Publications by authors named "Wai-Man Chan"

218 Publications

Optic Nerve Head and Retinal Abnormalities Associated with Congenital Fibrosis of the Extraocular Muscles.

Int J Mol Sci 2021 Mar 4;22(5). Epub 2021 Mar 4.

The University of Leicester Ulverscroft Eye Unit, Department of Neuroscience, Psychology and Behaviour, University of Leicester, RKCSB, PO Box 65, Leicester LE2 7LX, UK.

Congenital fibrosis of the extraocular muscles (CFEOM) is a congenital cranial dysinnervation disorder caused by developmental abnormalities affecting cranial nerves/nuclei innervating the extraocular muscles. Autosomal dominant CFEOM arises from heterozygous missense mutations of or . Although spatiotemporal expression studies have shown KIF21A and TUBB3 expression in developing retinal ganglion cells, it is unclear whether dysinnervation extends beyond the oculomotor system. We aimed to investigate whether dysinnervation extends to the visual system by performing high-resolution optical coherence tomography (OCT) scans characterizing retinal ganglion cells within the optic nerve head and retina. Sixteen patients with CFEOM were screened for mutations in , , and . Six patients had apparent optic nerve hypoplasia. OCT showed neuro-retinal rim loss. Disc diameter, rim width, rim area, and peripapillary nerve fiber layer thickness were significantly reduced in CFEOM patients compared to controls ( < 0.005). Situs inversus of retinal vessels was seen in five patients. Our study provides evidence of structural optic nerve and retinal changes in CFEOM. We show for the first time that there are widespread retinal changes beyond the retinal ganglion cells in patients with CFEOM. This study shows that the phenotype in CFEOM extends beyond the motor nerves.
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http://dx.doi.org/10.3390/ijms22052575DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7961960PMC
March 2021

Novel variants in TUBA1A cause congenital fibrosis of the extraocular muscles with or without malformations of cortical brain development.

Eur J Hum Genet 2021 May 1;29(5):816-826. Epub 2021 Mar 1.

F.M. Kirby Neurobiology Center, Boston Children's Hospital, Boston, MA, USA.

Variants in multiple tubulin genes have been implicated in neurodevelopmental disorders, including malformations of cortical development (MCD) and congenital fibrosis of the extraocular muscles (CFEOM). Distinct missense variants in the beta-tubulin encoding genes TUBB3 and TUBB2B cause MCD, CFEOM, or both, suggesting substitution-specific mechanisms. Variants in the alpha tubulin-encoding gene TUBA1A have been associated with MCD, but not with CFEOM. Using exome sequencing (ES) and genome sequencing (GS), we identified 3 unrelated probands with CFEOM who harbored novel heterozygous TUBA1A missense variants c.1216C>G, p.(His406Asp); c.467G>A, p.(Arg156His); and c.1193T>G, p.(Met398Arg). MRI revealed small oculomotor-innervated muscles and asymmetrical caudate heads and lateral ventricles with or without corpus callosal thinning. Two of the three probands had MCD. Mutated amino acid residues localize either to the longitudinal interface at which α and β tubulins heterodimerize (Met398, His406) or to the lateral interface at which tubulin protofilaments interact (Arg156), and His406 interacts with the motor domain of kinesin-1. This series of individuals supports TUBA1A variants as a cause of CFEOM and expands our knowledge of tubulinopathies.
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http://dx.doi.org/10.1038/s41431-020-00804-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8110841PMC
May 2021

KIF21A pathogenic variants cause congenital fibrosis of extraocular muscles type 3.

Ophthalmic Genet 2021 04 29;42(2):195-199. Epub 2020 Nov 29.

Department of Neurology, Boston Children's Hospital, Boston, Massachusetts, USA.

Congenital fibrosis of the extraocular muscles (CFEOM) is characterized by ptosis and non-progressive restrictive ophthalmoplegia. CFEOM1 is a stereotypical phenotype with isolated bilateral ptosis, bilateral ophthalmoplegia, absent upgaze, and globe infraduction. CFEOM3 is a more variable phenotype that can include unilateral disease, absent ptosis, residual upgaze, and/or orthotropia. Most cases of CFEOM1 result from recurrent heterozygous missense mutations and less commonly from recurrent heterozygous missense mutations. While most cases of CFEOM3 result from recurrent heterozygous missense mutations, several pedigrees harbored pathogenic variants in . Here, we asked if Lebanese pedigrees with CFEOM3 harbor pathogenic variants in or Families affected with congenital cranial dysinnervation disorders were prospectively recruited from the American University of Beirut pediatric ophthalmology clinic and included two probands with CFEOM. hotspot exons and coding sequence were sequenced. Available family members were sequenced for co-segregation analysis. Both families were found to have CFEOM3 and to harbor pathogenic variants in (OMIM 608283). A simplex proband with CFEOM3 from a consanguineous Iraqi family harbored a heterozygous c.2860 C > T variant (p.R954W); this variant accounts for the majority of reported mutations but is typically implicated in CFEOM1. A Lebanese father with CFEOM3 and his son with CFEOM1 segregated a heterozygous c.2830 G > C variant (p.E944Q), previously reported in an individual with CFEOM1. These results support prior reports of mutations as a rare cause of CFEOM3. These families are Middle Eastern or Chinese, supporting a genetic modifier in these populations.
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http://dx.doi.org/10.1080/13816810.2020.1852576DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7987873PMC
April 2021

Recurrent Rare Copy Number Variants Increase Risk for Esotropia.

Invest Ophthalmol Vis Sci 2020 08;61(10):22

Department of Ophthalmology, Boston Children's Hospital, Boston, Massachusetts, United States.

Purpose: To determine whether rare copy number variants (CNVs) increase risk for comitant esotropia.

Methods: CNVs were identified in 1614 Caucasian individuals with comitant esotropia and 3922 Caucasian controls from Illumina SNP genotyping using two Hidden Markov model (HMM) algorithms, PennCNV and QuantiSNP, which call CNVs based on logR ratio and B allele frequency. Deletions and duplications greater than 10 kb were included. Common CNVs were excluded. Association testing was performed with 1 million permutations in PLINK. Significant CNVs were confirmed with digital droplet polymerase chain reaction (ddPCR). Whole genome sequencing was performed to determine insertion location and breakpoints.

Results: Esotropia patients have similar rates and proportions of CNVs compared with controls but greater total length and average size of both deletions and duplications. Three recurrent rare duplications significantly (P = 1 × 10-6) increase the risk of esotropia: chromosome 2p11.2 (hg19, 2:87428677-87965359), spanning one long noncoding RNA (lncRNA) and two microRNAs (OR 14.16; 95% confidence interval [CI] 5.4-38.1); chromosome 4p15.2 (hg19, 4:25554332-25577184), spanning one lncRNA (OR 11.1; 95% CI 4.6-25.2); chromosome 10q11.22 (hg19, 10:47049547-47703870) spanning seven protein-coding genes, one lncRNA, and four pseudogenes (OR 8.96; 95% CI 5.4-14.9). Overall, 114 cases (7%) and only 28 controls (0.7%) had one of the three rare duplications. No case nor control had more than one of these three duplications.

Conclusions: Rare CNVs are a source of genetic variation that contribute to the genetic risk for comitant esotropia, which is likely polygenic. Future research into the functional consequences of these recurrent duplications may shed light on the pathophysiology of esotropia.
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http://dx.doi.org/10.1167/iovs.61.10.22DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7443120PMC
August 2020

Prevalence of metabolic syndrome in patients with psoriasis: a cross-sectional study in Singapore.

Singapore Med J 2020 Apr 2;61(4):194-199. Epub 2019 Dec 2.

Department of Dermatology, National Skin Centre, Singapore.

Introduction: Psoriasis is a chronic inflammatory condition that affects the skin and joints, and is associated with cardiovascular risk factors, including metabolic syndrome (MetS). We aimed to assess the prevalence of MetS in patients with psoriasis and determine whether there was a correlation between psoriasis severity and MetS in a Singapore population.

Methods: This was a cross-sectional study of patients with psoriasis, aged 18-69 years, who attended a tertiary dermatology referral centre in Singapore from October 2007 to February 2009. Fasting glucose, lipids, blood pressure, Psoriasis Area and Severity Index, and body mass index were measured. MetS was diagnosed in the presence of three or more criteria of the modified National Cholesterol Education Program Adult Treatment Panel III.

Results: Among 338 patients with psoriasis, there were 238 (70.4%) men and 100 (29.6%) women, who were Chinese (n = 228; 67.5%), Malay (n = 52; 15.4%) and Indian (n = 58; 17.2%). The prevalence of MetS was 45.1%. MetS was 44% more prevalent in patients older than 50 years (p = 0.02). Malay patients with psoriasis were significantly more likely to have hypertriglyceridaemia, elevated fasting plasma glucose and abdominal obesity. There was no significant correlation between psoriasis severity and risk of MetS.

Conclusion: The prevalence of MetS in patients with psoriasis in Singapore was 45.1%, or nearly threefold higher than the Singapore general population. Patients with psoriasis should be screened yearly for MetS and any modifiable cardiovascular risk factors should be actively controlled.
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http://dx.doi.org/10.11622/smedj.2019152DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7905140PMC
April 2020

Pathway-based meta-analysis for partially paired transcriptomics analysis.

Res Synth Methods 2020 Jan 10;11(1):123-133. Epub 2019 Nov 10.

School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.

Pathway-based differential expression analysis allows the incorporation of biological domain knowledge into transcriptomics analysis to enhance our understanding of disease mechanisms. To integrate information among multiple studies at the pathway level, pathway-based meta-analysis can be performed. Paired or partially paired samples are common in biomedical research. However, there are currently no existing pathway-based meta-analysis methods appropriate for paired or partially paired study designs. In this study, we developed a pathway-based meta-analysis approach for paired or partially paired samples. Meta-analysis on the transcriptomics profiles were conducted using p-value-based, rank-based, and effect size-based algorithms. The application of our approach was demonstrated using partially paired data from psoriasis transcriptomics studies. Upon combining six transcriptomics studies, genes related to the cell cycle and DNA replication pathways are found to be highly perturbed in psoriatic lesional skin samples. Results were validated externally with independent RNA-Seq data. Comparison with existing pathway meta-analysis methods revealed consistent results, with our method showing higher detection power. This study demonstrated the utility of our newly developed pathway-based meta-analysis that allows the incorporation of partially paired or paired samples. The proposed framework can be applied to omics data including but not limited to transcriptomics data.
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http://dx.doi.org/10.1002/jrsm.1381DOI Listing
January 2020

Congenital monocular elevation deficiency associated with a novel gene variant.

Br J Ophthalmol 2020 04 13;104(4):547-550. Epub 2019 Jul 13.

Ulverscroft Eye Unit, Department of Neuroscience, Psychology and Behaviour, University of Leicester, Leicester, UK.

Background: The genetic basis of monocular elevation deficiency (MED) is unclear. It has previously been considered to arise due to a supranuclear abnormality.

Methods: Two brothers with MED were referred to Leicester Royal Infirmary, UK from the local opticians. Their father had bilateral ptosis and was unable to elevate both eyes, consistent with the diagnosis of congenital fibrosis of extraocular muscles (CFEOM). Candidate sequencing was performed in all family members.

Results: Both affected siblings (aged 7 and 12 years) were unable to elevate the right eye. Their father had bilateral ptosis, left esotropia and bilateral limitation of elevation. Chin up head posture was present in the older sibling and the father. Bell's phenomenon and vertical rotational vestibulo-ocular reflex were absent in the right eye for both children. Mild bilateral facial nerve palsy was present in the older sibling and the father. Both siblings had slight difficulty with tandem gait. MRI revealed hypoplastic oculomotor nerve. Left anterior insular focal cortical dysplasia was seen in the older sibling. Sequencing of revealed a novel heterozygous variant (c.1263G>C, p.E421D) segregating with the phenotype. This residue is in the C-terminal H12 α-helix of β-tubulin and is one of three putative kinesin binding sites.

Conclusion: We show that familial MED can arise from a variant and could be considered a limited form of CFEOM. Neurological features such as mild facial palsy and cortical malformations can be present in patients with MED. Thus, in individuals with congenital MED, consideration may be made for mutation screening.
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http://dx.doi.org/10.1136/bjophthalmol-2019-314293DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6998158PMC
April 2020

Decreased ACKR3 (CXCR7) function causes oculomotor synkinesis in mice and humans.

Hum Mol Genet 2019 09;28(18):3113-3125

Department of Ophthalmology, Boston Children's Hospital, Boston, MA, USA.

Oculomotor synkinesis is the involuntary movement of the eyes or eyelids with a voluntary attempt at a different movement. The chemokine receptor CXCR4 and its ligand CXCL12 regulate oculomotor nerve development; mice with loss of either molecule have oculomotor synkinesis. In a consanguineous family with congenital ptosis and elevation of the ptotic eyelid with ipsilateral abduction, we identified a co-segregating homozygous missense variant (c.772G>A) in ACKR3, which encodes an atypical chemokine receptor that binds CXCL12 and functions as a scavenger receptor, regulating levels of CXCL12 available for CXCR4 signaling. The mutant protein (p.V258M) is expressed and traffics to the cell surface but has a lower binding affinity for CXCL12. Mice with loss of Ackr3 have variable phenotypes that include misrouting of the oculomotor and abducens nerves. All embryos show oculomotor nerve misrouting, ranging from complete misprojection in the midbrain, to aberrant peripheral branching, to a thin nerve, which aberrantly innervates the lateral rectus (as seen in Duane syndrome). The abducens nerve phenotype ranges from complete absence, to aberrant projections within the orbit, to a normal trajectory. Loss of ACKR3 in the midbrain leads to downregulation of CXCR4 protein, consistent with reports that excess CXCL12 causes ligand-induced degradation of CXCR4. Correspondingly, excess CXCL12 applied to ex vivo oculomotor slices causes axon misrouting, similar to inhibition of CXCR4. Thus, ACKR3, through its regulation of CXCL12 levels, is an important regulator of axon guidance in the oculomotor system; complete loss causes oculomotor synkinesis in mice, while reduced function causes oculomotor synkinesis in humans.
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http://dx.doi.org/10.1093/hmg/ddz137DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6737292PMC
September 2019

Altered White Matter Organization in the TUBB3 E410K Syndrome.

Cereb Cortex 2019 07;29(8):3561-3576

Harvard Medical School, Boston, MA, USA.

Seven unrelated individuals (four pediatric, three adults) with the TUBB3 E410K syndrome, harboring identical de novo heterozygous TUBB3 c.1228 G>A mutations, underwent neuropsychological testing and neuroimaging. Despite the absence of cortical malformations, they have intellectual and social disabilities. To search for potential etiologies for these deficits, we compared their brain's structural and white matter organization to 22 controls using structural and diffusion magnetic resonance imaging. Diffusion images were processed to calculate fractional anisotropy (FA) and perform tract reconstructions. Cortical parcellation-based network analysis and gyral topology-based FA analyses were performed. Major interhemispheric, projection and intrahemispheric tracts were manually segmented. Subjects had decreased corpus callosum volume and decreased network efficiency. While only pediatric subjects had diffuse decreases in FA predominantly affecting mid- and long-range tracts, only adult subjects had white matter volume loss associated with decreased cortical surface area. All subjects showed aberrant corticospinal tract trajectory and bilateral absence of the dorsal language network long segment. Furthermore, pediatric subjects had more tracts with decreased FA compared with controls than did adult subjects. These findings define a TUBB3 E410K neuroimaging endophenotype and lead to the hypothesis that the age-related changes are due to microscopic intrahemispheric misguided axons that are pruned during maturation.
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http://dx.doi.org/10.1093/cercor/bhy231DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6644882PMC
July 2019

Genome-Wide Association Study Identifies a Susceptibility Locus for Comitant Esotropia and Suggests a Parent-of-Origin Effect.

Invest Ophthalmol Vis Sci 2018 08;59(10):4054-4064

Department of Neurology, Boston Children's Hospital, Boston, Massachusetts, United States.

Purpose: To identify genetic variants conferring susceptibility to esotropia. Esotropia is the most common form of comitant strabismus, has its highest incidence in European ancestry populations, and is believed to be inherited as a complex trait.

Methods: White European American discovery cohorts with nonaccommodative (826 cases and 2991 controls) or accommodative (224 cases and 749 controls) esotropia were investigated. White European Australian and United Kingdom cohorts with nonaccommodative (689 cases and 1448 controls) or accommodative (66 cases and 264 controls) esotropia were tested for replication. We performed a genome-wide case-control association study using a mixed linear additive model. Meta-analyses of discovery and replication cohorts were then conducted.

Results: A significant association with nonaccommodative esotropia was discovered (odds ratio [OR] = 1.41, P = 2.84 × 10-09) and replicated (OR = 1.23, P = 0.01) at rs2244352 [T] located within intron 1 of the WRB (tryptophan rich basic protein) gene on chromosome 21 (meta-analysis OR = 1.33, P = 9.58 × 10-11). This single nucleotide polymorphism (SNP) is differentially methylated, and there is a statistically significant skew toward paternal inheritance in the discovery cohort. Meta-analysis of the accommodative discovery and replication cohorts identified an association with rs912759 [T] (OR = 0.59, P = 1.89 × 10-08), an intergenic SNP on chromosome 1p31.1.

Conclusions: This is the first genome-wide association study (GWAS) to identify significant associations in esotropia and suggests a parent-of-origin effect. Additional cohorts will permit replication and extension of these findings. Future studies of rs2244352 and WRB should provide insight into pathophysiological mechanisms underlying comitant strabismus.
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http://dx.doi.org/10.1167/iovs.18-24082DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6088800PMC
August 2018

Recessive MYF5 Mutations Cause External Ophthalmoplegia, Rib, and Vertebral Anomalies.

Am J Hum Genet 2018 07 7;103(1):115-124. Epub 2018 Jun 7.

Department of Neurology, Boston Children's Hospital, Boston, MA 02115, USA; F.M. Kirby Neurobiology Center, Boston Children's Hospital, Boston, MA 02115, USA; Department of Neurology, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of M.I.T. and Harvard, Cambridge, MA 02142, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA; Department Ophthalmology, Boston Children's Hospital, Boston, MA 02115, USA; Department of Ophthalmology, Harvard Medical School, Boston, MA 02115, USA. Electronic address:

MYF5 is member of the Myc-like basic helix-loop-helix transcription factor family and, in cooperation with other myogenic regulatory factors MYOD and MYF5, is a key regulator of early stages of myogenesis. Here, we report three consanguineous families with biallelic homozygous loss-of-function mutations in MYF5 who define a clinical disorder characterized by congenital ophthalmoplegia with scoliosis and vertebral and rib anomalies. The clinical phenotype overlaps strikingly with that reported in several Myf5 knockout mouse models. Affected members of two families share a haploidentical region that contains a homozygous 10 bp frameshift mutation in exon 1 of MYF5 (c.23_32delAGTTCTCACC [p.Gln8Leufs86]) predicted to undergo nonsense-mediated decay. Affected members of the third family harbor a homozygous missense change in exon 1 of MYF5 (c.283C>T [p.Arg95Cys]). Using in vitro assays, we show that this missense mutation acts as a loss-of-function allele by impairing MYF5 DNA binding and nuclear localization. We performed whole-genome sequencing in one affected individual with the frameshift mutation and did not identify additional rare variants in the haploidentical region that might account for differences in severity among the families. These data support the direct role of MYF5 in rib, spine, and extraocular muscle formation in humans.
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http://dx.doi.org/10.1016/j.ajhg.2018.05.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6035164PMC
July 2018

Uncovering Hidden Topics in Hong Kong Clinical Research Through Hospital Authority Convention Publications.

Stud Health Technol Inform 2017 ;245:624-628

JC School of Public Health and Primary Care, The Chinese University of Hong Kong, Hong Kong, China.

Uncovering clinical research trends allows us to understand the direction of healthcare services and is essential for longer-term healthcare planning. The Hospital Authority Convention is a mainstream annual healthcare conference that gathers up-to-date Hong Kong medical research. We propose to use state-of-the-art medical document mining and topic modelling methods to uncover latent themes and structures in the publications. We collected 742 articles from HA Convention from the year 2013 to 2016 and selected 56 publications from the category of "Clinical Safety and Quality Service" for further analysis. Applying natural language processing and Latent Dirichlet Allocation (LDA) methods, we identified 7 potential topics, namely: surgical operation, hospital discharge, medical error, nursing procedure, service performance assessment, patient and staff engagement, and admission algorithm and standardisation. This exploratory study demonstrates that key themes exist in the annual HA Convention and we observe potential changes in healthcare services focus over the years in the selected category.
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June 2018

Severely Crusted Cheilitis as an Initial Presentation of Systemic Lupus Erythematosus.

Indian J Dermatol 2017 Jul-Aug;62(4):440

National Skin Centre, Department of Dermatology, Singapore.

Lupus erythematosus (LE) is an autoimmune disease which may initially present solely with lip lesions. Due to a wide spectrum of presentation, these features may initially be misdiagnosed as other oral diseases such as lichen planus, erythema multiforme (EM), and actinic cheilitis, leading to a delay in diagnosis and treatment. We discuss a case of severely crusted cheilitis which was initially diagnosed as EM, with subsequent development of subacute cutaneous LE, and progression to systemic LE. We will discuss the clinical and histological features of lupus cheilitis.
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http://dx.doi.org/10.4103/ijd.IJD_559_16DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5527738PMC
August 2017

A defect in myoblast fusion underlies Carey-Fineman-Ziter syndrome.

Nat Commun 2017 07 6;8:16077. Epub 2017 Jul 6.

Neuromuscular and Neurogenetic Disorders of Childhood Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892-1477, USA.

Multinucleate cellular syncytial formation is a hallmark of skeletal muscle differentiation. Myomaker, encoded by Mymk (Tmem8c), is a well-conserved plasma membrane protein required for myoblast fusion to form multinucleated myotubes in mouse, chick, and zebrafish. Here, we report that autosomal recessive mutations in MYMK (OMIM 615345) cause Carey-Fineman-Ziter syndrome in humans (CFZS; OMIM 254940) by reducing but not eliminating MYMK function. We characterize MYMK-CFZS as a congenital myopathy with marked facial weakness and additional clinical and pathologic features that distinguish it from other congenital neuromuscular syndromes. We show that a heterologous cell fusion assay in vitro and allelic complementation experiments in mymk knockdown and mymk zebrafish in vivo can differentiate between MYMK wild type, hypomorphic and null alleles. Collectively, these data establish that MYMK activity is necessary for normal muscle development and maintenance in humans, and expand the spectrum of congenital myopathies to include cell-cell fusion deficits.
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http://dx.doi.org/10.1038/ncomms16077DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5504296PMC
July 2017

Human Schwann cells exhibit long-term cell survival, are not tumorigenic and promote repair when transplanted into the contused spinal cord.

Glia 2017 08 22;65(8):1278-1301. Epub 2017 May 22.

The Miami Project to Cure Paralysis, The Department of Neurological Surgery, The University of Miami Miller School of Medicine, Miami, Florida, 33136.

The transplantation of rodent Schwann cells (SCs) provides anatomical and functional restitution in a variety of spinal cord injury (SCI) models, supporting the recent translation of SCs to phase 1 clinical trials for human SCI. Whereas human (Hu)SCs have been examined experimentally in a complete SCI transection paradigm, to date the reported behavior of SCs when transplanted after a clinically relevant contusive SCI has been restricted to the use of rodent SCs. Here, in a xenotransplant, contusive SCI paradigm, the survival, biodistribution, proliferation and tumorgenicity as well as host responses to HuSCs, cultured according to a protocol analogous to that developed for clinical application, were investigated. HuSCs persisted within the contused nude rat spinal cord through 6 months after transplantation (longest time examined), exhibited low cell proliferation, displayed no evidence of tumorigenicity and showed a restricted biodistribution to the lesion. Neuropathological examination of the CNS revealed no adverse effects of HuSCs. Animals exhibiting higher numbers of surviving HuSCs within the lesion showed greater volumes of preserved white matter and host rat SC and astrocyte ingress as well as axon ingrowth and myelination. These results demonstrate the safety of HuSCs when employed in a clinically relevant experimental SCI paradigm. Further, signs of a potentially positive influence of HuSC transplants on host tissue pathology were observed. These findings show that HuSCs exhibit a favorable toxicity profile for up to 6 months after transplantation into the contused rat spinal cord, an important outcome for FDA consideration of their use in human clinical trials.
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http://dx.doi.org/10.1002/glia.23161DOI Listing
August 2017

Recommended Guidelines for Use of Intravitreal Aflibercept With a Treat-and-Extend Regimen for the Management of Neovascular Age-Related Macular Degeneration in the Asia-Pacific Region: Report From a Consensus Panel.

Asia Pac J Ophthalmol (Phila) 2017 May-Jun;6(3):296-302. Epub 2017 Mar 29.

Singapore National Eye Centre, Singapore.

Purpose: To summarize recommendations for the use of intravitreal aflibercept with a treat-and-extend regimen to manage neovascular age-related macular degeneration (nAMD) in the Asia-Pacific region. Although anti-vascular endothelial growth factor therapies have improved the quality of life of patients with nAMD, a leading cause of blindness and visual impairment, the high treatment frequency recommended by current guidelines places a significant burden on patients and healthcare providers.

Design: Recommended guidelines from a consensus panel.

Methods: An expert panel formed a consensus on recommendations for use of intravitreal aflibercept as treatment of nAMD in the Asia-Pacific region.

Results: After 3 initial monthly doses, treatment interval could be extended by 4-week increments, to a maximum of 12 weeks, in patients with inactive disease. Conversely, in active disease, treatment intervals should be shortened, by 4 weeks, or to 4 weeks in cases of severe recurrence. Treatment could be ceased in patients with stable disease activity after 12 months of treatment at 12-week intervals, as a means to prevent over treatent and lifelong injections.

Conclusions: These recommendations could potentially minimize the number of treatments while maintaining efficacy and improve compliance by reducing the number of clinic visits compared with existing recommendations.
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http://dx.doi.org/10.22608/APO.2016125DOI Listing
September 2017

Mutant α2-chimaerin signals via bidirectional ephrin pathways in Duane retraction syndrome.

J Clin Invest 2017 May 27;127(5):1664-1682. Epub 2017 Mar 27.

Duane retraction syndrome (DRS) is the most common form of congenital paralytic strabismus in humans and can result from α2-chimaerin (CHN1) missense mutations. We report a knockin α2-chimaerin mouse (Chn1KI/KI) that models DRS. Whole embryo imaging of Chn1KI/KI mice revealed stalled abducens nerve growth and selective trochlear and first cervical spinal nerve guidance abnormalities. Stalled abducens nerve bundles did not reach the orbit, resulting in secondary aberrant misinnervation of the lateral rectus muscle by the oculomotor nerve. By contrast, Chn1KO/KO mice did not have DRS, and embryos displayed abducens nerve wandering distinct from the Chn1KI/KI phenotype. Murine embryos lacking EPH receptor A4 (Epha4KO/KO), which is upstream of α2-chimaerin in corticospinal neurons, exhibited similar abducens wandering that paralleled previously reported gait alterations in Chn1KO/KO and Epha4KO/KO adult mice. Findings from Chn1KI/KI Epha4KO/KO mice demonstrated that mutant α2-chimaerin and EphA4 have different genetic interactions in distinct motor neuron pools: abducens neurons use bidirectional ephrin signaling via mutant α2-chimaerin to direct growth, while cervical spinal neurons use only ephrin forward signaling, and trochlear neurons do not use ephrin signaling. These findings reveal a role for ephrin bidirectional signaling upstream of mutant α2-chimaerin in DRS, which may contribute to the selective vulnerability of abducens motor neurons in this disorder.
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http://dx.doi.org/10.1172/JCI88502DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5409791PMC
May 2017

Biallelic mutations in human DCC cause developmental split-brain syndrome.

Nat Genet 2017 Apr 27;49(4):606-612. Epub 2017 Feb 27.

Division of Genetics and Genomics, Boston Children's Hospital, Boston, Massachusetts, USA.

Motor, sensory, and integrative activities of the brain are coordinated by a series of midline-bridging neuronal commissures whose development is tightly regulated. Here we report a new human syndrome in which these commissures are widely disrupted, thus causing clinical manifestations of horizontal gaze palsy, scoliosis, and intellectual disability. Affected individuals were found to possess biallelic loss-of-function mutations in the gene encoding the axon-guidance receptor 'deleted in colorectal carcinoma' (DCC), which has been implicated in congenital mirror movements when it is mutated in the heterozygous state but whose biallelic loss-of-function human phenotype has not been reported. Structural MRI and diffusion tractography demonstrated broad disorganization of white-matter tracts throughout the human central nervous system (CNS), including loss of all commissural tracts at multiple levels of the neuraxis. Combined with data from animal models, these findings show that DCC is a master regulator of midline crossing and development of white-matter projections throughout the human CNS.
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http://dx.doi.org/10.1038/ng.3804DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5374027PMC
April 2017

Impact of Overactive Bladder Step Therapy Policies on Medication Utilization and Expenditures Among Treated Medicare Members.

J Manag Care Spec Pharm 2017 Jan;23(1):27-37

1 Comprehensive Health Insights, Louisville, Kentucky.

Background: The impact of formulary management strategies on utilization and expenditures in overactive bladder (OAB) treatment has not been extensively investigated. In 2013, step therapy (ST) policies for 2 branded OAB treatments, mirabegron and fesoterodine, were removed from Humana Medicare Advantage Prescription Drug (MAPD) plans and Medicare prescription drug plans (PDP), allowing for an examination of the effect of ST policies on OAB medication use patterns and costs.

Objective: To assess the impact of removal of formulary restriction policies for mirabegron and fesoterodine on medication utilization patterns and costs associated with OAB treatment in Medicare patients.

Methods: A retrospective cross-sectional study design was utilized. Subjects included individuals enrolled in Humana MAPD plans or PDPs, aged ≥ 65 years, with ≥ 1 prescription for an OAB medication in 2013. Patient demographic characteristics, OAB medication utilization, and pharmacy cost trends in 2013 were described. OAB medication use was calculated as the number of 30-day-supply equivalent medication claims and reported as a percentage of the total number of 30-day-supply equivalent claims across all OAB products. OAB medication expenditures were calculated as a percentage of the sum of pharmacy costs for OAB medications and reported separately for each month and drug during 2013. Temporal trends of OAB medication utilization and expenditures in 2013 were calculated using ordinary least squares regression.

Results: Of 194,511 patients, trends in utilization of OAB medications indicated that on average, there was a statistically significant monthly increase in utilization of mirabegron (regression coefficient [B] = 274; P < 0.001; 95% CI: 218, 330), fesoterodine (B = 167; P < 0.001; 95% CI = 129, 205), oxybutynin extended release (ER; B = 357; P = 0.011; 95% CI = 99, 614), and trospium ER (B = 33; P = 0.001; 95% CI = 17, 50) and statistically significant decreases in utilization of solifenacin (B = -202; P = 0.048; 95% CI = -402, -2), tolterodine ER (B = -287; P = 0.002; 95% CI = -437, -137), darifenacin (B = -94; P < 0.001; 95% CI = -128, -61), and trospium immediate release (IR; B = -22; P = 0.001; 95% CI = -32, -12). Total OAB medication expenditures significantly increased an average of 0.12% for each month during the course of 2013 (B = 0.12; P = 0.026; 95% CI = 0.017, -0.223). While monthly oxybutynin IR utilization did not change significantly throughout 2013 (B = 228; P = 0.169; 95% CI = -114, -570), it demonstrated the largest average monthly expenditure increase (B = 0.082; P < 0.001; 95% CI = 0.056, 0.108). When removing oxybutynin IR costs from the total OAB medication costs, the trend in total OAB medication average monthly expenditures was not significant (B = 0.038; P = 0.365; 95% CI = -0.051, -0.126). An over 4-fold per-unit-cost increase for oxybutynin IR was noted.

Conclusions: Utilization of 2 branded OAB products increased in the months after ST removal with minimal cost impact. One of the possible reasons total OAB expenditures increased may have been due to the increased cost of the largest-volume generic product, oxybutynin IR.

Disclosures: This research was funded by Astellas Pharma Global Development and was conducted as part of the Astellas-Humana Research Collaboration. Ng, Kristy, Schermer, and Bradt are employees of Astellas. Astellas manufactures mirabegron (Myrbetriq) and solifenacin (VESIcare). Abbass, Caplan, Collins, and Suehs are employees of Comprehensive Health Insights, a subsidiary of Humana, which received funding from Astellas for this study. Suehs owns stock in Humana. Chan is an employee of Humana Pharmacy Solutions. Portions of this study were presented as a poster at Academy of Managed Care Pharmacy Nexus 2015; October 26-29, 2015; Orlando, Florida. Study concept and design were contributed by Ng, Chan, Suehs, and Abbass, along with Collins. Abbass took the lead in data collection, along with Collins and with assistance from Caplan, Chan, and Suehs. Data interpretation was provided by Kristy and Bradt, along with Abbass, Caplan, Ng, Suehs, Collins, and Chan. The manuscript was written primarily by Caplan, along with Schermer, Suehs, and Abbass, and revised by Caplan, Schermer, and Ng, along with the other authors.
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http://dx.doi.org/10.18553/jmcp.2017.23.1.27DOI Listing
January 2017

The adoption of the Reference Framework for diabetes care among primary care physicians in primary care settings: A cross-sectional study.

Medicine (Baltimore) 2016 Aug;95(31):e4108

School of Public Health and Primary Care, Chinese University of Hong Kong, Shatin, Hong Kong, HKSAR School of Public Health, Sun Yat-Sen University, Guangzhou, P.R. China General Practice and Primary Care, Institute of Health and Wellbeing, University of Glasgow, Glasgow, UK Department of Family Medicine, Hospital Authority, Hong Kong.

The prevalence of diabetes mellitus has been increasing both globally and locally. Primary care physicians (PCPs) are in a privileged position to provide first contact and continuing care for diabetic patients. A territory-wide Reference Framework for Diabetes Care for Adults has been released by the Hong Kong Primary Care Office in 2010, with the aim to further enhance evidence-based and high quality care for diabetes in the primary care setting through wide adoption of the Reference Framework.A valid questionnaire survey was conducted among PCPs to evaluate the levels of, and the factors associated with, their adoption of the Reference Framework.A total of 414 completed surveys were received with the response rate of 13.0%. The average adoption score was 3.29 (SD 0.51) out of 4. Approximately 70% of PCPs highly adopted the Reference Framework in their routine practice. Binary logistic regression analysis showed that the PCPs perceptions on the inclusion of sufficient local information (adjusted odds ratio [aOR] = 4.748, 95%CI 1.597-14.115, P = 0.005) and reduction of professional autonomy of PCPs (aOR = 1.859, 95%CI 1.013-3.411, P = 0.045) were more likely to influence their adoption level of the Reference Framework for diabetes care in daily practices.The overall level of guideline adoption was found to be relatively high among PCPs for adult diabetes in primary care settings. The adoption barriers identified in this study should be addressed in the continuous updating of the Reference Framework. Strategies need to be considered to enhance the guideline adoption and implementation capacity.
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http://dx.doi.org/10.1097/MD.0000000000004108DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4979772PMC
August 2016

Medication Adherence and Blood Pressure Control Among Hypertensive Patients With Coexisting Long-Term Conditions in Primary Care Settings: A Cross-Sectional Analysis.

Medicine (Baltimore) 2016 May;95(20):e3572

From the Community Research and Clinical Trials Unit, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou, P.R. China (YTL); JC School of Public Health and Primary Care, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong (YTL, KQLL, GKYL, WMC, SMG); School of Public Health, Sun Yat-Sen University, Guangzhou, P.R. China (HHXW); and Centre for Health and Social Care Improvement, University of Wolverhampton, Wolverhampton, UK (RLC).

Hypertension is a typical example of long-term disease posing formidable challenges to health care. One goal of antihypertensive therapy is to achieve optimal blood pressure (BP) control and reduce co-occurring chronic conditions (multimorbidity). This study aimed to assess the influence of multimorbidity on medication adherence, and to explore the association between poor BP control and multimorbidity, with implications for hypertension management.A cross-sectional design with multistage sampling was adopted to recruit Chinese hypertensive patients attending general out-patient clinics from 3 geographic regions in Hong Kong. A modified systemic sampling methodology with 1 patient as a sampling unit was used to recruit consecutive samples in each general out-patient clinic. Data were collected by face-to-face interviews using a standardized protocol. Poor BP control was defined as having systolic BP/diastolic BP ≥130/80 mm Hg for those with diabetes or chronic kidney disease; and ≥140/90 mm Hg for others. Medication adherence was assessed by a validated Chinese version of the Morisky Medication Adherence Scale. A simple unweighted enumeration was adopted to measure the combinations of coexisting long-term conditions. Binary logistic regression analysis was conducted with medication adherence and multimorbidity as outcome variables, respectively, after controlling for effects of patient-level covariates.The prevalence of multimorbidity was 47.4% (95% confidence interval [CI] 45.4%-49.4%) among a total of 2445 hypertensive patients. The proportion of subjects having 0, 1, and ≥2 additional long-term conditions was 52.6%, 29.1%, and 18.3%, respectively. The overall rate of poor adherence to medication was 46.6%, whereas the rate of suboptimal BP control was 48.7%. Albeit the influence of multimorbidity on medication adherence was not found to be statistically significant, patients with poorly controlled BP were more likely to have multimorbidity (adjusted odds ratio 2.07, 95% CI 1.70-2.53, P < 0.001). Diabetes was the most prevalent concomitant long-term condition among hypertensive patients with poor BP control (38.6%, 95% CI 35.8-41.4 vs 19.7%, 95% CI 17.5-21.9 for patients with good BP control, P < 0.001).Multimorbidity was common among hypertensive patients, and was associated with poor BP control. Subjects with coexisting diabetes, heart disease, or chronic kidney disorder should receive more clinical attention to achieve better clinical outcomes.
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http://dx.doi.org/10.1097/MD.0000000000003572DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4902400PMC
May 2016

Loss of MAFB Function in Humans and Mice Causes Duane Syndrome, Aberrant Extraocular Muscle Innervation, and Inner-Ear Defects.

Am J Hum Genet 2016 06 12;98(6):1220-1227. Epub 2016 May 12.

Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA; Department of Neurology, Boston Children's Hospital, Boston, MA 02115, USA; F.M. Kirby Neurobiology Center, Boston Children's Hospital, Boston, MA 02115, USA; Department of Neurology, Harvard Medical School, Boston, MA 02115, USA; Program in Neuroscience, Harvard Medical School, Boston, MA 02115, USA; Department of Ophthalmology, Boston Children's Hospital, Boston, MA 02115, USA; Department of Ophthalmology, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA. Electronic address:

Duane retraction syndrome (DRS) is a congenital eye-movement disorder defined by limited outward gaze and retraction of the eye on attempted inward gaze. Here, we report on three heterozygous loss-of-function MAFB mutations causing DRS and a dominant-negative MAFB mutation causing DRS and deafness. Using genotype-phenotype correlations in humans and Mafb-knockout mice, we propose a threshold model for variable loss of MAFB function. Postmortem studies of DRS have reported abducens nerve hypoplasia and aberrant innervation of the lateral rectus muscle by the oculomotor nerve. Our studies in mice now confirm this human DRS pathology. Moreover, we demonstrate that selectively disrupting abducens nerve development is sufficient to cause secondary innervation of the lateral rectus muscle by aberrant oculomotor nerve branches, which form at developmental decision regions close to target extraocular muscles. Thus, we present evidence that the primary cause of DRS is failure of the abducens nerve to fully innervate the lateral rectus muscle in early development.
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http://dx.doi.org/10.1016/j.ajhg.2016.03.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4908193PMC
June 2016

Long-Term Outcome of Half-Dose Verteporfin Photodynamic Therapy for the Treatment of Central Serous Chorioretinopathy (An American Ophthalmological Society Thesis).

Trans Am Ophthalmol Soc 2015 ;113:T8

Department of Ophthalmology & Visual Sciences, The Chinese University of Hong Kong, Hong Kong and Department of Ophthalmology, Hong Kong Sanatorium & Hospital, Happy Valley, Hong Kong.

Purpose: To evaluate whether half-dose verteporfin photodynamic therapy (PDT) is better than natural history for the treatment of central serous chorioretinopathy (CSC).

Methods: Retrospective review of consecutive CSC patients treated with half-dose verteporfin PDT or untreated with observation and a minimum follow-up of 36 months. The main outcome measures included mean change in visual acuity and CSC recurrence. Survival analysis was performed to compare the CSC recurrence rates between the two groups.

Results: A total of 192 eyes of 192 patients were included; 75 eyes were treated with half-dose verteporfin PDT and 117 were untreated. The mean follow-up duration was 74.1 months. At the last follow-up, the mean logMAR visual acuity was significantly better in the half-dose verteporfin PDT group compared with the untreated control group (P=.005). The mean visual improvement of the half-dose verteporfin PDT group at the last follow-up was 1.8 lines, compared with 0.0 line in the untreated control group (P<.001). Recurrence of CSC developed in 15 eyes (20%) in the half-dose verteporfin PDT group compared with 63 eyes (53.8%) in the untreated control group (P<.001). Survival analysis demonstrated that eyes treated with half-dose verteporfin PDT were significantly less likely to develop CSC recurrence compared with untreated controls (P<.001). Regression analysis showed that half-dose verteporfin PDT was the only significant factor in reducing the risk of CSC recurrence.

Conclusions: Half-dose verteporfin PDT for the treatment of CSC resulted in significantly better visual acuity outcomes and lower recurrence rate in the long term compared with untreated controls.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4692328PMC
July 2016

Two unique TUBB3 mutations cause both CFEOM3 and malformations of cortical development.

Am J Med Genet A 2016 Feb 6;170A(2):297-305. Epub 2015 Dec 6.

Department of Ophthalmology, Boston Children's Hospital, Boston, Massachusetts.

One set of missense mutations in the neuron specific beta tubulin isotype 3 (TUBB3) has been reported to cause malformations of cortical development (MCD), while a second set has been reported to cause isolated or syndromic Congenital Fibrosis of the Extraocular Muscles type 3 (CFEOM3). Because TUBB3 mutations reported to cause CFEOM had not been associated with cortical malformations, while mutations reported to cause MCD had not been associated with CFEOM or other forms of paralytic strabismus, it was hypothesized that each set of mutations might alter microtubule function differently. Here, however, we report two novel de novo heterozygous TUBB3 amino acid substitutions, G71R and G98S, in four patients with both MCD and syndromic CFEOM3. These patients present with moderately severe CFEOM3, nystagmus, torticollis, and developmental delay, and have intellectual and social disabilities. Neuroimaging reveals defective cortical gyration, as well as hypoplasia or agenesis of the corpus callosum and anterior commissure, malformations of hippocampi, thalami, basal ganglia and cerebella, and brainstem and cranial nerve hypoplasia. These new TUBB3 substitutions meld the two previously distinct TUBB3-associated phenotypes, and implicate similar microtubule dysfunction underlying both.
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http://dx.doi.org/10.1002/ajmg.a.37362DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4770801PMC
February 2016

Transforming cardiac rehabilitation into broad-based healthy lifestyle programs to combat noncommunicable disease.

Expert Rev Cardiovasc Ther 2016 29;14(1):23-36. Epub 2015 Oct 29.

h Cardiopulmonary Physiotherapy Laboratory , Federal University of Sao Carlos , Sao Carlos , Brazil.

The current incidence and prevalence of noncommunicable diseases (NCDs) is currently a cause for great concern on a global scale; future projections are no less disconcerting. Unhealthy lifestyle patterns are at the core of the NCD crisis; physical inactivity, excess body mass, poor nutrition and tobacco use are the primary lifestyle factors that substantially increase the risk of developing one or more NCDs. We have now come to recognize that healthy lifestyle interventions are a medical necessity that should be prescribed to all individuals. Perhaps the most well-established model for healthy lifestyle interventions in the current healthcare model is cardiac rehabilitation. To have any hope of improving the outlook for NCDs on a global scale, what is currently known as cardiac rehabilitation must transform into broad-based healthy lifestyle programing, with a shifted focus on primordial and primary prevention.
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http://dx.doi.org/10.1586/14779072.2016.1107475DOI Listing
July 2016

Dietary counselling has no effect on cardiovascular risk factors among Chinese Grade 1 hypertensive patients: a randomized controlled trial.

Eur Heart J 2015 10 11;36(38):2598-607. Epub 2015 Aug 11.

JC School of Public Health and Primary Care, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong.

Aims: To evaluate the effectiveness of Dietary Approaches to Stop Hypertension (DASH) by one-off dietary counselling on reducing cardiovascular risk factors among Chinese Grade 1 hypertensive patients in primary care.

Methods And Results: A parallel-group, randomized controlled trial (ChiCTR-TRC-13003014) was conducted among patients (40-70 years old) newly diagnosed with Grade 1 hypertension in primary care settings in Hong Kong. Subjects were randomized to usual care (standard education, control) (n = 275), or usual care plus DASH-based dietary counselling (intervention) (n = 281). The study endpoints included blood pressure (BP), lipid profile, and body mass index (BMI) at 6- and 12-months. Outcome data were available for 504 (90.6%) and 485 (87.2%) patients at 6 and 12 months, respectively. Blood pressure levels reduced in both groups at follow-ups. However, the intervention group did not show a significantly greater reduction in either systolic BP (-0.7 mmHg, 95%CI -3.0-1.5 at 6-month; -0.1 mmHg, 95%CI -2.4-2.2 at 12-month) or diastolic BP (-1.0 mmHg, 95%CI -2.7-0.7 at 6-month; -1.1 mmHg, 95%CI -2.9-0.6 at 12-month), when compared with the control group. The improvements in lipid profile and BMI were observed among all subjects, yet no significant differences were detected between intervention and control groups.

Conclusion: The DASH diet by one-off dietitian counselling which resembled the common primary care practice might confer no added long-term benefits on top of physician's usual care in optimizing cardiovascular risk factors. Physicians may still practice standard usual care, yet further explorations on different DASH delivery models are warranted to inform best clinical practice.
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http://dx.doi.org/10.1093/eurheartj/ehv329DOI Listing
October 2015

Satellite-Based Estimates of Long-Term Exposure to Fine Particles and Association with Mortality in Elderly Hong Kong Residents.

Environ Health Perspect 2015 Nov 24;123(11):1167-72. Epub 2015 Apr 24.

School of Public Health, The University of Hong Kong, Hong Kong, China.

Background: A limited number of studies on long-term effects of particulate matter with aerodynamic diameter < 2.5 μm (PM2.5) on health suggest it can be an important cause of morbidity and mortality. In Asia where air quality is poor and deteriorating, local data on long-term effects of PM2.5 to support policy on air quality management are scarce.

Objectives: We assessed long-term effects of PM2.5 on the mortality in a single Asian city.

Methods: For 10-13 years, we followed up a cohort of 66,820 participants ≥ 65 years of age who were enrolled and interviewed in all 18 Elderly Health Centres of the Department of Health, Hong Kong, in 1998-2001. Their residential addresses were geocoded into x- and y-coordinates, and their proxy exposures to PM2.5 at their addresses in 1 × 1 km grids were estimated from the U.S. National Aeronautics and Space Administration (NASA) satellite data. We used Cox regression models to calculate hazard ratios (HRs) of mortality associated with PM2.5.

Results: Mortality HRs per 10-μg/m3 increase in PM2.5 were 1.14 (95% CI: 1.07, 1.22) for all natural causes, 1.22 (95% CI: 1.08, 1.39) for cardiovascular causes, 1.42 (95% CI: 1.16, 1.73) for ischemic heart disease, 1.24 (95% CI: 1.00, 1.53) for cerebrovascular disease, and 1.05 (95% CI: 0.90, 1.22) for respiratory causes.

Conclusions: Our methods in using NASA satellite data provide a readily accessible and affordable approach to estimation of a sufficient range of individual PM2.5 exposures in a single city. This approach can expand the capacity to conduct environmental accountability studies in areas with few measurements of fine particles.

Citation: Wong CM, Lai HK, Tsang H, Thach TQ, Thomas GN, Lam KB, Chan KP, Yang L, Lau AK, Ayres JG, Lee SY, Chan WM, Hedley AJ, Lam TH. 2015. Satellite-based estimates of long-term exposure to fine particles and association with mortality in elderly Hong Kong residents. Environ Health Perspect 123:1167-1172; http://dx.doi.org/10.1289/ehp.1408264.
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http://dx.doi.org/10.1289/ehp.1408264DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4629733PMC
November 2015

Factors associated with grade 1 hypertension: implications for hypertension care based on the Dietary Approaches to Stop Hypertension (DASH) in primary care settings.

BMC Fam Pract 2015 Feb 27;16:26. Epub 2015 Feb 27.

JC School of Public Health and Primary Care, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong.

Background: A Reference Framework for Hypertension Care was recently developed by Hong Kong government to emphasise the importance of primary care for subjects with high blood pressure (BP). The Dietary Approaches to Stop Hypertension (DASH) interventional regime was recommended for patients aged 40-70 years with grade 1 hypertension (having systolic BP of 140-159 mmHg and/or diastolic BP of 90-99 mmHg). This study explored factors associated with grade 1 hypertension among subjects screened in primary care settings.

Methods: The study sample consisted of community dwellers (N = 10,693) enrolled in a primary care programme in which participants overall had similar characteristics when compared to the Hong Kong population census. Invitation phone calls were given by trained researchers to a randomly selected subjects (N = 2,673, [50% of total subjects aged 40-70 years]) between January and June 2013. BP and body mass index (BMI) were measured by trained clinical professionals according to a standard protocol. Interviewer-administered survey questionnaires were used to collect self-report information on socio-demographics, family history, and lifestyle characteristics. Multiple logistic regression analysis was performed to explore factors associated with grade 1 hypertension. Adjusted odds ratios (aORs) were estimated with 95% confidence intervals (CI).

Results: A total of 679 out of 2,673 subjects agreed to participate in the screening and completed the baseline assessment (100% completion rate), among which, 320 subjects (47.1%, [320/679]) were grade 1 hypertensive. Unhealthy diet (aOR = 2.19, 95%CI 1.04-4.62), irregular meals (aOR = 1.47, 95%CI 1.11-1.95), BMI >27.5 kg/m(2) (aOR = 1.87, 95%CI 1.53-2.27), duration of cigarette smoking (aOR = 1.83 per year), increased daily cigarette consumption (aOR  =1.59 per pack [20 cigarettes per pack]), duration of alcohol drinking (aOR = 1.65 per year), and higher frequency of weekly binge drinking (aOR = 1.87 per occasion) were independently associated with grade 1 hypertension. The increase in the number of risk factors combined significantly correlated with higher predicted probability of grade 1 hypertension.

Conclusions: Dietary-intake factors were significantly associated with grade 1 hypertension, echoing the recommendation in the Reference Framework on incorporating dietary-related intervention based on the DASH approach for hypertension care in primary care settings. The association between aggregate risk factors and grade 1 hypertension should also be taken into consideration in long-term preventive strategy.
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http://dx.doi.org/10.1186/s12875-015-0239-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4350626PMC
February 2015

Adiposity and influenza-associated respiratory mortality: a cohort study.

Clin Infect Dis 2015 May 2;60(10):e49-57. Epub 2015 Feb 2.

Infectious Disease Epidemiology Group, School of Public Health, Li Ka Shing Faculty of Medicine, University of Hong Kong School of Public Health at Hunter College, City University of New York, New York.

Background: Obesity was first noted as a risk factor for severe illness associated with pandemic H1N1 infection in 2009, but the relationship between obesity and seasonal influenza remains unclear.

Methods: We used data from a population-based cohort comprising 66 820 older (≥65 years) participants with a follow-up period from 1998 to 2012. The impact of influenza activity on respiratory mortality rates was estimated using a Cox proportional hazards model adjusted for comorbidities, meteorological factors, and other co-circulating respiratory viruses. We also tested whether the association of influenza with respiratory mortality varied with obesity and/or health status. As a control outcome, we similarly assessed the association of influenza with deaths from external causes, because these deaths should be unrelated to influenza.

Results: Seasonal influenza activity was associated with higher respiratory mortality (hazard ratio [HR], 1.13 for influenza activity in the influenza season vs noninfluenza season; 95% confidence interval [CI], 1.05-1.22). The effect of seasonal influenza was 19% greater in obese individuals than normal-weight individuals (HR, 1.19; 95% CI, 1.01-1.42). The marginally significant and greater effect modification of obesity status on the association between seasonal influenza and respiratory mortality was also observed among older people in good health (HR, 1.35; 95% CI, .97-1.87). No such relations were observed for death from external causes.

Conclusions: Obesity aggravates the effect of seasonal influenza on respiratory mortality. Priority for influenza vaccine should be considered for obese older people to decrease the burden of influenza.
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http://dx.doi.org/10.1093/cid/civ060DOI Listing
May 2015

Expanding the phenotypic spectrum and variability of endocrine abnormalities associated with TUBB3 E410K syndrome.

J Clin Endocrinol Metab 2015 Mar 5;100(3):E473-7. Epub 2015 Jan 5.

Harvard Reproductive Endocrine Sciences Center (R.B.), The Reproductive Endocrine Unit of the Department of Medicine (R.B.), Massachusetts General Hospital, Boston, Massachusetts 02114; Harvard Medical School (R.B., S.C., P.B.K., C.A., W.-M.C., E.C.E.), Boston, Massachusetts 02115; Department of Neurology (S.C., P.B.K., C.A., W.-M.C., E.C.E.), Kirby Neurobiology Center (S.C., C.A., W.-M.C., E.C.E.), and Department of Ophthalmology (S.E.M., E.C.E.), Boston Children's Hospital, Boston, Massachusetts 02115; and Howard Hughes Medical Institute (S.C., C.A., W.-M.C., E.C.E.), Chevy Chase, Maryland 20815.

Context: A heterozygous de novo c.1228G>A mutation (E410K) in the TUBB3 gene encoding the neuronal-specific β-tubulin isotype 3 (TUBB3) causes the TUBB3 E410K syndrome characterized by congenital fibrosis of the extraocular muscles (CFEOM), facial weakness, intellectual and social disabilities, and Kallmann syndrome (anosmia with hypogonadotropic hypogonadism). All TUBB3 E410K subjects reported to date are sporadic cases.

Objective: This study aimed to report the clinical, genetic, and molecular features of a familial presentation of the TUBB3 E410K syndrome.

Design: Case report of a mother and three affected children with clinical features of the TUBB3 E410K syndrome.

Setting: Academic Medical Center.

Main Outcome Measures: Genetic analysis of the TUBB3 gene and clinical evaluation of endocrine and nonendocrine phenotypes.

Results: A de novo TUBB3 c.1228G>A mutation arose in a female proband who displayed CFEOM, facial weakness, intellectual and social disabilities, and anosmia. However, she underwent normal sexual development at puberty and had three spontaneous pregnancies with subsequent autosomal-dominant inheritance of the mutation by her three boys. All sons displayed nonendocrine features of the TUBB3 E410K syndrome similar to their mother but, in addition, had variable features suggestive of additional endocrine abnormalities.

Conclusions: This first report of an autosomal-dominant inheritance of the TUBB3 c.1228G>A mutation in a family provides new insights into the spectrum and variability of endocrine phenotypes associated with the TUBB3 E410K syndrome. These observations emphasize the need for appropriate clinical evaluation and complicate genetic counseling of patients and families with this syndrome.
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http://dx.doi.org/10.1210/jc.2014-4107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4333039PMC
March 2015