2024 European Thyroid Association Guidelines on diagnosis and management of genetic disorders of thyroid hormone transport, metabolism and action.

Impaired sensitivity to thyroid hormones encompasses disorders with defective transport of hormones into cells, reduced hormone metabolism and resistance to hormone action. Mediated by heritable single gene defects, these rare conditions exhibit different patterns of discordant thyroid function associated with multisystem phenotypes. In this context, challenges include ruling out other causes of biochemical discordance, making a diagnosis using clinical features together with identification of pathogenic variants in causal genes and managing these rare disorders with a limited evidence base. For each condition, the present guidelines aim to inform clinical practice by summarising key clinical features and useful investigations, criteria for molecular genetic diagnosis and pathways for management and therapy. Specific, key recommendations were developed by combining the best research evidence available with the knowledge and clinical experience of panel members, to achieve a consensus.

The contribution of NaV1.6 to the efficacy of voltage-gated sodium channel inhibitors in wild type and NaV1.6 gain-of-function (GOF) mouse seizure control.

BACKGROUND AND PURPOSE: Inhibitors of voltage-gated sodium channels (NaVs) are important anti-epileptic drugs, but the contribution of specific channel isoforms is unknown since available inhibitors are non-selective. We aimed to create novel, isoform selective inhibitors of Nav channels as a means of informing the development of improved antiseizure drugs. EXPERIMENTAL APPROACH: We created a series of compounds with diverse selectivity profiles enabling block of NaV1.6 alone or together with NaV1.2. These novel NaV inhibitors were evaluated for their ability to inhibit electrically evoked seizures in mice with a heterozygous gain-of-function mutation (N1768D/+) in Scn8a (encoding NaV1.6) and in wild-type mice. KEY RESULTS: Pharmacologic inhibition of NaV1.6 in Scn8aN1768D/+ mice prevented seizures evoked by a 6-Hz shock. Inhibitors were also effective in a direct current maximal electroshock seizure assay in wild-type mice. NaV1.6 inhibition correlated with efficacy in both models, even without inhibition of other CNS NaV isoforms. CONCLUSIONS AND IMPLICATIONS: Our data suggest NaV1.6 inhibition is a driver of efficacy for NaV inhibitor anti-seizure medicines. Sparing the NaV1.1 channels of inhibitory interneurons did not compromise efficacy. Selective NaV1.6 inhibitors may provide targeted therapies for human Scn8a developmental and epileptic encephalopathies and improved treatments for idiopathic epilepsies.

Creatine homeostasis and the kidney: comparison between kidney transplant recipients and healthy controls.

Creatine is a natural nitrogenous organic acid that is integral to energy metabolism and crucial for proper cell functioning. The kidneys are involved in the first step of creatine production. With kidney transplantation being the gold-standard treatment for end-stage kidney disease, kidney transplant recipients (KTR) may be at risk of impaired creatine synthesis. We aimed to compare creatine homeostasis between KTR and controls. Plasma and urine concentrations of arginine, glycine, guanidinoacetate, creatine and creatinine were measured in 553 KTR and 168 healthy controls. Creatine intake was assessed using food frequency questionnaires. Iothalamate-measured GFR data were available in subsets of 157 KTR and 167 controls. KTR and controls had comparable body weight, height and creatine intake (all P > 0.05). However, the total creatine pool was 14% lower in KTR as compared to controls (651 ± 178 vs. 753 ± 239 mmol, P < 0.001). The endogenous creatine synthesis rate was 22% lower in KTR as compared to controls (7.8 ± 3.0 vs. 10.0 ± 4.1 mmol per day, P < 0.001). Despite lower GFR, the plasma guanidinoacetate and creatine concentrations were 21% and 41% lower in KTR as compared to controls (both P < 0.001). Urinary excretion of guanidinoacetate and creatine were 66% and 59% lower in KTR as compared to controls (both P < 0.001). In KTR, but not in controls, a higher measured GFR was associated with a higher endogenous creatine synthesis rate (std. beta: 0.21, 95% CI: 0.08; 0.33; P = 0.002), as well as a higher total creatine pool (std. beta: 0.22, 95% CI: 0.11; 0.33; P < 0.001). These associations were fully mediated (93% and 95%; P < 0.001) by urinary guanidinoacetate excretion which is consistent with production of the creatine precursor guanidinoacetate as rate-limiting factor. Our findings highlight that KTR have a disturbed creatine homeostasis as compared to controls. Given the direct relationship of measured GFR with endogenous creatine synthesis rate and the total creatine pool, creatine supplementation might be beneficial in KTR with low kidney function.Trial registration ID: NCT02811835.Trial registration URL: https://clinicaltrials.gov/ct2/show/NCT02811835 .

Relationship between youth cardiometabolic health and physical activity in medical records.

BACKGROUND: Thers is limited research examining modifiable cardiometabolic risk factors with a single-item health behavior question obtained during a clinic visit. Such information could support clinicians in identifying patients at risk for adverse cardiometabolic health. We investigated if children meeting physical activity or screen time recommendations, collected during clinic visits, have better cardiometabolic health than children not meeting recommendations. We hypothesized that children meeting either recommendation would have fewer cardiometabolic risk factors. METHODS AND FINDINGS: This cross-sectional study used data from electronic medical records (EMRs) between January 1, 2013 through December 30, 2017 from children (2-18 years) with a well child visits and data for ≥1 cardiometabolic risk factor (i.e., systolic and diastolic blood pressure, glycated hemoglobin, alanine transaminase, high-density and low-density lipoprotein, total cholesterol, and/or triglycerides). Physical activity and screen time were patient/caregiver-reported. Analyses included EMRs from 63,676 well child visits by 30,698 unique patients (49.3% female; 41.7% Black, 31.5% Hispanic). Models that included data from all visits indicated children meeting physical activity recommendations had reduced risk for abnormal blood pressure (odds ratio [OR] = 0.91, 95%CI 0.86, 0.97; p = 0.002), glycated hemoglobin (OR = 0.83, 95%CI 0.75, 0.91; p = 0.00006), alanine transaminase (OR = 0.85, 95%CI 0.79, 0.92; p = 0.00001), high-density lipoprotein (OR = 0.88, 95%CI 0.82, 0.95; p = 0.0009), and triglyceride values (OR = 0.89, 95%CI 0.83, 0.96; p = 0.002). Meeting screen time recommendations was not associated with abnormal cardiometabolic risk factors. CONCLUSION: Collecting information on reported adherence to meeting physical activity recommendations can provide clinicians with additional information to identify patients with a higher risk of adverse cardiometabolic health.

Shared Genetic Influences Between Loss-of-Control Eating and Body Mass Index in Adolescent Twins.

OBJECTIVE: Pediatric loss-of-control (LOC) eating is associated with high BMI and predicts binge-eating disorder and obesity onset with age. Research on the etiology of this common comorbidity has not explored the potential for shared genetic risk. This study examined genetic and environmental influences on LOC eating and its shared influence with BMI. METHOD: Participants were 499 monozygotic and 398 same-sex dizygotic twins (age = 17.38 years ± 0.67, BMIz = 0.03 ± 1.03, 54% female) from the Colorado Center for Antisocial Drug Dependence Study. LOC eating was assessed dichotomously. Self-reported height and weight were converted to BMIz. Univariate and bivariate twin models estimated genetic and environmental influences on LOC eating and BMIz. RESULTS: More girls (21%) than boys (9%, p < 0.001) reported LOC eating. The phenotypic correlation with BMIz was 0.03 in girls and 0.18 in boys. Due to the nonsignificant phenotypic correlation in girls, bivariate twin models were fit in boys only. Across all models, the best-fitting model included genetic and unique environmental effects. Genetic factors accounted for 0.51 (95% CI: 0.23, 0.73) of the variance of LOC eating in girls and 0.54 (0.18, 0.90) in boys. The genetic correlation between LOC eating and BMIz in boys was 0.45 (0.15, 0.75). DISCUSSION: Findings indicate moderate heritability of LOC eating in adolescence, while emphasizing the role of unique environmental factors. In boys, LOC eating and BMIz share a proportion of their genetic influences.

Towards Personalized TSH Reference Ranges: A Genetic and Population-Based Approach in Three Independent Cohorts.

Background: Serum thyroid-stimulating hormone (TSH) measurement is the diagnostic cornerstone for primary thyroid dysfunction. There is high inter-individual but limited intra-individual variation in TSH concentrations, largely due to genetic factors. The currently used wide population-based reference intervals may lead to inappropriate management decisions. Methods: A polygenic score (PGS) including 59 genetic variants was used to calculate genetically determined TSH reference ranges in a thyroid disease-free cohort (n = 6,834). Its effect on reclassification of diagnoses was investigated when compared to using population-based reference ranges. Next, results were validated in a second independent population-based thyroid disease-free cohort (n = 3,800). Potential clinical implications were assessed in a third independent population-based cohort including individuals without thyroid disease (n = 26,321) as well as individuals on levothyroxine (LT4) treatment (n = 1,132). Results: PGS was a much stronger predictor of individual TSH concentrations than FT4 (total variance in TSH concentrations explained 9.2-11.1% vs. 2.4-2.7%, respectively) or any other nongenetic factor (total variance in TSH concentrations explained 0.2-1.8%). Genetically determined TSH reference ranges differed significantly between PGS quartiles in all cohorts, while the differences in FT4 concentrations were absent or only minor. Up to 24.7-30.1% of individuals, previously classified as having subclinical hypo- and hyperthyroidism when using population-based TSH reference ranges, were reclassified as euthyroid when genetically determined TSH reference ranges were applied. Individuals in the higher PGS quartiles had a higher probability of being prescribed LT4 treatment compared to individuals from the lower PGS quartiles (3.3% in Q1 vs. 5.2% in Q4, Pfor trend =1.7 × 10-8). Conclusions: Individual genetic profiles have the potential to personalize TSH reference ranges, with large effects on reclassification of diagnosis and LT4 prescriptions. As the currently used PGS can only predict approximately 10% of inter-individual variation in TSH concentrations, it should be further improved when more genetic variants determining TSH concentrations are identified in future studies.

High LDL Particle and APOB Concentrations in Patients With Adrenal Cortical Adenomas: A Cross Sectional Study.

CONTEXT: Patients with nonfunctioning adenomas (NFA), adenomas with mild autonomous cortisol secretion (MACS) and Cushing syndrome (CS) demonstrate an increased cardiovascular risk. OBJECTIVE: To determine the extent of lipoprotein abnormalities in NFA, MACS, and CS. METHODS: We conducted a single-center cross-sectional study of patients with NFA (n = 167), MACS (n = 213), CS (n = 142) and referent subjects (n = 202) between January 2015 and July 2022. Triglyceride-rich lipoprotein particles (TRLP), low density lipoprotein particles (LDLP), high density lipoprotein particles (HDLP), their subclasses and sizes were measured using nuclear magnetic resonance spectroscopy. Multivariable logistic analyses were adjusted for age, sex, BMI, smoking, hypertension, diabetes and lipid lowering drug therapy. RESULTS: In age- and sex-adjusted analysis, all patients categories demonstrated increased very large TRLP, large TRLP and greater TRL size (odds ratio (OR) ranging from 1.22 to 2.08) and total LDLP (OR ranging from 1.22 to 1.75) and decreased LDL and HDL size compared to referent subjects. In fully adjusted analysis, LDLP concentrations remained elevated in all patient categories (odds ratios ranging from 1.31 to 1.84). Total cholesterol, LDL cholesterol, triglycerides and apolipoprotein B were also higher in all patient categories in age- and sex-adjusted analysis with apoB remaining elevated in all patient categories in fully adjusted analysis. Similar LDLP and apoB elevations were observed in all patient categories after excluding subjects on lipid lowering therapy. CONCLUSION: Patients with overt, mild, and even absent cortisol excess demonstrate lipoprotein profile abnormalities, in particular, high LDLP and apoB concentrations, which conceivably contribute to high cardiometabolic risk.

Circulating Trimethylamine-N-Oxide Is Elevated in Liver Transplant Recipients.

Liver transplant recipients (LTRs) have lower long-term survival rates compared with the general population. This underscores the necessity for developing biomarkers to assess post-transplantation mortality. Here we compared plasma trimethylamine-N-oxide (TMAO) levels with those in the general population, investigated its determinants, and interrogated its association with all-cause mortality in stable LTRs. Plasma TMAO was measured in 367 stable LTRs from the TransplantLines cohort (NCT03272841) and in 4837 participants from the population-based PREVEND cohort. TMAO levels were 35% higher in LTRs compared with PREVEND participants (4.3 vs. 3.2 µmol/L, p < 0.001). Specifically, TMAO was elevated in LTRs with metabolic dysfunction-associated steatotic liver disease, alcohol-associated liver disease, and polycystic liver disease as underlying etiology (p < 0.001 for each). Among LTRs, TMAO levels were independently associated with eGFR (std. ß = -0.43, p < 0.001) and iron supplementation (std. ß = 0.13, p = 0.008), and were associated with mortality (29 deaths during 8.6 years follow-up; log-rank test p = 0.017; hazard ratio of highest vs. lowest tertile 4.14, p = 0.007). In conclusion, plasma TMAO is likely elevated in stable LTRs, with impaired eGFR and iron supplementation as potential contributory factors. Our preliminary findings raise the possibility that plasma TMAO could contribute to increased mortality risk in such patients, but this need to be validated through a series of rigorous and methodical studies.

3,3',5-Triiodothyroacetic Acid Transporters.

Introduction: Thyroid hormone transporters are essential for thyroid hormones to enter target cells. Monocarboxylate transporter (MCT) 8 is a key transporter and is expressed at the blood-brain barrier (BBB), in neural cells and many other tissues. Patients with MCT8 deficiency have severe neurodevelopmental delays because of cerebral hypothyroidism and chronic sequelae of peripheral thyrotoxicosis. The T3 analog 3,3',5-triiodothyroacetic acid (TRIAC) rescued neurodevelopmental features in animal models mimicking MCT8 deficiency and improved key metabolic features in patients with MCT8 deficiency. However, the identity of the transporter(s) that facilitate TRIAC transport are unknown. Here, we screened candidate transporters that are expressed at the human BBB and/or brain-cerebrospinal fluid barrier and known thyroid hormone transporters for TRIAC transport. Materials and Methods: Plasma membrane expression was determined by cell surface biotinylation assays. Intracellular accumulation of 1 nM TRIAC was assessed in COS-1 cells expressing candidate transporters in Dulbecco's phosphate-buffered saline (DPBS)/0.1% glucose or Dulbecco's modified Eagle's medium (DMEM) with or without 0.1% bovine serum albumin (BSA). Expression of Slc22a8 was determined by fluorescent in situ hybridization in brain sections from wild-type and Mct8/Oatp1c1 knockout mice at postnatal days 12, 21, and 120. Results: In total, 59 plasma membrane transporters were selected for screening of TRIAC accumulation (n = 40 based on expression at the human BBB and/or brain-cerebrospinal fluid barrier and having small organic molecules as substrates; n = 19 known thyroid hormone transporters). Screening of the selected transporter panel showed that 18 transporters facilitated significant intracellular accumulation of TRIAC in DPBS/0.1% glucose or DMEM in the absence of BSA. In the presence of BSA, substantial transport was noted for SLCO1B1 and SLC22A8 (in DPBS/0.1% glucose and DMEM) and SLC10A1, SLC22A6, and SLC22A24 (in DMEM). The zebrafish and mouse orthologs of these transporters similarly facilitated intracellular accumulation of TRIAC. Highest Slc22a8 mRNA expression was detected in mouse brain capillary endothelial cells and choroid plexus epithelial cells at early postnatal time points, but was reduced at P120. Conclusions: Human SLC10A1, SLCO1B1, SLC22A6, SLC22A8, and SLC22A24 as well as their mouse and zebrafish orthologs are efficient TRIAC transporters. These findings contribute to the understanding of TRIAC treatment in patients with MCT8 deficiency and animal models thereof.

Evidence-based recruitment strategies for clinical research: Study personnel's and research participants' perceptions about successful methods of outreach for a U.S. Autism-Research Cohort.

Introduction: Under enrollment of participants in clinical research is costly and delays study completion to impact public health. Given that research personnel make decisions about which strategies to pursue and participants are the recipients of these efforts, we surveyed research staff (n = 52) and participants (n = 4,144) affiliated with SPARK (Simons Foundation Powering Autism for Knowledge) - the largest study of autism in the U.S. - to understand their perceptions of effective recruitment strategies. Methods: In Study 1, research personnel were asked to report recruitment strategies that they tried for SPARK and to indicate which ones they would and would not repeat/recommend. In Study 2, SPARK participants were asked to indicate all the ways they heard about the study prior to enrollment and which one was most influential in their decisions to enroll. Results: Staff rated speaking with a SPARK-study-team member (36.5%), speaking with a medical provider (19.2%), word of mouth (11.5%), and a live TV news story (11.5%) as the most successful strategies. Participants most often heard about SPARK via social media (47.0%), speaking with a medical provider (23.1%), and an online search (20.1%). Research personnel's and participants' views on effective recruitment strategies often differed, with the exception of speaking with a medical provider. Conclusion: Results suggest that a combination of strategies is likely to be most effective in reaching diverse audiences. Findings have implications for the selection of strategies that meet a study's specific needs, as well as recruitment-strategy "combinations" that may enhance the influence of outreach efforts.

Self-reported smoking, urine cotinine, and risk of type 2 diabetes: Findings from the PREVEND prospective cohort study.

BACKGROUND: Smoking is a major risk factor for type 2 diabetes (T2D), but the evidence has mostly relied on self-reports. We aimed to compare the associations of smoking exposure as assessed by self-reports and urine cotinine with T2D. METHODS: Using the PREVEND prospective study, smoking status was assessed at baseline by self-reports and urine cotinine in 4708 participants (mean age, 53 years) without a history of diabetes. Participants were classified as never, former, light current and heavy current smokers according to self-reports and analogous cut-offs for urine cotinine. Hazard ratios (HRs) with 95% CIs were estimated for T2D. RESULTS: During a median follow-up of 7.3 years, 259 participants developed T2D. Compared with self-reported never smokers, the multivariable adjusted HRs (95% CI) of T2D for former, light current, and heavy current smokers were 1.02 (0.75-1.4), 1.41 (0.89-2.22), and 1.30 (0.88-1.93), respectively. The corresponding adjusted HRs (95% CI) were 0.84 (0.43-1.67), 1.61 (1.12-2.31), and 1.58 (1.08-2.32), respectively, as assessed by urine cotinine. Urine cotinine-assessed but not self-reported smoking status improved T2D risk prediction beyond established risk factors. CONCLUSION: Urine cotinine assessed smoking status may be a stronger risk indicator and predictor of T2D compared to self-reported smoking status.

Corrigendum: Disentangling motivation and engagement: Exploring the role of effort in promoting greater conceptual and methodological clarity.

[This corrects the article DOI: 10.3389/fpsyg.2022.1045717.].

A Prospective Study of the Association Between Plasma Calprotectin Levels and New-Onset CKD in the General Population.

Introduction: Systemic inflammation has been associated with chronic kidney disease (CKD). In this study, we aimed to investigate a potential association between the plasma biomarker of inflammation calprotectin and new-onset CKD in a population-based cohort study. Methods: Individuals without CKD at baseline (n = 4662) who participated in the Prevention of REnal and Vascular ENd-stage Disease (PREVEND) prospective population-based cohort study in the Netherlands were included. Baseline plasma calprotectin levels were assessed in samples that had been stored at -80 °C. Occurrence of new-onset CKD was defined as a composite outcome of an estimated glomerular filtration rate (eGFR) <60 ml/min per 1.73 m2, urinary albumin excretion (UAE) >30 mg/24h, or both. Results: Baseline median (interquartile range) plasma calprotectin levels were 0.49 (0.35-0.68) mg/l and baseline median eGFR was 95.9 (interquartile range: 85.0-105.7) ml/min per 1.73 m2. After median follow-up of 8.3 (7.8-8.9) years, 467 participants developed new-onset CKD. Baseline plasma calprotectin levels were significantly associated with an increased risk of new-onset CKD (hazard ratio [HR] per doubling 1.28 [95% confidence interval, CI: 1.14-1.44], P < 0.001), independent of potentially confounding factors (HR 1.14 [95% CI: 1.01-1.29], P = 0.034), except for baseline high-sensitive C-reactive protein (hs-CRP) (HR 1.05 [0.91-1.21], P = 0.494). In secondary analyses, the association between plasma calprotectin and occurrence of UAE >30 mg/24h remained significant (HR 1.17 [1.02-1.34], P = 0.027), but not significantly so for the incidence of eGFR <60 ml/min per 1.73 m2 as individual outcome (HR 1.15 [0.92-1.43], P = 0.218). Conclusion: Higher plasma calprotectin levels are associated with an increased risk of developing CKD in the general population. This association is mitigated after adjustment for hs-CRP, and more pronounced with new-onset CKD defined by UAE.

Association of High-Density Lipoprotein Parameters and Risk of Heart Failure: A Multicohort Analysis.

BACKGROUND: High-density lipoprotein (HDL) is commonly characterized by its cholesterol concentration (HDL-C) and inverse association with atherosclerotic cardiovascular disease. OBJECTIVES: The authors sought to evaluate the association of HDL particle concentration (HDL-P), HDL particle size (HDL-size), HDL-C, and cholesterol content per particle (HDL-C/HDL-P) with risk of overall heart failure (HF) and subtypes. METHODS: Participants from the Atherosclerosis Risk In Communities Study, Dallas Heart Study, Multi-Ethnic Study of Atherosclerosis, and Prevention of Renal and Vascular End-stage Disease studies without HF history were included. Associations of HDL-P, HDL-size, HDL-C, and HDL-C/HDL-P with risk of overall HF, HF with reduced and preserved ejection fraction were assessed using adjusted Cox models. RESULTS: Among 16,925 participants (53.5% women; 21.8% Black), there were 612 incident HF events (3.6%) (HF with reduced ejection fraction, 309 [50.5%]; HF preserved ejection fraction, 303 [49.5%]) over median follow-up of 11.4 years. In adjusted models, higher HDL-P was significantly associated with lower HF risk (HR of highest vs lowest tertile of HDL-P: 0.76 [95% CI: 0.62-0.93]). Larger HDL-size was significantly associated with higher overall HF risk (HR of largest vs smallest tertile of HDL-size: 1.27 [95% CI: 1.03-1.58]). HF risk associated with HDL-P and HDL-size was similar for HF subtypes. In adjusted analyses, there was no significant association between HDL-C and HF risk. Higher HDL-C/HDL-P was significantly associated with higher overall HF risk (HR of highest vs lowest tertile of HDL-C/HDL-P: 1.29 [95% CI: 1.04-1.60]). CONCLUSIONS: Higher HDL-P was associated with a lower risk of HF. In contrast, larger HDL-size was associated with higher risk of HF and there was no significant association observed between HDL-C and HF risk after accounting for cardiovascular risk factors.

Evidence for strong genetic correlations among internalizing psychopathology and related self-reported measures using both genomic and twin/adoptive approaches.

The internalizing construct captures shared variance underlying risk for mood and anxiety disorders. Internalizing factors based on diagnoses (or symptoms) of major depressive disorder (MDD) and generalized anxiety disorder (GAD) are well established. Studies have also integrated self-reported measures of associated traits (e.g., questionnaires assessing neuroticism, worry, and rumination) onto these factors, despite having not tested the assumption that these measures truly capture the same sets of risk factors. This study examined the overlap among both sets of measures using converging approaches. First, using genomic structural equation modeling, we constructed internalizing factors based on genome-wide association studies (GWASs) of internalizing diagnoses (e.g., MDD) and traits associated with internalizing (neuroticism, loneliness, and reverse-scored subjective well-being). Results indicated the two factors were highly (rg = .79) but not perfectly genetically correlated (rg < 1.0, p < .001). Second, we constructed similar latent factors in a combined twin/adoption sample of adults from the Colorado Adoption/Twin Study of Lifespan Behavioral Development and Cognitive Aging. Again, both factors demonstrated strong overlap at the level of genetic (rg = .76, 95% confidence interval [CI] [0.40, 0.97]) and nonshared environmental influences (re = .80, 95% CI [0.53, 1.0]). Shared environmental influences were estimated near zero for both factors. Our findings are consistent with current frameworks of psychopathology, though they suggest there are some unique genetic influences captured by internalizing diagnosis compared to trait measures, with potentially more nonadditive genetic influences on trait measures. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

The Impact of Cognitive Behavioral Therapy on Sleep Problems in Autistic Children with Co-occurring Anxiety.

PURPOSE: This study seeks to examine the relationship between anxiety-symptom severity and sleep behaviors in autistic children receiving cognitive behavioral therapy (CBT). METHODS: We conducted a secondary-data analysis from a sample of 93 autistic youth, 4 to 14 years, participating in 24 weeks of CBT. Clinicians completed the Pediatric Anxiety Rating Scale (PARS) and parents completed the Children's Sleep Habits Questionnaire, Abbreviated/Short Form (CSHQ-SF) at baseline, mid-treatment, post-treatment and 3 months post-treatment. Mediation analysis evaluated the role of anxiety symptoms in mediating the effect of time in treatment on sleep. RESULTS: There was a negative association between time in treatment and scores on the CSHQ-SF (b = - 3.23, SE = 0.493, t = - 6.553, p < 0.001). Increased time in treatment was associated with decreased anxiety (b = - 4.66, SE = 0.405, t = - 11.507, p < 0.001), and anxiety symptoms decreased with CSHQ-SF scores (b = 0.322, SE = 0.112, t = 2.869, p = 0.005). The indirect effect of time in treatment on CSHQ-SF scores through PARS reduction was negative, but not statistically significant. CONCLUSION: Increased time in CBT was associated with decreased anxiety severity and improved sleep behaviors. Reductions in anxiety symptoms may mediate improvements in sleep problems, but larger sample sizes are necessary to explore this further.

Parent-Led Cognitive Behavioral Teletherapy for Anxiety in Autistic Youth: A Randomized Trial Comparing Two Levels of Therapist Support.

Parent-led cognitive behavioral therapy (CBT) is an efficient, promising form of therapy that may be well suited for autistic youth with anxiety disorders, though to date it has been minimally tested. In this study, 87 autistic youth (7 to 13 years old) with anxiety disorders and their parents were randomized to two forms of parent-led CBT in which parents led their child through a guided CBT workbook across 12 weeks: one with low therapist contact (four 30-minute telehealth calls), and one with standard therapist contact (ten 60-minute telehealth calls). Anxiety, functional impairment, and autism features significantly declined across therapy, without differences between groups. High satisfaction was reported in both groups, though significantly higher satisfaction ratings were reported in standard-contact CBT. Responder rates were 69% of completers at posttreatment (70% in standard contact, 68% in low contact) and 86% at 3-month follow-up (86% in standard contact, 87% in low contact). Low-contact CBT was estimated to incur an average cost of $755.70 per family compared with $1,978.34 in standard-contact CBT. Parent-led CBT with minimal or standard therapist contact both appear to be effective CBT delivery formats for autistic youth with anxiety disorders, with significant cost savings for low-contact CBT.

Motor unit firing rates increase in prepubescent youth following linear periodization resistance exercise training.

PURPOSE: The purpose was to examine the effects of 8-weeks (3 days/week) of linear periodization resistance exercise training (RET) on neuromuscular function in prepubescent youth. METHODS: Twenty-five healthy prepubescent youth (11 males, 14 females, age = 9.1 ± 0.8 years) completed the RET (n = 17) or served as controls (CON, n = 8). Isometric maximal voluntary contractions (MVCs) and trapezoidal submaximal contractions at 35 and 60% MVC of the right leg extensors were performed with surface electromyography (EMG) recorded from the leg extensors [vastus lateralis (VL), rectus femoris, and vastus medialis] and flexors (biceps femoris and semitendinosus). EMG amplitude of the leg extensors and flexors were calculated during the MVCs. Motor unit (MU) action potential trains were decomposed from the surface EMG of the VL for the 35 and 60% MVCs. MU firing rates and action potential amplitudes were regressed against recruitment threshold with the y-intercepts and slopes calculated for each contraction. Total leg extensor muscle cross-sectional area (CSA) was collected using ultrasound images. ANOVA models were used to examine potential differences. RESULTS: Isometric strength increased post-RET (P = 0.006) with no changes in leg extensor and flexor EMG amplitude. Furthermore, there were no changes in total CSA or the MU action potential amplitude vs. recruitment threshold relationships. However, there were increases in the firing rates of the higher-threshold MUs post-RET as indicated with greater y-intercepts (P = 0.003) from the 60% MVC and less negative slope (P = 0.004) of the firing rates vs. recruitment threshold relationships at 35% MVC. CONCLUSIONS: MU adaptations contribute to strength increases following RET in prepubescent youth.

An examination of early socioeconomic status and neighborhood disadvantage as independent predictors of antisocial behavior: A longitudinal adoption study.

The present study examined early socioeconomic status (SES) and neighborhood disadvantage (ND) as independent predictors of antisocial behavior (ASB) and addressed the etiology of the associations (i.e., genes versus the environment) using a longitudinal adoption design. Prospective data from the Colorado Adoption Project (435 adoptees, 598 nonadopted children, 526 biological grandparents of adoptees, 481 adoptive parents, and 617 nonadoptive parents including biological parents of unrelated siblings of adoptees) were examined. SES and ND were assessed during infancy and ASB was evaluated from ages four through 16 using parent and teacher report. Associations between predictors and ASB were compared across adoptive and nonadoptive families and sex. Early SES was a nominally significant, independent predictor of antisocial ASB, such that lower SES predicted higher levels of ASB in nonadoptive families only. ND was not associated with ASB. Associations were consistent across aggression and delinquency, and neither SES nor ND was associated with change in ASB over time. Nominally significant associations did not remain significant after controlling for multiple testing. As such, despite nonsignificant differences in associations across sex or adoptive status, we were unable to make definitive conclusions regarding the genetic versus environmental etiology of or sex differences in the influence of SES and ND on ASB. Despite inconclusive findings, in nonadoptees, results were consistent-in effect size and direction-with previous studies in the literature indicating that lower SES is associated with increased risk for ASB.