Search

Background: Little is known about the practices and resources employed by general practitioners (GPs) in Singapore to manage late-life depression. As the country is stepping up its efforts to promote collaborative care across community mental health and geriatric care, understanding GPs' current practices when managing late-life depression appears timely., Methods: This qualitative descriptive study explored the perspectives on late-life depression of 28 private GPs practicing in Singapore through online semi-structured group and individual interviews. GPs were purposively sampled across age, gender, and ethnicity. Analysis followed a reflexive thematic approach and focused on physician- and system-related factors., Findings: Clinical instinct, experience, and knowledge of appropriate resources for specific patients played an important role for GPs during late-life depression care. GPs paid particular attention to communicating with patients tactfully during initial assessments and diagnosis, although some GPs chose to be upfront with patients with whom they had already established rapport. Using non-English languages when communicating about depression could mitigate stigma in some cases but added confusion in others. GPs relied primarily on their own professional support network to manage late-life depression. Although GPs acknowledged the usefulness of public care services, they felt that collaborative care was hindered by a lack of efficient communication channels between providers and appropriate financial coverage to coordinate the frequently complex care of depressed older adults., Interpretation: Current resources and practices to manage late-life depression vary greatly between private GPs in Singapore. This needs to be considered during ongoing reforms to achieve effective collaborative care., Funding: This work was funded by the Division of Family Medicine Research Capabilities Building Budget under the project "Technology and Compassion: Improving Patient Outcomes Through Data Analytics and Patients' Voice in Primary Care" [NUHSRO/2022/049/NUSMed/DFM]., Competing Interests: The authors have no conflicting interests to declare., (© 2024 The Author(s).)

Background: Trastuzumab (Herceptin) can be administered intravenously (IV Herceptin) and subcutaneously, with similar efficacy and safety, but with differences in dosage and costs. Previous studies have evaluated the costs of both treatment approaches in the outpatient settings, but no study has compared the costs of IV Herceptin administered in outpatients with subcutaneous Herceptin administered at patients' homes (Homecare SC Herceptin)., Objectives: This study aimed to compare the per-patient costs of Homecare SC Herceptin versus IV Herceptin administered in a healthcare institution's outpatient setting in Singapore., Designs: We performed a model-based cost-minimization analysis to estimate and compare the per-patient annual costs associated with each treatment modality from a societal perspective., Methods: Direct cost comprised healthcare resources utilization: drug, consumables, manpower, facility and cardiac assessment. Indirect cost was valued using a human capital approach to account for productivity lost by patients. Monte Carlo simulations with 1000 iterations were performed to account for parameter uncertainties. Costs were reported in 2023 Singapore dollars., Results: The annual societal cost per patient receiving IV Herceptin ranged from S$64,194 to S$65,135, while for Homecare SC Herceptin, it ranged from S$25,865 to S$26,807. Homecare SC Herceptin reduced the annual cost burden by 58.8% and 59.7%, per non-metastatic and metastatic breast cancer patient, respectively. The primary cost contributor was drug therapy, comprising more than 90% of the total cost. Even when excluding the cost of drugs, Homecare SC Herceptin remained cheaper by S$1912 annually. The cost reduction is approximately 60% compared to IV Herceptin regardless of disease status, with a 100% probability that the decision to adopt Homecare SC Herceptin leads to cost savings in Singapore., Conclusion: Treatment of breast cancer with Homecare SC Herceptin is a cost-saving option compared to IV Herceptin., Competing Interests: The authors declare that there is no conflict of interest., (© The Author(s), 2024.)

Background: Detection and management of late-life depression largely relies on primary care. Yet in Singapore, older adults are unlikely to seek help for their mental health from their primary care providers. This qualitative descriptive study explores how late-life depression manifests to general practitioners (GPs) in the Singaporean primary care setting., Methods: Twenty-eight private GPs practicing in Singapore were asked about their clinical experience with late-life depression during semi-structured group and individual discussions conducted online. Participants were purposively sampled across age, gender, and ethnicity (Chinese, Malay, Indian). Transcripts were analysed with reflexive thematic analysis., Findings: To GPs, depression in older patients often manifests through somatic symptoms or subtle behavioural changes, only detectable through follow-ups or collateral history. GPs reported that older patients attribute depressive symptoms to normal ageing or do not mention them, particularly within an Asian culture encouraging stoic endurance. GPs perceived late-life depression as reactions to ageing-related stressors, with male, low-income, or institutionalised patients being at particular risk of insidious, severe depression. GPs noted ethnic differences regarding families' involvement in care, which they described as helpful, but sometimes stress-provoking for patients. Fear of burdensomeness or loss of autonomy/social role could prompt rejection of diagnosis and treatment in patients. GPs considered good patient-doctor rapport as a facilitator at every step of the care process, noting more favourable prognosis in care-concordant patients., Interpretation: Depression in older adults in Singapore can be covert, with favourable outcomes relying on GPs' ability to pick up on subtle changes, assess patients holistically, and build rapport with patients and families., Funding: This work was funded by the Division of Family Medicine Research Capabilities Building Budget under the project "Technology and Compassion: Improving Patient Outcomes Through Data Analytics and Patients' Voice in Primary Care" [NUHSRO/2022/049/NUSMed/DFM]., Competing Interests: The authors have no conflicting interests to declare., (© 2024 The Author(s).)

Purpose: To evaluate natural language processing (NLP) methods to infer metastatic sites from radiology reports., Methods: A set of 4,522 computed tomography (CT) reports of 550 patients with 14 types of cancer was used to fine-tune four clinical large language models (LLMs) for multilabel classification of metastatic sites. We also developed an NLP information extraction (IE) system (on the basis of named entity recognition, assertion status detection, and relation extraction) for comparison. Model performances were measured by F1 scores on test and three external validation sets. The best model was used to facilitate analysis of metastatic frequencies in a cohort study of 6,555 patients with 53,838 CT reports., Results: The RadBERT, BioBERT, GatorTron-base, and GatorTron-medium LLMs achieved F1 scores of 0.84, 0.87, 0.89, and 0.91, respectively, on the test set. The IE system performed best, achieving an F1 score of 0.93. F1 scores of the IE system by individual cancer type ranged from 0.89 to 0.96. The IE system attained F1 scores of 0.89, 0.83, and 0.81, respectively, on external validation sets including additional cancer types, positron emission tomography-CT ,and magnetic resonance imaging scans, respectively. In our cohort study, we found that for colorectal cancer, liver-only metastases were higher in de novo stage IV versus recurrent patients (29.7% v 12.2%; P < .001). Conversely, lung-only metastases were more frequent in recurrent versus de novo stage IV patients (17.2% v 7.3%; P < .001)., Conclusion: We developed an IE system that accurately infers metastatic sites in multiple primary cancers from radiology reports. It has explainable methods and performs better than some clinical LLMs. The inferred metastatic phenotypes could enhance cancer research databases and clinical trial matching, and identify potential patients for oligometastatic interventions.

Objective: To assess large language models on their ability to accurately infer cancer disease response from free-text radiology reports., Materials and Methods: We assembled 10 602 computed tomography reports from cancer patients seen at a single institution. All reports were classified into: no evidence of disease, partial response, stable disease, or progressive disease. We applied transformer models, a bidirectional long short-term memory model, a convolutional neural network model, and conventional machine learning methods to this task. Data augmentation using sentence permutation with consistency loss as well as prompt-based fine-tuning were used on the best-performing models. Models were validated on a hold-out test set and an external validation set based on Response Evaluation Criteria in Solid Tumors (RECIST) classifications., Results: The best-performing model was the GatorTron transformer which achieved an accuracy of 0.8916 on the test set and 0.8919 on the RECIST validation set. Data augmentation further improved the accuracy to 0.8976. Prompt-based fine-tuning did not further improve accuracy but was able to reduce the number of training reports to 500 while still achieving good performance., Discussion: These models could be used by researchers to derive progression-free survival in large datasets. It may also serve as a decision support tool by providing clinicians an automated second opinion of disease response., Conclusions: Large clinical language models demonstrate potential to infer cancer disease response from radiology reports at scale. Data augmentation techniques are useful to further improve performance. Prompt-based fine-tuning can significantly reduce the size of the training dataset., (© The Author(s) 2023. Published by Oxford University Press on behalf of the American Medical Informatics Association.)

Importance: Despite patients with cancer being at risk of poor outcomes from COVID-19, there are few published studies for vaccine efficacy in this group, with suboptimal immunogenicity and waning vaccine efficacy described in small studies being a concern., Objective: To assess the incidence rate of severe COVID-19 disease outcomes associated with the number of vaccine doses received and the waning of protection over time., Design, Setting, and Participants: A prospective multicenter observational cohort study was carried out over 2 time periods (September 15, 2021, to December 20, 2021 [delta wave], and January 20, 2022, to November 11, 2022 [omicron wave]) predominated by SARS-CoV-2 delta and omicron variants, respectively. Overall, 73 608 patients with cancer (23 217 active treatment, 50 391 cancer survivors) and 621 475 controls matched by age, sex, race and ethnicity, and socioeconomic status were included., Exposure: Vaccine doses received, from zero to 4 doses, and time elapsed since last vaccine dose., Outcomes: Competing-risk regression analyses were employed to account for competing risks of death in patients with cancer. Main outcomes were incidence rate ratios (IRRs) of COVID-19 infection, hospitalization, and severe disease (defined as requirement for supplemental oxygen, intensive care, or death). The IRRs stratified by time from last vaccine dose served as indicators of waning of vaccine effectiveness over time., Results: The mean (SD) age of actively treated patients with cancer, cancer survivors, and controls were 62.7 (14.7), 62.9 (12.6), and 61.8 (14.7) years, respectively. Of 73 608 patients with cancer, 27 170 (36.9%) were men; 60 100 (81.6%) were Chinese, 7432 (10.1%) Malay, 4597 (6.2%) Indian, and 1479 (2.0%) were of other races and ethnicities. The IRRs for the 3-dose and 4-dose vs the 2-dose group (reference) for COVID-19 hospitalization and severe disease were significantly lower during both the delta and omicron waves in cancer and control populations. The IRRs for severe disease in the 3-dose group for active treatment, cancer survivors, and controls were 0.14, 0.13, and 0.07 during the delta wave and 0.29, 0.19, and 0.21 during omicron wave, respectively. The IRRs for severe disease in the 4-dose group during the omicron wave were even lower at 0.13, 0.10 and 0.10, respectively. No waning of vaccine effectiveness against hospitalization and severe disease was seen beyond 5 months after a third dose, nor up to 5 months (the end of this study's follow-up) after a fourth dose., Conclusion: This cohort study provides evidence of the clinical effectiveness of mRNA-based vaccines against COVID-19 in patients with cancer. Longevity of immunity in preventing severe COVID-19 outcomes in actively treated patients with cancer, cancer survivors, and matched controls was observed at least 5 months after the third or fourth dose.

A polarization-insensitive planar patch antenna, which has a large embedded serial capacitance, is proposed for constructing a metal mountable tag by using merely a single radiator. The proposed antenna structure itself contains two flaps of patches, which are very closely overlapped, for generating a large capacitive reactance for reducing the resonant frequency of the tag. It has been found that the surface currents in the overlapped region are in the reverse direction as the large capacitance is virtually placed in series. This feature has been tactfully employed for producing a pair of orthogonal currents for designing the polarization-insensitive tag antenna and it can generate orthogonal fields in a unique way, making it readable from almost all directions at all points above the metal surface. For analyzing the impedance properties, an equivalent circuit was also constructed. This tag antenna is compact, and it can be read from ~ 15 m with 4W EIRP. Furthermore, the tag resonant frequency is shown to be unaffected much by its backing material. The proposed tag antenna is polarization-insensitve as it can be accessible from almost all directions on the metal., (© 2023. The Author(s).)

Aim: To evaluate the effectiveness of a nurse-led smartphone-based self-management programme (NSSMP) on improving self-efficacy, promoting diabetes self-care, increasing health-related quality of life (HRQoL) and decreasing HbA1c, acute complications and unplanned medical consultation for people with poorly controlled type 2 diabetes compared with a nurse-led diabetic service (NDS)., Design: A two-arm randomized controlled trial with repeated measures was conducted., Methods: Participants were recruited from June 2018 to September 2020. Eligible participants were assigned to either the intervention or control group randomly. Participants assigned to intervention group received the 6-month NSSMP, while those in the control group received existing NDS provided by the study hospital. Outcomes were measured at baseline, and at 3 and 6 months from baseline., Results: A total of 114 participants were recruited. There were no significant interactions between group and time for all the outcomes except for blood glucose testing activities (F = 4.742, p = .015). Both groups had reduced HbA1c over 6 months. The intervention group had a lower HbA1c than the control group at follow-ups, but the differences were not statistically significant. None of the participants had acute diabetes complications at follow-up. Similarly, the differences in the number of unplanned medical consultation at 6-month follow-up between two groups were statistically insignificant., Conclusion: The NSSMP is as effective as existing NDS provided by the study hospital in improving most of the outcomes. NSSMP can liberate valuable time for nurses to provide care to critically ill patients and supports healthcare resource constraints in the current COVID-19 pandemic., Impact: The existing diabetes service is labour intensive as nurses are required to deliver education, follow-up telephone calls to trace blood sugar monitoring and provide therapeutic consultations and necessary referrals. The outbreak of COVID-19 pandemic has added further strain on the overworked professionals. NSSMP provides an alternative programme that is just as effective, to reduce nurses' workload by delegating them back to the individuals through self-management strategies. This enables nurses to increase contact time with patients, and individuals to take onus of their disease through increased self-efficacy, facilitated by technology., Clinical Trial: This study is registered under clinical registration number NCT03088475., (© 2022 John Wiley & Sons Ltd.)

Aims: To describe a systematic process for the development of a nurse-led smartphone-based self-management programme for type 2 diabetes patients with poor glycaemic control in Singapore., Methods: A three-step process involving the application of a theoretical framework, evidence from literature, content validity, and pilot tests were conducted for the content and technical development of the programme. Content experts and lay patients evaluated the appropriateness, relevance, and comprehensibility of the newly developed Care4Diabetes application. A pilot randomized controlled trial was conducted with 40 patients recruited in Singapore. Twenty patients each were randomly allocated to the control and intervention groups. The study outcomes were collected at baseline and at 3 months thereafter., Results: The nurse-led smartphone-based self-management programme was developed with integration of the Care4Diabetes application and the web-portal system. The pilot results indicated that the effects of this smartphone-based programme on patient's health-related outcomes were comparable with those of the currently available nurse-led diabetes service., Conclusion: The smartphone-based self-management intervention was deemed effective, yet full-scale randomized controlled trials are still ongoing and the results of these may provide strong evidence of the effectiveness of such an approach in improving patient care., Impact: The uniqueness of this study lies in the integrated system used, which offers a clinical platform for diabetes nurses to provide personalized coaching and care to patients remotely, while monitoring patients' progress closely. By adopting such an approach, it would free up more time for nurses to cater to patients who are more critically in need of their direct attention., (© 2020 John Wiley & Sons Ltd.)

Background: Pertuzumab is a humanized anti-human epidermal growth factor receptor 2 (HER2) monoclonal antibody found in a Phase III clinical trial to significantly improve median survival in HER2 positive metastatic breast cancer (MBC) when used in combination with a taxane and Trastuzumab, and its clinical efficacy has transformed the therapeutic landscape of HER2-positive breast cancer. There are currently few reports on the pattern of use and value of Pertuzumab in real world settings. Our study describes the clinical efficacy and treatment costs of Pertuzumab in HER2-positive MBC treated in a tertiary cancer centre in Singapore in a predominantly Asian population., Aim: To investigate the clinical efficacy and treatment costs of Pertuzumab in HER2-positive MBC in an Asian population in Singapore., Methods: A retrospective study of 304 HER2-positive MBC patients seen at National Cancer Centre Singapore between 2011-2017 was conducted. Demographic and clinical data were extracted from electronic medical records. Clinical characteristics and billing data of patients who received Pertuzumab were compared with those who did not., Results: Thirty-one (62.0%) of the fifty (16.4%) patients who received Pertuzumab as first-line therapy. With a median follow-up of 21.5 mo, there was a statistically significant difference in the median overall survival between Pertuzumab and non-Pertuzumab groups [51.5 (95%CI: 35.8-60.0) vs 32.9 (95%CI: 28.1-37.5) mo; P = 0.0128]. Two (4.88%) patients in the Pertuzumab group experienced grade 3 (G3) cardiotoxicity. The median treatment cost incurred for total chemotherapy for the Pertuzumab group was 130456 Singapore Dollars compared to 34523 Singapore Dollars for the non-Pertuzumab group. The median percentage of total chemotherapy costs per patient in the Pertuzumab group spent on Pertuzumab was 50.3%., Conclusion: This study shows that Pertuzumab use in the treatment of metastatic breast cancer is associated with a significantly better survival and a low incidence of serious cardiotoxicity. However, the proportionate cost of Pertuzumab therapy remains high and further cost-effectiveness studies should be conducted., Competing Interests: Conflict-of-interest statement: There is no conflict of interest associated with any of the senior author or other coauthors who have contributed their effort in the manuscript. All the authors have no conflict of interest related to the manuscript., (©The Author(s) 2019. Published by Baishideng Publishing Group Inc. All rights reserved.)

Background: Early quadriceps muscle strength assessment after a total knee arthroplasty (TKA) provides timely information on progress, but little is known about the pain profile and predictive validity associated with common clinical muscle strength tests. This study aimed to, in patients with a recent TKA, examine the associations of isometric and isotonic quadriceps strength with gait speed, accounting for knee pain experienced during testing., Methods: A sample of 76 patients (mean age 68 years; 46 women) with a recent TKA (median, 1.5 months) participated. Quadriceps strength was measured on both limbs using a knee extension machine. Isotonic strength was assessed with a one-repetition maximum test. Isometric strength was measured at 40° and 70° of knee flexion using a custom-built load cell. To allow for valid comparisons between the tests, quadriceps strength symmetry ratios were calculated. Knee pain during testing was measured using an 11-point pain scale. Fast gait speed was measured using the 10-m walk test., Results: Compared with isotonic test, quadriceps strength ratio was higher for the 40° flexion isometric test (P = 0.01), and this difference may be explained by the lower knee pain intensity elicited during the isometric tests (P's < 0.001). All strength measures were closely associated with fast gait speed after adjustment for knee pain and covariates (P's < 0.001)., Conclusions: Early in the post-TKA period, isometric and isotonic strength tests may be used to assess quadriceps strength but these tests are not interchangeable. Isometric quadriceps testing may be preferable to isotonic testing as it was associated with lower knee pain intensity., (Copyright © 2018. Published by Elsevier Ltd.)

Purpose: Genetic modulation of donor tissue before corneal transplantation may have the potential to modulate alloimmunity and/or to prevent corneal endothelial cell death. This study was conducted to optimize adenovirus-mediated gene transfer to donor corneal endothelium and to delineate the kinetics of marker gene expression in syngeneic and allogeneic corneal grafts., Methods: BALB/c mouse corneas were incubated with replication-deficient adenovirus encoding green fluorescent protein (GFP) or empty vector ex vivo at a dose of 6 x 10(7) or 6 x 10(6) PFU at temperatures of 4 degrees C or 37 degrees C. After ex vivo infection, the donor corneas were transplanted orthotopically to BALB/c or C57BL/6 recipients. After transplantation, localization of GFP in the grafts was determined in cryosections of enucleated eyes, and GFP expression in the grafts was visualized in vivo by using epifluorescence microscopy over 12 weeks. All grafts were evaluated clinically by slit lamp biomicroscopy., Results: GFP expression was found to be restricted to the corneal endothelium. In vivo expression of GFP in syngeneic corneal grafts was demonstrated for up to 12 weeks. Syngeneic grafts incubated with the vector at 4 degrees C exhibited a more extensive and longer duration of expression of green fluorescence than grafts incubated at 37 degrees C. Moreover, the syngeneic grafts infected at 4 degrees C maintained their transparency, whereas those infected at 37 degrees C displayed a high degree of opacity. Corneal allogeneic grafts infected with a low dose of the vector displayed longer GFP expression and graft survival than the allogeneic grafts infected with a high dose of the viral vector., Conclusions: Adenoviral vector can selectively and efficiently deliver exogenous gene(s) to the endothelium of corneal grafts during hypothermic organ preservation. Gene expression is retained in vivo in corneal syngeneic grafts for longer periods than are allogeneic grafts.

Background and Purpose: Tissue factor (TF; an initiator of coagulation) and vascular endothelial growth factor (VEGF; a marker of angiogenesis) are involved in the hypercoagulable state associated with malignancy. We investigated their roles in chronic atrial fibrillation (AF), a condition also associated with increased risk of stroke and thromboembolism, as well as a prothrombotic or hypercoagulable state., Methods: We studied 25 patients with AF (20 men; mean+/-SD age, 62+/-13 years) who were compared with 2 control groups in sinus rhythm: 30 healthy control subjects (17 men; mean age, 60+/-9 years) and 35 patient control subjects with coronary artery disease (CAD; 27 men; mean age, 60+/-12 years). Plasma levels of TF, VEGF, and the VEGF receptor sFlt-1 were measured by enzyme-linked immunosorbent assay., Results: VEGF, sFlt-1, and TF were significantly different between the 3 groups, with abnormal levels in AF and CAD patients compared with control subjects (P<0.001, P=0.022, and P=0.008, respectively). Among the AF patients, TF levels were significantly correlated with VEGF (Spearman's r=0.65, P<0.001) and sFlt (r=0.54, P=0.006) levels. Only TF and VEGF levels were significantly correlated in CAD patients (r=0.39, P=0.02). There were no significant correlations among the healthy control subjects., Conclusions: Patients with chronic AF have high TF levels, in keeping with the prothrombotic state associated with this arrhythmia. The relationships between TF and VEGF and its receptor sFlt-1 in AF suggest a possible role for VEGF in the hypercoagulable state found in AF, as seen in malignancy and atherosclerosis.

Purpose: It has been reported that the platelet-derived growth factor (PDGF)-alpha receptor (alphaPDGFR) is required for experimental proliferative vitreoretinopathy (PVR) in rabbits. This study investigated which of the signaling enzymes downstream of the alphaPDGFR participate in PVR., Methods: A panel of cell lines that expressed alphaPDGFR signaling mutants were made and characterized. These cell lines were used in a rabbit model of PVR and in an in vitro collagen type I contraction assay., Results: Phosphoinositide 3-kinase (PI3K) and, to a lesser extent, phospholipase C (PLC)-gamma were the signaling enzymes required for the alphaPDGFR to mediate PVR. Furthermore, the cells lines that were the most effective at inducing PVR displayed the most potent activity in the in vitro contraction assay., Conclusions: PI3K and PLCgamma are necessary downstream effectors of the alphaPDGFR in experimental PVR. Consequently, these two signaling enzymes are required for one or more of the cellular responses (chemotaxis, proliferation, extracellular matrix production, contraction) that contribute to PVR.

Purpose: The work from numerous laboratories has led to the idea that the growth factors such as platelet-derived growth factor (PDGF) contribute to proliferative vitreoretinopathy (PVR) in experimental models of the disease, as well as in humans. In support of this idea, the authors have previously reported that cells unable to respond to PDGF had a greatly reduced PVR potential, compared with PDGF-responsive versions of the same cells. The goal of this study was to test the effect of blocking the output of the PDGF receptor in an experimental model of PVR., Methods: Polymerase chain reaction-based site-directed mutagenesis was used to generate point mutations in the human PDGF alpha receptor (alphaPDGFR) cDNA, which resulted in single amino acid substitutions. These changes were based on naturally occurring point mutations in the c-kit receptor tyrosine kinase, which suppresses the function of wild-type c-kit. A truncated alphaPDGFR was also made, in which the receptor ended just after the juxtamembrane domain. As with the point mutants, truncated receptors have been shown to block the action of wild-type receptors. All the alphaPDGFR mutants were introduced into cells that naturally express the wild-type receptor, and the PDGF-dependent output of the resultant cell lines was determined. In addition, the PVR potential of cell lines expressing the mutant receptors was tested in a PVR rabbit model., Results: Although the mutants differed in their ability to suppress PDGF-dependent signaling of the wild-type receptor, each mutant effectively blocked cell cycle progression. When expressed in rabbit conjunctival fibroblasts, a cell line that effectively induces PVR, the mutant receptors blocked PVR to various degrees. The most effective receptor was the truncated mutant., Conclusions: These data suggest that the alphaPDGFR plays an important role in PVR. In addition, these mutant receptors appear to have therapeutic potential for prevention of this blinding disease.

We tested the hypothesis that Src family kinases (SFK) contribute to c-Cbl-mediated degradation of the platelet-derived growth factor (PDGF) alpha receptor (alphaPDGFR). Using either a receptor mutant that does not engage SFKs (F72/74), or cells that that lack SFKs, we found that SFKs contributed to degradation of the alphaPDGFR. Overexpression of c-Cbl also reduced the receptor half-life, but only if the receptor was able to engage SFKs. In cultured cells, prolonging the half-life of the receptor correlated with enhanced signaling and more efficient S phase entry, whereas accelerating receptor degradation had the opposite effect. Consistent with these tissue culture findings, there was a statistically significant increase in the onset of a proliferative retinal disease when animals were injected with cells expressing the F72/74 receptor, as compared with cells expressing the WT receptor. Our findings suggest that SFKs cooperate with c-Cbl to negatively regulate the alphaPDGFR, and that the SFK/c-Cbl suppression of alphaPDGFR output is relevant to the onset and progression of a proliferative disease.

Purpose: The action of growth factors is thought to make a substantial contribution to the events leading to proliferative vitreoretinopathy (PVR). In this study, the importance of platelet-derived growth factor (PDGF) was tested in a rabbit model of PVR., Methods: The approach was to compare the extent of PVR induced by cells that do or do not express the receptors for PDGF and therefore differ in their ability to respond to PDGF., Results: Mouse embryo fibroblasts derived from PDGF receptor knock-out embryos that do not express either of the two PDGF receptors induced PVR poorly when injected into the eyes of rabbits that had previously undergone gas vitrectomy. Re-expression of the PDGF beta receptor in these cells did not improve the ability of the cells to cause PVR. In contrast, injection of cells expressing the PDGF alpha receptor resulted in stage 3 or higher PVR in 8 of 10 animals., Conclusions: These findings show that PDGF makes an important contribution to the development of PVR in this animal model. Furthermore, there is a marked difference between the two receptors for PDGF, and it is the PDGF alpha receptor that is capable of driving events that lead to PVR.

Purpose: To evaluate the antiproliferative properties of alpha-tocopherol and alpha-tocopheryl-acid-succinate in a rabbit model of proliferative vitreoretinopathy., Methods: Fifty-seven rabbits underwent gas-compression vitrectomy and gas/fluid exchange. Group 1 (n = 8): 50 micrograms alpha-tocopherol in 1 ml of 0.5% ethanol in balanced salt solution; Group 2 (n = 8): 50 micrograms alpha-tocopheryl-acid-succinate in 1 ml of 0.5% ethanol in balanced salt solution; Groups 3 (n = 4) and 4 (n = 2): 1 ml 0.5% ethanol in balanced salt solution; Groups 5 (n = 12) and 8 (n = 9): alpha-tocopherol in 1 ml silicone oil (12 mg/ml); Group 6 (n = 9): 1 ml silicone oil; Group 7 (n = 5): 1 ml balanced salt solution. Groups 1-3, and 5-7 also received fibroblasts and platelet-rich plasma injection. Fundus evaluation was performed during a four-week period. The eyes were enucleated for gross examination on day 28. Histopathology was performed on Group 4., Results: Alpha-tocopherol and alpha-tocopheryl-acid-succinate in saline solution delayed development of proliferative vitreoretinopathy, compared to the control group (statistically significant during the first week, Mann Whitney, p < 0.05). The alpha-tocopherol in the silicone-oil group delayed development of proliferative vitreoretinopathy, compared to the silicone-oil group during the second to fourth weeks (no statistically significant difference, p > 0.05)., Conclusions: Alpha-tocopherol and alpha-tocopheryl-acid-succinate in saline solution showed retardation of proliferative vitreoretinopathy traction retinal detachments. In silicone oil, alpha-tocopherol is slowly released and decreases the severity of proliferative vitreoretinopathy, especially during the second week of follow-up.

Purpose: To determine the antiproliferative activity in intravitreous retinoic acid (RA) dispersed in 1% sodium hyaluronate (HA)., Methods: Six groups of pigmented rabbits underwent gas-compression vitrectomy. Four days later, gas/HA or gas/balanced salt solution (BSS) exchange (1.0 m1) was performed in all rabbits. Groups A (n = 10) and B (n = 5) received intravitreous RA dissolved in 0.01 m1 of ethanol and dispersed in 1% HA (10 and 15 micrograms RA/m1, respectively). Group C (n = 10) received intravitreous RA dissolved in ethanol and dispersed in BSS (10 micrograms RA/m1). Groups D (n = 5) and F (n = 4) received 1 m1 of HA with ethanol; group E (n = 5) received 1 m1 of HA without ethanol. All groups except group F also received homologous fibroblasts and autologous, platelet-rich plasma intravitreously. The eyes were examined ophthalmoscopically for 1 month. Proliferative vitreoretinopathy (PVR) findings were graded according to the classification of Fastenberg et al. all group F eyes also were examined by light and electron microscopy., Results: RA in HA lessened PVR progression within 1 month when compared with HA injection controls and within 2 weeks when compared with the RA in BSS treatment group (both, p < 0.05). NO specific change attributable to ethanol was observed histopathologically., Conclusion: RA dissolved in ethanol and dispersed in HA could be useful to treat PVR when silicone oil is unnecessary.

Because contact lens wear causes changes in tear film and corneal metabolism and can render the cornea susceptible to bacterial invasion, we examined the role of contact lens wear in Pseudomonas aeruginosa (P. aeruginosa) keratitis and its relation to the early defense mechanism, specifically whether the acute polymorphonuclear leukocyte (PMN) response is altered by contact lens wear. Thirty-three rabbit eyes were examined in an experimental model for P. aeruginosa keratitis. The development of bacterial invasion and PMN migration into the wound was studied during various time intervals in either the presence or absence of a soft hydrogel contact lens (SCL). Scanning electron microscopy revealed massive PMN accumulation in the P. aeruginosa-inoculated corneas without SCL and some, but distinctively fewer, PMNs in the bacteria-inoculated eyes with SCL. These observations demonstrate that P. aeruginosa inoculation evokes massive PMN reaction and suggests that SCL wear actually delays this early host inflammatory response. Thus, SCL wear seems to act as a barrier for the PMNs that presumably derive from the tear film.

Bacterial adherence and colonization of biomedical prosthetic implants is one of the main causes for implant withdrawal. The abhesive (anti-adhesive) effect of poloxamer 407 on several Gram-positive and Gram-negative strains and the site of action of its effect have been investigated. Poloxamer 407 significantly inhibited 92-99% of Pseudomonas aeruginosa adherence to hydrophilic contact lenses (P < .05). This adherence inhibition was concentration-dependent. A reduction of about 50-60% was obtained for Staphylococcus strains, and 50-70% for Gram-negative strains other than Pseudomonas. The poloxamer seems to act on the bacteria surface, but not on the contact lens surface. Poloxamer 407 could potentially prevent implant-related infections and keratitis associated with contact lens wear, by inhibiting bacterial adherence onto the implant or contact lens surface.

Bacterial adherence to intraocular lenses (IOLs) could be the cause of endophthalmitis following cataract surgery and lens implantation. There are previous reports that heparin bound to the surface of poly(methyl methacrylate) (PMMA) IOLs reduces cell adhesion. In this study, the in vitro adherence of Staphylococcus epidermidis, Staphylococcus aureus, and Pseudomonas aeruginosa to regular PMMA IOLs and to heparin-surface-modified (HSM) PMMA IOLs was investigated. The three bacterial strains attached in significantly lower numbers to HSM-PMMA IOLs than to PMMA IOLs (P < .01). Heparin in solution also inhibited attachment of Staphylococcus epidermidis to regular PMMA IOLs. Heparin may reduce adherence by placing a highly hydrated layer between the bacteria and the IOL surface. Therefore, the use of HSM-PMMA IOLs could diminish the incidence of endophthalmitis.

Purpose: To evaluate, in vitro, the solubility and stability of all-trans RA in silicone oil (SiO) and, in vivo, the stability and the antiproliferative effect of all-trans RA in SiO on an experimental model of PVR., Methods: The solubility and stability of RA in SiO, in vitro and in vivo, were evaluated by HPLC. Rabbits underwent unilateral gas-compression vitrectomy and gas-SiO exchange. Rabbits received 10 micrograms (n = 17), 5 micrograms (n = 11), and 2 micrograms (n = 9) of all-trans RA in SiO, and SiO only (n = 12). All rabbits received an intravitreous injection of 150,000 fibroblasts., Results: RA is stable in SiO in vitro, but some isomerization from all-trans to 13-cis was observed under light exposure. In vivo, after 1 week, trace amounts of RA in SiO were observed in the controls and in the experimental animals, suggesting a steady state between the release of RA from the SiO and from the retina to the SiO. The rate of fractional retinal detachment was significantly lower in the animals that received 10 and 5 micrograms of RA than in the controls (P < 0.05). No statistical differences were found between the eyes treated with 10 and 5 micrograms of RA. Eyes that received 2 micrograms of RA showed no difference from the control group., Conclusions: The in vivo data suggest that retinoic acid might be useful as an antiproliferative agent in human eyes.

Pseudomonas aeruginosa adherence in vitro to perfilcon A (ionic, 71% H2O) extended wear soft contact lenses--both new and after 7 days of continuous wear on closed rabbit eyes--was found to be related directly to the bacterial concentration in the contaminating solution. Thirty rabbits wore perfilcon A lenses for 7 days with complete lid closure to mimic contact lens overwear. After 7 days, conjunctival cultures showed no growth of pathogens, but all corneas had developed epithelial cell exfoliation and/or epithelial defects and stromal edema. The lenses were then incubated in various concentrations (10(7), 10(6), 10(5), 10(4), and 10(2) colony-forming units per milliliter or saline control; n = 5/group) of P. aeruginosa suspensions and replaced on their respective corneas with tarsorrhaphies for an additional 48 h. By day 9, corneal thickness had increased significantly, and P. aeruginosa keratitis had developed in 13 of 25 bacterially exposed eyes but not in 5 control eyes. Although with decreasing P. aeruginosa concentration the prevalence of ulcerative microbial keratitis also decreased, the initial concentration of bacteria or the initial extent of soft contact lens-induced corneal damage had no influence on the ultimate clinical severity of the disease.

After 7 days of continuous wear, Acuvue (Vistakon, Jacksonville, FL, U.S.A.; etafilcon A) lenses were soaked in a Pseudomonas aeruginosa suspension (1.4 x 10(8) cfu/ml). New Acuvue lenses served as controls. A single strain of P aeruginosa harvested from a human corneal ulcer was used throughout the experiment. Lenses were examined by culture and scanning electron microscopy (SEM). We found significantly greater (p less than 0.05) bacterial attachment to new Acuvue lenses [culture, 3.1 x 10(4) (+/- 0.82 x 10(4)) cfu/mm2; SEM, 2.6 x 10(4) (+/- 0.47 x 10(4)) bacteria/mm2] compared with those previously worn [culture, 1.0 x 10(4) (+/- 0.17 x 10(4)) cfu/mm2; SEM, 0.73 x 10(4) (+/- 0.21 x 10(4)) bacteria/mm2]. No statistical difference was found among the individuals. Our findings demonstrate that the biological coating resulting from 1 week of continuous contact lens wear restricts P. aeruginosa attachment to the Acuvue lens when comparing new and used lenses.

Silicone oil (SiO) and fluorosilicone oil (FSiO) are injected into the vitreous cavity in difficult cases of retinal detachment surgery. SiO and FSiO contain linear and cyclic low-molecular-weight components (LMWC) that are thought to cause ocular toxicity. Using the purified oils (without LMWC) and some of the individual LMWC, the authors evaluated the relation of the LMWC to the short-term ocular toxicity of the oils. When octamethylcyclotetrasiloxane or other single small species of linear and cyclic LMWC of SiO were injected into the rabbit anterior chamber, severe inflammation and corneal edema were induced. The ocular responses to the single species of the LMWC of SiO decreased with an increase of the molecular weights. Cyclic LMWC of FSiO (a mixture of trimethyl-3,3,3-trifluoropropylcyclotrisiloxane and tetramethyl-3,3,3-trifluoropropylcyclotetrasiloxane) also induced inflammation and corneal edema. However, unpurified SiO and FSiO, as well as purified oils (via solvent fractionation), did not cause significant adverse ocular response, presumably because the amounts of LMWC (especially the smallest species) in the oils were relatively small. Using gas chromatography, the authors analyzed SiO and FSiO recovered from rabbit and human vitreous cavities up to 2 yr after injection. In most of the cases, the concentrations of LMWC in SiO decreased after injection. This is consistent with the possibility that LMWC diffused from the oils into the ocular tissues. The long-term effect of LMWC in intraocular SiO and FSiO has not been determined. However, diffusion of LMWC into ocular tissues may relate to the chronic ocular toxicity of the oils.

The authors determined the attachment of a single strain of Pseudomonas aeruginosa to seven brands of hydrogel soft contact lenses (SCLs): nonionic, low-water (polymacon and crofilcon); nonionic, high-water (lidofilcon); ionic, high-water (bufilcon, etafilcon, and perfilcon); and surface-neutralized, high-water (bufilcon). The lenses were exposed to a 1 X 10(8) colony-forming units (CFU)/ml P. aeruginosa suspension either when new and sterile or after 24 hr of continuous wear in rabbit eyes. Quantitative scanning electron microscopy showed that, regardless of lens type, significantly fewer bacteria attached to worn than to new SCLs (P less than 0.05). The bacterial attachment on new, unworn SCLs was significantly lower (Wilcoxon rank-sum test) (P less than 0.05) on polymacon and crofilcon than on all other lenses tested except perfilcon; on etafilcon than on bufilcon; and on perfilcon than on all SCLs tested except polymacon. The bacterial attachment on rabbit-worn SCLs was significantly lower (P less than 0.05) on polymacon than on all other lenses tested except crofilcon and perfilcon; on crofilcon than on bufilcon; on lidofilcon and on surface-neutralized bufilcon than on crofilcon and perfilcon; on etafilcon than on crofilcon, bufilcon, and perfilcon; and on perfilcon than on crofilcon and bufilcon. The results did not show a consistent relationship between hydration and surface charge and P. aeruginosa adherence. Among the SCLs tested, no one lens had a decisive advantage over another, because all, both new and worn, can bind amounts of P. aeruginosa that could potentially produce bacterial keratitis on predisposed eyes.

Elastofilcon A silcone rubber contact lenses induce less corneal swelling than no lens wear during sleep, and increasing the central thickness and volume of the lens does not influence its overnight performance. We sought to elucidate whether a silicone rubber lens can promote the distribution of atmospheric O2 on the cornea through a small interpalpebral opening under closed-eye conditions. Three groups of rabbit eyes comprised 12 eyes wearing Silflex (Dk 79.8 barrer) lenses, 12 with elastofilcon A (Dk 340 barrer) lenses, and 12 without lenses. All eyes were surgically closed overnight; six eyes in each group had a complete lid closure and six eyes had a partial tarsorrhaphy that left a small, central gap approximately 3 mm in length. When the lids were opened the next morning, the partially closed elastofilcon A eyes showed less corneal swelling (6.2 +/- 1.4%) than the partially closed no-lens eyes did (9.6 +/- 1.3%) (p less than 0.01), whereas the partially closed Silflex eyes were significantly more swollen (12.8 +/- 2.1%) (p = 0.01) than the other two partially closed groups were. The completely closed eyes showed no significant difference in corneal swelling among the groups. These results indicate that small lid gaps during sleep may lead to less corneal swelling when elastofilcon A lenses are used than with no lenses.

Silicone oil (SiO) and fluorosilicone oil (FSiO) are useful in difficult cases of retinal detachment surgery. Unidentified low-molecular-weight components (LMWC) and residual catalysts in SiO and FSiO have been implicated in the adverse reactions of the oils in the eye. The authors analyzed LMWC of SiO and FSiO using a gas chromatograph (GC) equipped with a 6-ft x 2-mm column packed with 3% SP-2250 and a flame-ionization detector. By commercially available standards and a homologous series plot, MD3M to MD23M (linear LMWC) and D4 to D30 (cyclic LMWC) were positively identified in commercial-grade 1000-centistokes (cs) SiO. Commercial-grade 12,500-cs SiO contained GC-detectable LMWC (up to MD28M and D30) at higher concentrations than commercial-grade 1000 cs SiO, although the weight percent of acetone-extractable LMWC (including those larger than MD28M and D30) was less in the former than in the latter. The GC-detectable LMWC in most medical-grade SiO were less than those in commercial-grade SiO. Tetramethylammonium siloxanolate (a residual catalyst) and tributylphosphine oxide (a heat-decomposition product of a polymerization catalyst) were tentatively identified in commercial- and medical-grade 12,500-cs SiO, respectively. Commercial-grade 1000- and 10,000-cs FSiO also contained LMWC, including F3 and/or F4 (cyclic LMWC). To eliminate LMWC from the oils, the authors developed a solvent fractionation method using acetone for SiO and hexane for FSiO. After continuous solvent extraction of SiO for 2 weeks and FSiO for 3 weeks, all measurable LMWC were eliminated from the oils.

We used a rabbit model to investigate the pathogenesis of soft contact lens-induced bacterial keratitis. Rabbit eyes underwent complete tarsorrhaphy for 7 days either with (group A, n = 14) or without (group B, n = 13) new sterile soft contact lenses. On day 7, an increase in mean corneal thickness (20.3% in group A and 17.2% in group B) was detected. New or rabbit-worn soft contact lenses were then inoculated with 10(7) colony-forming units of Pseudomonas aeruginosa or by 0.1 mL of P aeruginosa suspension. On day 9, conjunctival cultures of all eyes yielded P aeruginosa. Corneal infection developed in 11 of 14 eyes wearing new or worn, contaminated soft contact lenses. Bacterial keratitis did not develop in any of the 13 eyes inoculated with P aeruginosa suspension. Light and electron microscopy of infected eyes showed abundant polymorphonuclear neutrophils destroying the epithelium, basement membrane, and stroma. Few bacteria could be detected and only in the deep stroma. Since bacterial suspension alone caused no inflammation, soft contact lens-wear appears crucial to corneal infection in this model.

New perfilcon contact lenses (71% water) were placed on one eye of 36 rabbits under complete tarsorrhaphy for 7 days. The lenses were then removed, and 18 were incubated for 1 hour with a suspension of 1 x 10(8) colony-forming units per milliliter of Pseudomonas aeruginosa and replaced on their respective corneas. The remaining 18 eyes were inoculated with 0.1 mL of the P aeruginosa suspension; the lenses were not replaced. All eyes were again closed by tarsorrhaphy for 4, 8, 16, 24, 36 , or 48 hours. Ulcerative keratitis occurred in contact lens-wearing eyes only, as P aeruginosa penetrated the epithelium at 8 to 36 hours, and polymorphonuclear leukocyte migration began at 24 hours. Compared with conventional abrasion-wound models, the time course of infectious keratitis in this model was delayed, possibly due to less preexisting corneal trauma, but our findings suggest that soft contact lens wear facilitates bacterial invasion and also inhibits the host inflammatory response.

The corneal response to a complete tarsorrhaphy was studied in 46 rabbits for time periods up to 21 days. During the first 7 days of complete eyelid closure corneal thickness increased up to 18.4%, glycogen decreased 32.2%, and lactate rose 27.2%. A steep increase in corneal thickness to 89.8% appeared after 14 days, followed by decreasing values at 21 days, which was concomitant with the formation of extensive vascularized pannus. These results confirm previous findings that the partial pressure of O2 under closed eye conditions is substantially below physiologic requirements, affects endothelial pump capability, and results in major corneal swelling. When silicone contact lenses were fitted immediately before eyelid closure, corneal swelling 2 days after lid closure did not differ from that in eyes without lenses.

Bacterial viability in bacterial adherence to new soft contact lenses (SCLs) was studied by exposing polymacon and lidofilcon A lenses to Pseudomonas aeruginosa: L, live, untreated bacteria; H, bacteria heated for 1 h at 100 degrees C; and P, bacteria treated with 3% hydrogen peroxide for 1 h. Cultures of groups L, H, and P showed heavy, no, and minimal bacterial growth, respectively. Scanning electron microscopy (SEM) showed significantly less bacteria on new SCLs in groups H and P. Transmission electron microscopy (TEM) showed that bacterial shape was mostly preserved in all groups, with marked intracellular and cell membrane changes and breaks (groups H and P), margination of intracellular electron-dense material (group H), and central and peripheral vacuolation (group P). Adherence to new SCLs appears to be an active process, as killed or altered bacteria adhere less.

The oxygen transmissibility and hydration of new and used CSI, Hydrocurve II, and Hydromarc hydrogel contact lenses was determined at 37 degrees C. coatings that accumulated on used lenses were observed against a bright light and were graded in four classes from mild to severe. Some coated lenses had a statistically significant increase, and some a decrease in oxygen transmissibility compared with uncoated lenses. These differences are clinically unimportant, however. Although there seems to be a trend toward increased hydration and oxygen transmissibility with increased lens coating, statistically these relationships were found not to be linear. Failure of contact lenses after long-term wear must be due to causes other than a decrease in their oxygen transmissibility.

According to their solubility parameters, retinol and its derivatives, as well as cholesterol and other lipophilic substances, are predicted to dissolve in intraocular silicone and fluorosilicone oils. Calf retinas were extracted in vitro with these oils and the oils then analyzed spectrophotometrically. The following levels were found after extraction for 4 and 48 hours, respectively: for retinol, silicone oil, 0.5 and 3.7 micrograms/ml, and fluorosilicone oil, 0.5 and 3.3 micrograms/ml; for cholesterol, silicone oil, 0.5 and 6.4 micrograms/ml, and fluorosilicone oil, 0.8 and 3.7 micrograms/ml. In in vivo experiments, intraocular oils were removed from rabbit eyes at 4 days to 10 weeks after injection. The retinol levels were 1.7 to 11.4 micrograms/ml in silicone oil and 2.4 to 7.3 micrograms/ml in fluorosilicone oil; the cholesterol levels were 2.7 to 12.6 micrograms/ml in silicone oil and 7.5 to 15.6 micrograms/ml in fluorosilicone oil. Fluorosilicone and silicone oils (1000 cs) removed from human eyes at 7.3 and 102.0 weeks postoperatively had a retinol content of 5.4 and 2.9 micrograms/ml, respectively. Silicone oil of 1000 cs removed from a patient 51 weeks postoperatively and silicone oil of 12,500 cs removed 96 weeks postoperatively gave reaction characteristics for cholesterol, 230 and 99 micrograms/ml, respectively.

Silicone oil can dissolve about seven times more oxygen that can water. Placed in a depot between a rigid scleral lens and the corneal surface, silicone oil might thus be useful for treating severe dry-eye patients and for preventing exposure keratitis. To explore this possibility, generic (300, 500, 1000, and 12,500 cs) and medical-grade (1000 cs) silicone oils were tested on rabbit eyes. When oxygenated silicone oil was placed in a cup formed by the lids and hanging sutures and allowed to remain for 3 h on the eyes of anesthetized rabbits, the immediate reaction was mild epithelial edema. By 3 to 6 days later, the thickness of the epithelium and of the entire cornea had increased irregularly. The most common histologic finding was intracellular epithelial edema, particularly in the basal cell layer. The reaction was most intense for the generic oils of the lowest viscosities. The medical-grade oil was the best tolerated, but it too affected epithelial and corneal thickness. Ultrastructural studies of treated eyes showed abnormal epithelial surfaces but no major changes within the epithelial cells. Biochemical analysis showed some decrease of glycogen in the corneal epithelium of eyes kept under oxygenated medical-grade silicone oil. A smaller decrease of glycogen level persisted after 2 days exposure of the treated eye to air, suggesting that the corneal epithelium was injured by a mechanism other than hypoxia.

The physiochemical properties of a hydrogel used as a scleral buckling implant for retinal detachment surgery are described. The new material was prepared by simultaneous polymerization and crosslinking of 2-hydroxyethyl acrylate with methyl acrylate and ethylene diacrylate, in the presence of an inert diluent, ethylene glycol. At equilibrium swelling, the hydrogen absorbed 17% water and had a durometer hardness (DH) of 15 (Shore Durometer A-2). A unique property of this material was its swelling hysteresis; when the gel swollen in 70% ethanol was placed in water, it retained a high level of hydration (75% water) and softness (DH 8), and most of its elasticity and strength as well. Then the swelling decreased very slowly so that the implant reached its ultimate size at equilibrium swelling in ca. 1 year. This property is especially useful in the scleral buckling procedure, in which a soft implant indents the sclera over the detached retina until reattachment is achieved. In addition to this advantage, this hydrogel is more elastic and stronger than available hydrogels of similar softness.