Midwife continuity of care models versus other models of care for childbearing women.

BACKGROUND: Midwives are primary providers of care for childbearing women globally and there is a need to establish whether there are differences in effectiveness between midwife continuity of care models and other models of care. This is an update of a review published in 2016. OBJECTIVES: To compare the effects of midwife continuity of care models with other models of care for childbearing women and their infants. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Trials Register, ClinicalTrials.gov, and the WHO International Clinical Trials Registry Platform (ICTRP) (17 August 2022), as well as the reference lists of retrieved studies. SELECTION CRITERIA: All published and unpublished trials in which pregnant women are randomly allocated to midwife continuity of care models or other models of care during pregnancy and birth. DATA COLLECTION AND ANALYSIS: Two authors independently assessed studies for inclusion criteria, scientific integrity, and risk of bias, and carried out data extraction and entry. Primary outcomes were spontaneous vaginal birth, caesarean section, regional anaesthesia, intact perineum, fetal loss after 24 weeks gestation, preterm birth, and neonatal death. We used GRADE to rate the certainty of evidence. MAIN RESULTS: We included 17 studies involving 18,533 randomised women. We assessed all studies as being at low risk of scientific integrity/trustworthiness concerns. Studies were conducted in Australia, Canada, China, Ireland, and the United Kingdom. The majority of the included studies did not include women at high risk of complications. There are three ongoing studies targeting disadvantaged women. Primary outcomes Based on control group risks observed in the studies, midwife continuity of care models, as compared to other models of care, likely increase spontaneous vaginal birth from 66% to 70% (risk ratio (RR) 1.05, 95% confidence interval (CI) 1.03 to 1.07; 15 studies, 17,864 participants; moderate-certainty evidence), likelyreduce caesarean sections from 16% to 15% (RR 0.91, 95% CI 0.84 to 0.99; 16 studies, 18,037 participants; moderate-certainty evidence), and likely result in little to no difference in intact perineum (29% in other care models and 31% in midwife continuity of care models, average RR 1.05, 95% CI 0.98 to 1.12; 12 studies, 14,268 participants; moderate-certainty evidence). There may belittle or no difference in preterm birth (< 37 weeks) (6% under both care models, average RR 0.95, 95% CI 0.78 to 1.16; 10 studies, 13,850 participants; low-certainty evidence). We arevery uncertain about the effect of midwife continuity of care models on regional analgesia (average RR 0.85, 95% CI 0.79 to 0.92; 15 studies, 17,754 participants, very low-certainty evidence), fetal loss at or after 24 weeks gestation (average RR 1.24, 95% CI 0.73 to 2.13; 12 studies, 16,122 participants; very low-certainty evidence), and neonatal death (average RR 0.85, 95% CI 0.43 to 1.71; 10 studies, 14,718 participants; very low-certainty evidence). Secondary outcomes When compared to other models of care, midwife continuity of care models likely reduce instrumental vaginal birth (forceps/vacuum) from 14% to 13% (average RR 0.89, 95% CI 0.83 to 0.96; 14 studies, 17,769 participants; moderate-certainty evidence), and may reduceepisiotomy 23% to 19% (average RR 0.83, 95% CI 0.77 to 0.91; 15 studies, 17,839 participants; low-certainty evidence). When compared to other models of care, midwife continuity of care models likelyresult in little to no difference inpostpartum haemorrhage (average RR 0.92, 95% CI 0.82 to 1.03; 11 studies, 14,407 participants; moderate-certainty evidence) and admission to special care nursery/neonatal intensive care unit (average RR 0.89, 95% CI 0.77 to 1.03; 13 studies, 16,260 participants; moderate-certainty evidence). There may be little or no difference in induction of labour (average RR 0.92, 95% CI 0.85 to 1.00; 14 studies, 17,666 participants; low-certainty evidence), breastfeeding initiation (average RR 1.06, 95% CI 1.00 to 1.12; 8 studies, 8575 participants; low-certainty evidence), and birth weight less than 2500 g (average RR 0.92, 95% CI 0.79 to 1.08; 9 studies, 12,420 participants; low-certainty evidence). We are very uncertain about the effect of midwife continuity of care models compared to other models of care onthird or fourth-degree tear (average RR 1.10, 95% CI 0.81 to 1.49; 7 studies, 9437 participants; very low-certainty evidence), maternal readmission within 28 days (average RR 1.52, 95% CI 0.78 to 2.96; 1 study, 1195 participants; very low-certainty evidence), attendance at birth by a known midwife (average RR 9.13, 95% CI 5.87 to 14.21; 11 studies, 9273 participants; very low-certainty evidence), Apgar score less than or equal to seven at five minutes (average RR 0.95, 95% CI 0.72 to 1.24; 13 studies, 12,806 participants; very low-certainty evidence) andfetal loss before 24 weeks gestation (average RR 0.82, 95% CI 0.67 to 1.01; 12 studies, 15,913 participants; very low-certainty evidence). No maternal deaths were reported across three studies. Although the observed risk of adverse events was similar between midwifery continuity of care models and other models, our confidence in the findings was limited. Our confidence in the findings was lowered by possible risks of bias, inconsistency, and imprecision of some estimates. There were no available data for the outcomes: maternal health status, neonatal readmission within 28 days, infant health status, and birth weight of 4000 g or more. Maternal experiences and cost implications are described narratively. Women receiving care from midwife continuity of care models, as opposed to other care models, generally reported more positive experiences during pregnancy, labour, and postpartum. Cost savings were noted in the antenatal and intrapartum periods in midwife continuity of care models. AUTHORS' CONCLUSIONS: Women receiving midwife continuity of care models were less likely to experience a caesarean section and instrumental birth, and may be less likely to experience episiotomy. They were more likely to experience spontaneous vaginal birth and report a positive experience. The certainty of some findings varies due to possible risks of bias, inconsistencies, and imprecision of some estimates. Future research should focus on the impact on women with social risk factors, and those at higher risk of complications, and implementation and scaling up of midwife continuity of care models, with emphasis on low- and middle-income countries.

Childhood Adversity and Incident Psychotic Experiences in Early Adulthood: Cognitive and Psychopathological Mediators.

BACKGROUND AND HYPOTHESIS: Childhood adversity is often described as a potential cause of incident psychotic experiences, but the underlying mechanisms are not well understood. We aimed to examine the mediating role of cognitive and psychopathological factors in the relation between childhood adversity and incident psychotic experiences in early adulthood. STUDY DESIGN: We analyzed data from the Avon Longitudinal Study of Parents and Children, a large population-based cohort study. Childhood adversity was measured prospectively from birth to age 11 years, mediators (anxiety, depression, external locus of control [LoC], negative symptoms) were assessed at approximately 16 years of age, and incident psychotic experiences were assessed at ages 18 and 24 years. Mediation was examined via the counterfactual g-computation formula. STUDY RESULTS: In total, 7% of participants had incident suspected or definite psychotic experiences in early adulthood. Childhood adversity was related to more incident psychotic experiences (ORadjusted = 1.34, 95% CI = 1.21; 1.49), and this association was partially mediated via all mediators examined (proportion mediated: 19.9%). In separate analyses for each mediator, anxiety, depression, external LoC, and negative symptoms were all found to mediate the link between adversity and incident psychotic experiences. Accounting for potential confounders did not modify our results. CONCLUSIONS: Our study shows that cognitive biases as well as mood symptomatology may be on the causal pathway between early-life adversity and the development of psychotic experiences. Future studies should determine which mediating factors are most easily modifiable and most likely to reduce the risk of developing psychotic experiences.

Covalent Fragment Screening and Optimization Identifies the Chloroacetohydrazide Scaffold as Inhibitors for Ubiquitin C-terminal Hydrolase L1.

Dysregulation of the ubiquitin-proteasome systems is a hallmark of various disease states including neurodegenerative diseases and cancer. Ubiquitin C-terminal hydrolase L1 (UCHL1), a deubiquitinating enzyme, is expressed primarily in the central nervous system under normal physiological conditions, however, is considered an oncogene in various cancers, including melanoma, lung, breast, and lymphoma. Thus, UCHL1 inhibitors could serve as a viable treatment strategy against these aggressive cancers. Herein, we describe a covalent fragment screen that identified the chloroacetohydrazide scaffold as a covalent UCHL1 inhibitor. Subsequent optimization provided an improved fragment with single-digit micromolar potency against UCHL1 and selectivity over the closely related UCHL3. The molecule demonstrated efficacy in cellular assays of metastasis. Additionally, we report a ligand-bound crystal structure of the most potent molecule in complex with UCHL1, providing insight into the binding mode and information for future optimization.

Women's experiences of maternity care in the United Kingdom during the COVID-19 pandemic: A follow-up systematic review and qualitative evidence synthesis.

BACKGROUND: Maternity care services in the United Kingdom have undergone drastic changes due to pandemic-related restrictions. Prior research has shown maternity care during the pandemic was negatively experienced by women and led to poor physical and mental health outcomes in pregnancy. A synthesis is required of published research on women's experiences of maternity care during the latter half of the COVID-19 pandemic. AIM: To update a previous systematic review of maternity care experiences during the pandemic to June 2021, exploring experiences of maternity care specifically within the United Kingdom and how they may have changed, in order to inform future maternity services. METHODS: A systematic review of qualitative literature was conducted using comprehensive searches of five electronic databases and the Cochrane COVID Study Register, published between 1 June 2021 and 13 October 2022, and further updated to 30 September 2023. Thematic Synthesis was utilised for data synthesis. FINDINGS: Of 21,860 records identified, 27 studies were identified for inclusion. Findings included 14 descriptive themes across the five core concepts: (1)Care-seeking and experience; (2)Virtual care; (3)Self-monitoring; (4)COVID-19 vaccination; (5)Ethical future of maternity care. DISCUSSION: Our findings in the UK are consistent with those globally, and extend those of the previous systematic review, particularly about women's perceptions of the COVID-19 vaccine during pregnancy. CONCLUSION: Our findings suggest the following are important to women for future maternity care: personalisation and inclusiveness; clear and evidence-based communication to facilitate informed decision-making; and achieving balance between social commitments and time spent settling into motherhood.

Interventions targeting social determinants of mental disorders and the Sustainable Development Goals: a systematic review of reviews.

Globally, mental disorders account for almost 20% of disease burden and there is growing evidence that mental disorders are socially determined. Tackling the United Nations Sustainable Development Goals (UN SDGs), which address social determinants of mental disorders, may be an effective way to reduce the global burden of mental disorders. We conducted a systematic review of reviews to examine the evidence base for interventions that map onto the UN SDGs and seek to improve mental health through targeting known social determinants of mental disorders. We included 101 reviews in the final review, covering demographic, economic, environmental events, neighborhood, and sociocultural domains. This review presents interventions with the strongest evidence base for the prevention of mental disorders and highlights synergies where addressing the UN SDGs can be beneficial for mental health.

Physiologically-based pharmacokinetic modeling of the drug-drug interaction between ivacaftor and lefamulin in cystic fibrosis patients.

Lefamulin is being evaluated as a treatment for bacterial exacerbations in cystic fibrosis (CF). Ivacaftor is approved for the treatment of patients with CF. Lefamulin is a moderate CYP3A inhibitor and co-administration with ivacaftor may result in a drug-drug interaction (DDI). A CF population was built based on literature using the Simcyp Simulator. A previously developed and validated physiologically-based pharmacokinetic (PBPK) model for ivacaftor was used. A PBPK model for lefamulin was developed and verified. Predicted concentrations and pharmacokinetic (PK) parameters for both ivacaftor and lefamulin in healthy subjects and patients with CF were in reasonable agreement with observed data (within 1.4-fold, majority within 1.25-fold). The lefamulin model as a CYP3A4 perpetrator was validated using a different Ki value for oral (p.o.) and intravenous (i.v.) routes. The simulated changes in area under the curve of ivacaftor in patients with CF when co-administered with p.o. and i.v. lefamulin were weak-to-moderate. The predicted change in ivacaftor PK when co-administered with oral lefamulin was less than observed between ivacaftor and fluconazole. These results suggest a low liability for a DDI between lefamulin and ivacaftor in patients with CF.

Improved Satisfaction While Maintaining Safety and High Time in Range (TIR) With a Medtronic Investigational Enhanced Advanced Hybrid Closed-Loop (e-AHCL) System.

OBJECTIVE: To determine feasibility and compare acceptance of an investigational Medtronic enhanced advanced hybrid closed-loop (e-AHCL) system in adults with type 1 diabetes with earlier iterations. RESEARCH DESIGN AND METHODS: This nonrandomized three-stage (12 weeks each) exploratory study compared e-AHCL (Bluetooth-enabled MiniMed 780G insulin pump with automatic data upload [780G] incorporating an updated algorithm; calibration-free all-in-one disposable sensor; 7-day infusion set) preceded by a run-in (non-Bluetooth 780G [670G V4.0 insulin pump] requiring manual data upload; Guardian Sensor 3 [GS3] requiring calibration; 3-day infusion set), stage 1 (780G; GS3; 3-day infusion set), and stage 2 (780G; calibration-free Guardian Sensor 4; 3-day infusion set). Treatment satisfaction was assessed by Diabetes Technology Questionnaire (DTQ)-current (primary outcome) and other validated treatment satisfaction tools with glucose outcomes by continuous glucose monitoring metrics. RESULTS: Twenty-one of 22 (11 women) participants (baseline HbA1c 6.7%/50 mmol/mol) completed the study. DTQ-current scores favored e-AHCL (123.1 [17.8]) versus run-in (101.6 [24.2]) and versus stage 1 (110.6 [20.8]) (both P < 0.001) but did not differ from stage 2 (119.4 [16.0]; P = 0.271). Diabetes Medication System Rating Questionnaire short-form scores for "Convenience and Efficacy" favored e-AHCL over run-in and all stages. Percent time in range 70-180 mg/dL was greater with e-AHCL versus run-in and stage 2 (+2.9% and +3.6%, respectively; both P < 0.001). Percent times of <70 mg/dL for e-AHCL were significantly lower than run-in, stage 1, and stage 2 (-0.9%, -0.6%, and -0.5%, respectively; all P < 0.01). CONCLUSIONS: e-AHCL was feasible. User satisfaction increased compared with earlier Medtronic HCL iterations without compromising glucose control.

Creation of Novel Sensitive Probe Substrate and Moderate Inhibitor Models for a Comprehensive Prediction of CYP2C8 Interactions for Tucatinib.

A physiologically-based pharmacokinetic (PBPK) model was developed to simulate plasma concentrations of tucatinib (TUKYSA®) after single-dose or multiple-dose administration of 300 mg b.i.d. orally. This PBPK model was subsequently applied to support evaluation of drug-drug interaction (DDI) risk as a perpetrator resulting from tucatinib inhibition of CYP3A4, CYP2C8, CYP2C9, P-gp, or MATE1/2-K. The PBPK model was also applied to support evaluation of DDI risk as a victim resulting from co-administration with CYP3A4 or CYP2C8 inhibitors, or a CYP3A4 inducer. After refinement with clinical DDI data, the final PBPK model was able to recover the clinically observed single and multiple-dose plasma concentrations for tucatinib when tucatinib was administered as a single agent in healthy subjects. In addition, the final model was able to recover clinically observed plasma concentrations of tucatinib when administered in combination with itraconazole, rifampin, or gemfibrozil as well as clinically observed plasma concentrations of probe substrates of CYP3A4, CYP2C8, CYP2C9, P-gp, or MATE1/2-K. The PBPK model was then applied to prospectively predict the potential perpetrator or victim DDIs with other substrates, inducers, or inhibitors. To simulate a potential interaction with a moderate CYP2C8 inhibitor, two novel PBPK models representing a moderate CYP2C8 inhibitor and a sensitive CYP2C8 substrate were developed based on the existing PBPK models for gemfibrozil and rosiglitazone, respectively. The simulated population geometric mean area under the curve ratio of tucatinib with a moderate CYP2C8 inhibitor ranged from 1.98- to 3.08-fold, and based on these results, no dose modifications were proposed for moderate CYP2C8 inhibitors for the tucatinib label.

Evidence of Hematoma Prevention After Facelift.

Hematoma is a common complication after facelift procedures. Multiple factors have been shown to increase the risk of hematoma formation, such as male gender, anticoagulant medication use, perioperative hypertension, increased intrathoracic pressure, and operative technique. The purpose of this manuscript is to provide an overview of existing literature to provide surgeons with evidence-based recommendations on how to minimize hematoma risk during facelift surgery. A literature search for hematoma and facelift surgery was performed that identified 478 unique manuscripts. Abstracts were reviewed, excluding articles not describing facelift surgery, those written before 1970, studies with a sample size of fewer than 5 patients, non-English studies, and those that did not provide postoperative hematoma rates. Forty-five articles were included in this text, with their recommendations. Measures such as the prophylactic management of pain, nausea, and hypertension, the use of fibrin glue tissue sealants, the use of local anesthesia rather than general anesthesia, and strict blood pressure control of at least <140 mmHg were found to significantly reduce hematoma formation. Quilting sutures has shown benefit in some high-risk patients. Measures such as drains, compression dressings, perioperative use of selective serotonin reuptake inhibitors, and perioperative steroids had no significant effect on hematoma formation. In addition to appropriate patient selection and careful intraoperative hemostasis, many adjunct measures have been shown to reduce postoperative hematoma formation in facelift procedures.

Selenoprotein deficiency disorder predisposes to aortic aneurysm formation.

Aortic aneurysms, which may dissect or rupture acutely and be lethal, can be a part of multisystem disorders that have a heritable basis. We report four patients with deficiency of selenocysteine-containing proteins due to selenocysteine Insertion Sequence Binding Protein 2 (SECISBP2) mutations who show early-onset, progressive, aneurysmal dilatation of the ascending aorta due to cystic medial necrosis. Zebrafish and male mice with global or vascular smooth muscle cell (VSMC)-targeted disruption of Secisbp2 respectively show similar aortopathy. Aortas from patients and animal models exhibit raised cellular reactive oxygen species, oxidative DNA damage and VSMC apoptosis. Antioxidant exposure or chelation of iron prevents oxidative damage in patient's cells and aortopathy in the zebrafish model. Our observations suggest a key role for oxidative stress and cell death, including via ferroptosis, in mediating aortic degeneration.

Leptomeningeal Neural Organoid (LMNO) Fusions as Models to Study Meninges-Brain Signaling.

Neural organoids derived from human induced pluripotent stem cells (iPSCs) provide a model to study the earliest stages of human brain development, including neurogenesis, neural differentiation, and synaptogenesis. However, neural organoids lack supportive tissues and some non-neural cell types that are key regulators of brain development. Neural organoids have instead been co-cultured with non-neural structures and cell types to promote their maturation and model interactions with neuronal cells. One structure that does not form de novo with neural organoids is the meninges, a tri-layered structure that surrounds the CNS and secretes key signaling molecules required for mammalian brain development. Most studies of meninges-brain signaling have been performed in mice or using two-dimensional (2D) cultures of human cells, the latter not recapitulating the architecture and cellular diversity of the tissue. To overcome this, we developed a co-culture system of neural organoids generated from human iPSCs fused with fetal leptomeninges from mice with fluorescently labeled meninges (Col1a1-GFP). These proof-of-concept studies test the stability of the different cell types in the leptomeninges (fibroblast and macrophage) and the fused brain organoid (progenitor and neuron), as well as the interface between the organoid and meningeal tissue. We test the longevity of the fusion pieces after 30 days and 60 days in culture, describe best practices for preparing the meninges sample prior to fusion, and examine the feasibility of single or multiple meninges pieces fused to a single organoid. We discuss potential uses of the current version of the LMNO fusion model and opportunities to improve the system.

Real-world application of PBPK in drug discovery.

The utility of PBPK models in support of drug development has been well documented. During the discovery stage, PBPK has increasingly been applied for early risk assessment, prediction of human dose, toxicokinetic dose projection and early formulation assessment. Previous review articles have proposed model building and application strategies for PBPK-based first in human predictions with comprehensive descriptions of the individual components of PBPK models. This includes the generation of decision trees, based on comprehensive literature reviews, to guide the application of PBPK in the discovery setting. The goal of this mini review is to provide additional guidance on the real-world application of PBPK, in support of the discovery stage of drug development. In this mini review, our goal is to provide guidance on the typical steps involved in the development and application of a PBPK model during drug discovery to assist in decision making. We have illustrated our recommended approach through description of case examples, where PBPK has been successfully applied to aid in human PK projection, candidate selection and prediction of drug interaction liability for parent and metabolite. Through these case studies, we have highlighted fundamental issues, including pre-verification in preclinical species, the application of empirical scalars in the prediction of in vivo clearance from in vitro systems, in silico prediction of permeability and the exploration of aqueous and biorelevant solubility data to predict dissolution. In addition, current knowledge gaps have been highlighted and future directions proposed. Significance Statement Through description of three case studies, we have highlighted the fundamental principles of PBPK application during drug discovery. These include pre-verification of the model in preclinical species, application of empirical scalars where necessary in the prediction of clearance, in silico prediction of permeability, and the exploration of aqueous and biorelevant solubility data to predict dissolution. In addition, current knowledge gaps have been highlighted and future directions proposed.

Mouthparts of the bumblebee (Bombus terrestris) exhibit poor acuity for the detection of pesticides in nectar.

Bees are important pollinators of agricultural crops, but their populations are at risk when pesticides are used. One of the largest risks bees face is poisoning of floral nectar and pollen by insecticides. Studies of bee detection of neonicotinoids have reported contradictory evidence about whether bees can taste these pesticides in sucrose solutions and hence avoid them. Here, we use an assay for the detection of food aversion combined with single-sensillum electrophysiology to test whether the mouthparts of the buff-tailed bumblebee (Bombus terrestris) detect the presence of pesticides in a solution that mimicked the nectar of oilseed rape (Brassica napus). Bees did not avoid consuming solutions containing concentrations of imidacloprid, thiamethoxam, clothianidin, or sulfoxaflor spanning six orders of magnitude, even when these solutions contained lethal doses. Only extremely high concentrations of the pesticides altered spiking in gustatory neurons through a slight reduction in firing rate or change in the rate of adaptation. These data provide strong evidence that bumblebees cannot detect or avoid field-relevant concentrations of pesticides using information from their mouthparts. As bees rarely contact floral nectar with other body parts, we predict that they are at high risk of unwittingly consuming pesticides in the nectar of pesticide-treated crops.

Bees and other pollinators often encounter pesticides while collecting nectar and pollen from agricultural crops. Widely used to protect crops, pesticides are toxic to insects and have contributed to population declines in all bee species. One way that bees might be able to avoid pesticides is using their incredibly good sense of taste, which can detect subtle differences between sugary solutions. Therefore, if pesticides taste bitter to them, bumblebees may be able to avoid feeding treated crops. However, it was not clear if bees can taste pesticides. Previous studies investigating whether they can taste a group of pesticides called "neonicotinoids" gave contradictory results. Furthermore, explicit behavioural tests of their ability to taste pesticides had not been performed. To shed light on this, Parkinson et al. compared the responses of neurons within structures used for detecting taste in bumblees eating a pure sugar solution with those eating a solution containing pesticides. Experiments with a group of pesticides known as 'cholinergic' showed that neuron responses were the same whether the sugar solution contained pesticides or not. Secondly, by looking at bumblebee feeding behaviour, Parkinson et al. found that bees offered both pure and pesticide-laced sugar solutions would still drink the pesticide solution, even when it was toxic enough to make them very ill or kill them. This was the case regardless of which pesticide was used. The experiments showed that bumblebees cannot use their sense of taste to avoid drinking pesticide-laced nectar, which is an important finding for policymakers making decisions about the use of pesticides on agricultural crops. It is possible that bees simply have a poor sense of bitter taste. However, in the future, these methods could be used to identify a compound that tastes bad to bees. Including such a compound in pesticides, could deter bees from feeding on pesticide-treated crops that do not require pollination, and help to restore their declining populations.

Thermomechanical Properties of Virgin and Recycled Polypropylene-High-Density Polyethylene Blends.

This paper provides evidence and discusses the variability in the thermomechanical behaviour of virgin and recycled polypropylene/high-density polyethylene blends without the addition of other components, which is sparse in the literature. Understanding the performance variability in recycled polymer blends is of critical importance in order to facilitate the re-entering of recycled materials to the consumer market and, thus, contribute towards a circular economy. This is an area that requires further research due to the inhomogeneity of recycled materials. Therefore, the thermal and mechanical properties of virgin and recycled polypropylene/high-density polyethylene blends were investigated systematically. Differential scanning calorimetry concludes that both the recycled and virgin blends are immiscible. Generally, recycled blends have lower overall crystallinity and melting temperatures compared with virgin blends while, remarkably, their crystallisation temperatures are compared favourably. Dynamical mechanical analysis showed little variation in the storage modulus of recycled and virgin blends. However, the alpha and beta relaxation temperatures are lower in recycled blends due to structural deterioration. Deterioration in the thermal and mechanical properties of recycled blends is thought to be caused by the presence of contaminants and structural degradation during reprocessing, resulting in shorter polymeric chains and the formation of imperfect crystallites. The tensile properties of recycled blends are also affected by the recycling process. The Young's modulus and yield strength of the recycled blends are inferior to those of virgin blends due to the deterioration during the recycling process. However, the elongation at break of the recycled blends is higher compared with the virgin blends, possibly due to the plasticity effect of the low-molecular-weight chain fragments.

Brachial artery aneurysm and bilateral posterior circulation strokes in a young child with tuberous sclerosis complex.

Although tuberous sclerosis (TS) may affect many organs, vascular manifestations involving medium- and large-size vessels are rare. We present a young child with known TS who presented with bilateral posterior circulation infarcts and subsequently was found to have right-hand ischaemia secondary to a thrombosed brachial artery aneurysm. A wound on his right middle finger failed to heal with conservative management, and digital subtraction angiography and MR angiogram demonstrated a lack of bypass target with microcollateral supply of the forearm only. The right middle digit ischaemia was initially managed with right middle finger disarticulation at the metacarpophalangeal joint, but the wound failed to heal and the patient proceeded to a thumb-sparing carpo-metacarpal amputation. Aneurysms, stenotic-occlusive disease and embolic stroke are rare but important complications of TS.

Association between cumulative maternal exposures related to inflammation and child attention-deficit/hyperactivity disorder: A cohort study.

BACKGROUND: Preclinical studies suggest synergistic effects of maternal inflammatory exposures on offspring neurodevelopment, but human studies have been limited. OBJECTIVES: To examine the cumulative association and potential interactions between seven maternal exposures related to inflammation and child attention-deficit/hyperactivity disorder (ADHD). METHODS: We conducted a population-based cohort study of children born from July 2001 to December 2011 in New South Wales, Australia, and followed up until December 2014. Seven maternal exposures were identified from birth data and hospital admissions during pregnancy: autoimmune disease, asthma, hospitalization for infection, mood or anxiety disorder, smoking, hypertension, and diabetes. Child ADHD was identified from stimulant prescription records. Multivariable Cox regression assessed the association between individual and cumulative exposures and ADHD and potential interaction between exposures, controlling for potential confounders. RESULTS: The cohort included 908,770 children, one-third (281,724) with one or more maternal exposures. ADHD was identified in 16,297 children (incidence 3.5 per 1000 person-years) with median age of 7 (interquartile range 2) years at first treatment. Each exposure was independently associated with ADHD, and risk increased with additional exposures: one exposure (hazard ratio (HR) 1.59, 95% confidence interval (CI) 1.54, 1.65), two exposures (HR 2.25, 95% CI 2.13, 2.37), and three or more exposures (HR 3.28, 95% CI 2.95, 3.64). Positive interaction was found between smoking and infection. The largest effect size was found for cumulative exposure of asthma, infection, mood or anxiety disorder, and smoking (HR 6.12, 95% CI 3.47, 10.70). CONCLUSIONS: This study identifies cumulative effects of multiple maternal exposures related to inflammation on ADHD, most potentially preventable or modifiable. Future studies should incorporate biomarkers of maternal inflammation and consider gene-environment interactions.

A reductionist paradigm for high-throughput behavioural fingerprinting in Drosophila melanogaster.

Understanding how the brain encodes behaviour is the ultimate goal of neuroscience and the ability to objectively and reproducibly describe and quantify behaviour is a necessary milestone on this path. Recent technological progresses in machine learning and computational power have boosted the development and adoption of systems leveraging on high-resolution video recording to track an animal pose and describe behaviour in all four dimensions. However, the high temporal and spatial resolution that these systems offer must come as a compromise with their throughput and accessibility. Here, we describe coccinella, an open-source reductionist framework combining high-throughput analysis of behaviour using real-time tracking on a distributed mesh of microcomputers (ethoscopes) with resource-lean statistical learning (HCTSA/Catch22). Coccinella is a reductionist system, yet outperforms state-of-the-art alternatives when exploring the pharmacobehaviour in Drosophila melanogaster.

Meningeal origins and dynamics of perivascular fibroblast development on the mouse cerebral vasculature.

Perivascular fibroblasts (PVFs) are a fibroblast-like cell type that reside on large-diameter blood vessels in the adult meninges and central nervous system (CNS). PVFs contribute to fibrosis following injury but their homeostatic functions are not defined. PVFs were previously shown to be absent from most brain regions at birth and are only detected postnatally within the cerebral cortex. However, the origin, timing and cellular mechanisms of PVF development are not known. We used Col1a1-GFP and Col1a2-CreERT2 transgenic mice to track PVF development postnatally. Using lineage tracing and in vivo imaging we show that brain PVFs originate from the meninges and are first seen on parenchymal cerebrovasculature at postnatal day (P) 5. After P5, PVF coverage of the cerebrovasculature expands via local cell proliferation and migration from the meninges. Finally, we show that PVFs and perivascular macrophages develop concurrently. These findings provide the first complete timeline for PVF development in the brain, enabling future work into how PVF development is coordinated with cell types and structures in and around the perivascular spaces to support normal CNS vascular function.

Development and application of a PBPK modeling strategy to support antimalarial drug development.

As part of a collaboration between Medicines for Malaria Venture (MMV), Certara UK and Monash University, physiologically-based pharmacokinetic (PBPK) models were developed for 20 antimalarials, using data obtained from standardized in vitro assays and clinical studies within the literature. The models have been applied within antimalarial drug development at MMV for more than 5 years. During this time, a strategy for their impactful use has evolved. All models are described in the supplementary material and are available to researchers. Case studies are also presented, demonstrating real-world development and clinical applications, including the assessment of the drug-drug interaction liability between combination partners or with co-administered drugs. This work emphasizes the benefit of PBPK modeling for antimalarial drug development and decision making, and presents a strategy to integrate it into the research and development process. It also provides a repository of shared information to benefit the global health research community.

A comprehensive evaluation in clinic and physiologically-based pharmacokinetic modeling and simulation to confirm lack of cytochrome P450-mediated drug-drug interaction potential for pomotrelvir.

Pomotrelvir is a new chemical entity and potent direct-acting antiviral inhibitor of the main protease of coronaviruses. Here the cytochrome P450 (CYP)-mediated drug-drug interaction (DDI) potential of pomotrelvir was evaluated for major CYP isoforms, starting with in vitro assays followed by the basic static model assessment. The identified CYP3A4-mediated potential DDIs were evaluated clinically at a supratherapeutic dose of 1050 mg twice daily (b.i.d.) of pomotrelvir, including pomotrelvir coadministration with ritonavir (strong inhibitor of CYP3A4) or midazolam (sensitive substrate of CYP3A4). Furthermore, a physiologically-based pharmacokinetic (PBPK) model was developed within the Simcyp Population-based Simulator using in vitro and in vivo information and validated with available human pharmacokinetic (PK) data. The PBPK model was simulated to assess the DDI potential for CYP isoforms that pomotrelvir has shown a weak to moderate DDI in vitro and for CYP3A4 at the therapeutic dose of 700 mg b.i.d. To support the use of pomotrelvir in women of childbearing potential, the impact of pomotrelvir on the exposure of the representative oral hormonal contraceptive drugs ethinyl estradiol and levonorgestrel was assessed using the PBPK model. The overall assessment suggested weak inhibition of pomotrelvir on CYP3A4 and minimal impact of a strong CYP3A4 inducer or inhibitor on pomotrelvir PK. Therefore, pomotrelvir is not anticipated to have clinically meaningful DDIs at the clinical dose. These comprehensive in vitro, in clinic, and in silico efforts indicate that the DDI potential of pomotrelvir is minimal, so excluding patients on concomitant medicines in clinical studies would not be required.