PD-1 and CTLA-4 exert additive control of effector regulatory T cells at homeostasis.

At homeostasis, a substantial proportion of Foxp3+ T regulatory cells (Tregs) have an activated phenotype associated with enhanced TCR signals and these effector Treg cells (eTregs) co-express elevated levels of PD-1 and CTLA-4. Short term in vivo blockade of the PD-1 or CTLA-4 pathways results in increased eTreg populations, while combination blockade of both pathways had an additive effect. Mechanistically, combination blockade resulted in a reduction of suppressive phospho-SHP2 Y580 in eTreg cells which was associated with increased proliferation, enhanced production of IL-10, and reduced dendritic cell and macrophage expression of CD80 and MHC-II. Thus, at homeostasis, PD-1 and CTLA-4 function additively to regulate eTreg function and the ability to target these pathways in Treg cells may be useful to modulate inflammation.

Recent Updates in Psychopharmacology for the Core and Associated Symptoms of Autism Spectrum Disorder.

PURPOSE OF REVIEW: Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by core deficits in social communication and restricted, repetitive patterns of behavior. This article aims to review the recent literature pertaining to psychopharmacology for the core and associated symptoms of ASD including social impairment, repetitive behaviors, irritability, and language impairment. RECENT FINDINGS: Recent medication trials targeting social impairment in ASD have focused on neuropeptides (oxytocin and vasopressin) and memantine. None of these three medications has demonstrated consistent benefit for social impairment in ASD; however, additional studies are underway. Two double-blind, placebo-controlled studies on selective serotonin reuptake inhibitors (SSRIs) provide evidence against the use of SSRIs for repetitive behaviors in youth with ASD. Preliminary studies have investigated cannabidiol (CBD) for irritability in ASD but further studies are needed to demonstrate safety and efficacy. Finally, three double-blind, placebo-controlled studies provide preliminary evidence for folinic acid for the treatment of verbal language deficits in children with ASD. The identification of safe and effective pharmacological treatments to ameliorate the core and associated symptoms of ASD has proven difficult.

Professional language use by alumni of the Harvard Medical School Medical Language Program.

BACKGROUND: Despite the growing number of patients with limited English proficiency in the United States, not all medical schools offer medical language courses to train future physicians in practicing language-concordant care. Little is known about the long-term use of non-English languages among physicians who took language courses in medical school. We conducted a cross-sectional study to characterize the professional language use of Harvard Medical School (HMS) alumni who took a medical language course at HMS and identify opportunities to improve the HMS Medical Language Program. METHODS: Between October and November 2019, we sent an electronic survey to 803 HMS alumni who took a medical language course at HMS between 1991 and 2019 and collected responses. The survey had questions about the language courses and language use in the professional setting. We analyzed the data using descriptive statistics and McNemar's test for comparing proportions with paired data. The study was determined not to constitute human subjects research. RESULTS: The response rate was 26% (206/803). More than half of respondents (n = 118, 57%) cited their desire to use the language in their future careers as the motivation for taking the language courses. Twenty-eight (14%) respondents indicated a change from not proficient before taking the course to proficient at the time of survey whereas only one (0.5%) respondent changed from proficient to not proficient (McNemar's p-value < 0.0001). Respondents (n = 113, 56%) reported that clinical electives abroad influenced their cultural understanding of the local in-country population and their language proficiency. Only 13% (n = 27) of respondents have worked in a setting that required formal assessments of non-English language proficiency. CONCLUSIONS: HMS alumni of the Medical Language Program reported improved language proficiency after the medical language courses' conclusion, suggesting that the courses may catalyze long-term language learning. We found that a majority of respondents reported that the medical language courses influenced their desire to work with individuals who spoke the language of the courses they took. Medical language courses may equip physicians to practice language-concordant care in their careers.

Characterization of sleep habits and medication outcomes for sleep disturbance in children and adults with Angelman syndrome.

The objectives of this study were to characterize the sleep habits of 50 clinically referred individuals with Angelman syndrome (AS) and to retrospectively compare the effectiveness/tolerability of the three most commonly prescribed sleep medications in the sample. An experienced physician assigned a Clinical Global Impressions-Severity scale (CGI-S) score for each subject's AS-specific symptoms. Caregivers completed the Child Sleep Habits Questionnaire (CSHQ; screen for sleep problems in school-aged [4-10 years] children), a screening assessment for sleep problems. Caregivers provided information about medication trials targeting disturbed sleep, with the physician assigning a CGI-Improvement scale (CGI-I) score for each trial. Linear regression showed significant negative association between age and CSHQ score. In their lifetime, 72% of participants had taken a medication for sleep, most commonly melatonin, clonidine and trazodone. The majority continued these for 6 months or longer. With these medications, many demonstrated significant improvement in sleep disturbances, with no difference in odds of improvement between medications. Disturbed sleep was common in this cohort and significantly worse in younger-aged participants. The majority received at least one medication trial for disturbed sleep and each of the most commonly prescribed medication was effective for a substantial percentage of participants. Most participants remained on medication for at least 6 months, suggesting favorable tolerability.

Evidence against the "normalization" prediction of the early brain overgrowth hypothesis of autism.

BACKGROUND: The frequently cited Early Overgrowth Hypothesis of autism spectrum disorder (ASD) postulates that there is overgrowth of the brain in the first 2 years of life, which is followed by a period of arrested growth leading to normalized brain volume in late childhood and beyond. While there is consistent evidence for early brain overgrowth, there is mixed evidence for normalization of brain volume by middle childhood. The outcome of this debate is important to understanding the etiology and neurodevelopmental trajectories of ASD. METHODS: Brain volume was examined in two very large single-site samples of children, adolescents, and adults. The primary sample comprised 456 6-25-year-olds (ASD n = 240, typically developing controls (TDC) n = 216), including a large number of females (n = 102) and spanning a wide IQ range (47-158). The replication sample included 175 males. High-resolution T1-weighted anatomical MRI images were examined for group differences in total brain, cerebellar, ventricular, gray, and white matter volumes. RESULTS: The ASD group had significantly larger total brain, cerebellar, gray matter, white matter, and lateral ventricular volumes in both samples, indicating that brain volume remains enlarged through young adulthood, rather than normalizing. There were no significant age or sex interactions with diagnosis in these measures. However, a significant diagnosis-by-IQ interaction was detected in the larger sample, such that increased brain volume was related to higher IQ in the TDCs, but not in the ASD group. Regions-of-significance analysis indicated that total brain volume was larger in ASD than TDC for individuals with IQ less than 115, providing a potential explanation for prior inconsistent brain size results. No relationships were found between brain volume and measures of autism symptom severity within the ASD group. LIMITATIONS: Our cross-sectional sample may not reflect individual changes over time in brain volume and cannot quantify potential changes in volume prior to age 6. CONCLUSIONS: These findings challenge the "normalization" prediction of the brain overgrowth hypothesis by demonstrating that brain enlargement persists across childhood into early adulthood. The findings raise questions about the clinical implications of brain enlargement, since we find that it neither confers cognitive benefits nor predicts increased symptom severity in ASD.