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Joseph Anthony Tumbocon,1,2 Tina T Wong,3– 5 Thanendthire Sangapillai,6 Yung-Chang Yen,7 Sang-Woo Park,8 Hsien Han Lim,9 Ngamkae Ruangvaravate10 1Eye Institute, St. Luke’s Medical Center, Quezon City, Philippines; 2Department of Ophthalmology, St. Luke’s Medical Center College of Medicine, Quezon City, Philippines; 3Glaucoma Department, Singapore National Eye Centre, Singapore, Singapore; 4Cataract & Comprehensive Ophthalmology Department, Singapore Eye Research Institute, Singapore, Singapore; 5Ophthalmology & Visual Sciences, Duke-NUS Graduate Medical School, Singapore, Singapore; 6Tun Hussein Onn National Eye Hospital, Petaling Jaya, Selangor, Malaysia; 7Department of Ophthalmology, Chi Mei Medical Center, Tainan City, Taiwan; 8Department of Ophthalmology, Chonnam National University Medical School and Hospital, Gwangju, South Korea; 9Eye Centre, Sunway Medical Centre, Petaling Jaya, Selangor, Malaysia; 10Department of Ophthalmology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, ThailandCorrespondence: Joseph Anthony Tumbocon, Eye Institute, St. Luke’s Medical Center, 279 E Rodriguez Sr. Ave, Quezon City, Metro Manila, 1112, Philippines, Email jatumbocon@gmail.comBackground: Preserved prostaglandin analogs (PGAs) have been linked to ocular surface disease (OSD). While the benefits of preservative-low (PL) or -free (PF) Tafluprost (Santen Inc., Japan) were reported in real-world studies in Western countries, this is the first study in Asia to assess the effectiveness and safety of switching from preserved PGA to PL or PF-Tafluprost.Methods: We conducted a meta-analysis on studies that included adults (> 18 years of age) with a Corneal Fluorescein Staining Score (CFS) > 1. These individuals had switched to PL or PF-tafluprost after using a preserved PGA therapy for at least 3 months for glaucoma and were identified from Santen’s tafluprost study database. A total of six studies from South Korea, Philippines, Malaysia, Singapore, Thailand, Taiwan were pooled for analysis.Results: An intraocular pressure (IOP) reduction of 5.9% (0.91 mmHg) was seen in 265 patients. However, this result was not statistically significant (95% CI: − 3.64, 1.81; Figure 1). Among 132 patients, a 47.9% reduction in the CFS (95% CI: − 3.65, − 1.91) was seen. Tear film break-up (n=183) significantly increased by 1.06 seconds (95% CI: 0.65, 1.47). In 88 patients, the bulbar conjunctiva score decreased by − 0.46 (95% CI: − 0.81, − 0.10) and palpebral conjunctiva score decreased by − 0.42 (95% CI: − 0.67– 0.17). One or more new adverse reactions were reported in 3% of the individuals after switching.Conclusion: Tafluprost IOP reduction is comparable to other PGAs, with significant improvements in the ocular surface and minimal adverse reactions which were already previously reported.Keywords: ocular surface disease, glaucoma, preserved prostaglandins, tafluprost, PGA, preservative-free, preservative-low, Asian population, meta analysis

Dementia is increasing dramatically with an increasing elderly population. Pharmacological interventions are proven to have limited efficacy to treat many of the features of dementia. In such a situation, non-pharmacological means become important to help people with dementia, especially music therapy. The efficacy of music intervention on cognition has been barely explored in the literature, and the few studies that are available present inconsistent results. The aim of this systematic review is to have a meta-analysis on the effect of music therapy for improvements in cognitive functions as well as neuropsychiatric symptoms in the elderly with dementia.

Moumita Rakshit,1 Archana Gautam,1 Li Zhen Toh,2 Ying Shi Lee,2 Hui Ying Lai,1 Tina T Wong,1,2 Kee Woei Ng1,3– 5 1School of Materials Science and Engineering, Nanyang Technological University, Singapore 639798, Singapore; 2Ocular Therapeutics and Drug Delivery, Singapore Eye Research Institute, Singapore 169856, Singapore; 3Environmental Chemistry and Materials Centre, Nanyang Environment & Water Research Institute, Singapore 637141, Singapore; 4Skin Research Institute of Singapore, Singapore 138648, Singapore; 5Center for Nanotechnology and Nanotoxicology, Harvard T.H. Chan School of Public Health, Cambridge, MA 02115, USACorrespondence: Tina T Wong; Kee Woei Ng Tel +65 6322 8313; +65 6513 8294Email tina.wong.t.l@singhealth.com.sg; kwng@ntu.edu.sgBackground: Hydroxyapatite (HA) [Ca5(PO4)3(OH)] is a naturally occurring calcium phosphate which makes up 60– 70% of the dry weight of human bones. Nano-scale HA particles are increasingly being used as carriers for controlled and targeted delivery of bioactive agents like drugs, proteins, and nucleic acids due to their high porosity, negative charge, and biodegradability.Purpose: Although much effort has been devoted to understanding the delivery kinetics and effects of the payloads in such carriers, a thorough understanding of the influence of the carriers themselves is lacking.Methods: HA particles (300 μg/mL) were administered to primary human dermal fibroblasts (HDFs). The uptake and intracellular localization of the particles were determined by flow cytometry, confocal imaging, and transmission electron microscopy (TEM). Immunological assays and PCR were performed to determine the levels of pro-inflammatory cytokines and collagens in cell lysates and media supernatant.Results: The current study explores the effects of poly-dispersed HA particles on primary HDFs as a model system. The majority of the particles were determined to range between 150 and 200 nm in diameter. Upon exposure to HA suspensions, primary HDFs internalized the particles by endocytosis within 6 hours of exposure, showing maximum uptake at 72 hours following which the particles were exocytosed by 168 hours. This correlated to reduced secretion of various pro-inflammatory and pro-collagenic cytokines. Biochemical analysis further revealed a reduction in Type I collagen expression and secretion.Conclusion: HA particles have an immune-modulatory effect on dermal fibroblasts and reduce collagen production, which may impact the integrity of the extracellular matrix (ECM). This study demonstrates the need to consider the secondary effects of particulate carriers like HA, beyond basic cytotoxicity, in the specific tissue environment where the intended function is to be realized.Keywords: carrier particles, collagen expression, extracellular matrix, time-weighted average exposure

Liana J Tedesco,1 Hasani W Swindell,1 Forrest L Anderson,1 Eugene Jang,1 Tony T Wong,2 Jonathan K Kazam,2 R Kumar Kadiyala,3 Charles A Popkin1 1Center for Shoulder, Elbow and Sports Medicine, Columbia University Medical Center, New York, NY, USA; 2Department of Radiology, New York Presbyterian Hospital, New York, NY, USA; 3Department of Orthopedic Surgery, Columbia University Medical Center, New York, NY, USACorrespondence: Charles A PopkinColumbia University Medical Center, 622 West 168 St, PH – 11, New York, NY 10032, USAEmail cp2654@columbia.eduAbstract: Ice hockey continues to be a popular, fast-paced, contact sport enjoyed internationally. Due to the physicality of the game, players are at a higher risk of injury. In the 2010 Winter Olympics, men’s ice hockey had the highest injury rate compared to any other sport. In this review, we present a comprehensive analysis of evaluation and management strategies of common hand, wrist, and elbow injuries in ice hockey players. Future reseach focusing on the incidence and outcomes of these hand, wrist and elbow injuries in ice hockey players is warranted.Keywords: ice hockey, dorsal ulnotriquetral ligament, olecranon bursitis, Os styloideum, gamekeeper’s thumb

Valencia Hui Xian Foo,1 Sarah En Mei Tan,2 David Ziyou Chen,3 Shamira A Perera,1,4 Charumathi Sabayanagam,4,5 Eva Katie Fenwick,4,5 Tina T Wong,1,4,5 Ecosse L Lamoureux4–6 1Singapore National Eye Centre, Singapore; 2Tan Tock Seng Hospital, Singapore; 3Department of Ophthalmology, National University of Singapore and National University Health System, Singapore; 4Singapore Eye Research Institute, Singapore National Eye Centre, Singapore; 5Centre for Quantitative Medicine, Duke-NUS Medical School, Singapore; 6Centre for Eye Research Australia, University of Melbourne, Melbourne, VIC, Australia Objective: The aim of this study was to evaluate patients’ dissatisfaction with overall and specific aspects of a tertiary glaucoma service and to determine their independent factors, including intraocular pressure (IOP) and visual acuity (VA). Methods: Patients, aged ≥21 years, from a specialist glaucoma service in a tertiary eye hospital in Singapore for at least 6 months, were recruited for this cross-sectional study between March and June 2014. All consenting patients completed a 7-area glaucoma-specific satisfaction questionnaire and one item related to satisfaction with overall glaucoma care. We determined the top three areas of dissatisfaction and overall dissatisfaction with the glaucoma service. We also explored the independent factors associated with overall and specific areas of patients’ dissatisfaction with their glaucoma care, including VA and IOP by using logistic regression models. Results: Of the 518 patients recruited, 438 (84.6%) patients completed the study. Patients’ dissatisfaction with the overall glaucoma service was 7.5%. The three areas of glaucoma service with the highest dissatisfaction rates were as follows: 1) explanation of test results (24.8%); 2) explanation of glaucoma complications (23.7%); and 3) advice on managing glaucoma (23.5%). Patients who were dissatisfied with the overall service had a worse mean VA compared with satisfied patients (logarithm of the minimum angle of resolution =0.41±0.43 vs 0.27±0.49, p=0.005), whereas mean IOP remained well-controlled in both the groups (13.55±2.46 mmHg vs 14.82±2.86 mmHg, p=0.014). In adjusted models, factors associated with overall dissatisfaction with glaucoma care included a pre-university education and above (odds ratio [OR] =8.06, 95% CI =1.57–41.27) and lower IOP (OR =0.83, 95% CI =0.71–0.98). Conclusion: Although less than one tenth of glaucoma patients were dissatisfied with the overall glaucoma service, one in four patients were dissatisfied with three specific aspects of care. A lower IOP, ironically, and education level were associated with overall dissatisfaction. Improving patients’ understanding of glaucoma test results, glaucoma complications, and disease management may increase patient satisfaction levels. Keywords: physician-patient relations, perception, attitude to health, surveys and questionnaires, quality of health care

Semra Ozdemir,1,* Hong King Wu,1,* Eric A Finkelstein,1 Tina T Wong2 1Signature Program in Health Services and Systems Research, Duke-NUS Medical School Singapore, 2Glaucoma Department, Singapore National Eye Centre, Singapore *These authors contributed equally to this work Aim: The objectives of this study were to explore parents' views about their children's use of regular eye drops and whether they would consider a sustained-release subconjunctival injection as a replacement for daily drops.Methods: A survey was conducted with 134 parents of children with chronic eye diseases at the Singapore National Eye Centre. Parents were asked their views about their children’s use of eye drops and were then presented with a discrete choice experiment that, via a series of trade-off tasks, allowed for estimating demand for a series of hypothetical subconjunctival injections that varied along product features, including interval between administrations, risk of complications, out-of-pocket cost and whether it is recommended by the patient’s treating physician.Results: Results showed that the vast majority of parents did not find administration of eye drops to be inconvenient (78%) nor did children complain about using daily eye drops (78%). Furthermore, only about half of parents whose child missed doses stated concerns about the consequences of non-compliance. The discrete choice experiment revealed that only one in five parents would consider a subconjunctival injection for their children. These parents tended to be more concerned about the consequences of non-compliance with eye drops, had children who administered the drops themselves or had other chronic disease requiring regular medication. Among these parents, risk of complications had the largest effect on injection uptake.Conclusion: This study shows that parents do not find administration of daily eye drops to be a significant burden. As a result, most would not consider a subconjunctival injection unless risk of complications was extremely small. Keywords: sustained-release subconjunctival injection, parent preferences, children’s use of eye drops

Janice Lam,1,2 Tina T Wong,1–4 Louis Tong1–3,5 1Singapore National Eye Centre, Singapore; 2Singapore Eye Research Institute, Singapore; 3Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; 4School of Materials Science and Engineering, Nanyang Technological University, Singapore; 5Office of Clinical Sciences, Duke–National University of Singapore Graduate Medical School, Singapore Background: Our aim was to describe the demographics, risk factors, clinical signs, severity, and outcome of ocular surface disease (OSD) in 12 patients who had undergone trabeculectomy augmented with mitomycin C (MMC).Methods: Twelve glaucoma patients were referred to the Dry Eye Clinic (Singapore National Eye Centre) for further management of clinically significant OSD.Results: Of the 15 eyes from 12 patients, 14 were treated with MMC and one with 5-fluorouracil. Mean age was 69.3±10.6 years and two-thirds were male. The median interval before onset of dry eye symptoms after surgery was 13.5 months. Mean tear breakup time (TBUT) was 5.32 seconds and mean Schirmer score was 6.14 mm/5 min. Possible major risk factors for OSD in the cases include limbal stem cell deficiency occurring from exposure to antimetabolites, chronic use of antiglaucoma medications prior to surgery, and the preoperative status of the ocular surface prior to disease onset. Treatment of OSD resulted in improved best corrected visual acuity (BCVA) in 50% of the patients, with a median gain of two-line improvement in BCVA.Conclusion: OSD is a clinical problem often overlooked in patients who undergo antimetabolite-augmented filtration surgery. Recognition of the condition and appropriate treatment can improve patient symptoms and reduce health-care burdens on the economy. Keywords: cornea, glaucoma, ocular surface, trabeculectomy

Errol W Chan,1 Tina T Wong,2,3 Hla M Htoon,3 Ching L Ho,2 Donald T Tan,1,2,3 Jodhbir S Mehta2,3,4 1Department of Ophthalmology, National University Health System, Singapore; 2Singapore National Eye Centre, Singapore; 3Singapore Eye Research Institute, Singapore; 4Department of Clinical Sciences, Duke-NUS Graduate Medical School, Singapore Objective: To compare the 3-year incidence of de novo ocular hypertension (OHT) after Descemet stripping automated endothelial keratoplasty (DSAEK) and penetrating keratoplasty (PK). For DSAEK, to evaluate predictors for OHT and 2-year outcomes after OHT development. Methods: This was a review of the prospective Singapore Corneal Transplant Study at a single tertiary referral center. Consecutive DSAEKs and PKs for Fuchs’ endothelial dystrophy (FED) and pseudophakic bullous keratopathy (PBK) in eyes without pre-existing glaucoma were analyzed. OHT incidence after DSAEK and PK were compared using Kaplan–Meier survival analysis, and OHT risk factors identified using Cox proportional regression. OHT was defined: intraocular pressure (IOP) ≥ 24 mmHg or ≥ 10 mmHg from baseline. Secondary outcomes 2 years after OHT development in DSAEK were rates of glaucoma medical therapy failure, IOP success, graft failure and rejection, and best-spectacle corrected visual acuity (BSCVA). Results: There were 108 (96.4%) DSAEKs and 216 (96%) PKs. The 1-, 2- and 3-year de novo OHT incidence was not significantly different between DSAEK (36.1%, 47.2%, 47.2%, respectively) and PK (35.7%, 44.9%, 45.8%, respectively; P = 0.914). OHT incidence did not differ in subgroup analyses of multiple clinical variables (P > 0.1). OHT predictors after DSAEK were: fellow eye glaucoma (hazard ratio [HR] 3.20, P = 0.004), age

Feng-Yi Yang1, Ming-Che Teng1, Maggie Lu2, Hsiang-Fa Liang2, Yan-Ru Lee1, Chueh-Chuan Yen3, Muh-Lii Liang4,5, Tai-Tong Wong51Department of Biomedical Imaging and Radiological Sciences, National Yang-Ming University, Taipei, 2Drug Delivery Laboratory, Biomedical Technology and Device Research Laboratories, Industrial Technology Research Institute, Hsinchu, 3Division of Hematology and Oncology, Department of Medicine, Taipei Veterans General Hospital and National Yang-Ming University School of Medicine, Taipei, 4Institute of Clinical Medicine, National Yang-Ming University School of Medicine, Taipei, 5Department of Neurosurgery, Neurological Institute, Taipei Veterans General Hospital, Taipei, TaiwanBackground: High-dose tissue-specific delivery of therapeutic agents would be a valuable clinical strategy. We have previously shown that repeated transcranial focused ultrasound is able to increase the delivery of Evans blue significantly into brain tissue. The present study shows that repeated pulsed high-intensity focused ultrasound (HIFU) can be used to deliver high-dose atherosclerotic plaque-specific peptide-1 (AP-1)-conjugated liposomes selectively to brain tumors.Methods: Firefly luciferase (Fluc)-labeled human GBM8401 glioma cells were implanted into NOD-scid mice. AP-1-conjugated liposomal doxorubicin or liposomal doxorubicin alone was administered followed by pulsed HIFU and the doxorubicin concentration in the treated brains quantified by fluorometer. Growth of the labeled glioma cells was monitored through noninvasive bioluminescence imaging and finally the brain tissue was histologically examined after sacrifice.Results: Compared with the control group, the animals treated with 5 mg/kg injections of AP-1 liposomal doxorubicin or untargeted liposomal doxorubicin followed by repeated pulsed HIFU not only showed significantly enhanced accumulation of drug at the sonicated tumor site but also a significantly elevated tumor-to-normal brain drug ratio (P < 0.001). Combining repeated pulsed HIFU with AP-1 liposomal doxorubicin or untargeted liposomal doxorubicin has similar antitumor effects.Conclusion: This study demonstrates that targeted or untargeted liposomal doxorubicin, followed by repeated pulsed HIFU, is a promising high-dose chemotherapy method that allows the desired brain tumor region to be targeted specifically.Keywords: repeated focused ultrasound, interleukin-4 receptor, blood-brain barrier, brain tumor, target drug delivery

Feng-Yi Yang1,*, Hsin-Ell Wang1,*, Guan-Liang Lin1, Hui-Hsien Lin1, Tai-Tong Wong21Department of Biomedical Imaging and Radiological Sciences, School of Biomedical Science and Engineering, National Yang-Ming University, 2Department of Neurosurgery, Neurological Institute, Taipei Veterans General Hospital, Taipei, Taiwan *These authors contributed equally to this workPurpose: The purpose of this study was to evaluate the permeability of the blood–brain barrier after sonication by pulsed high-intensity focused ultrasound and to determine if such an approach increases the tumor:ipsilateral brain permeability ratio.Materials and methods: F98 glioma-bearing Fischer 344 rats were injected intravenously with Evans blue with or without blood–tumor barrier disruption induced by transcranial pulsed high-intensity focused ultrasound. Sonication was applied at a frequency of 1 MHz with a 5% duty cycle and a repetition frequency of 1 Hz. The permeability of the blood–brain barrier was assessed by the extravasation of Evans blue. Contrast-enhanced magnetic resonance images were used to monitor the gadolinium deposition path associated with transcranial pulsed high-intensity focused ultrasound, and the influencing size and location was also investigated. In addition, whole brain histological analysis was performed. The results were compared by two-tailed unpaired t-test.Results: The accumulation of Evans blue in brains and the tumor:ipsilateral brain permeability ratio of Evans blue were significantly increased after pulsed high-intensity focused ultrasound exposure. Evans blue injection followed by sonication showed an increase in the tumor:ipsilateral brain ratio of the target tumors (9.14:1) of about 2.23-fold compared with the control tumors (x4.09) on day 6 after tumor implantation. Magnetic resonance images showed that pulsed high-intensity focused ultrasound locally enhances the permeability of the blood–tumor barrier in the glioma-bearing rats.Conclusion: This method could allow enhanced synergistic effects with respect to other brain tumor treatment regimens.Keywords: focused ultrasound, blood–brain barrier, permeability, brain tumor, glioma

Jayaganesh V Natarajan1*, Marcus Ang2*, Anastasia Darwitan1, Sujay Chattopadhyay3, Tina T Wong2, Subbu S Venkatraman1 1Materials Science and Engineering, Nanyang Technological University, Singapore; 2Singapore Eye Research Institute, Singapore; 3Polymer Division, Indian Institute of Technology Roorkee, India*These authors contributed equally to this workPurpose: To report the development and therapeutic evaluation of a liposomal nanocarrier for sustained release of latanoprost, in the rabbit eye.Methods: We fabricated latanoprost-loaded egg-phosphatidylcholine (EggPC) liposomes using the film hydration technique. The delivery vehicles were nano-sized (Z avg = 109 ± 18 nm), had a narrow poly dispersity index (PDI = 0.19 ± 0.04), and a very high loading efficiency (94% ± 5%). Based on in vitro data, we evaluated this formulation for lowering intraocular pressure (IOP) in rabbit eyes. Following a single subconjunctival injection of the latanoprost loaded formulation, the eyes were clinically monitored and the IOP recorded.Results: Latanoprost-loaded EggPC liposomes demonstrated a high drug/lipid mole ratio of 0.181, remained stable for at least 6 months on storage (4°C), and at least 1 month at 25°C. A slow and sustained release of 60% of latanoprost was achieved by 14 days in the in vitro release study. The same formulation demonstrated a greater sustained IOP lowering effect compared with daily administration of topical latanoprost beyond 90 days (4.8 ± 1.5 vs 2.5 ± 0.9 mmHg; P < 0.001). No signs of inflammation were evident in the eyes from slit-lamp examination analysis.Conclusion: The loading required for a long-term sustained delivery of latanoprost for up to 90 days in the rabbit eyes was achieved with EggPC liposomes. A single injection of latanoprost-loaded EggPC liposomes can lower the IOP for up to 90 days, with a greater IOP lowering effect than daily topical administration of latanoprost.Keywords: nanomedicine, nanoliposomes, EggPC, latanoprost, sustained ocular delivery, glaucoma

Summary Muscular hamartoma is a well-demarcated tumour composed of smooth muscle and adipose tissue. We report the MRI findings of a patient with benign breast neoplasm. To the best of our knowledge, its appearance has not been previously reported. [ABSTRACT FROM AUTHOR]