Genetic associations between non-cognitive skills and academic achievement over development.

Non-cognitive skills, such as motivation and self-regulation, are partly heritable and predict academic achievement beyond cognitive skills. However, how the relationship between non-cognitive skills and academic achievement changes over development is unclear. The current study examined how cognitive and non-cognitive skills are associated with academic achievement from ages 7 to 16 years in a sample of over 10,000 children from England and Wales. The results showed that the association between non-cognitive skills and academic achievement increased across development. Twin and polygenic scores analyses found that the links between non-cognitive genetics and academic achievement became stronger over the school years. The results from within-family analyses indicated that non-cognitive genetic effects on academic achievement could not simply be attributed to confounding by environmental differences between nuclear families, consistent with a possible role for evocative/active gene-environment correlations. By studying genetic associations through a developmental lens, we provide further insights into the role of non-cognitive skills in academic development.

The Impact of Local Control on Overall Survival after Y-90 Selective Internal Radiotherapy of Liver Metastases in Oligometastatic Cancer: A Retrospective Analysis.

Y-90 Selective Internal Radiotherapy (SIRT) is an ablative therapy used for inoperable liver metastasis. The purpose of this investigation was to examine the impact of local control after SIRT on overall survival (OS) in oligometastatic patients. A retrospective, single-institution study identified oligometastatic patients with ≤5 non-intracranial metastases receiving unilateral or bilateral lobar Y-90 SIRT from 2009 to 2021. The primary endpoint was OS defined from Y-90 SIRT completion to the date of death or last follow-up. Local failure was classified as a progressive disease at the target lesion(s) by RECIST v1.1 criteria starting at 3 months after SIRT. With a median follow-up of 15.7 months, 33 patients were identified who had a total of 79 oligometastatic lesions treated with SIRT, with the majority histology of colorectal adenocarcinoma (n = 22). In total, 94% of patients completed the Y-90 lobectomy. Of the 79 individual lesions treated, 22 (27.8%) failed. Thirteen patients received salvage liver-directed therapy following intrahepatic failure; ten received repeat SIRT. Median OS (mOS) was 20.1 months, and 12-month OS was 68.2%. Intralesional failure was associated with worse 1 y OS (52.3% vs. 86.2%, p = 0.004). These results suggest that intralesional failure following Y-90 may be associated with inferior OS, emphasizing the importance of disease control in low-metastatic-burden patients.

Pattern of strength recovery differences Exist in Adolescent athletes after anterior cruciate ligament reconstruction when using quadriceps versus Hamstring tendon autograft.

OBJECTIVES: To compare the timeline for post-operative quadriceps and hamstrings strength recovery following anterior cruciate ligament reconstruction (ACLR) using either a quadriceps tendon (QT) or hamstring tendon (HT) autograft. METHODS: Patients (≤18 years) who underwent ACLR using autograft QT or HT were included. Isokinetic strength was extracted at 3, 6, and 12 months post-operatively. Effects of time and graft type on quadriceps or hamstring limb symmetry index (qLSI/hLSI) was assessed with two-way repeated measures ANOVA. Between group differences at each time point were assessed with unpaired t-tests. Chi-square and Kaplan-Meir analysis analyzed the proportions of subjects able to achieve ≥90% LSI. RESULTS: A total of 75 subjects (QT n = 38 HT n = 37,15.8 years) were included. There were significant differences in qLSI, with greater symmetry within the HT group at all time points. A higher proportion of subjects with HT grafts were able to achieve ≥90% qLSI within 12 months of surgery (81% vs 45%, p = 0.001). CONCLUSION: Compared to those with HT autografts, adolescents with QT autografts demonstrate a prolonged timeline for quadriceps recovery. While mean strength values above 90% are achieved, a significantly lower percentage of QT patients are able to achieve 90% qLSI by 12 months post-op.

Triple-Antibiotic Combination Exerts Effective Activity against Mycobacterium avium subsp. hominissuis Biofilm and Airway Infection in an In Vivo Murine Model.

OBJECTIVES: Slow-growing nontuberculous mycobacteria (NTMs) are highly prevalent and routinely cause opportunistic intracellular infectious disease in immunocompromised hosts. METHODS: The activity of the triple combination of antibiotics, clarithromycin (CLR), rifabutin (RFB), and clofazimine (CFZ), was evaluated and compared with the activity of single antibiotics as well as with double combinations in an in vitro biofilm assay and an in vivo murine model of Mycobacterium avium subsp. hominissuis (M. avium) lung infection. RESULTS: Treatment of 1-week-old biofilms with the triple combination exerted the strongest effect of all (0.12 ± 0.5 × 107 CFU/mL) in reducing bacterial growth as compared to the untreated (5.20 ± 0.5 × 107/mL) or any other combination (≥0.75 ± 0.6 × 107/mL) by 7 days. The treatment of mice intranasally infected with M. avium with either CLR and CFZ or the triple combination provided the greatest reduction in CLR-sensitive M. avium bacterial counts in both the lung and spleen compared to any single antibiotic or remaining double combination by 4 weeks posttreatment. After 4 weeks of treatment with the triple combination, there were no resistant colonies detected in mice infected with a CLR-resistant strain. No clear relationships between treatment and spleen or lung organ weights were apparent after triple combination treatment. CONCLUSIONS: The biofilm assay data and mouse disease model efficacy results support the further investigation of the triple-antibiotic combination.

Individual Prognostication of Disease Activity and Disability Worsening in Multiple Sclerosis With Retinal Layer Thickness z Scores.

BACKGROUND AND OBJECTIVES: Retinal optical coherence tomography (OCT) provides promising prognostic imaging biomarkers for future disease activity in multiple sclerosis (MS). However, raw OCT-derived measures have multiple dependencies, supporting the need for establishing reference values adjusted for possible confounders. The purpose of this study was to investigate the capacity for age-adjusted z scores of OCT-derived measures to prognosticate future disease activity and disability worsening in people with MS (PwMS). METHODS: We established age-adjusted OCT reference data using generalized additive models for location, scale, and shape for peripapillary retinal nerve fiber layer (pRNFL) and ganglion cell-inner plexiform layer (GCIP) thicknesses, involving 910 and 423 healthy eyes, respectively. Next, we transformed the retinal layer thickness of PwMS from 3 published studies into age-adjusted z scores (pRNFL-z and GCIP-z) based on the reference data. Finally, we investigated the association of pRNFL-z or GCIP-z as predictors with future confirmed disability worsening (Expanded Disability Status Scale score increase) or disease activity (failing of the no evidence of disease activity [NEDA-3] criteria) as outcomes. Cox proportional hazards models or logistic regression analyses were applied according to the original studies. Optimal cutoffs were identified using the Akaike information criterion as well as location with the log-rank and likelihood-ratio tests. RESULTS: In the first cohort (n = 863), 172 PwMS (24%) had disability worsening over a median observational period of 2.0 (interquartile range [IQR]:1.0-3.0) years. Low pRNFL-z (≤-2.04) were associated with an increased risk of disability worsening (adjusted hazard ratio (aHR) [95% CI] = 2.08 [1.47-2.95], p = 3.82e-5). In the second cohort (n = 170), logistic regression analyses revealed that lower pRNFL-z showed a higher likelihood for disability accumulation at the two-year follow-up (reciprocal odds ratio [95% CI] = 1.51[1.06-2.15], p = 0.03). In the third cohort (n = 78), 46 PwMS (59%) did not maintain the NEDA-3 status over a median follow-up of 2.0 (IQR: 1.9-2.1) years. PwMS with low GCIP-z (≤-1.03) had a higher risk of showing disease activity (aHR [95% CI] = 2.14 [1.03-4.43], p = 0.04). Compared with raw values with arbitrary cutoffs, applying the z score approach with optimal cutoffs showed better performance in discrimination and calibration (higher Harrell's concordance index and lower integrated Brier score). DISCUSSION: In conclusion, our work demonstrated reference cohort-based z scores that account for age, a major driver for disease progression in MS, to be a promising approach for creating OCT-derived measures useable across devices and toward individualized prognostication.

Oscillations in Neuronal Activity: A Neuron-Centered Spatiotemporal Model of the Unfolded Protein Response in Prion Diseases.

Many neurodegenerative diseases (NDs) are characterized by the slow spatial spread of toxic protein species in the brain. The toxic proteins can induce neuronal stress, triggering the Unfolded Protein Response (UPR), which slows or stops protein translation and can indirectly reduce the toxic load. However, the UPR may also trigger processes leading to apoptotic cell death and the UPR is implicated in the progression of several NDs. In this paper, we develop a novel mathematical model to describe the spatiotemporal dynamics of the UPR mechanism for prion diseases. Our model is centered around a single neuron, with representative proteins P (healthy) and S (toxic) interacting with heterodimer dynamics (S interacts with P to form two S's). The model takes the form of a coupled system of nonlinear reaction-diffusion equations with a delayed, nonlinear flux for P (delay from the UPR). Through the delay, we find parameter regimes that exhibit oscillations in the P- and S-protein levels. We find that oscillations are more pronounced when the S-clearance rate and S-diffusivity are small in comparison to the P-clearance rate and P-diffusivity, respectively. The oscillations become more pronounced as delays in initiating the UPR increase. We also consider quasi-realistic clinical parameters to understand how possible drug therapies can alter the course of a prion disease. We find that decreasing the production of P, decreasing the recruitment rate, increasing the diffusivity of S, increasing the UPR S-threshold, and increasing the S clearance rate appear to be the most powerful modifications to reduce the mean UPR intensity and potentially moderate the disease progression.

Sustained insulin treatment restoring metabolic status, body weight, and cognition in an anorexia nervosa-like animal model in mice.

INTRODUCTION: Anorexia Nervosa (AN) is a psycho-socio-biological disease characterized by severe weight loss as result of dieting and hyperactivity. Effective treatments are scarce, despite its significant prevalence and mortality. AN patients show lower basal insulin levels and increased metabolic clearance, leading to weight loss, cognitive deficits, and hormonal imbalances. Low-dose polymer insulin could potentially reverse these effects by restoring brain function, reducing fear of weight gain, encouraging food intake, and restoring fat depots. This study evaluates an insulin delivery system designed for sustained release and AN treatment. METHODS: AN-like model was established through dietary restriction (DR). On days 1-25, mice were on DR, and on days 26-31 they were on ad libitum regimen. An insulin-loaded delivery system was administered subcutaneously (1% w/w insulin). The impact of insulin treatment on gene expression in the hippocampus (cognition, regulation of stress, neurogenesis) and hypothalamus (eating behavior, mood) was assessed. Behavioral assays were conducted to evaluate motor activity and cognitive function. RESULTS: The delivery system demonstrated sustained insulin release, maintaining therapeutic plasma levels. Diet restriction mice treated with the insulin delivery system showed body weight restoration. Gene expression analysis revealed enhanced expression of CB1 and CB2 genes associated with improved eating behavior and cognition, while POMC expression was reduced. Insulin-polymer treatment restored cognitive function and decreased hyperactivity in the AN-like model. CONCLUSION: The PSA-RA-based insulin delivery system effectively restores metabolic balance, body weight, and cognitive function in the AN model. Its ability to steadily release insulin makes it a promising candidate for AN treatment."

Xyloglucan deficiency leads to a reduction in turgor pressure and changes in cell wall properties, affecting early seedling establishment.

Xyloglucan is believed to play a significant role in cell wall mechanics of dicot plants. Surprisingly, Arabidopsis plants defective in xyloglucan biosynthesis exhibit nearly normal growth and development. We investigated a mutant line, cslc-Δ5, lacking activity in all five Arabidopsis cellulose synthase like-C (CSLC) genes responsible for xyloglucan backbone biosynthesis. We observed that this xyloglucan-deficient line exhibited reduced cellulose crystallinity and increased pectin levels, suggesting the existence of feedback mechanisms that regulate wall composition to compensate for the absence of xyloglucan. These alterations in cell wall composition in the xyloglucan-absent plants were further linked to a decrease in cell wall elastic modulus and rupture stress, as observed through atomic force microscopy (AFM) and extensometer-based techniques. This raised questions about how plants with such modified cell wall properties can maintain normal growth. Our investigation revealed two key factors contributing to this phenomenon. First, measurements of turgor pressure, a primary driver of plant growth, revealed that cslc-Δ5 plants have reduced turgor, preventing the compromised walls from bursting while still allowing growth to occur. Second, we discovered the conservation of elastic asymmetry (ratio of axial to transverse wall elasticity) in the mutant, suggesting an additional mechanism contributing to the maintenance of normal growth. This novel feedback mechanism between cell wall composition and mechanical properties, coupled with turgor pressure regulation, plays a central role in the control of plant growth and is critical for seedling establishment in a mechanically challenging environment by affecting shoot emergence and root penetration.

General and specific patterns of cortical gene expression as spatial correlates of complex cognitive functioning.

Gene expression varies across the brain. This spatial patterning denotes specialised support for particular brain functions. However, the way that a given gene's expression fluctuates across the brain may be governed by general rules. Quantifying patterns of spatial covariation across genes would offer insights into the molecular characteristics of brain areas supporting, for example, complex cognitive functions. Here, we use principal component analysis to separate general and unique gene regulatory associations with cortical substrates of cognition. We find that the region-to-region variation in cortical expression profiles of 8235 genes covaries across two major principal components: gene ontology analysis suggests these dimensions are characterised by downregulation and upregulation of cell-signalling/modification and transcription factors. We validate these patterns out-of-sample and across different data processing choices. Brain regions more strongly implicated in general cognitive functioning (g; 3 cohorts, total meta-analytic N = 39,519) tend to be more balanced between downregulation and upregulation of both major components (indicated by regional component scores). We then identify a further 29 genes as candidate cortical spatial correlates of g, beyond the patterning of the two major components (|ß| range = 0.18 to 0.53). Many of these genes have been previously associated with clinical neurodegenerative and psychiatric disorders, or with other health-related phenotypes. The results provide insights into the cortical organisation of gene expression and its association with individual differences in cognitive functioning.

A comprehensive hierarchical comparison of structural connectomes in Major Depressive Disorder cases v. controls in two large population samples.

BACKGROUND: The brain can be represented as a network, with nodes as brain regions and edges as region-to-region connections. Nodes with the most connections (hubs) are central to efficient brain function. Current findings on structural differences in Major Depressive Disorder (MDD) identified using network approaches remain inconsistent, potentially due to small sample sizes. It is still uncertain at what level of the connectome hierarchy differences may exist, and whether they are concentrated in hubs, disrupting fundamental brain connectivity. METHODS: We utilized two large cohorts, UK Biobank (UKB, N = 5104) and Generation Scotland (GS, N = 725), to investigate MDD case-control differences in brain network properties. Network analysis was done across four hierarchical levels: (1) global, (2) tier (nodes grouped into four tiers based on degree) and rich club (between-hub connections), (3) nodal, and (4) connection. RESULTS: In UKB, reductions in network efficiency were observed in MDD cases globally (d = -0.076, pFDR = 0.033), across all tiers (d = -0.069 to -0.079, pFDR = 0.020), and in hubs (d = -0.080 to -0.113, pFDR = 0.013-0.035). No differences in rich club organization and region-to-region connections were identified. The effect sizes and direction for these associations were generally consistent in GS, albeit not significant in our lower-N replication sample. CONCLUSION: Our results suggest that the brain's fundamental rich club structure is similar in MDD cases and controls, but subtle topological differences exist across the brain. Consistent with recent large-scale neuroimaging findings, our findings offer a connectomic perspective on a similar scale and support the idea that minimal differences exist between MDD cases and controls.

The stability of cognitive abilities: A meta-analytic review of longitudinal studies.

Cognitive abilities, including general intelligence and domain-specific abilities such as fluid reasoning, comprehension knowledge, working memory capacity, and processing speed, are regarded as some of the most stable psychological traits, yet there exist no large-scale systematic efforts to document the specific patterns by which their rank-order stability changes over age and time interval, or how their stability differs across abilities, tests, and populations. Determining the conditions under which cognitive abilities exhibit high or low degrees of stability is critical not just to theory development but to applied contexts in which cognitive assessments guide decisions regarding treatment and intervention decisions with lasting consequences for individuals. In order to supplement this important area of research, we present a meta-analysis of longitudinal studies investigating the stability of cognitive abilities. The meta-analysis relied on data from 205 longitudinal studies that involved a total of 87,408 participants, resulting in 1,288 test-retest correlation coefficients among manifest variables. For an age of 20 years and a test-retest interval of 5 years, we found a mean rank-order stability of ρ = .76. The effect of mean sample age on stability was best described by a negative exponential function, with low stability in preschool children, rapid increases in stability in childhood, and consistently high stability from late adolescence to late adulthood. This same functional form continued to best describe age trends in stability after adjusting for test reliability. Stability declined with increasing test-retest interval. This decrease flattened out from an interval of approximately 5 years onward. According to the age and interval moderation models, minimum stability sufficient for individual-level diagnostic decisions (rtt = .80) can only be expected over the age of 7 and for short time intervals in children. In adults, stability levels meeting this criterion are obtained for over 5 years. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

The expanding role of sonography for the diagnosis of deep infiltrating endometriosis: Results of a large case series.

OBJECTIVE: To investigate the value of the sonographic identification of deep infiltrating endometriosis (DIE) in women presenting with complaints suggestive of DIE. Sonography findings were correlated with subsequent surgical exploration, and histologic verification. METHODS: A retrospective observational case series was investigated to document the ability of the use of sonography to accurately detect the presence of deep infiltrating endometriosis. The clinical observations were performed consistent with the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) recommendations for observational studies. Recognizing the real-world office setting for this may introduce the importance of the practical clinical aspects of diagnostic procedures in general. RESULTS: Three-dimensional transvaginal sonography was able to accurately identify deep invasive endometriosis in 92% of the 100 women subjectively complaining of the associated symptoms of endometriosis, who underwent sonography, surgical exploration, and pathologic analysis. Additional sonographic evidence of pelvic pathology was found during the course of this investigation, perhaps complementing other means for diagnosing endometriosis. CONCLUSION: Three-dimensional transvaginal sonography is a diagnostic tool that can effectively identify deep infiltrating endometriosis, which may otherwise go undetected and untreated. These findings should encourage the use of sonography for the detection of this subtype of endometriosis.

Beyond the factor indeterminacy problem using genome-wide association data.

Latent factors, such as general intelligence, depression and risk tolerance, are invoked in nearly all social science research where a construct is measured via aggregation of symptoms, question responses or other measurements. Because latent factors cannot be directly observed, they are inferred by fitting a specific model to empirical patterns of correlations among measured variables. A long-standing critique of latent factor theories is that the correlations used to infer latent factors can be produced by alternative data-generating mechanisms that do not include latent factors. This is referred to as the factor indeterminacy problem. Researchers have recently begun to overcome this problem by using information on the associations between individual genetic variants and measured variables. We review historical work on the factor indeterminacy problem and describe recent efforts in genomics to rigorously test the validity of latent factors, advancing the understanding of behavioural science constructs.

Effectiveness of Upadacitinib for Patients With Acute Severe Ulcerative Colitis: A Multicenter Experience.

INTRODUCTION: A significant proportion of patients with acute severe ulcerative colitis (ASUC) require colectomy. METHODS: Patients with ASUC treated with upadacitinib and intravenous corticosteroids at 5 hospitals are presented. The primary outcome was 90-day colectomy rate. Secondary outcomes included frequency of steroid-free clinical remission, adverse events, and all-cause readmissions. RESULTS: Of the 25 patients with ASUC treated with upadacitinib, 6 (24%) patients underwent colectomy, 15 (83%) of the 18 patients with available data and who did not undergo colectomy experienced steroid-free clinical remission (1 patient did not have complete data), 1 (4%) patient experienced a venous thromboembolic event, while 5 (20%) patients were readmitted. DISCUSSION: Upadacitinib along with intravenous corticosteroids may be an effective treatment for ASUC.

Expert opinion survey on Israel's food system: implications for food and health policies.

BACKGROUND: While there has been increasing global recognition and impetus for action to transform food systems towards greater food security, sustainability and better health outcomes, Israel has only recently begun to focus on the diverse challenges of its food system and its potential for transformation. METHODS: An expert opinion survey (n = 50) on Israel's food system was conducted as part of a larger study on the systemic features of Israel's food system transition to understand its policy gaps and find strategies towards a healthy and sustainable food system. The survey ranks the relevance and importance of food system challenges and policy preferences. Policy implications are then examined by identifying potential priorities, gaps and dissensus. RESULTS: The survey finds that there is a majority agreement (76%) that Israel's food policies are lacking or severely lacking. Respondents relate strongly to both concepts of nutritional security (90% think that access to nutritious food is relevant or highly relevant) and national food security (more than 80% perceive food security as part of national security). Respondents overwhelmingly recognize the benefits of Israeli agriculture with 60-90% agreeing or strongly agreeing that it benefits food security, economic value and national identity. Top-ranked problems include overall systemic problems such as the lack of national goals, strategic planning, and integrated policymaking across ministries, and specific ones such as food waste, costly farming inputs, and food affordability. The most preferred policy actions include establishing a national strategy for food and agriculture, making food affordable for vulnerable households, and incentivising sustainable farming methods. The key policy gaps include the lack of resilience in agriculture and the food system, insufficient data and knowledge for policy action, inadequate attention to the regulation of the food industry for better health and inadequate food policy attention for minority groups. CONCLUSIONS: Building on this study's findings, further policy research and implementation areas to be covered include government responsibility for universal food security, strategic systemic policies for food systems, prevention and preparedness for future crises, and promoting resilience. The way forward may best be through an inter-ministerial committee with the responsibility, budgets, mandate and executive authority to plan data-driven policies for a sustainable food system for Israel's future.

Deploying a national clinical text processing infrastructure.

OBJECTIVES: Clinical text processing offers a promising avenue for improving multiple aspects of healthcare, though operational deployment remains a substantial challenge. This case report details the implementation of a national clinical text processing infrastructure within the Department of Veterans Affairs (VA). METHODS: Two foundational use cases, cancer case management and suicide and overdose prevention, illustrate how text processing can be practically implemented at scale for diverse clinical applications using shared services. RESULTS: Insights from these use cases underline both commonalities and differences, providing a replicable model for future text processing applications. CONCLUSIONS: This project enables more efficient initiation, testing, and future deployment of text processing models, streamlining the integration of these use cases into healthcare operations. This project implementation is in a large integrated health delivery system in the United States, but we expect the lessons learned to be relevant to any health system, including smaller local and regional health systems in the United States.