Evaluation of early treatment with intravenous idursulfase and intrathecal idursulfase-IT on cognitive function in siblings with neuronopathic mucopolysaccharidosis II.

Mucopolysaccharidosis II (MPS II; Hunter syndrome; OMIM 309900) is a rare, X-linked, heterogeneous lysosomal storage disease. Approximately two-thirds of patients develop cognitive impairment, which is difficult to assess in clinical trials, partly owing to the variable nature of cognitive impairment. Analyzing data from siblings can help to minimize this heterogeneity. We report analyses of cognitive function from siblings with MPS II enrolled in clinical trials: a natural history study (NCT01822184), a randomized, open-label, phase 2/3 study of intravenous (IV) idursulfase with or without intrathecal idursulfase (idursulfase-IT; NCT02055118), and its extension (NCT2412787). Cognitive function was assessed using Differential Abilities Scales, Second Edition General Conceptual Ability (DAS-II GCA) scores; Bayley Scales of Infant and Toddler Development, Third Edition; and Vineland Adaptive Behavior Scales, Second Edition Adaptive Behavior Composite (VABS-II ABC). Seven sets of siblings (six pairs and one set of three) were included. All patients received IV idursulfase and 10 received subsequent idursulfase-IT. Younger siblings initiated IV idursulfase at an earlier age than their older sibling(s) in six of the sets; the younger sibling started treatment before 1 year of age in three sets. Monthly idursulfase-IT was generally associated with a stabilization of cognitive function: DAS-II GCA and VABS-II ABC scores were higher at age-matched assessments in the majority of those who either received idursulfase-IT earlier than their sibling or who received idursulfase-IT versus no idursulfase-IT. These data suggest that early initiation of intrathecal enzyme replacement therapy may stabilize or slow cognitive decline in some patients with neuronopathic MPS II.

Cognitive and adaptive behaviors associated with disease severity and genotype in patients with mucopolysaccharidosis II.

BACKGROUND: Mucopolysaccharidosis II (MPS II) is a rare, X-linked lysosomal storage disease caused by pathogenic variants of the iduronate-2-sulfatase gene (IDS) and is characterized by a highly variable disease spectrum. MPS II severity is difficult to predict based on IDS variants alone; while some genotypes are associated with specific phenotypes, the disease course of most genotypes remains unknown. This study aims to refine the genotype-phenotype categorization by combining information from the scientific literature with data from two clinical studies in MPS II. METHODS: Genotype, cognitive, and behavioral data from 88 patients in two clinical studies (NCT01822184, NCT02055118) in MPS II were analyzed post hoc in combination with published information on IDS variants from the biomedical literature through a semi-automated multi-stage review process. The Differential Ability Scales, second edition (DAS-II) and the Vineland Adaptive Behavior Scales™, second edition (VABS-II) were used to measure cognitive function and adaptive behavior. RESULTS: The most common category of IDS variant was missense (47/88, 53.4% of total variants). The mean (standard deviation [SD]) baseline DAS-II General Conceptual Ability (GCA) and VABS-II Adaptive Behavior Composite (ABC) scores were 74.0 (16.4) and 82.6 (14.7), respectively. All identified IDS complete deletions/large rearrangements (n = 7) and large deletions (n = 1) were associated with a published 'severe' or 'predicted severe' progressive neuronopathic phenotype, characterized by central nervous system involvement. In categories comprising more than one participant, mean baseline DAS-II GCA scores (SD) were lowest among individuals with complete deletions/large rearrangements 64.0 (9.1, n = 4) and highest among those with splice site variants 83.8 (14.2, n = 4). Mean baseline VABS-II ABC scores (SD) were lowest among patients with unclassifiable variants 79.3 (4.9, n = 3) and highest among those with a splice site variant 87.2 (16.1, n = 5), in variant categories with more than one participant. CONCLUSIONS: Most patients in the studies had an MPS II phenotype categorized as 'severe' or 'predicted severe' according to classifications, as reported in the literature. Patients with IDS complete deletion/large rearrangement variants had lower mean DAS-II GCA scores than those with other variants, as well as low VABS-II ABC, confirming an association with the early progressive 'severe' (neuronopathic) disease. These data provide a starting point to improve the classification of MPS II phenotypes and the characterization of the genotype-phenotype relationship.

Long-term open-label extension study of the safety and efficacy of intrathecal idursulfase-IT in patients with neuronopathic mucopolysaccharidosis II.

Enzyme replacement therapy with weekly infused intravenous (IV) idursulfase is effective in treating somatic symptoms of mucopolysaccharidosis II (MPS II; Hunter syndrome). A formulation of idursulfase for intrathecal administration (idursulfase-IT) is under investigation for the treatment of neuronopathic MPS II. Here, we report 36-month data from the open-label extension (NCT02412787) of a phase 2/3, randomized, controlled study (HGT-HIT-094; NCT02055118) that assessed the safety and efficacy of monthly idursulfase-IT 10 mg in addition to weekly IV idursulfase on cognitive function in children older than 3 years with MPS II and mild-to-moderate cognitive impairment. Participants were also enrolled in this extension from a linked non-randomized sub-study of children younger than 3 years at the start of idursulfase-IT therapy. The extension safety population comprised 56 patients who received idursulfase-IT 10 mg once a month (or age-adjusted dose for sub-study patients) plus IV idursulfase (0.5 mg/kg) once a week. Idursulfase-IT was generally well tolerated over the cumulative treatment period of up to 36 months. Overall, 25.0% of patients had at least one adverse event (AE) related to idursulfase-IT; most treatment-emergent AEs were mild in severity. Of serious AEs (reported by 76.8% patients), none were considered related to idursulfase-IT treatment. There were no deaths or discontinuations owing to AEs. Secondary efficacy analyses (in patients younger than 6 years at phase 2/3 study baseline; n = 40) indicated a trend for improved Differential Ability Scale-II (DAS-II) General Conceptual Ability (GCA) scores in the early idursulfase-IT versus delayed idursulfase-IT group (treatment difference over 36 months from phase 2/3 study baseline: least-squares mean, 6.8 [90% confidence interval: -2.1, 15.8; p = 0.2064]). Post hoc analyses of DAS-II GCA scores by genotype revealed a clinically meaningful treatment effect in patients younger than 6 years with missense variants of the iduronate-2-sulfatase gene (IDS) (least-squares mean [standard error] treatment difference over 36 months, 12.3 [7.24]). These long-term data further suggest the benefits of idursulfase-IT in the treatment of neurocognitive dysfunction in some patients with MPS II. After many years of extensive review and regulatory discussions, the data were found to be insufficient to meet the evidentiary standard to support regulatory filings.

Intrathecal idursulfase-IT in patients with neuronopathic mucopolysaccharidosis II: Results from a phase 2/3 randomized study.

Two-thirds of patients with mucopolysaccharidosis II (MPS II; Hunter syndrome) have cognitive impairment. This phase 2/3, randomized, controlled, open-label, multicenter study (NCT02055118) investigated the effects of intrathecally administered idursulfase-IT on cognitive function in patients with MPS II. Children older than 3 years with MPS II and mild-to-moderate cognitive impairment (assessed by Differential Ability Scales-II [DAS-II], General Conceptual Ability [GCA] score) who had tolerated intravenous idursulfase for at least 4 months were randomly assigned (2:1) to monthly idursulfase-IT 10 mg (n = 34) via an intrathecal drug delivery device (IDDD; or by lumbar puncture) or no idursulfase-IT treatment (n = 15) for 52 weeks. All patients continued to receive weekly intravenous idursulfase 0.5 mg/kg as standard of care. Of 49 randomized patients, 47 completed the study (two patients receiving idursulfase-IT discontinued). The primary endpoint (change from baseline in DAS-II GCA score at week 52 in a linear mixed-effects model for repeated measures analysis) was not met: although there was a smaller decrease in DAS-II GCA scores with idursulfase-IT than with no idursulfase-IT at week 52, this was not significant (least-squares mean treatment difference [95% confidence interval], 3.0 [-7.3, 13.3]; p = 0.5669). Changes from baseline in Vineland Adaptive Behavioral Scales-II Adaptive Behavior Composite scores at week 52 (key secondary endpoint) were similar in the idursulfase-IT (n = 31) and no idursulfase-IT (n = 14) groups. There were trends towards a potential positive effect of idursulfase-IT across DAS-II composite, cluster, and subtest scores, notably in patients younger than 6 years at baseline. In a post hoc analysis, there was a significant (p = 0.0174), clinically meaningful difference in change from baseline in DAS-II GCA scores at week 52 with idursulfase-IT (n = 13) versus no idursulfase-IT (n = 6) among those younger than 6 years with missense iduronate-2-sulfatase gene variants. Overall, idursulfase-IT reduced cerebrospinal glycosaminoglycan levels from baseline by 72.0% at week 52. Idursulfase-IT was generally well tolerated. These data suggest potential benefits of idursulfase-IT in the treatment of cognitive impairment in some patients with neuronopathic MPS II. After many years of extensive review and regulatory discussions, the data were found to be insufficient to meet the evidentiary standard to support regulatory filings.

Caregiver experiences and observations of intrathecal idursulfase-IT treatment in a phase 2/3 trial in pediatric patients with neuronopathic mucopolysaccharidosis II.

BACKGROUND: Approximately two-thirds of patients with mucopolysaccharidosis II (MPS II) have a severe, neuronopathic phenotype, characterized by somatic, cognitive, and behavioral issues. Current standard of care for the treatment of MPS II is enzyme replacement therapy with intravenous recombinant human iduronate-2-sulfatase (idursulfase). To target cognitive manifestations of MPS II, idursulfase has been formulated for intrathecal administration into the cerebrospinal fluid (idursulfase-IT). In accordance with recommendations for patient-focused drug development, semi-structured interviews were conducted to assess caregiver experiences and observations in a 52-week phase 2/3 trial of idursulfase-IT, in addition to intravenous idursulfase in pediatric patients with neuronopathic MPS II, or a substudy which enrolled patients younger than 3 years old, all of whom received idursulfase-IT. RESULTS: Overall, 46 caregivers providing care for 50 children (mean [range] age 7.9 [3-17] years at interview) took part in a single 60-min exit interview; six of these children had participated in the substudy. Qualitative and quantitative data were obtained demonstrating the burden of MPS II experienced by caregivers and their families. Following participation in the trials, 39 (78%) of the children were reported by their caregivers to have experienced improvements in the symptoms and impact of disease. Of those with improvements, 37 (95%) experienced cognitive improvements and 26 (67%) experienced emotional/behavioral improvements. Overall, 43 children (86%) were rated by caregivers as having moderate or severe symptoms before the trials; after the trials, 28 children (56%) were considered to have mild or no symptoms. For the six children who participated in the substudy, these proportions were 83% and 100%, respectively. Caregivers' qualitative descriptions of trial experiences suggested improvements in children's verbal and non-verbal functioning and spatial and motor skills, as well as a positive impact on family life. CONCLUSIONS: This study revealed caregiver-reported improvements in children's MPS II symptoms and the impact of the disease on patients and their families. There was a trend for cognitive improvement and a reduction in severity of MPS II symptoms. After many years of extensive review and regulatory discussions of idursulfase-IT, the clinical trial data were found to be insufficient to meet the evidentiary standard to support regulatory filings.

Clinical investigator perspectives on patient outcomes in children with neuronopathic mucopolysaccharidosis II during intrathecal idursulfase-IT treatment.

BACKGROUND: Mucopolysaccharidosis II (MPS II) is a rare lysosomal storage disease characterized by iduronate-2-sulfatase gene (IDS) deficiency and downstream glycosaminoglycan accumulation. Two-thirds of patients present with neuronopathic disease and evaluating cognitive function in these patients is challenging owing to limitations of currently available tests. During the clinical development of intrathecal idursulfase (idursulfase-IT), regulatory authorities requested qualitative data to further understand the neurocognitive changes observed by the investigators through the clinical trials. RESULTS: This qualitative study consisted of semi-structured interviews with all nine of the principal investigators who participated in the idursulfase-IT phase 2/3 (NCT02055118) and extension (NCT02412787) trials. These investigators enrolled the 56 patients with neuronopathic MPS II who qualified for the extension phase of the trial. The investigators were asked to rate the disease status of their patients. Of the 56 patients, 49 (88%) were rated as having disease that was improved/improving, stabilized or slowing progression compared with the expected outcomes with no treatment. Three patients were rated as worsening, while the remaining four patients were considered to have slowing progression or worsening disease. Similar results were demonstrated for patients aged from 3 to under 6 years at baseline, with 33 of 39 patients (85%) rated as having disease that was improved/improving, stabilized or slowing progression. Of the seven patients rated with slowing progression/worsening or worsening disease, five of them had an IDS variant other than missense, while two had a missense class variant. All the assigned improved/improving ratings were in patients receiving idursulfase-IT from the start of the phase 2/3 trial. Moreover, patients under 3 years of age at baseline were all rated as either improved/improving or stabilized disease. In a blinded review of patient profiles, investigators were requested to assign a disease status rating to 18 patients with large IDS deletions; 67% of these patients were rated as improved/improving or stabilized disease. CONCLUSIONS: This qualitative analysis provides a snapshot of clinicians' considerations when evaluating treatment in patients with neuronopathic MPS II, compared with the expected decline in cognitive function in the absence of treatment. The results highlight the importance of robust assessment tools in treatment evaluation.

A Systematic Literature Review on the Global Status of Newborn Screening for Mucopolysaccharidosis II.

A systematic literature review was conducted to determine the global status of newborn screening (NBS) for mucopolysaccharidosis (MPS) II (Hunter syndrome; OMIM 309900). Electronic databases were searched in July 2023 for articles referencing NBS for lysosomal storage diseases: 53 featured MPS II. Until recently, only Taiwan and two US states (Illinois and Missouri) formally screened newborns for MPS II, although pilot programs have been conducted elsewhere (Japan, New York, and Washington). In 2022, MPS II was added to the US Recommended Uniform Screening Panel, with increased uptake of NBS anticipated across the USA. While the overall MPS II birth prevalence, determined from NBS initiatives, was higher than in previous reports, it was lower in the USA (approximately 1 in 73,000 according to recent studies in Illinois and Missouri) than in Asia (approximately 1 in 15,000 in Japan). NBS programs typically rely on tandem mass spectrometry quantification of iduronate-2-sulfatase activity for first-tier testing. Diagnosis is often confirmed via molecular genetic testing and/or biochemical testing but may be complicated by factors such as pseudodeficiency alleles and variants of unknown significance. Evidence relating to MPS II NBS is lacking outside Taiwan and the USA. Although broad benefits of NBS are recognized, few studies specifically explored the perspectives of families of children with MPS II.

A post hoc analysis of Projected Retained Ability Scores (PRAS) for the longitudinal assessment of cognitive functioning in patients with neuronopathic mucopolysaccharidosis II receiving intrathecal idursulfase-IT.

BACKGROUND: Norm-based scores used to assess cognitive ability have clinical value when describing functioning of patients with neuronopathic disorders compared with unaffected, same-age peers. However, they have limitations when used to assess change in cognitive ability between two timepoints, especially in children with severe cognitive decline. Calculation of Projected Retained Ability Scores (PRAS) is a novel method developed to characterize absolute change in norm-based ability test scores. In this analysis, PRAS were calculated post hoc for children with mucopolysaccharidosis II (MPS II; Hunter syndrome) and early cognitive impairment in a 52-week phase 2/3 randomized controlled trial (RCT) and its extension study of intrathecal idursulfase (idursulfase-IT). Patients completing the first year of the extension after receiving idursulfase-IT in the RCT and extension (n = 32 of 34 enrolled) or the extension only (n = 15 of 15 enrolled) were categorized according to changes in Differential Ability Scales, Second Edition, General Conceptual Ability (DAS-II GCA) scores and PRAS at 1 and 2 years. Analyses were conducted in the overall population and a subpopulation aged < 6 years at baseline (idursulfase-IT in the RCT and extension [n = 27] and extension only [n = 12]). RESULTS: PRAS methodology differentiated patients with decreases in DAS-II GCA scores into three separate categories reflecting below-average cognitive growth rates, plateauing cognitive development, and deteriorating cognitive functioning. After 1 year in the RCT, 72.4% of patients who initiated idursulfase-IT had above-average or average cognitive growth rates in DAS-II GCA scores compared with 53.3% of those who did not receive idursulfase-IT; 6.9% versus 20.0% experienced deteriorating cognitive functioning. Similar results were seen in children aged < 6 years: 76% (idursulfase-IT group) versus 50% (no idursulfase-IT) had above-average or average cognitive growth rates in DAS-II GCA scores; 4% versus 17% had deteriorating cognitive functioning. The difference in the distributions of cognitive categories at 1 year in children aged < 6 years was significant (p = 0.048). At 2 years, the proportions of patients in different cognitive categories were more similar between treatment groups. CONCLUSIONS: PRAS methodology may help to differentiate changes in cognitive development in MPS II, and therefore may represent a valuable addition to existing approaches for interpreting changes in cognitive scores over time. TRIAL REGISTRATION: ClinicalTrials.gov NCT02055118 (registration date: 4 February 2014) and NCT02412787 (registration date: 9 April 2015).

Clinical Characteristics and Healthcare Resource Utilization for Patients with Mucopolysaccharidosis II (MPS II) in the United States: A Retrospective Chart Review.

Background: Mucopolysaccharidosis II (MPS II; Hunter syndrome) is a rare, X-linked, life-limiting lysosomal storage disease characterized by a deficiency in the activity of the enzyme iduronate-2-sulfatase. Accumulation of glycosaminoglycans in tissues and organs throughout the body causes cellular damage, leading to multisystemic disease manifestations. Patients generally require multidisciplinary care across a wide range of specialties. Objectives: The aims of this study were to assess the healthcare needs of patients with MPS II and to explore the impact of treatment on disease burden and healthcare resource utilization. Methods: A retrospective review of medical charts from 19 US sites was performed. Data were analyzed from 140 male patients diagnosed with MPS II (defined as a documented deficiency in iduronate-2-sulfatase) between 1997 and 2017. The prevalence and age at onset of clinical manifestations and extent and frequency of healthcare resource use were evaluated. Results: Of the patients in this study, 77.1% had received enzyme replacement therapy with intravenous idursulfase and 62.1% had cognitive impairment. The clinical burden among patients was substantial: almost all patients had ear, nose, and throat abnormalities (95.7%); musculoskeletal abnormalities (95.0%); and joint stiffness or abnormalities (90.7%). Of the most prevalent disease manifestations, facial dysmorphism and hepatosplenomegaly were documented the earliest (median age at first documentation of 3.8 years in both cases). Hospitalizations, emergency department visits, and outpatient visits were reported for 51.2%, 58.5%, and 93.5% of patients, respectively, with a frequency of 0.1, 0.2, and 3.0 per patient per year, respectively. Surgery was also common, with 91.1% of patients having undergone at least 1 surgical procedure. The clinical burden and prevalence and frequency of resource use were generally similar in patients who had received enzyme replacement therapy and in those who had not. Conclusions: These results add to our understanding of the natural history of MPS II and indicate that the disease burden and healthcare needs of patients with this progressive disease are extensive. Increased understanding of disease burden and resource use may enable the development of models of healthcare resource utilization in patients with MPS II and contribute to improvements in disease management and patient care.

Impact of the Timing of Enzyme Replacement Therapy Initiation and Cognitive Impairment Status on Outcomes for Patients with Mucopolysaccharidosis II (MPS II) in the United States: A Retrospective Chart Review.

Background: Mucopolysaccharidosis II (MPS II; Hunter syndrome; OMIM 309900) is a rare, X-linked, lysosomal storage disease caused by deficient iduronate-2-sulfatase activity. Accumulation of glycosaminoglycans results in multisystemic disease manifestations, which may include central nervous system involvement and cognitive impairment (CI). Patients with MPS II experience a high disease burden, leading to extensive healthcare resource utilization (HRU) and reduced quality of life. Objectives: This study aimed to assess the impact of timing of enzyme replacement therapy (ERT) initiation and CI status on the clinical characteristics and HRU of patients with MPS II. Methods: A retrospective medical chart review of 140 male patients who received a diagnosis of MPS II between 1997 and 2017 was performed at 19 US sites; data on disease manifestations and HRU stratified by age at ERT initiation or CI status were analyzed for the full study population and a subgroup of patients who received a diagnosis of MPS II before the age of 6 years. Results: In patients initiating ERT before 3 years of age, there was a trend toward lower symptom burden and HRU compared with patients who initiated ERT at an older age. Evaluation of developmental and behavioral signs and symptoms in the full study population showed that communication delay (70.0% of patients), cognitive delay (62.1%), behavioral problems (52.9%), and toileting delay (50.0%) were particularly common; earliest documented signs and symptoms were motor delay (median [range] age at first documentation: 4.2 [0.9-18.7] years) and behavioral problems (4.4 [0.6-13.7] years). Patients with CI generally experienced greater symptom burden and higher HRU than those without CI, with the most notable differences documented for communication and toileting delays. Formal cognitive testing was documented in <30% of cognitively impaired patients diagnosed with MPS II before the age of 6 years. Conclusions: Our findings reinforce previous recommendations for ERT to be initiated early to maximally benefit patients with MPS II, especially those younger than 3 years old. Cognitively impaired patients experience a particularly high disease burden and HRU. Patient care could be improved with early cognitive assessments and the development of treatments that address cognitive decline.

Prevalence of low pathogenicity avian influenza virus during 2005 in two U.S. live bird market systems.

Oropharyngeal and cloacal swabs were collected from poultry sold in two live bird market (LBM) systems to estimate the prevalence of low pathogenicity avian influenza virus (LPAIV) shedding during the summer and fall of 2005. Random sampling was conducted in three LBMs in Minnesota where 50 birds were sampled twice weekly for 4 wk, and in three LBMs in a California marketing system. A stratified systematic sampling method was used to collect samples from Southern California LBMs, where LPAIV was detected during routine surveillance. No LPAIV was detected in the LBM system in Minnesota where realtime reverse transcription-PCR (RT-PCR) was conducted on oropharyngeal samples. RT-PCR was performed on swabs taken from 290 of 14,000, 65 of 252, and 60 of 211 birds at the three Southern California LBMs. The number of samples collected was based on the number of birds, age of the birds, and number of species present in the LBM. Virus isolation, subtyping, and sequencing of the hemagglutinin, neuraminidase, and other internal protein genes was performed on AIV-positive samples. The estimated prevalence of LPAIV in California was 0.345% in an LBM/supply farm with multiple ages of Japanese quail, 3% in an LBM with multiple ages and strains of chickens present, and 49.8% in an LBM with multiple species, multiple strains, and multiple ages. The positive virus samples were all LPAIV H6N2 and closely related to viruses isolated from Southern California in 2001 and 2004. Little or no comingling of poultry may contribute to little or no LPAIV detection in the LBMs.

Projected Retained Ability Score (PRAS): A New Methodology for Quantifying Absolute Change in Norm-Based Psychological Test Scores Over Time.

A limitation of norm-based ability test scores is that they can only be used to evaluate relative change (compared with change in the norm sample), as opposed to absolute (raw) change in performance from Time 1 to Time 2. To address this limitation, a novel method (Projected Retained Ability Score [PRAS]) was developed to characterize absolute change in norm-based ability test scores. The PRAS method was applied to Differential Ability Scales®-Second Edition (DAS-II) General Conceptual Ability (GCA) scores in three cases of children with the neurodegenerative condition mucopolysaccharidosis type II (MPS II) who were assessed at two visits, 16 to 23 months apart. Although all three cases showed declines in norm-based GCA scores, the PRAS method revealed differences in absolute change in performance. The PRAS method allows for differentiation of slower-than-average improvement or stabilization versus deterioration of cognitive ability when norm-based scores decline from Time 1 to Time 2.

Analysis of cognitive ability and adaptive behavior assessment tools used in an observational study of patients with mucopolysaccharidosis II.

BACKGROUND: Mucopolysaccharidosis II (MPS II) is a rare lysosomal storage disease characterized by cognitive impairment in most patients. This post hoc analysis evaluated changes in cognitive function, adaptive behavior and functional outcomes in patients with neuronopathic MPS II over time. Fifty-five children with MPS II were enrolled in a 24-month observational study (NCT01822184). The Differential Ability Scales, second edition (DAS-II; early years battery for ages 2 years 6 months to 6 years 11 months, school age battery for ages 7 years to 17 years 11 months), Vineland Adaptive Behavior Scales, second edition (VABS-II) and the Hunter Syndrome-Functional Outcomes for Clinical Understanding Scale (HS-FOCUS) were performed at baseline and 3-month intervals over 2 years. A subgroup of 38 children with a DAS-II General Conceptual Ability (GCA) score of 55-85 (below average-very low abilities) at any time during the study were included in this analysis. RESULTS: Mean (standard deviation [SD]) early years DAS-II GCA score decreased from 73.4 (15.7, n = 22) at baseline to 62.7 (34.9, n = 6) at month 24. For the six patients with early years GCA assessments at baseline and month 24, mean (SD) GCA scores decreased from 72.3 (21.3) at baseline to 62.7 (34.9) at month 24. School age GCA scores were stable over 2 years: mean (SD) 72.4 (11.8, n = 10) at baseline; 74.3 (12.3, n = 8) at month 24. Mean (SD) VABS-II Adaptive Behavior Composite (ABC) scores were stable throughout the study (baseline, 81.8 [11.8, n = 36]; month 24, 81.0 [10.2, n = 13]). Some associations between items and domains of HS-FOCUS (p < 0.05) and DAS-II GCA and VABS-II ABC scores were shown, but there was no clear pattern of changes in HS-FOCUS over 2 years. CONCLUSIONS: The DAS-II measured changes in cognitive function over 2 years in younger patients with MPS II, whereas cognitive function in older patients remained stable. Further research is required to confirm the content validity of the DAS-II in different patient populations with MPS II. The VABS-II and HS-FOCUS were not sensitive tools for measuring behavioral and functional changes over 2 years. These findings may inform selection of appropriate cognitive and behavioral assessment tools for future studies.

Evaluating functional disability in clinical trials of lisdexamfetamine dimesylate in binge eating disorder using the Sheehan Disability Scale.

OBJECTIVES: This study examined Sheehan Disability Scale (SDS) performance in binge eating disorder (BED) and explored relationships between SDS and BED outcomes using data from three placebo-controlled lisdexamfetamine (LDX) studies (two short-term, dose-optimized studies and one double-blind, randomized-withdrawal study) in adults with Diagnostic and Statistical Manual of Mental Disorders, fourth edition, text revision (DSM-IV-TR)-defined BED. METHODS: Analyses evaluated the psychometric properties of the SDS. RESULTS: Confirmatory factor analysis supported a unidimensional total score in the short-term studies, with internal consistency (Cronbach's α) being 0.878. Total score exhibited good construct validity, with moderate and statistically significant correlations observed with Yale-Brown Obsessive Compulsive Scale modified for binge eating, Binge Eating Scale (BES), and EuroQol Group 5-Dimension 5-Level health status index scores. Known-groups validity analysis for the short-term studies demonstrated a significantly lower total score at end of study in participants considered "not ill" versus "ill" based on Clinical Global Impressions-Severity scores. SDS total score changes in the short-term studies were greater in responders than nonresponders based on binge eating abstinence or BES score. In the randomized-withdrawal study, SDS scores increased relative to baseline to a greater extent in participants randomized to placebo than LDX. CONCLUSIONS: These analyses support the reliability, validity, and responsiveness to change of the SDS in individuals with BED.

Transmission of low-pathogenicity avian influenza virus of subtype H6N2 from chickens to Pekin ducks and Japanese quail (Coturnix coturnix japonica).

In this experiment we evaluated the transmission characteristics of a chicken-adapted low-pathogenicity avian influenza virus (LPAIV) of subtype H6N2, from infected chickens to Japanese quail and Pekin ducks, which are commonly sold in live bird markets located in Southern California. The layout of the cages and bird-handling practices were similar to those found in Southern California live bird markets. Five out of 20 chickens were inoculated with LPAIV H6N2, and placed in direct contact with five chickens and in indirect contact with 10 chickens, 10 Japanese quail and 10 Pekin ducks. Transmission of LPAIV was followed in each bird daily for 15 days post inoculation by real-time reverse transcriptase-polymerase chain reaction testing of oropharyngeal and cloacal swab samples. This strain of H6N2 LPAIV, isolated from commercial poultry in California, was transmitted to chickens, quail, and ducks from chickens. An antibody response was detected in ducks by haemagglutination inhibition tests, but avian influenza virus was only detected by reverse transcriptase-polymerase chain reaction in one duck. Avian influenza virus was detected in quail (5 and 7 days post inoculation) before chickens (8 and 9 days post inoculation), all of which were in indirect contact with infected chickens; however, this difference was not statistically significant.

The live bird market system and low-pathogenic avian influenza prevention in southern California.

Although live bird markets (LBMs) have been associated with outbreaks of avian influenza (AI), there are some LBM systems where AI outbreaks are extremely rare events. The California LBMs have not had any detected avian influenza viruses (AIVs) since December 2005. Responses to a detailed questionnaire on the practices and characteristics of the participants in the California low-pathogenic (LP) AI control program have been described to characterize possible reasons for the lack of AI outbreaks in LBMs. Compliance with an LPAI control program that contains active surveillance, prevention, and rapid response measures by those involved in the LBM system, rendering services to dispose of carcasses, no wholesalers, and few third-party bird deliveries was associated with the lack of LPAIV circulating in the Southern California LBM system.

Alternate RASSF1 Transcripts Control SRC Activity, E-Cadherin Contacts, and YAP-Mediated Invasion.

Tumor progression to invasive carcinoma is associated with activation of SRC family kinase (SRC, YES, FYN) activity and loss of cellular cohesion. The hippo pathway-regulated cofactor YAP1 supports the tumorigenicity of RAS mutations but requires both inactivation of hippo signaling and YES-mediated phosphorylation of YAP1 for oncogenic activity. Exactly how SRC kinases are activated and hippo signaling is lost in sporadic human malignancies remains unknown. Here, we provide evidence that hippo-mediated inhibition of YAP1 is lost upon promoter methylation of the RAS effector and hippo kinase scaffold RASSF1A. We find that RASSF1A promoter methylation reduces YAP phospho-S127, which derepresses YAP1, and actively supports YAP1 activation by switching RASSF1 transcription to the independently transcribed RASSF1C isoform that promotes Tyr kinase activity. Using affinity proteomics, proximity ligation, and real-time molecular visualization, we find that RASSF1C targets SRC/YES to epithelial cell-cell junctions and promotes tyrosine phosphorylation of E-cadherin, ß-catenin, and YAP1. RASSF1A restricts SRC activity, preventing motility, invasion, and tumorigenesis in vitro and in vivo, with epigenetic inactivation correlating with increased inhibitory pY527-SRC in breast tumors. These data imply that distinct RASSF1 isoforms have opposing functions, which provide a biomarker for YAP1 activation and explain correlations of RASSF1 methylation with advanced invasive disease in humans. The ablation of epithelial integrity together with subsequent YAP1 nuclear localization allows transcriptional activation of ß-catenin/TBX-YAP/TEAD target genes, including Myc, and an invasive phenotype. These findings define gene transcript switching as a tumor suppressor mechanism under epigenetic control.