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1.  Bio-inspired Nanoparticulate Medical Glues for Minimally Invasive Tissue Repair 
Advanced healthcare materials  2015;4(16):2587-2596.
Delivery of tissue glues through small-bore needles or trocars is critical for sealing holes, affixing medical devices, or attaching tissues together during minimally invasive surgeries. Inspired by the granule-packaged glue delivery system of sandcastle worms, we have developed a nanoparticulate formulation of a viscous hydrophobic light-activated adhesive based on poly(glycerol sebacate)-acrylate. Negatively charged alginate was used to stabilize the nanoparticulate surface to significantly reduce its viscosity and to maximize injectability through small-bore needles. The nanoparticulate glues can be concentrated to ~30w/v% dispersions in water that remain localized following injection. With the trigger of a positively charged polymer (e.g., protamine), the nanoparticulate glues can quickly assemble into a viscous glue that exhibits rheological, mechanical and adhesive properties resembling the native poly(glycerol sebacate)-acrylate based glues. This platform should be useful to enable the delivery of viscous glues to augment or replace sutures and staples during minimally invasive procedures.
PMCID: PMC4715574  PMID: 26227833
medical adhesive; nanoparticle; bio-inspired; sandcastle worm glue; injectability
2.  Assessment of a multi-layered diffuse correlation spectroscopy method for monitoring cerebral blood flow in adults 
Biomedical Optics Express  2016;7(9):3659-3674.
Diffuse correlation spectroscopy (DCS) is a promising technique for brain monitoring as it can provide a continuous signal that is directly related to cerebral blood flow (CBF); however, signal contamination from extracerebral tissue can cause flow underestimations. The goal of this study was to investigate whether a multi-layered (ML) model that accounts for light propagation through the different tissue layers could successfully separate scalp and brain flow when applied to DCS data acquired at multiple source-detector distances. The method was first validated with phantom experiments. Next, experiments were conducted in a pig model of the adult head with a mean extracerebral tissue thickness of 9.8 ± 0.4 mm. Reductions in CBF were measured by ML DCS and computed tomography perfusion for validation; excellent agreement was observed by a mean difference of 1.2 ± 4.6% (CI95%: −31.1 and 28.6) between the two modalities, which was not significantly different.
PMCID: PMC5030039  PMID: 27699127
(170.3660) Light propagation in tissues; (170.3880) Medical and biological imaging; (170.1470) Blood or tissue constituent monitoring; (170.6935) Tissue characterization
3.  Near-Perfect Synaptic Integration by Nav1.7 in Hypothalamic Neurons Regulates Body Weight 
Cell  2016;165(7):1749-1761.
Neurons are well suited for computations on millisecond timescales, but some neuronal circuits set behavioral states over long time periods, such as those involved in energy homeostasis. We found that multiple types of hypothalamic neurons, including those that oppositely regulate body weight, are specialized as near-perfect synaptic integrators that summate inputs over extended timescales. Excitatory postsynaptic potentials (EPSPs) are greatly prolonged, outlasting the neuronal membrane time-constant up to 10-fold. This is due to the voltage-gated sodium channel Nav1.7 (Scn9a), previously associated with pain-sensation but not synaptic integration. Scn9a deletion in AGRP, POMC, or paraventricular hypothalamic neurons reduced EPSP duration, synaptic integration, and altered body weight in mice. In vivo whole-cell recordings in the hypothalamus confirmed near-perfect synaptic integration. These experiments show that integration of synaptic inputs over time by Nav1.7 is critical for body weight regulation and reveal a mechanism for synaptic control of circuits regulating long term homeostatic functions.
Graphical Abstract
•Hypothalamic neurons that regulate body weight are near-perfect synaptic integrators•Near-perfect synaptic integration is observed in hypothalamic neurons in vivo•Near-perfect synaptic integration depends on the voltage-gated sodium channel Nav1.7•Loss of Nav1.7 in hypothalamic neurons disrupts regulation of body weight
Neurons in the hypothalamus are capable of summing synaptic inputs received over long periods of time, providing insights into how long-term homeostatic functions like weight maintenance can be set by neural circuits.
PMCID: PMC4912688  PMID: 27315482
4.  CCNF mutations in amyotrophic lateral sclerosis and frontotemporal dementia 
Nature Communications  2016;7:11253.
Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are overlapping, fatal neurodegenerative disorders in which the molecular and pathogenic basis remains poorly understood. Ubiquitinated protein aggregates, of which TDP-43 is a major component, are a characteristic pathological feature of most ALS and FTD patients. Here we use genome-wide linkage analysis in a large ALS/FTD kindred to identify a novel disease locus on chromosome 16p13.3. Whole-exome sequencing identified a CCNF missense mutation at this locus. Interrogation of international cohorts identified additional novel CCNF variants in familial and sporadic ALS and FTD. Enrichment of rare protein-altering CCNF variants was evident in a large sporadic ALS replication cohort. CCNF encodes cyclin F, a component of an E3 ubiquitin–protein ligase complex (SCFCyclin F). Expression of mutant CCNF in neuronal cells caused abnormal ubiquitination and accumulation of ubiquitinated proteins, including TDP-43 and a SCFCyclin F substrate. This implicates common mechanisms, linked to protein homeostasis, underlying neuronal degeneration.
Ian Blair and colleagues use genome-wide linkage analysis and whole exome sequencing to identify mutations in the CCNF gene in large cohorts of amyotrophic lateral sclerosis and frontotemporal dementia patients. In addition to validating the mutations in international cohorts, the authors also show that mutant CCNF gene product affects ubiquitination and protein degradation in cultured cells.
PMCID: PMC4835537  PMID: 27080313
5.  A community-based cross-sectional immunisation survey in parents of primary school students 
Immunisation is a very important aspect of child health. Invasive pneumococcal and influenza diseases have been major vaccine-available communicable diseases. We surveyed demographics and attitudes of parents of primary school students who received pneumococcal conjugate vaccination (PCV) and compared them with those who did not receive pneumococcal vaccination. The survey was carried out in randomly selected primary schools in Hong Kong. Questionnaires were sent to nine primary schools between June and September 2014. Parents of 3,485 children were surveyed, and 3,479 (1,452 PCV immunised, 2,027 un-immunised) valid questionnaires were obtained. Demographic data were generally different between the two groups. PCV-immunised children were more likely to be female (57.0 vs. 52.2%, P=0.005), born in Hong Kong (94.2 vs. 92.3%, P=0.031), have a parent with tertiary education (49.2 vs. 31.8, P<0.0005), from the higher-income group (P=0.005), have suffered upper respiratory infections, pneumonia, otitis media or sinusitis (P=0.019), and have doctor visits in preceding 12 months (P=0.009). They were more likely to have received additional immunisations outside the Hong Kong Childhood Immunization Programme (64.0 vs. 30.6%, P<0.0005) at private practitioner clinics (91.1 vs. 83.5%, P<0.0005). Un-immunised children were more likely to live with senior relatives who had not received PCV. Their parents were less likely to be aware of public education programme on PCV and influenza immunisation, and children were less likely to have received influenza vaccination. The major reasons for PCV immunisations were parent awareness that pneumococcal disease could be severe and vaccines were efficacious in prevention. The major reasons for children not being immunised with PCV were concerns about vaccine side effects, cost, vaccine not efficacious or no recommendation by family doctor or government. In conclusion, PCV unimmunized children were prevalent during the study period. Reportedly, they were generally less likely to have received influenza and other childhood vaccines, and more likely to live with senior relatives who had not received PCV and influenza. These observations provide important demographic data for public health policy in childhood immunisation programme.
PMCID: PMC4823920  PMID: 27053378
6.  mTOR and differential activation of mitochondria orchestrate neutrophil chemotaxis 
The Journal of Cell Biology  2015;210(7):1153-1164.
Neutrophil chemotaxis is regulated by opposing autocrine purinergic signaling mechanisms, which are stimulated by mitochondrial ATP formation that is up-regulated via mTOR and P2Y2 receptors at the front and down-regulated via A2a receptors and cAMP/PKA signaling at the back of cells.
Neutrophils use chemotaxis to locate invading bacteria. Adenosine triphosphate (ATP) release and autocrine purinergic signaling via P2Y2 receptors at the front and A2a receptors at the back of cells regulate chemotaxis. Here, we examined the intracellular mechanisms that control these opposing signaling mechanisms. We found that mitochondria deliver ATP that stimulates P2Y2 receptors in response to chemotactic cues, and that P2Y2 receptors promote mTOR signaling, which augments mitochondrial activity near the front of cells. Blocking mTOR signaling with rapamycin or PP242 or mitochondrial ATP production (e.g., with CCCP) reduced mitochondrial Ca2+ uptake and membrane potential, and impaired cellular ATP release and neutrophil chemotaxis. Autocrine stimulation of A2a receptors causes cyclic adenosine monophosphate accumulation at the back of cells, which inhibits mTOR signaling and mitochondrial activity, resulting in uropod retraction. We conclude that mitochondrial, purinergic, and mTOR signaling regulates neutrophil chemotaxis and may be a pharmacological target in inflammatory diseases.
PMCID: PMC4586745  PMID: 26416965
7.  Pityriasis Rosea, Gianotti-Crosti Syndrome, Asymmetric Periflexural Exanthem, Papular-Purpuric Gloves and Socks Syndrome, Eruptive Pseudoangiomatosis, and Eruptive Hypomelanosis: Do Their Epidemiological Data Substantiate Infectious Etiologies? 
Infectious Disease Reports  2016;8(1):6418.
Many clinical and laboratory-based studies have been reported for skin rashes which may be due to viral infections, namely pityriasis rosea (PR), Gianotti-Crosti syndrome (GCS), asymmetric periflexural exanthem/unilateral laterothoracic exanthem (APE/ULE), papular-purpuric gloves and socks syndrome (PPGSS), and eruptive pseudo-angiomatosis (EP). Eruptive hypomelanosis (EH) is a newly discovered paraviral rash. Novel tools are now available to investigate the epidemiology of these rashes. To retrieve epidemiological data of these exanthema and analyze whether such substantiates or refutes infectious etiologies. We searched for articles published over the last 60 years and indexed by PubMed database. We then analyzed them for universality, demography, concurrent patients, temporal and spatial-temporal clustering, mini-epidemics, epidemics, and other clinical and geographical associations. Based on our criteria, we selected 55, 60, 29, 36, 20, and 4 articles for PR, GCS, APE/ULE, PPGSS, EP, and EH respectively. Universality or multiple-continental reports are found for all exanthema except EH. The ages of patients are compatible with infectious causes for PR, GCS, APE/ULE, and EH. Concurrent patients are reported for all. Significant patient clustering is demonstrated for PR and GCS. Mini-epidemics and epidemics have been reported for GCS, EP, and EH. The current epidemiological data supports, to a moderate extent, that PR, GCS, and APE could be caused by infectious agents. Support for PPGSS is marginal. Epidemiological evidences for infectious origins for EP and EH are inadequate. There might be growing epidemiological evidence to substantiate or to refute our findings in the future.
PMCID: PMC4815944  PMID: 27103975
papular acrodermatitis of childhood; paraviral exanthema; regression analyses with bootstrapped simulations; temporal clustering; unilateral mediothoracic exanthema
8.  Intrathecal Baclofen Pump Migration Into the Peritoneal Cavity: A Case Report 
Intrathecal baclofen pumps are valuable treatment options for those with cerebral palsy. Although subfascial baclofen pump placement is generally preferred over a subcutaneous pump placement due to lower infection rates, rare complications can occur with the subfascial approach such as pump migration.
Case Presentation:
The authors here describe a case of baclofen pump migration into the peritoneal cavity of a 26-year-old male patient with cerebral palsy, shunted hydrocephalus, and epilepsy. Because the patient’s pump could not be palpated on exam and hence refilled, imaging was undertaken, but did not reveal clear evidence of pump migration. Surgery afterward confirmed that the pump had migrated into the peritoneal cavity through a fascial defect. Baclofen pump had to be replaced instead subcutaneously as well as the patient later had to be readmitted for 2 ventriculoperitoneal shunt revisions due to progression of his hydrocephalus.
Intraperitoneal migration of a subfascially placed baclofen pump is a rare, yet serious complication, which has been reported only once in the literature. We advise neurosurgeons to have a low level of threshold in confirming the location of a baclofen pump with imaging and surgical exploration if necessary in order to avoid detrimental outcomes such as bowel perforation.
PMCID: PMC5018100  PMID: 27642571
Baclofen; Cerebral Palsy; Infusion Pumps; Implantable; Complications
9.  Associated with Health Care-Associated Infections in Cardiac Surgery 
Health care-associated infections (HAIs) are the most common noncardiac complications after cardiac surgery and are associated with increased morbidity and mortality. Current information about their economic burden is limited.
To determine the cost associated with major types of HAIs during the first 2 months after cardiac surgery.
Prospectively collected data from a multicenter observational study of the Cardiothoracic Surgery Clinical Trials Network, in which patients were monitored for infections for 65 days after surgery, were merged with related financial data, routinely collected by the University HealthSystem Consortium. Incremental length of stay (LOS) and cost associated with HAIs were estimated using generalized linear models, adjusting for patient demographics, clinical history, baseline laboratory values, and surgery type.
Among 4,320 cardiac surgery patients, mean age of 64 ± 13 years, 119 (2.8%) experienced a major HAI during the index hospitalization. The most common HAIs were pneumonia (48%), sepsis (20%) and C. Difficile colitis (18%). On average, the estimated incremental cost associated with a major HAI was nearly $38,000, of which 47% was related to intensive care unit services. The incremental LOS was 14 days. Overall, there were 849 readmissions, among these, 8.7% were attributed to major HAIs. The cost of readmissions due to major HAI was on average nearly three times as much as readmissions not related to HAI.
Hospital cost, length of stay, and readmissions are strongly associated with HAIs. These associations suggest the potential for large reductions in costs if HAIs following cardiac surgery can be reduced.
PMCID: PMC4293042  PMID: 25572505
10.  Quantitative Phosphoproteomics Reveals Crosstalk Between Phosphorylation and O-GlcNAc in the DNA Damage Response Pathway 
Proteomics  2015;15(0):591-607.
The modification of intracellular proteins by monosaccharides of O-linked β-N-acetylglucosamine (O-GlcNAc) is an essential and dynamic post-translational modification of metazoans. The addition and removal of O-GlcNAc is catalyzed by the O-GlcNAc transferase (OGT) and O-GlcNAcase, respectively. One mechanism by which O-GlcNAc is thought to mediate proteins is by regulating phosphorylation. To provide insight into the pathways regulated by O-GlcNAc, we have utilized stable isotope labeling of amino acids in cell culture (SILAC)-based quantitative proteomics to carry out comparisons of site-specific phosphorylation in OGT wild-type (WT) and Null cells. Quantitation of the phosphoproteome demonstrated that out of 5,529 phosphoserine, phosphothreonine and phosphotyrosine sites, 232 phosphosites were upregulated and 133 downregulated in the absence of O-GlcNAc. Collectively, these data suggest that deletion of OGT has a profound effect on the phosphorylation of cell cycle and DNA damage response proteins. Key events were confirmed by biochemical analyses and demonstrate a increase in the activating autophosphorylation event on ATM (Ser1987) and on ATM’s downstream targets p53, H2AX and Chk2. Together, these data support widespread changes in the phosphoproteome upon removal of O-GlcNAc, suggesting that O-GlcNAc regulates processes such as the cell cycle, genomic stability, and lysosomal biogenesis.
PMCID: PMC4564869  PMID: 25263469
OGT; ATM; Signal Transduction; Glycobiology; Glycosylation
11.  TALENs Facilitate Single-step Seamless SDF Correction of F508del CFTR in Airway Epithelial Submucosal Gland Cell-derived CF-iPSCs 
Cystic fibrosis (CF) is a recessive inherited disease associated with multiorgan damage that compromises epithelial and inflammatory cell function. Induced pluripotent stem cells (iPSCs) have significantly advanced the potential of developing a personalized cell-based therapy for diseases like CF by generating patient-specific stem cells that can be differentiated into cells that repair tissues damaged by disease pathology. The F508del mutation in airway epithelial cell-derived CF-iPSCs was corrected with small/short DNA fragments (SDFs) and sequence-specific TALENs. An allele-specific PCR, cyclic enrichment strategy gave ~100-fold enrichment of the corrected CF-iPSCs after six enrichment cycles that facilitated isolation of corrected clones. The seamless SDF-based gene modification strategy used to correct the CF-iPSCs resulted in pluripotent cells that, when differentiated into endoderm/airway-like epithelial cells showed wild-type (wt) airway epithelial cell cAMP-dependent Cl ion transport or showed the appropriate cell-type characteristics when differentiated along mesoderm/hematopoietic inflammatory cell lineage pathways.
PMCID: PMC5012545  PMID: 26730810
cystic fibrosis iPS cells; iPSC directed differentiation; polynucleotide gene targeting/genome editing; sequence-specific chimeric endonucleases; SFHR
12.  De novo transcriptome reconstruction and annotation of the Egyptian rousette bat 
BMC Genomics  2015;16:1033.
The Egyptian Rousette bat (Rousettus aegyptiacus), a common fruit bat species found throughout Africa and the Middle East, was recently identified as a natural reservoir host of Marburg virus. With Ebola virus, Marburg virus is a member of the family Filoviridae that causes severe hemorrhagic fever disease in humans and nonhuman primates, but results in little to no pathological consequences in bats. Understanding host-pathogen interactions within reservoir host species and how it differs from hosts that experience severe disease is an important aspect of evaluating viral pathogenesis and developing novel therapeutics and methods of prevention.
Progress in studying bat reservoir host responses to virus infection is hampered by the lack of host-specific reagents required for immunological studies. In order to establish a basis for the design of reagents, we sequenced, assembled, and annotated the R. aegyptiacus transcriptome. We performed de novo transcriptome assembly using deep RNA sequencing data from 11 distinct tissues from one male and one female bat. We observed high similarity between this transcriptome and those available from other bat species. Gene expression analysis demonstrated clustering of expression profiles by tissue, where we also identified enrichment of tissue-specific gene ontology terms. In addition, we identified and experimentally validated the expression of novel coding transcripts that may be specific to this species.
We comprehensively characterized the R. aegyptiacus transcriptome de novo. This transcriptome will be an important resource for understanding bat immunology, physiology, disease pathogenesis, and virus transmission.
Electronic supplementary material
The online version of this article (doi:10.1186/s12864-015-2124-x) contains supplementary material, which is available to authorized users.
PMCID: PMC4672546  PMID: 26643810
RNA-seq; Transcriptome; Genomics; Annotation; Database
Neuro-Oncology  2014;16(Suppl 5):v190.
Glioblastoma multiforme is the most common and lethal primary malignant brain tumor and radiation therapy is considered the standard of care in the adjuvant setting. Current radiation treatment planning guidelines recommend FLAIR MRI sequence with a 2 cm margin to encompass the subclinical tumor spread. However, the FLAIR modality extensively visualizes the surrounding edema, possibly leading to unnecessary radiation toxicity to healthy brain tissue. We hypothesize that we can optimize radiation therapy by using alternative MRI modalities or by decreasing clinical tumor volume margins to minimize toxicity without compromising accurate tumor targeting. We retrospectively collected data for 21 patients with pathology confirmed recurrence and created radiation treatment plans using ADC, ADC without FLAIR shine-through (ADCst), DWI, T1, and FLAIR. For the FLAIR both a 1 cm and 2 cm margin was used (FLAIR1 and FLAIR2). Boolean operators were used to calculate the accuracy of targeting tumor recurrence and excessive radiation volume compared to the standard FLAIR2 treatment plan. All MRI modalities had complete coverage of the recurrent tumor and the mean differences in accuracy between the different MRI modalities and FLAIR2 was not significant. However, there was a significant reduction in the excessive radiation volume compared to FLAIR2. ADCst had a 51.3% reduction, DWI 42.3%, T1 42.6%, and FLAIR1 44.6% reduction of excessive radiation volume compared to FLAIR2 (p < 0.05). ADC did not have a significant reduction of excessive radiation volume compared to FLAIR2. Our data support the hypothesis that using MRI modalities other than the standard FLAIR or decreasing the margin by 1cm may optimize radiation therapy for GBM patients by reducing unnecessary radiation dose to healthy brain tissue without compromising accuracy. By using new MRI modalities in radiation treatment planning or modifying clinical tumor volume margins we can decrease radiation toxicity to patients to improve their quality of life.
PMCID: PMC4218518
14.  A home-school-doctor model to break the barriers for uptake of human papillomavirus vaccine 
BMC Public Health  2015;15:935.
A high coverage of human papillomavirus (HPV) vaccination is required to achieve a clinically significant reduction in disease burden. Countries implementing free-of-charge national vaccination program for adolescent girls are still challenged by the sub-optimal uptake rate. Voluntary on-site school-based mass vaccination programs have demonstrated high coverage. Here, we tested whether this could be an option for countries without a government-supported vaccination program as in Hong Kong.
A Home-School-Doctor model was evolved based on extensive literature review of various health promotion models together with studies on HPV vaccination among adolescent girls. The outcome measure was uptake of vaccination. Factors associated with the outcome were measured by validated surveys in which 4,631 students from 24 school territory wide participated. Chi-square test was used to analyze association between the categorical variables and the outcome. Multivariate analysis was performed to identify independent variables associated with the outcome with vaccine group as case and non-vaccine group as control.
In multivariate analysis, parental perception of usefulness of the Home-School-Doctor model had a very high odds ratio for uptake of HPV vaccination (OR 26.6, 95 % CI 16.4, 41.9). Paying a reasonable price was another independent factor associated with increased uptake (OR 1.71, 95 % CI 1.39, 2.1 for those with parents willing to pay US$125-250 for vaccination). For parents and adolescents who were not sure where to get vaccination, this model was significantly associated with improved uptake rate (OR 1.66, 95 % CI 1.23, 2.23). Concerns with side effects of vaccine (OR 0.70, 95 % CI 0.55, 0.88), allowing daughters to make their own decisions (OR 0.49, 95 % CI 0.38, 0.64) and not caring much about daughters’ social life (95 % CI 0.45, 0.92) were factors associated with a lower uptake.
The findings of this study have added knowledge on how a school-based vaccination program would improve vaccine uptake rate even when the users need to pay. Our findings are consistent with other study that the most acceptable way to achieve high uptake of HPV vaccine is to offer voluntary school-based vaccination.
A model of care incorporating the efforts and expertise of academics and health professionals working closely with school can be applied to improve the uptake of vaccine among adolescent girls. Subsidized voluntary school-based vaccination scheme can be an option.
PMCID: PMC4578840  PMID: 26392084
Human Papillomavirus vaccination; Adolescent girls; Vaccine uptake; Home-school-doctor model
15.  Culture and gambling fallacies 
SpringerPlus  2015;4:510.
Euro-Canadians and Chinese typically hold different theories about change; Euro-Canadians often engage in linear thinking whereas Chinese often engage in non-linear thinking. The present research investigated the effects of culture-specific theories of change in two related gambling fallacies: the gambler’s fallacy (GF; the belief that one is due for a win after a run of losses) and the hot-hand fallacy (HHF; the belief that one’s winning streak is likely to continue). In Study 1, participants predicted the outcome of a coin toss following a sequence of tosses. Study 2 involved predicting and betting on the outcome of a basketball player’s shot following a sequence of shots. In Study 1, Asians (mainly Chinese) were significantly more likely than Euro-Canadians to believe that they would win (correctly predict the coin toss) after a series of losses (a non-linear thinking pattern), suggesting greater susceptibility to the gambler’s fallacy. In Study 2, Euro-Canadians were more likely than Chinese to predict outcomes consistent with a basketball player’s streaks (a linear thinking pattern), suggesting greater susceptibility to the hot hand fallacy. By illustrating the role of cultural differences in cognition, these findings contribute to our understanding of why certain cultural groups, such as Chinese, are more susceptible to gambling.
PMCID: PMC4573969  PMID: 26405630
Gambling; Culture; Gambling fallacy; Hot-hand fallacy
16.  Parental Attitudes and Factors Associated With Varicella Vaccination in Preschool and Schoolchildren in Hong Kong 
Medicine  2015;94(36):e1519.
This study investigates parental attitudes and factors associated with varicella vaccination among preschool and schoolchildren prior to introduction of the vaccine into Hong Kong's universal Childhood Immunization Program.
Fourteen kindergartens and 5 primary schools in Hong Kong were randomly selected in 2013. Parents of the students were invited to answer the self-administered questionnaires. Acquired information included demographic characteristics and socioeconomic statuses of families, children's history of chickenpox infection and vaccination, and reasons for getting children vaccinated. Logistic regression was applied to examine the factors associated with vaccination.
From the 3484 completed questionnaires, the calculated rates of varicella infection and vaccination were 20.7% and 69.0%, respectively. Barriers to vaccination included parental uncertainties about vaccine effectiveness, lack of recommendation from the government, and concerns on adverse effects. Overall, 71.8%, 69.0%, and 45.7% of the parents rated family doctors, specialists, and the government, respectively, as very important motivators of vaccination. Higher parental educational level and family income, better perceived knowledge of varicella and chance of infection, discussion with a family doctor, and positive health belief towards vaccination were associated with vaccination (all P < 0.05).
The rate of vaccination in Hong Kong was higher than that of some other countries that also did not include the vaccine in their routine immunization programs. More positive parental attitudes, higher socioeconomic status, and discussion with a family doctor are associated with greater vaccination rates. The important roles that health professionals and the government play in promoting varicella vaccination were emphasized.
PMCID: PMC4616659  PMID: 26356725
17.  A Targetable GATA2-IGF2 Axis Confers Aggressiveness in Lethal Prostate Cancer 
Cancer cell  2015;27(2):223-239.
Elucidating the determinants of aggressiveness in lethal prostate cancer may stimulate therapeutic strategies that improve clinical outcomes. We used experimental models and clinical databases to identify GATA2 as a regulator of chemotherapy resistance and tumorigenicity in this context. Mechanistically, direct upregulation of the growth hormone IGF2 emerged as a mediator of the aggressive properties regulated by GATA2. IGF2 in turn activated IGF1R and INSR as well as a downstream polykinase program. The characterization of this axis prompted a combination strategy whereby dual IGF1R/INSR inhibition restored the efficacy of chemotherapy and improved survival in preclinical models. These studies reveal a GATA2-IGF2 aggressiveness axis in lethal prostate cancer and identify a therapeutic opportunity in this challenging disease.
PMCID: PMC4356948  PMID: 25670080
18.  Characterization of the Specificity of O-GlcNAc Reactive Antibodies Under Conditions of Starvation and Stress 
Analytical biochemistry  2014;457:8-18.
The dynamic modification of nuclear, cytoplasmic, and mitochondrial proteins by O-linked β-N-acetyl-D-Glucosamine (O-GlcNAc) has been shown to regulate over 3,000 proteins in a manner analogous to protein phosphorylation. O-GlcNAcylation regulates the cellular stress response, the cell cycle, and is implicated in the etiology of neurodegeneration, type II diabetes, and cancer. The antibody CTD110.6 is often used to detect changes in the O-GlcNAc modification. Recently, it has been demonstrated that CTD110.6 recognizes N-linked N,N’-diacetylchitobiose, which is thought to accumulate in cells experiencing severe glucose deprivation. In this study, we have addressed two questions: 1) Which other antibodies used to detect O-GlcNAc cross-react with N-linked N,N’-diacetylchitobiose? 2) Does N-linked N,N’-diacetylchitobiose accumulate in response to other cellular stressors? To delineate between O-GlcNAc and N-linked N,N’-diacetylchitobiose, we developed a workflow that has been used to confirm the specificity of a variety of O-GlcNAc specific antibodies. Using this workflow we demonstrated that heat shock, osmotic stress, endoplasmic reticulum stress, oxidative stress, DNA damage, proteasomal inhibition, and ATP depletion induce O-GlcNAcylation but not N-linked N,N’-diacetylchitobiose. Moreover, we demonstrated that while glucose deprivation results in an induction in both O-GlcNAc and N-linked N,N’-diacetylchitobiose, the induction of N-linked N,N’-diacetylchitobiose is exacerbated by the removal of fetal bovine serum.
PMCID: PMC4113912  PMID: 24747005
CTD110.6; O-GlcNAc; nutrient deprivation; specificity; stress-response
19.  Health Disparity Still Exists in an Economically Well-Developed Society in Asia 
PLoS ONE  2015;10(6):e0130424.
The socioeconomic inequalities in child health continue to widen despite improved economy.
To investigate the correlation between socio-economic factors and health risk behaviors and psychosocial well-being of children in Hong Kong.
The null hypothesis is that for this particular developed region, there exists little or no correlation between social-economic factors and health risk behaviors and psychosocial well-being of children.
Cross sectional territory wide survey.
Caregivers of 7,000 children in kindergartens in Hong Kong.
Measuring tools
Youth Risk Behavior Surveillance questionnaire, health-related knowledge and hygienic practice questionnaire, and Children Behavior Checklist (CBCL).
Children were less likely to have somatic complaints and anxiety/depression as reflected by CBCL scores coming from families of higher income, not being recipients of social assistance, with fathers in employment, and with higher parental education. Children with only mother or father as caretakers had lower odds ratios (ORs) 0.71 (95% CI 0.58-0.89) and 0.53 (95% CI 0.33-0.84) respectively to have the habit of eating breakfast, whilst parental education at post-secondary level and higher family income had higher ORs 1.91 (95% CI 1.31-2.78), and 1.63 (95% CI 1.11-2.39). Fathers unemployed, relatives as main caretakers and living in districts with low median household inome incurred higher ORs, as 1.46 (95% CI 1.10-1.94),1.52 (95% CI 1.27-1.83) and 1.17 (95% CI 1.02-1.34) respectively, of watching television over two hours daily, whilst children with parental education at secondary level or above incurred lower OR 0.33 (95% CI 0.24-0.45). Children with parental education at post-secondary level and higher family income had lower ORs of 0.32 (95% CI 0.48-0.97) and 0.52 (95% CI 0.34-0.79) respectively, with regard to exposing to passive smoking, and reversed for those living in districts with lower median household income, lower family income and recipient of CSSA with ORs 1.24 (95% CI 1.06-1.44) and 1.6 (95% CI 1.09-2.37) respectively.
Null hypothesis was not supported. A strong gradient was still found to exist among different socio-economic groups for various health-related behaviors in developed society like Hong Kong.
PMCID: PMC4476700  PMID: 26098942
20.  Reliability and Validity of Conversion Formulas Between Comprehensive Osteopathic Medical Licensing Examination of the United States Level 1 and United States Medical Licensing Examination Step 1 
The Comprehensive Osteopathic Medical Licensing Examination of the United States (COMLEX-USA) Level 1 and United States Medical Licensing Examination (USMLE) Step 1 scores are important factors in the selection process of medical students into US residency programs.
The goals of this study were to investigate the correlation between the COMLEX-USA Level 1 and the USMLE Step 1 and to assess the accuracy of the existing formulas in predicting USMLE scores from COMLEX-USA scores.
A retrospective study of 1016 paired COMLEX-USA Level 1 and USMLE Step 1 scores was conducted. Formulas by Sarko et al and by Slocum and Louder were used to estimate USMLE Step 1 scores from COMLEX-USA Level 1 scores, and a paired t test between calculated USMLE Step 1 scores and actual USMLE Step 1 scores was performed.
During 2006–2012, 1016 of 1440 students (71%) took both the USMLE Step 1 and the COMLEX-USA Level 1 tests in the College of Osteopathic Medicine of the Pacific. The USMLE Step 1 scores were higher than those predicted by Slocum and Louder and by Sarko et al by an average of 14.16 ± 11.69 (P < .001) and 7.80 ± 12.48 (P < .001), respectively. A Pearson coefficient of 0.83 was observed. Regression analysis yielded the following formula: USMLE Step 1  =  0.2392 × COMLEX-USA Level 1 + 82.563 (R2  =  0.69577).
The USMLE Step 1 scores, on average, were higher than those predicted by the formulas derived by Slocum and Louder and by Sarko et al. Residency program directors should use caution when using formulas to derive USMLE Step 1 scores from COMLEX-USA Level 1 scores.
PMCID: PMC4054727  PMID: 24949132
21.  Associations between Parental Feeding Styles and Childhood Eating Habits: A Survey of Hong Kong Pre-School Children 
PLoS ONE  2015;10(4):e0124753.
Childhood obesity is a global public health issue, including in the Chinese setting, and its prevalence has increased dramatically throughout the last decade. Since the origins of childhood obesity may lie in the pre-school period, factors relating to very young children’s food consumption should be investigated. Parental influence, including feeding style, is the major determinant of childhood dietary behaviour through altering food provision and social environment. However, the applicability of previous research on parental feeding styles was limited by small sample size. To evaluate the influence of parental feeding styles on children's dietary patterns, a cross-sectional study was conducted among 4553 pre-schoolers in Hong Kong. Information was obtained about dietary intake and how regularly they had breakfast, using previous health surveillance surveys taken among primary school students. Parental feeding styles were assessed by a validated Parental Feeding Style Questionnaire and categorized into ‘instrumental feeding’, ‘emotional feeding’, ‘prompting and encouragement to eat’ and ‘control over eating’. Multivariable analysis was performed, adjusted for demographic information. Instrumental and/or emotional feeding was found to relate to inadequate consumption of fruit, vegetables and breakfast, and positively correlated with intake of high-energy-density food. Encouragement on eating was associated with more frequent consumption of fruits, vegetables, dairy products and breakfast. Control over eating correlated with more frequent consumption of fruits, vegetables and breakfast, and less consumption of dairy products and high-energy-density food. The present study has provided evidence on the associations between parental feeding styles and dietary patterns of Hong Kong pre-school children from a reasonably large population. Parents should avoid instrumental and emotional feeding, and implement control and encouragement to promote healthy food intake. Longitudinal studies and interventions on parental feeding style are required to confirm the research findings.
PMCID: PMC4416018  PMID: 25927836
22.  Erratum: Consumption of whole grains and cereal fiber and total and cause-specific mortality: prospective analysis of 367,442 individuals 
BMC Medicine  2015;13:85.
This is an Erratum to BMC Medicine 2015, 13:59, highlighting previously undeclared competing interests and including more information in the acknowledgements section.
Please see related article:
PMCID: PMC4403782  PMID: 25927590
23.  Consumption of whole grains and cereal fiber and total and cause-specific mortality: prospective analysis of 367,442 individuals 
BMC Medicine  2015;13:59.
Intakes of whole grains and cereal fiber have been inversely associated with the risk of chronic diseases; however, their relation with total and disease-specific mortality remain unclear. We aimed to prospectively assess the association of whole grains and cereal fiber intake with all causes and cause-specific mortality.
The study included 367,442 participants from the prospective NIH-AARP Diet and Health Study (enrolled in 1995 and followed through 2009). Participants with cancer, heart disease, stroke, diabetes, and self-reported end-stage renal disease at baseline were excluded.
Over an average of 14 years of follow-up, a total of 46,067 deaths were documented. Consumption of whole grains were inversely associated with risk of all-cause mortality and death from cancer, cardiovascular disease (CVD), diabetes, respiratory disease, infections, and other causes. In multivariable models, as compared with individuals with the lowest intakes, those in the highest intake of whole grains had a 17% (95% CI, 14–19%) lower risk of all-cause mortality and 11–48% lower risk of disease-specific mortality (all P for trend <0.023); those in the highest intake of cereal fiber had a 19% (95% CI, 16–21%) lower risk of all-cause mortality and 15–34% lower risk of disease-specific mortality (all P for trend <0.005). When cereal fiber was further adjusted, the associations of whole grains with death from CVD, respiratory disease and infections became not significant; the associations with all-cause mortality and death from cancer and diabetes were attenuated but remained significant (P for trend <0.029).
Consumption of whole grains and cereal fiber was inversely associated with reduced total and cause-specific mortality. Our data suggest cereal fiber is one potentially protective component.
PMCID: PMC4371798  PMID: 25858689
Cereal fiber; Mortality; Whole grains
24.  Association between phosphorus intake and bone health in the NHANES population 
Nutrition Journal  2015;14:28.
The objective of this study was to estimate the independent associations between intake of phosphorus (P) and bone health parameters such as bone mineral content (BMC) and bone mineral density (BMD). It provides odds ratio (OR) of osteoporosis with quartiles of P intake adjusted for covariates (i.e., age, gender, BMI, and consumption of calcium (Ca), protein, total dairy foods, and vitamin D as well as intakes of supplemental Ca, vitamin D, and multivitamins/minerals). Data came from males and females aged 13–99 years who participated in the 2005–2010 National Health and Nutrition Examination Survey (NHANES). Analyses showed that higher P intake was associated with higher Ca intake, and that dietary Ca:P ratios (0.51-0.62, with a mean of 0.60 for adults) were adequate in all age/gender groups. High intake of P was positively associated with BMC in female teenagers (Q4 vs. Q1: BMC, 30.9 ± 1.1 vs. 29.0 ± 0.5 g, P = 0.001). It was also positively associated with BMC and BMD as well as reduced risk of osteoporosis in adults >20 years of age (Q4 vs. Q1: OR of osteoporosis, 0.55; 95% confidence interval [CI], 0.39- 0.79; P = 0.001; BMC, 37.5 ± 0.4 vs. 36.70 ± 0.3 g, P < 0.01; BMD, 0.986 ± 0.004 vs. 0.966 ± 0.005 g/cm2, P < 0.05). The data suggest that high intake of P has no adverse effect on bone metabolism in populations with adequate Ca intake, and that it is also associated with positive bone parameters in some age/gender groups.
PMCID: PMC4389665  PMID: 25856461
Phosphorus intake; Bone mineral content; Bone mineral density; Osteoporosis
25.  High-resolution Genomic Surveillance of 2014 Ebolavirus Using Shared Subclonal Variants 
PLoS Currents  2015;7:ecurrents.outbreaks.c7fd7946ba606c982668a96bcba43c90.
Background: Viral outbreaks, such as the 2014 ebolavirus, can spread rapidly and have complex evolutionary dynamics, including coinfection and bulk transmission of multiple viral populations. Genomic surveillance can be hindered when the spread of the outbreak exceeds the evolutionary rate, in which case consensus approaches will have limited resolution. Deep sequencing of infected patients can identify genomic variants present in intrahost populations at subclonal frequencies (i.e. <50%). Shared subclonal variants (SSVs) can provide additional phylogenetic resolution and inform about disease transmission patterns. Methods: We use metrics from population genetics to analyze data from the 2014 ebolavirus outbreak in Sierra Leone and identify phylogenetic signal arising from SSVs. We use methods derived from information theory to measure a lower bound on transmission bottleneck size. Results and Conclusions: We identify several SSV that shed light on phylogenetic relationships not captured by consensus-based analyses. We find that transmission bottleneck size is larger than one founder population, yet significantly smaller than the intrahost effective population. Our results demonstrate the important role of shared subclonal variants in genomic surveillance.
PMCID: PMC4339230  PMID: 25737802
ebolavirus; genomic surveilance; intrahost variants; transmission bottleneck

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