Some theories have proposed that autistic individuals have difficulty learning predictive relationships. We tested this hypothesis using a serial reaction time task in which participants learned to ...predict the locations of a repeating sequence of target locations. We conducted a large-sample online study with 61 autistic and 71 neurotypical adults. The autistic group had slower overall reaction times, but demonstrated sequence-specific learning equivalent to the neurotypical group, consistent with other findings of typical procedural memory in autism. The neurotypical group, however, made significantly more prediction-related errors early in the experiment when the stimuli changed from repeated sequences to random locations, suggesting certain limited behavioural differences in the learning or utilization of predictive relationships for autistic adults.
Chronic thromboembolic pulmonary hypertension (CTEPH) is an under-diagnosed complication of acute pulmonary embolism (PE), whereby there is incomplete resolution of pulmonary emboli, which then ...become organized into obstructive fibrotic material with an associated small vessel vasculopathy. CTEPH is diagnosed by abnormal lung perfusion despite 3-months of oral anticoagulation with persistent pulmonary artery thromboembolic/ fibrotic material confirmed on cross sectional imaging and pulmonary hypertension on right heart catheterization. Without treatment the prognosis is bleak, but there are now three treatment modalities that are effective in treating patients with CTEPH: pulmonary endarterectomy (PEA) surgery, balloon pulmonary angioplasty (BPA) and medical therapy.
We provide a comprehensive review of the literature with particular emphasis on the epidemiology, pathophysiology, diagnosis, and the established and emerging treatments of CTEPH.
It is important to recognize that CTEPH is complication of an acute PE as there are effective and sometimes curative treatments available. In European and North American practice, PEA surgery remains the cornerstone of therapy in patients with CTEPH and accessible disease without significant comorbidity. For those patients with a disease burden that is inaccessible or fails to justify the risk of major surgery, initiating medical therapy and considering BPA is appropriate. Those with persistent pulmonary hypertension after PEA should also receive medical therapy and be considered for BPA or re-do endarterectomy. The available therapies are not necessarily mutually exclusive, and the treatment decision is often subjective and individualized, based on the local available expertise. Further research is needed to understand the optimal treatment strategy for patients and in particular to identify 'responders' and assess the synergies between these three treatment strategies.
Chronic thromboembolic pulmonary hypertension (CTEPH) is an important consequence of pulmonary embolism that is associated with abnormalities in haemostasis. We investigated the ADAMTS13-von ...Willebrand factor (VWF) axis in CTEPH, including its relationship with disease severity, inflammation,
groups and
genetic variants.ADAMTS13 and VWF plasma antigen levels were measured in patients with CTEPH (n=208), chronic thromboembolic disease without pulmonary hypertension (CTED) (n=35), resolved pulmonary embolism (n=28), idiopathic pulmonary arterial hypertension (n=30) and healthy controls (n=68). CTEPH genetic
associations and protein quantitative trait loci were investigated. ADAMTS13-VWF axis abnormalities were assessed in CTEPH and healthy control subsets by measuring ADAMTS13 activity, D-dimers and VWF multimeric size.Patients with CTEPH had decreased ADAMTS13 (adjusted β -23.4%, 95% CI -30.9- -15.1%, p<0.001) and increased VWF levels (β +75.5%, 95% CI 44.8-113%, p<0.001) compared to healthy controls. ADAMTS13 levels remained low after reversal of pulmonary hypertension by pulmonary endarterectomy surgery and were equally reduced in CTED. We identified a genetic variant near the
gene associated with ADAMTS13 protein that accounted for ∼8% of the variation in levels.The ADAMTS13-VWF axis is dysregulated in CTEPH. This is unrelated to pulmonary hypertension, disease severity or markers of systemic inflammation and implicates the ADAMTS13-VWF axis in CTEPH pathobiology.
Pegylated interferon plus ribavirin therapy for hepatitis C virus (HCV) fails in approximately half of genotype 1 patients. Treatment failure occurs either by nonresponse (minimal declines in viral ...titer) or relapse (robust initial responses followed by rebounds of viral titers during or after therapy). HCV is highly variable genetically. To determine if viral genetic differences contribute to the difference between response and relapse, we examined the inter-patient genetic diversity and mutation pattern in the full open reading frame HCV genotype 1a consensus sequences.
Pre- and post-therapy sequences were analyzed for 10 nonresponders and 10 relapsers from the Virahep-C clinical study. Pre-therapy interpatient diversity among the relapsers was higher than in the nonresponders in the viral NS2 and NS3 genes, and post-therapy diversity was higher in the relapsers for most of HCV's ten genes. Pre-therapy diversity among the relapsers was intermediate between that of the non-responders and responders to therapy. The average mutation rate was just 0.9% at the amino acid level and similar numbers of mutations occurred in the nonresponder and relapser sequences, but the mutations in NS2 of relapsers were less conservative than in nonresponders. Finally, the number and distribution of regions under positive selection was similar between the two groups, although the nonresponders had more foci of positive selection in E2.
The HCV sequences were unexpectedly stable during failed antiviral therapy, both nonresponder and relapser sequences were under selective pressure during therapy, and variation in NS2 may have contributed to the difference in response between the nonresponder and relapser groups. These data support a role for viral genetic variability in determining the outcome of anti-HCV therapy, with those sequences that are more distant from an optimal sequence being less able to resist the pressures of interferon-based therapy.
ClinicalTrials.gov NCT00038974.
Hepatitis C virus (HCV) is a common RNA virus that causes hepatitis and liver cancer. Infection is treated with IFN-alpha and ribavirin, but this expensive and physically demanding therapy fails in ...half of patients. The genomic sequences of independent HCV isolates differ by approximately 10%, but the effects of this variation on the response to therapy are unknown. To address this question, we analyzed amino acid covariance within the full viral coding region of pretherapy HCV sequences from 94 participants in the Viral Resistance to Antiviral Therapy of Chronic Hepatitis C (Virahep-C) clinical study. Covarying positions were common and linked together into networks that differed by response to therapy. There were 3-fold more hydrophobic amino acid pairs in HCV from nonresponding patients, and these hydrophobic interactions were predicted to contribute to failure of therapy by stabilizing viral protein complexes. Using our analysis to detect patterns within the networks, we could predict the outcome of therapy with greater than 95% coverage and 100% accuracy, raising the possibility of a prognostic test to reduce therapeutic failures. Furthermore, the hub positions in the networks are attractive antiviral targets because of their genetic linkage with many other positions that we predict would suppress evolution of resistant variants. Finally, covariance network analysis could be applicable to any virus with sufficient genetic variation, including most human RNA viruses.
Hepatitis C virus (HCV) has six major genotypes, and patients infected with genotype 1 respond less well to interferon-based therapy than other genotypes. African American patients respond to ...interferon alpha-based therapy at about half the rate of Caucasian Americans. The effect of HCV's genetic variation on treatment outcome in both racial groups is poorly understood.
We determined the near full-length pre-therapy consensus sequences from 94 patients infected with HCV genotype 1a or 1b undergoing treatment with peginterferon alpha-2a and ribavirin through the Virahep-C study. The sequences were stratified by genotype, race and treatment outcome to identify HCV genetic differences associated with treatment efficacy.
HCV sequences from patients who achieved sustained viral response were more diverse than sequences from non-responders. These inter-patient diversity differences were found primarily in the NS5A gene in genotype 1a and in core and NS2 in genotype 1b. These differences could not be explained by host selection pressures. Genotype 1b but not 1a African American patients had viral genetic differences that correlated with treatment outcome.
Higher inter-patient viral genetic diversity correlated with successful treatment, implying that there are HCV genotype 1 strains with intrinsic differences in sensitivity to therapy. Core, NS3 and NS5A have interferon-suppressive activities detectable through in vitro assays, and hence these activities also appear to function in human patients. Both preferential infection with relatively resistant HCV variants and host-specific factors appear to contribute to the unusually poor response to therapy in African American patients.
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