Reduced lateralization of multiple functional brain networks in autistic males.

BACKGROUND: Autism spectrum disorder has been linked to a variety of organizational and developmental deviations in the brain. One such organizational difference involves hemispheric lateralization, which may be localized to language-relevant regions of the brain or distributed more broadly. METHODS: In the present study, we estimated brain hemispheric lateralization in autism based on each participant's unique functional neuroanatomy rather than relying on group-averaged data. Additionally, we explored potential relationships between the lateralization of the language network and behavioral phenotypes including verbal ability, language delay, and autism symptom severity. We hypothesized that differences in hemispheric asymmetries in autism would be limited to the language network, with the alternative hypothesis of pervasive differences in lateralization. We tested this and other hypotheses by employing a cross-sectional dataset of 118 individuals (48 autistic, 70 neurotypical). Using resting-state fMRI, we generated individual network parcellations and estimated network asymmetries using a surface area-based approach. A series of multiple regressions were then used to compare network asymmetries for eight significantly lateralized networks between groups. RESULTS: We found significant group differences in lateralization for the left-lateralized Language (d = -0.89), right-lateralized Salience/Ventral Attention-A (d = 0.55), and right-lateralized Control-B (d = 0.51) networks, with the direction of these group differences indicating less asymmetry in autistic males. These differences were robust across different datasets from the same participants. Furthermore, we found that language delay stratified language lateralization, with the greatest group differences in language lateralization occurring between autistic males with language delay and neurotypical individuals. CONCLUSIONS: These findings evidence a complex pattern of functional lateralization differences in autism, extending beyond the Language network to the Salience/Ventral Attention-A and Control-B networks, yet not encompassing all networks, indicating a selective divergence rather than a pervasive one. Moreover, we observed an association between Language network lateralization and language delay in autistic males.

Obesity is associated with a higher incidence of rejection in patients on belatacept: A pooled analysis from the BENEFIT/BENEFIT-EXT clinical trials.

Though belatacept is administered with a weight-based dosing schema, there has been higher clearance reported in obese patients. Therefore, we evaluated the association between body mass index (BMI) and transplant outcomes in kidney transplant recipients who were randomized to cyclosporine- or belatacept-based immunosuppression in the BENEFIT and BENEFIT-EXT randomized clinical trials. A total of 666 and 543 patients underwent randomization and transplantation in BENEFIT and BENEFIT-EXT, respectively, of which 1056 had complete data and were included in this analysis. Patients were grouped categorically according to BMI: <25, 25 to <30, and ≥30 kg/m2. BMI did influence both the incidence and severity of acute rejection. Obese patients with BMI >30 kg/m2 in the low intensity belatacept group experienced significantly more rejection at 12 months than did patients with BMI <25 kg/m2 or BMI 25 to <30 kg/m2. In both the moderate intensity belatacept and low intensity belatacept groups, obese patients with BMI >30 kg/m2 experienced significantly more severe acute rejection than did patients with BMI < 25 kg/m2 or BMI 25 to <30 kg/m2. These results suggest that obese kidney transplant recipients are at an increased risk for acute rejection when under belatacept-based immunosuppression when compared to nonobese patients.

Tract- and gray matter- based spatial statistics show white matter and gray matter microstructural differences in autistic males.

Background: Autism spectrum disorder (ASD) is a neurodevelopmental condition commonly studied in the context of early childhood. As ASD is a life-long condition, understanding the characteristics of brain microstructure from adolescence into adulthood and associations to clinical features is critical for improving outcomes across the lifespan. In the current work, we utilized Tract Based Spatial Statistics (TBSS) and Gray Matter Based Spatial Statistics (GBSS) to examine the white matter (WM) and gray matter (GM) microstructure in neurotypical (NT) and autistic males. Methods: Multi-shell diffusion MRI was acquired from 78 autistic and 81 NT males (12-to-46-years) and fit to the DTI and NODDI diffusion models. TBSS and GBSS were performed to analyze WM and GM microstructure, respectively. General linear models were used to investigate group and age-related group differences. Within the ASD group, relationships between WM and GM microstructure and measures of autistic symptoms were investigated. Results: All dMRI measures were significantly associated with age across WM and GM. Significant group differences were observed across WM and GM. No significant age-by-group interactions were detected. Within the ASD group, positive relationships with WM microstructure were observed with ADOS-2 Calibrated Severity Scores. Conclusion: Using TBSS and GBSS our findings provide new insights into group differences of WM and GM microstructure in autistic males from adolescence into adulthood. Detection of microstructural differences across the lifespan as well as their relationship to the level of autistic symptoms will deepen to our understanding of brain-behavior relationships of ASD and may aid in the improvement of intervention options for autistic adults.

Elevated posaconazole trough concentrations are not associated with increased risk for posaconazole toxicity in lung transplant recipients.

OBJECTIVE: Posaconazole is used for prophylaxis and treatment of invasive fungal infections in lung transplant recipients (LTR). Previous studies have not described the relationship between elevated posaconazole trough concentrations and adverse drug reactions in this population. METHODS: This IRB-approved, retrospective cohort study at NewYork-Presbyterian Hospital included LTR who had posaconazole trough concentrations measured. The primary aim of this study was to evaluate elevated posaconazole trough concentrations and changes in liver function tests as well as QTc interval. A secondary aim of this study was to identify patient factors associated with elevated posaconazole trough levels. RESULTS: A total of 109 LTR were included. The average age was 58.1 years (IQR, 48-65), the majority were male (56%). A total of 932 trough levels were assessed with a median number of 8 (IQR, 5-15) levels per patient. The median posaconazole trough concentration was 1.7 mg/L (IQR, 1.1-2.5). Hepatotoxicity, as defined by common terminology criteria for adverse events (CTCAE), was observed in 73.4% of subjects, with the majority classified as grade 1 (67.5%). However, there was no correlation between elevated posaconazole levels and aspartate aminotransferase (r = .03), alanine aminotransferase (r = .04), alkaline phosphatase (r = .04), and total bilirubin (r = .02). There was also no correlation between posaconazole trough concentrations and QTc interval (r = .03). CONCLUSION: This analysis demonstrates that no correlation exists between whole blood posaconazole levels and hepatotoxicity or QTc prolongation. Based on these results, posaconazole dose reductions may not be warranted for posaconazole levels that are significantly above the therapeutic target to avert risk for hepatotoxicity or QTc prolongation.

Reduced Lateralization of Multiple Functional Brain Networks in Autistic Males.

Background: Autism spectrum disorder has been linked to a variety of organizational and developmental deviations in the brain. One such organizational difference involves hemispheric lateralization, which may be localized to language-relevant regions of the brain or distributed more broadly. Methods: In the present study, we estimated brain hemispheric lateralization in autism based on each participant's unique functional neuroanatomy rather than relying on group-averaged data. Additionally, we explored potential relationships between the lateralization of the language network and behavioral phenotypes including verbal ability, language delay, and autism symptom severity. We hypothesized that differences in hemispheric asymmetries in autism would be limited to the language network, with the alternative hypothesis of pervasive differences in lateralization. We tested this and other hypotheses by employing a cross-sectional dataset of 118 individuals (48 autistic, 70 neurotypical). Using resting-state fMRI, we generated individual network parcellations and estimated network asymmetries using a surface area-based approach. A series of multiple regressions were then used to compare network asymmetries for eight significantly lateralized networks between groups. Results: We found significant group differences in lateralization for the left-lateralized Language (d = -0.89), right-lateralized Salience/Ventral Attention-A (d = 0.55), and right-lateralized Control-B (d = 0.51) networks, with the direction of these group differences indicating less asymmetry in autistic individuals. These differences were robust across different datasets from the same participants. Furthermore, we found that language delay stratified language lateralization, with the greatest group differences in language lateralization occurring between autistic individuals with language delay and neurotypical individuals. Limitations: The generalizability of our findings is restricted due to the male-only sample and greater representation of individuals with high verbal and cognitive performance. Conclusions: These findings evidence a complex pattern of functional lateralization differences in autism, extending beyond the Language network to the Salience/Ventral Attention-A and Control-B networks, yet not encompassing all networks, indicating a selective divergence rather than a pervasive one. Furthermore, a differential relationship was identified between Language network lateralization and specific symptom profiles (namely, language delay) of autism.

Test-retest reliability of FreeSurfer-derived volume, area and cortical thickness from MPRAGE and MP2RAGE brain MRI images.

Background and purpose: Large MRI studies often pool data gathered from widely varying imaging sequences. Pooled data creates a potential source of variation in structural analyses which may cause misinterpretation of findings. The purpose of this study is to determine if data acquired using different scan sequences, head coils and scanners offers consistent structural measurements. Materials and methods: Participants (163 right-handed males: 82 typically developing controls, 81 participants with autism spectrum disorder) were scanned on the same day using an MPRAGE sequence with a 12-channel headcoil on a Siemens 3T Trio scanner and an MP2RAGE sequence with a 64-channel headcoil on a Siemens 3T Prisma scanner. Segmentation was performed using FreeSurfer to identify regions exhibiting variation between sequences on measures of volume, surface area, and cortical thickness. Intraclass correlation coefficient (ICC) and mean percent difference (MPD) were used as test-retest reproducibility measures. Results: ICC for total brain segmented volume yielded a 0.99 intraclass correlation, demonstrating high overall volumetric reproducibility. Comparison of individual regions of interest resulted in greater variation. Volumetric variability, although low overall, was greatest in the entorhinal cortex (ICC = 0.71), frontal (ICC = 0.60) and temporal (ICC = 0.60) poles. Surface area variability was greatest in the insula (ICC = 0.65), temporal (ICC = 0.64) and frontal (ICC = 0.68) poles. Cortical thickness was most variable in the frontal (ICC = 0.41) and temporal (ICC = 0.35) poles. Conclusion: Data collected on different scanners and head coils using MPRAGE and MP2RAGE are generally consistent for surface area and volume estimates. However, regional variability may constrain accuracy in some regions and cortical thickness measurements exhibit higher generalized variability.

COVID-19 therapeutics and outcomes among solid organ transplant recipients during the Omicron BA.1 era.

Treatment outcomes associated with the use of novel COVID-19 therapeutics in solid organ transplant recipients (SOTR) are not well described in the literature. The objective of this analysis was to characterize 30-day hospitalization and other key secondary endpoints experienced by outpatient SOTR with mild-moderate COVID-19 treated with nirmatrelvir/ritonavir (NR), sotrovimab, or no SARS-CoV-2 specific treatment. This IRB-approved, retrospective study included 154 SOTR with a documented positive SARS-CoV-2 infection between December 16, 2021 and January 19, 2022 (a predominant Omicron BA.1 period in New York City). Patients who received NR (N = 28) or sotrovimab (N = 51) experienced a lower rate of 30-day hospitalization or death as compared to those who received no specific treatment (N = 75) (p = .009). A total of three deaths occurred, all among patients who initially received no specific treatment prior to hospitalization. These results suggest a role for SARS-CoV-2 specific agents in the treatment of SOTR with COVID-19, and that there does not appear to be any difference in effectiveness when comparing NR versus sotrovimab.

Early clinical experience with nirmatrelvir/ritonavir for the treatment of COVID-19 in solid organ transplant recipients.

Nirmatrelvir/ritonavir (NR) use has not yet been described in solid organ transplant recipients (SOTRs) with mild COVID-19. The objective was to evaluate outcomes among SOTR and describe the drug-drug interaction of NR. This is an IRB-approved, retrospective study of all adult SOTR on a calcineurin inhibitor (CNI) or mammalian target of rapamycin inhibitor who were prescribed NR between December 28, 2021 and January 6, 2022. A total of 25 adult SOTR were included (n = 21 tacrolimus, n = 4 cyclosporine, n = 3 everolimus, n = 1 sirolimus). All patients were instructed to follow the following standardized protocol during treatment with 5 days of NR: hold tacrolimus or mTOR inhibitor or reduce cyclosporine dose to 20% of baseline daily dose. Four patients (16%) were hospitalized by day 30; one for infectious diarrhea and three for symptoms related to COVID-19. No patients died within 30 days of receipt of NR. Median tacrolimus level pre- and post-NR were 7.4 ng/ml (IQR, 6.6-8.6) and 5.2 (IQR, 3.6-8.7), respectively. Four patients experienced a supratherapeutic tacrolimus concentration after restarting tacrolimus post-NR. Our results show the clinically significant interaction between NR and immunosuppressive agents can be reasonably managed with a standardized dosing protocol. Prescribers should carefully re-introduce CNI after the NR course is complete.

Longitudinal Stability of Intellectual Functioning in Autism Spectrum Disorder: From Age 3 Through Mid-adulthood.

Intelligence (IQ) scores are used in educational and vocational planning for individuals with autism spectrum disorder (ASD) yet little is known about the stability of IQ throughout development. We examined longitudinal age-related IQ stability in 119 individuals with ASD (3-36 years of age at first visit) and 128 typically developing controls. Intelligence measures were collected over a 20-year period. In ASD, Full Scale (FSIQ) and Verbal (VIQ) Intelligence started lower in childhood and increased at a greater rate with age relative to the control group. By early adulthood, VIQ and working memory stabilized, whereas nonverbal and perceptual scores continued to change. Our results suggest that in individuals with ASD, IQ estimates may be dynamic in childhood and young adulthood.

Comparing weight-based dosing of tacrolimus XR in obese and non-obese renal transplant recipients.

The recommended initial weight-based dose of extended-release (XR) tacrolimus (Envarsus XR) in kidney transplant recipients (KTR) is 0.14 mg/kg/day. However, no data exist regarding dosing recommendations for obese patients specifically. The aim of this study was to evaluate weight-based dosing requirements in a cohort of obese KTR who were initiated on de novo tacrolimus XR post-transplantation. The primary outcome was weight-based dosing requirements (mg/kg/day) on post-operative day (POD) 7 and 14. Of the 254 KTR, 81 (31%) were obese. The median therapeutic dose on POD7 was 0.1 versus 0.12 vs. 0.14 mg/kg/day in the BMI > 30 kg/m2 , BMI 25-30 kg/m2 , and BMI < 25 kg/m2 , respectively, (p = .0001). This result was similar on POD14; median therapeutic dose was 0.09 versus 0.11 versus 0.15 mg/kg/day in the BMI > 30 kg/m2 , BMI 25-30 kg/m2 , and BMI < 25 kg/m2 , respectively, (p < .001). Therapeutic dose on POD7 and POD14 based on ideal body was similar in all cohorts (p = .238, p = .923, respectively). This finding was supported by a strong linear relationship between ideal body weight (IBW) and therapeutic dose (r = .929). In both obese and non-obese KTR, IBW had a stronger correlation with the therapeutic dose for tacrolimus XR.

Evidence for normal extra-axial cerebrospinal fluid volume in autistic males from middle childhood to adulthood.

Autism spectrum disorder has long been associated with a variety of organizational and developmental abnormalities in the brain. An increase in extra-axial cerebrospinal fluid volume in autistic individuals between the ages of 6 months and 4 years has been reported in recent studies. Increased extra-axial cerebrospinal fluid volume was predictive of the diagnosis and severity of the autistic symptoms in all of them, irrespective of genetic risk for developing the disorder. In the present study, we explored the trajectory of extra-axial cerebrospinal fluid volume from childhood to adulthood in both autism and typical development. We hypothesized that an elevated extra-axial cerebrospinal fluid volume would be found in autism persisting throughout the age range studied. We tested the hypothesis by employing an accelerated, multi-cohort longitudinal data set of 189 individuals (97 autistic, 92 typically developing). Each individual had been scanned between 1 and 5 times, with scanning sessions separated by 2-3 years, for a total of 439 T1-weighted MRI scans. A linear mixed-effects model was used to compare developmental, age-related changes in extra-axial cerebrospinal fluid volume between groups. Inconsistent with our hypothesis, we found no group differences in extra-axial cerebrospinal fluid volume in this cohort of individuals 3 to 42 years of age. Our results suggest that extra-axial cerebrospinal fluid volume in autistic individuals is not increased compared with controls beyond four years of age.

Less bleeding associated with apixaban versus other direct acting oral anticoagulation in solid organ transplant recipients.

BACKGROUND: The purpose of this study was to evaluate outcomes of bleeding and thrombosis resulting from the use of direct oral anticoagulants (DOACs) in a large cohort of solid organ transplant (SOT) recipients. METHODS: This was a single center, retrospective cohort study of adult kidney, heart, lung, and liver transplant recipients transplanted between August 2009 and May 2018. Patients were stratified into two groups: those who received apixaban (apixaban group) or those patients receiving either rivaroxaban or dabigatran (non-apixaban group). The primary endpoint was the cumulative incidence of bleeding while receiving DOAC therapy. The secondary endpoints were incidence of major bleeding and thrombosis at any time while receiving DOAC therapy. RESULTS: A total of 106 patients were included; 70 patients received apixaban and 36 patients received non-apixaban anticoagulation. Cumulative incidence of any bleeding was lower in the apixaban group compared to the non-apixaban group at both 90 days (4.9% vs. 16.1%) and 180 days (11.4% vs. 24.9%, P = .034). Cumulative incidence of major bleeding (P = .686) and thrombosis (P = .515) were similar between groups. DOAC dosing congruent with the package insert(s) was associated with a lower risk of thrombosis. CONCLUSION: Apixaban-based anticoagulation was associated with a lower cumulative incidence of any bleeding compared to non-apixaban DOACs.

A 16-year study of longitudinal volumetric brain development in males with autism.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder with unknown brain etiology. Our knowledge to date about structural brain development across the lifespan in ASD comes mainly from cross-sectional studies, thereby limiting our understanding of true age effects within individuals with the disorder that can only be gained through longitudinal research. The present study describes FreeSurfer-derived volumetric findings from a longitudinal dataset consisting of 607 T1-weighted magnetic resonance imaging (MRI) scans collected from 105 male individuals with ASD (349 MRIs) and 125 typically developing male controls (258 MRIs). Participants were six to forty-five years of age at their first scan, and were scanned up to 5 times over a period of 16 years (average inter-scan interval of 3.7 years). Atypical age-related volumetric trajectories in ASD included enlarged gray matter volume in early childhood that approached levels of the control group by late childhood, an age-related increase in ventricle volume resulting in enlarged ventricles by early adulthood and reduced corpus callosum age-related volumetric increase resulting in smaller corpus callosum volume in adulthood. Larger corpus callosum volume was related to a lower (better) ADOS score at the most recent study visit for the participants with ASD. These longitudinal findings expand our knowledge of volumetric brain-based abnormalities in males with ASD, and highlight the need to continue to examine brain structure across the lifespan and well into adulthood.

Explaining the association between repetition priming and source memory: No evidence for a contribution of recognition or fluency.

In a conjoint memory task (measuring repetition priming, recognition memory, and source memory), items recognised as previously studied and receiving correct source decisions also tend to show a greater magnitude of the repetition priming effect. These associations have been explained as arising from a single memory system or signal, rather than multiple distinct ones. In the present work, we examine whether the association between priming and source memory can alternatively be explained as being driven by recognition or fluency. We first reproduced the basic priming-source association (Experiment 1). In Experiments 2 and 3, we found that the association persisted even when the task was modified so that overt and covert recognition judgements were precluded. In Experiment 4, the association was again present even though fluency (as measured by identification response time) could not influence the source decision, although the association was notably weaker. These findings suggest that the association between priming and source memory is not attributable to a contribution of recognition or fluency; instead, the findings are consistent with a single-system account in which a common memory signal drives responding.