Association between refill compliance to oral bisphosphonate treatment, incident fractures, and health care costs--an analysis using national health databases.

SUMMARY: The study estimates the cost of poor and suboptimal refill compliance by estimating fracture costs and assessing the association between refill compliance with oral bisphosphonates and incident fractures using Danish health registers. Patients with poor and suboptimal refill compliance had more major osteoporotic fractures, and the direct costs related to hospital care, primary care, and pharmaceutical treatment for these excess fractures reached almost 14 M DKK (2.5 M USD) for the study population which compares to a national annual excess cost of around 17 M DKK (3.1 M USD) using 2011 prescription prevalence. INTRODUCTION: Adherence to oral anti-osteoporosis treatment has been shown in several studies to be relatively low and the potential impact on fracture burden is high. The aim of the study was to assess the association between refill compliance and all-cause health care costs. METHODS: A national dataset was extracted with all treatment-naive patients who began oral bisphosphonate (BP) treatment for osteoporosis in Denmark between 1997 and 2006 (N = 54,876, 87 % women). Patients who survived for at least 2 years (N = 47,176) were divided into groups based on Medication Possession Ratio (MPR). Logistic regressions were used to derive difference in the probability of incident fractures between the three MPR groups. Fracture costs (related to medication use, primary care practice, specialists, and hospitals) were derived by comparing cost 12 months before and after fracture. RESULTS: For alendronate, the adjusted risk of major osteoporotic fractures was significantly reduced (OR 0.768; 0.686-0.859), including fractures of the hip (0.718; 0.609-0.846) and humerus (0.54; 0.431-0.677) with MPR ≥ 0.8. The risk reduction was lower with etidronate. Over 2 years, a total of 171 hip fractures and 53 other major osteoporotic fractures were attributed to suboptimal or poor refill compliance, with an excess cost of 13.7 M DKK (2.5 M USD). CONCLUSIONS: Poor refill compliance is not unusual in patients on oral bisphosphonates, and we demonstrate that this is accompanied by excess major osteoporotic fractures and health care costs at the societal level.

Patient complexity and GPs' income under mixed remuneration.

Because of problems with recruiting GPs to deprived areas in Denmark, it has been discussed whether the mixed remuneration scheme is flexible enough to compensate GPs serving patients with high need for services. The objective is to assess how patient heterogeneity affects list size, income and total utility of GPs operating under a mixed remuneration scheme. We adapt the model by Iversen (2004) as a theoretical framework for analysing the consequences of patient heterogeneity in a mixed remuneration system. We use a data set of Danish solo practitioners to analyse the effect of patient complexity on list size and income. From the theoretical model we find that higher levels of patient complexity lead GPs to choose a lower list size, whereas the effect on income is ambiguous. The effect on total utility (income and leisure) is, however, shown to be negative. Using empirical data from 1039 solo practices we find that patient complexity reduces both list size and income and conclude that a mixed per capita and fee for service remuneration system does not fully compensate practices with more complex patients. Differentiated per capita payment may represent a means of ensuring fair and equal income of GPs.

Economic and health implications of routine CBCT examination before surgical removal of the mandibular third molar in the Danish population.

OBJECTIVES: This epidemiological study aimed to analyse economical and societal consequences in Denmark if CBCT is used routinely as a diagnostic method before removal of the mandibular third molar. Furthermore, the aim was to calculate the excess cancer incidence from this practice. METHODS: 17 representative dental clinics in the regions of Denmark were visited by two observers, who registered the total number of patients in each clinic, the number of removed mandibular third molars from patients' files together with the age and gender of these patients. The data were collected from 2008 to 2014. The total number of removed mandibular third molars in Denmark each year was derived from the collected data and information on patients' contacts with dentists from Statistics Denmark as a sum of contributions from each region. The contribution of a region was obtained as the number of removed mandibular third molars in the selected clinics in the region times the ratio of the number of patients in the selected clinics in the region to the total number of patients with contact to a general practitioner in the region in 2011. Existing knowledge on the costs for panoramic and CBCT imaging was used to calculate total costs. The cancer incidence was calculated from lifetime attributable risk curves based on linear risk assumptions. RESULTS: The selected clinics included 109,686 patients, and 1369 mandibular third molars had been surgically removed. Using data from Statistics Denmark gave an estimated annual number of removed mandibular third molars of 36,882 at a total cost of €6,633,400. The additional cancer incidence was estimated to be approximately 0.46 per year. CONCLUSIONS: The data should be used in a cost-effectiveness analysis of the clinical efficacy of CBCT imaging before removal of mandibular third molars.

MR technique for localization and verification procedures in episcleral brachytherapy.

Spatial definition of an intraocular tumor and subsequent determination of the actual position of an implanted eye plaque are essential for adequate ocular brachytherapy treatment planning. However, a method for verification of the plaque placement which would provide required 3-dimensional information is not available at present. In addition, tumor localization procedures, including ultrasonography and CT techniques, cannot always offer the precision needed for 3-dimensional definition of an intraocular target. This communication describes a magnetic resonance imaging technique specifically developed for both localization and verification procedures. A 1.5 Tesla magnetic resonance scanner, spin-echo pulse sequence (echo time 30 msec, repetition time 700 msec), and commercially available surface coil were used to obtain a series of transverse, coronal, and sagittal images of a slice thickness of 3 mm. Usually, eight scans in each of the three planes were needed for adequate coverage of the orbit. The required patient set-up and data acquisition time did not exceed 40 minutes. With a data matrix size of 256 X 256 pixels and 13 cm field of view, localization and verification were accomplished with a precision of 0.5 mm. Our results suggest that the magnetic resonance imaging technique permits precise integration of diagnostic and therapeutic procedures, and in addition provides adequate data for accurate treatment planning. We conclude that magnetic resonance imaging is the preferred diagnostic technique for episcleral brachytherapy.

Studies of tumor-infiltrating lymphocytes from a human choroidal melanoma.

Cell suspensions prepared enzymatically from an ocular choroidal melanoma were cultured in vitro in an effort to generate (1) melanoma tumor cell lines and (2) tumor-infiltrating lymphocytes cytotoxic for ocular melanoma cells. Even though histologic study of the tumor did not show "significant" infiltrating bone marrow-derived cells, lymphocytes were generated readily in cultures to which interleukin-2 was added. Phenotypic analysis of the cultured lymphocytes indicated that T-cells, natural killer (NK) cells, and lymphokine-activated killer (LAK) cells were present. Moreover, functional studies of the cultured lymphocytes revealed NK activity, LAK activity, and most importantly, tumor antigen-specific cytotoxic T-cell activity. It was concluded that it is possible to obtain tumor cell lines and tumor-infiltrating lymphocytes from ocular tumors, both of which would be required if cellular immunotherapy of ocular tumors is contemplated. In addition, these results indicate that ocular melanomas can express unique tumor-specific antigens and that the immune system of a patient with such an ocular tumor can perceive these tumor antigens because antigen-specific precursor cytotoxic T-cells were present in the tumor-containing eye at the time of enucleation. The theoretic and therapeutic implications of these findings are discussed.

Intravitreal tissue plasminogen activator treatment of experimental vitreous hemorrhage.

Intraocular recombinant DNA human tissue-type plasminogen activator (tPA) can promote rapid resolution of intracular fibrin clots and hyphema. The efficacy of intravitreal tPA in promoting the short-term clearance of vitreous hemorrhage was investigated. Five treatment groups with experimentally induced vitreous hemorrhage were studied. The extent of the vitreous hemorrhage was graded based on the visibility of retinal details in each quadrant. Two weeks following intravitreal tPA injection (50,000 IU), the nonvitrectomized group and gas vitrectomy groups, each of which received a single tPA injection, showed a statistically significant reduction of the vitreous hemorrhage, although this was thought to represent only a modest clinical effect. Tractional retinal detachments were noted to develop more frequently in tPA-treated eyes as compared with controls.

Fluorouracil therapy of intraocular Greene melanoma in the rabbit.

We evaluated the efficacy of intraocular and periocular fluorouracil treatment in an experimental iris tumor of the rabbit (Greene amelanotic melanoma). Four consecutive intravitreal injections of 1 mg of fluorouracil given twice weekly completely suppressed tumor growth in all treated eyes for six weeks if treatment was initiated 24 hours after tumor implantation. In contrast, all control eyes implanted with an equal number of Greene melanoma cells but treated with intravitreal saline developed massive tumor invasion of the iris within two weeks. Additional subconjunctival therapy following intravitreal therapy for two weeks was only slightly more effective than intravitreal therapy alone. If therapy was delayed for one week, the iris tumors became macroscopically visible and subsequent treatment with intravitreal and subconjunctival fluorouracil was of limited value in suppressing growth.

Slit-lamp fluid-gas exchange and other office procedures following vitreoretinal surgery.

Many complicated postoperative vitreoretinal cases require reoperations. It is possible to perform some of these procedures outside the operating room. We describe examining room techniques for fluid-gas exchange, fluid and gas aspiration, and adherent vitreous strand removal. We also discuss a slit-lamp technique for using sodium hyaluronate (Healon) following fluid-gas exchange to eliminate optical distortion from endothelial striae.

Retinal toxicity of human tissue plasminogen activator in vitrectomized rabbit eyes.

The retinal toxicity of human tissue plasminogen activator in normal rabbit eyes has recently been reported. We now report the retinal toxicity of tissue plasminogen activator in three groups of vitrectomized rabbit eyes. Group 1 underwent gas compression of the vitreous followed by tissue plasminogen activator injection in doses of 25, 50, and 100 micrograms (all doses were administered in 100 microL of fluid). Group 2 underwent lensectomy and vitrectomy followed by tissue plasminogen activator injection of 100 micrograms. Group 3 underwent lensectomy, vitrectomy, and complete fluid/gas exchange prior to injections of 12.5 and 25 micrograms of tissue plasminogen activator. Control eyes received 100 microL of balanced salt solution. In group 1, no retinal toxic reactions were observed after administration of 25 or 50 micrograms of tissue plasminogen activator, but all eyes receiving 100 micrograms demonstrated retinal damage on ophthalmoscopy, electroretinography, and light microscopy. In group 2, no retinal toxic reactions were seen after administration of 100 micrograms of tissue plasminogen activator. In group 3, two of 11 eyes receiving 25 micrograms of tissue plasminogen activator demonstrated toxic retinal changes by ophthalmoscopy, electroretinography, and light microscopy. These results suggest that gas compression of the vitreous does not significantly alter the toxic changes seen caused by tissue plasminogen activator. While lensectomy and vitrectomy appears to widen the therapeutic window for tissue plasminogen activator, the margin of safety is reduced with the addition of a large gas bubble.

Subretinal hemorrhage management by pars plana vitrectomy and internal drainage.

We reviewed 14 consecutive cases of subretinal hemorrhage involving the macula, in which surgery to remove the hemorrhage was performed by the authors between February 1984 and January 1989. All patients underwent pars plana vitrectomy and internal subretinal hemorrhage drainage. The causes of subretinal hemorrhages in group 1 were primary rhegmatogenous retinal detachments (three eyes), complications from scleral buckling procedures (three eyes), traumatic retinal detachments (two eyes), and sickle cell retinopathy associated with anticoagulation therapy after a pulmonary embolus (one eye). Group 2 consisted of five eyes with massive subretinal hemorrhage associated with age-related macular degeneration. In group 1, recurrent postoperative retinal detachment occurred in five eyes but reattachment was achieved in eight of the nine eyes, and final visual acuities were 20/400 or better in those eight eyes. In group 2, marked subretinal fibrosis occurred in two eyes. Although three eyes had improved visual acuities, final visual acuities were 5/200 or worse in all five eyes.

Biodegradable mechanical retinal fixation. A pilot study.

Mechanical retinal fixation is a useful tool in the armamentarium of vitreoretinal surgeons. Unfortunately, the use of metallic retinal tacks on a permanent basic mandates a retained intraocular foreign body that poses some potential for long-range toxic effects. Herein, we report the results of our initial experience with a temporary, biodegradable mechanical retinal fixation device ("biopin") in rabbits. When compared with metallic tacks, the biopins appeared to be well tolerated intraocularly, with minimal damage detectable at the light microscopic level. Disinsertion of the biopins occurred in 46% of the eyes within two weeks and in all eyes by four weeks. Initial signs of degradation of the biopins were observed at six weeks (median) in the ensectomized/vitrectomized eyes and at 12 weeks (median) in the nonvitrectomized eyes. Differences were found in the occurrence of retinal detachment between animals that underwent lensectomy/vitrectomy with insertion of two metallic tacks and animals that underwent insertion of one biopin without vitrectomy. The biopin has a potential as a vehicle for sustained release of pharmacologic agents to inhibit directly the development of vitreoretinal proliferation, thereby retarding or preventing subsequent retinal traction and detachment.

Retinal toxicity of recombinant tissue plasminogen activator in the rabbit.

We studied the dose-dependent retinal toxicity of the available commercial preparation of human recombinant tissue plasminogen activator in the normal rabbit eye. Tissue plasminogen activator was injected into the midvitreous cavity of albino rabbits in doses (per 100 microL) of 25, 50, 75, and 100 micrograms. Control eyes received 100 microL of balanced salt solution or tissue plasminogen activator vehicle. No evidence of a retinal toxic reaction was seen in eyes receiving 25 micrograms of tissue plasminogen activator. One of four eyes injected with 50 micrograms showed loss of photoreceptor cells by light microscopy. Severe retinal damage was seen by ophthalmoscopy, electroretinography, and light microscopy in three of four eyes receiving 75 micrograms of tissue plasminogen activator and in all eyes treated with 100 micrograms of tissue plasminogen activator or equivalent vehicle. These results suggest that the commercial recombinant tissue plasminogen activator formulation has a narrow margin of safety in nonvitrectomized eyes and that a component of the vehicle is the toxic factor.

Hypodermic stainless steel tacks and companion inserter designed for peripheral fixation of retina.

Mechanical fixation of the torn or cut edge of retina with 30-gauge hypodermic stainless steel tacks has been performed in 15 patients at the Bascom Palmer Eye Institute, Miami, and Miami Veterans Administration Medical Center with six to 18 months of follow-up. The companion tack inserter allows the surgeon to select an angle for the shaft of the tack in relation to the inserter to allow the tack to be driven perpendicularly into sclera even when the insertion is anterior to the equator. If residual detachment remains following fluid-gas exchange after preliminary placement of the retinal tacks, a given tack may be removed and reinserted to facilitate complete retinal reattachment. This utilitarian feature allows the surgeon to eliminate residual anteroposterior traction following complete membrane peeling by extending relaxing retinotomies and tacking the posterior cut edge of the retina securely between the ora serrata and the equator.

Predictors of scleral rupture and the role of vitrectomy in severe blunt ocular trauma.

We reviewed retrospectively 40 eyes that had received blunt trauma and had been explored for scleral rupture. Twenty-nine eyes had scleral rupture. Of these 29, ten had ruptures seen preoperatively. Nineteen had occult ruptures. The preoperative findings predictive of scleral rupture were a visual acuity of light perception or no light perception, an intraocular pressure of less than 10 mm Hg, hyphema, and chemosis. Of the 29 ruptures, 27 involved the superior hemisphere and 25 involved the anterior hemisphere of the globe. Ten of 29 eyes (34%) with scleral rupture and eight of 11 eyes (73%) without rupture achieved a final visual acuity of 5/200 or better over an average follow-up period of 6.7 months. Factors prognostic of ambulatory vision for eyes with ruptured and intact globes included an initial visual acuity of 5/200 or better, absence of scleral rupture, and a rupture length of less than 11 mm in eyes with ruptures. The vitrectomized eyes also had a better result, suggesting that early pars plana vitrectomy is of benefit in selected rupture cases.

The site of operating microscope light-induced injury on the human retina.

We determined the site of the focal illumination from the Zeiss OPMI-6 operating microscope on the retina of the phakic and aphakic human cadaver eye by directly observing the illuminating element image on the posterior scleral surface of the globe. With the eye straight ahead and the operating microscope level, the focal oval area of retinal illumination was located superior to the foveola in both the phakic and aphakic eye. Tilting the operating microscope 10 degrees toward the surgeon displaced the entire illuminating element image 0.50 mm below the foveola in the phakic eye and 0.25 mm below the foveola in the aphakic eye. Rotating the eye inferiorly 10 degrees displaced the entire illuminating element image 1.0 mm below the foveola in the phakic eye and 1.25 mm below the foveola in the aphakic eye. Centering the field of view superiorly (viewing the superior limbus) paradoxically displaced the illuminating element image inferiorly, resulting in central foveal illumination. Foveal light exposure was avoided in most eye positions by tilting the microscope at least 10 degrees toward the surgeon.

Results and complications in treated retinal breaks.

One hundred sixty-four patients (171 eyes) were treated for retinal breaks and the treatment outcomes were studied. One hundred two eyes were acutely symptomatic, 22 eyes were chronically symptomatic, and 47 eyes were asymptomatic. The reasons for further treatment in 38 of the 171 eyes (22%) included the following: (1) inadequate closure of the original break without detachment in eight eyes (5%), (2) new breaks without detachment in 15 eyes (9%), (3) an operation for retinal detachment caused by the original break in seven eyes (4%), or (4) retinal detachment caused by a new break in eight eyes (5%). Failure rates of treatment among acutely symptomatic, chronically symptomatic, and asymptomatic subgroups were not statistically significant. The risk of treatment failure was higher for aphakic and pseudophakic eyes, and in eyes with peripheral retinal abnormalities in the fellow eye. Among 38 patients with failed treatments, 20 (52%) returned for further examination within one month of initial treatment, whereas eight of the 38 patients with failed treatments (21%) returned six months or more after initial treatment. Peripheral retinal abnormalities were recognized initially in 65 of the 171 fellow eyes (38%) and subsequently developed in nine of the fellow eyes (5%) during the follow-up interval. Further treatment is often necessary after initial treatment of peripheral retinal breaks, emphasizing the need for careful long-term follow-up care.

Leber congenital amaurosis in siblings with diffuse dysmyelination.

Two brothers are described with the previously unrecognized combination of Leber amaurosis and abnormal myelin detected by magnetic resonance imaging. Both have evidence of delayed psychomotor development and one has autistic features. A possible relationship with infantile autism or a peroxisomal dysfunction syndrome is explored. No peroxisomal defect was found in these patients.

Image and surgery-related costs comparing cone beam CT and panoramic imaging before removal of impacted mandibular third molars.

OBJECTIVES: The aim of this prospective clinical study was to derive the absolute and relative costs of cone beam CT (CBCT) and panoramic imaging before removal of an impacted mandibular third molar. Furthermore, the study aimed to analyse the influence of different cost-setting scenarios on the outcome of the absolute and relative costs and the incremental costs related to surgery. METHODS: A randomized clinical trial compared complications following surgical removal of a mandibular third molar, where the pre-operative diagnostic method had been panoramic imaging or CBCT. The resources implied in the two methods were measured with health economic tools. The primary outcome was total costs defined as the sum of absolute imaging costs and incremental surgery-related costs. The basic variables were capital costs, operational costs, radiological costs, radiographic costs, overheads and patient resource utilization. Differences in resources used for surgical and post-surgical management were calculated for each patient. RESULTS: Converted to monetary units, the total costs for panoramic imaging equalized €49.29 and for CBCT examination €184.44. Modifying effects on this outcome such as differences in surgery time, treatment time for complications, pre- and post-surgical medication, sickness absence, specialist treatment and hospitalization were not statistically significant between the two diagnostic method groups. CONCLUSIONS: Costs for a CBCT examination were approximately four times the costs for panoramic imaging when used prior to removal of a mandibular third molar. The use of CBCT did not change the resources used for surgery, post-surgical treatment and patient complication management.