Cognitive and Social-Emotional Development in Girls With Fragile X Syndrome.

OBJECTIVES: To evaluate the developmental trajectory of key cognitive, social, and emotional features in girls with fragile X syndrome (FXS). METHODS: This longitudinal, parallel cohort study collected data between January 2018 and December 2022. Participants were evaluated 3 times with ∼12-18 months between visits. Participants included 65 girls with FXS, 6 to 16 years, and 52 age- and developmentally-matched girls without FXS. Participants' scores from direct assessment and caregiver report evaluated 3 cognitive domains (verbal abilities, nonverbal abilities, executive function) and 4 social-emotional domains (depression, general anxiety, social behavior, and social anxiety). RESULTS: Participants included 117 girls (mean [M] [SD] age at study entry: FXS M = 10.59 [3.00]; comparison M = 10.45 [2.40])). Omnibus tests showed 4 domains with significant group differences: Verbal (P < .0001, eg, Differential Abilities Scale-II(DAS-II), Picture Vocabulary (-6.25 [1.87])), nonverbal (P < .0001, eg, Kaufman Test of Educational Achievement, Third Edition, Brief Form, Math (-8.56 [2.90])), executive function (P < .0001, eg, NIH Toolbox List Sorting (-6.26 [1.48])), and social anxiety (P < .03, eg, Anxiety, Depression, and Mood Scale (ADAMS) Social Avoidance (1.50 [0.65])). Three domains had significant group by age interaction: Verbal (P < .04, eg, DAS-II, Word Definitions (-1.33 [0.55])), social behavior (P < .01, eg, Social Responsiveness Scale-2 Social Communication (1.57 [0.51])), and social anxiety (P < .01, eg, ADAMS Social Avoidance (0.46 [0.19])). CONCLUSIONS: These findings support the development of early, disorder specific interventions for girls with FXS targeting verbal and nonverbal skills, executive function, social behavior, and social anxiety.

Diagnosis, Risk Stratification, and Treatment of Pericarditis: A Review.

Importance: Pericarditis accounts for up to 5% of emergency department visits for nonischemic chest pain in North America and Western Europe. With appropriate treatment, 70% to 85% of these patients have a benign course. In acute pericarditis, the development of constrictive pericarditis (<0.5%) and pericardial tamponade (<3%) can be life-threatening. Observations: Acute pericarditis is diagnosed with presence of 2 or more of the following: sharp, pleuritic chest pain that worsens when supine (≈90%); new widespread electrocardiographic ST-segment elevation and PR depression (≈25%-50%); a new or increased pericardial effusion that is most often small (≈60%); or a pericardial friction rub (<30%). In North America and Western Europe, the most common causes of acute pericarditis are idiopathic or viral, followed by pericarditis after cardiac procedures or operations. Tuberculosis is the most common cause in endemic areas and is treated with antituberculosis therapy, with corticosteroids considered for associated constrictive pericarditis. Treatment of acute idiopathic and pericarditis after cardiac procedures or operations involves use of high-dose nonsteroidal anti-inflammatory drugs (NSAIDs), with doses tapered once chest pain has resolved and C-reactive protein level has normalized, typically over several weeks. These patients should receive a 3-month course of colchicine to relieve symptoms and reduce the risk of recurrence (37.5% vs 16.7%; absolute risk reduction, 20.8%). With a first recurrence of pericarditis, colchicine should be continued for at least 6 months. Corticosteroids are often used if pericarditis does not improve with NSAIDs and colchicine. In certain patients with multiple recurrences, which can occur for several years, interleukin 1 (IL-1) blockers have demonstrated efficacy and may be preferred to corticosteroids. Conclusions: Acute pericarditis is a common cause of nonischemic chest pain. Tuberculosis is the leading cause of pericarditis in endemic areas and is treated with antitubercular therapy. In North America and Western Europe, pericarditis is typically idiopathic, develops after a viral infection, or develops following cardiac procedures or surgery. Treatment with NSAIDs and colchicine leads to a favorable prognosis in most patients, although 15% to 30% of patients develop recurrence. Patients with multiple recurrent pericarditis can have a disease duration of several years or more, are often treated with corticosteroids, and IL-1 blockers may be used for selected patients as steroid-sparing therapy.

Predicting Long-Term Clinical Outcomes of Patients With Recurrent Pericarditis.

BACKGROUND: Recurrent pericarditis (RP) is a complex condition associated with significant morbidity. Prior studies have evaluated which variables are associated with clinical remission. However, there is currently no established risk-stratification model for predicting outcomes in these patients. OBJECTIVES: We developed a risk stratification model that can predict long-term outcomes in patients with RP and enable identification of patients with characteristics that portend poor outcomes. METHODS: We retrospectively studied a total of 365 consecutive patients with RP from 2012 to 2019. The primary outcome was clinical remission (CR), defined as cessation of all anti-inflammatory therapy with complete resolution of symptoms. Five machine learning survival models were used to calculate the likelihood of CR within 5 years and stratify patients into high-risk, intermediate-risk, and low-risk groups. RESULTS: Among the cohort, the mean age was 46 ± 15 years, and 205 (56%) were women. CR was achieved in 118 (32%) patients. The final model included steroid dependency, total number of recurrences, pericardial late gadolinium enhancement, age, etiology, sex, ejection fraction, and heart rate as the most important parameters. The model predicted the outcome with a C-index of 0.800 on the test set and exhibited a significant ability in stratification of patients into low-risk, intermediate-risk, and high-risk groups (log-rank test; P < 0.0001). CONCLUSIONS: We developed a novel risk-stratification model for predicting CR in RP. Our model can also aid in stratifying patients, with high discriminative ability. The use of an explainable machine learning model can aid physicians in making individualized treatment decision in RP patients.

Alterations in cortical and subcortical neuroanatomy and associations with behavior in females with fragile X syndrome.

AIM: To address substantial gaps in the literature on neuroanatomical variations in females with fragile X syndrome (FXS). METHOD: Surface-based modeling techniques were applied to the magnetic resonance imaging of 45 females with FXS (mean age = 10 years 9 months, range 6 years-16 years 4 months, SD = 2 years 9 months) and 33 age-matched and developmentally matched females without FXS to elucidate differences in cortical gray matter volume, surface area, and thickness. Gray matter volumes in subcortical regions were examined to ascertain differences in subcortical volume. RESULTS: In females with FXS, cortical volume was greater bilaterally in the occipital pole and smaller in the right postcentral gyrus. Seven regions demonstrated lower surface area in participants with FXS, while cortical thickness was significantly greater over the posterior and medial surfaces in the group with FXS. Subcortical region of interest analyses demonstrated greater volume in the caudate nucleus, globus pallidus, and nucleus accumbens in the group with FXS. Global gray matter volume, pial thickness, and surface area were associated with behavioral outcomes in the group with FXS but not in the comparison group. INTERPRETATION: Females with FXS demonstrated unique cortical and subcortical gray matter anatomy relative to a matched comparison group. These findings may be relevant to the pathogenesis of the FXS behavioral phenotype and provide insights into behavioral interventions targeted to this population.

Pericardial Diseases: International Position Statement on New Concepts and Advances in Multimodality Cardiac Imaging.

Pericardial diseases have gained renewed clinical interest, leading to a renaissance in the field. There have been many recent advances in pericardial diseases in both multimodality cardiac imaging of diagnoses, such as recurrent, transient constrictive and effusive-constrictive pericarditis, and targeted therapeutics, especially anti-interleukin (IL)-1 agents that affect the inflammasome as part of autoinflammatory pathophysiology. There remains a large educational gap for clinicians, leading to variability in evaluation and management of these patients. The latest pericardial imaging (American Society of Echocardiography, European Association of Cardiovascular Imaging) and clinical guidelines (European Society of Cardiology) are >8-10 years of age and may not reflect current practice. Recent clinical trials involving anti-IL-1 agents in recurrent pericarditis, including anakinra (AIRTRIP), rilonacept (RHAPSODY), and goflikicept have demonstrated their efficacy. The present document represents an international position statement from world leaders in the pericardial field, focusing on novel concepts and emphasizing the role of multimodality cardiac imaging as well as new therapeutics in pericardial diseases.

Malignant Pericardial Effusion: A Systematic Review.

Background: Malignant pericardial effusion (Eff) is often asymptomatic and has an unknown prevalence, due to its occult presentation. The condition often is identified postmortem on autopsy, and it is associated with a poor prognosis. Given the late presentation of malignant pericardial Effs, a minimal volume of literature has examined the epidemiology, clinical characteristics, and outcomes of these complex patients. We conducted a systematic review to advance present understanding of this condition. Methods: A search of 4 databases resulted in 41 case reports meeting criteria. Inclusion criteria were being a patient aged > 18 years who presented with pericardial Eff in the setting of malignancy. Intervention was medical and/or surgical therapy, and the outcome was mortality. Results: For the 41 patients included, the median age was 54 years, and the majority were male patients (58%). Dyspnea was the leading symptom (90%), and cardiac tamponade was present in 78% of cases. Common cancers included lung, gastrointestinal, and renal neoplasms (59%). Pericardiocentesis occurred in 98% of cases, with a median fluid extraction volume of 1000 mL. Death occurred in 44%, primarily due to disease progression and/or metastasis. Conclusions: This study presents the largest systematic review on malignancy-induced pericardial Effs to date. Notably, solid tumours, and specifically lung adenocarcinomas, are common culprits. Malignant pericardial Effs are often severe, with a majority of patients presenting with cardiac tamponade. Overall, treatment options are limited, and the associated mortality rate is high.

Contexte: L'épanchement péricardique malin (EPM) est un état généralement asymptomatique, de prévalence inconnue en raison de son tableau clinique occulte. Il est souvent reconnu post-mortem, à l'autopsie, et est associé à un pronostic médiocre. En raison de la consultation tardive pour un EPM, les données publiées relatives à l'épidémiologie, aux caractéristiques cliniques et à l'issue de ces cas complexes sont limitées. Nous avons réalisé une analyse systématique dans le but d'élargir les connaissances sur cette affection. Méthodologie: Une recherche réalisée dans quatre bases de données a permis de repérer 41 rapports de cas qui répondaient aux critères de recherche. Les critères d'inclusion étaient les suivants : être âgé de plus de 18 ans; présenter un épanchement péricardique en présence d'un cancer; intervention pharmacologique et/ou chirurgicale; issue mortelle. Résultats: L'âge médian des 41 patients inclus était de 54 ans; la majorité d'entre eux étaient des hommes (58 %). Le symptôme principal était la dyspnée (90 %), et une tamponnade cardiaque était présente dans 78 % des cas. Les cancers les plus fréquents étaient le cancer du poumon, le cancer gastro-intestinal et les néoplasmes rénaux (59 %). Une péricardiocentèse a été réalisée dans 98 % des cas. Le volume de drainage médian était de 1 000 mL. Quarante-quatre pour cent des sujets sont décédés, principalement en raison de la progression de la maladie et/ou de métastases. Conclusions: Cette étude est la plus vaste analyse systématique réalisée à ce jour sur l'EPM. Les tumeurs solides, et plus particulièrement les adénocarcinomes pulmonaires, sont des causes fréquentes. L'EPM est souvent grave, la majorité des patients présentant une tamponnade cardiaque. Les traitements disponibles sont généralement limités, et le taux de mortalité associé est élevé.

Are the Reference Values for the Provocative Concentration of Methacholine Appropriate for Children?

Background: Preliminary data in a randomly selected pediatric cohort study in 8-year-olds suggested a rate of positivity to a methacholine challenge test that was unexpectedly high, roughly 30%. The current recommendation for a negative methacholine test is a 20% decrease in the forced expiratory volume in one second at a dose greater than 400 µg. This was derived from studies in adults using the obsolete English Wright nebulizer. One explanation for the high incidence of positivity in the study in 8-year-olds could be that children deposit more methacholine on a µg/kg basis than adults, due to differences in their breathing patterns. The purpose of this study was to determine if pediatric breathing patterns could result in a higher dose of methacholine depositing in the lungs of children based on µg/kg body weight compared with adults. Methods: An AeroEclipse Breath Actuated nebulizer delivered methacholine aerosol, generated from a 16 mg/mL solution, for one minute, using age-appropriate breathing patterns for a 70 kg adult and a 30 and 50 kg child produced by a breathing simulator. Predicted lung deposition was calculated from the collected dose of methacholine on a filter placed at the nebulizer outport, multiplied by the fraction of the aerosol mass contained in particles ≤5 µm. The dose of methacholine on the inspiratory filter was assayed by high performance liquid chromatography (HPLC). Particle size was measured using laser diffraction technology. Results: The mean (95% confidence intervals) predicted pulmonary dose of methacholine was 46.1 (45.4, 46.8), 48.6 (45.3, 51.9), and 36.1 (34.2, 37.9) µg/kg body weight for the 30 kg child, 50 kg child, and 70 kg adult, respectively. Conclusions: On a µg/kg body weight, the predicted pulmonary dose of methacholine was greater with the pediatric breathing patterns than with the adult pattern.

Longitudinal cardiac magnetic resonance imaging following clinical response to rilonacept and prior to recurrence upon treatment suspension: a RHAPSODY subgroup analysis.

AIMS: In the phase 3 trial, RHAPSODY, rilonacept effectively resolved active pericarditis recurrences, and long-term treatment led to sustained pericarditis recurrence risk reduction. Prior analysis suggested association between higher late gadolinium enhancement (LGE) at baseline and more rapid recurrence upon rilonacept suspension after 12 weeks of treatment. This subgroup analysis assessed the utility of longitudinal serial cardiac magnetic resonance (CMR) imaging for tracking clinical improvement and predicting post-treatment-cessation outcomes to help guide clinical decision making. METHODS AND RESULTS: At an 18-month decision milestone (18MDM) in the RHAPSODY long-term extension, investigators decided if patients would continue rilonacept, suspend rilonacept for off-treatment observation, or discontinue the study. Pericardial thickness, pericardial edema (T2-STIR), and LGE were determined at baseline and 18MDM by an imaging core lab blinded to clinical data, and pericarditis recurrence was investigator-assessed. CMR results in patients with data at both baseline and 18MDM (n=13) showed that pericardial thickness, T2-STIR, and LGE were reduced during rilonacept treatment. Among patients with CMR data who suspended rilonacept at the 18MDM (n=7), 5 (71%) had a pericarditis recurrence within 1-4 months of rilonacept suspension, despite all having had none/trace LGE (n=7) and negative T2-STIR (n=7) at the 18MDM and 2 having received prophylactic colchicine. CONCLUSIONS: Continued clinical improvement during prolonged rilonacept treatment corresponded with improvement on CMR, including reduced pericardial thickness, resolution of pericardial edema, and resolution of LGE. However, none/trace LGE at 18MDM while on treatment did not predict absence of pericarditis recurrence upon subsequent rilonacept suspension in this size-limited subgroup.

Left ventricular diastolic dysfunction in non-myocardial disorders.

This article reviews and discusses non-myocardial disorders which represent diagnostic challenges when evaluating patients for suspected heart failure with preserved left ventricular ejection fraction. This includes pre-capillary pulmonary hypertension, which is important to differentiate from post-capillary hypertension caused by left sided heart disease. The impact of electrical disorders on LV diastolic function is also reviewed, and includes a discussion of left bundle branch, which has both a direct effect on LV diastolic function, as well as a long-term effect due to remodeling. Furthermore, evaluation of diastolic function in patients with atrial fibrillation is discussed. Pericardial diseases are reviewed as well as effects of a normal pericardium on diastolic function in failing hearts. Finally, the article reviews how valvular diseases impact LV diastolic function.

Absence of Pericarditis Recurrence in Rilonacept-Treated Patients With COVID-19 and SARS-CoV-2 Vaccination: Results From the RHAPSODY Long-term Extension.

Background: Rilonacept inhibits the interleukin-1 pathway, and extended treatment in patients with recurrent pericarditis (RP) reduced recurrence risk by 98% in the phase 3 trial, RHAPSODY long-term extension (LTE). Severe acute respiratory syndrome (SARS)-CoV-2 vaccination and/or infection may trigger pericarditis recurrence, and in clinical practice, it is unknown whether to continue rilonacept during SARS-CoV-2 infection. This post-hoc analysis of the RHAPSODY LTE aimed to inform rilonacept management in RP patients vaccinated against SARS-CoV-2 or who contract COVID-19. Methods: Analysis was conducted from May 2020 to June 2022. The LTE portion of RHAPSODY LTE enabled up to 24 months of additional open-label rilonacept treatment beyond the pivotal study. Rilonacept efficacy data in preventing pericarditis recurrence were assessed, and concomitant SARS-CoV-2 vaccination and COVID-19 adverse event data were evaluated. Results: No pericarditis recurrences were temporally associated with vaccination. Sixteen COVID-19 cases were reported; 10 in 30 unvaccinated or partially vaccinated patients (33%) vs 6 of 44 fully vaccinated patients (14%; P = 0.04). Twelve of 16 patients (75%) were receiving rilonacept at the time of infection, and none experienced pericarditis recurrence. One pericarditis recurrence occurred in the peri-COVID-19 period in 1 of 4 patients who had stopped rilonacept treatment > 4.5 months prior. COVID-19 severity was mild in 13 patients, moderate in 2, and severe in 1. Conclusions: Full vaccination effectively reduced COVID-19 events in patients treated with rilonacept. Vaccination or COVID-19 during rilonacept treatment did not increase pericarditis recurrence. Continued rilonacept treatment in patients contracting COVID-19 did not worsen disease severity, whereas rilonacept interruption increased pericarditis recurrence, supporting a recommendation for continued rilonacept treatment for RP during vaccination or COVID-19. ClinicalTrialsgov identifier: NCT03737110.

Contexte: Le rilonacept inhibe la voie de l'interleukine-1 et, d'après les résultats de la période de prolongation à long terme de l'essai de phase III RHAPSODY, la poursuite du traitement par cet agent chez les patients atteints de péricardite récidivante a réduit le risque de récidive de 98 %. La vaccination contre le syndrome respiratoire aigu sévère (SRAS)-CoV-2 ou l'infection à ce virus pourrait toutefois déclencher une récidive de la péricardite, et dans la pratique clinique, on ignore s'il vaut mieux poursuivre le traitement par rilonacept pendant l'infection à SRAS-CoV-2. Cette analyse post-hoc de la période de prolongation à long terme de l'essai RHAPSODY vise à orienter la gestion du rilonacept chez les patients atteints de péricardite récidivante qui sont vaccinés contre le SRAS-CoV-2 ou qui contractent la COVID-19. Méthodologie: L'analyse a été effectuée de mai 2020 à juin 2022. La période de prolongation à long terme de l'essai RHAPSODY a permis d'accumuler des données en mode ouvert pendant une période allant jusqu'à 24 mois au-delà de l'étude pivot. Les données sur l'efficacité du rilonacept en prévention de la récidive de péricardite ont été évaluées, tout comme les données sur la vaccination concomitante contre le SRAS-CoV-2 et les cas de COVID-19. Résultats: Aucune récidive de la péricardite n'a pu être associée sur le plan temporel avec la vaccination. Au total, 16 cas de COVID-19 ont été signalés, dont 10 chez les patients non vaccinés ou partiellement vaccinés sur 30 (33 %) et 6 chez les patients complètement vaccinés sur 44 (14 %; p = 0,04). De ces 16 patients, 12 (75 %) prenaient du rilonacept au moment de l'infection et aucun n'a connu de récidive de la péricardite. Une récidive de la péricardite s'est produite dans la période suivant la COVID-19 chez 1 des 4 patients qui avaient cessé de prendre le rilonacept > 4,5 mois auparavant. La COVID-19 a été légère chez 13 patients, modérée chez 2 patients et sévère chez 1 patient. Conclusions: La vaccination complète a réduit efficacement les cas de COVID-19 chez les patients traités par le rilonacept. La vaccination ou l'infection à SRAS-CoV-2 pendant le traitement par rilonacept n'a pas augmenté le risque de récidive de la péricardite. La poursuite du traitement par rilonacept chez les patients atteints de COVID-19 n'a pas aggravé la sévérité de la maladie, tandis que l'interruption du traitement a augmenté le risque de récidive de la péricardite, ce qui plaide en faveur de la recommandation de poursuivre le traitement de la péricardite récidivante par le rilonacept pendant la vaccination ou la COVID-19. Numéro d'identification ClinicalTrialsgov: NCT03737110.

Pericardial Diseases and Best Practices for Pericardiectomy: JACC State-of-the-Art Review.

Remarkable advances have occurred in the understanding of the pathophysiology of pericardial diseases and the role of multimodality imaging in this field. Medical therapy and surgical options for pericardial diseases have also evolved substantially. Pericardiectomy is indicated for chronic or irreversible constrictive pericarditis, refractory recurrent pericarditis despite optimal medical therapy, or partial agenesis of the pericardium with a complication (eg, herniation). A multidisciplinary evaluation before pericardiectomy is essential for optimal patient outcomes. Overall, given the good outcomes reported, radical pericardiectomy on cardiopulmonary bypass, if feasible, is the preferred approach. Due to patient complexity, as well as the technical aspects of the surgery, pericardiectomy should be performed at high-volume centers that have the required expertise. The current review highlights the essential features of this multidisciplinary approach from diagnosis to recovery in patients undergoing pericardiectomy.

Alterations in Neural Activation During Facial Emotion Processing in Adolescent Male Participants With Klinefelter Syndrome.

OBJECTIVE: Klinefelter syndrome (KS) is the most common sex-chromosome aneuploidy (47,XXY), affecting 1 in 500 male participants. The phenotype of male participants with KS includes both physical features, such as tall stature and testicular insufficiency, and behavioral alterations, including difficulties in social functioning, anxiety, and depression. Studies examining underlying neural alterations associated with the behavioral phenotype, however, are sparse. We aimed to address this gap in knowledge using functional magnetic resonance imaging in conjunction with an emotion processing paradigm. METHOD: Functional magnetic resonance imaging was conducted on 38 children and adolescents with KS ( Mage = 12.85, SD = 2.45) and 47 typical developing (control) boys ( Mage = 12.04, SD = 1.82) as they completed a facial emotion processing task. Group differences in activation occurring during the processing of angry versus neutral faces were examined while controlling for age. RESULTS: The results indicated that relative to typically developing boys, boys with KS exhibited anomalous increases in activation of frontal, temporal, and occipital cortices. Within the KS group, secondary analyses indicated that greater activation in these regions was associated with more internalizing symptoms (e.g., anxiety, depression, withdrawn behaviors) and greater social impairments (e.g., social cognition, social communication, social motivation, social communication and interaction, functional communication). CONCLUSION: The findings from this study indicate a possible neural correlation for difficulties in social and emotional function in KS and add to a growing body of research aimed at increasing our understanding of neural biomarkers in this condition. Future studies that examine the influence of testosterone-replacement therapy on these differences are warranted.

Evaluation of left ventricular filling pressure by echocardiography in patients with atrial fibrillation.

BACKGROUND: Echocardiography is widely used to evaluate left ventricular (LV) diastolic function in patients suspected of heart failure. For patients in sinus rhythm, a combination of several echocardiographic parameters can differentiate between normal and elevated LV filling pressure with good accuracy. However, there is no established echocardiographic approach for the evaluation of LV filling pressure in patients with atrial fibrillation. The objective of the present study was to determine if a combination of several echocardiographic and clinical parameters may be used to evaluate LV filling pressure in patients with atrial fibrillation. RESULTS: In a multicentre study of 148 atrial fibrillation patients, several echocardiographic parameters were tested against invasively measured LV filling pressure as the reference method. No single parameter had sufficiently strong association with LV filling pressure to be recommended for clinical use. Based on univariate regression analysis in the present study, and evidence from existing literature, we developed a two-step algorithm for differentiation between normal and elevated LV filling pressure, defining values ≥ 15 mmHg as elevated. The parameters in the first step included the ratio between mitral early flow velocity and septal mitral annular velocity (septal E/e'), mitral E velocity, deceleration time of E, and peak tricuspid regurgitation velocity. Patients who could not be classified in the first step were tested in a second step by applying supplementary parameters, which included left atrial reservoir strain, pulmonary venous systolic/diastolic velocity ratio, and body mass index. This two-step algorithm classified patients as having either normal or elevated LV filling pressure with 75% accuracy and with 85% feasibility. Accuracy in EF ≥ 50% and EF < 50% was similar (75% and 76%). CONCLUSIONS: In patients with atrial fibrillation, no single echocardiographic parameter was sufficiently reliable to be used clinically to identify elevated LV filling pressure. An algorithm that combined several echocardiographic parameters and body mass index, however, was able to classify patients as having normal or elevated LV filling pressure with moderate accuracy and high feasibility.

Longitudinal Changes in Functional Neural Activation and Sensitization During Face Processing in Fragile X Syndrome.

BACKGROUND: Fragile X syndrome (FXS) is a genetic condition associated with increased risk for social anxiety and avoidance. Using functional near-infrared spectroscopy (fNIRS), we previously demonstrated aberrant neural activity responding to faces in young girls with FXS cross-sectionally. Here, we tested the hypothesis that abnormalities in neural activation and sensitization would increase with age in 65 girls with FXS (ages 6-16 years) relative to an age-matched control group of 52 girls who had comparable cognitive function and clinical symptoms. METHODS: fNIRS data were collected at 2 time points (mean [SD] = 2.8 [0.6] years apart) during a face processing task. Linear mixed-effect models examined longitudinal neural profiles in girls with FXS and control participants. Correlational analysis was performed to examine associations between neural sensitization (increasing neural response to repeated stimuli) and clinical ratings. RESULTS: In the FXS group, 24 participants had 1 fNIRS scan, and 32 had 2 scans. In the control group, 28 participants had 1 fNIRS scan, and 22 had 2 scans. Brain activations in the superior frontal gyrus were higher in girls with FXS than control participants at both time points. Neural sensitization also increased in girls with FXS at a higher rate than control participants in the superior frontal gyrus when responding to upright faces. For the FXS group, sensitization in the superior frontal gyrus positively correlated with longitudinal increases in anxiety and social avoidance scores. CONCLUSIONS: Girls with FXS show increasingly abnormal neural activation and sensitization responding to faces over time. Aberrant neural sensitization in girls with FXS is associated with longitudinal changes in anxiety and social skills.

Associations between brain network, puberty, and behaviors in boys with Klinefelter syndrome.

BACKGROUND: Klinefelter syndrome (KS), also referred to as XXY syndrome, is a significant but inadequately studied risk factor for neuropsychiatric disability. Whether alterations in functional brain connectivity or pubertal delays are associated with aberrant cognitive-behavioral outcomes in individuals with KS is largely unknown. In this observational study, we investigated KS-related alterations in the resting-state brain network, testosterone level, and cognitive-behavioral impairment in adolescents with Klinefelter syndrome. METHODS: We recruited 46 boys with KS, ages 8 to 17 years, and 51 age-matched typically developing (TD) boys. All participants underwent resting-state functional magnetic resonance imaging scans, pubertal, and cognitive-behavioral assessments. Resting-state functional connectivity and regional brain activity of the participants were assessed. RESULTS: We found widespread alterations in global functional connectivity among the inferior frontal gyrus, temporal-parietal area, and hippocampus in boys with KS. Aberrant regional activities, including enhanced fALFF in the motor area and reduced ReHo in the caudate, were also found in the KS group compared to the TD children. Further, using machine learning methods, brain network alterations in these regions accurately differentiated boys with KS from TD controls. Finally, we showed that the alterations of brain network properties not only effectively predict cognitive-behavioral impairment in boys with KS, but also appear to mediate the association between total testosterone level and language ability, a cognitive domain at particular risk for dysfunction in this condition. CONCLUSION: Our results offer an informatic neurobiological foundation for understanding cognitive-behavioral impairments in individuals with KS and contribute to our understanding of the interplay between pubertal status, brain function, and cognitive-behavioral outcome in this population.

Childhood exposure to organophosphate pesticides: Functional connectivity and working memory in adolescents.

BACKGROUND: Early life exposure to organophosphate (OP) pesticides is linked with adverse neurodevelopment and brain function in children. However, we have limited knowledge of how these exposures affect functional connectivity, a measure of interaction between brain regions. To address this gap, we examined the association between early life OP pesticide exposure and functional connectivity in adolescents. METHODS: We administered functional near-infrared spectroscopy (fNIRS) to 291 young adults with measured prenatal or childhood dialkylphosphates (DAPs) in the Center for the Health Assessment of Mothers and Children of Salinas (CHAMACOS) study, a longitudinal study of women recruited during pregnancy and their offspring. We measured DAPs in urinary samples collected from mothers during pregnancy (13 and 26 weeks) and children in early life (ages 6 months, 1, 2, 3, and 5 years). Youth underwent fNIRS while they performed executive function and semantic language tasks during their 18-year-old visit. We used covariate-adjusted regression models to estimate the associations of prenatal and childhood DAPs with functional connectivity between the frontal, temporal, and parietal regions, and a mediation model to examine the role of functional connectivity in the relationship between DAPs and task performance. RESULTS: We observed null associations of prenatal and childhood DAP concentrations and functional connectivity for the entire sample. However, when we looked for sex differences, we observed an association between childhood DAPs and functional connectivity for the right interior frontal and premotor cortex after correcting for the false discovery rate, among males, but not females. In addition, functional connectivity appeared to mediate an inverse association between DAPs and working memory accuracy among males. CONCLUSION: In CHAMACOS, a secondary analysis showed that adolescent males with elevated childhood OP pesticide exposure may have altered brain regional connectivity. This altered neurofunctional pattern in males may partially mediate working memory impairment associated with childhood DAP exposure.

Immune checkpoint inhibitors and pericardial disease: a systematic review.

INTRODUCTION: Despite the growing use of immune checkpoint inhibitors (ICI) in cancer treatment, data regarding ICI-associated pericardial disease are primarily derived from case reports and case series. ICI related pericardial disease can be difficult to diagnose and is associated with significant morbidity. We conducted a systematic review to further characterize the epidemiology, clinical presentation, and outcomes of this patient population. METHODS: A search of four databases resulted in 31 studies meeting inclusion criteria. Patients > 18 years old who presented with ICI mediated pericardial disease were included. Intervention was medical + surgical therapy and outcomes were development of cardiac tamponade, morbidity, and mortality. RESULTS: Thirty- eight patients across 31 cases were included. Patients were majority male (72%) with a median age of 63. Common symptoms included dyspnea (59%) and chest pain (32%), with 41% presenting with cardiac tamponade. Lung cancer (81%) was the most prevalent, and nivolumab (61%) and pembrolizumab (34%) were the most used ICIs. Pericardiocentesis was performed in 68% of patients, and 92% experienced symptom improvement upon ICI cessation. Overall mortality was 16%. DISCUSSION: This study provides the most comprehensive analysis of ICI-mediated pericardial disease to date. Patients affected were most commonly male with lung cancer treated with either Nivolumab or Pembrolizumab. Diagnosis may be challenging in the setting of occult presentation with normal EKG and physical exam as well as delayed onset from therapy initiation. ICI-associated pericardial disease demonstrates high morbidity and mortality, as evidenced by a majority of patients requiring pericardiocentesis.