Occurrence and seasonal variation of Perkinsus sp. Infection in wild mollusk populations from coastal waters of Qingdao, northern China.

Perkinsosis has been recognized as one of the major threats to natural and farmed bivalve populations, many of which are of commercial as well as environmental significance. Three Perkinsus species have been identified in China, and the Manila clam (Ruditapes philippinarum) was the most frequently infected species in northern China. Although the occurrence and seasonal variation of Perkinsus spp. have previously been examined, the pathological characteristics of these infections in wild Manila clams and sympatric species in China have seldom been reported. In the present study, the prevalence and intensity of Perkinsus infection in wild populations of Manila clams and 10 sympatric species from three sites were investigated by Ray's fluid thioglycolate medium (RFTM) assay seasonally across a single year. Perkinsus infection was only identified in Manila clams, with a high prevalence (274/284 = 96.48 %) and low intensity (89.8 % with a Mackin value ≤ 2, suggesting generally low-intensity infections) throughout the year. Heavily infected clams were mainly identified in Tianheng in January, which displayed no macroscopic signs of disease. An overview of the whole visceral mass section showed that the trophozoites mostly aggregated in gills and connective tissue of the digestive tract, to a lesser extent in the mantle and foot, and even less frequently in adductor muscle and connective tissues of the gonad. PCR and ITS-5.8S rRNA sequencing of 93 representative RFTM-positive samples revealed a 99.69 to 100 % DNA sequence identity to Perkinsus olseni. Unexpectedly, significantly higher infection intensities were usually identified in January and April when the Condition Index (CI) was relatively high. We propose that factors associated with the anthropogenic harvesting pressure and irregular disturbances should be responsible for the uncommon seasonal infection dynamics of perkinsosis observed in the present study.

Dilated cardiomyopathy and chronic cardiac inflammation: Pathogenesis, diagnosis and therapy.

Dilated cardiomyopathy (DCM) is typically defined by left ventricular dilation and systolic dysfunction in the absence of a clear precipitant. Idiopathic disease is common; up to 50% of patients with DCM have no cause found despite imaging, genetic and biopsy assessments. Treatment remains focused on managing symptoms, reducing the risk of sudden cardiac death and ameliorating the structural and electrical complications of disease progression. In the absence of aetiology-specific treatments, the condition remains associated with a poor prognosis; mortality is approximately 40% at 10 years. The role of immune-mediated inflammatory injury in the development and progression of DCM was first proposed over 30 years ago. Despite the subsequent failures of three large clinical trials of immunosuppressive treatment (ATTACH, RENEWAL and the Myocarditis Treatment Trial), evidence for an abnormal adaptive immune response in DCM remains significant. In this review, we summarise and discuss available evidence supporting immune dysfunction in DCM, with a specific focus on cellular immunity. We also highlight current clinical and experimental treatments. We propose that the success of future immunosuppressive treatment trials in DCM will be dependent on the deep immunophenotyping of patients, to identify those with active inflammation and/or an abnormal immune response who are most likely to respond to therapy.

Strong recommendations from low certainty evidence: a cross-sectional analysis of a suite of national guidelines.

BACKGROUND: Clinical guidelines should be based on a thorough evaluation of the evidence and generally include a rating of the quality of evidence and assign a strength to recommendations. Grading of Recommendations Assessment, Development and Evaluation (GRADE) guidance warns against making strong recommendations when the certainty of the evidence is low or very low, but has identified five paradigmatic situations (e.g. life-threatening situations) where this may be justified. AIMS AND OBJECTIVES: We aimed to characterize the strength of recommendations and certainty of the evidence in Irish National Clinical Guidelines using the GRADE approach. METHODS: All National Clinical Guidelines from the National Clinical Effectiveness Committee (NCEC) website using the GRADE approach (fully or partially) were included. All recommendations and their corresponding certainty of the evidence, strength of recommendations and justifications were extracted. Authors classified instances of strong recommendations with low certainty evidence (referred to as discordant recommendations) into one of the five paradigmatic situations. Descriptive statistics were calculated. RESULTS: From the 29 NCEC Clinical Guidelines available at the time of analysis, we identified 8 guidelines using GRADE with a total of 240 recommendations; 38 recommendations did not use the GRADE approach and were excluded. Half of the included guidelines focused on emergency situations. In the final dataset of 202 recommendations, 151 (74.7%) were classified as strong and 51 (25.3%) as conditional. Of the 151 strong recommendations, 55 (36.4%) were supported by high or moderate certainty evidence and 96 (63.6%) by low or very low certainty evidence and were considered discordant. Of these 96 discordant recommendations, 55 (73.7%) were consistent with one of the five paradigmatic situations. However, none were specifically described as such within the guidelines. CONCLUSIONS: The proportion of discordant recommendations identified in this analysis was higher than some previous international studies (range of all strong recommendations being discordant 30-50%), but similar to other guidelines focused on emergency situations. The majority of discordant recommendations could be mapped to one of the five situations, but no National Clinical Guideline explicitly referenced this. Guideline developers require further guidance to enable greater transparency in the reporting of the reasons for discordant recommendations.

Selective Aerobic Oxidation of Csp3-H Bonds Catalyzed by Yeast-Derived Nitrogen, Phosphorus, and Oxygen Codoped Carbon Materials.

Nitrogen, phosphorus, and oxygen codoped carbon catalysts were successfully synthesized using dried yeast powder as a pyrolysis precursor. The yeast-derived heteroatom-doped carbon (yeast@C) catalysts exhibited outstanding performance in the oxidation of Csp3-H bonds to ketones and esters, giving excellent product yields (of up to 98% yield) without organic solvents at low O2 pressure (0.1 MPa). The catalytic oxidation protocol exhibited a broad range of substrates (38 examples) with good functional group tolerance, excellent regioselectivity, and synthetic utility. The yeast-derived heteroatom-doped carbon catalysts showed good reusability and stability after recycling six times without any significant loss of activity. Experimental results and DFT calculations proved the important role of N-oxide (N+-O-) on the surface of yeast@C and a reasonable carbon radical mechanism.

Paired miRNA and RNA sequencing provides a first insight into molecular defense mechanisms of Scapharca broughtonii during ostreid herpesvirus-1 infection.

Ostreid herpesvirus 1 (OsHV-1) infection caused mortalities with relevant economic losses in bivalve aquaculture industry worldwide. Initially described as an oyster pathogen, OsHV-1 can infect other bivalve species, like the blood clam Scapharca broughtonii. However, at present, little is known about the molecular interactions during OsHV-1 infection in the blood clam. We produced paired miRNA and total RNA-seq data to investigate the blood clam transcriptional changes from 0 to 72 h after experimental infection with OsHV-1. High-throughput miRNA sequencing of 24 libraries revealed 580 conserved and 270 new blood clam miRNAs, whereas no genuine miRNA was identified for OsHV-1. Total 88-203 differently expressed miRNAs were identified per time point, mostly up-regulated and mainly targeting metabolic pathways. Most of the blood clam mRNAs, in contrast, were down-regulated up to 60 h post-injection, with the trend analysis revealing the activation of immune genes only when comparing the early and latest stage of infection. Taken together, paired short and long RNA data suggested a miRNA-mediated down-regulation of host metabolic and energetic processes as a possible antiviral strategy during early infection stages, whereas antiviral pathways appeared upregulated only at late infection.

A single-center pilot study in Malaysia on the clinical utility of whole-exome sequencing for inborn errors of immunity.

Primary immunodeficiency diseases refer to inborn errors of immunity (IEI) that affect the normal development and function of the immune system. The phenotypical and genetic heterogeneity of IEI have made their diagnosis challenging. Hence, whole-exome sequencing (WES) was employed in this pilot study to identify the genetic etiology of 30 pediatric patients clinically diagnosed with IEI. The potential causative variants identified by WES were validated using Sanger sequencing. Genetic diagnosis was attained in 46.7% (14 of 30) of the patients and categorized into autoinflammatory disorders (n = 3), diseases of immune dysregulation (n = 3), defects in intrinsic and innate immunity (n = 3), predominantly antibody deficiencies (n = 2), combined immunodeficiencies with associated and syndromic features (n = 2) and immunodeficiencies affecting cellular and humoral immunity (n = 1). Of the 15 genetic variants identified, two were novel variants. Genetic findings differed from the provisional clinical diagnoses in seven cases (50.0%). This study showed that WES enhances the capacity to diagnose IEI, allowing more patients to receive appropriate therapy and disease management.

Smoking, life expectancy, and chronic disease in South Korea, Singapore, and the United States: A microsimulation model.

The substantial social and economic burden attributable to smoking is well-known, with heavy smokers at higher risk of chronic disease and premature mortality than light smokers and nonsmokers. In aging societies with high rates of male smoking such as in East Asia, smoking is a leading preventable risk factor for extending lives (including work-lives) and healthy aging. However, little is known about whether smoking interventions targeted at heavy smokers relative to light smokers lead to disproportionately larger improvements in life expectancy and prevalence of chronic diseases and how the effects vary across populations. Using a microsimulation model, we examined the health effects of smoking reduction by simulating an elimination of smoking among subgroups of smokers in South Korea, Singapore, and the United States. We found that life expectancy would increase by 0.2 to 1.5 years among light smokers and 2.5 to 3.7 years among heavy smokers. Whereas both interventions led to an increased life expectancy and decreased the prevalence of chronic diseases in all three countries, the life-extension benefits were greatest for those who would otherwise have been heavy smokers. Our findings illustrate how smoking interventions may have significant economic and social benefits, especially for life extension, that vary across countries.

Hindrances of peripherally inserted central catheter care of leukemia patients: a qualitative study.

OBJECTIVE: A peripherally inserted central catheter (PICC) needs regular care. However, clinical observations found that some discharged leukemia patients in mainland China had not complied with the requirement of regular care. Our study aims to explore the facilitators and hindrances of regular cares of PICC in leukemia patients with the Colaizzi phenomenon analysis. METHODS: This qualitative report used the descriptive phenomenological method to collect information and was conducted in accordance with the COREQ checklist. By purposive sampling, 11 leukemia patients with PICC were selected and interviewed in the Department of Hematology of a first-class hospital in Wuhan (central China). The interviews were conducted from March 2016 to May 2017. RESULTS: Two facilitators for PICC care were extracted through interviews, including fear of nosocomial infection and convenience for treatment. Eleven hindrances were summarized, including high costs, unavailability of local services, worries about affecting family members, a lack of health awareness, inconvenient transportations, fluke minds, physical discomfort, fears of leukemia and chemotherapy, short chemotherapy intervals, damage to appearance, and no insurance coverage of costs. CONCLUSION: Leukemia patients' compliance with PICC care was hindered by several factors. The improvement of PICC care may need joint efforts of patients, nursing professionals, hospitals' managerial staff, and governments.

MRI-based radiomics model for preoperative prediction of 5-year survival in patients with hepatocellular carcinoma.

BACKGROUND: Recurrence is the major cause of mortality in patients with resected HCC. However, without a standard approach to evaluate prognosis, it is difficult to select candidates for additional therapy. METHODS: A total of 201 patients with HCC who were followed up for at least 5 years after curative hepatectomy were enrolled in this retrospective, multicentre study. A total of 3144 radiomics features were extracted from preoperative MRI. The random forest method was used for radiomics signature building, and five-fold cross-validation was applied. A radiomics model incorporating the radiomics signature and clinical risk factors was developed. RESULTS: Patients were divided into survivor (n = 97) and non-survivor (n = 104) groups based on the 5-year survival after surgery. The 30 most survival-related radiomics features were selected for the radiomics signature. Preoperative AFP and AST were integrated into the model as independent clinical risk factors. The model demonstrated good calibration and satisfactory discrimination, with a mean AUC of 0.9804 and 0.7578 in the training and validation sets, respectively. CONCLUSIONS: This radiomics model is a valid method to predict 5-year survival in patients with HCC and may be used to identify patients for clinical trials of perioperative therapies and for additional surveillance.

In situ hybridization revealed wide distribution of Haliotid herpesvirus 1 in infected small abalone, Haliotis diversicolor supertexta.

Ganglioneuritis was the primary pathologic change in infected abalone associated with Haliotid herpesvirus 1 (HaHV-1) infection, which eventually became known as abalone viral ganglioneuritis (AVG). However, the distribution of HaHV-1 in the other tissues and organs of infected abalone has not been systemically investigated. In the present study, the distribution of HaHV-1-CN2003 variant in different organs of small abalone, Haliotis diversicolor supertexta, collected at seven different time points post experimental infection, was investigated with histopathological examination and in situ hybridization (ISH) of HaHV-1 DNA. ISH signals were first observed in pedal ganglia at 48 h post injection, and were consistently observed in this tissue of challenged abalone. At the same time, increased cellularity accompanied by ISH signals was observed in some peripheral ganglia of mantle and kidney. At the end of infection period, lesions and co-localized ISH signals in infiltrated cells were detected occasionally in the mantle and hepatopancreas. Transmission electron microscope analysis revealed the presence of herpes-like viral particles in haemocyte nuclei of infected abalone. Our results indicated that, although HaHV-1-CN2003 was primarily neurotropic, it could infect other tissues including haemocytes.

A-to-I editing of Malacoherpesviridae RNAs supports the antiviral role of ADAR1 in mollusks.

BACKGROUND: Adenosine deaminase enzymes of the ADAR family are conserved in metazoans. They convert adenine into inosine in dsRNAs and thus alter both structural properties and the coding potential of their substrates. Acting on exogenous dsRNAs, ADAR1 exerts a pro- or anti-viral role in vertebrates and Drosophila. RESULTS: We traced 4 ADAR homologs in 14 lophotrochozoan genomes and we classified them into ADAD, ADAR1 or ADAR2, based on phylogenetic and structural analyses of the enzymatic domain. Using RNA-seq and quantitative real time PCR we demonstrated the upregulation of one ADAR1 homolog in the bivalve Crassostrea gigas and in the gastropod Haliotis diversicolor supertexta during Ostreid herpesvirus-1 or Haliotid herpesvirus-1 infection. Accordingly, we demonstrated an extensive ADAR-mediated editing of viral RNAs. Single nucleotide variation (SNV) profiles obtained by pairing RNA- and DNA-seq data from the viral infected individuals resulted to be mostly compatible with ADAR-mediated A-to-I editing (up to 97%). SNVs occurred at low frequency in genomic hotspots, denoted by the overlapping of viral genes encoded on opposite DNA strands. The SNV sites and their upstream neighbor nucleotide indicated the targeting of selected adenosines. The analysis of viral sequences suggested that, under the pressure of the ADAR editing, the two Malacoherpesviridae genomes have evolved to reduce the number of deamination targets. CONCLUSIONS: We report, for the first time, evidence of an extensive editing of Malacoherpesviridae RNAs attributable to host ADAR1 enzymes. The analysis of base neighbor preferences, structural features and expression profiles of molluscan ADAR1 supports the conservation of the enzyme function among metazoans and further suggested that ADAR1 exerts an antiviral role in mollusks.

Susceptibility of two abalone species, Haliotis diversicolor supertexta and Haliotis discus hannai, to Haliotid herpesvirus 1 infection.

Abalone viral ganglioneuritis (AVG), caused by Haliotid herpesvirus-1 (HaHV-1) infection, has been reported as the main cause of mortality and heavy losses of wild and cultivated abalone in Taiwan and Australia since 2003. HaHV-1 DNA has also been reported in diseased abalone collected in early 2000s in China. However, no data is available about the susceptibility, disease process and pathological changes of HaHV-1 infection in the primary cultivated abalone species in China. In the present study, two cultivated abalone species, Haliotis diversicolor supertexta and Haliotis discus hannai, were challenged with HaHV-1-CN2003 collected in 2003 in China using three different methods. Results showed that H. diversicolor supertexta was highly susceptible to HaHV-1-CN2003 infection and suffered acute mortality using all three challenge methods. H. discus hannai was not susceptible to the viral infection. Histopathology combined with transmission electron microscopy and quantitative PCR analysis revealed that the tropism of HaHV-1-CN2003 includes both neural tissue and haemocytes.

Synthesis and In Vitro Evaluation of Caffeoylquinic Acid Derivatives as Potential Hypolipidemic Agents.

A series of novel caffeoylquinic acid derivatives of chlorogenic acid have been designed and synthesized. Biological evaluation indicated that several synthesized derivatives exhibited moderate to good lipid-lowering effects on oleic acid-elicited lipid accumulation in HepG2 liver cells. Particularly, derivatives 3d, 3g, 4c and 4d exhibited more potential lipid-lowering effect than the positive control simvastatin and chlorogenic acid. Further studies on the mechanism of 3d, 3g, 4c and 4d revealed that the lipid-lowering effects were related to their regulation of TG levels and merit further investigation.

Inclined emitting slotted single-mode laser with 1.7° vertical divergence angle for PIC applications.

In this Letter, a new type of single-mode slotted laser used for an on-chip light source in photonic integrated circuits is proposed. An inclined light beam with a low vertical divergence angle can be directly coupled into the surface grating of the silicon to form an integrated light source. Experimentally, a III-V laser with a 54.6° inclined angle and a vertical divergence angle of 1.7° is achieved by introducing a kind of specially distributed microstructure. The side mode suppression ratio is better than 45 dB, and the continuous wave output power reaches 6.5 mW at room temperature. We report the inclined emitting microstructured single-mode laser with a low divergence angle for the first time, to the best of our knowledge.

Dual transcriptomic analysis of Ostreid herpesvirus 1 infected Scapharca broughtonii with an emphasis on viral anti-apoptosis activities and host oxidative bursts.

The ark shell, Scapharca (Anadara) broughtonii, is an economically important marine shellfish species in Northwestern Pacific. Mass mortalities of ark shell adults related to Ostreid herpesvirus-1 (OsHV-1) infection have occurred frequently since 2012. However, due to the lack of transcriptomic resource of ark shells, the molecular mechanisms underpinning the virus-host interaction remains largely undetermined. In the present study, we resolved the dual transcriptome changes of OsHV-1 infected ark shell with Illumina sequencing. A total of 44 M sequence reads were generated, of which 67,119 reads were mapped to the OsHV-1 genome. De novo assembly of host reads resulted in 276,997 unigenes. 74,529 (26.90%), 47,653 (17.20%) and 19, 611 (7.07%) unigenes were annotated into GO, KOG and KEGG database, respectively. According to RSEM expression values, we identified 2998 differentially expressed genes (DEGs) between control and challenged groups, which included 2065 up-regulated unigenes and 933 down-regulated unigenes. Further analysis of functional pathways indicated that OsHV-1 could inhibit host cell apoptosis mainly by the up-regulation of inhibitor of apoptosis protein (IAP), and thus facilitating its successful replication. While host hemoglobins could induce oxidative burst by suppressing its peroxidase activity, and thus defense against OsHV-1 infection. Although we reported a narrow expression of the OsHV-1 genome compared to Crassostrea gigas infection, we highlighted several common viral genes highly expressed in the two hosts, suggesting an important functional role. This study offers insights into the pathogenesis mechanisms of OsHV-1 infection in bivalve mollusks of the Arcidae family.

Abiraterone or Enzalutamide in Advanced Castration-Resistant Prostate Cancer: An Indirect Comparison.

BACKGROUND: To perform a comparative effectiveness analyses between enzalutamide and abiraterone acetate in both the pre-docetaxel and post-docetaxel settings based on published phase III randomized trials. METHODS: The primary measure of efficacy was the posterior probability that enzalutamide outperforms abiraterone acetate (AA) with prednisone in terms of overall survival (OS) on average. Indirect meta-estimates were generated from four randomized studies in the context of a Bayesian hierarchical model with study-specific efficacy estimates meta-analyzed on the log scale. RESULTS: We found weak evidence that enzalutamide outperforms AA with prednisone in terms of OS in the pre-docetaxel and post-docetaxel settings. However, we found strong evidence that enzalutamide outperforms AA with prednisone in terms of radiographic PFS, time until PSA progression, and PSA response rate in both the pre- and post-docetaxel settings. Rates of grade 3 or worse adverse events were broadly similar between treatment (enzalutamide or AA) and control arms (placebo or placebo with prednisone) in all included randomized studies. CONCLUSIONS: There is strong evidence that enzalutamide outperforms AA with prednisone in terms of radiographic PFS and PSA progression and PSA response rate but not OS in the pre and post-docetaxel settings. These results may further guide clinicians in making treatment recommendations for patients with advanced prostate cancer. Prostate 77: 639-646, 2017. © 2017 Wiley Periodicals, Inc.

Experimental infection of adult Scapharca broughtonii with Ostreid herpesvirus SB strain.

We investigated the susceptibility of ark shell, Scapharca broughtonii, adults to Ostreid herpesvirus SB strain (OsHV-1-SB) through experimental infection by intramuscular injection assays. Results showed the onset of mortality occurred at 3days post injection, one day after the water turbidity became evident in rearing tanks. The mortality curves for the challenged group were similar to those observed at affected hatcheries. Histological lesions, herpesvirus-like particles and high OsHV-1-SB quantities were detected in challenged ark shells. This is the first study to successfully reproduce OsHV-1 disease in Arcoida species, and very few studies in adult bivalves (over 24months old).

Applicability of Bipolar Charge Analyzer (BOLAR) in Characterizing the Bipolar Electrostatic Charge Profile of Commercial Metered Dose Inhalers (MDIs).

PURPOSE: To investigate the applicability of Bipolar Charge Analyzer (BOLAR), a new commercial instrument developed by Dekati Ltd., in simultaneously characterizing the bipolar electrostatic charge profile and measuring the size distribution of commercial metered dose inhalers (MDIs). METHODS: Intal Forte(®) (sodium cromoglycate), Tilade(®) (nedocromil sodium), Ventolin(®) (salbutamol sulphate), and QVAR(®) (beclomethasone dipropionate) were used as model MDIs in this study. Three individual actuations of each MDI were introduced into the BOLAR at an air flow rate of 60 l/min. Charge and mass profiles for each actuation were determined. RESULTS: The BOLAR was found to have better performance in collecting valid charge data (≥80%) than valid mass data (≥50%). In all tested products, both positively and negatively charged particles were found in five defined size fractions between zero and 11.6 µm, with the charge magnitude decreased with increasing particle size. The net charge profiles obtained from the BOLAR qualitatively agreed with the results reported previously. In all suspension type MDIs, negligible masses were detected in the smallest size fraction (<0.95 µm), for which the charge was most likely caused by the propellant and excipients. QVAR was the only solution MDI tested and the charge and mass profiles were significantly different from the suspension-type MDIs. Its mass profile was found to follow closely with the charge profile. CONCLUSIONS: Positively and negatively charged MDI particles of different size fractions and their corresponding charge-to-mass profiles were successfully characterized by the BOLAR.

Clarifying the best interests standard: the elaborative and enumerative strategies in public policy-making.

One recurring criticism of the best interests standard concerns its vagueness, and thus the inadequate guidance it offers to care providers. The lack of an agreed definition of 'best interests', together with the fact that several suggested considerations adopted in legislation or professional guidelines for doctors do not obviously apply across different groups of persons, result in decisions being made in murky waters. In response, bioethicists have attempted to specify the best interests standard, to reduce the indeterminacy surrounding medical decisions. In this paper, we discuss the bioethicists' response in relation to the state's possible role in clarifying the best interests standard. We identify and characterise two clarificatory strategies employed by bioethicists -elaborative and enumerative-and argue that the state should adopt the latter. Beyond the practical difficulties of the former strategy, a state adoption of it would inevitably be prejudicial in a pluralistic society. Given the gravity of best interests decisions, and the delicate task of respecting citizens with different understandings of best interests, only the enumerative strategy is viable. We argue that this does not commit the state to silence in providing guidance to and supporting healthcare providers, nor does it facilitate the abuse of the vulnerable. Finally, we address two methodological worries about adopting this approach at the state level. The adoption of the enumerative strategy is not defeatist in attitude, nor does it eventually collapse into (a form of) the elaborative strategy.

Accommodating Autistics and Treating Autism: Can We Have Both?

One of the central claims of the neurodiversity movement is that society should accommodate the needs of autistics, rather than try to treat autism. People have variously tried to reject this accommodation thesis as applicable to all autistics. One instance is Pier Jaarsma and Stellan Welin, who argue that the thesis should apply to some but not all autistics. They do so via separating autistics into high- and low-functioning, on the basis of IQ and social effectiveness or functionings. I reject their grounds for separating autistics. IQ is an irrelevant basis for separating autistics. Charitably rendering it as referring to more general capacities still leaves us mistaken about the roles they play in supporting the accommodation thesis. The appeal to social effectiveness or functionings relies on standards that are inapplicable to autistics, and which risks being deaf to the point of their claims. I then consider if their remaining argument concerning autistic culture may succeed independently of the line they draw. I argue that construing autistics' claims as beginning from culture mistakes their status, and may even detract from their aims. Via my discussion of Jaarsma and Welin, I hope to point to why the more general strategy of separating autistics, in response to the accommodation thesis, does not fully succeed. Finally, I sketch some directions for future discussions, arguing that we should instead shift our attention to consider another set of questions concerning the costs and extent of change required to accommodate all autistics.