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Failed fixation of intracapsular hip fractures in young patients is associated with high morbidity and cost. Accordingly, we set out to determine the association between unsatisfactory post-operative imaging (judged by two fellowship-trained trauma consultants and a senior trainee) and the risk of subsequent reoperation, including adjustment for potential confounding variables. Ninety-four (94) patients aged <60 were included in the study from a single major trauma centre. Exhausted patients (19%) required further surgery, with the most common reason being avascular necrosis (n=10) followed by non-union (n=6). Univariate analysis found only smokers and unsatisfactory fracture reduction to be predictive of failure (p < 0.05). Other demographics and recognised scoring systems from the literature were poor predictors of failure apart from the Haiduewych classification system, utilised to assess the quality of reduction, which showed a trend towards significance (p0.053). Multivariate analysis showed smoking and unsatisfactory fracture reduction to be strong predictors of failure (p<0.05). In those with unsatisfactory fracture reduction, 50% required reoperation compared to 17.5% of those with satisfactory reduction. This study highlights the key principles of ensuring adequate intraoperative reduction and fixation, in keeping with GIRFT principles. Avoiding secondary reoperation is crucial to prevent long-term negative outcomes for this typically high functional demand group of patients. We recommend regular, consultant peer review of post-operative imaging as a method of identifying substandard fracture fixations and those at risk of failure. This will allow opportunities for teaching, clinical improvement, and multidisciplinary team (MDT) discussions of at-risk patients.
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Aurora A kinase, a cell division regulator, is frequently overexpressed in various cancers, provoking genome instability and resistance to antimitotic chemotherapy. Localization and enzymatic activity of Aurora A are regulated by its interaction with the spindle assembly factor TPX2. We have used fragment-based, structure-guided lead discovery to develop small molecule inhibitors of the Aurora A-TPX2 protein-protein interaction (PPI). Our lead compound, CAM2602, inhibits Aurora A:TPX2 interaction, binding Aurora A with 19 nM affinity. CAM2602 exhibits oral bioavailability, causes pharmacodynamic biomarker modulation, and arrests the growth of tumor xenografts. CAM2602 acts by a novel mechanism compared to ATP-competitive inhibitors and is highly specific to Aurora A over Aurora B. Consistent with our finding that Aurora A overexpression drives taxane resistance, these inhibitors synergize with paclitaxel to suppress the outgrowth of pancreatic cancer cells. Our results provide a blueprint for targeting the Aurora A-TPX2 PPI for cancer therapy and suggest a promising clinical utility for this mode of action.
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Individuals who belong to a sexual minority are at greater risk of adverse health and social outcomes. These effects are observed during adolescence when many mental health problems, such as depression, first emerge. Here, we used a network analytic approach to better understand the role that sexual minority status plays in the association between depression, interpersonal difficulties and substance use in a large sample of mid-adolescents. In doing so, we used data from 8017 fourteen year olds from the UK's Millennium Cohort Study, of which 490 self-identified as belonging to a sexual minority. We found that sexual minority status was highly central in the network and connected to multiple adverse outcomes, sometimes directly and sometimes indirectly. The largest single association was between sexual minority status and depression, and this link mediated multiple negative associations with being in a sexual minority. The shortest path to drinking, poor social support and closeness with parents and victimization occurred via depression. The shortest path to smoking and drug use occurred via conduct problems. We also identified three distinct profiles of adverse outcomes among those belonging to a sexual minority, highlighting the heterogeneous nature of this group.
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PURPOSE: This study aims to develop and externally validate a treatment algorithm to predict nonoperative treatment success or failure in patients with anterior cruciate ligament (ACL) rupture. METHODS: Data were used from two completed studies of adult patients with ACL ruptures: the Conservative versus Operative Methods for Patients with ACL Rupture Evaluation study (development cohort) and the KNee osteoArthritis anterior cruciate Ligament Lesion study (validation cohort). The primary outcome variable is nonoperative treatment success or failure. Potential predictor variables were collected, entered into the univariable logistic regression model and then incorporated into the multivariable logistic regression model for constructing the treatment algorithm. Finally, predictive performance and goodness-of-fit were assessed and externally validated by discrimination and calibration measures. RESULTS: In the univariable logistic regression model, a stable knee measured with the pivot shift test and a posttrauma International Knee Documentation Committee (IKDC) score <50 were predictive of needing an ACL reconstruction. Age >30 years and a body mass index > 30 kg/m2 were predictive for not needing an ACL reconstruction. Age, pretrauma Tegner score, the outcome of the pivot shift test and the posttrauma IKDC score are entered into the treatment algorithm. The predictability of needing an ACL reconstruction after nonoperative treatment (discrimination) is acceptable in both the development and the validation cohort: area under the curve = resp. 0.69 (95% confidence interval [CI]: 0.58-0.81) and 0.68 (95% CI: 0.58-0.78). CONCLUSION: This study shows that the treatment algorithm can acceptably predict whether an ACL injury patient will have a(n) (un)successful nonoperative treatment (discrimination). Calibration of the treatment algorithm suggests a systematical underestimation of the need for ACL reconstruction. Given the limitations regarding the sample size of this study, larger data sets must be constructed to improve the treatment algorithm further. LEVEL OF EVIDENCE: Level II.
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OBJECTIVE: To assess the presence of early degenerative changes on Magnetic Resonance Imaging (MRI) 24 months after a traumatic meniscal tear and to compare these changes in patients treated with arthroscopic partial meniscectomy or physical therapy plus optional delayed arthroscopic partial meniscectomy. DESIGN: We included patients aged 18-45 years with a recent onset, traumatic, MRI verified, isolated meniscal tear without radiographic osteoarthritis. Patients were randomized to arthroscopic partial meniscectomy or standardized physical therapy with optional delayed arthroscopic partial meniscectomy. MRIs at baseline and 24 months were scored using the MRI Osteoarthritis Knee Score (MOAKS). We compared baseline MRIs to healthy controls aged 18-40 years. The outcome was the progression of bone marrow lesions (BMLs), cartilage defects and osteophytes after 24 months in patients. RESULTS: We included 99 patients and 50 controls. At baseline, grade 2 and 3 BMLs were present in 26% of the patients (n = 26), compared to 2% of the controls (n = 1) (between group difference 24% (95% CI 15% to 34%)). In patients, 35% (n = 35) had one or more cartilage defects grade 1 or higher, compared to 2% of controls (n = 1) (between group difference 33% (95% CI 23% to 44%)). At 24 months MRI was available for 40 patients randomized to arthroscopic partial meniscectomy and 41 patients randomized to physical therapy. At 24 months 30% (n = 12) of the patients randomized to arthroscopic partial meniscectomy showed BML worsening, compared to 22% (n = 9) of the patients randomized to physical therapy (between group difference 8% (95% CI -11% to 27%)). Worsening of cartilage defects was present in 40% (n = 16) of the arthroscopic partial meniscectomy group, compared to 22% (n = 9) of the physical therapy group (between group difference 18% (95% CI -2% to 38%)). Of the patients who had no cartilage defect at baseline, 33% of the arthroscopic partial meniscectomy group had a new cartilage defect at follow-up compared to 14% of the physical therapy group. Osteophyte worsening was present in 18% (n = 7) of the arthroscopic partial meniscectomy group and 15% (n = 6) of the physical therapy group (between group difference 3% (95% CI -13% to 19%)). CONCLUSIONS: Our results might suggest more worsening of BMLs and cartilage defects with arthroscopic partial meniscectomy compared to physical therapy with optional delayed arthroscopic partial meniscectomy at 24-month follow-up in young patients with isolated traumatic meniscal tears without radiographic OA.
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Developmental prosopagnosia (DP) is characterised by difficulties recognising face identities and is associated with diverse co-occurring object recognition difficulties. The high co-occurrence rate and heterogeneity of associated difficulties in DP is an intrinsic feature of developmental conditions, where co-occurrence of difficulties is the rule, rather than the exception. However, despite its name, cognitive and neural theories of DP rarely consider the developmental context in which these difficulties occur. This leaves a large gap in our understanding of how DP emerges in light of the developmental trajectory of face recognition. Here, we argue that progress in the field requires re-considering the developmental origins of differences in face recognition abilities, rather than studying the end-state alone. In practice, considering development in DP necessitates a re-evaluation of current approaches in recruitment, design, and analyses.
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Reconocimiento Facial , Prosopagnosia , Humanos , Percepción Visual , Reconocimiento Visual de ModelosRESUMEN
The widely acknowledged detrimental impact of early adversity on child development has driven efforts to understand the underlying mechanisms that may mediate these effects within the developing brain. Recent efforts have begun to move beyond associating adversity with the morphology of individual brain regions towards determining if and how adversity might shape their interconnectivity. However, whether adversity effects a global shift in the organisation of whole-brain networks remains unclear. In this study, we assessed this possibility using parental questionnaire and diffusion imaging data from The Avon Longitudinal Study of Parents and Children (ALSPAC, N = 913), a prospective longitudinal study spanning more than 20 years. We tested whether a wide range of adversities-including experiences of abuse, domestic violence, physical and emotional cruelty, poverty, neglect, and parental separation-measured by questionnaire within the first seven years of life were significantly associated with the tractography-derived connectome in young adulthood. We tested this across multiple measures of organisation and using a computational model that simulated the wiring economy of the brain. We found no significant relationships between early exposure to any form of adversity and the global organisation of the structural connectome in young adulthood. We did detect local differences in the medial prefrontal cortex, as well as an association between weaker brain wiring constraints and greater externalising behaviour in adolescence. Our results indicate that further efforts are necessary to delimit the magnitude and functional implications of adversity-related differences in connectomic organization. RESEARCH HIGHLIGHTS: Diverse prospective measures of the early-life environment do not predict the organisation of the DTI tractography-derived connectome in young adulthood Wiring economy of the connectome is weakly associated with externalising in adolescence, but not internalising or cognitive ability Further work is needed to establish the scope and significance of global adversity-related differences in the structural connectome.
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Encéfalo , Conectoma , Humanos , Estudios Longitudinales , Estudios Prospectivos , Encéfalo/fisiología , Encéfalo/diagnóstico por imagen , Femenino , Masculino , Adulto Joven , Adolescente , Niño , Experiencias Adversas de la Infancia , Adulto , Imagen de Difusión Tensora , Preescolar , Encuestas y Cuestionarios , Lactante , Desarrollo Infantil/fisiologíaRESUMEN
Understanding the viscoelastic behavior of pediatric brain tissue is critical to interpret how external mechanical forces affect head injury in children. However, knowledge of the viscoelastic properties of pediatric brain tissue is limited, and this reduces the biofidelity of developed numeric simulations of the pediatric head in analysis of brain injury. Thus, it is essential to characterize the viscoelastic behavior of pediatric brain tissue in various loading conditions and to identify constitutive models. In this study, the pediatric porcine brain tissue was investigated in compression with determine the viscoelasticity under small and large strain, respectively. A range of frequencies between 0.1 and 40 Hz was applied to determine frequency-dependent viscoelastic behavior via dynamic mechanical analysis, while brain samples were divided into three strain rate groups of 0.01/s, 1/s and 10/s for compression up to 0.3 strain level and stress relaxation to obtain time-dependent viscoelastic properties. At frequencies above 20 Hz, the storage modulus did not increase, while the loss modulus increased continuously. With strain rate increasing from 0.01/s to 10/s, the mean stress at 0.1, 0.2 and 0.3 strain increased to approximate 6.8, 5.6 and 4.4 times, respectively. The brain compressive response was sensitive to strain rate and frequency. The characterization of brain tissue will be valuable for development of head protection systems and prediction of brain injury.
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Encéfalo , Fuerza Compresiva , Elasticidad , Estrés Mecánico , Animales , Viscosidad , Encéfalo/fisiología , Factores de Tiempo , Porcinos , Sus scrofa , Módulo de ElasticidadRESUMEN
BACKGROUND: The mechanosensory lateral line system is an important sensory modality in fishes, informing multiple behaviours related to survival including finding food and navigating in dark environments. Given its ecological importance, we may expect lateral line morphology to be under disruptive selection early in the ecological speciation process. Here we quantify the lateral line system morphology of two ecomorphs of the cichlid fish Astatotilapia calliptera in crater Lake Masoko that have diverged from common ancestry within the past 1,000 years. RESULTS: Based on geometric morphometric analyses of CT scans, we show that the zooplanktivorous benthic ecomorph that dominates the deeper waters of the lake has large cranial lateral line canal pores, relative to those of the nearshore invertebrate-feeding littoral ecomorph found in the shallower waters. In contrast, fluorescence imaging revealed no evidence for divergence between ecomorphs in the number of either superficial or canal neuromasts. We illustrate the magnitude of the variation we observe in Lake Masoko A. calliptera in the context of the neighbouring Lake Malawi mega-radiation that comprises over 700 species. CONCLUSIONS: These results provide the first evidence of divergence in this often-overlooked sensory modality in the early stages of ecological speciation, suggesting that it may have a role in the broader adaptive radiation process.
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Cíclidos , Sistema de la Línea Lateral , Animales , Cíclidos/genética , Cíclidos/anatomía & histología , Lagos , Análisis de Secuencia de ADN , MalauiRESUMEN
Neurodevelopment is not merely a process of brain maturation, but an adaptation to constraints unique to each individual and to the environments we co-create. However, our theoretical and methodological toolkits often ignore this reality. There is growing awareness that a shift is needed that allows us to study divergence of brain and behaviour across conventional categorical boundaries. However, we argue that in future our study of divergence must also incorporate the developmental dynamics that capture the emergence of those neurodevelopmental differences. This crucial step will require adjustments in study design and methodology. If our ultimate aim is to incorporate the developmental dynamics that capture how, and ultimately when, divergence takes place then we will need an analytic toolkit equal to these ambitions. We argue that the over reliance on group averages has been a conceptual dead-end with regard to the neurodevelopmental differences. This is in part because any individual differences and developmental dynamics are inevitably lost within the group average. Instead, analytic approaches which are themselves new, or simply newly applied within this context, may allow us to shift our theoretical and methodological frameworks from groups to individuals. Likewise, methods capable of modelling complex dynamic systems may allow us to understand the emergent dynamics only possible at the level of an interacting neural system.
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Encéfalo , Proyectos de Investigación , HumanosRESUMEN
FEBS Open Bio is committed to not only publishing sound science but also to supporting early-career researchers and the scientific community as a whole. In this editorial, we look back at how the journal recognised and rewarded excellent research in 2023 and look forward to 2024.
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Edición , Investigadores , HumanosRESUMEN
Parental socioeconomic status (SES) is a well-established predictor of children's neurocognitive development. Several theories propose that specific cognitive skills are particularly vulnerable. However, this can be challenging to test, because cognitive assessments are not pure measures of distinct neurocognitive processes, and scores across different tests are often highly correlated. Aside from one previous study by Tucker-Drob, little research has tested if associations between SES and cognition are explained by differences in general cognitive ability rather than specific cognitive skills. Using structural equation modelling (SEM), we tested if parental SES is associated with individual cognitive test scores after controlling for latent general cognitive ability. Data from three large-scale cohorts totalling over 16,360 participants from the UK and USA (ages 6-19) were used. Associations between SES and cognitive test scores are mainly (but not entirely) explained through general cognitive ability. Socioeconomic advantage was associated with particularly strong vocabulary performance, unexplained by general ability. When controlling for general cognitive ability, socioeconomic disadvantage was associated with better executive functions. Better characterizing relationships between cognition and adversity is a crucial first step toward designing interventions to narrow socioeconomic gaps. RESEARCH HIGHLIGHTS: Understanding environmental influences on cognitive development is a crucial goal for developmental science-parental socioeconomic status (SES) is one of the strongest predictors. Several theories have proposed that specific cognitive skills, such as language or certain executive functions, are particularly susceptible to socioeconomic adversity. Using structural equation modelling, we tested whether SES predicts specific cognitive and academic tests after controlling for latent general cognitive ability across three large-scale cohorts. SES moderately predicted latent general cognitive ability, but associations with specific cognitive skills were mainly small, with a few exceptions.
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Lenguaje , Clase Social , Niño , Humanos , Cognición , Función Ejecutiva , PadresRESUMEN
Prostate cancer is the second most common cancer in men worldwide. [18F]FDG PET/CT imaging, a well-known and effective technique for detecting malignancies, has not been considered a useful tool for prostate cancer imaging by many because of its perceived low [18F]FDG uptake. Incidentally detected focal [18F]FDG uptake in the prostate is not uncommon, and typically benign. Imaging features that would increase concern for an underlying prostatic carcinoma, include focal uptake in the periphery near the gland margin without calcifications. [18F]FDG PET/CT imaging provides little value in the initial staging of prostate cancer, particularly in the era of prostate specific membrane antigen (PSMA) radiotracer. In cases of biochemical recurrence, the value of [18F]FDG PET/CT increases notably when Grade group 4 or 5 and elevated PSA levels are present. Active research is underway for theranostic approaches to prostate cancer, including [177Lu]Lu-PSMA therapy. Dual tracer staging using FDG and PSMA imaging significantly enhances the accuracy of disease site assessment. Specifically, the addition of [18F]FDG PET/CT imaging allows for the evaluation of discordant disease (PSMA negative/FDG positive). The maximal benefit from [177Lu]Lu-PSMA therapy relies on significant PSMA accumulation across all disease sites, and the identification of discordant disease suggests that these patients may derive less benefit from the treatment. The genuine value of [18F]FDG PET/CT imaging lies in advanced prostate cancer, PSMA-negative disease, as a prognostic biomarker, and the realm of new targeted theranostic agents.
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Tomografía Computarizada por Tomografía de Emisión de Positrones , Neoplasias de la Próstata , Masculino , Humanos , Tomografía Computarizada por Tomografía de Emisión de Positrones/métodos , Fluorodesoxiglucosa F18 , Antígeno Prostático Específico , Neoplasias de la Próstata/diagnóstico por imagen , Neoplasias de la Próstata/terapia , Neoplasias de la Próstata/patología , Tomografía de Emisión de Positrones , Radioisótopos de GalioRESUMEN
Aims: The aim of this study was to evaluate the cost-effectiveness of arthroscopic partial meniscectomy versus physical therapy plus optional delayed arthroscopic partial meniscectomy in young patients aged under 45 years with traumatic meniscal tears. Methods: We conducted a multicentre, open-labelled, randomized controlled trial in patients aged 18 to 45 years, with a recent onset, traumatic, MRI-verified, isolated meniscal tear without knee osteoarthritis. Patients were randomized to arthroscopic partial meniscectomy or standardized physical therapy with an optional delayed arthroscopic partial meniscectomy after three months of follow-up. We performed a cost-utility analysis on the randomization groups to compare both treatments over a 24-month follow-up period. Cost utility was calculated as incremental costs per quality-adjusted life year (QALY) gained of arthroscopic partial meniscectomy compared to physical therapy. Calculations were performed from a healthcare system perspective and a societal perspective. Results: A total of 100 patients were included: 49 were randomized to arthroscopic partial meniscectomy and 51 to physical therapy. In the physical therapy group, 21 patients (41%) received delayed arthroscopic partial meniscectomy during follow-up. Over 24 months, patients in the arthroscopic partial meniscectomy group had a mean 0.005 QALYs lower quality of life (95% confidence interval -0.13 to 0.14). The cost-utility ratio was -160,000/QALY from the healthcare perspective and -223,372/QALY from the societal perspective, indicating that arthroscopic partial meniscectomy incurs additional costs without any added health benefit. Conclusion: Arthroscopic partial meniscectomy is arthroscopic partial meniscectomy is unlikely to be cost-effective in treating young patients with isolated traumatic meniscal tears compared to physical therapy as a primary health intervention. Arthroscopic partial meniscectomy leads to a similar quality of life, but higher costs, compared to physical therapy plus optional delayed arthroscopic partial meniscectomy.
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Meniscectomía , Osteoartritis de la Rodilla , Humanos , Meniscectomía/efectos adversos , Análisis Costo-Beneficio , Calidad de Vida , Modalidades de Fisioterapia , Osteoartritis de la Rodilla/cirugía , Osteoartritis de la Rodilla/etiología , Artroscopía/efectos adversos , Meniscos Tibiales/cirugíaRESUMEN
BACKGROUND: After talocrural arthrodesis, adjacent joints (subtalar, talonavicular, and calcaneocuboid) are often affected by osteoarthritis (OA)). It is unclear if OA is pre-existing to talocrural arthrodesis, or whether it develops after talocrural arthrodesis. This retrospective study is unique because it is the first study with preoperative and follow-up computed tomography (CT). The aim of this study is to investigate whether OA develops in adjacent joints after talocrural arthrodesis or if OA is already pre-existing. In addition, associations between degree of OA and patient-reported outcomes are investigated. METHODS: Patients were selected from electronic files, and adjacent joint OA was assessed on preoperative CT and bilateral follow-up CT. Patient-reported outcomes were collected. RESULTS: Twenty-three patients were included with an average follow-up time of 7 years (SD = 2). In participants without pre-existing OA, OA significantly progressed in all adjacent joints. In participants with pre-existing OA, OA progressed in the subtalar joint. Patient-reported outcomes were not correlated to OA. CONCLUSIONS: Osteoarthritis in the adjacent joints progresses after talocrural arthrodesis, especially in participants without pre-existing OA. The severity of OA is not related to patient-reported outcomes. Therefore, the clinical impact of the progression of OA seems to be limited. LEVEL OF EVIDENCE: Level III: retrospective.
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AIM: The triple network model of psychopathology posits that altered connectivity between the Salience (SN), Central Executive (CEN), and Default Mode Networks (DMN) may underlie neurodevelopmental conditions. However, this has yet to be tested in a transdiagnostic sample of young people. METHOD: We investigated this in 175 children (60 girls) that represent a heterogeneous population who are experiencing neurodevelopmental difficulties in cognition and behavior, and 60 comparison children (33 girls). Hyperactivity/impulsivity and inattention were assessed by parent-report. Resting-state functional Magnetic Resonance Imaging data were acquired and functional connectivity was calculated between independent network components and regions of interest. We then examined whether connectivity between the SN, CEN and DMN was dimensionally related to hyperactivity/impulsivity and inattention, whilst controlling for age, gender, and motion. RESULTS: Hyperactivity/impulsivity was associated with increased functional connectivity between the SN, CEN, and DMN in at-risk children, whereas it was associated with decreased functional connectivity between the CEN and DMN in comparison children. These effects replicated in an adult parcellation of brain function and when using increasingly stringent exclusion criteria for in-scanner motion. CONCLUSION: Triple network connectivity characterizes transdiagnostic neurodevelopmental difficulties with hyperactivity/impulsivity. We suggest that this may arise from delayed network segregation, difficulties sustaining CEN activity to regulate behavior, and/or a heightened developmental mismatch between neural systems implicated in cognitive control relative to those implicated in reward/affect processing.
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Trastornos Mentales , Red Nerviosa , Adulto , Femenino , Niño , Humanos , Adolescente , Encéfalo , Cognición/fisiología , Corteza Cerebral , Vías Nerviosas/diagnóstico por imagen , Imagen por Resonancia Magnética/métodos , Mapeo Encefálico/métodosRESUMEN
Mitral valve function depends on its complex geometry and tissue health, with alterations in shape and tissue response affecting the long-term restorarion of function. Previous computational frameworks for biomechanical assessment are mostly based on patient-specific geometries; however, these are not flexible enough to yield a variety of models and assess mitral closure for individually tuned morphological parameters or material property representations. This study details the finite element approach implemented in our previously developed toolbox to assess mitral valve biomechanics and showcases its flexibility through the generation and biomechanical evaluation of different models. A healthy valve geometry was generated and its computational predictions for biomechanics validated against data in the literature. Moreover, two mitral valve models including geometric alterations associated with disease were generated and analysed. The healthy mitral valve model yielded biomechanical predictions in terms of valve closure dynamics, leaflet stresses and papillary muscle and chordae forces comparable to previous computational and experimental studies. Mitral valve function was compromised in geometries representing disease, expressed by the presence of regurgitating areas, elevated stress on the leaflets and unbalanced subvalvular apparatus forces. This showcases the flexibility of the toolbox concerning the generation of a range of mitral valve models with varying geometric definitions and material properties and the evaluation of their biomechanics.
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Insuficiencia de la Válvula Mitral , Válvula Mitral , Humanos , Válvula Mitral/fisiología , Fenómenos Biomecánicos , Análisis de Elementos Finitos , Músculos Papilares/fisiología , Modelos CardiovascularesRESUMEN
Human pluripotent stem cell (hPSC)-derived tissues can be used to model diseases in cell types that are challenging to harvest and study at-scale, such as neutrophils. Neutrophil dysregulation, specifically neutrophil extracellular trap (NET) formation, plays a critical role in the prognosis and progression of multiple diseases, including COVID-19. While hPSCs can generate limitless neutrophils (iNeutrophils) to study these processes, current differentiation protocols generate heterogeneous cultures of granulocytes and precursors. Here, we describe a method to improve iNeutrophil differentiations through the deletion of GATA1. GATA1 knockout (KO) iNeutrophils are nearly identical to primary neutrophils in form and function. Unlike wild-type iNeutrophils, GATA1 KO iNeutrophils generate NETs in response to the physiologic stimulant lipopolysaccharide, suggesting they are a more accurate model when performing NET inhibitor screens. Furthermore, through deletion of CYBB, we demonstrate that GATA1 KO iNeutrophils are a powerful tool in determining involvement of a given protein in NET formation.
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The impact of socioeconomic status (SES) on early child development is well-established, but the mediating role of parental mental health is poorly understood. Data were obtained from The Avon Longitudinal Study of Parents and Children (ALSPAC; n = 13,855), including measures of early SES (age 8 months), key aspects of development during mid-late childhood (ages 7-8 years), and maternal mental health during early childhood (ages 0-3 years). In the first year of life, better maternal mental health was shown to weaken the negative association between SES and child mental health. Better maternal mental health was additionally shown to weaken the association between SES and child cognitive ability. These findings highlight the variability and complexity of the mediating role of parental mental health on child development. They further emphasise the importance of proximal factors in the first year of life, such as parental mental health, in mediating key developmental outcomes.
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Early adversity can change educational, cognitive, and mental health outcomes. However, the neural processes through which early adversity exerts these effects remain largely unknown. We used generative network modeling of the mouse connectome to test whether unpredictable postnatal stress shifts the constraints that govern the organization of the structural connectome. A model that trades off the wiring cost of long-distance connections with topological homophily (i.e., links between regions with shared neighbors) generated simulations that successfully replicate the rodent connectome. The imposition of early life adversity shifted the best-performing parameter combinations toward zero, heightening the stochastic nature of the generative process. Put simply, unpredictable postnatal stress changes the economic constraints that reproduce rodent connectome organization, introducing greater randomness into the development of the simulations. While this change may constrain the development of cognitive abilities, it could also reflect an adaptive mechanism that facilitates effective responses to future challenges.