Modelling Fatigue Crack Growth in High-Density Polyethylene and Acrylonitrile Butadiene Styrene Polymers.

Prior studies into fatigue crack growth (FCG) in fibre-reinforced polymer composites have shown that the two methodologies of Simple-Scaling and the Hartman-Schijve crack growth equation, which is based on relating the FCG rate to the Schwalbe crack driving force, Δκ, were able to account for differences observed in the measured delamination growth curves. The present paper reveals that these two approaches are also able to account for differences seen in plots of the rate of crack growth, da/dt, versus the range of the imposed stress intensity factor, ΔK, associated with fatigue tests on different grades of high-density polyethylene (HDPE) polymers, before and after electron-beam irradiation, and for tests conducted at different R ratios. Also, these studies are successfully extended to consider FCG in an acrylonitrile butadiene styrene (ABS) polymer that is processed using both conventional injection moulding and additive-manufactured (AM) 3D printing.

Quantitative evaluation of trastuzumab deruxtecan pharmacokinetics and pharmacodynamics in mouse models of varying degrees of HER2 expression.

Trastuzumab deruxtecan (T-DXd; DS-8201; ENHERTU®) is a human epithelial growth factor receptor 2 (HER2)-directed antibody drug conjugate (ADC) with demonstrated antitumor activity against a range of tumor types. Aiming to understand the relationship between antigen expression and downstream efficacy outcomes, T-DXd was administered in tumor-bearing mice carrying NCI-N87, Capan-1, JIMT-1, and MDA-MB-468 xenografts, characterized by varying HER2 levels. Plasma pharmacokinetics (PK) of total antibody, T-DXd, and released DXd and tumor concentrations of released DXd were evaluated, in addition to monitoring γΗ2AX and pRAD50 pharmacodynamic (PD) response. A positive relationship was observed between released DXd concentrations in tumor and HER2 expression, with NCI-N87 xenografts characterized by the highest exposures compared to the remaining cell lines. γΗ2AX and pRAD50 demonstrated a sustained increase over several days occurring with a time delay relative to tumoral-released DXd concentrations. In vitro investigations of cell-based DXd disposition facilitated the characterization of DXd kinetics across tumor cells. These outputs were incorporated into a mechanistic mathematical model, utilized to describe PK/PD trends. The model captured plasma PK across dosing arms as well as tumor PK in NCI-N87, Capan-1, and MDA-MB-468 models; tumor concentrations in JIMT-1 xenografts required additional parameter adjustments reflective of complex receptor dynamics. γΗ2AX longitudinal trends were well characterized via a unified PD model implemented across xenografts demonstrating the robustness of measured PD trends. This work supports the application of a mechanistic model as a quantitative tool, reliably projecting tumor payload concentrations upon T-DXd administration, as the first step towards preclinical-to-clinical translation.

Lichen biomonitoring to assess spatial variability, potential sources and human health risks of polycyclic aromatic hydrocarbons (PAHs) and airborne metal concentrations in Manchester (UK).

Airborne metals and organic pollutants are linked to severe human health impacts, i.e. affecting the nervous system and being associated with cancer. Airborne metals and polycyclic aromatic hydrocarbons (PAHs) in urban environments are derived from diverse sources, including combustion and industrial and vehicular emissions, posing a threat to air quality and subsequently human health. A lichen biomonitoring approach was used to assess spatial variability of airborne metals and PAHs, identify potential pollution sources and assess human health risks across the City of Manchester (UK). Metal concentrations recorded in lichen samples were highest within the city centre area and along the major road network, and lichen PAH profiles were dominated by 4-ring PAHs (189.82 ng g-1 in Xanthoria parietina), with 5- and 6-ring PAHs also contributing to the overall PAH profile. Cluster analysis and pollution index factor (PIF) calculations for lichen-derived metal concentrations suggested deteriorated air quality being primarily linked to vehicular emissions. Comparably, PAH diagnostic ratios identified vehicular sources as a primary cause of PAH pollution across Manchester. However, local more complex sources (e.g. industrial emissions) were further identified. Human health risk assessment found a "moderate" risk for adults and children by airborne potential harmful element (PHEs) concentrations, whereas PAH exposure in Manchester is potentially linked to 1455 (ILCR = 1.45 × 10-3) cancer cases (in 1,000,000). Findings of this study indicate that an easy-to-use lichen biomonitoring approach can aid to identify hotspots of impaired air quality and potential human health impacts by airborne metals and PAHs across an urban environment, particularly at locations that are not continuously covered by (non-)automated air quality measurement programmes.

Evaluation of intensive community care services for young people with psychiatric emergencies: study protocol for a multi-centre parallel-group, single-blinded randomized controlled trial with an internal pilot phase.

BACKGROUND: Over 3000 young people under the age of 18 are admitted to Tier 4 Child and Adolescent Mental Health Services (CAMHS) inpatient units across the UK each year. The average length of hospital stay for young people across all psychiatric units in the UK is 120 days. Research is needed to identify the most effective and efficient ways to care for young people (YP) with psychiatric emergencies. This study aims to evaluate the clinical effectiveness and cost-effectiveness of intensive community care service (ICCS) compared to treatment as usual (TAU) for young people with psychiatric emergencies. METHODS: This is a multicentre two-arm randomized controlled trial (RCT) with an internal pilot phase. Young people aged 12 to < 18 considered for admission at participating NHS organizations across the UK will be randomized 1:1 to either TAU or ICCS. The primary outcome is the time to return to or start education, employment, or training (EET) at 6 months post-randomization. Secondary outcomes will include evaluations of mental health and overall well-being and patient satisfaction. Service use and costs and cost-effectiveness will also be explored. Intention-to-treat analysis will be adopted. The trial is expected to be completed within 42 months, with an internal pilot phase in the first 12 months to assess the recruitment feasibility. A process evaluation using visual semi-structured interviews will be conducted with 42 young people and 42 healthcare workers. DISCUSSION: This trial is the first well-powered randomized controlled trial evaluating the clinical and cost-effectiveness of ICCS compared to TAU for young people with psychiatric emergencies in Great Britain. TRIAL REGISTRATION: ISRCTN ISRCTN42999542, Registration on April 29, 2020.

On Cyclic-Fatigue Crack Growth in Carbon-Fibre-Reinforced Epoxy-Polymer Composites.

The growth of cracks between plies, i.e., delamination, in continuous fibre polymer matrix composites under cyclic-fatigue loading in operational aircraft structures has always been a very important factor, which has the potential to significantly decrease the service life of such structures. Whilst current designs are based on a 'no growth' design philosophy, delamination growth can nevertheless arise in operational aircraft and compromise structural integrity. To this end, the present paper outlines experimental and data reduction procedures for continuous fibre polymer matrix composites, based on a linear elastic fracture mechanics approach, which are capable of (a) determining and computing the fatigue crack growth (FCG) rate, da/dN, curve; (b) providing two different methods for determining the mandated worst-case FCG rate curve; and (c) calculating the fatigue threshold limit, below which no significant FCG occurs. Two data reduction procedures are proposed, which are based upon the Hartman-Schijve approach and a novel simple-scaling approach. These two different methodologies provide similar worst-case curves, and both provide an upper bound for all the experimental data. The calculated FCG threshold values as determined from both methodologies are also in very good agreement.

Comparison of Tumor Binding Across Tumor Types and Cell Lines to Support Free Drug Considerations for Oncology Drug Discovery.

Tumor binding is an important parameter to derive unbound tumor concentration to explore pharmacokinetics (PK) and pharmacodynamics (PD) relationships for oncology disease targets. Tumor binding was evaluated using eleven matrices, including various commonly used ex vivo human and mouse xenograft and syngeneic tumors, tumor cell lines and liver as a surrogate tissue. The results showed that tumor binding is highly correlated among the different tumors and tumor cell lines except for the mouse melanoma (B16F10) tumor type. Liver fraction unbound (fu) has a good correlation with B16F10 tumor binding. Liver also demonstrates a two-fold equivalency, on average, with binding of other tumor types when a scaling factor is applied. Predictive models were developed for tumor binding, with correlations established with LogD (acids), predicted muscle fu (neutrals) and measured plasma protein binding (bases) to estimate tumor fu when experimental data are not available. Many approaches can be applied to obtain and estimate tumor binding values. One strategy proposed is to use a surrogate tumor tissue, such as mouse xenograft ovarian cancer (OVCAR3) tumor, as a surrogate for tumor binding (except for B16F10) to provide an early assessment of unbound tumor concentrations for development of PK/PD relationships.

Following the children of depressed parents from childhood to adult life: A focus on mood and anxiety disorders.

Background: Parental depression increases risk for anxiety and depression in offspring. The transition from adolescence to adulthood is a common risk period for onset of such disorders. However, relatively few studies have considered development of these disorders from childhood to adulthood including multiple assessments during this transition period. Method: Offspring of depressed parents aged 9-17 years at baseline were followed prospectively for 13 years (n = 337). Average length of follow-up was 16 months between the first and second waves, 13 months between the second and third, and 8 years between the third and fourth. Current (3-month) psychopathology was assessed at each wave using diagnostic interviews. We derived estimates of 3-month prevalence, age at first diagnosis, course and comorbidity of disorders. Social functioning in adult life was assessed at the final wave and we assessed how prior and current disorder impacted adult functioning. Results: A quarter of young people met criteria for a mood disorder and a third for anxiety disorder at least once. Mood and anxiety disorder prevalence increased from 4.5% and 15.8% respectively in childhood (9-11 years) to 22.3% and 20.9% respectively by age 23-28. Increased prevalence across the transition from adolescence to adulthood was particularly marked in males, while prevalence increased earlier in adolescence in females. Age at first diagnosis varied widely (mood disorder mean = 16.5 years (range 9-26); anxiety disorder mean = 14.5 years (range 9-28)). Over half (52%) reported functional impairment in early adulthood, 31% harmful alcohol use, and 10% self-harm or a suicide attempt. Both previous and current mood or anxiety disorder were associated with functional impairment in early adulthood. Conclusions: There is a prolonged risk period for mood and anxiety disorders in this group, with prevalence peaking in early adulthood. This highlights the need for prolonged vigilance and effective targeted interventions in the offspring of depressed parents.

Treatment of Diabetic Macular Edema or Macular Edema Following Retinal Vein Occlusion Based on Repeated Injection of the Dexamethasone Intravitreal Implant: A Retrospective Real-World Analysis.

Purpose: To assess the "real world" utility of repeated injection with the dexamethasone intravitreal implant (DEX) in routine practice. Methods: This was a retrospective, single-center analysis of consecutive patients with diabetic macular edema, or macular edema following retinal vein occlusion, treated with DEX. None had received prior intravitreal steroid treatment. DEX was implanted as per the manufacturer's instructions. Results: Seventy-eight individuals (95 eyes) were included (50.0% female; mean age: 68.1 ± 12.4 years; mean duration of macular edema: 13.2 ± 12.9 months). Thirty-three eyes (34.7%) had received previous treatment with an anti-vascular endothelial growth factor (anti-VEGF) and/or laser. Thirty eyes (31.6%) underwent one round of DEX implantation; the remainder received 2-5 cycles (total: 225 cycles). Initial DEX treatment led to significant increases in visual acuity (VA) at 6 weeks (mean change: 4.6 letters; P=0.004). Greater VA improvements during the first treatment cycle were associated with inferior baseline VA (P=0.02), borderline associated with baseline central macular thickness (CMT; P=0.06), and independent of prior anti-VEGF treatment (P=0.39). In an analysis of all DEX injections, VA improvements were robust across cycles 1 and 2 but reduced in cycle 3 (P=0.03). CMT improvements did not differ based on injection number (P=0.20). Increases in intraocular pressure (IOP) were largest over the first 6 weeks (but rebounded towards baseline more rapidly) in cycle 1 versus cycles 2 and 3 (P<0.001). IOP rises were typically manageable with topical medications. Conclusion: This analysis confirms the broad utility of DEX and may inform decision-making in routine practice.

Supplementation of minerals and vitamins influences optimal targeted selective treatment thresholds for the control of gastro-intestinal nematodes in lambs.

Targeted Selective Treatment (TST) is a gastrointestinal nematode (GIN) control strategy where anthelmintic treatment decisions are made at an individual animal level. TST has been proven to reduce anthelmintic use and subsequently slow down anthelmintic resistance development, however questions remain regarding optimal TST methods and their applicability across farms. In this study, the influence of Mineral and Vitamin (MV) supplementation on optimal energy utilisation (EU) TST thresholds was assessed on three Welsh farms. In total, 360 lambs were split into two groups, MV supplemented and control, and were treated with an anthelmintic against GIN at the midway point of the experiment. Lambs that improved their EU efficiency post treatment were deemed to have benefited from anthelmintic treatment. Optimal EU TST thresholds was determined for each treatment group per farm using Youden's J statistic where the treatment threshold retrospectively exhibiting the greatest combined sensitivity and specificity in correctly identifying lambs benefiting from treatment was deemed to be optimal. Results demonstrated that the optimal EU TST threshold was higher in MV supplemented groups at 0.72, 0.71 and 0.56 versus 0.58, 0.67, 0.51 for control groups on each respective farm. Identification of lambs for TST was more effective when using an optimised EU TST threshold, compared to when using the standard EU TST threshold of 0.66. The study highlights that applying standard EU TST thresholds may not be appropriate on all commercial farms with factors including MV status as noted in this study likely to influence optimal EU TST thresholds. Additional refinement of TST systems can further strengthen their applicability across sheep flocks.

Production of volatile fatty acids by anaerobic digestion of biowastes: Techno-economic and life cycle assessments.

Production of volatile fatty acids from food waste and lignocellulosic materials has potential to avoid emissions from their production from petrochemicals and provide valuable feedstocks. Techno-economic and life cycle assessments of using food waste and grass to produce volatile fatty acids through anaerobic digestion have been conducted. Uncertainty and sensitivity analysis for both assessments were done to enable a robust forecast of key-aspects of the technology deployment at industrial scale. Results show low environmental impact of volatile fatty acid with food wastes being the most beneficial feedstock with global warming potential varying from -0.21 to 0.01 CO2 eq./kg of product. Food wastes had the greatest economic benefit with a breakeven selling price of 1.11-1.94 GBP/kg (1.22-2.33 USD) of volatile fatty acids in the product solution determined through sensitivity analysis. Anaerobic digestion of wastes is therefore a promising alternative to traditional volatile fatty acid production routes, providing economic and environmental benefits.

Discovery of a highly potent, selective, orally bioavailable inhibitor of KAT6A/B histone acetyltransferases with efficacy against KAT6A-high ER+ breast cancer.

KAT6A, and its paralog KAT6B, are histone lysine acetyltransferases (HAT) that acetylate histone H3K23 and exert an oncogenic role in several tumor types including breast cancer where KAT6A is frequently amplified/overexpressed. However, pharmacologic targeting of KAT6A to achieve therapeutic benefit has been a challenge. Here we describe identification of a highly potent, selective, and orally bioavailable KAT6A/KAT6B inhibitor CTx-648 (PF-9363), derived from a benzisoxazole series, which demonstrates anti-tumor activity in correlation with H3K23Ac inhibition in KAT6A over-expressing breast cancer. Transcriptional and epigenetic profiling studies show reduced RNA Pol II binding and downregulation of genes involved in estrogen signaling, cell cycle, Myc and stem cell pathways associated with CTx-648 anti-tumor activity in ER-positive (ER+) breast cancer. CTx-648 treatment leads to potent tumor growth inhibition in ER+ breast cancer in vivo models, including models refractory to endocrine therapy, highlighting the potential for targeting KAT6A in ER+ breast cancer.

Digital technologies to support adolescents with depression and anxiety: review.

Depression and anxiety are common in adolescents, but most affected will not get any formal help. Digital mental health technologies (i.e. resources and interventions to support and improve mental health) are a potential way to extend the reach and increase adolescents' access to therapies, at a relatively low cost. Many young people can access the internet and mobile technologies, including in low- and middle-income countries. There has been increased interest in integrating technologies in a range of settings, especially because of the effect of the COVID-19 pandemic on adolescent mental health, at a time when services are under pressure. This clinical review gives an overview of digital technologies to support the prevention and management of depression and anxiety in adolescence. The technologies are presented in relation to their technological approaches, underlying psychological or other theories, setting, development, evaluations to date and how they might be accessed. There is also a discussion of the potential benefits, challenges and future developments in this field.

The Metabolism of Lufotrelvir, a Prodrug Investigated for the Treatment of SARS-COV2 in Humans Following Intravenous Administration.

The metabolism of lufotrelvir, a novel phosphate prodrug of PF-00835231 for the treatment of COVID-19, was evaluated in healthy human volunteers and clinical trial participants with COVID-19 following intravenous infusion. The prodrug was completely converted to PF-00835231 that was subsequently cleared by hydrolysis, hydroxylation, ketoreduction, epimerization, renal clearance, and secretion into the feces. The main circulating metabolite was a hydrolysis product (M7) that was present at concentrations greater than PF-00835231, and this was consistent between healthy volunteers and participants with COVID-19. On administration of [14C]lufotrelvir, only 63% of the dose was obtained in excreta over 10 days and total drug-related material demonstrated a prolonged terminal phase half-life in plasma. A considerable portion of the labeled material was unextractable from fecal homogenate and plasma. The position of the carbon-14 atom in the labeled material was at a leucine carbonyl, and pronase digestion of the pellet derived from extraction of the fecal homogenate showed that [14C]leucine was released. SIGNIFICANCE STATEMENT: Lufotrelvir is an experimental phosphate prodrug intravenous therapy investigated for the potential treatment of COVID-19 in a hospital setting. The overall metabolism of lufotrelvir was determined in human healthy volunteers and clinical trial participants with COVID-19. Conversion of the phosphate prodrug to the active drug PF-00835231 was complete and the subsequent metabolic clearance of the active drug was largely via amide bond hydrolysis. Substantial drug-related material was not recovered due to loss of the carbon-14 label to endogenous metabolism.

Validation of the Strengths and Difficulties Questionnaire (SDQ) emotional subscale in assessing depression and anxiety across development.

Emotional disorders are common in childhood, and their prevalence sharply increases during adolescence. The Strengths and Difficulties Questionnaire (SDQ) is widely used for screening emotional and behavioural difficulties in children and young people, but little is known about the accuracy of the emotional subscale (SDQ-E) in detecting emotional disorders, and whether this changes over development. Such knowledge is important in determining whether symptom changes across age are due to developmental or measurement differences. This study assessed the validity of the SDQ-E and two individual items (low mood and general worry) in differentiating between cases and non-cases of Major Depressive Disorder (MDD), Generalised Anxiety Disorder (GAD), and other anxiety disorders across ages 7, 10, 13, 15, and 25 years in a UK population cohort. Analyses showed moderate accuracy of the subscale in discriminating cases of MDD (AUC = 0.67-0.85), and high accuracy for discriminating cases of GAD (AUC = 0.80-0.93) and any anxiety disorder (AUC = 0.74-0.83) compared to non-cases. The SDQ-E performed well across ages and sex, and generally performed better than the two individual items. Together our findings validate the SDQ-E as a screen for emotional disorders during childhood, adolescence, and early adulthood, and as a tool for longitudinal research on depression and anxiety disorders.

The Epidemiology of Domain-Specific Physical Activity in New Zealand Adults: A Nationally Representative Cross-Sectional Survey.

BACKGROUND: Surveillance of domain-specific physical activity (PA) helps to target interventions to promote PA. We examined the sociodemographic correlates of domain-specific PA in New Zealand adults. METHODS: A nationally representative sample of 13,887 adults completed the International PA Questionnaire-long form in 2019/20. Three measures of total and domain-specific (leisure, travel, home, and work) PA were calculated: (1) weekly participation, (2) mean weekly metabolic energy equivalent minutes (MET-min), and (3) median weekly MET-min among those who undertook PA. Results were weighted to the New Zealand adult population. RESULTS: The average contribution of domain-specific activity to total PA was 37.5% for work activities (participation = 43.6%; median participating MET-min = 2790), 31.9% for home activities (participation = 82.2%; median participating MET-min = 1185), 19.4% for leisure activities (participation = 64.7%; median participating MET-min = 933), and 11.2% for travel activities (participation = 64.0%; median MET-min among participants = 495). Women accumulated more home PA and less work PA than men. Total PA was higher in middle-aged adults, with diverse patterns by age within domains. Maori accumulated less leisure PA than New Zealand Europeans but higher total PA. Asian groups reported lower PA across all domains. Higher area deprivation was negatively associated with leisure PA. Sociodemographic patterns varied by measure. For example, gender was not associated with total PA participation, but men accumulated higher MET-min when taking part in PA than women. CONCLUSIONS: Inequalities in PA varied by domain and sociodemographic group. These results should be used to inform interventions to improve PA.

Further development and feasibility randomised controlled trial of a digital programme for adolescent depression, MoodHwb: study protocol.

INTRODUCTION: A digital programme, MoodHwb, was codesigned with young people experiencing or at high risk of depression, parents/carers and professionals, to provide support for young people with their mood and well-being. A preliminary evaluation study provided support for the programme theory and found that MoodHwb was acceptable to use. This study aims to refine the programme based on user feedback, and to assess the acceptability and feasibility of the updated version and study methods. METHODS AND ANALYSIS: Initially, this study will refine MoodHwb with the involvement of young people, including in a pretrial acceptability phase. This will be followed by a multicentre feasibility randomised controlled trial comparing MoodHwb plus usual care with a digital information pack plus usual care. Up to 120 young people aged 13-19 years with symptoms of depression and their parents/carers will be recruited through schools, mental health services, youth services, charities and voluntary self-referral in Wales and Scotland. The primary outcomes are the feasibility and acceptability of the MoodHwb programme (including usage, design and content) and of trial methods (including recruitment and retention rates), assessed 2 months postrandomisation. Secondary outcomes include potential impact on domains including depression knowledge and stigma, help-seeking, well-being and depression and anxiety symptoms measured at 2 months postrandomisation. ETHICS AND DISSEMINATION: The pretrial acceptability phase was approved by the Cardiff University School of Medicine Research Ethics Committee (REC) and the University of Glasgow College of Medicine, Veterinary and Life Sciences REC. The trial was approved by Wales NHS REC 3 (21/WA/0205), the Health Research Authority(HRA), Health and Care Research Wales (HCRW), university health board Research and Development (R&D) departments in Wales, and schools in Wales and Scotland. Findings will be disseminated in peer-reviewed open-access journals, at conferences and meetings, and online to academic, clinical, and educational audiences and the wider public. TRIAL REGISTRATION NUMBER: ISRCTN12437531.

A PKPD Case Study: Achieving Clinically Relevant Exposures of AZD5991 in Oncology Mouse Models.

Capturing human equivalent drug exposures preclinically is a key challenge in the translational process. Motivated by the need to recapitulate the pharmacokinetic (PK) profile of the clinical stage Mcl-1 inhibitor AZD5991 in mice, we describe the methodology used to develop a refined mathematical model relating clinically relevant concentration profiles to efficacy. Administration routes were explored to achieve target exposures matching the clinical exposure of AZD5991. Intravenous infusion using vascular access button (VAB) technology was found to best reproduce clinical target exposures of AZD5991 in mice. Exposure-efficacy relationships were evaluated, demonstrating that dissimilar PK profiles result in differences in target engagement and efficacy outcomes. Thus, these data underscore the importance of accurately ascribing key PK metrics in the translational process to enable clinically meaningful predictions of efficacy.