Integrating the family stress model within a longitudinal sibling-adoption study of adolescent externalizing behavior.

Using a sample of linked adopted children, adoptive and birth parents (N = 561), and biological siblings residing in the birth parent home (N = 191), we examined the role of genetics within family stress processes. We tested parental hostility (7 years) as a mediator of the associations between socioeconomic strain and rearing parent psychopathology (4 years) and adolescent externalizing behaviors (11 years) in adoptive and biological parent homes. Next, we examined parent social support (4 years) as a moderator of paths from socioeconomic strain and parent psychopathology to parental hostility. Parental hostility significantly mediated effects of socioeconomic strain and parent psychopathology on adolescent externalizing behaviors in biological and adoptive parent homes, respectively. Equivalence testing of the paths to adolescent externalizing behaviors across family types indicated a negligible role of passive gene-environment correlation. Parent social support significantly attenuated the effect of parent psychopathology on parental hostility in biological families. Birth parent externalizing behaviors were not significantly associated with adoptee externalizing behaviors nor adoptive parent hostility, suggesting negligible heritable risk or evocative gene-environment processes. Full- and half-sibling correlations indicated that children's unique rearing contexts contributed to the parenting they received and the externalizing behavior they exhibited. Implications for intervention are discussed.

Optimising height-growth predicts trait responses to water availability and other environmental drivers.

Future changes in climate, together with rising atmospheric CO 2 ${\text{CO}}_{2}$ , may reorganise the functional composition of ecosystems. Without long-term historical data, predicting how traits will respond to environmental conditions-in particular, water availability-remains a challenge. While eco-evolutionary optimality theory (EEO) can provide insight into how plants adapt to their environment, EEO approaches to date have been formulated on the assumption that plants maximise carbon gain, which omits the important role of tissue construction and size in determining growth rates and fitness. Here, we show how an expanded optimisation framework, focussed on individual growth rate, enables us to explain shifts in four key traits: leaf mass per area, sapwood area to leaf area ratio (Huber value), wood density and sapwood-specific conductivity in response to soil moisture, atmospheric aridity, CO 2 ${\text{CO}}_{2}$ and light availability. In particular, we predict that as conditions become increasingly dry, height-growth optimising traits shift from resource-acquisitive strategies to resource-conservative strategies, consistent with empirical responses across current environmental gradients of rainfall. These findings can explain both the shift in traits and turnover of species along existing environmental gradients and changing future conditions and highlight the importance of both carbon assimilation and tissue construction in shaping the functional composition of vegetation across climates.

Effectiveness of art therapy interventions for treating pain and anxiety in adolescents in the emergency department.

OBJECTIVE: To evaluate the effectiveness of art therapy in reducing pain and anxiety in adolescents with painful conditions treated in the ED. METHODS: We conducted a prospective pilot study of patients 12-18 years old presenting with a painful condition to a tertiary-care children's hospital ED. Primary outcome was pain intensity measured using the Verbal Numerical Rating Scale (scored 0-10); a decrease of ≥ 20% was clinically significant. Anxiety was measured using the short-form six-item State-Trait Anxiety Inventory (scored 20-80: 20-40 = zero-low anxiety; 41-60 = moderate anxiety; 61-80 = high anxiety); a change from higher to lower category was clinically significant. Outcomes were measured at baseline, immediately after, and 1 h after art therapy completion. A standardized interview was conducted immediately after art therapy completion. RESULTS: We enrolled a convenience sample of 50 patients. Mean duration of art therapy was 34.7 min. Mean baseline pain was 6.2 and decreased by 23.2% (95% CI 14.9-31.5) and 28.6% (95% CI 9.2-48), immediately after and 1 h after art therapy completion, respectively. Mean baseline anxiety was 48 (moderate) and decreased to 38 (low) and 43 (moderate) at the same time points, respectively. Forty-eight patients (96%) reported feelings of relaxation, decreased pain intensity, and/or empowerment (e.g., "Very relaxing"; "I didn't feel as much pain"; "Really showed my emotions"; "A way to explain to doctors what I'm feeling and what parts hurt"). CONCLUSION: Art therapy may be associated with clinically significant decreases and qualitative improvements in pain and anxiety in adolescents with painful conditions being treated in the ED. This novel treatment may improve the holistic care of adolescents with painful conditions in the ED.

ABSTRAIT: OBJECTIF: Évaluer l'efficacité de l'art-thérapie dans la réduction de la douleur et de l'anxiété chez les adolescents atteints de troubles douloureux traités à l'urgence. MéTHODES: Étude pilote prospective de patients âgés de 12 à 18 ans se présentant avec une affection douloureuse à un service d'urgence pour enfants de soins tertiaires. Le critère de jugement principal était l'intensité de la douleur mesurée à l'aide de l'échelle d'évaluation numérique verbale (cote de 0 à 10); une diminution de 20 % était cliniquement significative. L'anxiété a été mesurée à l'aide du questionnaire abrégé à six éléments State-Trait Anxiety Inventory (score 20-80 : 20-40 = zéro-faible anxiété; 41-60 = anxiété modérée; 61-80 = anxiété élevée); un changement de la catégorie supérieure à la catégorie inférieure était cliniquement significatif. Les résultats ont été mesurés au départ, immédiatement après et une heure après la fin de l'art-thérapie. Une entrevue normalisée a été menée immédiatement après la fin de l'art-thérapie. RéSULTATS: Nous avons recruté un échantillon de commodité de 50 patients. La durée moyenne de l'art-thérapie était de 34,7 minutes. La douleur moyenne au départ était de 6,2 et diminuait de 23,2 % (IC à 95 % 14,9-31,5) et de 28,6 % (IC à 95 % 9,2-48), immédiatement après et 1 heure après la fin de l'art-thérapie, respectivement. L'anxiété moyenne au départ était de 48 (modérée) et a diminué à 38 (faible) et 43 (modérée) au même moment, respectivement. Quarante-huit patients (96 %) ont signalé des sentiments de relaxation, une diminution de l'intensité de la douleur et/ou de l'autonomisation (p. ex., « Très relaxant ¼; « Je n'ai pas ressenti autant de douleur ¼; « Vraiment montré mes émotions ¼; « Une façon d'expliquer aux médecins ce que je ressens et ce qui fait mal ¼). CONCLUSIONS: L'art-thérapie peut être associée à des diminutions cliniquement significatives et à des améliorations qualitatives de la douleur et de l'anxiété chez les adolescents atteints de troubles douloureux traités à l'urgence. Ce nouveau traitement peut améliorer les soins holistiques des adolescents souffrant de troubles douloureux aux urgences.

Interpersonal Violence-Related Trauma Among South African Children.

INTRODUCTION: Injuries account for a major portion of disability-adjusted life years in children globally, and low-and middle-income countries are disproportionally affected. While injuries due to motor vehicle collisions and self-harm have been well-characterized in pediatric populations in South Africa, injuries related to interpersonal violence (IPV) are less understood. Our study aims to characterize patterns of injury, management, and outcomes for pediatric patients presenting with IPV-related injuries in a South African trauma center. METHODS: We performed a retrospective review of trauma patients ≤18 y of age presenting to the Pietermaritzburg Metropolitan Trauma Service in Gray's Hospital in South Africa from 2012 to 2022, comparing those with injuries resulting from IPV to those with non-IPV injuries. Patients' and injury pattern characteristics and outcomes were descriptively analyzed. RESULTS: Out of 2155 trauma admissions, 500 (23.2%) had IPV-related injuries. Among patients with IPV-related injuries, the median age was 16.0 y. 407 (81.4%) patients were male. 271 (54.2%) patients experienced blunt trauma, 221 (44.2%) had penetrating trauma, and 3 (0.6%) suffered both. The most common weapons were knives (21.6%), stones (11.2%), and firearms (11.0%). The most commonly injured regions were the head (56.4%), abdomen (20.8%), and thorax (19.2%). 19.6% underwent surgical intervention, and 14.4% were referred out for subspecialty care. 1.4% patients died, and 1.2% returned to Pietermaritzburg Metropolitan Trauma Service within 30 d of discharge. CONCLUSIONS: IPV patients are a distinctive subgroup of pediatric trauma patients with different demographics, patterns of injury, and clinical needs. Further research is needed to better understand the unique needs of this neglected population.

Contemporary surgical management of pediatric non-rhabdomyosarcoma soft tissue sarcoma.

Non-rhabdomyosarcoma soft tissue sarcoma (STS) comprises most STS in pediatric patients. It is a diverse set of over 30 histologic subtypes. Treatment is based on risk group determined by tumor size, grade, and the presence of metastases. Surgical resection is a cornerstone of therapy, as tumors are often resistant to chemotherapy or radiation. While patients with isolated tumors less than 5 cm may undergo upfront resection, strong consideration should be given to neoadjuvant chemoradiotherapy to ensure negative margins at surgical resection and optimal outcomes. Sentinel lymph node biopsy is strongly recommended for clear cell and epithelioid sarcomas. The most common metastatic site is the lung, and metastases should be resected at the end of therapy, when feasible. Unfortunately, many high-risk patients progress on therapy, and alternative strategies including earlier metastatic control require investigation.

Rapidly progressive coronary atherosclerosis in a young male: a retrospective advanced CCT phenotype analysis.

We present a real-life case of a very young man with multiple risk factors who progressed rapidly from minimally obstructive non-calcified plaque on computed tomography angiography (CCTA) to severe three-vessel coronary disease presenting with STEMI. It questions the reliability of zero coronary calcium in high-risk subgroups like familial hypercholesterolemia, high Lp(a), and the young. While CCTA can accurately visualize non-calcified plaque, its interpretation requires expertise and clinical judgment should consider both imaging and clinical risk factors for management. Advanced plaque quantification, peri-coronary (PCAT), and epicardial (EAT) adipose tissue could help better-stratified patients but the evidence-based clinical application remains unknown.

Analysis of Macronutrients in Soil Using Impedimetric Multisensor Arrays.

The need to increase food production to address the world population growth can only be fulfilled with precision agriculture strategies to increase crop yield with minimal expansion of the cultivated area. One example is site-specific fertilization based on accurate monitoring of soil nutrient levels, which can be made more cost-effective using sensors. This study developed an impedimetric multisensor array using ion-selective membranes to analyze soil samples enriched with macronutrients (N, P, and K), which is compared with another array based on layer-by-layer films. The results obtained from both devices are analyzed with multidimensional projection techniques and machine learning methods, where a decision tree model algorithm chooses the calibrations (best frequencies and sensors). The multicalibration space method indicates that both devices effectively distinguished all soil samples tested, with the ion-selective membrane setup presenting a higher sensitivity to K content. These findings pave the way for more environmentally friendly and efficient agricultural practices, facilitating the mapping of cropping areas for precise fertilizer application and optimized crop yield.

Enhanced silicate weathering accelerates forest carbon sequestration by stimulating the soil mineral carbon pump.

Enhanced silicate rock weathering (ERW) is an emerging strategy for carbon dioxide removal (CDR) from the atmosphere to mitigate anthropogenic climate change. ERW aims at promoting soil inorganic carbon sequestration by accelerating geochemical weathering processes. Theoretically, ERW may also impact soil organic carbon (SOC), the largest carbon pool in terrestrial ecosystems, but experimental evidence for this is largely lacking. Here, we conducted a 2-year field experiment in tropical rubber plantations in the southeast of China to evaluate the effects of wollastonite powder additions (0, 0.25, and 0.5 kg m-2) on both soil organic and inorganic carbon at 0-10 cm depth. We found that ERW significantly increased the concentration of SOC and HCO3 -, but the increases in SOC were four and eight times higher than that of HCO3 - with low- and high-level wollastonite applications. ERW had positive effects on the accrual of organic carbon in mineral-associated organic matter (MAOM) and macroaggregate fractions, but not on particulate organic matter. Path analysis suggested that ERW increased MAOM mainly by increasing the release of Ca, Si, and Fe, and to a lesser extent by stimulating root growth and microbial-derived carbon inputs. Our study indicates that ERW with wollastonite can promote SOC sequestration in stable MOAM in surface soils through both the soil mineral carbon pump and microbial carbon pump. These effects may have been larger than the inorganic CDR during our experiment. We argue it is essential to account for the responses of SOC in the assessments of CDR by ERW.

Hybrid Nanoparticle-Hydrogel Systems for Drug Delivery Depots and Other Biomedical Applications.

Hydrogel-based depots typically tend to remain where injected and have excellent biocompatibility but are relatively poor at controlling drug release. Nanoparticles (NPs) typically have the opposite properties. The smaller the NPs are, the more likely they are to leave the site of injection. Their biocompatibility is variable depending on the material but can be poor. However, NPs can be good at controlling drug release. In these and other properties, combining NPs and hydrogels can leverage their advantages and negate their disadvantages. This review highlights the rationale for hybrid NP-hydrogel systems in drug delivery, the basic methods of producing them, and examples where combining the two systems addressed specific problems.

The extracellular heparan sulfatase SULF2 limits myeloid IFNß signaling and Th17 responses in inflammatory arthritis.

Heparan sulfate (HS) proteoglycans are important regulators of cellular responses to soluble mediators such as chemokines, cytokines and growth factors. We profiled changes in expression of genes encoding HS core proteins, biosynthesis enzymes and modifiers during macrophage polarisation, and found that the most highly regulated gene was Sulf2, an extracellular HS 6-O-sulfatase that was markedly downregulated in response to pro-inflammatory stimuli. We then generated Sulf2+/- bone marrow chimeric mice and examined inflammatory responses in antigen-induced arthritis, as a model of rheumatoid arthritis. Resolution of inflammation was impaired in myeloid Sulf2+/- chimeras, with elevated joint swelling and increased abundance of pro-arthritic Th17 cells in synovial tissue. Transcriptomic and in vitro analyses indicated that Sulf2 deficiency increased type I interferon signaling in bone marrow-derived macrophages, leading to elevated expression of the Th17-inducing cytokine IL6. This establishes that dynamic remodeling of HS by Sulf2 limits type I interferon signaling in macrophages, and so protects against Th17-driven pathology.

Genome-wide and cell-type-selective profiling of in vivo small noncoding RNA:target RNA interactions by chimeric RNA sequencing.

Small noncoding RNAs (sncRNAs) regulate biological processes by impacting post-transcriptional gene expression through repressing the translation and levels of targeted transcripts. Despite the clear biological importance of sncRNAs, approaches to unambiguously define genome-wide sncRNA:target RNA interactions remain challenging and not widely adopted. We present CIMERA-seq, a robust strategy incorporating covalent ligation of sncRNAs to their target RNAs within the RNA-induced silencing complex (RISC) and direct detection of in vivo interactions by sequencing of the resulting chimeric RNAs. Modifications are incorporated to increase the capacity for processing low-abundance samples and permit cell-type-selective profiling of sncRNA:target RNA interactions, as demonstrated in mouse brain cortex. CIMERA-seq represents a cohesive and optimized method for unambiguously characterizing the in vivo network of sncRNA:target RNA interactions in numerous biological contexts and even subcellular fractions. Genome-wide and cell-type-selective CIMERA-seq enhances researchers' ability to study gene regulation by sncRNAs in diverse model systems and tissue types.

3D surface defect map for assessing buccolingual profile of single tooth gaps following alveolar ridge preservation.

AIM: A new, non-invasive approach suggests using single intraoral optical scanning to analyze the ridge profile of single-tooth gaps following alveolar ridge preservation in the absence of a baseline scan. This method involves creating a three-dimensional (3D) surface map to identify and assess contour changes and ridge profiles based on the adjacent teeth. MATERIALS AND METHODS: The present study was designed as a cross-sectional pilot analysis on a convenience sample of patients undergoing alveolar ridge preservation. Intraoral optical scans were taken on 23 patients, capturing data from 30 edentulous sites. The digital models were then imported into an image analysis software for a 3D surface defect map analysis performed by one examiner. This analysis characterized the buccolingual profile of the single tooth gap relative to the adjacent teeth. 10 linear divergence points, spaced 0.5 mm apart in a corona-apical direction, were identified at the midfacial aspect of the sites. Based on these points the sites were plotted and grouped in three different buccolingual profiles (linear, concave, and convex). Clinical parameters including Keratinized mucosa Width (KMW), and soft tissue phenotype with Colorvue biotype probes were also recorded. RESULTS: Three different buccolingual patterns (linear, convex, and concave) were identified. Seven sites exhibited a linear profile, 10 sites displayed a concave shape, and 13 showed a convex profile. The linear profile had surface discrepancies similar to the neighboring teeth. In contrast, the convex profile revealed mid-buccal discrepancy localized only at the crestal aspect, while the concave had an extended divergence ranging from 1 to 5 mm below the soft tissue margin. Univariate and multiple logistic regression analyses did not reveal any statistically significant variables influencing profilometric analysis; however, when combining phenotype and KMW, thick phenotypes demonstrated a higher proportion of concavity (OR = 4.83) compared to thin ones, suggesting a significant trend. With every 1 mm of increase in KMW, the probability of showing a concavity decreased (p = 0.057). CONCLUSION: A 3D surface defect map represents a useful tool for objectively quantifying ridge defects and profiles by assessing profilometric and surface differences compared to adjacent dentition using a single intraoral scan. This method also indicates that KMW may play a critical role in preventing concavity defects. The 3D defect map can guide decision-making during soft tissue augmentation procedures by emphasizing the specific location of the defect and providing more detailed insights into its localization. These parameters can enable the tailoring of flap management and soft tissue grafting strategies to address the patient's individual needs.

SGLT2 inhibitors activate pantothenate kinase in the human heart.

Inhibitors of sodium glucose cotransporter-2 (SGLT2i) demonstrate strong symptomatic and mortality benefits in the treatment of heart failure but appear to do so independently of SGLT2. The relevant pharmacologic target of SGLT2i remains unclear. We show here that SGLT2i directly activate pantothenate kinase 1 (PANK1), the rate-limiting enzyme that initiates the conversion of pantothenate (vitamin B5) to coenzyme-A (CoA), an obligate co-factor for all major pathways of fuel use in the heart. Using stable-isotope infusion studies, we show that SGLT2i promote pantothenate consumption, activate CoA synthesis, rescue decreased levels of CoA in human failing hearts, and broadly stimulate fuel use in ex vivo perfused human cardiac blocks from patients with heart failure. Furthermore, we show that SGLT2i bind to PANK1 directly at physiological concentrations and promote PANK1 enzymatic activity in assays with purified components. Novel in silico dynamic modeling identified the site of SGLT2i binding on PANK1 and indicated a mechanism of activation involving prevention of allosteric inhibition of PANK1 by acyl-CoA species. Finally, we show that inhibition of PANK1 prevents SGLT2i-mediated increased contractility of isolated adult human cardiomyocytes. In summary, we demonstrate robust and specific off-target activation of PANK1 by SGLT2i, promoting CoA synthesis and efficient fuel use in human hearts, providing a likely explanation for the remarkable clinical benefits of SGLT2i.

Climate impacts of critical mineral supply chain bottlenecks for electric vehicle deployment.

New tailpipe emissions standards aim to increase electric vehicle (EV) sales in the United States. Here, we analyze the associated critical mineral supply chain constraints and enumerate the climate consequences of these constraints. Our work yields five findings. First, the proposed standard necessitates replacing at least 10.21 million new internal combustion engine vehicles with EVs between 2027 and 2032. Second, based on economically viable and geologically available mineral reserves, manufacturing sufficient EVs is plausible and reduces up to 457.3 million tons of CO2e. Third, mineral production capacities in the United States and amongst allies support the deployment of 5.09 million vehicles between 2027 and 2032, well short of compliance target. Fourth, this shortfall produces at least 59.54 million tons of CO2e in lost lifecycle emissions benefits. Fifth, limited production of battery-grade graphite and cobalt may represent particularly profound constraints. Pathways that afford comparable emission reductions are subsequently explored.

Identification of Rare Antigen-Specific T Cells from Mouse Lungs with Peptide:Major Histocompatibility Complex Tetramers.

The identification and characterization of antigen-specific T cells during health and disease remains a key to improving our understanding of immune pathophysiology. The technical challenges of tracking antigen-specific T cell populations within the endogenous T cell repertoire have been greatly advanced by the development of peptide:MHC tetramer reagents. These fluorescently labeled soluble multimers of MHC class I or class II molecules complexed to antigenic peptide epitopes bind directly to T cells with corresponding T cell receptor (TCR) specificity and can, therefore, identify antigen-specific T cell populations in their native state without a requirement for a functional response induced by ex vivo stimulation. For exceedingly rare populations, tetramer-bound T cells can be magnetically enriched to increase the sensitivity and reliability of detection. As the investigation of tissue-resident T cell immunity deepens, there is a pressing need to identify antigen-specific T cells that traffic to and reside in nonlymphoid tissues. In this protocol, we present a detailed set of instructions for the isolation and characterization of antigen-specific T cells present within mouse lungs. This involves the isolation of T cells from digested lung tissue followed by a general T cell magnetic enrichment step and tetramer staining for flow cytometry analysis and sorting. The steps highlighted in this protocol utilize common techniques and readily available reagents, making it accessible for nearly any researcher engaged in mouse T cell immunology, and are highly adaptable for a variety of downstream analyses of any low frequency antigen-specific T cell population residing within the lungs.

Telehealth visit type and patient-reported outcomes among patients with cancer.

BACKGROUND: Relaxed licensing restrictions on telehealth use during the COVID-19 pandemic allowed broad use irrespective of visit type. As these telehealth waivers expire, optimal uses of telehealth must be assessed to inform policy and clinical care. We evaluated patient experience associated with telehealth and in-person new or established visits. METHODS: Patients seen in-person and via telehealth for urologic cancer care from August 2019 to June 2022 received a survey on satisfaction with care, perceptions of communication during their visit, travel time, travel costs, and days of work missed. We assessed survey responses with descriptive statistics. RESULTS: Surveys were completed for 1,031 patient visits (N = 494 new visits, N = 537 established visits). Satisfaction rates were high for all visit modalities among new and established patients (mean score range 59.9-60.7 [maximum 63], P > 0.05). Patient-rated quality of the encounter did not differ by visit type and modality (P > 0.05, for nearly all comparisons). New in-person patient visits were associated with significantly higher travel costs (mean $496.10, SD $1021) compared with new telehealth visits (mean $26.60, SD $141; P < 0.001); 27% of new in-person patients required plane travel and 41% required a hotel stay (P < 0.001 vs. 0.8% and 3.2% of new telehealth patients, respectively). CONCLUSIONS: Satisfaction outcomes among patients with urologic cancer receiving new patient telehealth care equaled those of new patients cared for in-person while costs were significantly lower. Offering telehealth exemption beyond COVID-19 licensing waivers to include new patient visits would allow for ongoing delivery of high-quality urologic cancer care irrespective of geographic location.

Durability of Response With Selpercatinib in Patients With RET-Activated Thyroid Cancer: Long-Term Safety and Efficacy From LIBRETTO-001.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.LIBRETTO-001 is a registrational phase I/II, single-arm, open-label study of selpercatinib in patients with RET (REarranged during Transfection)-activated cancers (ClinicalTrials.gov identifier: NCT03157128). We present long-term safety and efficacy from LIBRETTO-001 in patients with RET-mutant medullary thyroid cancer (MTC; n = 324) and RET fusion-positive thyroid cancer encompassing different histological subtypes (TC; n = 66). At the data cutoff of January 2023, the objective response rate was 82.5% among patients with cabozantinib/vandetanib-naïve MTC and 95.8% among patients with treatment-naïve TC. At a median follow-up time of 42.4 and 44.0 months in patients with cabozantinib/vandetanib-naïve and pretreated MTC, the median progression-free survival (PFS) was not reached and 41.4 months, respectively. At a median follow-up time of 24.9 and 30.4 months in patients with treatment-naïve and pretreated TC, the median PFS was not reached and 27.4 months, respectively. Three-year PFS rates were 75.2% and 87.3% among patients with cabozantinib/vandetanib-naïve MTC and treatment-naïve TC, respectively. Median PFS was similar to median duration of response for each patient group. The safety profile of selpercatinib was consistent with previous reports. With an additional follow-up of 37 months and 228 more patients from the last disclosure, selpercatinib continued to provide durable and robust responses in treatment-naïve and previously treated patients with RET-mutant MTC and RET fusion-positive TC.

An axis of genetic heterogeneity in autism is indexed by age at diagnosis and is associated with varying developmental and mental health profiles.

There is growing recognition that earliest signs of autism need not clearly manifest in the first three years of life. To what extent is this variation in developmental trajectories associated with age at autism diagnosis? Does the genetic profile of autism vary with age at autism diagnosis? Using longitudinal data from four birth cohorts, we demonstrate that two different trajectories of socio-emotional behaviours are associated with age at diagnosis. We further demonstrate that the age at autism diagnosis is partly heritable (h 2 SNP = 0.12, s.e.m = 0.01), and is associated with two moderately correlated (r g = 0.38, s.e.m = 0.07) autism polygenic factors. One of these factors is associated with earlier diagnosis of autism, lower social and communication abilities in early childhood. The second factor is associated with later autism diagnosis, increased socio-emotional difficulties in adolescence, and has moderate to high positive genetic correlations with Attention-Deficit/Hyperactivity Disorder, mental health conditions, and trauma. Overall, our research identifies an axis of heterogeneity in autism, indexed by age at diagnosis, which partly explains heterogeneity in autism and the profiles of co-occurring neurodevelopmental and mental health profiles. Our findings have important implications for how we conceptualise autism and provide one model to explain some of the diversity within autism.

From pre-clinical efficacy to promising clinical trials that delay Type 1 diabetes.

Recent advancements in immunology and islet biology have unveiled remarkable prospects for the postponement of Type 1 diabetes (T1D) through the strategic modulation of the immune system. In this Perspective, we discuss the pharmaceutical strides achieved, traversing from pre-clinical validation to the execution of impactful clinical trials. We begin with the initial investigations involving cyclosporine and glucocorticoids in rodent models, such as the non-obese diabetic (NOD) mouse, which guided early clinical trials. We then discuss the pre-clinical studies using suitable mouse models that eventually led to contemporary clinical trials targeting immune cell functionality and cytokine signaling pathways. Collectively, these discoveries promote the exciting paradigm of immune system modulation to mitigate autoimmunity, which continues to broaden. Notably, the use of baricitinib, a potent JAK1/2 inhibitor, and teplizumab, an anti-CD3 monoclonal antibody, represent discrete methodologies converging upon a singular outcome: the preservation of islet beta-cell functionality. The latter interventional strategies build on the original idea that tempering specific facets of the immune system will generate therapeutic benefit. Enthusiasm from these discoveries stems from efficacy with reduced side effects when compared with past approaches. The success of therapeutic intervention(s) in pre-clinical studies, combined with knowledge about stages of progression to clinical T1D, have ultimately encouraged the design of more successful clinical trials targeting highly specific populations at risk. Collectively, these findings instill a profound sense of optimism, suggesting that the prevention and even reversal of T1D may soon be within reach.