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 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.

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.

Response of canine soft tissue sarcomas to radiation or radiation plus hyperthermia: a randomized phase II study.

Sixty-four dogs with spontaneous soft tissue sarcomas without evidence of metastases were stratified by tumour volume and randomized to receive graded doses of radiotherapy (XRT) alone or radiotherapy plus hyperthermia (HT). An improvement in duration of local control was achieved with the addition of hyperthermia as compared with XRT alone (Wilcoxon, p = 0.040; log rank, p = 0.064). Overall frequency of late complications was not different for the two treatment arms when comparing across equivalent XRT dose groups. Frequency of distant metastases after therapy completion was not significantly different for the two treatment arms at 1 year (7.4% for XRT versus 20% for HT plus XRT) or 2 years (11.5% for XRT versus 25% for HT plus XRT) post therapy. These results suggest that a therapeutic gain was achieved for this group of tumour-bearing animals. Uni- and multivariate analyses were performed to examine the potential for various factors to influence treatment outcome. Patient related variables included tumour stage, histologic subtype and grade and tumour site. Treatment related variables included total radiation dose and 15 descriptors of temperature distributions achieved during hyperthermia. When considering patient related factors, tumour histology, grade and location were important predictors of time to minimum volume, but only tumour location influenced time to tumour regrowth. When considering treatment related factors, radiation dose was not significantly correlated with time to minimum volume or time to local regrowth, but it was correlated with probability for late normal tissue damage in the XRT alone group (p = 0.005). For the hyperthermia treatments, 13 of 15 tumour temperature distribution descriptors were correlated with time to minimum volume, but none were correlated with time to local regrowth. These results suggest that caution should be used in interpreting the value of temperature distribution descriptors in predicting for long-term local control after hyperthermia and radiotherapy, based on analysis of short-term responses.

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.

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.

The effect of hydralazine dose on blood perfusion changes during hyperthermia.

Experiments were performed to determine the dose-related effects of the intravenous administration of a vasodilator (hydralazine) on normal muscle blood perfusion during localized hyperthermia. Fourteen anaesthetized outbred canines were investigated, seven receiving the recommended dose level of 0.5 mg/kg and seven receiving one-quarter of that level. The changes in blood perfusion were estimated using two methods: calculation of an effective blood perfusion magnitude and the use of state and parameter estimation techniques. Both methods showed that the changes in blood perfusion induced by the hydralazine were significant, and that the differences between the results for the two drug doses were not significantly different. This suggests that low doses may be useful in humans, giving the same resultant blood perfusion increase but with a decreased patient risk relative to standard therapeutic doses of hydralazine. While the trends in the blood perfusion changes were the same for both calculation methods the effective perfusion method frequently yielded blood perfusion magnitudes significantly different from those obtained using the state and parameter estimation technique. The differences are postulated to be due to the fact that the effective perfusion values include conduction effects, thus overpredicting the amount of perfusion present. Thus, while the effective blood perfusion can be used as a qualitative indication of blood perfusion changes under certain conditions, we do not recommend its use as a quantitative measure of perfusion.

Clinical evaluation of hyperthermia equipment: the University of Arizona Institutional Report for the NCI Hyperthermia Equipment Evaluation Contract.

Two-hundred and fifteen independent sites in 203 patients were treated with hyperthermia at the University of Arizona from 10/81 through 3/86 under the auspices of this contract. In the head and neck, a site dominated by superficial tumors, air-coupled and water-coupled microwave applicators yielded the best results. Similarly in the thorax, also dominated by superficial tumors, water-coupled microwave applicators were best. In the abdomen and pelvis, sites dominated by deep tumors, only interstitial radiofrequency (RF) heating, an invasive technique useful only in selected cases, was capable of consistently producing therapeutic temperatures. Toxicity appeared to be site-related, and treatment discomfort was especially common in abdominal and pelvic sites. In conclusion, while superficial sites were readily heated using propagative electromagnetic devices, these devices were ineffective and poorly tolerated at deeper sites. Effective deep hyperthermia was best produced with interstitial techniques, and further development of these techniques using RF electrodes, implantable microwave antennas and thermoregulating ferromagnetic seeds, as well as scanned, focussed-ultrasound techniques, holds promise for effective heating of deep visceral sites.

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.

Results of a phase I regional hyperthermia device evaluation: microwave annular array versus radiofrequency induction coil.

The safety and efficacy of two devices in producing elevated temperatures in bulky deep tumours was evaluated in 11 patients with 12 tumours. Nine of 11 patients had pelvic tumours. Each patient was given a separate trial heating with the microwave annular phased microwave array system (APAS) and the radiofrequency concentric magnetic induction coil (MI), and evaluation was based upon paired comparison of power-limiting patient tolerance endpoints as well as intratumoural temperatures achieved. Toxicity was minimal with either device. On average, 66 per cent of intra-tumoural (IT) temperatures reached greater than 41 degrees C with the APAS, and 12 per cent of IT temperatures reached greater than 41 degrees C with the MI (P less than 0.001). Thirty-two per cent of IT temperatures were greater than 42 degrees C with the APAS, compared to 7 per cent with MI (P less than 0.001). Although the annular microwave array is more complex to use, it has a significantly higher likelihood of achieving temperatures in the therapeutic range near 42 degrees C in deep pelvic tumours than does the magnetic induction coil.

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.

Estimation of therapeutic gain in clinical trials involving hyperthermia and radiotherapy.

It is clear from discussions in this paper that phase III testing of hyperthermia in human patients must proceed in a cautious and stepwise fashion. Because of the risks of increasing late effects, either due to direct thermal damage or thermo-radiosensitization of normal tissues, it is not prudent to proceed with such testing in sites where there is a risk of excessive normal tissue heating. The correlations between temperature and prognosis in heated tumours implies that sites and techniques should be chosen where the chance of achieving relatively uniform heating are maximized. Methods of quality assurance are of equal importance and need to be carefully designed. Even then, retrospective analyses with temperature variations used as prognostic covariates are essential. Other factors, such as tumour volume and radiotherapy dose should be carefully controlled in experimental and control groups. Finally, protocol compliance is a real problem which will cause problems in interpretation of results, especially in studies designed to look at hyperthermic time-dose fractionation.

Cervical Chlamydia trachomatis infection in university women: relationship to history, contraception, ectopy, and cervicitis.

Endocervical Chlamydia trachomatis infection was found in 13 of 162 volunteer female university students (8%). Infection was correlated with younger age (p less than 0.05), less than or equal to 4 years of intercourse (p less than 0.05), a history of gonorrhea (p less than 0.01), and exposure to a partner with urethritis (p less than 0.01). Women who used intrauterine or barrier contraception had less infection (2%) than did women who used oral contraception (14.3%, p less than 0.05) or none at all (10.7%, p less than 0.05). Infection was strongly associated with a cervicitis score calculated from erythema, ectopy, discharge, and secretions that contained white blood cells (p less than 0.0001). By multivariate analysis, a proposed clinical approach was arrived at for testing for chlamydial organisms all women with cervicitis who were not using barrier contraception. The positive predictive value of this approach for chlamydial infection was 28%, and the negative predictive value 98.4%. Cervical ectopy was increased in women who used oral contraception (p less than 0.01), and infection was increased in women with ectopy, regardless of their contraceptive method (p less than 0.001). These results will aid in more rapid diagnosis of endocervical chlamydial infection and in the choice of contraception in young women and high-prevalence groups.

Local control and distant metastases in primary canine malignant melanomas treated with hyperthermia and/or radiotherapy.

Forty-three dogs with primary malignant melanoma were randomized to receive radiotherapy alone (XRT) or hyperthermia plus radiotherapy (delta + XRT). Tumour responses were analysed in terms of complete response rates, rate of one year disease free survival and the incidence and time to develop distant metastasis. The frequency of complete responses (CR) was greater with adjuvant heat (76 per cent vs 21 per cent for XRT; P = 0.001). A trend towards an improvement in one year disease free survival was observed with delta + XRT (23.8 per cent) as compared with XRT (7.7 per cent), but the difference was not statistically significant. The frequency of distant metastases was not different between the two treatments. Descriptors of intratumoural temperatures achieved during therapy indicated that higher CR rates could be achieved with higher minima. When minima were less than and greater than 20 Equivalent minutes at 43 degrees C (Eq43) the CR rates were 64 and 90 per cent, respectively. One year disease free survival rates and frequencies of distant metastases seemed to be correlated with the intratumoural temperatures as well. This was reflected in analyses examining temperature minima and maxima. Examination of patterns of failure suggested that the most plausible explanation for the correlation between intratumoural temperature and metastases was the high local failure rate (70 per in the heated group). The results of this study emphasize the need for further investigation of the influence of local hyperthermia as a part of curative therapy on the frequency of distant metastases.