Psychosocial interventions for autistic children and adolescents delivered by non-specialists in low- and middle-income countries: a scoping review.

Background: Most autistic individuals reside in low- and middle-income countries (LMIC) and have limited access to medical providers and specialists. Support for delivery of psychosocial interventions by non-specialists is growing to address this mental health care gap. This scoping review involved a systematic analysis of studies of non-specialist delivered psychosocial interventions for children and adolescents diagnosed with autism and living in low- and middle-income countries. Methods: The primary objective of this review was to identify psychosocial interventions for autistic children and adolescents in LMIC delivered by non-specialists (parent, teacher, peer, community, multi-level) and to summarize resulting effects on targeted outcomes. The search strategy was completed in four databases with predetermined inclusion and exclusion criteria. The systematic search generated 3,601 articles. A total of 18 studies met inclusion/exclusion criteria. Data extraction was completed, and results summarized by; (1) participant sample; (2) intervention procedures; (3) implementation by non-specialists; (4) effect on evaluated outcomes; and (5) assessment of risk of bias. Studies examined a range of child and adolescent outcomes including assessment of communication skills, social skills, motor skills, functional and adaptive behaviors, emotional regulation, attention and engagement, sensory challenges, depression, anxiety, and quality of life. Several studies also evaluated intervention effects on family relationships, parent/caregiver stress and parent/caregiver mental health. Results: Collectively, the 18 studies included a total of 952 ASC participants ranging in age from 2 to 16 years. Of the included studies, 8 studies were parent/caregiver-mediated, 1 study was peer-mediated, 2 studies were teacher-mediated, and 7 studies included multi-level non-specialist mediated components. Effects on evaluated outcomes are reported. Conclusion: Non-specialist delivered interventions for autistic children and adolescents are effective for an array of outcomes and are particularly well suited for low- and middle-income countries. Implications for future research are discussed.

Dose-Dependent Von Willebrand Factor Inhibition by Aptamer BB-031 Correlates with Thrombolysis in a Microfluidic Model of Arterial Occlusion.

Von Willebrand Factor (VWF) plays a critical role in thrombus formation, stabilization, and propagation. Previous studies have demonstrated that targeted inhibition of VWF induces thrombolysis when administered in vivo in animal models of ischemic stroke. The study objective was to quantify dose-dependent inhibition of VWF-platelet function and its relationship with thrombolysis using BB-031, an aptamer that binds VWF and inhibits its function. VWF:Ac, VWF:RCo, T-TAS, and ristocetin-induced impedance aggregometry were used to assess BB-031-mediated inhibition of VWF. Reductions in original thrombus surface area and new deposition during administration of treatment were measured in a microfluidic model of arterial thrombolysis. Rotational thromboelastometry was used to assess changes in hemostasis. BB-031 induced maximal inhibition at the highest dose (3384 nM) in VWF:Ac, and demonstrated dose-dependent responses in all other assays. BB-031, but not vehicle, induced recanalization in the microfluidic model. Maximal lytic efficacy in the microfluidic model was seen at 1692 nM and not 3384 nM BB-031 when assessed by surface area. Minor changes in ROTEM parameters were seen at 3384 nM BB-031. Targeted VWF inhibition by BB-031 results in clinically measurable impairment of VWF function, and specifically VWF-GPIb function as measured by VWF:Ac. BB-031 also induced thrombolysis as measured in a microfluidic model of occlusion and reperfusion. Moderate correlation between inhibition and lysis was observed. Additional studies are required to further examine off-target effects of BB-031 at high doses, however, these are expected to be above the range of clinical targeted dosing.

Importance of Intraoperative Neuromonitoring Parameters in Predicting Temporary Recurrent Laryngeal Nerve Palsy Following Thyroid Surgery for Malignancy.

Recurrent laryngeal nerve (RLN) palsy is one of the feared complications following thyroid surgery. Intraoperative neuromonitoring (IONM) has been used as an adjunct to reduce this complication. In the present study, we attempted to evaluate the IONM parameters such as latency, current requirement, and baseline amplitude that could predict temporary RLN palsy along with factors that could influence these parameters during thyroid surgery. This was a retrospective study of patients who underwent hemi, total, or completion thyroidectomy for cancer at our institute between June 1, 2017 to May 31, 2019 in whom IONM was used during surgery. The study consisted of 84 consecutive patients with 138 nerves at risk. The RLN palsy rate in our study was 5% (n = 7). Patients with low baseline amplitude and/or requiring higher current to maintain normal baseline amplitude were often associated with temporary RLN palsy. In the multivariate analysis, age > 40 years (p = 0.001, OR = 4.14) influenced the baseline EMG amplitude the most. The intraoperative current management was influenced by advanced pT stage (p = 0.001, OR = 2.87), and structural nerve injury (p = 0.001, OR = 3.15). Patients with low baseline amplitude and/or requiring higher current to maintain normal baseline amplitude were often associated with temporary RLN palsy. Factors such as age, pT stage, and structural nerve injury influenced the IONM stimulation and recording parameters.

Ethnic Disparities in Atherosclerotic Cardiovascular Disease Incidence and Prevalence Among Rheumatoid Arthritis Patients in the United States: a Systematic Review.

OBJECTIVE: Rheumatoid arthritis (RA) is associated with increased atherosclerotic cardiovascular disease (ASCVD). General population cohorts have shown African American individuals to have greater and Hispanic Americans to have lower cardiovascular disease prevalence when compared with non-Hispanic white individuals; however, the reasons for these findings are not clear. This systematic review seeks to describe the incidence and prevalence of ASCVD stratified by race/ethnicity within the US RA population. METHODS: MEDLINE, Embase, and Cochrane databases were searched for studies that reported incidence or prevalence of ASCVD (including, but not limited to, fatal and nonfatal stroke, myocardial infarction, and cardiovascular death) in those with RA. Abstracts and full texts were screened separately for inclusion by two reviewers, with a third reviewer to resolve discrepancies. RESULTS: We screened 2625 abstracts and fully reviewed 138 manuscripts. Twenty-one were included that cited at a minimum the percentage of non-Hispanic whites in their population. No publication meeting entry criteria initially stratified ASCVD by race/ethnicity. The average prevalent ASCVD in RA is 46.9% (95% CI: 46.8-47) (range of prevalent ASCVD: 30%-47%). The average incident ASCVD is 8.2% (95% CI: 8.14-8.25) (range of incident ASCVD 1%-46%). CONCLUSION: In this systematic review, we found a paucity of data on racially/ethnically diverse RA patients and ASCVD outcomes. Future studies should report the prevalence of ASCVD in various races/ethnicities with RA in the United States. These data would help inform clinicians on how best to manage cardiovascular disease risk in RA.

FDA's new pharmaceutical quality initiative: Knowledge-aided assessment & structured applications.

This paper describes a new FDA's pharmaceutical quality assessment system: Knowledge-aided Assessment & Structured Application (KASA). The KASA system is designed to: 1) capture and manage knowledge during the lifecycle of a drug product; 2) establish rules and algorithms for risk assessment, control, and communication; 3) perform computer-aided analyses of applications to compare regulatory standards and quality risks across applications and facilities; and 4) provide a structured assessment that minimizes text-based narratives and summarization of provided information. When fully developed and implemented, KASA will enrich the effectiveness, efficiency, and consistency of regulatory quality oversight through lifecycle management of products and facilities, and information sharing in a standardized and structured format. Ultimately, KASA will advance FDA's focus on pharmaceutical quality, the foundation for ensuring the safety and efficacy of drugs.

Concomitant polymorphs of 1,3-bis(3-fluorophenyl)urea.

Hydrogen bonding between urea functionalities is a common structural motif employed in crystal-engineering studies. Crystallization of 1,3-bis(3-fluorophenyl)urea, C13H10F2N2O, from many solvents yielded concomitant mixtures of at least two polymorphs. In the monoclinic form, one-dimensional chains of hydrogen-bonded urea molecules align in an antiparallel orientation, as is typical of many diphenylureas. In the orthorhombic form, one-dimensional chains of hydrogen-bonded urea molecules have a parallel orientation rarely observed in symmetrically substituted diphenylureas.

Co-crystal formation based on structural matching.

A co-crystal is defined as a single crystalline structure composed of two or more components with no proton transfer which are solid at room temperature. Our group has come up with the following rationale selection of co-formers for initial co-crystal screening: 1) selection of co-formers with the highest potential for hydrogen bonding with the API and 2) selection of co-formers with diversity of secondary structural characteristics. We demonstrate the feasibility of this technique with a Novartis drug candidate A. In the first tier, 20 co-formers were screened and two hits were identified. By examining the two co-formers, which worked from the first round, a second round of screening was undertaken with more focused chemical matter. Nineteen co-crystal formers closely related to the two hits in the first screen were screened in the second tier. From this screen five hits were identified. All the hits were compared for their physical and chemical stability and dissolution profile. Based on the comparison 4-aminobenzoic co-crystal was chosen for in-vivo comparison with the free form. The co-crystal had 12 times higher exposure than the free form thus overcoming the solubility limited exposure.

Predicting psychotic-like experiences during sensory deprivation.

AIMS: This study aimed to establish the contribution of hallucination proneness, anxiety, suggestibility, and fantasy proneness to psychotic-like experiences (PLEs) reported during brief sensory deprivation. METHOD: Twenty-four high and 22 low hallucination-prone participants reported on PLEs occurring during brief sensory deprivation and at baseline. State/trait anxiety, suggestibility, and fantasy proneness were also measured. RESULTS: Both groups experienced a significant increase in PLEs in sensory deprivation. The high hallucination prone group reported more PLEs both at baseline and in sensory deprivation. They also scored significantly higher on measures of state/trait anxiety, suggestibility, and fantasy proneness, though these did not explain the effects of group or condition. Regression analysis found hallucination proneness to be the best predictor of the increase in PLEs, with state anxiety also being a significant predictor. Fantasy proneness and suggestibility were not significant predictors. CONCLUSION: This study suggests the increase in PLEs reported during sensory deprivation reflects a genuine aberration in perceptual experience, as opposed to increased tendency to make false reports due to suggestibility of fantasy proneness. The study provides further support for the use of sensory deprivation as a safe and effective nonpharmacological model of psychosis.

Psychotic-like experiences and their cognitive appraisal under short-term sensory deprivation.

AIMS: This study aimed to establish and compare the effects of brief sensory deprivation on individuals differing in trait hallucination proneness. METHOD: Eighteen participants selected for high hallucination proneness were compared against 18 participants rating low on this trait. The presence of psychotic-like experiences (PLEs), and participants' cognitive appraisals of these, was evaluated in three different settings: at baseline, in a "secluded office" environment, and in light-and-sound sensory deprivation. RESULTS: Psychotic-like experiences were experienced significantly more often in sensory deprivation for both groups. In particular, both experienced slight increases in perceptual distortions and anhedonia in seclusion, and these increased further during sensory deprivation. Highly hallucination prone individuals showed a significantly greater increase in perceptual distortions in sensory deprivation than did non-prone individuals suggesting a state-trait interaction. Their appraisals of these anomalous experiences were compared to both clinical and non-clinical individuals experiencing psychotic symptoms in everyday life. CONCLUSION: Short-term sensory deprivation is a potentially useful paradigm to model psychotic experiences, as it is a non-pharmacological tool for temporarily inducing psychotic-like states and is entirely safe at short duration. Experiences occur more frequently, though not exclusively, in those at putative risk of a psychotic disorder. The appraisals of anomalous experiences arising are largely consistent with previous observations of non-clinical individuals though importantly lacked the general positivity of the latter.

Design and synthesis of lactam-thiophene carboxylic acids as potent hepatitis C virus polymerase inhibitors.

Herein we report the successful incorporation of a lactam as an amide replacement in the design of hepatitis C virus NS5B Site II thiophene carboxylic acid inhibitors. Optimizing potency in a replicon assay and minimizing potential risk for CYP3A4 induction led to the discovery of inhibitor 22a. This lead compound has a favorable pharmacokinetic profile in rats and dogs.

BAG-2 acts as an inhibitor of the chaperone-associated ubiquitin ligase CHIP.

Cellular protein quality control involves a close interplay between molecular chaperones and the ubiquitin/proteasome system. We recently identified a degradation pathway, on which the chaperone Hsc70 delivers chaperone clients, such as misfolded forms of the cystic fibrosis transmembrane conductance regulator (CFTR), to the proteasome. The cochaperone CHIP is of central importance on this pathway, because it acts as a chaperone-associated ubiquitin ligase. CHIP mediates the attachment of a ubiquitin chain to a chaperone-presented client protein and thereby stimulates its proteasomal degradation. To gain further insight into the function of CHIP we isolated CHIP-containing protein complexes from human HeLa cells and analyzed their composition by peptide mass fingerprinting. We identified the Hsc70 cochaperone BAG-2 as a main component of CHIP complexes. BAG-2 inhibits the ubiquitin ligase activity of CHIP by abrogating the CHIP/E2 cooperation and stimulates the chaperone-assisted maturation of CFTR. The activity of BAG-2 resembles that of the previously characterized Hsc70 cochaperone and CHIP inhibitor HspBP1. The presented data therefore establish multiple mechanisms to control the destructive activity of the CHIP ubiquitin ligase in human cells.