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1.  Canine and Human Visual Cortex Intact and Responsive Despite Early Retinal Blindness from RPE65 Mutation 
PLoS Medicine  2007;4(6):e230.
Background
RPE65 is an essential molecule in the retinoid-visual cycle, and RPE65 gene mutations cause the congenital human blindness known as Leber congenital amaurosis (LCA). Somatic gene therapy delivered to the retina of blind dogs with an RPE65 mutation dramatically restores retinal physiology and has sparked international interest in human treatment trials for this incurable disease. An unanswered question is how the visual cortex responds after prolonged sensory deprivation from retinal dysfunction. We therefore studied the cortex of RPE65-mutant dogs before and after retinal gene therapy. Then, we inquired whether there is visual pathway integrity and responsivity in adult humans with LCA due to RPE65 mutations (RPE65-LCA).
Methods and Findings
RPE65-mutant dogs were studied with fMRI. Prior to therapy, retinal and subcortical responses to light were markedly diminished, and there were minimal cortical responses within the primary visual areas of the lateral gyrus (activation amplitude mean ± standard deviation [SD] = 0.07% ± 0.06% and volume = 1.3 ± 0.6 cm3). Following therapy, retinal and subcortical response restoration was accompanied by increased amplitude (0.18% ± 0.06%) and volume (8.2 ± 0.8 cm3) of activation within the lateral gyrus (p < 0.005 for both). Cortical recovery occurred rapidly (within a month of treatment) and was persistent (as long as 2.5 y after treatment). Recovery was present even when treatment was provided as late as 1–4 y of age. Human RPE65-LCA patients (ages 18–23 y) were studied with structural magnetic resonance imaging. Optic nerve diameter (3.2 ± 0.5 mm) was within the normal range (3.2 ± 0.3 mm), and occipital cortical white matter density as judged by voxel-based morphometry was slightly but significantly altered (1.3 SD below control average, p = 0.005). Functional magnetic resonance imaging in human RPE65-LCA patients revealed cortical responses with a markedly diminished activation volume (8.8 ± 1.2 cm3) compared to controls (29.7 ± 8.3 cm3, p < 0.001) when stimulated with lower intensity light. Unexpectedly, cortical response volume (41.2 ± 11.1 cm3) was comparable to normal (48.8 ± 3.1 cm3, p = 0.2) with higher intensity light stimulation.
Conclusions
Visual cortical responses dramatically improve after retinal gene therapy in the canine model of RPE65-LCA. Human RPE65-LCA patients have preserved visual pathway anatomy and detectable cortical activation despite limited visual experience. Taken together, the results support the potential for human visual benefit from retinal therapies currently being aimed at restoring vision to the congenitally blind with genetic retinal disease.
The study by Samuel Jacobson and colleagues suggests that retinal gene therapy can improve retinal, visual pathway, and visual cortex responses to light stimulation, even after prolonged periods of blindness and in congenitally blind patients.
Editors' Summary
Background.
The eye captures light but the brain is where vision is experienced. Treatments for childhood blindness at the eye level are ready, but it is unknown whether the brain will be receptive to an improved neural message. Normal vision begins as photoreceptor cells in the retina (the light-sensitive tissue lining the inside of the eye) convert visual images into electrical impulses. These impulses are sent along the optic nerve to the visual cortex, the brain region where they are interpreted. The conversion of light into electrical impulses requires the activation of a molecule called retinal, which is subsequently recycled by retinal pigment epithelium (RPE) cells neighboring the retina. One of the key enzymes of the recycling reactions is encoded by a gene called RPE65. Genetic changes (mutations) in RPE65 cause an inherited form of blindness called Leber congenital amaurosis (LCA). In this disease, retinal is not recycled and as a result, the photoreceptor cells cannot work properly and affected individuals have poor or nonexistent vision from birth. Previous studies in dog and mouse models of the human disease have demonstrated that the introduction of a functional copy of RPE65 into the RPE cells using a harmless virus (gene therapy) dramatically restores retinal activity. Very recently, a pioneering gene therapy operation took place in London (UK) where surgeons injected a functional copy of RPE65 into the retina of a man with LCA. Whether this operation results in improved vision is not known at this time.
Why Was This Study Done?
Gene therapy corrects the retinal defects in animal models of LCA but whether the visual pathway from the retina to the visual cortex of the brain can respond normally to the signals sent by the restored retina is not known. Early visual experience is thought to be necessary for the development of a functional visual cortex, so replacing the defective RPE65 gene might not improve the vision of people with LCA. In this study, the researchers have studied the visual cortex of RPE65-deficient dogs before and after gene therapy to see whether the therapy affects the activity of the visual cortex. They have also investigated visual pathway integrity and responsiveness in adults with LCA caused by RPE65 mutations. If the visual pathway is disrupted in these patients, they reasoned, gene therapy might not restore their vision.
What Did the Researchers Do and Find?
The researchers used a technique called functional magnetic resonance imaging (fMRI) to measure light-induced brain activity in RPE65-deficient dogs before and after gene therapy. They also examined the reactions of the dogs' pupils to light (in LCA, the pupils do not contract normally in response to light because there is reduced signal transmission along the visual pathway). Finally, they measured the electrical activity of the dogs' retinas in response to light flashes—the retinas of patients with LCA do not react to light. Gene therapy corrected the defective retinal and visual pathway responses to light in the RPE65-deficient dogs and, whereas before treatment there was no response in the visual cortex to light stimulation in these dogs, after treatment, its activity approached that seen in normal dogs. The recovery of cortical responses was permanent and occurred soon after treatment, even in animals that were 4 years old when treated. Next, using structural MRI, the researchers studied human patients with LCA and found that the optic nerve diameter in young adults was within the normal range and that the structure of the visual cortex was very similar to that of normal individuals. Finally, using fMRI, they found that, although the visual cortex of patients with LCA did not respond to dim light, its reaction to bright light was comparable to that of normal individuals.
What Do These Findings Mean?
The findings from the dog study indicate that retinal gene therapy rapidly improves retinal, visual pathway, and visual cortex responses to light stimulation, even in animals that have been blind for years. In other words, in the dog model of LCA at least, all the components of the visual system remain receptive to visual inputs even after long periods of visual deprivation. The findings from the human study also indicate that the visual pathway remains anatomically intact despite years of disuse and that the visual cortex can be activated in patients with LCA even though these people have very limited visual experience. Taken together, these findings suggest that successful gene therapy of the retina might restore some functional vision to people with LCA but proof will have to await the outcomes of several clinical trials ongoing or being planned in Europe and the USA.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0040230.
General information on gene therapy is available from the Oak Ridge National Laboratory
Information is provided by the BBC about gene therapy for Leber congenital amaurosis (includes an audio clip from a doctor about the operation)
The National Institutes of Health/National Eye Institute (US) provides information about an ongoing gene therapy trial of RPE65-Leber congenital amaurosis
ClinicalTrials.gov gives details on treatment trials for Leber congenital amaurosis
The Foundation Fighting Blindness has a fact sheet on Leber congenital amaurosis (site includes Microsoft Webspeak links that read some content aloud)
The Foundation for Retinal Research has a fact sheet on Leber congenital amaurosis
Find more detailed information on Leber congenital amaurosis and the gene mutations that cause it from GeneReviews
WonderBaby, information for parents of babies with Leber congenital amaurosis
doi:10.1371/journal.pmed.0040230
PMCID: PMC1896221  PMID: 17594175
2.  Toward the development of a cortically based visual neuroprosthesis 
Journal of neural engineering  2009;6(3):035001.
Motivated by the success of cochlear implants for deaf patients, we are now facing the goal of creating a visual neuroprosthesis designed to interface with the occipital cortex as a means through which a limited but useful sense of vision could be restored in profoundly blind patients. We review the most important challenges regarding this neuroprosthetic approach and emphasize the need for basic human psychophysical research on the best way of presenting complex stimulating patterns through multiple microelectrodes. Continued research will hopefully lead to the development of and design specifications for the first generation of a cortically based visual prosthesis system.
doi:10.1088/1741-2560/6/3/035001
PMCID: PMC2941645  PMID: 19458403
3.  Collagen Cross-Linking Using Riboflavin and Ultraviolet-A for Corneal Thinning Disorders 
Executive Summary
Objective
The main objectives for this evidence-based analysis were to determine the safety and effectiveness of photochemical corneal collagen cross-linking with riboflavin (vitamin B2) and ultraviolet-A radiation, referred to as CXL, for the management of corneal thinning disease conditions. The comparative safety and effectiveness of corneal cross-linking with other minimally invasive treatments such as intrastromal corneal rings was also reviewed. The Medical Advisory Secretariat (MAS) evidence-based analysis was performed to support public financing decisions.
Subject of the Evidence-Based Analysis
The primary treatment objective for corneal cross-linking is to increase the strength of the corneal stroma, thereby stabilizing the underlying disease process. At the present time, it is the only procedure that treats the underlying disease condition. The proposed advantages for corneal cross-linking are that the procedure is minimally invasive, safe and effective, and it can potentially delay or defer the need for a corneal transplant. In addition, corneal cross-linking does not adversely affect subsequent surgical approaches, if they are necessary, or interfere with corneal transplants. The evidence for these claims for corneal cross-linking in the management of corneal thinning disorders such as keratoconus will be the focus of this review.
The specific research questions for the evidence review were as follows:
Technical: How technically demanding is corneal cross-linking and what are the operative risks?
Safety: What is known about the broader safety profile of corneal cross-linking?
Effectiveness - Corneal Surface Topographic Affects:
What are the corneal surface remodeling effects of corneal cross-linking?
Do these changes interfere with subsequent interventions, particularly corneal transplant known as penetrating keratoplasty (PKP)?
Effectiveness -Visual Acuity:
What impacts does the remodeling have on visual acuity?
Are these impacts predictable, stable, adjustable and durable?
Effectiveness - Refractive Outcomes: What impact does remodeling have on refractive outcomes?
Effectiveness - Visual Quality (Symptoms): What impact does corneal cross-linking have on vision quality such as contrast vision, and decreased visual symptoms (halos, fluctuating vision)?
Effectiveness - Contact lens tolerance: To what extent does contact lens intolerance improve after corneal cross-linking?
Vision-Related QOL: What is the impact of corneal cross-linking on functional visual rehabilitation and quality of life?
Patient satisfaction: Are patients satisfied with their vision following the procedure?
Disease Process:
What impact does corneal cross-linking have on the underling corneal thinning disease process?
Does corneal cross-linking delay or defer the need for a corneal transplant?
What is the comparative safety and effectiveness of corneal cross-linking compared with other minimally invasive treatments for corneal ectasia such as intrastromal corneal rings?
Clinical Need: Target Population and Condition
Corneal ectasia (thinning) disorders represent a range of disorders involving either primary disease conditions, such as keratoconus (KC) and pellucid marginal corneal degeneration, or secondary iatrogenic conditions, such as corneal thinning occurring after laser in situ keratomileusis (LASIK) refractive surgery.
Corneal thinning is a disease that occurs when the normally round dome-shaped cornea progressively thins causing a cone-like bulge or forward protrusion in response to the normal pressure of the eye. The thinning occurs primarily in the stroma layers and is believed to be a breakdown in the collagen process. This bulging can lead to irregular astigmatism or shape of the cornea. Because the anterior part of the cornea is responsible for most of the focusing of the light on the retina, this can then result in loss of visual acuity. The reduced visual acuity can make even simple daily tasks, such as driving, watching television or reading, difficult to perform.
Keratoconus is the most common form of corneal thinning disorder and involves a noninflammatory chronic disease process of progressive corneal thinning. Although the specific cause for the biomechanical alterations in the corneal stroma is unknown, there is a growing body of evidence suggesting that genetic factors may play an important role. Keratoconus is a rare disease (< 0.05% of the population) and is unique among chronic eye diseases because it has an early onset, with a median age of 25 years. Disease management for this condition follows a step-wise approach depending on disease severity. Contact lenses are the primary treatment of choice when there is irregular astigmatism associated with the disease. Patients are referred for corneal transplants as a last option when they can no longer tolerate contact lenses or when lenses no longer provide adequate vision.
Keratoconus is one of the leading indications for corneal transplants and has been so for the last 3 decades. Despite the high success rate of corneal transplants (up to 20 years) there are reasons to defer it as long as possible. Patients with keratoconus are generally young and a longer-term graft survival of at least 30 or 40 years may be necessary. The surgery itself involves lengthy time off work and postsurgery, while potential complications include long-term steroid use, secondary cataracts, and glaucoma. After a corneal transplant, keratoconus may recur resulting in a need for subsequent interventions. Residual refractive errors and astigmatism can remain challenges after transplantation, and high refractive surgery and regraft rates in KC patients have been reported. Visual rehabilitation or recovery of visual acuity after transplant may be slow and/or unsatisfactory to patients.
Description of Technology/Therapy
Corneal cross-linking involves the use of riboflavin (vitamin B2) and ultraviolet-A (UVA) radiation. A UVA irradiation device known as the CXL® device (license number 77989) by ACCUTECH Medical Technologies Inc. has been licensed by Health Canada as a Class II device since September 19, 2008. An illumination device that emits homogeneous UVA, in combination with any generic form of riboflavin, is licensed by Health Canada for the indication to slow or stop the progression of corneal thinning caused by progressive keratectasia, iatrogenic keratectasia after laser-assisted in situ keratomileusis (LASIK) and pellucid marginal degeneration. The same device is named the UV-X® device by IROCMedical, with approvals in Argentina, the European Union and Australia.
UVA devices all use light emitting diodes to generate UVA at a wavelength of 360-380 microns but vary in the number of diodes (5 to 25), focusing systems, working distance, beam diameter, beam uniformity and extent to which the operator can vary the parameters. In Ontario, CXL is currently offered at over 15 private eye clinics by refractive surgeons and ophthalmologists.
The treatment is an outpatient procedure generally performed with topical anesthesia. The treatment consists of several well defined procedures. The epithelial cell layer is first removed, often using a blunt spatula in a 9.0 mm diameter under sterile conditions. This step is followed by the application of topical 0.1% riboflavin (vitamin B2) solution every 3 to 5 minutes for 25 minutes to ensure that the corneal stroma is fully penetrated. A solid-state UVA light source with a wavelength of 370 nm (maximum absorption of riboflavin) and an irradiance of 3 mW/cm2 is used to irradiate the central cornea. Following treatment, a soft bandage lens is applied and prescriptions are given for oral pain medications, preservative-free tears, anti-inflammatory drops (preferably not nonsteroidal anti-inflammatory drugs, or NSAIDs) and antibiotic eye drops. Patients are recalled 1 week following the procedure to evaluate re-epithelialization and they are followed-up subsequently.
Evidence-Based Analysis Methods
A literature search was conducted on photochemical corneal collagen cross-linking with riboflavin (vitamin B2) and ultraviolet-A for the management of corneal thinning disorders using a search strategy with appropriate keywords and subject headings for CXL for literature published up until April 17, 2011. The literature search for this Health Technology Assessment (HTA) review was performed using the Cochrane Library, the Emergency Care Research Institute (ECRI) and the Centre for Reviews and Dissemination. The websites of several other health technology agencies were also reviewed, including the Canadian Agency for Drugs and Technologies in Health (CADTH) and the United Kingdom’s National Institute for Clinical Excellence (NICE). The databases searched included OVID MEDLINE, MEDLINE IN-Process and other Non-Indexed Citations such as EMBASE.
As the evidence review included an intervention for a rare condition, case series and case reports, particularly for complications and adverse events, were reviewed. A total of 316 citations were identified and all abstracts were reviewed by a single reviewer for eligibility. For those studies meeting the eligibility criteria, full-text articles were obtained. Reference lists were also examined for any additional relevant studies not identified through the search.
Inclusion Criteria
English-language reports and human studies
patients with any corneal thinning disorder
reports with CXL procedures used alone or in conjunction with other interventions
original reports with defined study methodology
reports including standardized measurements on outcome events such as technical success, safety effectiveness, durability, vision quality of life or patient satisfaction
systematic reviews, meta-analyses, randomized controlled trials, observational studies, retrospective analyses, case series, or case reports for complications and adverse events
Exclusion Criteria
nonsystematic reviews, letters, comments and editorials
reports not involving outcome events such as safety, effectiveness, durability, vision quality or patient satisfaction following an intervention with corneal implants
reports not involving corneal thinning disorders and an intervention involving CXL
Summary of Evidence Findings
In the Medical Advisory Secretariat evidence review on corneal cross-linking, 65 reports (16 case reports) involving 1403 patients were identified on the use of CXL for managing corneal thinning disorders. The reports were summarized according to their primary clinical indication, whether or not secondary interventions were used in conjunction with CXL (referred to as CXL-Plus) and whether or not it was a safety-related report.
The safety review was based on information from the cohort studies evaluating effectiveness, clinical studies evaluating safety, treatment response or recovery, and published case reports of complications. Complications, such as infection and noninfectious keratitis (inflammatory response), reported in case reports, generally occurred in the first week and were successfully treated with topical antibiotics and steroids. Other complications, such as the cytotoxic effects on the targeted corneal stroma, occurred as side effects of the photo-oxidative process generated by riboflavin and ultraviolet-A and were usually reversible.
The reports on treatment effectiveness involved 15 pre-post longitudinal cohort follow-up studies ranging from follow-up of patients’ treated eye only, follow-up in both the treated and untreated fellow-eye; and follow-up in the treated eye only and a control group not receiving treatment. One study was a 3-arm randomized control study (RCT) involving 2 comparators: one comparator was a sham treatment in which one eye was treated with riboflavin only; and the other comparator was the untreated fellow-eye. The outcomes reported across the studies involved statistically significant and clinically relevant improvements in corneal topography and refraction after CXL. In addition, improvements in treated eyes were accompanied by worsening outcomes in the untreated fellow-eyes. Improvements in corneal topography reported at 6 months were maintained at 1- and 2-year follow-up. Visual acuity, although not always improved, was infrequently reported as vision loss. Additional procedures such as the use of intrastromal corneal ring segments, intraocular lenses and refractive surgical practices were reported to result in additional improvements in topography and visual acuity after CXL.
Considerations for Ontario Health System
The total costs of providing CXL therapy to keratoconus patients in Ontario was calculated based on estimated physician, clinic, and medication costs. The total cost per patient was approximately $1,036 for the treatment of one eye, and $1,751 for the treatment of both eyes. The prevalence of keratoconus was estimated at 4,047 patients in FY2011, with an anticipated annual incidence (new cases) of about 148 cases. After distributing the costs of CXL therapy for the FY2011 prevalent keratoconus population over the next 3 years, the estimated average annual cost was approximately $2.1 million, of which about $1.3 million would be physician costs specifically.
Conclusion
Corneal cross-linking effectively stabilizes the underlying disease, and in some cases reverses disease progression as measured by key corneal topographic measures. The affects of CXL on visual acuity are less predictable and the use of adjunct interventions with CXL, such as intrastromal corneal ring segments, refractive surgery, and intraocular lens implants are increasingly employed to both stabilize disease and restore visual acuity. Although the use of adjunct interventions have been shown to result in additional clinical benefit, the order, timing, and risks of performing adjunctive interventions have not been well established.
Although there is potential for serious adverse events with corneal UVA irradiation and photochemical reactions, there have been few reported complications. Those that have occurred tended to be related to side effects of the induced photochemical reactions and were generally reversible. However, to ensure that there are minimal complications with the use of CXL and irradiation, strict adherence to defined CXL procedural protocols is essential.
Keywords
Keratoconus, corneal cross-linking, corneal topography, corneal transplant, visual acuity, refractive error.
PMCID: PMC3377552  PMID: 23074417
4.  Phakic Intraocular Lenses for the Treatment of Refractive Errors 
Executive Summary
Objective
The objective of this analysis is to review the effectiveness, safety, and cost-effectiveness of phakic intraocular lenses (pIOLs) for the treatment of myopia, hyperopia, and astigmatism.
Clinical Need: Condition and Target Population
Refractive Errors
Refractive errors occur when the eye cannot focus light properly. In myopia (near- or short-sightedness), distant objects appear blurry because the axis of the eye is too long or the cornea is too steep, so light becomes focused in front of the retina. Hyperopia (far sightedness) occurs when light is focused behind the retina causing nearby objects to appear blurry. In astigmatism, blurred or distorted vision occurs when light is focused at two points rather than one due to an irregularly shaped cornea or lens.
Refractive errors are common worldwide, but high refractive errors are less common. In the United States, the prevalence of high myopia (≤ −5 D) in people aged 20 to 39, 40 to 59, and 60 years and older is 7.4% (95% confidence interval [CI], 6.5% – 8.3%), 7.8% (95% CI, 6.4% – 8.6%), and 3.1% (95% CI, 2.2% – 3.9%), respectively. The prevalence of high hyperopia (≥ 3 D) is 1.0% (95% CI, .6% – 1.4%), 2.4% (95% CI, 1.7% – 3.0%), and 10.0% (95% CI, 9.1% – 10.9%) for the same age groupings. Finally, the prevalence of astigmatism (≥ 1 D cylinder) is 23.1% (95% CI, 21.6% – 24.5%), 27.6% (95% CI, 25.8% – 29.3%) and 50.1% (48.2% – 52.0%).
Low Vision
According to the Ontario Schedule of Benefits, low visual acuity is defined by a best spectacle corrected visual acuity (BSCVA) of 20/50 (6/15) or less in the better eye and not amenable to further medical and/or surgical treatment. Similarly, the Ontario Assistive Devices Program defines low vision as BSCVA in the better eye in the range of 20/70 or less that cannot be corrected medically, surgically, or with ordinary eyeglasses or contact lenses.
Estimates of the prevalence of low vision vary. Using the criteria of BSCVA ranging from 20/70 to 20/160, one study estimated that 35.6 per 10,000 people in Canada have low vision. The 2001 Participation and Activity Limitation Survey (PALS) found that 594,350 (2.5%) Canadians had “difficulty seeing ordinary newsprint or clearly seeing the face of someone from 4 m,” and the Canadian National Institute for the Blind (CNIB) registry classified 105,000 (.35%) Canadians as visually disabled.
Phakic Intraocular Lenses (pIOL)
A phakic intraocular lens (pIOL) is a supplementary lens that is inserted into the anterior or posterior chamber of the eye to correct refractive errors (myopia, hyperopia, and astigmatism). Unlike in cataract surgery, the eye’s natural crystalline lens is not removed when the pIOL is inserted, so the eye retains its accommodative ability. In Canada and the United States, iris-fixated (anterior chamber lenses that are anchored to the iris with a claw) and posterior chamber lenses are the only types of pIOLs that are licensed by Health Canada and the Food and Drug Administration, respectively.
Evidence-Based Analysis Method
Research Questions & Methodology
What are the effectiveness, cost-effectiveness, and safety of pIOLs for the treatment of myopia, hyperopia, and astigmatism?
Do certain subgroups (e.g. high myopia and low vision) benefit more from pIOLs?
How do pIOLs compare with alternative surgical treatment options (LASIK, PRK, and CLE)?
Using appropriate keywords, a literature search was conducted up to January 2009. Systematic reviews, meta-analyses, randomized controlled trials, and observational studies with more than 20 eyes receiving pIOLs were eligible for inclusion. The primary outcomes of interest were uncorrected visual acuity (UCVA), predictability of manifest refraction spherical equivalent (MRSE), and adverse events. The GRADE approach was used to systematically and explicitly evaluate the quality of evidence.
Summary of Findings
The search identified 1,131 citations published between January 1, 2003, and January 16, 2009. Including a health technology assessment (HTA) identified in the bibliography review, 30 studies met the inclusion criteria: two HTAs; one systematic review; 20 pre-post observational studies; and seven comparative studies (five pIOL vs. LASIK, one pIOL vs. PRK, and one pIOL vs. CLE).
Both HTAs concluded that there was good evidence of the short-term efficacy and safety of pIOLs, however, their conclusions regarding long-term safety differed. The 2006 HTA found convincing evidence of long-term safety, while the 2009 HTA found no long-term evidence about the risks of complications including cataract development, corneal damage, and retinal detachment.
The systematic review of adverse events found that cataract development (incidence rate of 9.6% of eyes) is a substantial risk following posterior chamber pIOL implantation, while chronic endothelial cell loss is a safety concern after iris-fixated pIOL implantation. Adverse event rates varied by lens type, but they were more common in eyes that received posterior chamber pIOLs.
The evidence of pIOL effectiveness is based on pre-post case series. These studies reported a variety of outcomes and different follow-up time points. It was difficult to combine the data into meaningful summary measures as many time points are based on a single study with a very small sample size. Overall, the efficacy evidence is low to very low quality based on the GRADE Working Group Criteria.
For all refractive errors (low to high), most eyes experienced a substantial increase in uncorrected visual acuity (UCVA) with more than 75% of eyes achieving UCVA of 20/40 or better at all postoperative time points. The proportion of eyes that achieved postoperative UCVA 20/20 or better varied substantially according type of lens used and the type of refractive error being corrected, ranging from about 30% of eyes that received iris-fixated lenses for myopia to more than 78% of eyes that received posterior chamber toric lenses for myopic astigmatism.
Predictability of manifest refraction spherical equivalent (MRSE) within ± 2.0 D was very high (≥ 90%) for all types of lenses and refractive error. At most time points, more than 50% of eyes achieved a MRSE within ± 0.5 D of emmetropia and at least 85% within ± 1.0 D. Predictability was lower for eyes with more severe preoperative refractive errors. The mean postoperative MRSE was less than 1.0 D in all but two studies.
Safety, defined as a loss of two or more Snellen lines of best spectacle corrected visual acuity (BSCVA), was high for all refractive errors and lens types. Losses of two or more lines of BSCVA were uncommon, occurring in fewer than 2% of eyes that had received posterior chamber pIOLs for myopia, and less than 1% of eyes that received iris-fixated lens implantation for myopia. Most eyes did not experience a clinically significant change in BSCVA (i.e. loss of one line, no change, or gain of one line), but 10% to 20% of eyes gained two or more lines of BSCVA.
The pIOL outcomes for UCVA, predictability, BSCVA, and adverse events were compared with FDA targets and safety values for refractive surgery and found to meet or exceed these targets at most follow-up time points. The results were then stratified to examine the efficacy of pIOLs for high refractive errors. There was limited data for many outcomes and time points, but overall the results were similar to those for all levels of refractive error severity.
The studies that compared pIOLs with LASIK, PRK, and CLE for patients with moderate to high myopia and myopic astigmatism showed that pIOLs performed better than these alternative surgical options for the outcomes of:
UCVA,
predictability and stability of MRSE,
postoperative MRSE,
safety (measured as clinically significant loss of BSCVA), and
gains in BSCVA.
Correction of refractive cylinder (astigmatism) was the only outcome that favoured refractive surgery over pIOLs. This was observed for both toric and non-toric pIOLs (toric pIOLs correct for astigmatism, non-toric pIOLs do not).
Common adverse events in the LASIK groups were diffuse lamellar keratitis and striae in the corneal flap. In the pIOL groups, lens repositioning and lens opacities (both asymptomatic and visually significant cataracts) were the most commonly observed adverse events. These studies were determined to be of low to very low evidence quality based on the GRADE Working Group Criteria.
Keywords
Eye, myopia, hyperopia, astigmatism, phakic intraocular lens, LASIK, PRK, uncorrected visual acuity, best corrected visual acuity, refractive errors, clear lens extraction
PMCID: PMC3377525  PMID: 23074518
5.  Effectiveness of conventional versus virtual reality based vestibular rehabilitation in the treatment of dizziness, gait and balance impairment in adults with unilateral peripheral vestibular loss: a randomised controlled trial 
Background
Unilateral peripheral vestibular loss results in gait and balance impairment, dizziness and oscillopsia. Vestibular rehabilitation benefits patients but optimal treatment remains unkown. Virtual reality is an emerging tool in rehabilitation and provides opportunities to improve both outcomes and patient satisfaction with treatment. The Nintendo Wii Fit Plus® (NWFP) is a low cost virtual reality system that challenges balance and provides visual and auditory feedback. It may augment the motor learning that is required to improve balance and gait, but no trials to date have investigated efficacy.
Methods/Design
In a single (assessor) blind, two centre randomised controlled superiority trial, 80 patients with unilateral peripheral vestibular loss will be randomised to either conventional or virtual reality based (NWFP) vestibular rehabilitation for 6 weeks. The primary outcome measure is gait speed (measured with three dimensional gait analysis). Secondary outcomes include computerised posturography, dynamic visual acuity, and validated questionnaires on dizziness, confidence and anxiety/depression. Outcome will be assessed post treatment (8 weeks) and at 6 months.
Discussion
Advances in the gaming industry have allowed mass production of highly sophisticated low cost virtual reality systems that incorporate technology previously not accessible to most therapists and patients. Importantly, they are not confined to rehabilitation departments, can be used at home and provide an accurate record of adherence to exercise. The benefits of providing augmented feedback, increasing intensity of exercise and accurately measuring adherence may improve conventional vestibular rehabilitation but efficacy must first be demonstrated.
Trial registration
Clinical trials.gov identifier: NCT01442623
doi:10.1186/1472-6815-12-3
PMCID: PMC3394213  PMID: 22449224
Rehabilitation; Vestibular diseases; Nintendo Wii Fit Plus®; Virtual reality; Postural balance; Dizziness; Vertigo; Gait; Visual acuity; Feedback sensory
6.  Humans ignore motion and stereo cues in favour of a fictional stable world 
Current biology : CB  2006;16(4):428-432.
Summary
As a human observer moves through the world, their eyes acquire a changing sequence of images. The information from this sequence is sufficient to determine the structure of a 3-D scene, up to a scale factor determined by the distance that the eyes have moved [1, 2]. There is good evidence that the human visual system accounts for the distance the observer has walked [3, 4] and the separation of the eyes [5-8] when judging the scale, shape and distance of objects. However, using an immersive virtual reality environment we created a scene that provided consistent information about scale from both distance walked and binocular vision and yet observers failed to notice when this scene expanded or contracted. This failure led to large errors in judging the size of objects. The pattern of errors cannot be explained by assuming a visual reconstruction of the scene with an incorrect estimate of interocular separation or distance walked. Instead, it is consistent with a Bayesian model of cue integration in which the efficacy of motion and disparity cues is greater at near viewing distances. Our results imply that observers are more willing to adjust their estimate of interocular separation or distance walked than to accept that the scene has changed in size.
doi:10.1016/j.cub.2006.01.019
PMCID: PMC2833396  PMID: 16488879
7.  Stem cell therapy: facts and fiction 
Facts, Views & Vision in ObGyn  2012;4(3):195-197.
This opinion paper is a brief overview of the current state of the translation of stem cell therapy from the bench to the clinic. The hype generated by the great medical potential of stem cells has lead to hundreds of clinics worldwide claiming to have the cure for every imaginable condition. This fraudulent practice is far from the reality of scientists and bona fide companies. Much effort is put into addressing all the hurdles we have been encountering for the safe use of stem cells in therapy. By now, a significant number of clinical trials are booking very exciting progress, opening a realistic path to the use of these amazing cells in regenerative medicine.
PMCID: PMC3991398  PMID: 24753907
Embryonic stem cells; induced pluripotent stem cells; stem cell therapy; clinical trial; regenerative medicine; safety
8.  Improved content aware scene retargeting for retinitis pigmentosa patients 
Background
In this paper we present a novel scene retargeting technique to reduce the visual scene while maintaining the size of the key features. The algorithm is scalable to implementation onto portable devices, and thus, has potential for augmented reality systems to provide visual support for those with tunnel vision. We therefore test the efficacy of our algorithm on shrinking the visual scene into the remaining field of view for those patients.
Methods
Simple spatial compression of visual scenes makes objects appear further away. We have therefore developed an algorithm which removes low importance information, maintaining the size of the significant features. Previous approaches in this field have included seam carving, which removes low importance seams from the scene, and shrinkability which dynamically shrinks the scene according to a generated importance map. The former method causes significant artifacts and the latter is inefficient. In this work we have developed a new algorithm, combining the best aspects of both these two previous methods. In particular, our approach is to generate a shrinkability importance map using as seam based approach. We then use it to dynamically shrink the scene in similar fashion to the shrinkability method. Importantly, we have implemented it so that it can be used in real time without prior knowledge of future frames.
Results
We have evaluated and compared our algorithm to the seam carving and image shrinkability approaches from a content preservation perspective and a compression quality perspective. Also our technique has been evaluated and tested on a trial included 20 participants with simulated tunnel vision. Results show the robustness of our method at reducing scenes up to 50% with minimal distortion. We also demonstrate efficacy in its use for those with simulated tunnel vision of 22 degrees of field of view or less.
Conclusions
Our approach allows us to perform content aware video resizing in real time using only information from previous frames to avoid jitter. Also our method has a great benefit over the ordinary resizing method and even over other image retargeting methods. We show that the benefit derived from this algorithm is significant to patients with fields of view 20° or less.
doi:10.1186/1475-925X-9-52
PMCID: PMC2949883  PMID: 20846440
9.  Clinical and Laboratory Evaluation of Peripheral Prism Glasses for Hemianopia 
Purpose
Homonymous hemianopia (the loss of vision on the same side in each eye) impairs the ability to navigate and walk safely. We evaluated peripheral prism glasses as a low vision optical device for hemianopia in an extended wearing trial.
Methods
Twenty-three patients with complete hemianopia (13 right) with neither visual neglect nor cognitive deficit enrolled in the 5-visit study. To expand the horizontal visual field, patients’ spectacles were fitted with both upper and lower Press-On™ Fresnel prism segments (each 40 prism diopters) across the upper and lower portions of the lens on the hemianopic (“blind”) side. Patients were asked to wear these spectacles as much as possible for the duration of the study, which averaged 9 (range: 5 to 13) weeks. Clinical success (continued wear, indicating perceived overall benefit), visual field expansion, perceived direction and perceived quality of life were measured.
Results
Clinical Success: 14 of 21 (67%) patients chose to continue to wear the peripheral prism glasses at the end of the study (2 patients did not complete the study for non-vision reasons). At long-term follow-up (8 to 51 months), 5 of 12 (42%) patients reported still wearing the device. Visual Field Expansion: Expansion of about 22 degrees in both the upper and lower quadrants was demonstrated for all patients (binocular perimetry, Goldmann V4e). Perceived Direction: Two patients demonstrated a transient adaptation to the change in visual direction produced by the peripheral prism glasses. Quality of Life: At study end, reduced difficulty noticing obstacles on the hemianopic side was reported.
Conclusions
The peripheral prism glasses provided reported benefits (usually in obstacle avoidance) to 2/3 of the patients completing the study, a very good success rate for a vision rehabilitation device. Possible reasons for long-term discontinuation and limited adaptation of perceived direction are discussed.
doi:10.1097/OPX.0b013e31819f9e4d
PMCID: PMC2680467  PMID: 19357552
low vision; prism adaptation; rehabilitation; prism treatment; visual impairment; traumatic brain injury; stroke
10.  Revision of visual impairment definitions in the International Statistical Classification of Diseases 
BMC Medicine  2006;4:7.
Background
The existing definitions of visual impairment in the International Statistical Classification of Diseases are based on recommendations made over 30 years ago. New data and knowledge related to visual impairment that have accumulated over this period suggest that these definitions need to be revised.
Discussion
Three major issues need to be addressed in the revision of these definitions. First, the existing definitions are based on best-corrected visual acuity, which exclude uncorrected refractive error as a cause of visual impairment, leading to substantial underestimation of the total visual impairment burden by about 38%. Second, the cut-off level of visual impairment to define blindness in the International Statistical Classification of Diseases is visual acuity less than 3/60 in the better eye, but with increasing human development the visual acuity requirements are also increasing, suggesting that a level less than 6/60 be used to define blindness. Third, the International Statistical Classification of Diseases uses the term 'low vision' for visual impairment level less than blindness, which causes confusion with the common use of this term for uncorrectable vision requiring aids or rehabilitation, suggesting that alternative terms such as moderate and mild visual impairment would be more appropriate for visual impairment less severe than blindness. We propose a revision of the definitions of visual impairment in the International Statistical Classification of Diseases that addresses these three issues. According to these revised definitions, the number of blind persons in the world defined as presenting visual acuity less than 6/60 in the better eye would be about 57 million as compared with the World Health Organization estimate of 37 million using the existing International Statistical Classification of Diseases definition of best-corrected visual acuity less than 3/60 in the better eye, and the number of persons in the world with moderate visual impairment defined as presenting visual acuity less than 6/18 to 6/60 in the better eye would be about 202 million as compared with the World Health Organization estimate of 124 million persons with low vision defined as best-corrected visual acuity less than 6/18 to 3/60 in the better eye.
Conclusion
Our suggested revision of the visual impairment definitions in the International Statistical Classification of Diseases takes into account advances in the understanding of visual impairment. This revised classification seems more appropriate for estimating and tracking visual impairment in the countries and regions of the world than the existing classification in the International Statistical Classification of Diseases.
doi:10.1186/1741-7015-4-7
PMCID: PMC1435919  PMID: 16539739
11.  Pulmonary Rehabilitation for Patients With Chronic Pulmonary Disease (COPD) 
Executive Summary
In July 2010, the Medical Advisory Secretariat (MAS) began work on a Chronic Obstructive Pulmonary Disease (COPD) evidentiary framework, an evidence-based review of the literature surrounding treatment strategies for patients with COPD. This project emerged from a request by the Health System Strategy Division of the Ministry of Health and Long-Term Care that MAS provide them with an evidentiary platform on the effectiveness and cost-effectiveness of COPD interventions.
After an initial review of health technology assessments and systematic reviews of COPD literature, and consultation with experts, MAS identified the following topics for analysis: vaccinations (influenza and pneumococcal), smoking cessation, multidisciplinary care, pulmonary rehabilitation, long-term oxygen therapy, noninvasive positive pressure ventilation for acute and chronic respiratory failure, hospital-at-home for acute exacerbations of COPD, and telehealth (including telemonitoring and telephone support). Evidence-based analyses were prepared for each of these topics. For each technology, an economic analysis was also completed where appropriate. In addition, a review of the qualitative literature on patient, caregiver, and provider perspectives on living and dying with COPD was conducted, as were reviews of the qualitative literature on each of the technologies included in these analyses.
The Chronic Obstructive Pulmonary Disease Mega-Analysis series is made up of the following reports, which can be publicly accessed at the MAS website at: http://www.hqontario.ca/en/mas/mas_ohtas_mn.html.
Chronic Obstructive Pulmonary Disease (COPD) Evidentiary Framework
Influenza and Pneumococcal Vaccinations for Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Smoking Cessation for Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Community-Based Multidisciplinary Care for Patients With Stable Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Pulmonary Rehabilitation for Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Long-term Oxygen Therapy for Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Noninvasive Positive Pressure Ventilation for Acute Respiratory Failure Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Noninvasive Positive Pressure Ventilation for Chronic Respiratory Failure Patients With Stable Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Hospital-at-Home Programs for Patients With Acute Exacerbations of Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Home Telehealth for Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Cost-Effectiveness of Interventions for Chronic Obstructive Pulmonary Disease Using an Ontario Policy Model
Experiences of Living and Dying With COPD: A Systematic Review and Synthesis of the Qualitative Empirical Literature
For more information on the qualitative review, please contact Mita Giacomini at: http://fhs.mcmaster.ca/ceb/faculty member_giacomini.htm.
For more information on the economic analysis, please visit the PATH website: http://www.path-hta.ca/About-Us/Contact-Us.aspx.
The Toronto Health Economics and Technology Assessment (THETA) collaborative has produced an associated report on patient preference for mechanical ventilation. For more information, please visit the THETA website: http://theta.utoronto.ca/static/contact.
Objective
The objective of this evidence-based review was to determine the effectiveness and cost-effectiveness of pulmonary rehabilitation in the management of chronic obstructive pulmonary disease (COPD).
Technology
Pulmonary rehabilitation refers to a multidisciplinary program of care for patients with chronic respiratory impairment that is individually tailored and designed to optimize physical and social performance and autonomy. Exercise training is the cornerstone of pulmonary rehabilitation programs, though they may also include components such as patient education and psychological support. Pulmonary rehabilitation is recommended as the standard of care in the treatment and rehabilitation of patients with COPD who remain symptomatic despite treatment with bronchodilators.
For the purpose of this review, the Medical Advisory Secretariat focused on pulmonary rehabilitation programs as defined by the Cochrane Collaboration—that is, any inpatient, outpatient, or home-based rehabilitation program lasting at least 4 weeks that includes exercise therapy with or without any form of education and/or psychological support delivered to patients with exercise limitations attributable to COPD.
Research Questions
What is the effectiveness and cost-effectiveness of pulmonary rehabilitation compared with usual care (UC) for patients with stable COPD?
Does early pulmonary rehabilitation (within 1 month of hospital discharge) in patients who had an acute exacerbation of COPD improve outcomes compared with UC (or no rehabilitation)?
Do maintenance or postrehabilitation programs for patients with COPD who have completed a pulmonary rehabilitation program improve outcomes compared with UC?
Research Methods
Literature Search
Search Strategy
For Research Questions 1and 2, a literature search was performed on August 10, 2010 for studies published from January 1, 2004 to July 31, 2010. For Research Question 3, a literature search was performed on February 3, 2011 for studies published from January 1, 2000 to February 3, 2011. Abstracts were reviewed by a single reviewer and, for those studies meeting the eligibility criteria, full-text articles were obtained. Reference lists and health technology assessment websites were also examined for any additional relevant studies not identified through the systematic search.
Inclusion Criteria
Research questions 1 and 2:
published between January 1, 2004 and July 31, 2010
randomized controlled trials, systematic reviews, and meta-analyses
COPD study population
studies comparing pulmonary rehabilitation with UC (no pulmonary rehabilitation)
duration of pulmonary rehabilitation program ≥ 6 weeks
pulmonary rehabilitation program had to include at minimum exercise training
Research question 3:
published between January 1, 2000 and February 3, 2011
randomized controlled trials, systematic reviews, and meta-analyses
COPD study population
studies comparing a maintenance or postrehabilitation program with UC (standard follow-up)
duration of pulmonary rehabilitation program ≥ 6 weeks
initial pulmonary rehabilitation program had to include at minimum exercise training
Exclusion Criteria
Research questions 1, 2, and 3:
grey literature
duplicate publications
non-English language publications
study population ≤ 18 years of age
studies conducted in a palliative population
studies that did not report primary outcome of interest
Additional exclusion criteria for research question 3:
studies with ≤ 2 sessions/visits per month
Outcomes of Interest
The primary outcomes of interest for the stable COPD population were exercise capacity and health-related quality of life (HRQOL). For the COPD population following an exacerbation, the primary outcomes of interest were hospital readmissions and HRQOL. The primary outcomes of interest for the COPD population undertaking maintenance programs were functional exercise capacity and HRQOL.
Quality of Evidence
The quality of each included study was assessed taking into consideration allocation concealment, randomization, blinding, power/sample size, withdrawals/dropouts, and intention-to-treat analyses.
The quality of the body of evidence was assessed as high, moderate, low, or very low according to the GRADE Working Group criteria. The following definitions of quality were used in grading the quality of the evidence:
Summary of Findings
Research Question 1: Effect of Pulmonary Rehabilitation on Outcomes in Stable COPD
Seventeen randomized controlled trials met the inclusion criteria and were included in this review.
The following conclusions are based on moderate quality of evidence.
Pulmonary rehabilitation including at least 4 weeks of exercise training leads to clinically and statistically significant improvements in HRQOL in patients with COPD.1
Pulmonary rehabilitation also leads to a clinically and statistically significant improvement in functional exercise capacity2 (weighted mean difference, 54.83 m; 95% confidence interval, 35.63–74.03; P < 0.001).
Research Question 2: Effect of Pulmonary Rehabilitation on Outcomes Following an Acute Exacerbation of COPD
Five randomized controlled trials met the inclusion criteria and are included in this review. The following conclusion is based on moderate quality of evidence.
Pulmonary rehabilitation (within 1 month of hospital discharge) after acute exacerbation significantly reduces hospital readmissions (relative risk, 0.50; 95% confidence interval, 0.33–0.77; P = 0.001) and leads to a statistically and clinically significant improvement in HRQOL.3
Research Question 3: Effect of Pulmonary Rehabilitation Maintenance Programs on COPD Outcomes
Three randomized controlled trials met the inclusion criteria and are included in this review. The conclusions are based on a low quality of evidence and must therefore be considered with caution.
Maintenance programs have a nonsignificant effect on HRQOL and hospitalizations.
Maintenance programs have a statistically but not clinically significant effect on exercise capacity (P = 0.01). When subgrouped by intensity and quality of study, maintenance programs have a statistically and marginally clinically significant effect on exercise capacity.
PMCID: PMC3384375  PMID: 23074434
12.  Low vision in east African blind school students: need for optical low vision services. 
AIMS--There is increasing awareness of the needs of children with low vision, particularly in developing countries where programmes of integrated education are being developed. However, appropriate low vision services are usually not available or affordable. The aims of this study were, firstly, to assess the need for spectacles and optical low vision devices in students with low vision in schools for the blind in Kenya and Uganda; secondly, to evaluate inexpensive locally produced low vision devices; and, finally, to evaluate simple methods of identifying those low vision students who could read N5 to N8 print after low vision assessment. METHODS--A total of 230 students were examined (51 school and 16 university students in Uganda and 163 students in Kenya, aged 5-22 years), 147 of whom had a visual acuity of less than 6/18 to perception of light in the better eye at presentation. After refraction seven of the 147 achieved 6/18 or better. Eighty two (58.6%) of the 140 students with low vision (corrected visual acuity in the better eye of less than 6/18 to light perception) had refractive errors of more than 2 dioptres in the better eye, and 38 (27.1%) had more than 2 dioptres of astigmatism. RESULTS--Forty six per cent of students with low vision (n = 64) could read N5-N8 print unaided or with spectacles, as could a further 33% (n = 46) with low vision devices. Low vision devices were indicated in a total of 50 students (35.7%). The locally manufactured devices could meet two thirds of the need. CONCLUSION--A corrected distance acuity of 1/60 or better had a sensitivity of 99.1% and a specificity of 56.7% in predicting the ability to discern N8 print or better. The ability to perform at least two of the three simple tests of functional vision had a sensitivity of 95.5% and a specificity of 63.3% in identifying the students able to discern N8 or better.
Images
PMCID: PMC505266  PMID: 7488599
13.  Visual Impairment Secondary to Congenital Glaucoma in Children: Visual Responses, Optical Correction and Use of Low Vision Aids 
Clinics (Sao Paulo, Brazil)  2009;64(8):725-730.
INTRODUCTION
Congenital glaucoma is frequently associated with visual impairment due to optic nerve damage, corneal opacities, cataracts and amblyopia. Poor vision in childhood is related to global developmental problems, and referral to vision habilitation/rehabilitation services should be without delay to promote efficient management of the impaired vision.
OBJECTIVE
To analyze data concerning visual response, the use of optical correction and prescribed low vision aids in a population of children with congenital glaucoma.
METHOD
The authors analyzed data from 100 children with congenital glaucoma to assess best corrected visual acuity, prescribed optical correction and low vision aids.
RESULTS
Fifty-five percent of the sample were male, 43% female. The mean age was 6.3 years. Two percent presented normal visual acuity levels, 29% mild visual impairment, 28% moderate visual impairment, 15% severe visual impairment, 11% profound visual impairment, and 15% near blindness. Sixty-eight percent received optical correction for refractive errors. Optical low vision aids were adopted for distance vision in 34% of the patients and for near vision in 6%. A manual monocular telescopic system with 2.8 × magnification was the most frequently prescribed low vision aid for distance, and for near vision a +38 diopter illuminated stand magnifier was most frequently prescribed.
DISCUSSION AND CONCLUSION
Careful low vision assessment and the appropriate prescription of optical corrections and low vision aids are mandatory in children with congenital glaucoma, since this will assist their global development, improving efficiency in daily life activities and promoting social and educational inclusion.
doi:10.1590/S1807-59322009000800003
PMCID: PMC2728183  PMID: 19690654
Blindness; Glaucoma; Low Vision; Rehabilitation; Refractive Errors
14.  The FiCTION dental trial protocol – filling children’s teeth: indicated or not? 
BMC Oral Health  2013;13:25.
Background
There is a lack of evidence for effective management of dental caries (decay) in children’s primary (baby) teeth and an apparent failure of conventional dental restorations (fillings) to prevent dental pain and infection for UK children in Primary Care. UK dental schools’ teaching has been based on British Society of Paediatric Dentistry guidance which recommends that caries in primary teeth should be removed and a restoration placed. However, the evidence base for this is limited in volume and quality, and comes from studies conducted in either secondary care or specialist practices. Restorations provided in specialist environments can be effective but the generalisability of this evidence to Primary Care has been questioned.
The FiCTION trial addresses the Health Technology Assessment (HTA) Programme’s commissioning brief and research question “What is the clinical and cost effectiveness of restoration caries in primary teeth, compared to no treatment?” It compares conventional restorations with an intermediate treatment strategy based on the biological (sealing-in) management of caries and with no restorations.
Methods/Design
This is a Primary Care-based multi-centre, three-arm, parallel group, patient-randomised controlled trial. Practitioners are recruiting 1461 children, (3–7 years) with at least one primary molar tooth where caries extends into dentine. Children are randomized and treated according to one of three treatment approaches; conventional caries management with best practice prevention, biological management of caries with best practice prevention or best practice prevention alone.
Baseline measures and outcome data (at review/treatment during three year follow-up) are assessed through direct reporting, clinical examination including blinded radiograph assessment, and child/parent questionnaires.
The primary outcome measure is the incidence of either pain or infection related to dental caries.
Secondary outcomes are; incidence of caries in primary and permanent teeth, patient quality of life, cost-effectiveness, acceptability of treatment strategies to patients and parents and their experiences, and dentists’ preferences.
Discussion
FiCTION will provide evidence for the most clinically-effective and cost-effective approach to managing caries in children’s primary teeth in Primary Care. This will support general dental practitioners in treatment decision making for child patients to minimize pain and infection in primary teeth. The trial is currently recruiting patients.
Trial registration
Protocol ID: NCTU: ISRCTN77044005
doi:10.1186/1472-6831-13-25
PMCID: PMC3698078  PMID: 23725316
Dental caries; Caries prevention; Primary teeth; Prevention; Paediatric Dentistry; Restoration; Fillings; RCT; Primary care
15.  Rapid Assessment of Avoidable Blindness in Western Rwanda: Blindness in a Postconflict Setting 
PLoS Medicine  2007;4(7):e217.
Background
The World Health Organization estimates that there were 37 million blind people in 2002 and that the prevalence of blindness was 9% among adults in Africa aged 50 years or older. Recent surveys indicate that this figure may be overestimated, while a survey from southern Sudan suggested that postconflict areas are particularly vulnerable to blindness. The aim of this study was to conduct a Rapid Assessment for Avoidable Blindness to estimate the magnitude and causes of visual impairment in people aged ≥ 50 y in the postconflict area of the Western Province of Rwanda, which includes one-quarter of the population of Rwanda.
Methods and Findings
Clusters of 50 people aged ≥ 50 y were selected through probability proportionate to size sampling. Households within clusters were selected through compact segment sampling. Visual acuity (VA) was measured with a tumbling “E” chart, and those with VA below 6/18 in either eye were examined by an ophthalmologist. The teams examined 2,206 people (response rate 98.0%). The unadjusted prevalence of bilateral blindness was 1.8% (95% confidence interval [CI] 1.2%–2.4%), 1.3% (0.8%–1.7%) for severe visual impairment, and 5.3% (4.2%–6.4%) for visual impairment. Most bilateral blindness (65%) was due to cataract. Overall, the vast majority of cases of blindness (80.0%), severe visual impairment (67.9%), and visual impairment (87.2%) were avoidable (i.e.. due to cataract, refractive error, aphakia, trachoma, or corneal scar). The cataract surgical coverage was moderate; 47% of people with bilateral cataract blindness (VA < 3/60) had undergone surgery. Of the 29 eyes that had undergone cataract surgery, nine (31%) had a best-corrected poor outcome (i.e., VA < 6/60). Extrapolating these estimates to Rwanda's Western Province, among the people aged 50 years or above 2,565 are expected to be blind, 1,824 to have severe visual impairment, and 8,055 to have visual impairment.
Conclusions
The prevalence of blindness and visual impairment in this postconflict area in the Western Province of Rwanda was far lower than expected. Most of the cases of blindness and visual impairment remain avoidable, however, suggesting that the implementation of an effective eye care service could reduce the prevalence further.
A survey of 2,250 people aged 50 y or over in Rwanda, based on clusters of 50 people, found a much lower prevalence of blindness than expected.
Editors' Summary
Background.
VISION 2020, a global initiative that aims to eliminate avoidable blindness, has estimated that 75% of blindness worldwide is treatable or preventable. The WHO estimates that in Africa, around 9% of adults aged over 50 are blind. Some data suggest that people living in regions affected by violent conflict are more likely to be blind than those living in unaffected regions. Currently no data exist on the likely prevalence of blindness in Rwanda, a central African country that is rebuilding following the 1994 genocide and civil war. Parts of the country, such as the Western Province, currently have no eye care services at all, but the government is trying to plan what services are necessary for this part of the country.
Why Was This Study Done?
These researchers wanted to collect data that would help them estimate the number of people suffering from avoidable blindness in Western Province, Rwanda, and to find out the main causes of blindness in this region. The approach they adopted is known as the Rapid Assessment of Avoidable Blindness (RAAB).
What Did the Researchers Do and Find?
This research project used survey methods based on the 2002 Rwandan national census. The researchers used the census to produce a list of settlements in Western Province, together with the number of individuals living in each settlement. Settlements were randomly picked from the list using a technique that was more likely to pick out bigger settlements than smaller ones. Each settlement was then divided into “cells,” with each cell containing around 500–700 people. One cell was randomly chosen from each settlement. Then, the researchers visited households within the cells, making sure that they visited 50 people aged over 50 y within each cell. They followed a standard procedure for collecting information from each person included in the survey. Each individual was examined by a nurse to measure their clearness of sight (“visual acuity”), using a Snellen chart (a chart with several rows of letters, where the size of the letters gets smaller as you go down the rows). The people being surveyed were examined by an ophthalmologist and the main cause of blindness was recorded, as well as general information on age, sex, details of any cataract operations, and why a cataract operation had not been done if one was needed.
Around 2 million people live in Western Province. The researchers included 2,250 people in the survey, for whom detailed examinations were done for 2,206 survey participants. Overall, 1.8% of the individuals examined were blind in both eyes. The main causes of blindness in the individuals surveyed were avoidable, and included cataract (clouding of the lens), focusing problems, and scarring of the cornea. Although 65% of cases of blindness were caused by cataract, and the availability of cataract surgery for those who needed it was reasonable, the outcomes of surgery were judged to be poor.
What Do These Findings Mean?
>The overall proportion of individuals in this survey who were found to be blind was quite low—1.8% instead of the expected prevalence of 9%. The researchers estimated that the overall proportion of blind people in all age groups in this region of Rwanda would be around 0.2%, and they calculated that 365 cataract surgeries would be needed in the region every year to meet international targets for correcting cataracts. It is not clear why the prevalence of blindness was lower than expected in this survey; one factor might be the low proportion of people in the 50 y age group in the Rwandan population. However, this survey suggests that most of the cases of blindness in this population are avoidable, and the data produced here are important in planning future eye care services within Rwanda.
PLoS Medicine, as a leading general medical journal, would not usually publish the results of a survey of blindness (or any other medical condition) in just one part of one country. The editors felt this one was of particular interest for several reasons. There has previously been very little information about blindness prevalence in Rwanda. The idea of Rapid Assessment of Avoidable Blindness (RAAB) is also fairly new. Furthermore, the results are a striking contrast with what was found in two studies that we recently published from the southern Sudan (see below for references), another part of Africa that has experienced devastating conflict. The Sudan studies found a very much higher prevalence of blindness. However, it must be noted that the fighting in the Sudan continued over a much longer period (several decades) and the Sudanese environment is different in many respects; for example, it is much drier (which raises the risk of blindness due to trachoma) and many people live in extremely remote locations.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0040217
World Health Organization Health Topics maintains a minisite on blindness that includes links to fact sheets, statistics, official publications, and other information
Wikipedia has an entry on visual acuity (clearness of sight), including details of how acuity is measured (note: Wikipedia is an internet encyclopedia anyone can edit)
The World Health Organization publishes detailed country health profiles, including one for Rwanda (click on the relevant country name to download a PDF fact sheet)
VISION 2020 is a global initiative aiming to eliminate avoidable blindness by the year 2020. Its Web site provides information on the main causes of avoidable blindness
Two papers recently published in PLoS Medicine about blindness in the war-afflicted southern Sudan dealt with overall blindness prevalence (Ngondi J, Ole-Sempele F, Onsarigo A, Matende I, Baba S, et al. [2006] Prevalence and causes of blindness and low vision in southern Sudan. PLoS Med 3: e477) and blindness due to trachoma (Ngondi J, Ole-Sempele F, Onsarigo A, Matende I, Baba S, et al. [2006] Blinding trachoma in postconflict southern Sudan. PLoS Med 3: e478)
doi:10.1371/journal.pmed.0040217
PMCID: PMC1904464  PMID: 17608561
16.  Novel Insights in the Rehabilitation of Neglect 
Visuospatial neglect due to right hemisphere damage, usually a stroke, is a major cause of disability, impairing the ability to perform a whole range of everyday life activities. Conventional and long-established methods for the rehabilitation of neglect like visual scanning training, optokinetic stimulation, or limb activation training have produced positive results, with varying degrees of generalization to (un)trained tasks, lasting from several minutes up to various months after training. Nevertheless, some promising novel approaches to the remediation of left visuospatial neglect have emerged in the last decade. These new therapy methods can be broadly classified into four categories. First, non-invasive brain stimulation techniques by means of transcranial magnetic stimulation (TMS) or transcranial direct current stimulation (tDCS), after a period of mainly diagnostic utilization, are increasingly applied as neurorehabilitative tools. Second, two classes of drugs, dopaminergic and noradrenergic, have been investigated for their potential effectiveness in rehabilitating neglect. Third, prism adaptation treatment has been shown to improve several neglect symptoms consistently, sometimes during longer periods of time. Finally, virtual reality technologies hold new opportunities for the development of effective training techniques for neglect. They provide realistic, rich, and highly controllable training environments. In this paper the degree of effectiveness and the evidence gathered to support the therapeutic claims of these new approaches is reviewed and discussed. The conclusion is that for all these approaches there still is insufficient unbiased evidence to support their effectiveness. Further neglect rehabilitation research should focus on the maintenance of therapy results over time, on a more functional evaluation of treatment effects, on the design and execution of true replication studies and on the exploration of optimal combinations of treatments.
doi:10.3389/fnhum.2013.00780
PMCID: PMC3828556  PMID: 24298249
visuospatial neglect; treatment outcome; stroke; rehabilitation; novel treatments
17.  Management of Chronic Pressure Ulcers 
Executive Summary
In April 2008, the Medical Advisory Secretariat began an evidence-based review of the literature concerning pressure ulcers.
Please visit the Medical Advisory Secretariat Web site, http://www.health.gov.on.ca/english/providers/program/mas/tech/tech_mn.html to review these titles that are currently available within the Pressure Ulcers series.
Pressure ulcer prevention: an evidence based analysis
The cost-effectiveness of prevention strategies for pressure ulcers in long-term care homes in Ontario: projections of the Ontario Pressure Ulcer Model (field evaluation)
Management of chronic pressure ulcers: an evidence-based analysis
Objective
The Medical Advisory Secretariat (MAS) conducted a systematic review on interventions used to treat pressure ulcers in order to answer the following questions:
Do currently available interventions for the treatment of pressure ulcers increase the healing rate of pressure ulcers compared with standard care, a placebo, or other similar interventions?
Within each category of intervention, which one is most effective in promoting the healing of existing pressure ulcers?
Background
A pressure ulcer is a localized injury to the skin and/or underlying tissue usually over a bony prominence, as a result of pressure, or pressure in conjunction with shear and/or friction. Many areas of the body, especially the sacrum and the heel, are prone to the development of pressure ulcers. People with impaired mobility (e.g., stroke or spinal cord injury patients) are most vulnerable to pressure ulcers. Other factors that predispose people to pressure ulcer formation are poor nutrition, poor sensation, urinary and fecal incontinence, and poor overall physical and mental health.
The prevalence of pressure ulcers in Ontario has been estimated to range from a median of 22.1% in community settings to a median of 29.9% in nonacute care facilities. Pressure ulcers have been shown to increase the risk of mortality among geriatric patients by as much as 400%, to increase the frequency and duration of hospitalization, and to decrease the quality of life of affected patients. The cost of treating pressure ulcers has been estimated at approximately $9,000 (Cdn) per patient per month in the community setting. Considering the high prevalence of pressure ulcers in the Ontario health care system, the total cost of treating pressure ulcers is substantial.
Technology
Wounds normally heal in 3 phases (inflammatory phase, a proliferative phase of new tissue and matrix formation, and a remodelling phase). However, pressure ulcers often fail to progress past the inflammatory stage. Current practice for treating pressure ulcers includes treating the underlying causes, debridement to remove necrotic tissues and contaminated tissues, dressings to provide a moist wound environment and to manage exudates, devices and frequent turning of patients to provide pressure relief, topical applications of biologic agents, and nutritional support to correct nutritional deficiencies. A variety of adjunctive physical therapies are also in use.
Method
Health technology assessment databases and medical databases were searched from 1996 (Medline), 1980 (EMBASE), and 1982 (CINAHL) systematically up to March 2008 to identify randomized controlled trials (RCTs) on the following treatments of pressure ulcers: cleansing, debridement, dressings, biological therapies, pressure-relieving devices, physical therapies, nutritional therapies, and multidisciplinary wound care teams. Full literature search strategies are reported in appendix 1. English-language studies in previous systematic reviews and studies published since the last systematic review were included if they had more than 10 subjects, were randomized, and provided objective outcome measures on the healing of pressure ulcers. In the absence of RCTs, studies of the highest level of evidence available were included. Studies on wounds other than pressure ulcers and on surgical treatment of pressure ulcers were excluded. A total of 18 systematic reviews, 104 RCTs, and 4 observational studies were included in this review.
Data were extracted from studies using standardized forms. The quality of individual studies was assessed based on adequacy of randomization, concealment of treatment allocation, comparability of groups, blinded assessment, and intention-to-treat analysis. Meta-analysis to estimate the relative risk (RR) or weighted mean difference (WMD) for measures of healing was performed when appropriate. A descriptive synthesis was provided where pooled analysis was not appropriate or not feasible. The quality of the overall evidence on each intervention was assessed using the grading of recommendations assessment, development, and evaluation (GRADE) criteria.
Findings
Findings from the analysis of the included studies are summarized below:
Cleansing
There is no good trial evidence to support the use of any particular wound cleansing solution or technique for pressure ulcers.
Debridement
There was no evidence that debridement using collagenase, dextranomer, cadexomer iodine, or maggots significantly improved complete healing compared with placebo.
There were no statistically significant differences between enzymatic or mechanical debridement agents with the following exceptions:
Papain urea resulted in better debridement than collagenase.
Calcium alginate resulted in a greater reduction in ulcer size compared to dextranomer.
Adding streptokinase/streptodornase to hydrogel resulted in faster debridement.
Maggot debridement resulted in more complete debridement than conventional treatment.
There is limited evidence on the healing effects of debridement devices.
Dressings
Hydrocolloid dressing was associated with almost three-times more complete healing compared with saline gauze.
There is evidence that hydrogel and hydropolymer may be associated with 50% to 70% more complete healing of pressure ulcers than hydrocolloid dressing.
No statistically significant differences in complete healing were detected among other modern dressings.
There is evidence that polyurethane foam dressings and hydrocellular dressings are more absorbent and easier to remove than hydrocolloid dressings in ulcers with moderate to high exudates.
In deeper ulcers (stage III and IV), the use of alginate with hydrocolloid resulted in significantly greater reduction in the size of the ulcers compared to hydrocolloid alone.
Studies on sustained silver-releasing dressing demonstrated a tendency for reducing the risk of infection and promoting faster healing, but the sample sizes were too small for statistical analysis or for drawing conclusions.
Biological Therapies
The efficacy of platelet-derived growth factors (PDGFs), fibroblast growth factor, and granulocyte-macrophage colony stimulating factor in improving complete healing of chronic pressure ulcers has not been established.
Presently only Regranex, a recombinant PDGF, has been approved by Health Canada and only for treatment of diabetic ulcers in the lower extremities.
A March 2008 US Food and Drug Administration (FDA) communication reported increased deaths from cancers in people given three or more prescriptions for Regranex.
Limited low-quality evidence on skin matrix and engineered skin equivalent suggests a potential role for these products in healing refractory advanced chronic pressure ulcers, but the evidence is insufficient to draw a conclusion.
Adjunctive Physical Therapy
There is evidence that electrical stimulation may result in a significantly greater reduction in the surface area and more complete healing of stage II to IV ulcers compared with sham therapy. No conclusion on the efficacy of electrotherapy can be drawn because of significant statistical heterogeneity, small sample sizes, and methodological flaws.
The efficacy of other adjunctive physical therapies [electromagnetic therapy, low-level laser (LLL) therapy, ultrasound therapy, ultraviolet light therapy, and negative pressure therapy] in improving complete closure of pressure ulcers has not been established.
Nutrition Therapy
Supplementation with 15 grams of hydrolyzed protein 3 times daily did not affect complete healing but resulted in a 2-fold improvement in Pressure Ulcer Scale for Healing (PUSH) score compared with placebo.
Supplementation with 200 mg of zinc three times per day did not have any significant impact on the healing of pressure ulcers compared with a placebo.
Supplementation of 500 mg ascorbic acid twice daily was associated with a significantly greater decrease in the size of the ulcer compared with a placebo but did not have any significant impact on healing when compared with supplementation of 10 mg ascorbic acid three times daily.
A very high protein tube feeding (25% of energy as protein) resulted in a greater reduction in ulcer area in institutionalized tube-fed patients compared with a high protein tube feeding (16% of energy as protein).
Multinutrient supplements that contain zinc, arginine, and vitamin C were associated with a greater reduction in the area of the ulcers compared with standard hospital diet or to a standard supplement without zinc, arginine, or vitamin C.
Firm conclusions cannot be drawn because of methodological flaws and small sample sizes.
Multidisciplinary Wound Care Teams
The only RCT suggests that multidisciplinary wound care teams may significantly improve healing in the acute care setting in 8 weeks and may significantly shorten the length of hospitalization. However, since only an abstract is available, study biases cannot be assessed and no conclusions can be drawn on the quality of this evidence.
PMCID: PMC3377577  PMID: 23074533
18.  Progress Toward Development of a Multichannel Vestibular Prosthesis for Treatment of Bilateral Vestibular Deficiency 
This article reviews vestibular pathology and the requirements and progress made in the design and construction of a vestibular prosthesis. Bilateral loss of vestibular sensation is disabling. When vestibular hair cells are injured by ototoxic medications or other insults to the labyrinth, the resulting loss of sensory input disrupts vestibulo-ocular reflexes (VORs) and vestibulo-spinal reflexes that normally stabilize the eyes and body. Affected individuals suffer poor vision during head movement, postural instability, chronic disequilibrium, and cognitive distraction. Although most individuals with residual sensation compensate for their loss over time, others fail to do so and have no adequate treatment options. A vestibular prosthesis analogous to cochlear implants but designed to modulate vestibular nerve activity during head movement should improve quality of life for these chronically dizzy individuals. We describe the impact of bilateral loss of vestibular sensation, animal studies supporting feasibility of prosthetic vestibular stimulation, the current status of multichannel vestibular sensory replacement prosthesis development, and challenges to successfully realizing this approach in clinical practice. In bilaterally vestibular-deficient rodents and rhesus monkeys, the Johns Hopkins multichannel vestibular prosthesis (MVP) partially restores the three-dimensional (3D) VOR for head rotations about any axis. Attempts at prosthetic vestibular stimulation of humans have not yet included the 3D eye movement assays necessary to accurately evaluate VOR alignment, but these initial forays have revealed responses that are otherwise comparable to observations in animals. Current efforts now focus on refining electrode design and surgical technique to enhance stimulus selectivity and preserve cochlear function, optimizing stimulus protocols to improve dynamic range and reduce excitation–inhibition asymmetry, and adapting laboratory MVP prototypes into devices appropriate for use in clinical trials.
doi:10.1002/ar.22581
PMCID: PMC4058831  PMID: 23044664
vestibular; prosthesis; implant; areflexia; labyrinth; hypofunction; dizziness; oscillopsia
19.  Dry Age-Related Macular Degeneration: Mechanisms, Therapeutic Targets, and Imaging 
Investigative Ophthalmology & Visual Science  2013;54(14):ORSF68-ORSF80.
Age-related macular degeneration is the leading cause of irreversible visual dysfunction in individuals over 65 in Western Society. Patients with AMD are classified as having early stage disease (early AMD), in which visual function is affected, or late AMD (generally characterized as either “wet” neovascular AMD, “dry” atrophic AMD or both), in which central vision is severely compromised or lost. Until recently, there have been no therapies available to treat the disorder(s). Now, the most common wet form of late-stage AMD, choroidal neovascularization, generally responds to treatment with anti–vascular endothelial growth factor therapies. Nevertheless, there are no current therapies to restore lost vision in eyes with advanced atrophic AMD. Oral supplementation with the Age-Related Eye Disease Study (AREDS) or AREDS2 formulation (antioxidant vitamins C and E, lutein, zeaxanthin, and zinc) has been shown to reduce the risk of progression to advanced AMD, although the impact was in neovascular rather than atrophic AMD. Recent findings, however, have demonstrated several features of early AMD that are likely to be druggable targets for treatment. Studies have established that much of the genetic risk for AMD is associated with complement genes. Consequently, several complement-based therapeutic treatment approaches are being pursued. Potential treatment strategies against AMD deposit formation and protein and/or lipid deposition will be discussed, including anti-amyloid therapies. In addition, the role of autophagy in AMD and prevention of oxidative stress through modulation of the antioxidant system will be explored. Finally, the success of these new therapies in clinical trials and beyond relies on early detection, disease typing, and predicting disease progression, areas that are currently being rapidly transformed by improving imaging modalities and functional assays.
doi:10.1167/iovs.13-12757
PMCID: PMC3864379  PMID: 24335072
drusen; complement; autophagy; functional imaging; therapeutic targets
20.  Noninvasive Positive Pressure Ventilation for Chronic Respiratory Failure Patients With Stable Chronic Obstructive Pulmonary Disease (COPD) 
Executive Summary
In July 2010, the Medical Advisory Secretariat (MAS) began work on a Chronic Obstructive Pulmonary Disease (COPD) evidentiary framework, an evidence-based review of the literature surrounding treatment strategies for patients with COPD. This project emerged from a request by the Health System Strategy Division of the Ministry of Health and Long-Term Care that MAS provide them with an evidentiary platform on the effectiveness and cost-effectiveness of COPD interventions.
After an initial review of health technology assessments and systematic reviews of COPD literature, and consultation with experts, MAS identified the following topics for analysis: vaccinations (influenza and pneumococcal), smoking cessation, multidisciplinary care, pulmonary rehabilitation, long-term oxygen therapy, noninvasive positive pressure ventilation for acute and chronic respiratory failure, hospital-at-home for acute exacerbations of COPD, and telehealth (including telemonitoring and telephone support). Evidence-based analyses were prepared for each of these topics. For each technology, an economic analysis was also completed where appropriate. In addition, a review of the qualitative literature on patient, caregiver, and provider perspectives on living and dying with COPD was conducted, as were reviews of the qualitative literature on each of the technologies included in these analyses.
The Chronic Obstructive Pulmonary Disease Mega-Analysis series is made up of the following reports, which can be publicly accessed at the MAS website at: http://www.hqontario.ca/en/mas/mas_ohtas_mn.html.
Chronic Obstructive Pulmonary Disease (COPD) Evidentiary Framework
Influenza and Pneumococcal Vaccinations for Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Smoking Cessation for Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Community-Based Multidisciplinary Care for Patients With Stable Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Pulmonary Rehabilitation for Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Long-term Oxygen Therapy for Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Noninvasive Positive Pressure Ventilation for Acute Respiratory Failure Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Noninvasive Positive Pressure Ventilation for Chronic Respiratory Failure Patients With Stable Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Hospital-at-Home Programs for Patients With Acute Exacerbations of Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Home Telehealth for Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Cost-Effectiveness of Interventions for Chronic Obstructive Pulmonary Disease Using an Ontario Policy Model
Experiences of Living and Dying With COPD: A Systematic Review and Synthesis of the Qualitative Empirical Literature
For more information on the qualitative review, please contact Mita Giacomini at: http://fhs.mcmaster.ca/ceb/faculty_member_giacomini.htm.
For more information on the economic analysis, please visit the PATH website: http://www.path-hta.ca/About-Us/Contact-Us.aspx.
The Toronto Health Economics and Technology Assessment (THETA) collaborative has produced an associated report on patient preference for mechanical ventilation. For more information, please visit the THETA website: http://theta.utoronto.ca/static/contact.
Objective
The objective of this health technology assessment was to determine the effectiveness and cost-effectiveness of noninvasive ventilation for stable chronic obstructive pulmonary disease (COPD).
Clinical Need: Condition and Target Population
Noninvasive ventilation is used for COPD patients with chronic respiratory failure. Chronic respiratory failure in COPD patients may be due to the inability of the pulmonary system to coordinate ventilation, leading to adverse arterial levels of oxygen and carbon dioxide. Noninvasive ventilation in stable COPD patients has the potential to improve quality of life, prolong survival, and improve gas exchange and sleep quality in patients who are symptomatic after optimal therapy, have hypercapnia or nocturnal hypoventilation and mild hypercapnia, and are frequently hospitalized.
Technology
Noninvasive positive pressure ventilation (NPPV) is any form of positive ventilatory support without the use of an endotracheal tube. For stable COPD, the standard of care when using noninvasive ventilation is bilevel positive airway pressure (BiPAP). Bilevel positive airway pressure involves both inspiratory and expiratory pressure, high during inspiration and lower during expiration. It acts as a pressure support to accentuate a patient’s inspiratory efforts. The gradient between pressures maintains alveolar ventilation and helps to reduce carbon dioxide levels. Outpatients typically use BiPAP at night. Additional advantages of using BiPAP include resting of respiratory muscles, decreased work of breathing, and control of obstructive hypopnea.
Research Question
What is the effectiveness and cost-effectiveness of noninvasive ventilation, compared with no ventilation while receiving usual care, for stable COPD patients?
Research Methods
Literature Search
Search Strategy
A literature search was performed on December 3, 2010, using OVID MEDLINE, OVID MEDLINE In-Process and Other Non-Indexed Citations, OVID EMBASE, EBSCO Cumulative Index to Nursing & Allied Health Literature (CINAHL), the Wiley Cochrane Library, and the Centre for Reviews and Dissemination database for studies published from January 1, 2004 to December 3, 2010. Abstracts were reviewed by a single reviewer and, for those studies meeting the eligibility criteria, full-text articles were obtained. Reference lists were also examined for any additional relevant studies not identified through the search. When the reviewer was unsure of the eligibility of articles, a second clinical epidemiologist and then a group of epidemiologists reviewed these until consensus was reached.
Inclusion Criteria
full-text English language articles,
studies published between January 1, 2004 and December 3, 2010,
journal articles that report on the effectiveness or cost-effectiveness of noninvasive ventilation,
clearly described study design and methods, and
health technology assessments, systematic reviews, meta-analyses, randomized controlled trials (RCTs).
Exclusion Criteria
non-English papers
animal or in vitro studies
case reports, case series, or case-case studies
cross-over RCTs
studies on noninvasive negative pressure ventilation (e.g., iron lung)
studies that combine ventilation therapy with other regimens (e.g., daytime NPPV plus exercise or pulmonary rehabilitation)
studies on heliox with NPPV
studies on pulmonary rehabilitation with NPPV
Outcomes of Interest
mortality/survival
hospitalizations/readmissions
length of stay in hospital
forced expiratory volume
arterial partial pressure of oxygen
arterial partial pressure of carbon dioxide
dyspnea
exercise tolerance
health-related quality of life
Note: arterial pressure of oxygen and carbon dioxide are surrogate outcomes.
Statistical Methods
A meta-analysis and an analysis of individual studies were performed using Review Manager Version 5. For continuous data, a mean difference was calculated, and for dichotomous data, a relative risk ratio was calculated for RCTs. For continuous variables with mean baseline and mean follow-up data, a change value was calculated as the difference between the 2 mean values.
Quality of Evidence
The quality of each included study was assessed taking into consideration allocation concealment, randomization, blinding, power/sample size, withdrawals/dropouts, and intention-to-treat analyses.
The quality of the body of evidence was assessed as high, moderate, low, or very low according to the GRADE Working Group criteria. The following definitions of quality were used in grading the quality of the evidence:
Summary of Findings
Conclusions
The following conclusions refer to stable, severe COPD patients receiving usual care.
Short-Term Studies
Based on low quality of evidence, there is a beneficial effect of NPPV compared with no ventilation on oxygen gas exchange, carbon dioxide gas exchange, and exercise tolerance measured using the 6 Minute Walking Test.
Based on very low quality of evidence, there is no effect of NPPV therapy on lung function measured as forced expiratory volume in 1 second (Type II error not excluded).
Long-Term Studies
Based on moderate quality of evidence, there is no effect of NPPV therapy for the outcomes of mortality, lung function measured as forced expiratory volume in 1 second, and exercise tolerance measured using the 6 Minute Walking Test.
Based on low quality of evidence, there is no effect of NPPV therapy for the outcomes of oxygen gas exchange and carbon dioxide gas exchange (Type II error not excluded).
Qualitative Assessment
Based on low quality of evidence, there is a beneficial effect of NPPV compared with no ventilation for dyspnea based on reduced Borg score or Medical Research Council dyspnea score.
Based on moderate quality of evidence, there is no effect of NPPV therapy for hospitalizations.
Health-related quality of life could not be evaluated.
PMCID: PMC3384378  PMID: 23074437
21.  Stepping on Obstacles with a Sensory Substitution Device on the Lower Leg: Practice without Vision Is More Beneficial than Practice with Vision 
PLoS ONE  2014;9(6):e98801.
Practice is essential for an adapted use of sensory substitution devices. Understanding the learning process is therefore a fundamental issue in this field of research. This study presents a novel sensory substitution device worn on the lower leg and uses the device to study learning. The device includes 32 vibrotactile actuators that each vibrate as a function of the distance to the nearest surface in a particular direction. Participants wearing the device were asked to approach an object and to step on the object. Two 144-trial practice conditions were compared in a pretest-practice-posttest design. Participants in the first condition practiced with vibrotactile stimulation while blindfolded. Participants in the second condition practiced with vibrotactile stimulation along with normal vision. Performance was relatively successful, both types of practice led to improvements in performance, and practice without vision led to a larger reduction in the number of errors than practice with vision. These results indicate that distance-based sensory substitution is promising in addition to the more traditional light-intensity-based sensory substitution and that providing appropriate sensorimotor couplings is more important than applying the stimulation to highly sensitive body parts. The observed advantage of practice without vision over practice with vision is interpreted in terms of the guidance hypothesis of feedback and learning.
doi:10.1371/journal.pone.0098801
PMCID: PMC4046982  PMID: 24901843
22.  Using a Virtual Cortical Module Implementing a Neural Field Model to Modulate Brain Rhythms in Parkinson's Disease 
We propose a new method for selective modulation of cortical rhythms based on neural field theory, in which the activity of a cortical area is extensively monitored using a two-dimensional microelectrode array. The example of Parkinson's disease illustrates the proposed method, in which a neural field model is assumed to accurately describe experimentally recorded activity. In addition, we propose a new closed-loop stimulation signal that is both space- and time- dependent. This method is especially designed to specifically modulate a targeted brain rhythm, without interfering with other rhythms. A new class of neuroprosthetic devices is also proposed, in which the multielectrode array is seen as an artificial neural network interacting with biological tissue. Such a bio-inspired approach may provide a solution to optimize interactions between the stimulation device and the cortex aiming to attenuate or augment specific cortical rhythms. The next step will be to validate this new approach experimentally in patients with Parkinson's disease.
doi:10.3389/fnins.2010.00045
PMCID: PMC2920509  PMID: 20730081
brain stimulation; dysrhythmia; neural field model; Parkinson's disease; neuroprosthetic devices
23.  A Case-Control Study to Assess the Relationship between Poverty and Visual Impairment from Cataract in Kenya, the Philippines, and Bangladesh 
PLoS Medicine  2008;5(12):e244.
Background
The link between poverty and health is central to the Millennium Development Goals (MDGs). Poverty can be both a cause and consequence of poor health, but there are few epidemiological studies exploring this complex relationship. The aim of this study was to examine the association between visual impairment from cataract and poverty in adults in Kenya, Bangladesh, and the Philippines.
Methods and Findings
A population-based case–control study was conducted in three countries during 2005–2006. Cases were persons aged 50 y or older and visually impaired due to cataract (visual acuity < 6/24 in the better eye). Controls were persons age- and sex-matched to the case participants with normal vision selected from the same cluster. Household expenditure was assessed through the collection of detailed consumption data, and asset ownership and self-rated wealth were also measured. In total, 596 cases and 535 controls were included in these analyses (Kenya 142 cases, 75 controls; Bangladesh 216 cases, 279 controls; Philippines 238 cases, 180 controls). Case participants were more likely to be in the lowest quartile of per capita expenditure (PCE) compared to controls in Kenya (odds ratio = 2.3, 95% confidence interval 0.9–5.5), Bangladesh (1.9, 1.1–3.2), and the Philippines (3.1, 1.7–5.7), and there was significant dose–response relationship across quartiles of PCE. These associations persisted after adjustment for self-rated health and social support indicators. A similar pattern was observed for the relationship between cataract visual impairment with asset ownership and self-rated wealth. There was no consistent pattern of association between PCE and level of visual impairment due to cataract, sex, or age among the three countries.
Conclusions
Our data show that people with visual impairment due to cataract were poorer than those with normal sight in all three low-income countries studied. The MDGs are committed to the eradication of extreme poverty and provision of health care to poor people, and this study highlights the need for increased provision of cataract surgery to poor people, as they are particularly vulnerable to visual impairment from cataract.
Hannah Kuper and colleagues report a population-based case-control study conducted in three countries that found an association between poverty and visual impairment from cataract.
Editors' Summary
Background.
Globally, about 45 million people are blind. As with many other conditions, avoidable blindness (preventable or curable blindness) is a particular problem for people in developing countries—90% of blind people live in poor regions of the world. Although various infections and disorders can cause blindness, cataract is the most common cause. In cataract, which is responsible for half of all cases of blindness in the world, the lens of the eye gradually becomes cloudy. Because the lens focuses light to produce clear, sharp images, as cataract develops, vision becomes increasingly foggy or fuzzy, colors become less intense, and the ability to see shapes against a background declines. Eventually, vision may be lost completely. Cataract can be treated with an inexpensive, simple operation in which the cloudy lens is surgically removed and an artificial lens is inserted into the eye to restore vision. In developed countries, this operation is common and easily accessible but many poor countries lack the resources to provide the operation to everyone who needs it. In addition, blind people often cannot afford to travel to the hospitals where the operation, which also may come with a fee, is done.
Why Was This Study Done?
Because blindness may reduce earning potential, many experts believe that poverty and blindness (and, more generally, poor health) are inextricably linked. People become ill more often in poor countries than in wealthy countries because they have insufficient food, live in substandard housing, and have limited access to health care, education, water, and sanitation. Once they are ill, their ability to earn money may be reduced, which increases their personal poverty and slows the economic development of the whole country. Because of this potential link between health and poverty, improvements in health are at the heart of the United Nations Millennium Development Goals, a set of eight goals established in 2000 with the primary aim of reducing world poverty. However, few studies have actually investigated the complex relationship between poverty and health. Here, the researchers investigate the association between visual impairment from cataract and poverty among adults living in three low-income countries.
What Did the Researchers Do and Find?
The researchers identified nearly 600 people aged 50 y or more with severe cataract-induced visual impairment (“cases”) primarily through a survey of the population in Kenya, Bangladesh, and the Philippines. They matched each case to a normally sighted (“control”) person of similar age and sex living nearby. They then assessed a proxy for the income level, measured as “per capita expenditure” (PCE), of all the study participants (people with cataracts and controls) by collecting information about what their households consumed. The participants' housing conditions and other assets and their self-rated wealth were also measured. In all three countries, cases were more likely to be in the lowest quarter (quartile) of the range of PCEs for that country than controls. In the Philippines, for example, people with cataract-affected vision were three times more likely than normally sighted controls to have a PCE in the lowest quartile than in the highest quartile. The risk of cataract-related visual impairment increased as PCE decreased in all three countries. Similarly, severe cataract-induced visual impairment was more common in those who owned fewer assets and those with lower self-rated wealth. However, there was no consistent association between PCE and the level of cataract-induced visual impairment.
What Do These Findings Mean?
These findings show that there is an association between visual impairment caused by cataract and poverty in Kenya, Bangladesh, and the Philippines. However, because the financial circumstances of the people in this study were assessed after cataracts had impaired their sight, this study does not prove that poverty is a cause of visual impairment. A causal connection between poverty and cataract can only be shown by determining the PCEs of normally sighted people and following them for several years to see who develops cataract. Nevertheless, by confirming an association between poverty and blindness, these findings highlight the need for increased provision of cataract surgery to poor people, particularly since cataract surgery has the potential to improve the quality of life for many people in developing countries at a relatively low cost.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050244.
This study is further discussed in a PLoS Medicine Perspective by Susan Lewallen
The MedlinePlus encyclopedia contains a page on cataract, and MedlinePlus also provides a list of links to further information about cataract (in English and Spanish)
VISION 2020, a global initiative for the elimination of avoidable blindness launched by the World Health Organization and the International Agency for the Prevention of Blindness, provides information in several languages about many causes of blindness, including cataract. It also has an article available for download on blindness, poverty, and development
Information is available from the World Health Organization on health and the Millennium Development Goals (in English, French, and Spanish)
The International Centre for Eye Health carries out research and education activities to improve eye health and eliminate avoidable blindness with a focus on populations with low incomes
doi:10.1371/journal.pmed.0050244
PMCID: PMC2602716  PMID: 19090614
24.  Ophthalmic and visual profile of guide dog owners in Scotland 
BACKGROUND/AIMS—Out of an estimated 90 000 visually impaired people in Scotland, 509 make use of a guide dog. Initial research in Northern Ireland suggests that the ophthalmic profile of guide dog owners (GDOs) is highly specific. The aim of this study was to compare the ophthalmic and visual characteristics of Scottish GDOs with other groups of visually impaired people.
METHODS—A random sample of GDOs from central and northern Scotland (n=82) underwent a detailed assessment of residual vision (distance and near acuity, visual fields, contrast, and glare sensitivity). Comparative data were obtained from two populations of visually impaired non-GDOs—one group attending hospital ophthalmic and low vision clinics (n=50) the other social services rehabilitation clients (n=35). All participants completed a questionnaire to elicit ophthalmic history, age, and registration details.
RESULTS—GDOs were found to be significantly younger and more profoundly visually impaired than non-GDOs. The main causes of visual impairment were retinitis pigmentosa (23%), optic atrophy (15%), and retinopathy of prematurity (7%). Ninety nine per cent of GDOs were registered blind and had been visually impaired for an average of 39 years. Only 31% were totally blind.
CONCLUSION—GDOs represent a unique minority of the visually impaired population. Epidemiological registration trends would suggest that the numbers of young profoundly visually impaired people are unlikely to increase relative to their elderly counterparts. This has implications on the future demand for guide dog ownership.

 Keywords: ophthalmic profile; visual profile; guide dog owners; Scotland
PMCID: PMC1722993  PMID: 10434873
25.  Post-penetrating keratoplasty glaucoma 
Indian Journal of Ophthalmology  2008;56(4):269-277.
Post-penetrating keratoplasty (post-PK) glaucoma is an important cause of irreversible visual loss and graft failure. The etiology for this disorder is multifactorial, and with the use of new diagnostic equipment, it is now possible to elucidate the exact pathophysiology of this condition. A clear understanding of the various mechanisms that operate during different time frames following PK is essential to chalk out the appropriate management algorithms. The various issues with regard to its management, including the putative risk factors, intraocular pressure (IOP) assessment post-PK, difficulties in monitoring with regard to the visual fields and optic nerve evaluation, are discussed. A step-wise approach to management starting from the medical management to surgery with and without metabolites and the various cycloablative procedures in cases of failed filtering procedures and excessive perilimbal scarring is presented. Finally, the important issue of minimizing the incidence of glaucoma following PK, especially through the use of oversized grafts and iris tightening procedures in the form of concomitant iridoplasty are emphasized. It is important to weigh the risk-benefit ratio of any modality used in the treatment of this condition as procedures aimed at IOP reduction, namely trabeculectomy with antimetabolites, and glaucoma drainage devices can trigger graft rejection, whereas cyclodestructive procedures can not only cause graft failure but also precipitate phthisis bulbi. Watchful expectancy and optimal time of intervention can salvage both graft and vision in this challenging condition.
PMCID: PMC2636159  PMID: 18579984
Glaucoma; penetrating keratoplasty; iridoplasty; trabeculectomy

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