An Outer Membrane Vesicle-Based Permeation Assay (OMPA) for Assessing Bacterial Bioavailability

When searching for new antibiotics against Gram-negative bacterial infections, a better understanding of the permeability across the cell envelope and tools to discriminate high from low bacterial bioavailability compounds are urgently needed. Inspired by the phospholipid vesicle-based permeation assay (PVPA), which is designed to predict non-facilitated permeation across phospholipid membranes, outer membrane vesicles (OMVs) of Escherichia coli either enriched or deficient of porins are employed to coat filter supports for predicting drug uptake across the complex cell envelope. OMVs and the obtained in vitro model are structurally and functionally characterized using cryo-TEM, SEM, CLSM, SAXS, and light scattering techniques. In vitro permeability, obtained from the membrane model for a set of nine antibiotics, correlates with reported in bacterio accumulation data and allows to discriminate high from low accumulating antibiotics. In contrast, the correlation of the same data set generated by liposome-based comparator membranes is poor. This better correlation of the OMV-derived membranes points to the importance of hydrophilic membrane components, such as lipopolysaccharides and porins, since those features are lacking in liposomal comparator membranes. This approach can offer in the future a high throughput screening tool with high predictive capacity or can help to identify compound- and bacteria-specific passive uptake pathways

Dexamethasone intravitreal implant in previously treated patients with diabetic macular edema : Subgroup analysis of the MEAD study

Background: Dexamethasone intravitreal implant 0.7 mg (DEX 0.7) was approved for treatment of diabetic macular edema (DME) after demonstration of its efficacy and safety in the MEAD registration trials. We performed subgroup analysis of MEAD study results to evaluate the efficacy and safety of DEX 0.7 treatment in patients with previously treated DME. Methods: Three-year, randomized, sham-controlled phase 3 study in patients with DME, best-corrected visual acuity (BCVA) of 34.68 Early Treatment Diabetic Retinopathy Study letters (20/200.20/50 Snellen equivalent), and central retinal thickness (CRT) 65300 \u3bcm measured by time-domain optical coherence tomography. Patients were randomized to 1 of 2 doses of DEX (0.7 mg or 0.35 mg), or to sham procedure, with retreatment no more than every 6 months. The primary endpoint was 6515-letter gain in BCVA at study end. Average change in BCVA and CRT from baseline during the study (area-under-the-curve approach) and adverse events were also evaluated. The present subgroup analysis evaluated outcomes in patients randomized to DEX 0.7 (marketed dose) or sham based on prior treatment for DME at study entry. Results: Baseline characteristics of previously treated DEX 0.7 (n = 247) and sham (n=261) patients were similar. In the previously treated subgroup, mean number of treatments over 3 years was 4.1 for DEX 0.7 and 3.2 for sham, 21.5 % of DEX 0.7 patients versus 11.1 % of sham had 6515-letter BCVA gain from baseline at study end (P = 0.002), mean average BCVA change from baseline was +3.2 letters with DEX 0.7 versus +1.5 letters with sham (P = 0.024), and mean average CRT change from baseline was -126.1 \u3bcm with DEX 0.7 versus -39.0 \u3bcm with sham(P < 0.001). Cataract-related adverse events were reported in 70.3 % of baseline phakic patients in the previously treated DEX 0.7 subgroup; vision gains were restored following cataract surgery. Conclusions: DEX 0.7 significantly improved visual and anatomic outcomes in patients with DME previously treated with laser, intravitreal anti-vascular endothelial growth factor, intravitreal triamcinolone acetonide, or a combination of these therapies. The safety profile of DEX 0.7 in previously treated patients was similar to its safety profile in the total study population

Towards a specific outcome instrument for spinal trauma : How to measure function and health

Study Design. Validation study. Objective. To investigate the most valid, reliable, and comprehensible response scale for spinal trauma patients to compare their current level of function and health with their preinjury state. Summary of Background Data. In the context of a main project of the AOSpine Knowledge Forum Trauma to develop a disease-specific outcome instrument for adult spinal trauma patients, the need to identify a response scale that uniquely reflects the degree to which a spine trauma patient has returned to his or her preinjury state is crucial. Methods. In the first phase, 3 different question formats and 3 different response formats were investigated in a questionnaire, which was administered twice. Based on the results of the first phase, in the second phase, a modified questionnaire was administered once to a second group of patients to investigate 5 different response formats: 0–10 Numeric Rating Scale-11, 0–100 Numeric Rating Scale-101, Visual Analogue Scale, Verbal Rating Scale, and Adjective Scale. All patients were interviewed in a semistructured fashion to identify their preferences. Multiple statistical analyses were performed: test-retest reliability, internal consistency, and discriminant validity. Results. Twenty eligible patients were enrolled in the first phase and 59 in the second phase. The initial phase revealed the highest preference for 1 specific question format (60.0% and 86.7% after the first and second administration of the questionnaire, respectively). The second phase showed the Verbal Rating Scale as the most preferred response format (35.6%). The semistructured interviews revealed that overall, a subgroup of patients preferred a verbal response format (42.4%), and another group of patients preferred a numerical response format (49.1%). The statistical analysis showed good to excellent psychometric properties for all formats. Conclusion. The most preferred question and response formats were identified for use in a disease-specific outcome instrument for spinal trauma patients

Reliability and validity of the adapted Dutch version of the revised Scoliosis Research Society 22-item questionnaire

Background context As in other fields of medicine, there is an increasing interest among orthopedic surgeons to measure health-related quality of life in adolescent idiopathic scoliosis patients and to evaluate the burden of disease and the effectiveness of different treatment strategies. The development of the revised Scoliosis Research Society 22-item patient questionnaire (SRS-22r) enabled a comprehensive evaluation of health-related quality of life of these patients. Over the years, the SRS-22r gained wide acceptance and has been used in several different countries, languages, and cultures. The SRS-22r has not been translated into Dutch to date. Purpose To translate the SRS-22r into Dutch and adapt it cross-culturally as outlined by international guidelines and to test its psychometric properties to measure health-related quality of life of adolescent idiopathic scoliosis patients in the Netherlands. Study design/setting A cross-sectional, multicenter validation study. Patient sample A total of 135 adolescent idiopathic scoliosis patients (mean age 15.1 years old) of three major scoliosis centers in the Netherlands were enrolled in this study. Ninety-two (68%) subjects completed the Dutch SRS-22r, Child Health Questionnaire (CHQ)-CF87 (golden standard for adolescents), and Short Form (SF)-36 (golden standard for adults). Two weeks later, 73 (79%) of 92 respondents returned a second SRS-22r. Demographics, curve type, Risser stage, and treatment status were documented. Outcome measures Floor and ceiling effects, internal consistency, reproducibility, concurrent validity, and discriminative ability of the Dutch version of the SRS-22r questionnaire. Methods For content analysis, SRS-22r domain scores (function, pain, self-image, mental health, and satisfaction with management) were explored and floor and ceiling effects were determined. Cronbach's α was calculated for internal consistency of each domain of the questionnaires and reproducibility was assessed by test-retest reliability analysis. Using Pearson's correlation coefficient, comparison of the domains of the Dutch SRS-22r with the domains of the SF-36 and Child Health Questionnaire-CF87 assessed the concurrent validity. Differences in SRS-22r domain scores between untreated patients with different curve severity determined the discriminative ability of the questionnaire. Results The SRS-22r domains as well as the SF-36 and CHQ-CF87 domains demonstrated no floor effects, but the function, pain, and satisfaction with management domains had ceiling effects, indicating the proportion of subjects with the maximum score between 19.6% and 33.0%. Internal consistency was very satisfactory for all SRS-22r domains: Cronbach's α was between 0.718 and 0.852. By omitting question 15, the internal consistency of the function domain increased from 0.746 to 0.827. Test-retest reliability was ≥0.799 for all SRS-22r domains. The function, pain, mental health, and self-image domains correlated under the 0.001 significance level with the corresponding CHQ-CF87 and SF-36 domains. The satisfaction with management domain did not correlate with the other questionnaires. The SRS-22r had the ability to detect differences between groups with different curve severity; patients with a severe scoliotic curvature had significantly lower pain and self-image domain scores than patients with relatively mild scoliosis. Conclusions The Dutch SRS-22r had the properties needed for the measurement of patient perceived health-related quality of life of adolescent idiopathic scoliosis patients in the Netherlands. The Dutch SRS-22r could be used for the longitudinal follow-up of adolescent idiopathic scoliosis patients from adolescence to adulthood and for establishing the effects of conservative or invasive surgical treatment

Missed low-grade infection in suspected aseptic loosening has no consequences for the survival of total hip arthroplasty

Contains fulltext : 152486.pdf (publisher's version ) (Open Access)Background and purpose - Aseptic loosening and infection are 2 of the most common causes of revision of hip implants. Antibiotic prophylaxis reduces not only the rate of revision due to infection but also the rate of revision due to aseptic loosening. This suggests under-diagnosis of infections in patients with presumed aseptic loosening and indicates that current diagnostic tools are suboptimal. In a previous multicenter study on 176 patients undergoing revision of a total hip arthroplasty due to presumed aseptic loosening, optimized diagnostics revealed that 4-13% of the patients had a low-grade infection. These infections were not treated as such, and in the current follow-up study the effect on mid- to long-term implant survival was investigated. Patients and methods - Patients were sent a 2-part questionnaire. Part A requested information about possible re-revisions of their total hip arthroplasty. Part B consisted of 3 patient-related outcome measure questionnaires (EQ5D, Oxford hip score, and visual analog scale for pain). Additional information was retrieved from the medical records. The group of patients found to have a low-grade infection was compared to those with aseptic loosening. Results - 173 of 176 patients from the original study were included. In the follow-up time between the revision surgery and the current study (mean 7.5 years), 31 patients had died. No statistically significant difference in the number of re-revisions was found between the infection group (2 out of 21) and the aseptic loosening group (13 out of 152); nor was there any significant difference in the time to re-revision. Quality of life, function, and pain were similar between the groups, but only 99 (57%) of the patients returned part B. Interpretation - Under-diagnosis of low-grade infection in conjunction with presumed aseptic revision of total hip arthroplasty may not affect implant survival

Missed low-grade infection in suspected aseptic loosening has no consequences for the survival of total hip arthroplasty: 173 patients followed for 6 to 9 years

BACKGROUND AND PURPOSE: Aseptic loosening and infection are 2 of the most common causes of revision of hip implants. Antibiotic prophylaxis reduces not only the rate of revision due to infection but also the rate of revision due to aseptic loosening. This suggests under-diagnosis of infections in patients with presumed aseptic loosening and indicates that current diagnostic tools are suboptimal. In a previous multicenter study on 176 patients undergoing revision of a total hip arthroplasty due to presumed aseptic loosening, optimized diagnostics revealed that 4-13% of the patients had a low-grade infection. These infections were not treated as such, and in the current follow-up study the effect on mid- to long-term implant survival was investigated. PATIENTS AND METHODS: Patients were sent a 2-part questionnaire. Part A requested information about possible re-revisions of their total hip arthroplasty. Part B consisted of 3 patient-related outcome measure questionnaires (EQ5D, Oxford hip score, and visual analog scale for pain). Additional information was retrieved from the medical records. The group of patients found to have a low-grade infection was compared to those with aseptic loosening. RESULTS: 173 of 176 patients from the original study were included. In the follow-up time between the revision surgery and the current study (mean 7.5 years), 31 patients had died. No statistically significant difference in the number of re-revisions was found between the infection group (2 out of 21) and the aseptic loosening group (13 out of 152); nor was there any significant difference in the time to re-revision. Quality of life, function, and pain were similar between the groups, but only 99 (57%) of the patients returned part B. INTERPRETATION: Under-diagnosis of low-grade infection in conjunction with presumed aseptic revision of total hip arthroplasty may not affect implant survival