A fluorophotometric comparison of anterior chamber riboflavin delivery via corneal application and fornix instillation.

INTRODUCTION AND OBJECTIVES: We investigated whether riboflavin self-administration by patients could be a feasible option for corneal cross-linking, given the considerable resources required to impregnate the cornea with riboflavin. We analysed whether administering riboflavin in the inferior fornix (the site of self-administration) results in non-inferior riboflavin concentrations as when applied directly on the cornea (the site of administration by medical personnel). PATIENTS AND METHODS: We conducted a prospective study to evaluate riboflavin concentrations at six time-points (baseline, 5, 15, 30, 45 and 60min) in 18 healthy volunteers for each of two application sites: cornea and fornix. Anterior chamber riboflavin (Peschke® TE 0.25%) concentrations were measured by fluorophotometry (Fluorotron™ Master FM-2). RESULTS: For the two application sites cornea and fornix, participants did not differ in terms of age and sex. At baseline, the autofluorescence in the anterior chamber was 16.7ng/mL (SD 5.5) and 14.6ng/mL (SD 4.6) (P=.221). After 30min, anterior chamber fluorescein concentrations had risen to 55.1ng/mL (SD 25.5) and 46.1ng/mL (SD 25.1) (P=.293) without a further relevant increase by 60min. CONCLUSIONS: This study found that applying riboflavin drops in the inferior fornix was non-inferior to applying it directly to the cornea, based on fluorophotometric measurements of anterior chamber riboflavin concentrations. This suggests that self-application of riboflavin is feasible in terms of corneal riboflavin impregnation.

Endotypes of chronic rhinosinusitis with nasal polyps with and without NSAID â€" intolerance.

BACKGROUND: Chronic rhinosinusitis with nasal polyps (CRSwNP) is a type 2-dominated inflammatory disease of the upper air- ways. A subgroup of patients with CRSwNP suffer from intolerance to nonsteroidal anti-inflammatory drugs (NSAID) and develop NSAID-exacerbated respiratory disease (NERD). The aim of the study was to compare the cytokine based inflammatory endotype of nasal secretions of CRSwNP patients with and without NSAID intolerance. METHODS: Nasal secretions were collected from twenty-six patients suffering from CRSwNP, thirteen with NERD and thirteen without NSAID intolerance. As control, nasal secretions were collected from fifteen healthy donors. Tryptase and ten human cyto- kines were analyzed: interleukin (IL)-4, IL-5, IL-6, IL-8, IL-12p70, IL-13, IL-17A, IL-23, IFN-g, and TNF-a by a cytokine multiple array on a Luminex 200 platform. RESULTS: Grade of polyposis and frequency of polyp surgery was more severe in NERD- compared to non-NERD patients. IL-6 and IL-5 in CRSwNP was significantly increased compared to healthy participants. IL-5 and IL-13 were significantly increased in subjects suffering from NERD compared to CRSwNP patients without NERD. CONCLUSION: We identified IL-13 as a possible specific biomarker in nasal secretions of patients with NERD, which allows us to differentiate between CRSwNP with vs. without NERD. The characterization of inflammatory endotypes in CRSwNP enables the introduction of the best available therapy in the context of precision medicine.

Painful swelling after a noxious event and the development of complex regional pain syndrome 1: A one-year prospective study.

BACKGROUND: The timing of diagnosis of complex regional pain syndrome (CRPS) 1 remains a challenge due to the large heterogeneity of clinical presentations. We describe the distribution and differences in outcomes and clinical manifestations between time points and patient groups with and without CRPS 1 following an initiating event. METHODS: Prospective cohort study with a consecutive registration of patients presenting with painful swelling of the affected extremity after an initiating event and follow-up visits after 3, 6 and 12 months. RESULTS: Forty-two patients were enrolled (37 females, mean age 55.1 years). At baseline, 35 participants (83%, females n = 30) fulfilled the diagnostic criteria for CRPS 1. At 3 months, 19 out of the initial 35 CRPS 1 patients (54%) did not meet the diagnostic criteria anymore. Besides our inclusion criteria of a painful swelling, early manifestations indicating a CRPS 1 primarily include an impaired quality of life (SF-35, EQ5-D), more pain (NRS, MPQ) and restricted range of motion. CONCLUSIONS: CRPS 1 develops within 8 weeks following a noxious event. Although many CRPS 1 patients reach partial remission within the first 3 months, signs and symptoms do not improve significantly at 1 year. In order to identify prognostic risk factors large prospective cohort studies are needed. SIGNIFICANCE: This prospective cohort study follows patients with complaints most suspected for complex regional pain syndrome (CRPS) 1. CRPS 1 develops within 8 weeks following a noxious event. Although many CRPS 1 patients reach partial remission within the 3 months, symptoms do not improve significantly at 1 year.

Ocular pulse amplitude as a diagnostic adjunct in giant cell arteritis.

BACKGROUND: To develop an algorithm based on the ocular pulse amplitude (OPA) to predict the probability of a positive temporal artery biopsy (TAB) result in the acute phase of suspected giant cell arteritis (GCA). METHODS: Unilateral TAB was performed and ipsilateral OPA measurements were taken by Dynamic Contour Tonometry. Among the clinical signs and laboratory findings tested in univariate analyses, OPA, Erythrocyte Sedimentation Rate (ESR) and thrombocyte count showed a strong association with a positive TAB result. Algorithm parameters were categorized into three groups (OPA >3.5, 2.5-3.5, and <2.5 mm Hg; ESR <25, 25-60, and >60 mm/h; thrombocyte count <250'000, 250'000-500'000, and >500'000/µl). Score values (0, 1, and 2) were attributed to each group, resulting in a total score range from 0 to 6. A univariate logistic regression analysis using the GCA diagnosis as the dependent and the total score as the independent variate was fitted and probability estimates were calculated. RESULTS: Thirty-one patients with suspected GCA undergoing TAB during an eighteen-month observation period were enrolled. Twenty patients showed histologically proven GCA. Four patients had score values ≤2, fourteen between 3 and 4, and thirteen of ≥5. The corresponding estimated probabilities of GCA were<7, 52.6, and >95%. CONCLUSION: The present study confirms previous findings of reduced OPA levels, elevated ESR, and elevated thrombocyte counts in GCA. It indicates that a sum score based on OPA, ESR, and thrombocyte count can be helpful in predicting TAB results, especially at the upper and the lower end of the sum score range.

Blood flow velocity measured using the Retinal Function Imager predicts successful ranibizumab treatment in neovascular age-related macular degeneration: early prospective cohort study.

PURPOSE: Anti-VEGF treatment has a potent vasoconstrictive effect. Early changes of retinal blood flow velocity (RBFV) measured using the Retinal Function Imager (RFI) combined with indicators of vascular status may help in predicting the visual outcome 1 month post injection in patients with neovascular age-related macular degeneration (nvAMD) under ranibizumab treatment. To develop a simple prediction model based on the change in RBFV 3 days post injection and indicators of a patient's vascular status to assess the probability of a successful visual outcome 1 month post injection. METHODS: RBFV measured using RFI were prospectively collected pre-injection and 3 days post injection in 18 eyes of 15 patients. Indicators of vascular status (history of hypertension, diabetes mellitus without retinal affection, and smoking) were assessed by medical history. By univariate analyses, parameters associated with visual outcome were weighted (-1 to 6 points). A multivariate logistic regression model with the categorized visual outcome parameter (≥0 letters gained after 1 month) as the dependent variate and the sum score as the independent variate (continuous scale) was used to estimate the score value-specific probabilities of letters gained ≥0 1 month post injection. RESULTS: The indicators of vascular status negatively influenced the likelihood of a letter gain ≥0 whereas an increase in the arterial RBFV strongly increased it. The area under the receiver operating characteristics curve for these parameters investigated was 0.71 (95% CI: 0.43-1.00). CONCLUSION: Changes in the arterial RBFV following 3 days after ranibizumab injection combined with three indicators of the vascular status identified nvAMD patients with favorable visual outcome accurately.

Diagnostic accuracy of the Amsler grid and the preferential hyperacuity perimetry in the screening of patients with age-related macular degeneration: systematic review and meta-analysis.

OBJECTIVE: To clarify the screening potential of the Amsler grid and preferential hyperacuity perimetry (PHP) in detecting or ruling out wet age-related macular degeneration (AMD). EVIDENCE ACQUISITION: Medline, Scopus and Web of Science (by citation of reference) were searched. Checking of reference lists of review articles and of included articles complemented electronic searches. Papers were selected, assessed, and extracted in duplicate. EVIDENCE SYNTHESIS: Systematic review and meta-analysis. Twelve included studies enrolled 903 patients and allowed constructing 27 two-by-two tables. Twelve tables reported on the Amsler grid and its modifications, twelve tables reported on the PHP, one table assessed the MCPT and two tables assessed the M-charts. All but two studies had a case-control design. The pooled sensitivity of studies assessing the Amsler grid was 0.78 (95% confidence intervals; 0.64-0.87), and the pooled specificity was 0.97 (95% confidence intervals; 0.91-0.99). The corresponding positive and negative likelihood ratios were 23.1 (95% confidence intervals; 8.4-64.0) and 0.23 (95% confidence intervals; 0.14-0.39), respectively. The pooled sensitivity of studies assessing the PHP was 0.85 (95% confidence intervals; 0.80-0.89), and specificity was 0.87 (95% confidence intervals; 0.82-0.91). The corresponding positive and negative likelihood ratios were 6.7 (95% confidence intervals; 4.6-9.8) and 0.17 (95% confidence intervals; 0.13-0.23). No pooling was possible for MCPT and M-charts. CONCLUSION: Results from small preliminary studies show promising test performance characteristics both for the Amsler grid and PHP to rule out wet AMD in the screening setting. To what extent these findings can be transferred to a real clinic practice still needs to be established.

Effects and adverse events after CXL for keratoconus are independent of age: a 1-year follow-up study.

PURPOSE: To compare the effect, failure rate and the risks of corneal cross-linking (CXL) in keratoconus patients aged ≥35 years to patients <35 years. METHODS: In 141 eyes of 116 keratoconus patients we compared the changes in best phoropter-corrected visual acuity (BCVA) and maximum keratometry values (Kmax) before and 12 months after CLX in patients aged ≥35 years (n=34, 38 eyes) to the cohort of patients below 35 years of age. RESULTS: Overall, CXL significantly improved BCVA from 0.487 logMAR (95% confidence interval (CI) 0.426-0.548) by -0.197 logMAR (95% CI -0.243 to -0.150; P<0.001) and reduced Kmax from 48.96 diopter (Dpt) by -1.33 Dpt (95% CI -1.85 to -0.81: P<0.001). Age ≥35 years had no effect on the changes of BCVA (-0.02 (95% CI -0.13 to 0.09); P=0.757) or Kmax (0.58 (95%CI -0.51 to 1.68); P=0.294) as compared with younger patients. In 54 patients (55 eyes, 38.5%) aged <35 years and in 18 patients (18 eyes, 47.4%) aged ≥35 years, BCVA increased by ≥2 Snellen lines. Failure (increase in Kmax ≥1 Dpt) was observed in 17 eyes (16.5%) of patients aged <35 years and in 3 eyes (7.9%) of patients aged ≥35 years during the 12-month follow-up period. Adverse outcomes (loss of ≥2 Snellen lines) occurred in 4 (3.9%) eyes of patients aged <35 years and 1 (2.6%) eye of a patient aged ≥35 years. CONCLUSION: Effects and adverse events of CXL treatment do not seem to differ between subjects younger or older than 35 years.

Concordance of qualitative bone scintigraphy results with presence of clinical complex regional pain syndrome 1: meta-analysis of test accuracy studies.

BACKGROUND: To date, no attempt has been made to investigate the agreement between qualitative bone scintigraphy (BS) and the presence of complex regional pain syndrome 1 (CRPS 1) and the agreement between a negative BS in the absence of CRPS 1. AIMS: To summarize the existing evidence quantifying the concordance of qualitative BS in the presence or absence of clinical CRPS 1. DATA SOURCES: We searched Medline, Embase, Dare and the Cochrane Library and screened bibliographies of all included studies. STUDY ELIGIBILITY CRITERIA: We selected diagnostic studies investigating the association between qualitative BS results and the clinical diagnosis of CRPS 1. The minimum requirement for inclusion was enough information to fill the two-by-two tables. RESULTS: Twelve studies met our inclusion criteria and were included in the meta-analysis. The pooled mean sensitivity of 12 two-by-two tables was 0.87 (95% CI, 0.68-0.97) and specificity was 0.69 (95% CI, 0.47-0.85). The pooled mean sensitivity for the subgroup with clearly defined diagnostic criteria (seven two-by-two tables) was 0.80 (95% CI, 0.44-0.95) and specificity was 0.73 (95% CI, 0.40-0.91). CONCLUSIONS: Based on this study, clinicians must be advised that a positive BS is not necessarily concordant with presence of absence or CRPS 1. Given the moderate level of concordance between a positive BS in the absence of clinical CRPS 1, discordant results potentially impede the diagnosis of CRPS 1.

Bayesian bivariate meta-analysis of diagnostic test studies using integrated nested Laplace approximations.

For bivariate meta-analysis of diagnostic studies, likelihood approaches are very popular. However, they often run into numerical problems with possible non-convergence. In addition, the construction of confidence intervals is controversial. Bayesian methods based on Markov chain Monte Carlo (MCMC) sampling could be used, but are often difficult to implement, and require long running times and diagnostic convergence checks. Recently, a new Bayesian deterministic inference approach for latent Gaussian models using integrated nested Laplace approximations (INLA) has been proposed. With this approach MCMC sampling becomes redundant as the posterior marginal distributions are directly and accurately approximated. By means of a real data set we investigate the influence of the prior information provided and compare the results obtained by INLA, MCMC, and the maximum likelihood procedure SAS PROC NLMIXED. Using a simulation study we further extend the comparison of INLA and SAS PROC NLMIXED by assessing their performance in terms of bias, mean-squared error, coverage probability, and convergence rate. The results indicate that INLA is more stable and gives generally better coverage probabilities for the pooled estimates and less biased estimates of variance parameters. The user-friendliness of INLA is demonstrated by documented R-code.

Would you sell a kidney in a regulated kidney market? Results of an exploratory study.

BACKGROUND: It is often claimed that a regulated kidney market would significantly reduce the kidney shortage, thus saving or improving many lives. Data are lacking, however, on how many people would consider selling a kidney in such a market. METHODS: A survey instrument, developed to assess behavioural dispositions to and attitudes about a hypothetical regulated kidney market, was given to Swiss third-year medical students. RESULTS: Respondents' (n = 178) median age was 23 years. Their socioeconomic status was high or middle (94.6%). 48 (27%) considered selling a kidney in a regulated kidney market, of whom 31 (66%) would sell only to overcome a particularly difficult financial situation. High social status and male gender was the strongest predictor of a disposition to sell. 32 of all respondents (18%) supported legalising a regulated kidney market. This attitude was not associated with a disposition to sell a kidney. 5 respondents (2.8%) endorsed a market and considered providing a kidney to a stranger if and only if paid. 4 of those 5 would sell only under financial duress. CONCLUSIONS: Current understanding of a regulated kidney market is insufficient. It is unclear whether a regulated market would result in a net gain of kidneys. Most possible kidney vendors would only sell in a particularly difficult financial situation, raising concerns about the validity of consent and inequities in the provision of organs. Further empirical and normative analysis of these issues is required. Any calls to implement and evaluate a regulated kidney market in pilot studies are therefore premature.

Comparison of risk factors predicting return to work between patients with subacute and chronic non-specific low back pain: systematic review.

The objective of the study was to provide an inventory of predictive instruments and their constituting parameters associated with return to work in patients with subacute (2-10 weeks pain duration) and chronic (10-24 weeks pain duration) non-specific low back pain (NSLBP). Data sources included systematic review in Medline, Embase, Cinahl, Central, PEDro, Psyndex, PsychInfo/PsycLit, and Sociofile up to September 2008, in reference lists of systematic reviews on risk factors, and of included studies. For the systematic review, two reviewers independently assessed study eligibility and quality, and extracted data. Disagreements were resolved by consensus. Risk factors were inventorised and grouped into a somatic and psychosocial domain. 23 studies reporting on subacute and 16 studies reporting on chronic patients were included. The studies on subacute patients reported on a total of 56 biomedical factors out of which 35 (63%) were modifiable and 61 psychosocial factors out of which 51 (84%) were modifiable. The corresponding values in studies on chronic patients were 44 biomedical [27 (62%) modifiable] and 61 [40 (66%) modifiable] respectively. Our data suggest that the interdisciplinary approach in patients at risk to develop persistent NSLBP is justified in both, the subacute and chronic disease stages. Psychosocial interventions might be more effective in subacute stages since a higher proportion of modifiable risk factors were identified in that group.

Comparison of dynamic contour tonometry with Goldmann applanation tonometry following Descemet's stripping automated endothelial keratoplasty (DSAEK).

BACKGROUND: Intraocular pressure (IOP) measurements using Goldmann applanation tonometry (GAT) are influenced by central corneal thickness (CCT) whereas dynamic contour tonometry (DCT) allows for IOP measurements independent of CCT. After Descemet's stripping automated endothelial keratoplasty (DSAEK) the CCT is, compared to healthy eyes, increased. The objective of this prospective study was to compare IOP measurements obtained by DCT and GAT in patients after a DSAEK procedure. PATIENTS AND METHODS: DCT and GAT were performed 3 and/or 6 months after DSAEK. Comparison of means was performed using the Wilcoxon signed-ranks test. RESULTS: In total, 50 IOP measurements on 33 eyes were obtained. Mean CCT was 621 (+/- 60) microm. Overall correlation between GAT and DCT was good, however, in some patients a remarkable difference between pressure readings of up to 10.8 mmHg was observed. Mean IOP readings obtained by DCT were significantly higher (20.9 +/- 5.9 mmHg) than those obtained by GAT (19.1 +/- 6.5 mmHg; p = 0.0002). However, the difference between GAT and DCT readings was not influenced by the thickness of the transplanted lamella. DISCUSSION: The well-known difference in mean pressure readings between DCT and GAT was not affected by the increase in CCT following DSAEK. IOP readings with the GAT seem not to be influenced by the increase in CCT. Because of the remarkable differences in individual pairs of IOP measurements, both GAT and DCT should be used after DSAEK.

A systematic review of treatment options for dermal photosensitivity in erythropoietic protoporphyria.

Erythropoietic protoporphyria (EPP) is a rare inherited disease characterized by dermal photosensitivity due to the accumulation of photosensitizer protoporphyrin IX. We performed a systematic database search on studies related to treatment of EPP. A total of 25 relevant studies were retrieved, 16 of them dealing with the application of beta-carotene. Two studies were found on each of the three substances, n-acetyl-cysteine (NAC), cysteine, and dihydroxyacetone/Lawson (henna). In addition, single studies on vitamin C, canthaxanthin and UVB treatment respectively, were located. The total number of patients in the 25 studies was 454, including 337 patients in the various beta-carotene trials. Most studies were published in the 1970's. Efficacy criteria were not standardized. Only 5 of the 25 studies were randomized and controlled trials; the rest were either open-label, uncontrolled studies or retrospective case reports. Four of the five well-designed studies suggested lack of efficacy of beta-carotene, NAC and vitamin C. The results of the beta-carotene studies were strongly contradictory and efficacy was inversely correlated with study quality. Our data confirm the opinion of experts in the field who are much more skeptical as to its efficacy than were early proponents of treatment with this agent. We conclude, that the available data are insufficient to prove efficacy of any treatments studied so far in EPP. We emphasize the necessity of high quality efficacy studies in porphyrias and in other rare diseases.

Development of a predictive model for estimating the probability of treatment success one year after total shoulder replacement - cohort study.

OBJECTIVE: To Estimate the probability of treatment success 1 year after a total shoulder arthroplasty by developing a model based on preoperative clinical factors. METHOD: Between June 2003 and December 2006, 140 patients undergoing shoulder operations were assessed for age, gender, current rheumatoid arthritis, Short Form (SF) 36 physical and mental sum scores, previous shoulder operations, the Disabilities of Arm, Shoulder and Hand (DASH) symptom and function scores, the Shoulder Pain and Disability Index (SPADI), and insurance status. One year after the operation a Constant score of 80 or more out of 100 indicated successful treatment. Patient variables were analyzed with a logistic regression model augmented in a stepwise manner and bootstrapped 100 times. Variables selected at least 33 times were incorporated into a final model and the Area under the Receiver Operating Characteristics Curve (aROC) was calculated. RESULTS: There were 47/140 (33.6%) successful treatments. The probability of success was reduced in patients with previous shoulder operations (Odds Ratio [O.R.] 0.17, 95% Confidence Interval (95%CI) 0.04-0.85; P=0.03) and older than 75 years (O.R. 0.21, 95%CI 0.05-0.77; P=0.02). The probability of success increased in patients with a higher SF 36 mental sum score (O.R. 1.03, 95%CI 0.96-1.09, P=0.42) and a higher DASH function score (O.R. 1.05, 95%CI 1.02-1.07, P=0.001). The aROC was 0.79 (0.70-0.88) indicating that the model has a high predictive capacity. CONCLUSION: Once validated this model based on four preoperative clinical factors offers a prediction of whether a patient will respond to treatment 1 year after total shoulder arthroplasty.

[Diagnosis: meanders and shortcuts]. / Diagnose: Irrwege und Abkürzungen.

Diagnosis is knowing about the probability of an illness in a particular patient. Relevant steps in establishing a diagnosis are: gathering of information (history and results of physical examination), defining attributes, to mentally represent the clinical problem and to compare it with memorized illness scripts. From this follows a list of potential illnesses which could explain the clinical signs and symptoms. The next step is to distill the most likely diagnosis by gathering further information about the patient. Most diagnostic errors occur during the information gathering and by interpreting the information.

[Ocular pulse amplitude: a new biometrical parameter for the diagnose of glaucoma?]. / Okuläre Pulsamplitude als biometrischer Messwert in der Glaukomdiagnostik.

BACKGROUND: Dynamic contour tonometry (DCT) enables accurate transcorneal measurements of the intraocular pressure and ocular pulse amplitude (OPA). In this study, we investigated whether this new biometrical parameter can characterize different glaucoma types and serve as a helpful tool in the diagnosis and therapy of the disease. PATIENTS AND METHODS: A total of 441 eyes of 222 patients were included. Pressure measurements were performed with contour and applanation tonometry. RESULTS: Mean OPA was 3.1+/-1.4 mmHg. Eyes with ocular hypertension showed significantly higher OPA values (3.6+/-1.3 mmHg) than healthy eyes (3.1+/-1.4 mmHg) and eyes with low-tension glaucoma (2.9+/-1.4 mmHg). After trabeculectomy, the values were significantly lower (2.4+/-1.3 mmHg) than in healthy eyes. CONCLUSION: The size of the OPA seems to be characteristic for different types of glaucoma and directly dependent on intraocular pressure levels. Further investigation is indicated to clarify its diagnostic usefulness.

[Elementary structure of a study]. / Elemente einer Studie.

Medical research provides evidence in three gnostic domains; etiognosis, diagnosis and prognosis. The occurrence relation, the domain and the study population characterize every medical study. The determinant and the outcome define the occurrence relation. The domain defines the type of situation in which the occurrence relation is explored. The study population contains representatives of the domain whose experience is captured within the study.

[Study designs]. / Studiendesigns.

Methods design follows object design. The study question defines which study design is most appropriate. The ideal study design provides the most valid results. Sometimes, practicality reasons or costs (efficiency) impede using the ideal design. Researchers need to weigh the consequences of suboptimal design elements against the risk of bias.

[Managerial considerations in research]. / Management eines Forschungsprojektes.

Basics for proper research are good ideas, know how and adequate resources. Essential to accomplish a research project in an efficient way is thorough planning. A research project can be divided in four organizational units. Writing of the protocol, which includes details about all relevant aspects, e.g. the research question, study design, time table and budget, second, details on data collection, third, data analysis and fourth, writing a report or manuscript for publication. A thoroughly developed protocol facilitates the communication between all involved persons and permits an efficient management of a research project.