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Hoi Nam Tse,1 Cee Zhung Steven Tseng,1 King Ying Wong,2 Kwok Sang Yee,2 Lai Yun Ng1 1Medical and Geriatric Department, Respiratory Unit, Kwong Wah Hospital, 2Department of Tuberculosis and Chest Unit, Wong Tai Sin Hospital, Hong Kong, People’s Republic of China Introduction: Performing lung function test in geriatric patients has never been an easy task. With well-established evidence indicating impaired small airway function and air trapping in patients with geriatric COPD, utilizing forced oscillation technique (FOT) as a supplementary tool may aid in the assessment of lung function in this population. Aims: To study the use of FOT in the assessment of airflow limitation and air trapping in geriatric COPD patients. Study design: A cross-sectional study in a public hospital in Hong Kong. ClinicalTrials.gov ID: NCT01553812. Methods: Geriatric patients who had spirometry-diagnosed COPD were recruited, with both FOT and plethysmography performed. “Resistance” and “reactance” FOT parameters were compared to plethysmography for the assessment of air trapping and airflow limitation. Results: In total, 158 COPD subjects with a mean age of 71.9±0.7 years and percentage of forced expiratory volume in 1 second of 53.4±1.7 L were recruited. FOT values had a good correlation (r=0.4–0.7) to spirometric data. In general, X values (reactance) were better than R values (resistance), showing a higher correlation with spirometric data in airflow limitation (r=0.07–0.49 vs 0.61–0.67), small airway (r=0.05–0.48 vs 0.56–0.65), and lung volume (r=0.12–0.29 vs 0.43–0.49). In addition, resonance frequency (Fres) and frequency dependence (FDep) could well identify the severe type (percentage of forced expiratory volume in 1 second

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.

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., (© 2024 The Author(s). Journal of Inherited Metabolic Disease published by John Wiley & Sons Ltd on behalf of SSIEM.)

Competing Interests: IZ and JJ are employees of PRECISIONheor, who received funding from Alexion Pharmaceuticals to support this work. BY, AK, and KY are employees and stockholders of Alexion Pharmaceuticals, AstraZeneca Rare Disease. The authors declare that this study received funding from Alexion Pharmaceuticals. The funder had the following involvement in the study: decision to submit it for publication and provision of publication fees.

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., (© 2024. The Author(s).)

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., (© 2024. The Author(s).)

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)., (© 2023. The Author(s).)

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., Competing Interests: Declaration of Competing Interest David Merberg, Madhusudan Natarajan, Scarlett Wang, David A.H. Whiteman and Yuna Wu are employees of Takeda Development Center Americas, Inc., and stockholders of Takeda Pharmaceuticals Company Limited. Karen S. Yee (now with Alexion Pharmaceuticals, Inc., AstraZeneca Rare Disease) and David Alexanderian (now with Merck, Inc.) were employees of Takeda and stockholders of Takeda Pharmaceuticals Company Limited at the time of the study and of the writing of the manuscript., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

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., Competing Interests: Declaration of Competing Interest Joseph Muenzer has received consulting fees/other remuneration from Denali Therapeutics, JCR Pharmaceuticals, REGENXBIO, Sangamo Therapeutics, Sanofi Genzyme, and Takeda (Shire); has participated in advisory boards for BioMarin Pharmaceutical, Denali Therapeutics, JCR Pharmaceuticals, Sanofi Genzyme, and Takeda; and has received research support from BioMarin Pharmaceutical, Denali Therapeutics, and Takeda. Barbara K. Burton has received consulting fees/other remuneration from Alexion Pharmaceuticals, Applied Therapeutics, BioMarin Pharmaceutical, Capsida Biotherapeutics, Denali Therapeutics, Horizon Therapeutics, JCR Pharmaceuticals, Moderna, Passage Bio, Sanofi Genzyme, Sio Gene Therapies, Takeda, and Ultragenyx Pharmaceutical; has participated in advisory boards or similar committees for Alexion Pharmaceuticals, BioMarin Pharmaceutical, and Takeda; and has received research support from Alexion Pharmaceuticals, BioMarin Pharmaceutical, Denali Therapeutics, Homology Medicines, JCR Pharmaceuticals, Sangamo Therapeutics, Takeda, and Ultragenyx Pharmaceutical. Paul Harmatz has received consulting fees/other remuneration from Aeglea, Alexion Pharmaceuticals, ArmaGen, AVROBIO, Audentes, BioMarin Pharmaceutical, Capsida Biotherapeutics, Chiesi, Denali Therapeutics, Enzyvant, Fondazione Telethon, Inventiva Pharma, JCR Pharmaceuticals, Orphazyme, Paradigm, PTC Therapeutics, REGENXBIO, Sangamo Therapeutics, Sanofi Genzyme, Takeda, and Ultragenyx Pharmaceutical; and has received research support from Alexion Pharmaceuticals, ArmaGen, BioMarin Pharmaceutical, Denali Therapeutics, Enzyvant, Inventiva Pharma, JCR Pharmaceuticals, Orphazyme, QED Therapeutics, REGENXBIO, Sangamo Therapeutics, Swedish Orphan Biovitrum, Takeda, and Ultragenyx Pharmaceutical. Luis González Gutiérrez-Solana has received consulting fees/other remuneration from BioMarin Pharmaceutical, Sanofi Genzyme, Takeda, and Ultragenyx Pharmaceutical; and has received research support from Takeda. Matilde Ruiz-Garcia has received consulting fees/other remuneration and research support from Takeda. Simon A. Jones has received consulting fees/other remuneration from Alexion Pharmaceuticals, AVROBIO, BioMarin Pharmaceutical, Denali Therapeutics, Orchard Therapeutics, REGENXBIO, Sanofi Genzyme, Takeda, and Ultragenyx Pharmaceutical; and has received research support from Takeda. Nathalie Guffon has received research support from BioMarin Pharmaceutical, Chiesi, Sanofi Genzyme, Takeda, and Ultragenyx Pharmaceutical. Michal Inbar-Feigenberg has received consulting fees from Takeda; has participated in advisory boards for Sanofi Genzyme, Takeda, and Ultragenyx Pharmaceutical; is a member of the medical advisory board for the Canadian MPS Society and Allied Diseases; is Chair of the Garrod Association Guideline Committee; and has received research support from the Canadian Institute for Health Research, Sanofi Genzyme, Takeda, and Ultragenyx Pharmaceutical. Drago Bratkovic has received research support from Takeda. Michael Hale was an employee of Takeda Development Center Americas, Inc. at the time of this study, and is a stockholder of Takeda Pharmaceuticals Company Limited. Yuna Wu is an employee of Takeda Development Center Americas, Inc.; and is a stockholder of Takeda Pharmaceuticals Company Limited. Karen S. Yee is an employee of Takeda Development Center Americas, Inc.; a stockholder of Takeda Pharmaceuticals Company Limited, and is an unpaid member of the Critical Path Institute PRO consortium and Rare Disease COA consortium, sponsored by Takeda. David A.H. Whiteman is an employee of Takeda Development Center Americas, Inc. and a stockholder of Takeda Pharmaceuticals Company Limited. David Alexanderian was an employee of Takeda Development Center Americas, Inc. at the time of this study and of the writing of the manuscript, and is a stockholder of Takeda Pharmaceuticals Company Limited., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

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., Competing Interests: Declaration of Competing Interest Joseph Muenzer has received consulting fees/other remuneration from Denali Therapeutics, JCR Pharmaceuticals, REGENXBIO, Sangamo Therapeutics, Sanofi Genzyme, and Takeda (Shire); has participated in advisory boards for BioMarin Pharmaceutical, Denali Therapeutics, JCR Pharmaceuticals, Sanofi Genzyme, and Takeda; and has received research support from BioMarin Pharmaceutical, Denali Therapeutics, and Takeda. Barbara K. Burton has received consulting fees/other remuneration from Alexion Pharmaceuticals, Applied Therapeutics, BioMarin Pharmaceutical, Capsida Biotherapeutics, Denali Therapeutics, Horizon Therapeutics, JCR Pharmaceuticals, Moderna, Passage Bio, Sanofi Genzyme, Sio Gene Therapies, Takeda, and Ultragenyx Pharmaceutical; has participated in advisory boards or similar committees for Alexion Pharmaceuticals, BioMarin Pharmaceutical, and Takeda; and has received research support from Alexion Pharmaceuticals, BioMarin Pharmaceutical, Denali Therapeutics, Homology Medicines, JCR Pharmaceuticals, Sangamo Therapeutics, Takeda, and Ultragenyx Pharmaceutical. Paul Harmatz has received consulting fees/other remuneration from Aeglea, Alexion Pharmaceuticals, ArmaGen, AVROBIO, Audentes, BioMarin Pharmaceutical, Capsida Biotherapeutics, Chiesi, Denali Therapeutics, Enzyvant, Fondazione Telethon, Inventiva Pharma, JCR Pharmaceuticals, Orphazyme, Paradigm, PTC Therapeutics, REGENXBIO, Sangamo Therapeutics, Sanofi Genzyme, Takeda, and Ultragenyx Pharmaceutical; and has received research support from Alexion Pharmaceuticals, ArmaGen, BioMarin Pharmaceutical, Denali Therapeutics, Enzyvant, Inventiva Pharma, JCR Pharmaceuticals, Orphazyme, QED Therapeutics, REGENXBIO, Sangamo Therapeutics, Swedish Orphan Biovitrum, Takeda, and Ultragenyx Pharmaceutical. Luis González Gutiérrez-Solana has received consulting fees/other remuneration from BioMarin Pharmaceutical, Sanofi Genzyme, Takeda, and Ultragenyx Pharmaceutical; and has received research support from Takeda. Matilde Ruiz-Garcia has received consulting fees/other remuneration and research support from Takeda. Simon A. Jones has received consulting fees/other remuneration from Alexion Pharmaceuticals, AVROBIO, BioMarin Pharmaceutical, Denali Therapeutics, Orchard Therapeutics, REGENXBIO, Sanofi Genzyme, Takeda, and Ultragenyx Pharmaceutical; has participated in advisory boards or similar committees for Takeda; and has received research support from Takeda. Nathalie Guffon has received research support from BioMarin Pharmaceutical, Chiesi, Sanofi Genzyme, Takeda, and Ultragenyx Pharmaceutical. Michal Inbar-Feigenberg has received consulting fees from Takeda; has participated in advisory boards for Sanofi Genzyme, Takeda, and Ultragenyx Pharmaceutical; is a member of the medical advisory board for the Canadian MPS Society and Allied Diseases; is Chair of the Garrod Association Guideline Committee; and has received research support from the Canadian Institute for Health Research, Sanofi Genzyme, Takeda, and Ultragenyx Pharmaceutical. Drago Bratkovic has received research support from Takeda. Michael Hale was an employee of Takeda Development Center Americas, Inc. at the time of this study. Yuna Wu is an employee of Takeda Development Center Americas, Inc.; is a stockholder of Takeda Pharmaceuticals Company Limited; and is an unpaid member of the Critical Path Institute PRO consortium and Rare Disease COA consortium, sponsored by Takeda. Karen S. Yee is an employee of Takeda Development Center Americas, Inc. and a stockholder of Takeda Pharmaceuticals Company Limited. David A.H. Whiteman is an employee of Takeda Development Center Americas, Inc. and a stockholder of Takeda Pharmaceuticals Company Limited. David Alexanderian was an employee of Takeda Development Center Americas, Inc. at the time of this study and the writing of the manuscript, and is a stockholder of Takeda Pharmaceuticals Company Limited., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

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., Competing Interests: K.S.Y. is a full-time employee of Takeda Development Center Americas, Inc. and stockholder of Takeda Pharmaceuticals Company Limited. D.A. was a full-time employee of Takeda Development Center Americas, Inc. at the time of this analysis, and is a current employee of Affinia Therapeutics Inc. and a stockholder of Takeda Pharmaceuticals Company Limited. Y.F. was a full-time employee of ICON plc, a contract research organization contracted for this chart review, at the time of this analysis and is a current employee of IQVIA. X.R. is a full-time employee of Takeda Development Center Americas, Inc. and a stockholder of Takeda Pharmaceuticals Company Limited. B.S. is a full-time employee of ICON plc, a contract research organization contracted for this chart review. O.A. is a full-time employee of Takeda Development Center Americas, Inc. and a stockholder of Takeda Pharmaceuticals Company Limited.

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., Competing Interests: OA is a full-time employee of Takeda Development Center Americas, Inc. and stockholder of Takeda Pharmaceutical Company Limited. KM was an employee of ICON plc, a contract research organization contracted for this chart review, at the time this study was conducted. SS was an employee of ICON plc, a contract research organization contracted for this chart review, at the time this study was conducted. DA was a full-time employee of Takeda Development Centers Americas, Inc. at the time this manuscript was prepared and a stockholder of Takeda Pharmaceutical Company Limited. KSY was a full-time employee of Takeda Development Centers Americas, Inc. and a stockholder of Takeda Pharmaceutical Company Limited.

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., (© 2021. The Author(s).)

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., (© 2020 The Authors. International Journal of Methods in Psychiatric Research published by John Wiley & Sons Ltd.)

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.

Introduction: Depression is associated with a poorer quality of life and higher rate of COPD exacerbations and mortality. However, with multiple confounding factors, 'independent' risk factor for depression among COPD patients remains ambiguous. Our study aims to identify independent risk factors for depression by specifically evaluating for any independent relationship between frequent exacerbations and various domains of the BODE index on depression., Methods: This study is a cross-sectional study, conducted in Hong Kong SAR. Age and comorbidity-matched COPD and control subjects were recruited. Depressive symptoms were measured by a validated Chinese version of the Geriatric Depression Scale (GDS-15 items). Prevalence rates of depressive symptoms were compared between COPD and control groups. Predictors for depression (GDS ≥ 8) were determined using univariate and multivariate analyses., Results: A total of 161 patients (89 and 72 patients, mean ages 75.2 and 75.6 in COPD and control group, respectively) were recruited. Higher prevalence rate of significant depressive symptoms was seen in COPD patients (20.2 vs. 4.2 %, p = 0.006*). Univariate analysis suggested that predictors for depression in COPD patients included (i) exacerbation frequencies in prior year, (ii) dyspnea level, (iii) BMI, (iv) functional status (Barthel index, 6MWD, activity domain of SGRQ), and (v) BODE index. In multivariate analysis, only the 'exacerbation frequencies in prior year' (OR 1.46, p = 0.042*) and 'dyspnea level' (MMRC) (OR 2.75, p = 0.001*) remained significant independent predictors for depression in COPD patients., Conclusions: A high prevalence of depressive symptoms was observed in COPD patients. 'Frequent exacerbation phenotype' remained a significant independent predictor for depressive symptoms in COPD. Among the BODE index domains, dyspnea level is the most important predictor for depression in COPD patients.

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, β-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 β-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., (Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Severe maxillary hypoplasia in cleft patients is caused by a combination of pathogenic and iatrogenic factors. In this work, the authors investigated anatomical deficiencies in dentition for predicting Le Fort I maxillary advancement surgery for severe maxillary hypoplasia in cleft patients., Methods: Cleft lip-cleft palate and cleft palate patients older than 14 years of age were reviewed for demographics, dental anomalies, and Le Fort I advancement. Chi-square tests, t tests, and multivariate logistic regression analyses were performed to delineate the contribution of quantity and position of dental agenesis to maxillary advancement surgery., Results: In the 114 patients reviewed (mean age, 19.2 years), 64.0 percent were male patients, 71.9 percent had dental agenesis, and 59.6 percent required Le Fort I advancement. In patients who did not exhibit dental agenesis, 18.8 percent required Le Fort I advancement compared with 74.4 percent of patients with dental agenesis (p < 0.0001). Le Fort I advancement surgery was increased to 76.3 percent when dental agenesis was at the lateral incisor position (p < 0.0001) and 86.4 percent when patients were missing two or more teeth (p < 0.0001). Both sella-to-nasion-to-A point angle (p = 0.003) and A point-to-nasion-to-B point angle (p = 0.04) measurements were decreased in patients missing dentition at the lateral incisor position. Adjusting for multiple missing teeth and orthodontic compensations, multivariate logistic regression analyses demonstrated that lateral incisor agenesis is an independent predictor for Le Fort I advancement surgery (OR, 4.4; 95 percent CI, 1.42 to 13.64; p = 0.01)., Conclusions: Lateral incisor agenesis correlated to maxillary hypoplasia and independently predicted the need for Le Fort I advancement in cleft patients, potentially as an anatomical readout of intrinsic growth deficiency., Clinical Question/level of Evidence: Risk, III.

Genomic instability is a key hallmark of cancer leading to tumour heterogeneity and therapeutic resistance. BRCA2 has a fundamental role in error-free DNA repair but also sustains genome integrity by promoting RAD51 nucleofilament formation at stalled replication forks. CDK2 phosphorylates BRCA2 (pS3291-BRCA2) to limit stabilizing contacts with polymerized RAD51; however, how replication stress modulates CDK2 activity and whether loss of pS3291-BRCA2 regulation results in genomic instability of tumours are not known. Here we demonstrate that the Hippo pathway kinase LATS1 interacts with CDK2 in response to genotoxic stress to constrain pS3291-BRCA2 and support RAD51 nucleofilaments, thereby maintaining genomic fidelity during replication stalling. We also show that LATS1 forms part of an ATR-mediated response to replication stress that requires the tumour suppressor RASSF1A. Importantly, perturbation of the ATR-RASSF1A-LATS1 signalling axis leads to genomic defects associated with loss of BRCA2 function and contributes to genomic instability and 'BRCA-ness' in lung cancers.

Background: Although high-dose N-acetylcysteine (NAC) has been suggested to reduce COPD exacerbations, it is unclear which category of patients with COPD would benefit most from NAC treatment. The objective of this study was to compare the effect of high-dose NAC (600 mg bid) between high-risk and low-risk Chinese patients with COPD., Methods: Patients with spirometry-confirmed stable COPD were randomized to treatment with either NAC 600 mg bid or placebo in addition to their usual treatments. Patients were followed up every 16 weeks for a total of 1 year. Further analysis was performed according to each patient's exacerbation risk at baseline as defined by the current GOLD (Global Initiative for Chronic Obstructive Lung Disease) strategy to analyze the effect of high-dose NAC in high-risk and low-risk patients., Results: Of the 120 patients with COPD randomized (men, 93.2%; mean age, 70.8 ± 0.74 years; prebronchodilator FEV₁, 53.9 ± 2.0%; baseline characteristics comparable between treatment groups), 108 (NAC, 52; placebo, 56) completed the 1-year study. For high-risk patients (n = 89), high-dose NAC compared with placebo significantly reduced exacerbation frequency (0.85 vs 1.59 [P = .019] and 1.08 vs 2.22 [P = .04] at 8 and 12 months, respectively), prolonged time to first exacerbation (P = .02), and increased the probability of being exacerbation free at 1 year (51.3% vs 24.4%, P = .013). This beneficial effect of high-dose NAC vs placebo was not significant in low-risk patients., Conclusions: High-dose NAC (600 mg bid) for 1 year reduces exacerbations and prolongs time to first exacerbation in high-risk but not in low-risk Chinese patients with COPD., Trial Registry: ClinicalTrials.gov; No.: NCT01136239; URL: www.clinicaltrials.gov.

Background: The mucolytic and antioxidant effects of N-acetylcysteine (NAC) may have great value in COPD treatment. However, beneficial effects have not been confirmed in clinical studies, possibly due to insufficient NAC doses and/or inadequate outcome parameters used. The objective of this study was to investigate high-dose NAC plus usual therapy in Chinese patients with stable COPD., Methods: The 1-year HIACE (The Effect of High Dose N-acetylcysteine on Air Trapping and Airway Resistance of Chronic Obstructive Pulmonary Disease-a Double-blinded, Randomized, Placebo-controlled Trial) double-blind trial conducted in Kwong Wah Hospital, Hong Kong, randomized eligible patients aged 50 to 80 years with stable COPD to NAC 600 mg bid or placebo after 4-week run-in. Lung function parameters, symptoms, modified Medical Research Council (mMRC) dyspnea and St. George's Respiratory Questionnaire (SGRQ) scores, 6-min walking distance (6MWD), and exacerbation and admission rates were measured at baseline and every 16 weeks for 1 year., Results: Of 133 patients screened, 120 were eligible (93.2% men; mean age, 70.8±0.74 years; %FEV1 53.9±2.0%). Baseline characteristics were similar in the two groups. At 1 year, there was a significant improvement in forced expiratory flow 25% to 75% (P=.037) and forced oscillation technique, a significant reduction in exacerbation frequency (0.96 times/y vs 1.71 times/y, P=.019), and a tendency toward reduction in admission rate (0.5 times/y vs 0.8 times/y, P=.196) with NAC vs placebo. There were no significant between-group differences in mMRC dypsnea score, SGRQ score, and 6MWD. No major adverse effects were reported., Conclusion: In this study, 1-year treatment with high-dose NAC resulted in significantly improved small airways function and decreased exacerbation frequency in patients with stable COPD., Trial Registry: ClinicalTrials.gov; No.: NCT01136239; URL: www.clinicaltrials.gov.

Resorbable plating systems have been adapted into routine use for craniofacial reconstruction in children. After implantation in some patients, the area around the plates can develop palpable and visible fibrous capsules, with underlying bone resorption and a significant foreign-body giant cell reaction. The reaction is usually self-limited. We report a case in which Langerhans cell histiocytosis was resected, and then recurred at the sites of resorbing plate and screw placement in association with a foreign-body giant cell reaction., (© 2014 S. Karger AG, Basel.)

RASSF1A (Ras association domain containing family 1A), a tumor suppressor gene that is frequently inactivated in human cancers, is phosphorylated by ataxia telangiectasia mutated (ATM) on Ser131 upon DNA damage, leading to activation of a p73-dependent apoptotic response. A single-nucleotide polymorphism located in the region of the key ATM activation site of RASSF1A predicts the conversion of alanine (encoded by the major G allele) to serine (encoded by the minor T allele) at residue 133 of RASSF1A (p.Ala133Ser). Secondary protein structure prediction studies suggest that an alpha helix containing the ATM recognition site is disrupted in the serine isoform of RASSF1A (RASSF1A-p.133Ser). In this study, we observed a reduced ability of ATM to recruit and phosphorylate RASSF1A-p.133Ser upon DNA damage. RASSF1A-p.133Ser failed to activate the MST2/LATS pathway, which is required for YAP/p73-mediated apoptosis, and negatively affected the activation of p53, culminating in a defective cellular response to DNA damage. Consistent with a defective p53 response, we found that male soft tissue sarcoma patients carrying the minor T allele encoding RASSF1A-p.133Ser exhibited poorer tumor-specific survival and earlier age of onset compared with patients homozygous for the major G allele. Our findings propose a model that suggests a certain subset of the population have inherently weaker p73/p53 activation due to inefficient signaling through RASSF1A, which affects both cancer incidence and survival., (©2012 AACR)

Glucocorticoids serve as important therapeutic agents in diseases of inflammation, but clinical use, especially in advanced septic shock, remains controversial because of the unpredictable response. Prior studies correlate human glucocorticoid receptor (hGR) isoforms with a decreased response to steroid therapy. Further analysis of additional hGR isoforms may improve the understanding of the steroid response. Ninety-seven human volunteers' blood samples were surveyed for hGR isoforms. An isoform matching National Center for Biotechnology Informatics (NCBI) hGRα (hGR NCBI) served as a reference. Two isoforms were of particular interest-one isoform had three nonsynonymous single-nucleotide polymorphisms (SNPs) (hGR NS-1), and the second had a single-nucleotide deletion (hGR DL-1) resulting in a truncated protein. Transactivation potentials were measured using a luciferase reporter assay. Human glucocorticoid receptor NS-1 had activity more than twice of hGR NCBI, whereas hGR DL-1 demonstrated less than 10% of the activity of hGR NCBI. Cotransfection of two isoforms revealed that the presence of hGR NS-1 increased transactivation potential, whereas hGR DL-1 decreased activity. Synthetic constructs isolating individual and paired SNPs of hGR NS-1 were created to identify the SNP responsible for hyperactivity. Transactivation studies revealed a SNP within the ligand-binding domain exerted the greatest influence over hyperactivity. In evaluating the response to hydrocortisone, hGR NCBI and hGR NS-1 displayed an increased dose-dependent response, but hGR NS-1 had a response more than twice hGR NCBI. Characterization of the novel hyperactive hGR NS-1 provides insight into a possible mechanism underlying the unpredictable response to steroid treatment.

Anxiety and depression could reduce the quality of life, and exacerbate physical symptoms and even mortality amongst patients with coronary heart disease (CHD). The aim of this study was to investigate the incidence of anxiety and depression in patients with acute CHD. In a period from March to December 2008, the views of 108 CHD patients, hospitalized in a tertiary hospital, were solicited using Hospital Anxiety and Depression Scale (HADS) and sociodemographic questionnaires. Patients with CHD had a low level anxiety and depression scores. There was significant differences in the total HADS score of participants stratified for marital status (P=0.027) or co-morbidity of diseases (P=0.012). Also, there were significant differences in the scores of depression subscale stratified for marital status (P=0.021) or co-morbidity of disease (P=0.007). However, there was no significant difference between the total HADS score or depression subscale score of the participants stratified based on age, gender, race, education, or income. Moreover, unmarried CHD respondents possessed higher depression level compared to the married respondents, and CHD respondents with co-morbid diseases showed a high level of depression. The findings might be taken as evidence to suggest that CHD patients should be evaluated early for the detection of anxiety and depression for appropriate referral and support.

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.

Hypermethylation of CpG islands in the RASSF1 promoter is one of the most frequent events identified in human cancer. The epigenetic-driven loss of RASSF1A protein expression is observed more often in tumors of higher grade and correlates with a decreased responsiveness to DNA-damaging therapy. Ras association domain-containing family 1A (RASSF1A) promotes apoptosis by signaling through the MST2 and LATS1 kinases, leading to stabilization of the YAP1/p73 transcriptional complex. Here we provide evidence for a new pathway linking DNA damage signaling to RASSF1A via the main sensor of double-strand breaks in cells, ataxia telangiectasia mutated (ATM). We show that, upon DNA damage, RASSF1A is phosphorylated by ATM on Ser131 and is involved in the activation of both MST2 and LATS1, leading to the stabilization of p73. Furthermore, lung and ovarian tumor cell lines that retain RASSF1A expression commonly harbor polymorphisms in the region of Ser131, and our analysis shows that the S131F polymorphism conveys resistance to DNA-damaging agents. Thus, we present a novel DNA damage pathway emanating from ATM that is frequently disabled in tumors via epigenetic silencing of RASSF1 or mutation of an ATM phosphorylation site.

Integrated positron emission tomography combined with plain computed tomography is commonly employed as the diagnostic tool for patients presenting with lung opacities. This technology is non-invasive and does not put the patient at risk of contrast reaction. We report a case of a man who presented with fever, septicaemia, and a left apical lung opacity on chest radiography. His positron emission tomography and plain computed tomography scans showed increased uptake by the left apical lung opacity together with a huge anterior mediastinal mass, suggestive of lung cancer with mediastinal lymph node involvement, and a right upper lobe shadow. After an initial futile bronchoscopy, an endobronchial ultrasound-guided transbronchial needle aspiration of the mediastinal node was planned but a contrast computed tomographic scan of the thorax revealed no significantly enlarged mediastinal lymph nodes. The differential diagnoses of these findings, together with the limitations of positron emission tomography and plain computed tomography, are discussed.

Many theories about the modes of avian influenza virus (AIV) transmission have been proposed, but few have been quantified, and none within a flock or live bird market (LBM) setting where birds are often kept in stacked cages. We describe a novel experimental design and the results collected for the purpose of estimating transmission rates specific to the potential modes of AIV transmission within an LBM. Chickens of the strains and ages found in California LBMs were inoculated with low pathogenicity AIV H6N2. Aerosol exposure was found to be the most important route of transmission for this H6N2 AIV. The handling of infectious chickens resulted in the transmission of H6N2 AIV, though the virus was not detectible by rRT-PCR. Chickens with fecal exposure to infected birds (median=8.0 DPI) had detectable virus earlier than in those with aerosol exposure only (median=10.0 DPI). Changes in the hemagglutinin sequence were not found to be associated with oropharyngeal or cloacal shedding in this study.

The p53-inducible BH3-only protein PUMA is a key mediator of p53-dependent apoptosis, and PUMA has been shown to function by activating Bax and mitochondrial outer membrane permeabilization. In this study, we describe an ability of PUMA to induce autophagy that leads to the selective removal of mitochondria. This function of PUMA depends on Bax/Bak and can be reproduced by overexpression of Bax. The induction of autophagy coincides with cytochrome c release, and taken together the results suggest that PUMA functions through Bax to induce mitochondrial autophagy in response to mitochondrial perturbations. Surprisingly, inhibition of PUMA or Bax-induced autophagy dampens the apoptotic response, suggesting that under some circumstances the selective targeting of mitochondria for autophagy can enhance apoptosis.

High pathogenic (HP) H5N1 avian influenza (AI) infection has been reported in domestic poultry, wildlife, and human populations since 1996. Risk of infection is associated with direct contact with infected birds. The mode of H5N1 spread from Asia to Europe, Africa and the Far East is unclear; risk factors such as legal and illegal domestic poultry and exotic bird trade, and migratory bird movements have been documented. Measures used to control disease such as culling, stamping out, cleaning and disinfection, and vaccination have not been successful in eradicating H5N1 in Asia, but have been effective in Europe.

Background: Transforming growth factor-beta(1) (TGF-beta(1)), a multifunctional cytokine, has been implicated to be responsible for the increased deposition of extracellular matrix in the airways, and increased submucosal collagen expression in chronic obstructive pulmonary disease (COPD). We determined plasma TGF-beta(1) levels in patients with COPD and explored its association with common functional polymorphisms of TGF-beta(1) gene at C-509T and T869C in the development of COPD in a case-control study., Methods: Stable COPD patients who were ever smokers, and age and pack-years smoked matched healthy controls (n = 205 in each group) were recruited for measurement of plasma TGF-beta(1) levels using commercially available ELISA kit, and genotyped at C-509T and T869C functional polymorphisms of TGF-beta(1) gene using polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP)., Results: COPD patients had significantly elevated plasma TGF-beta(1) levels in comparison to healthy controls irrespective of the genotypes. Allele frequencies and genotype distributions at both polymorphic sites were not different among COPD patients or controls. TGF-beta(1) levels were inversely correlated (Pearson's correlation analysis) with FEV(1) (% predicted) (p < 0.001) and FVC (% predicted) (p < 0.001)., Conclusion: The findings of elevated plasma TGF-beta(1) levels in patients with COPD suggest that TGF-beta(1) may play a role in COPD pathogenesis. The C-509T and T869C functional polymorphisms of TGF-beta(1) gene do not represent a genetic predisposition to COPD susceptibility in Hong Kong Chinese patients.

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.

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.

Severe sepsis remains an important cause of death, particularly among trauma and burn patients. The severity of the systemic inflammatory response after trauma or burns and susceptibility to sepsis vary among individuals. One possible mechanism is through differential effects on glucocorticoid receptor (GR) expression by pro-inflammatory mediators (e.g. lipopolysaccharide signaling). In a mouse burn model, we demonstrated differential GR levels, size, and transcriptional activity in CD14 knockout (KO) mice when compared to wild-type (C57BL/6J) after injury. Sequence analysis revealed only 8 CAG repeats in the GR transactivation domain in the CD14 KO; the wild-type contained seventeen. A survey of genomic DNA from 51 mouse strains demonstrated CAG repeat length range from 7 - 17. We then studied the effect of polymorphism in CAG repeat length on GR activity. Fragments with CAG repeats varying from 8-40 (8, 17, 30, 38, and 40) were engineered and shuttled into the wild-type GR expression vector. The resulting plasmids were then co-transfected with a glucocorticoid response element linked to a luciferase in order to compare their transactivation potentials. Transactivation potential was highest in the 17-CAG GR. The effect of GR polymorphisms on GR activity warrants more research as this data suggests a mechanism for the individual differences in response to steroid treatment and the response to injury.

This study was conducted to evaluate the efficacy of Saccharomyces boulardii in acute diarrhea. One hundred hospitalized children in Myanmar (age range = 3 months to 10 years) were included. Fifty were treated with S. boulardii for five days in addition to oral rehydration solution (ORS) and 50 were given ORS alone (control group) in an alternating order. The mean duration of diarrhea was 3.08 days in the S. boulardii group and 4.68 days (P < 0.05) in the control group. Stools had a normal consistency on day 3 in 38 (76%) of 50 patients in the S. boulardii group compared with only 12 (24%) of 50 in the control group (P = 0.019). On day 2, 27 (54%) of 50 had less than three stools per day in the S. boulardii group compared with only 15 (30%) of 50 in the control group (P = 0.019). Saccharomyces boulardii shortens the duration of diarrhea and normalizes stool consistency and frequency. The shortening of the duration of diarrhea results in a social and economic benefits.

The BH3-only protein PUMA plays an important role in the activation of apoptosis in response to p53. In different studies, PUMA has been described to function by either directly activating the pro-apoptotic proteins Bax and Bak, or by neutralizing anti-apoptotic members of the Bcl2 family. We have examined the contribution of regions of PUMA other than the BH3 domain to its localization and function. Although the hydrophobic domain in the C-terminus of PUMA is necessary for efficient mitochondrial localization of PUMA itself, PUMA proteins lacking this region can still induce apoptosis and localize to the mitochondria through binding to Bcl2. Even a nuclear localization signal (NLS)-tagged PUMA protein retains apoptotic activity and can be efficiently relocalized from the nucleus after interaction with ectopically expressed Bcl2, underscoring the efficiency of this interaction. Interestingly, unlike the Bcl2 interaction, the binding of PUMA to Bax is severely compromised by the loss of the C-terminal domain of PUMA. However, since the loss of the C-terminus does not compromise the ability of PUMA to induce cell death, our results indicate that the key apoptotic function of PUMA is through interaction with anti-apoptotic proteins such as Bcl2.

Recent studies have suggested that the straightforward role of p53 as a transcription factor that functions by inducing apoptotic target genes to eliminate developing tumor cells is only part of a much more complicated story. There is now a firm body of evidence supporting a transcriptionally independent activity of p53 as a functional, if not structural, homologue of the BH3-only proteins. Although this information adds another nuance to the mechanism by which p53 can induce apoptosis, further studies indicate that the apoptotic function of p53 represents only a part of its tumor suppressive activity. Although complicating our understanding of p53, these new insights may also provide some exciting new targets for the design of therapeutics that can reactivate p53 in cancers.

Objectives: To determine the clinical presentation, findings, and outcomes of older adults (> 60) with severe acute respiratory syndrome (SARS) and compare these with a control group of younger patients (< or or =60)., Design: Retrospective cohort study., Setting: A community-based, acute hospital in Hong Kong., Participants: All adult inpatients with a clinical diagnosis of SARS., Measurements: Clinical presentations, investigations, treatment, and 30- and 150-day mortality., Results: There were 52 young and 25 older patients with a mean age +/- standard deviation of 39.5+/-11.7 and 72.1+/-7.2, respectively. Fever, chills, and diarrhea were more common in younger patients, whereas decrease in appetite and general condition occurred only in older patients. The prevalence of positive reverse-transcriptase polymerase chain reaction for SARS-associated coronavirus (SARS-CoV) in nasopharyngeal secretions and stool samples was similar in the two groups. The prevalence of positive serological tests for SARS-CoV was significantly lower in older patients (42% vs 92%, P<.001). This was largely due to incomplete testing in elderly patients. Older patients were more likely to develop secondary nosocomial infection, be admitted to an intensive care unit, and require mechanical ventilation. The cumulative 30- and 150-day mortality rates were 3.8% and 7.6%, respectively, in young patients with SARS and 56% and 60%, respectively, in older patients (P<.001)., Conclusion: Older patients with SARS more often presented with nonspecific symptoms, and the prognosis was poor. Reverse-transcriptase polymerase chain reaction was useful in diagnosing SARS in older patients, but the role of serological tests in individual elderly is limited.

A novel Bax-associating protein, named MAP-1 (Modulator of Apoptosis), has been identified in a yeast two-hybrid screen. MAP-1 contains a BH3-like (BH: Bcl-2 homology) motif and mediates caspase-dependent apoptosis in mammalian cells when overexpressed. MAP-1 homodimerizes and associates with the proapoptotic Bax and the prosurvival Bcl-2 and Bcl-X(L) of the Bcl-2 family in vitro and in vivo in mammalian cells. Mutagenesis analyses revealed that the BH3-like domain in MAP-1 is not required for its association with Bcl-X(L) but is required for association with Bax and for mediating apoptosis. Interestingly, in contrast to other Bax-associating proteins such as Bcl-X(L) and Bid, which require the BH3 and BH1 domains of Bax, respectively, for binding, the binding of MAP-1 to Bax appears to require all three BH domains (BH1, BH2, and BH3) of Bax, because point mutation of the critical amino acid in any one of these domains is sufficient to abolish its binding to MAP-1. These data suggest that MAP-1 mediates apoptosis through a mechanism that involves binding to Bax.