The group-based social skills training SOSTA-FRA in children and adolescents with high functioning autism spectrum disorder - study protocol of the randomised, multi-centre controlled SOSTA - net trial

Background: Group-based social skills training (SST) has repeatedly been recommended as treatment of choice in high-functioning autism spectrum disorder (HFASD). To date, no sufficiently powered randomised controlled trial has been performed to establish efficacy and safety of SST in children and adolescents with HFASD. In this randomised, multi-centre, controlled trial with 220 children and adolescents with HFASD it is hypothesized, that add-on group-based SST using the 12 weeks manualised SOSTA–FRA program will result in improved social responsiveness (measured by the parent rated social responsiveness scale, SRS) compared to treatment as usual (TAU). It is further expected, that parent and self reported anxiety and depressive symptoms will decline and pro-social behaviour will increase in the treatment group. A neurophysiological study in the Frankfurt HFASD subgroup will be performed pre- and post treatment to assess changes in neural function induced by SST versus TAU. Methods/design: The SOSTA – net trial is designed as a prospective, randomised, multi-centre, controlled trial with two parallel groups. The primary outcome is change in SRS score directly after the intervention and at 3 months follow-up. Several secondary outcome measures are also obtained. The target sample consists of 220 individuals with ASD, included at the six study centres. Discussion: This study is currently one of the largest trials on SST in children and adolescents with HFASD worldwide. Compared to recent randomised controlled studies, our study shows several advantages with regard to in- and exclusion criteria, study methods, and the therapeutic approach chosen, which can be easily implemented in non-university-based clinical settings. Trial registration: ISRCTN94863788 – SOSTA – net: Group-based social skills training in children and adolescents with high functioning autism spectrum disorder

Alpha-Synuclein Pathology Coincides With Increased Number of Early Stage Neural Progenitors in the Adult Hippocampus

Alpha-synuclein pathology driven impairment in adult neurogenesis was proposed as a potential cause of, or at least contributor to, memory impairment observed in both patients and animal models of Parkinson’s disease (PD) and Dementia with Lewy Bodies (DLB). Mice overexpressing wild-type alpha-synuclein under the Thy-1 promoter (Thy1-aSyn, line 61) uniquely replicate early cognitive deficits together with multiple other characteristic motor and non-motor symptoms, alpha-synuclein pathology and dopamine loss. Here we report overt intracellular accumulation of phosphorylated alphasynuclein in the hippocampus of these transgenic mice. To test whether this alters adult neurogenesis and total number of mature neurons, we employed immunohistochemistry and an unbiased stereology approach to quantify the distinct neural progenitor cells and neurons in the hippocampal granule cell layer and subgranular zone of 6 (prodromal stage) and 16-month (dopamine loss) old Thy1-aSyn mice. Surprisingly, we observed an increase in the number of early stage, i.e., Pax6 expressing, progenitors whereas the numbers of late stage, i.e., Tbr2 expressing, progenitors and neurons were not altered. Astroglia marker was increased in the hippocampus of transgenic mice, but this was not specific to the regions where adult neurogenesis takes place, arguing against a commitment of additional early stage progenitors to the astroglia lineage. Together, this uncovers a novel aspect of alpha-synuclein pathology in adult neurogenesis. Studying its mechanisms in Thy1-aSyn mice could lead to discovery of effective therapeutic interventions for cognitive dysfunction in PD and DLB

Vocational and Psychosocial Outcomes of Work Re-Integration Programs for Individuals with Severe Mental Illness: A Rapid Systematic Review

Indiana University Purdue University IndianapolisThere are an estimated 11.2 million adults in the United States with a serious mental illness and this population is 6-7 times more likely to be unemployed. A systematic review of the literature related to work re-integration programs for individuals with severe mental illness was conducted to determine the role of occupational therapy in this area of practice. This included a comprehensive review of 25 studies that addressed many of the interventions commonly used in vocational and supported employment programs for individuals with severe mental illness and related mental health disorders. Findings reveal that various types of work re-integration programs result in competitive work attainment, increased job tenure, improved quality of life, and improved psychosocial factors. Occupational therapy could facilitate interventions related to work re-integration that improve vocational and non-vocational outcomes for this population. The literature over work re-integration programs is limited and more research is needed in order to understand the correlation between those with SMI and employment outcomes.Occupational Therap

Bait flavor preference and immunogenicity of ONRAB baits in domestic dogs on the Navajo Nation, Arizona

Rabies is responsible for an estimated 59,000 human deaths worldwide, and domestic dogs are the primary reservoir and vector of the disease. Among some nations, widespread vaccination has led to elimination of rabies in domestic dogs, yet dogs are still susceptible to rabies infection from interactions with wildlife reservoirs. On Tribal lands in the United States, less than 20% of domestic dogs are vaccinated for rabies, and parenteral vaccination is often unfeasible. Oral rabies vaccination may provide a solution, but a suitable bait flavor and vaccine must be identified. We evaluated 5 bait flavors (bacon, cheese, egg, fish, and sweet) in pairwise flavor-preference trials using placebo Ultralite baits in 26 domestic dogs on the Navajo Nation, Arizona. Each bait flavor was offered a total of 104 times. In all paired comparisons, bacon was more frequently preferred to the alternative. The sweet flavor (the flavor used operationally for oral rabies vaccine (ORV) distribution in Canada) was least preferred. Forty domestic dogs were offered baits containing ONRAB ORV: 14 received the sweet-flavored bait packet and 26 received bacon-flavored baits. Serum was collected from dogs before vaccination and at day 14 and 30 or 37 days after vaccination. Thirty-seven dogs consumed the baits, 2 baits (both sweet flavored) were chewed and spit out, and 1 (sweet flavored) was swallowed without apparent chewing (gulped). Eight dogs had preexisting rabies virus neutralizing antibody (RVNA) titers and 13 naïve dogs failed to seroconvert during the study period. Overall, 27 dogs (67.5%) showed increased RVNA titers after vaccination, including 1 dog who chewed and spit out the bait and all dogs with positive baseline RVNA titers. Geometric mean titers for all dogs that seroconverted during the study period peaked at day 14 (1.2 IU/ mL; n = 24) and decreased slightly by the final sampling day (0.8 IU/mL; n = 27).We conclude that bacon flavor may be a suitable bait flavor for ORV distribution in loosely kept or free-roaming domestic dogs. Seroconversion among dogs who ingested ONRAB-filled baits was variable. Why 13 dogs who consumed ORV baits failed to seroconvert remains unknown. Additional research to improve seroconversion rates in domestic dogs after vaccination with ONRAB is recommended

Bait flavor preference and immunogenicity of ONRAB baits in domestic dogs on the Navajo Nation, Arizona

Rabies is responsible for an estimated 59,000 human deaths worldwide, and domestic dogs are the primary reservoir and vector of the disease. Among some nations, widespread vaccination has led to elimination of rabies in domestic dogs, yet dogs are still susceptible to rabies infection from interactions with wildlife reservoirs. On Tribal lands in the United States, less than 20% of domestic dogs are vaccinated for rabies, and parenteral vaccination is often unfeasible. Oral rabies vaccination may provide a solution, but a suitable bait flavor and vaccine must be identified. We evaluated 5 bait flavors (bacon, cheese, egg, fish, and sweet) in pairwise flavor-preference trials using placebo Ultralite baits in 26 domestic dogs on the Navajo Nation, Arizona. Each bait flavor was offered a total of 104 times. In all paired comparisons, bacon was more frequently preferred to the alternative. The sweet flavor (the flavor used operationally for oral rabies vaccine (ORV) distribution in Canada) was least preferred. Forty domestic dogs were offered baits containing ONRAB ORV: 14 received the sweet-flavored bait packet and 26 received bacon-flavored baits. Serum was collected from dogs before vaccination and at day 14 and 30 or 37 days after vaccination. Thirty-seven dogs consumed the baits, 2 baits (both sweet flavored) were chewed and spit out, and 1 (sweet flavored) was swallowed without apparent chewing (gulped). Eight dogs had preexisting rabies virus neutralizing antibody (RVNA) titers and 13 naïve dogs failed to seroconvert during the study period. Overall, 27 dogs (67.5%) showed increased RVNA titers after vaccination, including 1 dog who chewed and spit out the bait and all dogs with positive baseline RVNA titers. Geometric mean titers for all dogs that seroconverted during the study period peaked at day 14 (1.2 IU/ mL; n = 24) and decreased slightly by the final sampling day (0.8 IU/mL; n = 27).We conclude that bacon flavor may be a suitable bait flavor for ORV distribution in loosely kept or free-roaming domestic dogs. Seroconversion among dogs who ingested ONRAB-filled baits was variable. Why 13 dogs who consumed ORV baits failed to seroconvert remains unknown. Additional research to improve seroconversion rates in domestic dogs after vaccination with ONRAB is recommended

The structure of Herpesvirus Fusion Glycoprotein B-Bilayer Complex reveals the protein-membrane and lateral protein-protein interaction

Glycoprotein B (gB) is a key component of the complex herpesvirus fusion machinery. We studied membrane interaction of two gB ectodomain forms and present an electron cryotomography structure of the gB-bilayer complex. The two forms differed in presence or absence of the membrane proximal region (MPR) but showed an overall similar trimeric shape. The presence of the MPR impeded interaction with liposomes. In contrast, the MPR-lacking form interacted efficiently with liposomes. Lateral interaction resulted in coat formation on the membranes. The structure revealed that interaction of gB with membranes was mediated by the fusion loops and limited to the outer membrane leaflet. The observed intrinsic propensity of gB to cluster on membranes indicates an additional role of gB in driving the fusion process forward beyond the transient fusion pore opening and subsequently leading to fusion pore expansion

Spatial mapping of hematopoietic clones in human bone marrow

UNLABELLED: Clonal hematopoiesis (CH) is the expansion of somatically mutated cells in the hematopoietic compartment of individuals without hematopoietic dysfunction. Large CH clones (i.e., \u3e2% variant allele fraction) predispose to hematologic malignancy, but CH is detected at lower levels in nearly all middle-aged individuals. Prior work has extensively characterized CH in peripheral blood, but the spatial distribution of hematopoietic clones in human bone marrow is largely undescribed. To understand CH at this level, we developed a method for spatially aware somatic mutation profiling and characterized the bone marrow of a patient with polycythemia vera. We identified the complex clonal distribution of somatic mutations in the hematopoietic compartment, the restriction of somatic mutations to specific subpopulations of hematopoietic cells, and spatial constraints of these clones in the bone marrow. This proof of principle paves the way to answering fundamental questions regarding CH spatial organization and factors driving CH expansion and malignant transformation in the bone marrow. SIGNIFICANCE: CH occurs commonly in humans and can predispose to hematologic malignancy. Although well characterized in blood, it is poorly understood how clones are spatially distributed in the bone marrow. To answer this, we developed methods for spatially aware somatic mutation profiling to describe clonal heterogeneity in human bone marrow. See related commentary by Austin and Aifantis, p. 139

A novel dual action monolithic thermosetting hydrogel loaded with lidocaine and metronidazole as a potential treatment for alveolar osteitis

Alveolar osteitis is a complication that can occur after tooth extraction, whereby exposed bone results in severe throbbing pain for the patient and can be prone to infection. The current treatment options are widely regarded as sub-optimal. The aim of this project was to investigate in vitro the plausibility of a dual-action monolithic drug-loaded thermosensitive hydrogel that undergoes thermal gelation within the tooth socket and releases both anaesthetic and antimicrobial agents. Hydrogels containing different levels of lidocaine HCl and metronidazole were prepared based upon Carbopol 934P NF and Pluronic F-127 blends. Membrane-less drug release was determined from the set hydrogels into phosphate buffered saline (PBS) at 37 °C as a function of time, following analysis by HPLC. Gelation characteristics and hydrogel dissolution characteristics were also determined. At 23.38% Pluronic F-127, sol-gel transition commenced at 23 °C and gelation was completely at 37 °C (physiological temperature). Setting times varied with Pluronic content and there was an inverse relationship between drug release and Pluronic content. Sustained and dose dependent release of both drugs was observed at therapeutically relevant levels over 24 h, via a combination of diffusion, dissolution and surface erosion processes. Based on the amounts of drugs released, it was determined that hydrogels containing up to 0.5% lidocaine and 0.1% metronidazole exhibited low risk of cytotoxicity to primary human gingival fibroblasts. In an in vivo scenario, the sol-phase formulation would make contact with all inner surfaces of a tooth socket prior to transitioning to monolithic gel-phase and provide sustained release of lidocaine and metronidazole at sub-toxic levels, thereby providing simultaneous pain relief, protection from ingress of debris and potentially pathological bacteria

Mechanism of Neutralization of Herpes Simplex Virus by Antibodies Directed at the Fusion Domain of Glycoprotein B

Glycoprotein B (gB), the fusogen of herpes simplex virus (HSV), is a class III fusion protein with a trimeric ectodomain of known structure for the postfusion state. Seen by negative-staining electron microscopy, it presents as a rod with three lobes (base, middle, and crown). gB has four functional regions (FR), defined by the physical location of epitopes recognized by anti-gB neutralizing monoclonal antibodies (MAbs). Located in the base, FR1 contains two internal fusion loops (FLs) and is the site of gB-lipid interaction (the fusion domain). Many of the MAbs to FR1 are neutralizing, block cell-cell fusion, and prevent the association of gB with lipid, suggesting that these MAbs affect FL function. Here we characterize FR1 epitopes by using electron microscopy to visualize purified Fab-gB ectodomain complexes, thus confirming the locations of several epitopes and localizing those of MAbs DL16 and SS63. We also generated MAb-resistant viruses in order to localize the SS55 epitope precisely. Because none of the epitopes of our anti-FR1 MAbs mapped to the FLs, we hyperimmunized rabbits with FL1 or FL2 peptides to generate polyclonal antibodies (PAbs). While the anti-FL1 PAb failed to bind gB, the anti-FL2 PAb had neutralizing activity, implying that the FLs become exposed during virus entry. Unexpectedly, the anti-FL2 PAb (and the anti-FR1 MAbs) bound to liposome-associated gB, suggesting that their epitopes are accessible even when the FLs engage lipid. These studies provide possible mechanisms of action for HSV neutralization and insight into how gB FR1 contributes to viral fusion. IMPORTANCE: For herpesviruses, such as HSV, entry into a target cell involves transfer of the capsid-encased genome of the virus to the target cell after fusion of the lipid envelope of the virus with a lipid membrane of the host. Virus-encoded glycoproteins in the envelope are responsible for fusion. Antibodies to these glycoproteins are important biological tools, providing a way of examining how fusion works. Here we used electron microscopy and other techniques to study a panel of anti-gB antibodies. Some, with virus-neutralizing activity, impair gB-lipid association. We also generated a peptide antibody against one of the gB fusion loops; its properties provide insight into the way the fusion loops function as gB transits from its prefusion form to an active fusogen