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Individuals with autism spectrum disorder (ASD) experience behavioral and emotional symptoms hypothesized to arise from "emotion dysregulation" (ED), difficulty modulating emotional experience, expression, and intensity in an acceptable and contextually appropriate manner. We developed Regulating Together (RT)--an intensive-outpatient, caregiver-assisted group program to meet the ASD + ED intervention critical need. A within-subjects trial was conducted (5-week-control lead-in period, 5-week-treatment, and 5-and 10-weeks-post-treatment follow-ups). Forty-four youth with ASD + ED (25 8-12, 19 13-18 yr-olds, 88% male, mean FSIQ of 96) participated. Improvements were found in reactivity, emotion regulation knowledge, and flexibility post-treatment and 10-weeks post-treatment. A reduction in inpatient hospitalization rates by 16% from the 12 months pre-RT to 12 months post-RT was observed. RT shows promise to reduce ED in ASD.

This article summarizes technical advances contained in the fifth major release of the Q-Chem quantum chemistry program package, covering developments since 2015. A comprehensive library of exchange-correlation functionals, along with a suite of correlated many-body methods, continues to be a hallmark of the Q-Chem software. The many-body methods include novel variants of both coupled-cluster and configuration-interaction approaches along with methods based on the algebraic diagrammatic construction and variational reduced density-matrix methods. Methods highlighted in Q-Chem 5 include a suite of tools for modeling core-level spectroscopy, methods for describing metastable resonances, methods for computing vibronic spectra, the nuclear-electronic orbital method, and several different energy decomposition analysis techniques. High-performance capabilities including multithreaded parallelism and support for calculations on graphics processing units are described. Q-Chem boasts a community of well over 100 active academic developers, and the continuing evolution of the software is supported by an "open teamware" model and an increasingly modular design.

Quantum chemistry in the form of density functional theory (DFT) calculations is a powerful numerical experiment for predicting intermolecular interaction energies. However, no chemical insight is gained in this way beyond predictions of observables. Energy decomposition analysis (EDA) can quantitatively bridge this gap by providing values for the chemical drivers of the interactions, such as permanent electrostatics, Pauli repulsion, dispersion, and charge transfer. These energetic contributions are identified by performing DFT calculations with constraints that disable components of the interaction. This review describes the second-generation version of the absolutely localized molecular orbital EDA (ALMO-EDA-II). The effects of different physical contributions on changes in observables such as structure and vibrational frequencies upon complex formation are characterized via the adiabatic EDA. Example applications include red- versus blue-shifting hydrogen bonds; the bonding and frequency shifts of CO, N2, and BF bound to a [Ru(II)(NH3)5]2 + moiety; and the nature of the strongly bound complexes between pyridine and the benzene and naphthalene radical cations. Additionally, the use of ALMO-EDA-II to benchmark and guide the development of advanced force fields for molecular simulation is illustrated with the recent, very promising, MB-UCB potential.

Energy decomposition analysis (EDA) based on absolutely localized molecular orbitals (ALMOs) decomposes the interaction energy between molecules into physically interpretable components like geometry distortion, frozen interactions, polarization, and charge transfer (CT, also sometimes called charge delocalization) interactions. In this work, a numerically exact scheme to decompose the CT interaction energy into pairwise additive terms is introduced for the ALMO-EDA using density functional theory. Unlike perturbative pairwise charge-decomposition analysis, the new approach does not break down for strongly interacting systems, or show significant exchange-correlation functional dependence in the decomposed energy components. Both the energy lowering and the charge flow associated with CT can be decomposed. Complementary occupied-virtual orbital pairs (COVPs) that capture the dominant donor and acceptor CT orbitals are obtained for the new decomposition. It is applied to systems with different types of interactions including DNA base-pairs, borane-ammonia adducts, and transition metal hexacarbonyls. While consistent with most existing understanding of the nature of CT in these systems, the results also reveal some new insights into the origin of trends in donor-acceptor interactions.

Intermolecular interactions between radicals and closed-shell molecules are ubiquitous in chemical processes, ranging from the benchtop to the atmosphere and extraterrestrial space. While energy decomposition analysis (EDA) schemes for closed-shell molecules can be generalized for studying radical-molecule interactions, they face challenges arising from the unique characteristics of the electronic structure of open-shell species. In this work, we introduce additional steps that are necessary for the proper treatment of radical-molecule interactions to our previously developed unrestricted Absolutely Localized Molecular Orbital (uALMO)-EDA based on density functional theory calculations. A "polarize-then-depolarize" (PtD) scheme is used to remove arbitrariness in the definition of the frozen wavefunction, rendering the ALMO-EDA results independent of the orientation of the unpaired electron obtained from isolated fragment calculations. The contribution of radical rehybridization to polarization energies is evaluated. It is also valuable to monitor the wavefunction stability of each intermediate state, as well as their associated spin density profiles, to ensure the EDA results correspond to a desired electronic state. These radical extensions are incorporated into the "vertical" and "adiabatic" variants of uALMO-EDA for studies of energy changes and property shifts upon complexation. The EDA is validated on two model complexes, H2O˙F and FH˙OH. It is then applied to several chemically interesting radical-molecule complexes, including the sandwiched and T-shaped benzene dimer radical cation, complexes of pyridine with benzene and naphthalene radical cations, binary and ternary complexes of the hydroxyl radical with water (˙OH(H2O) and ˙OH(H2O)2), and the pre-reactive complexes and transition states in the ˙OH + HCHO and ˙OH + CH3CHO reactions. These examples suggest that this second generation uALMO-EDA is a useful tool for furthering one's understanding of both energetic and property changes associated with radical-molecule interactions.

Dysregulation of glutamate neurotransmission plays a critical role in autism spectrum disorder (ASD) pathophysiology and is a primary target for core deficit research treatment trials. The mechanism of action of ketamine has striking overlap with the theory of ASD as a disorder of synaptic communication and neuronal networks. This two-dose, double-blind, placebo controlled, cross-over pilot trial of intranasal (IN) ketamine targeting core social impairment included individuals with ASD (N = 21) between 14 and 29 years. Participants were randomized to received two doses of IN ketamine (30 and 50 mg) and two doses of matching placebo. No significant impact was noted on the Aberrant Behavior Checklist Social Withdraw subscale. The IN ketamine was well tolerated, with only transient mild adverse effects.

The neural correlates distinguishing youth with Autism Spectrum Disorder (ASD-) and ASD with co-occurring Attention Deficit Hyperactivity Disorder (ASD+) are poorly understood despite significant phenotypic and prognostic differences. Paired-pulse transcranial magnetic stimulation (TMS) measures, including intracortical facilitation (ICF), short interval cortical inhibition (SICI), and cortical silent period (CSP) were measured in an age matched cohort of youth with ASD- (n = 20), ASD + (n = 29), and controls (TDC) (n = 24). ASD- and ASD+ groups did not differ by IQ or social functioning; however, ASD+ had significantly higher inattention and hyperactivity ratings. ICF (higher ratio indicates greater facilitation) in ASD+ (Mean 1.0, SD 0.19) was less than ASD- (Mean 1.3, SD 0.36) or TDC (Mean 1.2, SD 0.24) (F2,68 = 6.5, p = 0.003; post-hoc tests, ASD+ vs either TDC or ASD-, p ≤ 0.05). No differences were found between groups for SICI or age corrected active/resting motor threshold (AMT/RMT). Across all ASD youth (ASD- and ASD+), ICF was inversely correlated with worse inattention (Conners-3 Inattention (r = -0.41; p

Metabolic dysfunction-associated steatotic liver disease (MASLD), previously termed non-alcoholic fatty liver disease (NAFLD), is defined as steatotic liver disease (SLD) in the presence of one or more cardiometabolic risk factor(s) and the absence of harmful alcohol intake. The spectrum of MASLD includes steatosis, metabolic dysfunction-associated steatohepatitis (MASH, previously NASH), fibrosis, cirrhosis and MASH-related hepatocellular carcinoma (HCC). This joint EASL–EASD–EASO guideline provides an update on definitions, prevention, screening, diagnosis and treatment for MASLD. Case-finding strategies for MASLD with liver fibrosis, using non-invasive tests, should be applied in individuals with cardiometabolic risk factors, abnormal liver enzymes and/or radiological signs of hepatic steatosis, particularly in the presence of type 2 diabetes or obesity with additional metabolic risk factor(s). A stepwise approach using blood-based scores (such as the fibrosis-4 index [FIB-4]) and, sequentially, imaging techniques (such as transient elastography) is suitable to rule-out/in advanced fibrosis, which is predictive of liver-related outcomes. In adults with MASLD, lifestyle modification—including weight loss, dietary changes, physical exercise and discouraging alcohol consumption—as well as optimal management of comorbidities—including use of incretin-based therapies (e.g. semaglutide, tirzepatide) for type 2 diabetes or obesity, if indicated—is advised. Bariatric surgery is also an option in individuals with MASLD and obesity. If locally approved and dependent on the label, adults with non-cirrhotic MASH and significant liver fibrosis (stage ≥2) should be considered for a MASH-targeted treatment with resmetirom, which demonstrated histological effectiveness on steatohepatitis and fibrosis with an acceptable safety and tolerability profile. No MASH-targeted pharmacotherapy can currently be recommended for the cirrhotic stage. Management of MASH-related cirrhosis includes adaptations of metabolic drugs, nutritional counselling, surveillance for portal hypertension and HCC, as well as liver transplantation in decompensated cirrhosis. [ABSTRACT FROM AUTHOR]

Introduction/Aims: Studies have demonstrated that certain genotypes in Duchenne muscular dystrophy (DMD) have milder or more severe phenotypes. These studies included individuals treated and not treated with corticosteroids and multiple sites with potentially varying standards of care. We aimed to assess genotype–phenotype correlations for age at loss of ambulation (LoA) in a large cohort of individuals with DMD treated with corticosteroids at one center. Methods: In this retrospective review of medical records, encounters were included for individuals diagnosed with DMD if prescribed corticosteroids, defined as daily deflazacort or prednisone or high‐dose weekend prednisone, for 12 consecutive months. Encounters were excluded if the participants were taking disease‐modifying therapy. Data were analyzed using survival analysis for LoA and Fisher's exact tests to assess the percentage of late ambulatory (>14 years old) individuals for selected genotypes. Results: Overall, 3948 encounters from 555 individuals were included. Survival analysis showed later age at LoA for exon 44 skip amenable (p =.004), deletion exons 3–7 (p <.001) and duplication exon 2 (p =.043) cohorts and earlier age at LoA for the exon 51 skip amenable cohort (p <.001) when compared with the rest of the cohort. Individuals with deletions of exons 3–7 had significantly more late ambulatory individuals than other cohorts (75%), while those with exon 51 skip amenable deletions had significantly fewer (11.9%) compared with other cohorts. Discussion: This confirms previous observations of genotype–phenotype correlations in DMD and enhances information for trial design and clinical management. [ABSTRACT FROM AUTHOR]

Introduction: Autistic children and adolescents frequently experience emotion dysregulation, or difficulties with appropriately modifying their emotional reactions. Caregivers of autistic teens frequently seek psychotherapy support for navigating challenges associated with emotion dysregulation. During the COVID-19 pandemic, access to clinical services became limited, with interventions halted or transitioned into a telehealth format. Methods: This study evaluates the feasibility, acceptability, and initial efficacy of a telehealth adaptation to an existing intervention for emotion dysregulation for children and teens with autism, Regulating Together. A within-subjects trial was conducted for Child (ages 8-12) and Teen groups (ages 13-18). The trial consisted of a 5-week-control lead-in period, a 5-week-intervention, and 5-and 10- weeks-post-intervention follow-ups. Results: Twenty-eight youth with ASD + ED (n=13 Child and n=15 Teens, 71% male) participated. We observed a 93% retention rate across both groups. Improvements were found in reactivity, irritability, emotion and behavioral regulation, and flexibility immediately post-intervention and 10-weeks postintervention in both groups. Additional improvements in dysphoria, cognitive regulation, and emotional control were observed in teens. Discussion: Our results suggest promising improvements in ED through telehealth delivery of an emotion regulation intervention in autistic children and adolescents, along with possible improvements in accessibility of this intervention. [ABSTRACT FROM AUTHOR]

Gremlin-1 has been implicated in liver fibrosis in metabolic dysfunction- associated steatohepatitis (MASH) via inhibition of bone morphogenetic protein (BMP) signalling and has thereby been identified as a potential therapeutic target. Using rat in vivo and human in vitro and ex vivo model systems of MASH fibrosis, we show that neutralisation of Gremlin-1 activity with monoclonal therapeutic antibodies does not reduce liver inflammation or liver fibrosis. Still, Gremlin-1 was upregulated in human and rat MASH fibrosis, but expression was restricted to a small subpopulation of COL3A1/THY1+ myofibroblasts. Lentiviral overexpression of Gremlin-1 in LX-2 cells and primary hepatic stellate cells led to changes in BMP- related gene expression, which did not translate to increased fibrogenesis. Furthermore, we show that Gremlin-1 binds to heparin with high affinity, which prevents Gremlin-1 from entering systemic circulation, prohibiting Gremlin-1-mediated organ crosstalk. Overall, our findings suggest a redundant role for Gremlin-1 in the pathogenesis of liver fibrosis, which is unamenable to therapeutic targeting. [ABSTRACT FROM AUTHOR]

Objective: We evaluated changes in cognitive domains after neurosurgical lesioning of cortical sites with significant high‐gamma power modulations (HGM) during a visual naming task, although these sites were found language‐negative on standard‐of‐care electrical stimulation mapping (ESM). Methods: In drug‐resistant epilepsy patients who underwent resection/ablation after stereo‐electroencephalography (SEEG), we computed reliable change indices (RCIs) from a battery of presurgical and 1‐year postsurgical neuropsychological assessments. We modeled RCIs as a function of lesioning even one HGM language site, number of HGM language sites lesioned, and the magnitude of naming‐related HGM. The analyses were adjusted for 1‐year seizure freedom, operated hemispheres, and the volumes of surgical lesions. Results: In 37 patients with 4455 SEEG electrode contacts (1839 and 2616 contacts in right and left hemispheres, respectively), no ESM language sites were lesioned. Patients with lesioning of even one HGM language site showed significantly lower RCIs for Peabody Picture Vocabulary Test (PPVT), working memory, and verbal learning immediate (VLI) scores. RCI declines with higher number of HGM language sites lesioned were seen in PPVT (slope [β] = −.10), working memory (β = −.10), VLI (β = −.14), and letter–word identification (LWI; β = −.14). No neuropsychological domains improved after lesioning of HGM language sites. Significant effects of the HGM magnitude at lesioned sites were seen on working memory (β = −.31), story memory immediate (β = −.27), verbal learning recognition (β = −.18), LWI (β = −.16), spelling (β = −.49), and passage comprehension (β = −.33). Because working memory was significantly affected in all three analyses, patients with maximal working memory decline were examined post hoc, revealing that all such patients had HGM naming sites lesioned in the posterior quadrants of either hemisphere. Significance: HGM language mapping should be used as an adjunct to ESM in clinical practice and may help counsel patients/families about postsurgical cognitive deficits. [ABSTRACT FROM AUTHOR]