Estimating the contribution of subclinical tuberculosis disease to transmission: An individual patient data analysis from prevalence surveys.

Background: Individuals with bacteriologically confirmed pulmonary tuberculosis (TB) disease who do not report symptoms (subclinical TB) represent around half of all prevalent cases of TB, yet their contribution to Mycobacterium tuberculosis (Mtb) transmission is unknown, especially compared to individuals who report symptoms at the time of diagnosis (clinical TB). Relative infectiousness can be approximated by cumulative infections in household contacts, but such data are rare. Methods: We reviewed the literature to identify studies where surveys of Mtb infection were linked to population surveys of TB disease. We collated individual-level data on representative populations for analysis and used literature on the relative durations of subclinical and clinical TB to estimate relative infectiousness through a cumulative hazard model, accounting for sputum-smear status. Relative prevalence of subclinical and clinical disease in high-burden settings was used to estimate the contribution of subclinical TB to global Mtb transmission. Results: We collated data on 414 index cases and 789 household contacts from three prevalence surveys (Bangladesh, the Philippines, and Viet Nam) and one case-finding trial in Viet Nam. The odds ratio for infection in a household with a clinical versus subclinical index case (irrespective of sputum smear status) was 1.2 (0.6-2.3, 95% confidence interval). Adjusting for duration of disease, we found a per-unit-time infectiousness of subclinical TB relative to clinical TB of 1.93 (0.62-6.18, 95% prediction interval [PrI]). Fourteen countries across Asia and Africa provided data on relative prevalence of subclinical and clinical TB, suggesting an estimated 68% (27-92%, 95% PrI) of global transmission is from subclinical TB. Conclusions: Our results suggest that subclinical TB contributes substantially to transmission and needs to be diagnosed and treated for effective progress towards TB elimination. Funding: JCE, KCH, ASR, NS, and RH have received funding from the European Research Council (ERC) under the Horizon 2020 research and innovation programme (ERC Starting Grant No. 757699) KCH is also supported by UK FCDO (Leaving no-one behind: transforming gendered pathways to health for TB). This research has been partially funded by UK aid from the UK government (to KCH); however, the views expressed do not necessarily reflect the UK government's official policies. PJD was supported by a fellowship from the UK Medical Research Council (MR/P022081/1); this UK-funded award is part of the EDCTP2 programme supported by the European Union. RGW is funded by the Wellcome Trust (218261/Z/19/Z), NIH (1R01AI147321-01), EDTCP (RIA208D-2505B), UK MRC (CCF17-7779 via SET Bloomsbury), ESRC (ES/P008011/1), BMGF (OPP1084276, OPP1135288 and INV-001754), and the WHO (2020/985800-0).

Causes of hypercapnic respiratory failure: a population-based case-control study.

OBJECTIVE: There are no population-based data on the relative importance of specific causes of hypercapnic respiratory failure (HRF). We sought to quantify the associations between hospitalisation with HRF and potential antecedent causes including chronic obstructive pulmonary disease (COPD), obstructive sleep apnea, and congestive cardiac failure. We used data on the prevalence of these conditions to estimate the population attributable fraction for each cause. METHODS: A case-control study was conducted among residents aged ≥ 40 years from the Liverpool local government area in Sydney, Australia. Cases were identified from hospital records based on PaCO2 > 45 mmHg. Controls were randomly selected from the study population using a cluster sampling design. We collected self-reported data on medication use and performed spirometry, limited-channel sleep studies, venous sampling for N-terminal pro-brain natriuretic peptide (NT-proBNP) levels, and sniff nasal inspiratory pressure (SNIP) measurements. Logistic regression analyses were performed using directed acyclic graphs to identify covariates. RESULTS: We recruited 42 cases and 105 controls. HRF was strongly associated with post-bronchodilator airflow obstruction, elevated NT-proBNP levels, reduced SNIP measurements and self-reported opioid medication use. There were no differences in the apnoea-hypopnea index or oxygen desaturation index between groups. COPD had the highest population attributable fraction (42%, 95% confidence interval 18% to 59%). CONCLUSIONS: COPD, congestive cardiac failure, and self-reported use of opioid medications, but not obstructive sleep apnea, are important causes of HRF among adults over 40 years old. No single cause accounts for the majority of cases based on the population attributable fraction.

Impact of growth, gonadal hormones, adiposity and the sodium-to-potassium ratio on longitudinal adolescent measures of blood pressure at puberty.

Blood pressure (BP) rises rapidly at puberty. While this is partly due to normal development, factors like excess adiposity and a high intake of dietary sodium relative to potassium may contribute to a true increase in hypertension risk. This study aimed to assess the relative impact of growth, gonadal hormones, adiposity and the sodium-to-potassium ratio (Na:K) on longitudinal BP measures at puberty. This study analysed data from a three-year longitudinal cohort study of pubertal adolescents. Anthropometry, body composition (bio-electrical impedance), serum testosterone and oestradiol (mass spectrometry) were measured annually. Na:K was measured from three-monthly urine samples. These variables were used to predict annual BP measures using mixed modelling and ordinal regression. Data from 325 adolescents (11.7 ± 1.0 y; 55% male) were analysed, showing typical growth patterns at puberty. Systolic BP increased over time in both sexes (p < 0.01), with boys exhibiting a significantly steeper rise compared to girls. Adiposity variables (BMI z-score, percent body fat, fat mass, waist-to-height ratio) strongly and consistently predicted systolic and diastolic BP in both sexes (all p < 0.05). Systolic BP was also significantly and positively related to height (p < 0.05). No associations with BP were identified in either sex for gonadal hormones or Na:K. Similar results were obtained when BP was classified into hypertension categories. Relative to other developmental and diet-related variables tested, adiposity was found to be the strongest most consistent predictor of BP in pubertal adolescents. Findings highlight the importance of dedicated youth obesity management interventions and policy measures for reducing long-term hypertension and cardiovascular disease risks.Australian New Zealand Clinical Trials Registry ACTRN12617000964314.

Causes of hypercapnic respiratory failure and associated in-hospital mortality.

BACKGROUND AND OBJECTIVE: Hypercapnic respiratory failure (HRF) can occur due to severe respiratory disease but also because of multiple coexistent causes. There are few data on the prevalence of antecedent causes for HRF and the effect of these causes on prognosis, especially where study inclusion has not been biased with respect to primary diagnosis, interventions received or clinical outcome. We sought to determine the prevalence of pre-specified conditions among patients with HRF and to determine the effect of these causes on in-hospital mortality. METHODS: Cross-sectional study of patients with HRF from 2013 to 2017. Inclusion criteria were PaCO2  >45 mm Hg and pH ≤7.45. Causes of interest were identified using diagnosis codes from hospital records. We used directed acyclic graphs to inform logistic regression models for the outcome of in-hospital death. RESULTS: We identified 873 persons with HRF in the study period. Mean (SD) age was 69 years and 50.4% were males. Acidosis (pH <7.35) was present in 488 (55%) cases. Most (83%) had one or more of the following: obstructive lung disease, lower respiratory tract infection, congestive cardiac failure, sleep disordered breathing, neuromuscular disease, opioid or benzodiazepine use. In-hospital mortality was 12.8%. Obstructive lung disease and cardiac failure were associated with a lower risk of death, whereas respiratory tract infection and neuromuscular disease were associated with increased risk of death. CONCLUSION: HRF is associated with a range of potentially causative conditions, which significantly impact hospital survival. Systematic evaluation of patients with HRF may increase detection of treatable comorbidities.

Feasibility and preliminary efficacy of iConquerFear: a self-guided digital intervention for fear of cancer recurrence.

PURPOSE: Approximately 50% of cancer survivors experience moderate-severe fear of cancer recurrence (FCR). Self-guided digital interventions have potential to address the high level of FCR-related unmet needs at scale, but existing digital interventions have demonstrated variable engagement and efficacy. This study aimed to evaluate the feasibility and preliminary efficacy of iConquerFear, a five-module self-guided digital FCR intervention. METHODS: Eligible curatively treated breast cancer survivors were recruited. Participants reporting clinically significant FCR (≥ 13 on the Fear of Cancer Recurrence Inventory-Short Form; FCRI-SF) were given access to iConquerFear. Feasibility was indicated by > 50% of eligible participants enrolling in iConquerFear and recording moderate (≥ 120 min) or greater usage. Preliminary efficacy was evaluated via changes in self-reported FCR severity, anxiety, depression, intrusions and metacognitions from baseline to immediately and 3 months post-intervention. RESULTS: Fifty-four (83%) of 65 eligible participants enrolled in iConquerFear; six subsequently withdrew. Thirty-nine (83%) participants recorded moderate (n = 24; 120-599 min) or high (n = 15; ≥ 600 min) usage. Engagement levels increased with participant age (p = 0.043), but were lower in participants with higher baseline FCR (p = 0.028). Qualitative feedback indicated engagement was sometimes limited by difficulties with navigation and relating to featured survivors. Participants reported significantly improved FCR (mean reduction (95%CI): baseline to post-intervention - 3.44 (- 5.18, - 1.71), baseline to 3-month follow-up - 4.52 (- 6.25, - 2.78), p = < 0.001). CONCLUSION: iConquerFear is a feasible and potentially efficacious intervention for reducing FCR in breast cancer survivors. Easier navigation and more relatable examples may enhance engagement. IMPLICATIONS FOR CANCER SURVIVORS: iConquerFear may help address moderate but burdensome FCR levels in cancer survivors.

Associations Between Ambient Particulate Air Pollution and Cognitive Function in Indonesian Children Living in Forest Fire-Prone Provinces.

Smoke from forest fires can reach hazardous levels for extended periods of time. We aimed to determine if there is an association between particulate matter ≤2.5 µm in aerodynamic diameter (PM2.5) and living in a forest fire-prone province and cognitive function. We used data from the Indonesian Family and Life Survey. Cognitive function was assessed by the Ravens Colored Progressive Matrices (RCPM). We used regression models to estimate associations between PM2.5 and living in a forest fire-prone province and cognitive function. In multivariable models, we found very small positive relationships between PM2.5 levels and RCPM scores (PM2.5 level at year of survey: ß = 0.1%; 95% confidence interval (CI) [0.01, 0.19%]). There were no differences in RCPM scores for children living in forest fire-prone provinces compared with children living in non-forest fire-prone provinces (mean difference = -1.16%, 95% CI [-2.53, 0.21]). RCPM scores were lower for children who had lived in a forest fire-prone province all their lives compared with children who lived in a non-forest fire-prone province all their life (ß = -1.50%; 95% CI [-2.94, -0.07]). Living in a forest fire-prone province for a prolonged period of time negatively affected cognitive scores after adjusting for individual factors.

Tree pollen exposure is associated with reduced lung function in children.

BACKGROUND: Allergic disease is a recognized global epidemic and a significant cause of ill health and poor quality of life. The prevalence of pollen allergy is high throughout the world, and pollen exposure itself plays a role in emergency department presentations and hospitalizations for asthma. Lung function and airway inflammation are important measures of asthma activity and control. OBJECTIVE: To examine associations between exposure to multiple pollen types and lung function and markers of airway inflammation at 8 and 14 years of age, and to explore potential modification by residential greenness. METHODS: A cohort of high-risk children living in Sydney, Australia had spirometry and fractional exhaled nitric oxide (FeNO) measured at 8 and 14 years of age. Ambient pollen concentration on the day of lung function measurement and up to three days prior was used as the exposure measure. Residential greenness was derived from satellite imagery. We modelled the association between six pollen types and lung function and FeNO. We also assessed modifying effects of residential greenness. RESULTS: Casuarina, cypress and Pinus pollen in the air the day before measurement and 3 days prior respectively, were associated with reduced lung function in 8-year-olds. The pollen exposures were associated with decreases in FEV1 and FVC; however, the FEV1 /FVC ratio was not affected. Effect modification by greenness was not observed due to loss of power. CONCLUSIONS & CLINICAL RELEVANCE: Airborne tree pollen of cypress, Casuarina and Pinus and not grass in some regions may be detrimental to childhood lung function.

Ability of the LACE index to predict 30-day hospital readmissions in patients with community-acquired pneumonia.

BACKGROUND AND OBJECTIVE: Hospital readmissions within 30 days are used as an indicator of quality of hospital care. We aimed to evaluate the ability of the LACE (Length of stay, Acuity of admission, Comorbidities based on Charlson comorbidity score and number of Emergency visits in the last 6 months) index to predict the risk of 30-day readmissions in patients hospitalised for community-acquired pneumonia (CAP). METHODS: In this retrospective cohort study a LACE index score was calculated for patients with a principal diagnosis of CAP admitted to a tertiary hospital in Sydney, Australia. The predictive ability of the LACE score for 30-day readmissions was assessed using receiver operator characteristic curves with C-statistic. RESULTS: Of 3996 patients admitted to hospital for CAP at least once, 8.0% (n=327) died in hospital and 14.6% (n=584) were readmitted within 30 days. 17.8% (113 of 636) of all 30-day readmissions were again due to CAP, followed by readmissions for chronic obstructive pulmonary disease, heart failure and chest pain. The LACE index had moderate discriminative ability to predict 30-day readmission (C-statistic=0.6395) but performed poorly for the prediction of 30-day readmissions due to CAP (C-statistic=0.5760). CONCLUSIONS: The ability of the LACE index to predict all-cause 30-day hospital readmissions is comparable to more complex pneumonia-specific indices with moderate discrimination. For the prediction of 30-day readmissions due to CAP, the performance of the LACE index and modified risk prediction models using readily available variables (sex, age, specific comorbidities, after-hours, weekend, winter or summer admission) is insufficient.

Bumpy and Smoother Pathways of Puberty Hormone Change: A Novel Way to Define Gonadal Hormone Trajectories in Adolescents.

CONTEXT: The study of gonadal hormone effects on adolescent wellbeing has been limited by logistical challenges. Urine hormone profiling offers new opportunities to understand the health and behavioral implications of puberty hormones. OBJECTIVE: To characterize pubertal change in urinary testosterone and estradiol among male and female adolescents, respectively. DESIGN: Three-year prospective cohort study. SETTING: Australian regional community. PARTICIPANTS: 282 (163 male) normally developing adolescents aged 11.8 ± 1.0 years at baseline. MAIN OUTCOME MEASURE: Quarterly urine measurements of testosterone and estradiol (mass spectrometry); annual anthropometric assessment and Tanner stage (TS) self-report. RESULTS: Two-class sigmoidal and quadratic growth mixture models (centered on age at TS3) were identified as best-fit for describing testosterone (male) and estradiol (female) change. Classes 1 (male: 63%; female: 82%) and 2 (male: 37%; female: 18%) were respectively named the "stable" and "unstable" trajectories, characterized by different standard deviation of quarterly hormone change and magnitude of hormone peaks and troughs (all P < 0.001). Compared with class 1 (stable), class 2 males were taller at baseline (154 vs 151 cm), reported earlier and faster TS progression (P < 0.01), and showed higher serum testosterone levels at baseline and 3 years (P ≤ 0.01). Class 2 females exhibited smaller height and weight gains over the 3 years and had higher baseline serum estradiol (249 vs 98 pmol/L; P = 0.002) than class 1. CONCLUSIONS: Adolescents showed 2 distinct urinary gonadal hormone trajectories, characterized by stability of change over time, which were not associated with consistent anthropometric differences. Results provide a methodology for studying gonadal hormone impacts on other aspects of biopsychosocial wellbeing. Identification of potential "at-risk" hormone groups would be important for planning supportive interventions.

Self-rated Tanner stage and subjective measures of puberty are associated with longitudinal gonadal hormone changes.

Introduction In large community-based studies of puberty, Tanner staging by a clinician is often not possible. We compared self-rated Tanner staging and other subjective ratings of pubertal development with serum hormone levels measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS) to reassess the utility of self-rated pubertal stage using highly sensitive and specific hormone analysis. Methods Adolescents and their parents enrolled in the Adolescent Rural Cohort study of Hormones and health, Education, environments and Relationships (ARCHER) answered annual survey questions on pubertal development. Annually, adolescents provided blood samples for serum testosterone and estradiol measured by LC-MS/MS. Results Longitudinally, self-rated Tanner stage was positively associated with serum testosterone and estradiol levels in both sexes. Confirmation by adolescent and parent that puberty had commenced was associated with higher gonadal hormone levels in both sexes. Parent and adolescent responses demonstrated 'fair' to 'moderate' agreement. Conclusions Over a 3-year follow-up, self-rated Tanner staging and simple questions regarding pubertal onset and development are positively associated with adolescent gonadal hormone concentrations in serum measured by mass spectrometry. Thus, self-report of puberty stage still has a role in large community-based studies where physical examination is not feasible.

Weight Gain Trajectories from Birth to Adolescence and Cardiometabolic Status in Adolescence.

OBJECTIVE: To assess the influence of the trajectory of weight gain from birth to adolescence on cardiovascular and metabolic risk. We studied childhood body mass index (BMI) trajectories from birth to age 14 years and cardiometabolic risk factors at age 14 years. STUDY DESIGN: In total, 410 children with weight and height measurements were assessed from birth throughout childhood, from the Childhood Asthma Prevention Study, a prospective community-based cohort. BMI trajectory groups were determined by latent basis growth mixture models. Of these subjects, 190 had detailed cardiometabolic risk factors assessed at age 14 years. RESULTS: Three BMI trajectory groups were identified; normal BMI, "early rising" excess BMI from 2 years, and "late rising" excess BMI from 5 years. Differences were found between normal and excess BMI in children at 14 years of age. In addition, children with an early rising BMI trajectory had statistically significantly higher central adiposity and a more atherogenic lipoprotein profile at age 14 years than children with a late rising BMI trajectory (P < .05). No differences between BMI trajectory groups in vascular structure or function was identified at age 14 years. CONCLUSIONS: Earlier onset of an elevated BMI trajectory persisting from birth to age 14 years results in an unfavorable cardiometabolic risk profile at age 14 years, including central adiposity and more atherogenic lipoproteins, independent of achieved BMI.

Asthma and atopy prevalence are not reduced among former tuberculosis patients compared with controls in Lima, Peru.

BACKGROUND: Although there are theoretical reasons for believing that asthma and atopy may be negatively correlated with tuberculosis, epidemiological studies have had conflicting findings. OBJECTIVE: To determine if people with confirmed tuberculosis were less likely to be atopic and less likely to have atopic disease including asthma compared to those with no previous tuberculosis. METHODS: Patients in Lima, Peru with a prior history of tuberculosis were identified from clinic records in this cohort study. A representative sample of individuals without a prior tuberculosis diagnosis was recruited from the same community. Allergen skin prick testing was performed to classify atopic status. Allergic rhinitis was identified by history. Asthma was defined by symptoms and spirometry. Eosinophilic airway inflammation was measured using exhaled nitric oxide levels. RESULTS: We evaluated 177 patients with, and 161 individuals without, previous tuberculosis. There was a lower prevalence of atopy among people with prior tuberculosis on univariate analysis (odds ratio 0.57; 95% confidence interval 0.37-0.88) but, after adjustment for potential confounders, this was no longer statistically significant (aOR 0.64, 95% CI 0.41-1.01). The prevalence of allergic rhinitis (aOR 0.76, 95% CI 0.47 to 1.24 and asthma (aOR 1.18, 95% CI 0.69 to 2.00) did not differ significantly between the two groups. We also found no significant difference in the prevalence of elevated exhaled nitric oxide (aOR 1.30, 95% CI 0.78 to 2.17) or a combined index of atopic disease (aOR 0.86, 95% CI 0.54 to 1.36). CONCLUSION: In this urban environment in a middle-income country, prior tuberculosis may be associated with a reduced risk of atopy but does not protect against asthma and atopic disease.

Early and late childhood telomere length predict subclinical atherosclerosis at age 14 yrs. - The CardioCAPS study.

INTRODUCTION: Carotid Intima Media Thickness (CIMT) is a marker of subclinical atherosclerosis, associated with cardiovascular risk in adults. Telomere length (TL) is a marker of cellular ageing. We sought to determine whether telomere length in early childhood and/or at 14-years is associated with CIMT in adolescence, in a community-based cohort study. METHODS: 118 children had TL measured at mean age 3.6-years and 165 children had TL and CIMT, measured at 14-years, from the community-based Childhood Asthma Prevention Study. RESULTS: TL in early childhood was significantly inversely associated with CIMT at 14 years, p = 0.04. TL in teenage life was also significantly inversely associated with CIMT at 14 years, p = 0.03. This latter association was no longer significant, however, after adjusting for early life TL. CONCLUSION: TL measured in early childhood and adolescence is significantly associated with CIMT at 14-years, suggesting that telomere length is a biological marker or even early determinant of late cardiovascular risk.

Performance of the LACE index to predict 30-day hospital readmissions in patients with chronic obstructive pulmonary disease.

BACKGROUND AND OBJECTIVE: Patients hospitalized for acute exacerbation of chronic obstructive pulmonary disease (COPD) have a high 30-day hospital readmission rate, which has a large impact on the health care system and patients' quality of life. The use of a prediction model to quantify a patient's risk of readmission may assist in directing interventions to patients who will benefit most. The objective of this study was to calculate the rate of 30-day readmissions and evaluate the accuracy of the LACE index (length of stay, acuity of admission, co-morbidities, and emergency department visits within the last 6 months) for 30-day readmissions in a general hospital population of COPD patients. METHODS: All patients admitted with a principal diagnosis of COPD to Liverpool Hospital, a tertiary hospital in Sydney, Australia, between 2006 and 2016 were included in the study. A LACE index score was calculated for each patient and assessed using receiver operator characteristic curves. RESULTS: During the study period, 2,662 patients had 5,979 hospitalizations for COPD. Four percent of patients died in hospital and 25% were readmitted within 30 days; 56% of all 30-day readmissions were again due to COPD. The most common reasons for readmission, following COPD, were heart failure, pneumonia, and chest pain. The LACE index had moderate discriminative ability to predict 30-day readmission (C-statistic =0.63). CONCLUSION: The 30-day hospital readmission rate was 25% following hospitalization for COPD in an Australian tertiary hospital and as such comparable to international published rates. The LACE index only had moderate discriminative ability to predict 30-day readmission in patients hospitalized for COPD.

Chronic airflow obstruction after successful treatment of multidrug-resistant tuberculosis.

Cross-sectional studies reveal an association between tuberculosis (TB) and chronic airflow obstruction, but cannot adequately address confounding. We hypothesised that treated pulmonary TB is an independent risk factor for chronic airflow obstruction. The Pulmones Post TB cohort study enrolled participants from Lima, Peru, aged 10-70 years with a history of drug-susceptible (DS)- or multidrug-resistant (MDR)-TB who had completed treatment and were clinically cured. Unexposed participants without TB were randomly selected from the same districts. We assessed respiratory symptoms, relevant environmental exposures, and spirometric lung function pre- and post-bronchodilator. In total, 144 participants with DS-TB, 33 with MDR-TB and 161 unexposed participants were fully evaluated. Compared with unexposed participants, MDR-TB patients had lower lung volumes (adjusted mean difference in forced vital capacity -370 mL, 95% CI -644- -97) and post-bronchodilator airflow obstruction (adjusted OR 4.89, 95% CI 1.27-18.78). Participants who had recovered from DS-TB did not have lower lung volumes than unexposed participants, but were more likely to have a reduced forced expiratory volume in 1 s/forced vital capacity ratio <0.70 (adjusted OR 2.47, 95% CI 1.01-6.03). Individuals successfully treated for TB may experience long-lasting sequelae. Interventions facilitating earlier TB treatment and management of chronic respiratory disease should be explored.

Sex differences in aortic augmentation index in adolescents.

BACKGROUND: Augmentation index (AIx) is a noninvasive measure of pulse wave reflection. AIx is associated with cardiovascular disease. Adult women have a higher AIx than men, but the factors determining this sex-related difference remain to be determined. METHODS: To examine factors associated with AIx in adolescents, participants in the Childhood Asthma Prevention Study, followed from birth, were assessed at age 14 years, with AIx standardized to a heart rate of 75/min (AIx_75) and pulse wave velocity. Associations of AIx_75 and pulse wave velocity with height, change in height, and measures of puberty were assessed. RESULTS: AIx_75 was higher in women compared to men [-24.5 (12.1) versus -32.3 (12.4)%; P < 0.001]. Lower AIx_75 was significantly related to greater change in height between 8 and 14 years, but not to achieved height. The sex difference in AIx was not independently related to puberty variables. Differences between sexes included early life weight gain, lipids, height, BMI-Z-score, change in height from 8 to 14 years, and age at peak height velocity. Change in AIx_75 from 8 to 14 years was highly associated with change in height (m) from 8 to 14 years (B = -88.8, 95% confidence interval -137.3 to -40.3, P =  < 0.001). The difference between sexes established at 8 years was not amplified from 8 to 14 years. CONCLUSION: AIx is higher in girls than boys at 14 years and is closely associated with change in height between 8 and 14 years. Measures of puberty do not appear to independently influence the sex difference in AIx in adolescents.