Slower pace in early walking onset is related to communication, motor skills, and adaptive function in autistic toddlers.

The onset of walking is a major developmental milestone in early childhood and is critical to the development of language and social communication. Delays in walking have been described in individuals with ASD. Yet, less is known about the quality of early gait development in toddlers with ASD and the relationship to motor skills, social communication, and language. Quantitative measures of locomotion can improve our ability to evaluate subtle and specific motor differences in toddlers with ASD and their relationship to other developmental domains. We used quantitative gait analysis to evaluate locomotion in toddlers with ASD (n = 51) and compared these data to a reference chronological aged (CA) and mental aged (MA) matched typically developing (TD) cohort (n = 45). We also examined the relationship of quantitative gait metrics to developmental measures among toddlers with ASD. We found that although toddlers with ASD achieved a typical age range of walking onset, they exhibited a pattern of slower pace compared to the TD cohort when matched by CA and MA. We also found that slower measures of pace were associated with lower developmental scores of communication, motor skills, and adaptive function. Our findings improve characterization of locomotion in toddlers with ASD and the relationship of motor skills to other developmental domains.

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.

Characterization of Tumor-immune Microenvironment by High-throughput Image Analysis of CD8 Immunohistochemistry Combined With Modified Masson's Trichrome.

With the advent of checkpoint inhibitors, there is increasing need to study the dynamics of CD8+ T-cells in the tumor microenviroment. In this article, we describe a semi-automated method to quantify and interrogate spatial relationships between T-cells and collagenous stroma in human and mouse tissue samples. The assay combines CD8 immunohistochemistry with modified Masson's trichrome. Slides are scanned and digital images are analyzed using an adjustable MATLAB algorithm, allowing for high-throughput quantification of cytotoxic T-cells and collagen. This method provides a flexible tool for unbiased quantification of T-cells and their interactions with tumor cells and tumor microenvironment in tissue samples.

Building a best-in-class automated de-identification tool for electronic health records through ensemble learning.

The presence of personally identifiable information (PII) in natural language portions of electronic health records (EHRs) constrains their broad reuse. Despite continuous improvements in automated detection of PII, residual identifiers require manual validation and correction. Here, we describe an automated de-identification system that employs an ensemble architecture, incorporating attention-based deep-learning models and rule-based methods, supported by heuristics for detecting PII in EHR data. Detected identifiers are then transformed into plausible, though fictional, surrogates to further obfuscate any leaked identifier. Our approach outperforms existing tools, with a recall of 0.992 and precision of 0.979 on the i2b2 2014 dataset and a recall of 0.994 and precision of 0.967 on a dataset of 10,000 notes from the Mayo Clinic. The de-identification system presented here enables the generation of de-identified patient data at the scale required for modern machine-learning applications to help accelerate medical discoveries.

Use of a Standardized Tool to Identify Women at Risk for Hereditary Breast and Ovarian.

OBJECTIVE: To increase rates of identification and genetic counseling referral for women at risk of hereditary breast and ovarian cancer (HBOC). DESIGN: Evidence-based practice improvement initiative. SETTING/LOCAL PROBLEM: Private suburban obstetric and gynecologic (OB/GYN) practice in Tennessee with no standardized process for HBOC risk assessment or referral to genetic services. PARTICIPANTS: Provider-led women's health care teams delivering well-woman care for women ages 18 years and older. INTERVENTION/MEASUREMENTS: We implemented the use of a standardized familial risk assessment tool and clinical decision-making algorithm. Preimplementation and postimplementation risk identification and genetic services referral rates were measured, as was clinicians' compliance with using the risk assessment tool. The aim of the initiative was to increase identification and referral rates by 25 percentage points. RESULTS: Women at risk of HBOC in the postimplementation group were 25.9 times more likely to be identified as being at risk (OR = 25.88, 95% confidence interval [10.78, 62.14]) and 31.5 times more likely to be offered referral to genetic counseling (OR = 31.50, 95% CI [13.37, 74.22]) compared with those in the preimplementation group. Rates of risk identification and referral to genetic counseling for women at risk of HBOC improved by 58.2 and 69.3 percentage points, respectively, surpassing the aims of this initiative and showing statistical significance of p < .001 for both indices. CONCLUSION: The use of a standardized risk assessment tool and process for HBOC risk identification and genetic referral resulted in a significant increase in the identification and referral of women at risk in this setting. Early identification of women with HBOC is a crucial first step in increasing the use of enhanced screening and interventions that can reduce HBOC-associated cancer morbidity and mortality.

Safety and efficacy of (+)-epicatechin in subjects with Friedreich's ataxia: A phase II, open-label, prospective study.

BACKGROUND: (+)-Epicatechin (EPI) induces mitochondrial biogenesis and antioxidant metabolism in muscle fibers and neurons. We aimed to evaluate safety and efficacy of (+)-EPI in pediatric subjects with Friedreich's ataxia (FRDA). METHODS: This was a phase II, open-label, baseline-controlled single-center trial including 10 participants ages 10 to 22 with confirmed FA diagnosis. (+)-EPI was administered orally at 75 mg/d for 24 weeks, with escalation to 150 mg/d at 12 weeks for subjects not showing improvement of neuromuscular, neurological or cardiac endpoints. Neurological endpoints were change from baseline in Friedreich's Ataxia Rating Scale (FARS) and 8-m timed walk. Cardiac endpoints were changes from baseline in left ventricular (LV) structure and function by cardiac magnetic resonance imaging (MRI) and echocardiogram, changes in cardiac electrophysiology, and changes in biomarkers for heart failure and hypertrophy. RESULTS: Mean FARS/modified (m)FARS scores showed nonstatistically significant improvement by both group and individual analysis. FARS/mFARS scores improved in 5/9 subjects (56%), 8-m walk in 3/9 (33%), 9-peg hole test in 6/10 (60%). LV mass index by cardiac MRI was significantly reduced at 12 weeks (P = .045), and was improved in 7/10 (70%) subjects at 24 weeks. Mean LV ejection fraction was increased at 24 weeks (P = .008) compared to baseline. Mean maximal septal thickness by echocardiography was increased at 24 weeks (P = .031). There were no serious adverse events. CONCLUSION: (+)-EPI was well tolerated over 24 weeks at up to 150 mg/d. Improvement was observed in cardiac structure and function in subset of subjects with FRDA without statistically significant improvement in primary neurological outcomes. SYNOPSIS: A (+)-epicatechin showed improvement of cardiac function, nonsignificant reduction of FARS/mFARS scores, and sustained significant upregulation of muscle-regeneration biomarker follistatin.

"Decompression of tension pneumothorax in a trauma patient -first use of a novel decompression colorimetric capnography device in human patient".

Tension pneumothorax is a common cause of mortality in trauma. Tension pneumothorax is the confinement of respired gases within the pleural cavity at increasing pressure resulting in hemodynamic collapse. Decompression is crucial in management. Emergency needle thoracostomy is a life-saving maneuver that allows atmospheric pressure equilibration and partial restoration of cardiac filling. Needle decompressions are usually performed under noisy, tense, and stressful circumstances, and objective assessment of success is difficult in the field. A device which is simple that objectively informs operators of successful decompression would be clinically useful. In previous work, we have demonstrated end-expiratory gas and gaseous composition of tension pneumothorax are similar due to increased carbon dioxide partial pressure relative to atmospheric gas composition. Therefore, a simple solution to objective needle decompression may be colorimetric capnography.We report a case of 58-year-old male treated by EMS following a motorcycle accident with left-sided chest pain, hypoxia, hypotension, and clinical findings of tension pneumothorax. Needle decompression with colorimetric capnography using the device indicated decompression of his tension pneumothorax, with appropriate temporizing success.

Human Cancers Express TRAILshort, a Dominant Negative TRAIL Splice Variant, Which Impairs Immune Effector Cell Killing of Tumor Cells.

PURPOSE: TNF-related apoptosis inducing ligand (TRAIL) expression by immune cells contributes to antitumor immunity. A naturally occurring splice variant of TRAIL, called TRAILshort, antagonizes TRAIL-dependent cell killing. It is unknown whether tumor cells express TRAILshort and if it impacts antitumor immunity. EXPERIMENTAL DESIGN: We used an unbiased informatics approach to identify TRAILshort expression in primary human cancers, and validated those results with IHC and ISH. TRAILshort-specific mAbs were used to determine the effect of TRAILshort on tumor cell sensitivity to TRAIL, and to immune effector cell dependent killing of autologous primary tumors. RESULTS: As many as 40% of primary human tumors express TRAILshort by both RNA sequencing and IHC analysis. By ISH, TRAILshort expression is present in tumor cells and not bystander cells. TRAILshort inhibition enhances cancer cell lines sensitivity to TRAIL-dependent killing both in vitro and in immunodeficient xenograft mouse models. Immune effector cells isolated from patients with B-cell malignancies killed more autologous tumor cells in the presence compared with the absence of TRAILshort antibody (P < 0.05). CONCLUSIONS: These results identify TRAILshort in primary human malignancies, and suggest that TRAILshort blockade can augment the effector function of autologous immune effector cells.See related commentary by de Miguel and Pardo, p. 5546.

The Tumor Suppressor BAP1 Regulates the Hippo Pathway in Pancreatic Ductal Adenocarcinoma.

The deubiquitinating enzyme BAP1 is mutated in a hereditary cancer syndrome with a high risk for mesothelioma and melanocytic tumors. Here, we show that pancreatic intraepithelial neoplasia driven by oncogenic mutant KrasG12D progressed to pancreatic adenocarcinoma in the absence of BAP1. The Hippo pathway was deregulated in BAP1-deficient pancreatic tumors, with the tumor suppressor LATS exhibiting enhanced ubiquitin-dependent proteasomal degradation. Therefore, BAP1 may limit tumor progression by stabilizing LATS and thereby promoting activity of the Hippo tumor suppressor pathway. SIGNIFICANCE: BAP1 is mutated in a broad spectrum of tumors. Pancreatic Bap1 deficiency causes acinar atrophy but combines with oncogenic Ras to produce pancreatic tumors. BAP1-deficient tumors exhibit deregulation of the Hippo pathway.See related commentary by Brekken, p. 1624.

Comparison of Mortality and Major Cardiovascular Events Among Adults With Type 2 Diabetes Using Human vs Analogue Insulins.

Importance: The comparative cardiovascular safety of analogue and human insulins in adults with type 2 diabetes who initiate insulin therapy in usual care settings has not been carefully evaluated using machine learning and other rigorous analytic methods. Objective: To examine the association of analogue vs human insulin use with mortality and major cardiovascular events. Design, Setting, and Participants: This retrospective cohort study included 127 600 adults aged 21 to 89 years with type 2 diabetes at 4 health care delivery systems who initiated insulin therapy from January 1, 2000, through December 31, 2013. Machine learning and rigorous inference methods with time-varying exposures were used to evaluate associations of continuous exposure to analogue vs human insulins with mortality and major cardiovascular events. Data were analyzed from September 1, 2017, through June 30, 2018. Exposures: On the index date (first insulin dispensing), participants were classified as using analogue insulin with or without human insulin or human insulin only. Main Outcomes and Measures: Overall mortality, mortality due to cardiovascular disease (CVD), myocardial infarction (MI), stroke or cerebrovascular accident (CVA), and hospitalization for congestive heart failure (CHF) were evaluated. Marginal structural modeling (MSM) with inverse probability weighting was used to compare event-free survival in separate per-protocol analyses. Adjusted and unadjusted hazard ratios and cumulative risk differences were based on logistic MSM parameterizations for counterfactual hazards. Propensity scores were estimated using a data-adaptive approach (machine learning) based on 3 nested covariate adjustment sets. Sensitivity analyses were conducted to address potential residual confounding from unmeasured differences in risk factors across delivery systems. Results: The 127 600 participants (mean [SD] age, 59.4 [12.6] years; 68 588 men [53.8%]; mean [SD] body mass index, 32.3 [7.1]) had a median follow-up of 4 quarters (interquartile range, 3-9 quarters) and experienced 5464 deaths overall (4.3%), 1729 MIs (1.4%), 1301 CVAs (1.0%), and 3082 CHF hospitalizations (2.4%). There were no differences in adjusted hazard ratios for continuous analogue vs human insulin exposure during 10 quarters for overall mortality (1.15; 95% CI, 0.97-1.34), CVD mortality (1.26; 95% CI, 0.86-1.66), MI (1.11; 95% CI, 0.77-1.45), CVA (1.30; 95% CI, 0.81-1.78), or CHF hospitalization (0.93; 95% CI, 0.75-1.11). Conclusions and Relevance: Insulin-naive adults with type 2 diabetes who initiate and continue treatment with human vs analogue insulins had similar observed rates of major cardiovascular events, CVD mortality, and overall mortality.

Therapeutic resistance and susceptibility is shaped by cooperative multi-compartment tumor adaptation.

Emerging research suggests that multiple tumor compartments can influence treatment responsiveness and relapse, yet the search for therapeutic resistance mechanisms remains largely focused on acquired genomic alterations in cancer cells. Here we show how treatment-induced changes occur in multiple tumor compartments during tumor relapse and can reduce benefit of follow-on therapies. By using serial biopsies, next-generation sequencing, and single-cell transcriptomics, we tracked the evolution of multiple cellular compartments within individual lesions during first-line treatment response, relapse, and second-line therapeutic interventions in an autochthonous model of melanoma. We discovered that although treatment-relapsed tumors remained genetically stable, they converged on a shared resistance phenotype characterized by dramatic changes in tumor cell differentiation state, immune infiltration, and extracellular matrix (ECM) composition. Similar alterations in tumor cell differentiation were also observed in more than half of our treatment-relapsed patient tumors. Tumor cell-state changes were coincident with ECM remodeling and increased tumor stiffness, which alone was sufficient to alter tumor cell fate and reduce treatment responses in melanoma cell lines in vitro. Despite the absence of acquired mutations in the targeted pathway, resistant tumors showed significantly decreased responsiveness to second-line therapy intervention within the same pathway. The ability to preclinically model relapse and refractory settings-while capturing dynamics within and crosstalk between all relevant tumor compartments-provides a unique opportunity to better design and sequence appropriate clinical interventions.

Translation to Practice: Accelerating the Cycle of Innovation to Impact.

The Office of Translation to Practice (OTP) is housed in the Center for Clinical and Translational Sciences at Mayo Clinic. Established in 2015, the office was tasked with developing and managing novel tools, mechanisms, and processes to facilitate and accelerate the translation of products, such as drugs, biological agents, and medical devices, into practice. Since its inception, the OTP is credited with creating valuable services through several strategic alliances and active scientific and project management involvement. The OTP continues to move forward to assist Mayo Clinic physicians and scientists to interact effectively with internal and external collaborators to advance translational projects that will benefit patients. Best practices, innovations, and nascent successes of the OTP are presented and discussed herein.

Characterization of functional brain connectivity towards optimization of music selection for therapy: a fMRI study.

Background: Music therapy, a nontraditional approach to patient care, has long been used to achieve a wide variety of positive results. To deepen our understanding of the connection and therapeutic potential of music, the effect of music therapy and music medicine (music administered to individuals without an interactive therapeutic relationship) on the brain remains a topic of active research. Objective: This study is aimed at investigating the effect of different music genres and individualized music selection on brain functional connectivity (FC) measured by functional magnetic resonance imaging (fMRI). Methods: Twelve healthy subjects listened to five excerpts: Bach with and without visual guide (unfamiliar), self-selected familiar music, Gagaku (unfamiliar music) and Chaplin (spoken word) while undergoing a block design fMRI study. fMRI datasets were imported into CONN (Matlab toolbox) and graph networks were created for 132 anatomical regions in MNI space. Group connectivity for each soundtrack was quantified and statistically analyzed using the R package. Results: Complex interactions between brain regions, cerebellar regions (713), superior frontal gyrus (178) and parahippocampus (223), were highest for self-selected music. Brain regions involving sound processing, memory retrieval, semantic processing and motor areas were continuously activated for all five excerpts; however, most connections were formed in language processing regions for the Bach excerpt. Conclusion: Functional brain connectivity varied by soundtrack with the largest degree of connectivity found consistently for self-selected and unfamiliar (Bach, Gagaku) music. Incorporating individualized music listening into existing therapy paradigms may positively contribute to standard protocol for stroke rehabilitation and prevention.

Micro-CT imaging and structural analysis of glomeruli in a model of Adriamycin-induced nephropathy.

Glomeruli number and size are important for determining the pathogenesis of glomerular disease, chronic kidney disease, and hypertension. Moreover, renal injury can occur in specific cortical layers and alter glomerular spatial distribution. In this study, we present a comprehensive structural analysis of glomeruli in a model of Adriamycin (doxorubicin) nephropathy. Glomeruli are imaged (micro-CT at 10 × 10 × 10 µm3) in kidney specimens from C57Bl/6 mouse cohorts: control treated with saline ( n = 9) and Adriamycin treated with 20 mg/kg Adriamycin ( n = 7). Several indices were examined, including glomerular number, glomerular volume, glomerular volume heterogeneity, and spatial density at each glomerulus and in each cortical layer (superficial, midcortical, and juxtamedullary). In the Adriamycin-treated animals, glomerular number decreased significantly in the left kidney [control: 8,298 ± 221, Adriamycin: 6,781 ± 630 (mean ± SE)] and right kidney (control: 7,317 ± 367, Adriamycin: 5,522 ± 508), and glomerular volume heterogeneity increased significantly in the left kidney (control: 0.642 ± 0.015, Adriamycin: 0.786 ± 0.018) and right kidney (control: 0.739 ± 0.016, Adriamycin: 0.937 ± 0.023). Glomerular spatial density was not affected. Glomerular volume heterogeneity increased significantly in the superficial and midcortical layers of the Adriamycin cohort. Adriamycin did not affect glomerular volume or density metrics in the juxtamedullary region, suggesting a compensatory mechanism of juxtamedullary glomeruli to injury in the outer cortical layers. Left/right asymmetry was observed in kidney size and various glomeruli metrics. The methods presented here can be used to evaluate renal disease models with subtle changes in glomerular endowment locally or across the entire kidney, and they provide an imaging tool to investigate diverse interventions and therapeutic drugs.

AlphaE Integrin Expression Is Increased in the Ileum Relative to the Colon and Unaffected by Inflammation.

BACKGROUND: Recent findings suggest that αE expression is enriched on effector T cells and that intestinal αE+ T cells have increased expression of inflammatory cytokines. αE integrin expression is a potential predictive biomarker for response to etrolizumab, a monoclonal antibody against ß7 integrin that targets both α4ß7 and αEß7. We evaluated the prevalence and localization of αE+ cells as well as total αE gene expression in healthy and inflammatory bowel disease patients. METHODS: αE+ cells were identified in ileal and colonic biopsies by immunohistochemistry and counted using an automated algorithm. Gene expression was assessed by quantitative reverse-transcriptase polymerase chain reaction. RESULTS: In both healthy and inflammatory bowel disease patients, significantly more αE+ cells were present in the epithelium and lamina propria of ileal compared with colonic biopsies. αE gene expression levels were also significantly higher in ileal compared with colonic biopsies. Paired biopsies from the same patient showed moderate correlation of αE expression between the ileum and colon. Inflammation did not affect αE expression, and neither endoscopy nor histology scores correlated with αE gene expression. αE expression was not different between patients based on concomitant medication use except 5-aminosalicylic acid. CONCLUSION: αE+ cells, which have been shown to have inflammatory potential, are increased in the ileum in comparison with the colon in both Crohn's disease and ulcerative colitis, as well as in healthy subjects. In inflammatory bowel disease patients, αE levels are stable, regardless of inflammatory status or most concomitant medications, which could support its use as a biomarker for etrolizumab.

Functional MRI connectivity of children with autism and low verbal and cognitive performance.

Background: Functional neuroimaging research in autism spectrum disorder has reported patterns of decreased long-range, within-network, and interhemispheric connectivity. Research has also reported increased corticostriatal connectivity and between-network connectivity for default and attentional networks. Past studies have excluded individuals with autism and low verbal and cognitive performance (LVCP), so connectivity in individuals more significantly affected with autism has not yet been studied. This represents a critical gap in our understanding of brain function across the autism spectrum. Methods: Using behavioral support procedures adapted from Nordahl, et al. (J Neurodev Disord 8:20-20, 2016), we completed non-sedated structural and functional MRI scans of 56 children ages 7-17, including LVCP children (n = 17, mean IQ = 54), children with autism and higher performance (HVCP, n = 20, mean IQ = 106), and neurotypical children (NT, n = 19, mean IQ = 111). Preparation included detailed intake questionnaires, video modeling, behavioral and anxiety reduction techniques, active noise-canceling headphones, and in-scan presentation of the Inscapes movie paradigm from Vanderwal et al. (Neuroimage 122:222-32, 2015). A high temporal resolution multiband echoplanar fMRI protocol analyzed motion-free time series data, extracted from concatenated volumes to mitigate the influence of motion artifact. All participants had > 200 volumes of motion-free fMRI scanning. Analyses were corrected for multiple comparisons. Results: LVCP showed decreased within-network connectivity in default, salience, auditory, and frontoparietal networks (LVCP < HVCP) and decreased interhemispheric connectivity (LVCP < HVCP=NT). Between-network connectivity was higher for LVCP than NT between default and dorsal attention and frontoparietal networks. Lower IQ was associated with decreased connectivity within the default network and increased connectivity between default and dorsal attention networks. Conclusions: This study demonstrates that with moderate levels of support, including readily available techniques, information about brain similarities and differences in LVCP individuals can be further studied. This initial study suggested decreased network segmentation and integration in LVCP individuals. Further imaging studies of LVCP individuals with larger samples will add to understanding of origins and effects of autism on brain function and behavior.

Both HIV-Infected and Uninfected Cells Express TRAILshort, Which Confers TRAIL Resistance upon Bystander Cells within the Microenvironment.

TNF-related apoptosis-inducing ligand (TRAIL) was initially described to induce apoptosis of tumor cells and/or virally infected cells, although sparing normal cells, and has been implicated in the pathogenesis of HIV disease. We previously identified TRAILshort, a TRAIL splice variant, in HIV-infected patients and characterized it as being a dominant negative ligand to subvert TRAIL-mediated killing. Herein, using single-cell genomics we demonstrate that TRAILshort is produced by HIV-infected cells, as well as by uninfected bystander cells, and that the dominant stimulus which induces TRAILshort production are type I IFNs and TLR7, TLR8, and TLR9 agonists. TRAILshort has a short t1/2 by virtue of containing a PEST domain, which targets the protein toward the ubiquitin proteasome pathway for degradation. Further we show that TRAILshort binds preferentially to TRAIL receptors 1 and 2 with significantly reduced interaction with the decoy TRAIL receptors 3 and 4. Recombinant TRAILshort is sufficient to protect cells against TRAIL-induced killing, whereas immunodepletion of TRAILshort with a specific Ab restores TRAIL sensitivity. Importantly we show that TRAILshort is shed in microvesicles into the cellular microenvironment and therefore confers TRAIL resistance not only on the cell which produces it, but also upon neighboring bystander cells. These results establish a novel paradigm for understanding and overcoming TRAIL resistance, in particular how HIV-infected cells escape immune elimination by the TRAIL:TRAILshort receptor axis.

Clinical management of pressure control ventilation: An algorithmic method of patient ventilatory management to address "forgotten but important variables".

Pressure controlled ventilation is a common mode of ventilation used to manage both adult and pediatric populations. However, there is very little evidence that distinguishes the efficacy of pressure controlled ventilation over that of volume controlled ventilation in the adult population. This gap in the literature may be due to the absence of a consistent and systematic algorithm for managing pressure controlled ventilation. This article provides a brief overview of the applications of both pressure controlled ventilation and volume controlled ventilation and proposes an algorithmic approach to the management of patients receiving pressure controlled ventilation. This algorithmic approach highlights the need for clinicians to have a comprehensive conceptual understanding of mechanical ventilation, pulmonary physiology, and interpretation of ventilator graphics in order to best care for patients receiving pressure controlled ventilation. The objective of identifying a systematic approach to managing pressure controlled ventilation is to provide a more generalizable and equitable approach to management of the ICU patient. Ideally, a consistent approach to managing pressure controlled ventilation in the adult population will glean more reliable information regarding actual patient outcomes, as well as the efficacy of pressure controlled ventilation when compared to volume controlled ventilation.

Longitudinal development of thalamic and internal capsule microstructure in autism spectrum disorder.

The thalamus is a key sensorimotor relay area that is implicated in autism spectrum disorder (ASD). However, it is unknown how the thalamus and white-matter structures that contain thalamo-cortical fiber connections (e.g., the internal capsule) develop from childhood into adulthood and whether this microstructure relates to basic motor challenges in ASD. We used diffusion weighted imaging in a cohort-sequential design to assess longitudinal development of the thalamus, and posterior- and anterior-limbs of the internal capsule (PLIC and ALIC, respectively) in 89 males with ASD and 56 males with typical development (3-41 years; all verbal). Our results showed that the group with ASD exhibited different developmental trajectories of microstructure in all regions, demonstrating childhood group differences that appeared to approach and, in some cases, surpass the typically developing group in adolescence and adulthood. The PLIC (but not ALIC nor thalamus) mediated the relation between age and finger-tapping speed in both groups. Yet, the gap in finger-tapping speed appeared to widen at the same time that the between-group gap in the PLIC appeared to narrow. Overall, these results suggest that childhood group differences in microstructure of the thalamus and PLIC become less robust in adolescence and adulthood. Further, finger-tapping speed appears to be mediated by the PLIC in both groups, but group differences in motor speed that widen during adolescence and adulthood suggest that factors beyond the microstructure of the thalamus and internal capsule may contribute to atypical motor profiles in ASD. Autism Res 2018, 11: 450-462. © 2017 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Microstructure of the thalamus, a key sensory and motor brain area, appears to develop differently in individuals with autism spectrum disorder (ASD). Microstructure is important because it informs us of the density and organization of different brain tissues. During childhood, thalamic microstructure was distinct in the ASD group compared to the typically developing group. However, these group differences appeared to narrow with age, suggesting that the thalamus continues to dynamically change in ASD into adulthood.