Psychological, social and everyday visual impact of diabetic macular oedema and diabetic retinopathy: a systematic review.

AIMS: To synthesize the evidence on the impact of diabetic retinopathy and diabetic macular oedema from the patient perspective. METHODS: A systematic literature review was conducted using MEDLINE Complete, PsycINFO, EMBASE and AMED. We included articles investigating the impact of the condition on quality of life, symptoms, visual functioning, activities of daily living, well-being, social functioning, and financial status. The studies evaluated were observational, including cross-sectional, prospective cohort and retrospective cohort designs. Outcome data were extracted and synthesized. RESULTS: Searches yielded 5114 publications. After screening, 85 studies were included, measuring the following outcomes: visual functioning (n=46); quality of life (n=22); well-being (n=16); functional status (n=5); work (n=4); and visual task performance (n=2). Diabetic retinopathy has a considerable impact on visual functioning and this is greater in people with greater disease severity. Diabetic retinopathy significantly limits activities including working, driving, walking and reading, and has the potential to have a negative impact on psychological well-being. CONCLUSIONS: Diabetic retinopathy is associated with poor self-reported visual functioning, well-being, and health-related quality of life. Ability to perform basic everyday tasks appears to diminish with disease severity. Some studies suggest impaired mobility and problems with work, but there are gaps in this evidence.

The utility of thermal dose as a predictor of tumor and normal tissue responses to combined radiation and hyperthermia.

A total of 236 dogs and cats with a variety of cancers were randomized to receive radiation (XRT) or heat plus XRT. In those tumors which were heated, thermal gradients developed which varied in temperature minima and maxima. The influence of the thermal gradient characteristics on tumor and normal tissue responses was examined by correlation of response with the magnitude of gradient minima and maxima. Using multivariate analysis, the influence of other factors such as tumor histology, volume, site, heat treatment method, and number of heat fractions on tumor response was examined. Of all factors examined, tumor volume and non-site-specific average minimum equivalent min at 43 degrees emerged as consistent predictors of both complete response rate (p less than 0.001) and duration response (p less than 0.05). No significant enhancement of moist desquamation or late fibrosis was seen for heat + XRT versus XRT alone. The incidence of direct thermal injury to skin was positively correlated with maximum intratumoral equivalent min at 43 degrees. These results indicate that a therapeutic gain is achievable with heat + XRT, but successful application of the therapy is dependent on achieving high tumor thermal gradient minima and low maxima.

Influence of the duration of topical 13-cis-retinoic acid treatment on inhibition of mouse skin tumor promotion.

The effect of the time and duration of retinoid treatment on the inhibition of Stage II tumor promotion by 12-O-tetradecanoylphorbol-13-acetate (TPA) was studied in CD-1 mice. All mice were initiated with 400 nmol of benzo(a)pyrene and received Stage I tumor promotion (3.2 nmol of TPA twice weekly for 2 wk). Animals were then randomized into groups which received 13-cis-retinoic acid during early, middle, or late Stage II promotion. 13-cis-Retinoic acid pretreatments starting on Day 1, Wk 8, or Wk 23 of Stage II promotion resulted in 47, 28, or 19% inhibition, respectively, of TPA-induced tumor formation. One-half of the mice receiving 13-cis-retinoic acid at Day 1 or Wk 8 were removed from the retinoid treatments at Wk 23, the time of cessation of TPA promotion. The inhibition of tumor formation remained constant during the 15-wk observation period after cessation of retinoid treatment, suggesting that retinoid inhibition of mouse skin tumor promotion is stable in the absence of further promotion and preceded the step of irreversible conversion of promoter dependence to promoter independence.

Importance of minimum tumor temperature in determining early and long-term responses of spontaneous canine and feline tumors to heat and radiation.

A total of 130 dogs and cats with squamous cell carcinomas, melanomas, fibrosarcomas, mammary adenocarcinomas, or mast cell sarcomas were randomized to receive radiation (XRT) or heat plus XRT. Time-temperature data for each monitored tumor location were converted to degree-minutes or equivalent min at 43 degrees (Eq43). Response rates and durations of response were compared for subgroups of histology, volume, site, and heat treatment method. Thermal gradients existed in all heated tumors. The influence of these gradients on tumor response was examined by correlation of response with degree-minutes and Eq43 minima, maxima, averages, and ranges. A pattern emerged from these analyses linking dose minima, maxima, and ranges with prognostic subgroups as classified by volume, site, or treatment method. The data indicated that the coolest part of the tumor governed the biological response to combined heat + XRT. Tumors which received a minimum of 35 Eq43 had significantly longer durations of response than did those receiving XRT alone or less than 3 Eq43 (p less than or equal to 0.006 and 0.014, respectively; log-rank test). Furthermore, broad temperature ranges were associated with power-limiting "hot spots" and invariably led to underheating in other areas of tumor. Multivariate analysis found minimum Eq43 on the first treatment to be the best predictor of long-term response (p less than 0.05). Other biological covariates of site, volume, and histology contributed strength to the model, which was independent of Eq43 (p less than 0.05).

Correlation between initial and long-term responses of spontaneous pet animal tumors to heat and radiation or radiation alone.

Most early-phase testing of new therapeutic modalities involves analysis of initial tumor response as opposed to estimation of long-term response. In this study, the validity of initial response rates to predict long-term responses was examined for tumors treated with radiotherapy alone compared with heat combined with radiotherapy. A total of 130 pet animals with either squamous cell carcinomas, melanomas, fibrosarcomas, mammary adenocarcinomas, or mast cell sarcomas were randomized to receive either radiation alone (XRT) or heat + radiation (delta + XRT). Responses to treatment were evaluated by response rates and response duration. The complete response (CR) rates were consistently higher for delta + XRT than for XRT across different histology groups. The combined therapy led to prolonged tumor response in all histological subgroups except melanomas, which had a longer response duration when treated with XRT alone (p = 0.043). This was in spite of a relatively high CR rate in that group (100% versus 12.5% for delta + XRT and XRT, respectively). In contrast, while no significant improvement in CR rate was observed for dermal squamous cell carcinomas treated with delta + XRT (XRT = 52.9%; delta + XRT = 68.8%), a significant improvement in response duration was noted (p = 0.002). These are two examples where CR rate did not predict long-term response. When all histological subgroups were combined (except melanomas), the CR rate was higher (p less than 0.001), and response duration was prolonged (p = 0.031) for delta + XRT compared to XRT alone.

Unexpected toxicity associated with use of body surface area for dosing melphalan in the dog.

A multiinstitutional Phase I study using i.v. melphalan was conducted in dogs with spontaneously occurring neoplasia. Melphalan was administered at 7.5, 10, 11.25, 12.5, and 20 mg/m2 of body surface area. Disproportionately greater toxicity was observed in small dogs. Seven of the eight dogs (88%) weighing less than 14 kg experienced severe myelosuppression (neutropenia, less than 1500/mm3; and/or thrombocytopenia, less than 80,000/mm3), whereas only three of 13 dogs (23%) weighing greater than 14 kg developed severe myelosuppression (P = 0.016). We concluded that small dogs are at greater risk of developing bone marrow toxicity from i.v. melphalan than large dogs if body surface area is used to calculate the dose. Although both body surface area and weight were found to be significantly correlated with severity of toxicity, melphalan-induced toxicity in dogs can be more accurately estimated by body weight than by surface area, P = 0.008 versus P = 0.022, respectively. It may be necessary to prescribe antineoplastic agents that are eliminated by processes not primarily under metabolic influence or that produce side effects on tissue not correlated to basal metabolic rate on a parameter other than body surface area. In dogs, melphalan should be dosed on a weight basis, and treatment groups should be stratified by weight in randomized clinical studies, particularly when the weight range of treated subjects is great.

The UK Neovascular AMD Database Report 3: inter-centre variation in visual acuity outcomes and establishing real-world measures of care.

PurposeInternational variations in visual acuity (VA) outcomes of eyes treated for neovascular age-related macular degeneration (nAMD) are well-documented, but intra-country inter-centre regional variations are not known. These data are important for national quality outcome indicators. We aimed to determine intra-country and inter-centre regional variations in outcomes for treatment of nAMD.Patients and methodsProspective multicentre national database study of 13 UK centres that treated patients according to a set protocol (three loading doses, followed by Pro-Re-Nata retreatment). A total of 5811 treatment naive eyes of 5205 patients received a total of 36 206 ranibizumab injections over 12 months.ResultsMean starting VA between centres varied from 48.9 to 59.9 ETDRS letters. Mean inter-centre VA change from baseline to 12 months varied from +6.9 letters to -0.6 letters (mean of +2.5 letters). The proportion of eyes achieving VA of 70 letters or more varied between 21.9 and 48.7% at 12 months. Median number of injections (visits) at each centre varied from 5 to 8 (9 to 12), with an overall median of 6 (11). Age, starting VA, number of injections, and visits, but not gender were significantly associated with variation in these VA outcomes (P<0.01). Significant variation between centres persisted even after adjusting for these factors.ConclusionThere are modest differences in VA outcomes between centres in the UK. These differences are influenced, but not completely explained, by factors such as patient age, starting VA, number of injections, and visits. These data provide an indication of the VA outcomes that are achievable in real-world settings.

Density-Dependent Effects of an Invasive Ant on a Ground-Dwelling Arthropod Community.

It is frequently assumed that an invasive species that is ecologically or economically damaging in one region, will typically be so in other environments. The Argentine ant Linepithema humile (Mayr) is listed among the world's worst invaders. It commonly displaces resident ant species where it occurs at high population densities, and may also reduce densities of other ground-dwelling arthropods. We investigated the effect of varying Argentine ant abundance on resident ant and nonant arthropod species richness and abundance in seven cities across its range in New Zealand. Pitfall traps were used to compare an invaded and uninvaded site in each city. Invaded sites were selected based on natural varying abundance of Argentine ant populations. Argentine ant density had a significant negative effect on epigaeic ant abundance and species richness, but hypogaeic ant abundance and species richness was unaffected. We observed a significant decrease in Diplopoda abundance with increasing Argentine ant abundance, while Coleoptera abundance increased. The effect on Amphipoda and Isopoda depended strongly on climate. The severity of the impact on negatively affected taxa was reduced in areas where Argentine ant densities were low. Surprisingly, Argentine ants had no effect on the abundance of the other arthropod taxa examined. Morphospecies richness for all nonant arthropod taxa was unaffected by Argentine ant abundance. Species that are established as invasive in one location therefore cannot be assumed to be invasive in other locations based on presence alone. Appropriate management decisions should reflect this knowledge.

Structural changes of the choroid in sarcoid- and tuberculosis-related granulomatous uveitis.

AIM: The aim of this study is to characterise the choroidal features of patients diagnosed with sarcoid- and tuberculosis (TB)-associated granulomatous uveitis using spectral domain optical coherence tomography (OCT). METHODS: Twenty-seven patients (27 eyes) diagnosed with sarcoid- (13 eyes) and TB (14 eyes)-related uveitis were included in this retrospective, cross-sectional study. Over a six-month period, patients diagnosed with sarcoid and TB granulomatous uveitis were scanned using enhanced depth imaging OCT. Clinical and demographical characteristics were recorded, including the method of diagnosis, disease activity, site of inflammation (anterior or posterior), treatments, and visual acuity (VA). Manual segmentation of the choroidal layers was performed using custom image analysis software. RESULTS: The main outcome measure was OCT-derived thickness measurements of the choroid and choroidal sublayers (Haller's large vessel and Sattler's medium vessel layers) at the macula region. The ratio of Haller's large vessel to Sattler's medium vessel layer was significantly different at the total macula circle in eyes diagnosed with TB uveitis (1.47 (=140.71/95.72 µm)) compared with sarcoid uveitis (1.07 (=137.70/128.69 µm)) (P=0.001). A thinner choroid was observed in eyes with a VA ≥0.3 LogMAR (Snellen 6/12; 198.1 µm (interquartile range (IQR)=147.0-253.4 µm) compared with those with VA <0.3 LogMAR (292.4 µm (IQR=240.1-347.6 µm)) at the total macula circle (P=0.004). At the foveal central subfield, the median choroidal thickness was 336.8 µm (IQR=272.3-375.4 µm) in active compared with 239.3 µm (IQR=195.3-330.9 µm) in quiescent disease (P=0.04). CONCLUSION: A disproportionately enlarged Sattler's layer may indicate a diagnosis of sarcoid-related uveitis, and choroidal thickening may be a feature of active granulomatous uveitis.

Analysis of prognostic variables in hyperthermia treatment of 161 patients.

From 1977-1982, 161 patients were treated using hyperthermia as an adjuvant in Phase I trials. Microwave applicators (MW), capacitively coupled plates (RF plates), interstitial localized current fields (LCF), and magnetic induction heating (MI) techniques were used together with radiation in 135 patients, with chemotherapy in 10 patients, and alone in 16 patients. Tumor volume response categories were no response (NR, less than 50% decrease); partial response (PR, 50% less than or equal to volume decrease less than 100%); and complete response (CR, complete disappearance). The CR rates and total response rates (CR + PR) were 38/160 (24%) and 90/160 (56%), respectively. There were highly significant differences among techniques in CR vs PR + NR (p = .001), and in CR + PR vs NR (p less than .0005). Response did not vary significantly with histologic category. Overall toxicity was 16%, and did not vary significantly with technique (p = .193). In the patient group treated with hyperthermia and radiation, multivariate analysis revealed that a set of three variables had prognostic importance for CR: technique (p = .011), radiation dose (p = .019), and tumor volume (p = .001, negatively correlated). A good correlation also existed between CR and the minimum tumor temperature averaged over all treatments, TMIN (p less than .0005). Temperature variables themselves were correlated with tumor volume. Minimum T correlated negatively with volume (p = .017) and TMAX correlated positively with volume (p = .026). In fewer than 50% of patients could minimum T greater than 40.7 degrees C be achieved. Our conclusions are: TMIN, tumor volume, radiation dose, and heating technique have prognostic value for initial response; variation in CR vs technique reflects variation in tumor volume treated and in minimum temperature achieved with these techniques; and acute toxicity of treatment is infrequent, but serious toxicity is possible with the interstitial technique.

Preliminary results of a phase III trial of spontaneous animal tumors to heat and/or radiation: early normal tissue response and tumor volume influence on initial response.

A Phase III randomized trial was initiated to test the relative efficacies of heat alone, radiation alone and heat plus radiation using spontaneous malignancies in pet animals. Heat alone was inferior to the other two treatment arms as demonstrated by a significantly higher non-response rate and shorter response duration. The ratio of complete response rates (CR) for heat plus radiation to radiation alone or the thermal relative risk (TRR) was greater for tumors greater than 10 cm3 as compared to those less than 10 cm3 (TRR = 4.8 and 1.4, respectively). The overall TRR for complete responses was 2.3. The CR data for the combined therapy arm indicate at least an additive effect between heat and radiation for small tumors but most likely a synergistic effect in the larger tumor group. Based on the data currently available, no significant difference in response duration is observed between the two radiation arms, although a nonsignificant advantage to the combination therapy exists. Normal tissue effects were evaluated by incidence of full moist desquamation within the irradiated volume, late fibrosis and bone necrosis. Since the radiation skin dose depended upon the technique being used it was possible to estimate the dose to achieve moist desquamation in 50% of the animals (DD50) by a logistic regression model as being 3728 +/- 344 rad for radiation alone. Significant lowering of the DD50 was not observed for the addition of heat to radiation. Low patient numbers where intact skin was heated prevented an accurate analysis of the effect, however.

Local-regional recurrence in breast cancer after mastectomy and adriamycin-based adjuvant chemotherapy: evaluation of the role of postoperative radiotherapy.

In an attempt to determine whether patients treated for breast cancer with radical or modified radical mastectomy and adjuvant chemotherapy benefit from postoperative radiotherapy, 400 women with Stages II-III breast cancer who received adjuvant chemotherapy based on the combination of Adriamycin and Cytoxan were analyzed retrospectively. Prognostic features which predicted a high risk of isolated local-regional relapse were identified. Thirty-eight percent of these patients were also treated with postoperative radiation in addition to adjuvant chemotherapy and were compared to those patients treated only with adjuvant chemotherapy. With a median follow-up of 60 months, 15% of the patients reviewed developed local-regional disease as the first site of relapse without concommitant systemic relapse. When examined univariately, stage of disease, tumor size, nodal status, and estrogen receptor status were strong prognostic variables. Age, cell type, location of tumor within the breast, menstrual status, radiation dose, and type of treatment were not significantly related to isolated local-regional relapse. However, patients who received postoperative radiation were significantly more advanced in their disease condition. When the factors were examined multivariately, the type of treatment along with stage of disease were found to be statistically significant prognostic indicators. About half of the patients were tested for estrogen receptor status. Multivariate analysis performed on this subset of patients showed that estrogen receptor status, type of treatment, and axillary nodal status were significant predictors of the risk of isolated local-regional relapse. This study suggests that patients treated with mastectomy and Adriamycin and Cytoxan-based adjuvant chemotherapy may benefit from postoperative radiation in reducing the risk of isolated local-regional recurrence.

Dose-rate dependence of heat radiosensitization.

The dose rate dependence of heat radiosensitization was studied using rat astrocytoma cells in culture and a clinically relevant protocol of heat dose and heat radiation sequence. Cells were treated with a minimally toxic heat dose of 43 degrees C for 30 minutes, after which they were irradiated with varying doses of radiation at dose rates ranging from 0.567 to 300 cGy/min. This heat dose substantially reduced the extrapolation number (n), but had little effect on Do of the radiation survival curve at dose rates of 50 cGy/min or greater. At dose rates less than 10 cGy/min, 43 degrees C for 30 min had little effect on n and only for the lowest dose rate studied (0.567 cGy/min) was there a significant reduction in Do (60%). The thermal enhancement ratio did not vary inversely with radiation dose rate over the dose rate range studied but, instead, was maximal at the two dose rate extremes (0.567 and 300 cGy/min). These data demonstrate that a clinically relevant heat dose enhances very low dose rate, as well as high dose rate, ionizing radiation, but suggest that little benefit is to be gained from using dose rates intermediate between conventional radiotherapeutic high dose rates or dose rates representative of interstitial implants.

Regional hyperthermia by magnetic induction in a beagle dog model: analysis of thermal dosimetry.

We have investigated magnetic induction heating techniques for achieving normal tissue hyperthermia in a beagle dog model to clarify the physics and physiology of "regional heating," to develop an animal model of regional heating in humans, and to develop a method of rapid regional heating in dogs for a normal visceral tissue toxicity study. Heating was done with a concentric coil or a coaxial pair of coils applied to the abdominal region, and with or without surface cooling blankets in each case. Thermometers were placed at multiple visceral and subcutaneous sites including an intraarterial thermocouple at the aortic arch level. With either electrode arrangement and no surface cooling, whole-body hyperthermia ( WBH ) at 42 degrees C was produced within 30 to 55 min with 250 W applied power; the 42 degrees C state could be maintained with 40 to 60 W of power. Thermal gradients in these cases reflected nonuniform power deposition superimposed upon arterial temperature elevation. With surface cooling blankets added, systemic heating was significantly reduced, and temperature gradients again reflected the nonuniform power deposition. Regional heating in a dog produces WBH unless sufficient surface cooling is used to provide a heat dissipation rate balancing the heat absorption rate; this latter case best models the use of inductive techniques in humans. The coaxial pair of coils, without surface cooling, produced rapid WBH and the visceral temperature maximum and minimum were within Tesoph + 0.21 degrees C and Tesoph - 0.07 degrees C, respectively (95% confidence index; Tesoph = esophageal temperature). This is an appropriate technique for the proposed toxicity study.

Randomized trials in orthopaedics: why, how, and when?

There is increasing recognition that major new medical therapies should be rigorously evaluated before they are put into general clinical use. Randomized controlled trials provide the most unbiased assessment of the risks and benefits of such therapies. In this article, the most important aspects of the design and execution of a randomized clinical trial in orthopaedics are discussed. These include the reasons for and mechanisms of randomization, appropriate selection of patients and therapy, reasons for the blinding of therapy, types of measures of outcome that can be used, aspects of sample-size calculation and analysis of data, and ethics of randomized controlled trials.

Cross-infection risk of felt-tipped marker pens in cataract surgery.

PURPOSE: To assess the potential of bacterial transmission using felt-tipped marker pens on forehead skin before cataract surgery. METHODS: A total of 64 marker pens taken from clinical stock were tested. Forty-eight new pens were cultured in the laboratory. They were first left to desiccate for 0, 4, and 16 h, then dipped into solutions of 0.5 Macfarlane's concentration of coagulase negative staphylococci (CNS), methicillin-resistant Staphylococcus aureus (MRSA) and coliforms, and transferred onto the culture medium after 5, 10, 30, and 120 min intervals of exposure to air. A further 16 pens were collected after routine clinical use for 5 working days and cultured. RESULTS: Positive cultures were observed in 100% of pens at 0 min, and 44.4% at 5 min after the organism was exposed to air. Escherichia coli showed least transmissibility with no growth in all plates after 5 min of exposure. Only MRSA showed heavy growth after 10 min of exposure. No pattern emerged with reference to the length of time; each pen was left to desiccate. No growth was observed in the cultures of all 16 marking pens after clinical use. CONCLUSIONS: The potential for transmission of bacteria through felt-tipped marker pens has not been explored in cataract surgery. This study demonstrated that a theoretical risk of transmission exists in a laboratory setting, and survival times of the bacteria decreased with time. This suggests that the interval in which patients are marked with the same pen may play a role in bacterial transmission.

Punctate inner choroidopathy-associated choroidal neovascular membranes during pregnancy.

UNLABELLED: PURPOSE AND MATERIALS: Punctate inner choroidopathy (PIC), first described by Watzke et al(1), is a disease in young women of child-bearing age. We present three cases of PIC-associated choroidal neovascular membrane (CNVM) occurring during pregnancy, and discuss associated investigative and treatment dilemmas. RESULTS: All three patients described showed evidence of recurrence of CNVM during their pregnancy. None underwent FFA but benefited from OCT monitoring. Different therapeutic strategies were adopted in each of our cases. Case 1, with a history of spontaneous CNVM regression, was managed conservatively. Cases 2 and 3 chose steroid treatment to their better-seeing eye. All cases remained stable postpartum. DISCUSSION: Management of PIC-related CNVM creates diagnostic and therapeutic challenges. The problem is exacerbated as the pathology is often sequentially bilateral and sight threatening. Owing to the rarity of such cases, there is a paucity of evidence on which to base the treatment strategies. A history of pregnancy should always be elicited before investigation with FFA, and women warned of the potential for disease exacerbation with limited therapeutic options during pregnancy. CONCLUSIONS: spontaneous resolution of CNVM is common in PIC, and should be borne in mind while treating pregnant women. Peri/intraocular steroid injection represents a reasonable option for sight-threatening CNVM in the better-seeing eye.