In this paper we review the impact of DSM-III and its successors on the field of autism—both in terms of clinical work and research. We summarize the events leading up to the inclusion of autism as a ...“new” official diagnostic category in DSM-III, the subsequent revisions of the DSM, and the impact of the official recognition of autism on research. We discuss the uses of categorical vs. dimensional approaches and the continuing tensions around broad vs. narrow views of autism. We also note some areas of current controversy and directions for the future.
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant of concern evades antibody-mediated immunity that comes from vaccination or infection with earlier variants due to ...accumulation of numerous spike mutations. To understand the Omicron antigenic shift, we determined cryo-electron microscopy and x-ray crystal structures of the spike protein and the receptor-binding domain bound to the broadly neutralizing sarbecovirus monoclonal antibody (mAb) S309 (the parent mAb of sotrovimab) and to the human ACE2 receptor. We provide a blueprint for understanding the marked reduction of binding of other therapeutic mAbs that leads to dampened neutralizing activity. Remodeling of interactions between the Omicron receptor-binding domain and human ACE2 likely explains the enhanced affinity for the host receptor relative to the ancestral virus.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission leads to the emergence of variants, including the B.1.617.2 (Delta) variant of concern that is causing a new wave of ...infections and has become globally dominant. We show that these variants dampen the in vitro potency of vaccine-elicited serum neutralizing antibodies and provide a structural framework for describing their immune evasion. Mutations in the B.1.617.1 (Kappa) and Delta spike glycoproteins abrogate recognition by several monoclonal antibodies via alteration of key antigenic sites, including remodeling of the Delta amino-terminal domain. The angiotensin-converting enzyme 2 binding affinities of the Kappa and Delta receptor binding domains are comparable to the Wuhan-Hu-1 isolate, whereas B.1.617.2+ (Delta+) exhibits markedly reduced affinity.
Cytokines were the first modern immunotherapies to produce durable responses in patients with advanced cancer, but they have only modest efficacy and limited tolerability
. In an effort to identify ...alternative cytokine pathways for immunotherapy, we found that components of the interleukin-18 (IL-18) pathway are upregulated on tumour-infiltrating lymphocytes, suggesting that IL-18 therapy could enhance anti-tumour immunity. However, recombinant IL-18 previously did not demonstrate efficacy in clinical trials
. Here we show that IL-18BP, a high-affinity IL-18 decoy receptor, is frequently upregulated in diverse human and mouse tumours and limits the anti-tumour activity of IL-18 in mice. Using directed evolution, we engineered a 'decoy-resistant' IL-18 (DR-18) that maintains signalling potential but is impervious to inhibition by IL-18BP. Unlike wild-type IL-18, DR-18 exerted potent anti-tumour effects in mouse tumour models by promoting the development of poly-functional effector CD8
T cells, decreasing the prevalence of exhausted CD8
T cells that express the transcriptional regulator of exhaustion TOX, and expanding the pool of stem-like TCF1
precursor CD8
T cells. DR-18 also enhanced the activity and maturation of natural killer cells to effectively treat anti-PD-1 resistant tumours that have lost surface expression of major histocompatibility complex class I molecules. These results highlight the potential of the IL-18 pathway for immunotherapeutic intervention and implicate IL-18BP as a major therapeutic barrier.
Individuals with autism spectrum disorder (ASD) are at increased risk for experiencing one or more co-occurring psychiatric conditions. When present, these conditions are associated with additional ...impairment and distress. It is therefore crucial that clinicians and researchers adequately understand and address these challenges. However, due to symptom overlap, diagnostic overshadowing, and ambiguous symptom presentation in ASD, the assessment of co-occurring conditions in ASD is complex and challenging. Likewise, individual difference factors, such as age, intellectual functioning, and gender, may influence the presentation of co-occurring symptoms. Relatedly, a transdiagnostic framework may offer utility in assessing and treating co-occurring conditions. However, with the exception of anxiety disorders, treatment research for co-occurring psychiatric conditions in ASD is relatively limited. Therefore, the present paper aims to summarize and review available research on the most common co-occurring psychiatric disorders in ASD, with a focus on estimated population-based prevalence rates, diagnostic challenges, the influence of individual differences, and assessment guidelines. The utility of a transdiagnostic framework for conceptualizing co-occurring disorders in ASD is discussed, and the state of treatment research for co-occurring disorders is summarized. This study concludes with a summary of the extant literature, as well as recommendations for future research.
Insulin resistance is one of the defining features of type 2 diabetes and the metabolic syndrome and accompanies many other clinical conditions, ranging from obesity to lipodystrophy to ...glucocorticoid excess. Extraordinary efforts have gone into defining the mechanisms that underlie insulin resistance, with most attention focused on altered signalling as well as mitochondrial and endoplasmic reticulum stress. Here, nuclear mechanisms of insulin resistance, including transcriptional and epigenomic effects, will be discussed. Three levels of control involving transcription factors, transcriptional cofactors, and chromatin‐modifying enzymes will be considered. Well‐studied examples of the first include PPAR‐γ in adipose tissue and the glucocorticoid receptor and FoxO1 in a variety of insulin‐sensitive tissues. These proteins work in concert with cofactors such as PGC‐1α and CRTC2, and chromatin‐modifying enzymes including DNA methyltransferases and histone acetyltransferases, to regulate key genes that promote insulin‐stimulated glucose uptake, gluconeogenesis or other pathways that affect systemic insulin action. Furthermore, genetic variation associated with increased risk of type 2 diabetes is often related to altered transcription factor binding, either by affecting the transcription factor itself, or more commonly by changing the binding affinity of a noncoding regulatory region. Finally, several avenues for therapeutic exploitation in the battle against metabolic disease will be discussed, including small‐molecule inhibitors and activators of these factors and their related pathways.
Content List – Read more articles from the symposium: 12th Key Symposium ‐ Insulin Resistance in Common Diseases.
Abstract Superparamagnetic iron oxide nanoparticles (SPIONs) have proven to be highly effective contrast agents for the magnetic resonance imaging diagnosis of solid tumors. This review examines the ...various techniques that are available to selectively target SPIONs toward a wide variety of cancerous tissues, with specific attention given to how the surface properties imparted by various targeting ligands affect the particles tissue distribution and pharmacokinetics. An in-depth examination of the various human cell lines utilized to test the assorted targeting methods is also presented, as well as an overview of the various types of cancer against which each targeting method has been utilized for both in vivo and in vitro studies. From the Clinical Editor Functionalized superparamagnetic iron oxide nanoparticles (SPIONs) are very potent negative contrast materials for magnetic resonance imaging-based diagnosis. This comprehensive review examines techniques that selectively target SPIONs toward a wide variety of malignancies.
Ornamental fishes are among the most popular and fastest growing categories of pets in the United States (U.S.). The global scope and scale of the ornamental fish trade and growing popularity of pet ...fish in the U.S. are strong indicators of the myriad economic and social benefits the pet industry provides. Relatively little is known about the microbial communities associated with these ornamental fishes or the aquarium water in which they are transported and housed. Using conventional molecular approaches and next generation high-throughput amplicon sequencing of 16S ribosomal RNA gene hypervariable regions, we characterized the bacterial community of aquarium water containing common goldfish (Carassius auratus) and Chinese algae eaters (Gyrinocheilus aymonieri) purchased from seven pet/aquarium shops in Rhode Island and identified the presence of potential pathogens. Our survey identified a total of 30 phyla, the most common being Proteobacteria (52%), Bacteroidetes (18%) and Planctomycetes (6%), with the top four phyla representing >80% of all sequences. Sequences from our water samples were most closely related to eleven bacterial species that have the potential to cause disease in fishes, humans and other species: Coxiella burnetii, Flavobacterium columnare, Legionella birminghamensis, L. pneumophila, Vibrio cholerae, V. mimicus. V. vulnificus, Aeromonas schubertii, A. veronii, A. hydrophila and Plesiomonas shigelloides. Our results, combined with evidence from the literature, suggest aquarium tank water harboring ornamental fish are an understudied source for novel microbial communities and pathogens that pose potential risks to the pet industry, fishes in trade, humans and other species.
The ambitious development agenda of the Sustainable Development Goals (SDGs) requires substantial investments across several sectors, including for SDG 3 (healthy lives and wellbeing). No estimates ...of the additional resources needed to strengthen comprehensive health service delivery towards the attainment of SDG 3 and universal health coverage in low-income and middle-income countries have been published.
We developed a framework for health systems strengthening, within which population-level and individual-level health service coverage is gradually scaled up over time. We developed projections for 67 low-income and middle-income countries from 2016 to 2030, representing 95% of the total population in low-income and middle-income countries. We considered four service delivery platforms, and modelled two scenarios with differing levels of ambition: a progress scenario, in which countries' advancement towards global targets is constrained by their health system's assumed absorptive capacity, and an ambitious scenario, in which most countries attain the global targets. We estimated the associated costs and health effects, including reduced prevalence of illness, lives saved, and increases in life expectancy. We projected available funding by country and year, taking into account economic growth and anticipated allocation towards the health sector, to allow for an analysis of affordability and financial sustainability.
We estimate that an additional $274 billion spending on health is needed per year by 2030 to make progress towards the SDG 3 targets (progress scenario), whereas US$371 billion would be needed to reach health system targets in the ambitious scenario—the equivalent of an additional $41 (range 15–102) or $58 (22–167) per person, respectively, by the final years of scale-up. In the ambitious scenario, total health-care spending would increase to a population-weighted mean of $271 per person (range 74–984) across country contexts, and the share of gross domestic product spent on health would increase to a mean of 7·5% (2·1–20·5). Around 75% of costs are for health systems, with health workforce and infrastructure (including medical equipment) as the main cost drivers. Despite projected increases in health spending, a financing gap of $20–54 billion per year is projected. Should funds be made available and used as planned, the ambitious scenario would save 97 million lives and significantly increase life expectancy by 3·1–8·4 years, depending on the country profile.
All countries will need to strengthen investments in health systems to expand service provision in order to reach SDG 3 health targets, but even the poorest can reach some level of universality. In view of anticipated resource constraints, each country will need to prioritise equitably, plan strategically, and cost realistically its own path towards SDG 3 and universal health coverage.
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