important roles in promoting physical activity in groups at risk of developing an inactive lifestyle, such as people with spinal cord injury (SCI). Tailored counselling is a promising tool to promote and improve physical activity levels. To support professionals to effectively have a conversation about physical activity with clients with SCI, evidence-based training and resources are needed. This project aimed to (1) co-develop an e-learning course on best practices for SCI physical activity counselling and, (2) examine the effectiveness and usability of this course., Methods: Guided by the technology-enhanced learning (TEL) evaluation framework, we used a systematic, multistep approach to co-develop and evaluate an e-learning course. The development process was informed by input and feedback from a diverse group of end-users and experts (n > 160) via online surveys and (think-aloud) interviews. A randomized controlled trial was used to compare learning outcomes (post-knowledge and self-efficacy) between participants who completed the course (intervention group) and the wait-listed control group. Usability, learning experiences, and satisfaction were assessed among all participants., Results: Forty-one participants (21 intervention-group; 20 control-group) with various backgrounds (e.g., lifestyle counsellors, physiotherapists, occupational therapists, recreation therapists, fitness trainers) enrolled in the randomized controlled trial. After completing the course, participants in the intervention group showed significantly improved knowledge on the best practices for SCI physical activity counselling and higher self-efficacy for using these best practices in conversations with clients with SCI compared to the control group (p <.001). Participants reported above average usability scores, positive learning experiences, and high levels of satisfaction when completing the course., Conclusion: We used a systematic, multi-step, theory-informed approach to co-develop and evaluate an evidence-based e-learning course on SCI physical activity counselling to support professionals to promote physical activity in their daily practices. The overall positive findings demonstrate that the e-learning course is feasible and ready for further implementation in various health and community settings. Implementation of the e-learning course can help professionals improve the physical activity support they provide to their clients, and subsequently increase physical activity participation in people with SCI., (© 2024. The Author(s).)

Context: Estimating the return on investment for public health services, tailored to the state level, is critical for demonstrating their value and making resource allocation decisions. However, many health departments have limited staff capacity and expertise to conduct economic analyses in-house., Program: We developed a user-friendly, interactive Excel-based spreadsheet model that health departments can use to estimate the impact of increases or decreases in sexually transmitted infection (STI) prevention funding on the incidence and direct medical costs of chlamydia, gonorrhea, syphilis, and STI-attributable HIV infections. Users tailor results to their jurisdictions by entering the size of their population served; the number of annual STI diagnoses; their prior annual funding amount; and their anticipated new funding amount. The interface was developed using human-centered design principles, including focus groups with 15 model users to collect feedback on an earlier model version and a usability study on the prototype with 6 model users to finalize the interface., Implementation: The STI Prevention Allocation Consequences Estimator ("SPACE Monkey 2.0") model will be publicly available as a free downloadable tool., Evaluation: In the usability testing of the prototype, participants provided overall positive feedback. They appreciated the clear interpretations, outcomes expressed as direct medical costs, functionalities to interact with the output and copy charts into external applications, visualization designs, and accessible information about the model's assumptions and limitations. Participants provided positive responses to a 10-item usability evaluation survey regarding their experiences with the prototype., Discussion: Modeling tools that synthesize literature-based estimates and are developed with human-centered design principles have the potential to make evidence-based estimates of budget changes widely accessible to health departments., Competing Interests: The authors declare they have no conflicts of interest.

Aim: To investigate the effects of frailty and co-morbidities on short and medium-term outcome following emergency colorectal cancer surgery., Methods: Data of patients who underwent emergency colorectal cancer operations between January 2013 and December 2016 were reviewed retrospectively. Collected data included demographic and operative variables, clinical frailty scale (CFS), Charlson comorbidity index (CCI) and cause of death with minimum 3 years follow-up., Results: Three-hundred and six patients (median age 72, range 18-100 years) underwent emergency colorectal cancer surgery; Some 74 (24.2%) patients had metastatic cancer at the time of emergency surgery, 77 (25.2%) were frail (CFS ≥4), while 118 (38.6%) were comorbid (CCI of ≥8). Thirty-day mortality was 4.2% (13 patients) and a further 12 patients died within 90 days (8.2%). By 1 year 73 (23.9%) patients had died, and by 3 years 151 (49.3%) patients died. Frailty did not impact 30-day mortality (6.5% vs 3.5%, p = 0.26) but frail patients (CFS ≥4) had a higher mortality rate at 90 days (16.9% vs 5.2%, p < 0.05), 1 year (37.7% vs 19.2%, p < 0.05) and 3 years (61.0% vs 45.4%, p < 0.05). Similarly, higher comorbidity (CCI ≥8) did not impact 30-day mortality (5.9% vs 3.2%, p = 0.25), but they had a higher mortality rate at 90 days (14.4% vs 4.3%, p < 0.05), 1 year (40.7% vs 13.3%, p < 0.05), and 3 years (76.3% vs 32.4%, p < 0.05)., Conclusion: Thirty-day mortality after emergency colorectal cancer surgery in frail and comorbid patients are similar to that of the general population., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2023 Royal College of Surgeons of Edinburgh (Scottish charity number SC005317) and Royal College of Surgeons in Ireland. Published by Elsevier Ltd. All rights reserved.)