Sex and intelligence quotient differences in age of diagnosis among youth with attention-deficit hyperactivity disorder.

OBJECTIVES: Attention-deficit/hyperactivity disorder (ADHD) is the most common neurodevelopmental condition and is characterized by inattention, hyperactivity, and impulsivity. Research suggests that some populations, such as females and individuals with high intelligence quotients may be a risk for late ADHD diagnosis and subsequent treatment. Our goal is to advance our understanding of ADHD diagnosis, by examining (1) how child sex and cognitive abilities together are related to the age of diagnosis and (2) whether symptom presentation, current internalizing and externalizing symptoms, and demographic factors are related to age of diagnosis. METHODS: Our analyses contained children who completed the required tests (N = 568) from a pre-existing dataset of 1380 children with ADHD from the Province of Ontario Neurodevelopmental Disorders (POND) Network (pond-network.ca). First, we conducted a moderation analysis with sex as the predictor, cognitive abilities as the moderator, and age of diagnosis as the outcome. Second, we conducted correlation analyses examining how symptom presentation, current internalizing and externalizing symptoms, and demographic factors are related to age of diagnosis. RESULTS: Higher IQ was related to a later age of diagnosis. Higher hyperactive-impulsive symptoms and externalizing symptoms were related to an earlier age of diagnosis. Internalizing symptoms were trend associated with a later age of diagnosis in girls. Higher socioeconomic status and non-White maternal ethnicity were related to later age of diagnosis. CONCLUSIONS: IQ, sex, ADHD symptomology, internalizing symptoms, externalizing symptoms, and socio-demographic factors affect the age of diagnosis.

Examining the interaction between prenatal stress and polygenic risk for attention-deficit/hyperactivity disorder on brain growth in childhood: Findings from the DREAM BIG consortium.

This study explored the interactions among prenatal stress, child sex, and polygenic risk scores (PGS) for attention-deficit/hyperactivity disorder (ADHD) on structural developmental changes of brain regions implicated in ADHD. We used data from two population-based birth cohorts: Growing Up in Singapore Towards healthy Outcomes (GUSTO) from Singapore (n = 113) and Generation R from Rotterdam, the Netherlands (n = 433). Prenatal stress was assessed using questionnaires. We obtained latent constructs of prenatal adversity and prenatal mood problems using confirmatory factor analyses. The participants were genotyped using genome-wide single nucleotide polymorphism arrays, and ADHD PGSs were computed. Magnetic resonance imaging scans were acquired at 4.5 and 6 years (GUSTO), and at 10 and 14 years (Generation R). We estimated the age-related rate of change for brain outcomes related to ADHD and performed (1) prenatal stress by sex interaction models, (2) prenatal stress by ADHD PGS interaction models, and (3) 3-way interaction models, including prenatal stress, sex, and ADHD PGS. We observed an interaction between prenatal stress and ADHD PGS on mean cortical thickness annual rate of change in Generation R (i.e., in individuals with higher ADHD PGS, higher prenatal stress was associated with a lower rate of cortical thinning, whereas in individuals with lower ADHD PGS, higher prenatal stress was associated with a higher rate of cortical thinning). None of the other tested interactions were statistically significant. Higher prenatal stress may promote a slower brain developmental rate during adolescence in individuals with higher ADHD genetic vulnerability, whereas it may promote a faster brain developmental rate in individuals with lower ADHD genetic vulnerability.

Measuring Absolute Coronary Flow and Microvascular Resistance by Thermodilution: JACC Review Topic of the Week.

Diagnosing coronary microvascular dysfunction remains challenging, primarily due to the lack of direct measurements of absolute coronary blood flow (Q) and microvascular resistance (Rµ). However, there has been recent progress with the development and validation of continuous intracoronary thermodilution, which offers a simplified and validated approach for clinical use. This technique enables direct quantification of Q and Rµ, leading to precise and accurate evaluation of the coronary microcirculation. To ensure consistent and reliable results, it is crucial to follow a standardized protocol when performing continuous intracoronary thermodilution measurements. This document aims to summarize the principles of thermodilution-derived absolute coronary flow measurements and propose a standardized method for conducting these assessments. The proposed standardization serves as a guide to ensure the best practice of the method, enhancing the clinical assessment of the coronary microcirculation.

Allogeneic hematopoietic cell transplantation is effective for p47phox chronic granulomatous disease: A Primary Immune Deficiency Treatment Consortium study.

BACKGROUND: P47phox (neutrophil cytosolic factor-1) deficiency is the most common cause of autosomal recessive chronic granulomatous disease (CGD) and is considered to be associated with a milder clinical phenotype. Allogeneic hematopoietic cell transplantation (HCT) for p47phox CGD is not well-described. OBJECTIVES: We sought to study HCT for p47phox CGD in North America. METHODS: Thirty patients with p47phox CGD who received allogeneic HCT at Primary Immune Deficiency Treatment Consortium centers since 1995 were included. RESULTS: Residual oxidative activity was present in 66.7% of patients. In the year before HCT, there were 0.38 CGD-related infections per person-years. Inflammatory diseases, predominantly of the lungs and bowel, occurred in 36.7% of the patients. The median age at HCT was 9.1 years (range 1.5-23.6 years). Most HCTs (90%) were performed after using reduced intensity/toxicity conditioning. HCT sources were HLA-matched (40%) and -mismatched (10%) related donors or HLA-matched (36.7%) and -mismatched (13.3%) unrelated donors. CGD-related infections after HCT decreased significantly to 0.06 per person-years (P = .038). The frequency of inflammatory bowel disease and the use of steroids also decreased. The cumulative incidence of graft failure and second HCT was 17.9%. The 2-year overall and event-free survival were 92.3% and 82.1%, respectively, while at 5 years they were 85.7% and 77.0%, respectively. In the surviving patients evaluated, ≥95% donor myeloid chimerism at 1 and 2 years after HCT was 93.8% and 87.5%, respectively. CONCLUSIONS: Patients with p47phox CGD suffer from a significant disease burden that can be effectively alleviated by HCT. Similar to other forms of CGD, HCT should be considered for patients with p47phox CGD.

The effects of tibial tuberosity avulsion and repair on tibial plateau angle in dogs.

AIMS: To assess whether tibial tuberosity avulsion injury and subsequent surgical repair in skeletally immature dogs are associated with changes in tibial plateau angle (TPA) at skeletal maturity. METHODS: Skeletally mature (> 18 months of age) dogs that had previously undergone unilateral surgery when 4-8 months of age to repair tibial tuberosity avulsion were enrolled. Bilateral, mediolateral stifle radiographs were taken. TPA was measured digitally from the radiographs independently by two readers and compared between sides within dogs. As the number of dogs that would be enrolled for the main part of the study was unknown, to understand how the variation between left and right stifles within dogs would affect the power of the main study, 29 client-owned, skeletally mature dogs without stifle pathology were recruited prior to the main study for bilateral, mediolateral projection stifle radiographs. Variation in the differences in TPA between left and right stifles was used to estimate the likely power of the major part of the study for different numbers of enrolled dogs. RESULTS: From 29 dogs enrolled in the power assessment, the SD of the differences between left and right stifles was 2.1°. With 10 dogs (20 stifles) enrolled within the main part of the study, and if the SD of the differences between operated and non-operated stifles within a dog was the same as the SD of the differences between non-operated stifles within a dog (2.1°), the study would have power ≥ 0.8 if the mean difference in TPA between operated and non-operated stifles was ≥ 2.1°.Ten dogs were enrolled in phase II of the study. In 8/10 of these dogs, the TPA in the operated stifle was less than in the non-operated stifle. The mean TPA on the operated stifle was 6.4° less than on the non-operated stifle (95% CI = 2.4-10.3° less; p = 0.002). For surgery between 4 and 8 months of age, TPA at maturity increased by 2.7° (95% CI = 1.1-4.3°; p = 0.001) for each additional month of age at surgery. CONCLUSIONS AND CLINICAL RELEVANCE: Based on this study, surgical repair of tibial tuberosity avulsion in skeletally immature dogs is associated with a smaller TPA at skeletal maturity. However, causality cannot be established from this cross-sectional study, and this association may be because stifles with a smaller TPA are predisposed to tibial tuberosity avulsion.

Associations between serum health biomarker concentrations and reproductive performance, accounting for milk yield, in pasture-based Holstein cows in southeastern Australia.

In this single cohort study, we investigated associations between the concentrations of a suite of serum biomarkers measured in the first 30 d of lactation and subsequent reproductive performance measured as mating start date to conception intervals, in pasture-based Holstein cows. A secondary objective was to examine associations between biomarker concentrations and 305-d milk yield to assess whether any positive associations between biomarker concentration and reproductive performance were explained by reduced milk production. The data used had been collected as part of an ongoing project from 2017 to 2020 to compile a data set from a large population of lactating dairy cows. Biomarkers measured were those associated with energy balance (ß-hydroxybutyrate [BHB] and nonesterified fatty acids [NEFA]), protein nutritional status (urea and albumin), immune status (globulin, albumin to globulin ratio and haptoglobin), and macromineral status (calcium and magnesium). Associations between biomarker concentrations and mating start date to conception interval were investigated using Cox proportional hazard models, using between 634 and 1,121 lactations (varying by biomarker) from 632 to 1,103 cows and 11 to 17 mating periods from 10 to 13 herds. Based on hazard ratio (HR) estimates and associated 95% confidence intervals (CI), hazard of conception on any particular day of the herds' mating periods was positively associated with the concentrations of albumin (HR = 1.09; 95% CI: 1.05-1.12), albumin to globulin ratio (HR = 2.82; 95% CI: 1.66-4.79), calcium (HR = 2.01; 95% CI: 1.18-3.43), and magnesium (HR = 2.17; 95% CI: 1.01-4.66), and negatively associated with globulin concentration (HR = 0.98; 95% CI: 0.97 to 1.00). There was also some evidence that NEFA concentration was negatively associated (HR = 0.76; 95% CI: 0.57 to 1.01), and urea concentration positively associated (HR = 1.05; 95% CI: 0.99 to 1.11), with reproductive performance, but no evidence that BHB and haptoglobin concentrations were associated with reproductive performance. Except for NEFA, presence and direction of the associations between the biomarker and milk yield were not discordant with that for reproductive performance. Also, except for NEFA, we found no substantial evidence of nonlinear relationships between biomarker concentration and either reproductive performance or milk yield. Correlations between biomarker concentrations were generally weak, indicating that multibiomarker panels may collectively predict reproductive performance better than any single biomarker. We noted substantial variation in the concentrations of all biomarkers within, and for some biomarkers, between herd-year groups. Collectively, these results indicate that there may be scope to improve biomarker concentrations through nutritional, management, and genetic interventions, and by association, reproductive performance and milk yield may also improve.

Adverse Life Experiences and Brain Function: A Meta-Analysis of Functional Magnetic Resonance Imaging Findings.

Importance: Adverse life experiences have been proposed to contribute to diverse mental health problems through an association with corticolimbic functioning. Despite compelling evidence from animal models, findings from studies in humans have been mixed; activation likelihood estimation (ALE) meta-analyses have failed to identify a consistent association of adverse events with brain function. Objective: To investigate the association of adversity exposure with altered brain reactivity using multilevel kernel density analyses (MKDA), a meta-analytic approach considered more robust than ALE to small sample sizes and methodological differences between studies. Data Sources: Searches were conducted using PsycInfo, Medline, EMBASE, and Web of Science from inception through May 4, 2022. The following search term combinations were used for each database: trauma, posttraumatic stress disorder (PTSD), abuse, maltreatment, poverty, adversity, or stress; and functional magnetic resonance imaging (fMRI) or neuroimaging; and emotion, emotion regulation, memory, memory processing, inhibitory control, executive functioning, reward, or reward processing. Study Selection: Task-based fMRI studies within 4 domains (emotion processing, memory processing, inhibitory control, and reward processing) that included a measure of adverse life experiences and whole-brain coordinate results reported in Talairach or Montreal Neurological Institute space were included. Conference abstracts, books, reviews, meta-analyses, opinions, animal studies, articles not in English, and studies with fewer than 5 participants were excluded. Data Extraction and Synthesis: Using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses reporting guideline, 2 independent reviewers assessed abstracts and full-text articles for entry criteria. A third reviewer resolved conflicts and errors in data extraction. Data were pooled using a random-effects model and data analysis occurred from August to November 2022. Main Outcomes and Measures: Peak activation x-axis (left-right), y-axis (posterior-anterior), and z-axis (inferior-superior) coordinates were extracted from all studies and submitted to MKDA meta-analyses. Results: A total of 83 fMRI studies were included in the meta-analysis, yielding a combined sample of 5242 participants and 801 coordinates. Adversity exposure was associated with higher amygdala reactivity (familywise error rate corrected at P < .001; x-axis = 22; y-axis = -4; z-axis = -17) and lower prefrontal cortical reactivity (familywise error rate corrected at P < .001; x-axis = 10; y-axis = 60; z-axis = 10) across a range of task domains. These altered responses were only observed in studies that used adult participants and were clearest among those who had been exposed to severe threat and trauma. Conclusions and Relevance: In this meta-analysis of fMRI studies of adversity exposure and brain function, prior adversity exposure was associated with altered adult brain reactivity to diverse challenges. These results might better identify how adversity diminishes the ability to cope with later stressors and produces enduring susceptibility to mental health problems.

Integrome signatures of lentiviral gene therapy for SCID-X1 patients.

Lentiviral vector (LV)-based gene therapy holds promise for a broad range of diseases. Analyzing more than 280,000 vector integration sites (VISs) in 273 samples from 10 patients with X-linked severe combined immunodeficiency (SCID-X1), we discovered shared LV integrome signatures in 9 of 10 patients in relation to the genomics, epigenomics, and 3D structure of the human genome. VISs were enriched in the nuclear subcompartment A1 and integrated into super-enhancers close to nuclear pore complexes. These signatures were validated in T cells transduced with an LV encoding a CD19-specific chimeric antigen receptor. Intriguingly, the one patient whose VISs deviated from the identified integrome signatures had a distinct clinical course. Comparison of LV and gamma retrovirus integromes regarding their 3D genome signatures identified differences that might explain the lower risk of insertional mutagenesis in LV-based gene therapy. Our findings suggest that LV integrome signatures, shaped by common features such as genome organization, may affect the efficacy of LV-based cellular therapies.

Impact of Post-PCI FFR Stratified by Coronary Artery.

BACKGROUND: Low fractional flow reserve (FFR) after percutaneous coronary intervention (PCI) has been associated with adverse clinical outcomes. Hitherto, this assessment has been independent of the epicardial vessel interrogated. OBJECTIVES: This study sought to assess the predictive capacity of post-PCI FFR for target vessel failure (TVF) stratified by coronary artery. METHODS: We performed a systematic review and individual patient-level data meta-analysis of randomized clinical trials and observational studies with protocol-recommended post-PCI FFR assessment. The difference in post-PCI FFR between left anterior descending (LAD) and non-LAD arteries was assessed using a random-effect models meta-analysis of mean differences. TVF was defined as a composite of cardiac death, target vessel myocardial infarction, and clinically driven target vessel revascularization. RESULTS: Overall, 3,336 vessels (n = 2,760 patients) with post-PCI FFR measurements were included in 9 studies. The weighted mean post-PCI FFR was 0.89 (95% CI: 0.87-0.90) and differed significantly between coronary vessels (LAD = 0.86; 95% CI: 0.85 to 0.88 vs non-LAD = 0.93; 95% CI: 0.91-0.94; P < 0.001). Post-PCI FFR was an independent predictor of TVF, with its risk increasing by 52% for every reduction of 0.10 FFR units, and this was mainly driven by TVR. The predictive capacity for TVF was poor for LAD arteries (AUC: 0.52; 95% CI: 0.47-0.58) and moderate for non-LAD arteries (AUC: 0.66; 95% CI: 0.59-0.73; LAD vs non-LAD arteries, P = 0.005). CONCLUSIONS: The LAD is associated with a lower post-PCI FFR than non-LAD arteries, emphasizing the importance of interpreting post-PCI FFR on a vessel-specific basis. Although a higher post-PCI FFR was associated with improved prognosis, its predictive capacity for events differs between the LAD and non-LAD arteries, being poor in the LAD and moderate in the non-LAD vessels.

Intestinal microbiome and metabolome signatures in patients with chronic granulomatous disease.

BACKGROUND: Chronic granulomatous disease (CGD) is caused by defects in any 1 of the 6 subunits forming the nicotinamide adenine dinucleotide phosphate oxidase complex 2 (NOX2), leading to severely reduced or absent phagocyte-derived reactive oxygen species production. Almost 50% of patients with CGD have inflammatory bowel disease (CGD-IBD). While conventional IBD therapies can treat CGD-IBD, their benefits must be weighed against the risk of infection. Understanding the impact of NOX2 defects on the intestinal microbiota may lead to the identification of novel CGD-IBD treatments. OBJECTIVE: We sought to identify microbiome and metabolome signatures that can distinguish individuals with CGD and CGD-IBD. METHODS: We conducted a cross-sectional observational study of 79 patients with CGD, 8 pathogenic variant carriers, and 19 healthy controls followed at the National Institutes of Health Clinical Center. We profiled the intestinal microbiome (amplicon sequencing) and stool metabolome, and validated our findings in a second cohort of 36 patients with CGD recruited through the Primary Immune Deficiency Treatment Consortium. RESULTS: We identified distinct intestinal microbiome and metabolome profiles in patients with CGD compared to healthy individuals. We observed enrichment for Erysipelatoclostridium spp, Sellimonas spp, and Lachnoclostridium spp in CGD stool samples. Despite differences in bacterial alpha and beta diversity between the 2 cohorts, several taxa correlated significantly between both cohorts. We further demonstrated that patients with CGD-IBD have a distinct microbiome and metabolome profile compared to patients without CGD-IBD. CONCLUSION: Intestinal microbiome and metabolome signatures distinguished patients with CGD and CGD-IBD, and identified potential biomarkers and therapeutic targets.

The programmed death ligand 1 interactome demonstrates bidirectional signaling coordinating immune suppression and cancer progression in head and neck squamous cell carcinoma.

BACKGROUND: The programmed cell death protein 1 (PD-1) and programmed death ligand 1 (PD-L1) are validated cancer targets; however, emerging mechanisms and impact of PD-L1 intracellular signaling on cancer behavior are poorly understood. METHODS: We investigated the cancer cell intrinsic role of PD-L1 in multiple patient-derived models in vitro and in vivo. PD-L1 overexpression, knockdown, and PD-L1 intracellular domain (PD-L1-ICD) deletion (Δ260-290PD-L1) models were assessed for key cancer properties: clonogenicity, motility, invasion, and immune evasion. To determine how PD-L1 transduces signals intracellularly, we used the BioID2 platform to identify the PD-L1 intracellular interactome. Both human papillomavirus-positive and negative patient-derived xenografts were implanted in NOD-scid-gamma and humanized mouse models to investigate the effects of recombinant PD-1, anti-PD-L1, and anti-signal transducer and activator of transcription 3 (STAT3) in vivo. RESULTS: PD-L1 intracellular signaling increased clonogenicity, motility, and invasiveness in multiple head and neck squamous cell carcinoma (HNSCC) models, and PD-1 binding enhanced these effects. Protein proximity labeling revealed the PD-L1 interactome, distinct for unbound and bound PD-1, which initiated cancer cell-intrinsic signaling. PD-L1 binding partners interleukin enhancer binding factors 2 and 3 (ILF2-ILF3) transduced their effect through STAT3. Δ260-290PD-L1 disrupted signaling and reversed pro-growth properties. In humanized HNSCC in vivo models bearing T-cells, PD-1 binding triggered PD-L1 signaling, and dual PD-L1 and STAT3 inhibition were required to achieve tumor control. CONCLUSIONS: Upon PD-1 binding, the PD-L1 extracellular and intracellular domains exert a synchronized effect to promote immune evasion by inhibiting T-cell function while simultaneously enhancing cancer cell-invasive properties.

Measuring the effect of newborn screening on survival after haematopoietic cell transplantation for severe combined immunodeficiency: a 36-year longitudinal study from the Primary Immune Deficiency Treatment Consortium.

BACKGROUND: Severe combined immunodeficiency (SCID) is fatal unless durable adaptive immunity is established, most commonly through allogeneic haematopoietic cell transplantation (HCT). The Primary Immune Deficiency Treatment Consortium (PIDTC) explored factors affecting the survival of individuals with SCID over almost four decades, focusing on the effects of population-based newborn screening for SCID that was initiated in 2008 and expanded during 2010-18. METHODS: We analysed transplantation-related data from children with SCID treated at 34 PIDTC sites in the USA and Canada, using the calendar time intervals 1982-89, 1990-99, 2000-09, and 2010-18. Categorical variables were compared by χ2 test and continuous outcomes by the Kruskal-Wallis test. Overall survival was estimated by the Kaplan-Meier method. A multivariable analysis using Cox proportional hazards regression models examined risk factors for HCT outcomes, including the variables of time interval of HCT, infection status and age at HCT, trigger for diagnosis, SCID type and genotype, race and ethnicity of the patient, non-HLA-matched sibling donor type, graft type, GVHD prophylaxis, and conditioning intensity. FINDINGS: For 902 children with confirmed SCID, 5-year overall survival remained unchanged at 72%-73% for 28 years until 2010-18, when it increased to 87% (95% CI 82·1-90·6; n=268; p=0·0005). For children identified as having SCID by newborn screening since 2010, 5-year overall survival was 92·5% (95% CI 85·8-96·1), better than that of children identified by clinical illness or family history in the same interval (79·9% [69·5-87·0] and 85·4% [71·8-92·8], respectively [p=0·043]). Multivariable analysis demonstrated that the factors of active infection (hazard ratio [HR] 2·41, 95% CI 1·56-3·72; p<0·0001), age 3·5 months or older at HCT (2·12, 1·38-3·24; p=0·001), Black or African-American race (2·33, 1·56-3·46; p<0·0001), and certain SCID genotypes to be associated with lower overall survival during all time intervals. Moreover, after adjusting for several factors in this multivariable analysis, HCT after 2010 no longer conveyed a survival advantage over earlier time intervals studied (HR 0·73, 95% CI 0·43-1·26; p=0·097). This indicated that younger age and freedom from infections at HCT, both directly driven by newborn screening, were the main drivers for recent improvement in overall survival. INTERPRETATION: Population-based newborn screening has facilitated the identification of infants with SCID early in life, in turn leading to prompt HCT while avoiding infections. Public health programmes worldwide can benefit from this definitive demonstration of the value of newborn screening for SCID. FUNDING: National Institute of Allergy and Infectious Diseases, Office of Rare Diseases Research, and National Center for Advancing Translational Sciences.