Increased Antifungal Drug Resistance in Clinical Isolates of Cryptococcus neoformans in Uganda

Cryptococcal antigen screening is recommended among people living with AIDS when entering HIV care with a CD4 count of <100 cells/μl, and preemptive fluconazole monotherapy treatment is recommended for those with subclinical cryptococcal antigenemia. Yet, knowledge is limited of current antimicrobial resistance in Africa. We examined antifungal drug susceptibility in 198 clinical isolates collected from Kampala, Uganda, between 2010 and 2014 using the CLSI broth microdilution assay. In comparison with two previous studies from 1998 to 1999 that reported an MIC₅₀ of 4 μg/ml and an MIC₉₀ of 8 μg/ml prior to widespread human fluconazole and agricultural azole fungicide usage, we report an upward shift in the fluconazole MIC₅₀ to 8 μg/ml and an MIC₉₀ value of 32 μg/ml, with 31% of isolates with a fluconazole MIC of ≥16 μg/ml. We observed an amphotericin B MIC₅₀ of 0.5 μg/ml and an MIC₉₀ of 1 μg/ml, of which 99.5% of isolates (197 of 198 isolates) were still susceptible. No correlation between MIC and clinical outcome was observed in the context of amphotericin B and fluconazole combination induction therapy. We also analyzed Cryptococcus susceptibility to sertraline, with an MIC₅₀ of 4 μg/ml, suggesting that sertraline is a promising oral, low-cost, available, novel medication and a possible alternative to fluconazole. Although the CLSI broth microdilution assay is ideal to standardize results, limit human bias, and increase assay capacity, such assays are often inaccessible in low-income countries. Thus, we also developed and validated an assay that could easily be implemented in a resource-limited setting, with similar susceptibility results (P = 0.52).     

Shear bond strength of orthodontic brackets to enamel after application of a caries infiltrant

Objective:To examine differences in the shear bond strength of orthodontic brackets on differently mineralized enamel surfaces after applying a caries infiltrant or conventional adhesive.Materials and Methods:A total of 320 bovine incisors were assigned to eight pretreated groups, and the shear force required for debonding was recorded. Residual adhesive was evaluated by light microscopy using the adhesive remnant index. Statistical analysis included Kolmogorov-Smirnov, analysis of variance (ANOVA), and Scheffé tests.Results:The highest bond strength (18.8 ± 4.4 MPa) was obtained after use of the caries infiltrant. More residual adhesive and fewer enamel defects were observed on infiltrated enamel surfaces. Brackets on demineralized enamel produced multiple enamel defects.Conclusions:Acceptable bond strengths were obtained with all material combinations. A caries-infiltrant applied before bracket fixation has a protective effect, especially on demineralized enamel.     

Metabolic programming and PDHK1 control CD4+ T cell subsets and inflammation

Activation of CD4⁺ T cells results in rapid proliferation and differentiation into effector and regulatory subsets. CD4⁺ effector T cell (Teff) (Th1 and Th17) and Treg subsets are metabolically distinct, yet the specific metabolic differences that modify T cell populations are uncertain. Here, we evaluated CD4⁺ T cell populations in murine models and determined that inflammatory Teffs maintain high expression of glycolytic genes and rely on high glycolytic rates, while Tregs are oxidative and require mitochondrial electron transport to proliferate, differentiate, and survive. Metabolic profiling revealed that pyruvate dehydrogenase (PDH) is a key bifurcation point between T cell glycolytic and oxidative metabolism. PDH function is inhibited by PDH kinases (PDHKs). PDHK1 was expressed in Th17 cells, but not Th1 cells, and at low levels in Tregs, and inhibition or knockdown of PDHK1 selectively suppressed Th17 cells and increased Tregs. This alteration in the CD4⁺ T cell populations was mediated in part through ROS, as N-acetyl cysteine (NAC) treatment restored Th17 cell generation. Moreover, inhibition of PDHK1 modulated immunity and protected animals against experimental autoimmune encephalomyelitis, decreasing Th17 cells and increasing Tregs. Together, these data show that CD4⁺ subsets utilize and require distinct metabolic programs that can be targeted to control specific T cell populations in autoimmune and inflammatory diseases.     

Prophylaxis with Teicoplanin and Cefuroxime Reduces the Rate of Prosthetic Joint Infection after Primary Arthroplasty

The aim of this study was to compare the prosthetic joint infection (PJI) rate after total joint arthroplasty in two consecutive periods of treatment with different antibiotic prophylaxes: cefuroxime versus cefuroxime plus teicoplanin. We retrospectively reviewed 1,896 patients who underwent total hip arthroplasty or total knee arthroplasty between March 2010 and February 2013. From March 2010 to August 2011, patients received 1.5 g of cefuroxime during induction of anesthesia and another 1.5 g 2 h later (the C group). From September 2011, 800 mg of teicoplanin was added to cefuroxime (the CT group). Throughout the period studied, there were no variations in pre- or postoperative protocols. Univariate and multivariate analyses were performed to evaluate independent predictors of PJI. There were 995 (55.7%) patients in the C group and 791 (44.3%) in the CT group. Patients in the CT group had a significantly lower PJI rate than patients in the C group (1.26% versus 3.51%, P = 0.002). There were no infections due to Staphylococcus aureus in the CT group (0% versus 1.6% in the C group, P < 0.001). A stepwise forward Cox regression model identified male sex (hazard ratio [HR], 3.85; 95% confidence interval [CI], 2.09 to 7.18), a body mass index of ≥35 kg/m² (HR, 2.93; 95% CI, 1.37 to 6.27), the presence of lung disease (HR, 2.46; 95% CI, 1.17 to 5.15), and red blood cell transfusion (HR, 3.70; 95% CI, 1.89 to 7.23) to be independent variables associated with a higher risk of PJI. The addition of teicoplanin was associated with a lower risk of infection (HR, 0.35; 95% CI, 0.17 to 0.74). In conclusion, the addition of teicoplanin to cefuroxime during primary arthroplasty was associated with a significant reduction in the global PJI rate due to a reduction of infections caused by Gram-positive bacteria.     

Differences in participation based on self-esteem in power and manual wheelchair users on a university campus: a pilot study

Objectives: To examine the relationship of self-esteem and wheelchair type with participation of young adult manual and power wheelchair users with diverse physical disabilities. Design: Cross-sectional survey study. Setting: Large University Campus. Participants: A convenience sample of college students (N?=?39) with self-reported physical disabilities who are full time wheelchair users (>40 per week) and are two or more years post illness or injury. Interventions: Not applicable. Main outcome measures: The Rosenberg Self-Esteem Scale was used to measure self-esteem, and the Craig Handicap Assessment and Reporting Technique was used to measure participation. Results: Self-esteem correlated highly with cognitive independence (CI) (r?=?0.58), mobility (r?=?0.67) and social integration (SI) (r?=?0.52). Use of manual wheelchair was significantly related to higher levels of CI and mobility while longer use of any wheelchair (power or manual) was significantly associated with higher levels of mobility and SI. In addition higher self-esteem independently predicted a significant proportion of the variance in CI, mobility and SI, while type of wheelchair predicted a significant proportion of the variance in CI (p?Conclusions: High self-esteem was found to be the strongest predictor of participation in a population of young adults with mobility limitations. Better understanding of the factors influencing participation may help to facilitate new interventions to minimize the disparities between persons with disabilities and their able bodied peers.

• Implication for Rehabilitation

• A total of 46.8% of wheelchair users report the desire for increased community participant but face significant barriers.

• The type of wheelchair has been identified as having a large impact on participation.

• This study found self-esteem to be the strongest predictor of participation, which is notable because self-esteem is a characteristic that is potentially modifiable with treatment.