In vitro and in vivo biological assessment of dual drug-loaded coaxial nanofibers for the treatment of corneal abrasion

The treatment of corneal abrasion currently involves the topical administration of antibiotics, with moxifloxacin HCl (0.5% w/v) eye drops being one of the most widely used treatments. Our previous work (Tawfik et al., 2020) involved the development of coaxial poly-lactic-co-glycolic acid (PLGA) and polyvinylpyrrolidone (PVP) nanofibers loaded with the antibiotic moxifloxacin HCl and the anti-scarring agent pirfenidone in the core (PVP) and shell (PLGA) respectively, with a view to the system comprising an ocular insert for the combination therapy of corneal abrasion. In this study, we examine the antimicrobial, anti-scarring and pharmacokinetic properties of the fibers alongside consideration of their toxicity and propensity for irritation. Minimum inhibitory concentration and zone of inhibition studies against S. aureus and P. aeruginosa were performed, while fibroblast cell viability and α-smooth muscle actin (α-SMA, a biomarker for scar formation) were measured using MTT and Western Blot assays, respectively. Pharmacokinetic studies and efficacy against infection were performed using a rabbit model, while ocular irritancy was assessed using the Draize test. The studies demonstrated that the antimicrobial activity of the moxifloxacin HCl was preserved following encapsulation into the nanofibers, while the downregulation of α-SMA was demonstrated using concentrations below the IC20 values (concentration required to decrease corneal fibroblast viability by no more than 20%). The pharmacokinetic study showed retention and sustained release of the moxifloxacin HCl over a 24-hour period, in contrast to equivalent eye drops which required four times daily dosing. Evidence of low level (according to the MMTS scale) irritation was detected for the nanofiber systems. Overall, the study has demonstrated that the dual drug-loaded nanofiber system shows potential for once daily dosing as an ocular insert for the treatment of corneal abrasion

Physiologically-based pharmacokinetic modeling for single and multiple dosing regimens of ceftriaxone in healthy and chronic kidney disease populations: a tool for model-informed precision dosing

Introduction: Ceftriaxone is one of commonly prescribed beta-lactam antibiotics with several label and off-label clinical indications. A high fraction of administered dose of ceftriaxone is excreted renally in an unchanged form, and it may accumulate significantly in patients with impaired renal functions, which may lead to toxicity.Methods: In this study, we employed a physiologically-based pharmacokinetic (PBPK) modeling, as a tool for precision dosing, to predict the biological exposure of ceftriaxone in a virtually-constructed healthy and chronic kidney disease patient populations, with subsequent dosing optimizations. We started developing the model by integrating the physicochemical properties of the drug with biological system information in a PBPK software platform. A PBPK model in an adult healthy population was developed and evaluated visually and numerically with respect to experimental pharmacokinetic data. The model performance was evaluated based on the fold error criteria of the predicted and reported values for different pharmacokinetic parameters. Then, the model was applied to predict drug exposure in CKD patient populations with various degrees of severity.Results: The developed PBPK model was able to precisely describe the pharmacokinetic behavior of ceftriaxone in adult healthy population and in mild, moderate, and severe CKD patient populations. Decreasing the dose by approximately 25% in mild and 50% in moderate to severe renal disease provided a comparable exposure to the healthy population. Based on the simulation of multiple dosing regimens in severe CKD population, it has been found that accumulation of 2 g every 24 h is lower than the accumulation of 1 g every 12 h dosing regimen.Discussion: In this study, the observed concentration time profiles and pharmacokinetic parameters for ceftriaxone were successfully reproduced by the developed PBPK model and it has been shown that PBPK modeling can be used as a tool for precision dosing to suggest treatment regimens in population with renal impairment

Does a local financial incentive scheme reduce inequalities in the delivery of clinical care in a socially deprived community? A longitudinal data analysis.

BACKGROUND: Socioeconomic deprivation is associated with inequalities in health care and outcomes. Despite concerns that the Quality and Outcomes Framework pay-for-performance scheme in the UK would exacerbate inequalities in primary care delivery, gaps closed over time. Local schemes were promoted as a means of improving clinical engagement by addressing local health priorities. We evaluated equity in achievement of target indicators and practice income for one local scheme. METHODS: We undertook a longitudinal survey over four years of routinely recorded clinical data for all 83 primary care practices. Sixteen indicators were developed that covered five local clinical and public health priorities: weight management; alcohol consumption; learning disabilities; osteoporosis; and chlamydia screening. Clinical indicators were logit transformed from a percentage achievement scale and modelled allowing for clustering of repeated measures within practices. This enabled our study of target achievements over time with respect to deprivation. Practice income was also explored. RESULTS: Higher practice deprivation was associated with poorer performance for five indicators: alcohol use registration (OR 0.97; 95 % confidence interval 0.96,0.99); recorded chlamydia test result (OR 0.97; 0.94,0.99); osteoporosis registration (OR 0.98; 0.97,0.99); registration of repeat prednisolone prescription (OR 0.98; 0.96,0.99); and prednisolone registration with record of dual energy X-ray absorptiometry (DEXA) scan/referral (OR 0.92; 0.86,0.97); practices in deprived areas performed better for one indicator (registration of osteoporotic fragility fracture (OR 1.26; 1.04,1.51). The deprivation-achievement gap widened for one indicator (registered females aged 65-74 with a fracture referred for a DEXA scan; OR 0.97; 0.95,0.99). Two other indicators indicated a similar trend over two years before being withdrawn (registration of fragility fracture and over-75 s with a fragility fracture assessed and treated for osteoporosis risk). For one indicator the deprivation-achievement gap reduced over time (repeat prednisolone prescription (OR 1.01; 1.01,1.01). Larger practices and those serving more affluent areas earned more income per patient than smaller practices and those serving more deprived areas (t = -3.99; p =0.0001). CONCLUSIONS: Any gaps in achievement between practices were modest but mostly sustained or widened over the duration of the scheme. Given that financial rewards may not reflect the amount of work undertaken by practices serving more deprived patients, future pay-for-performance schemes also need to address fairness of rewards in relation to workload

Incentivised chronic disease management and the inverse equity hypothesis: findings from a longitudinal analysis of Scottish primary care practice-level data

Background: The inverse equity hypothesis asserts that new health policies initially widen inequality, then attenuate inequalities over time. Since 2004, the UK’s pay-for-performance scheme for chronic disease management (CDM) in primary care general practices (the Quality and Outcomes Framework) has permitted practices to except (exclude) patients from attending annual CDM reviews, without financial penalty. Informed dissent (ID) is one component of exception rates, applied to patients who have not attended due to refusal or non-response to invitations. ‘Population achievement’ describes the proportion receiving care, in relation to those eligible to receive it, including excepted patients. Examination of exception reporting (including ID) and population achievement enables the equity impact of the UK pay-for-performance contract to be assessed. We conducted a longitudinal analysis of practice-level rates and of predictors of ID, overall exceptions and population achievement for CDM to examine whether the inverse equity hypothesis holds true. Methods: We carried out a retrospective, longitudinal study using routine primary care data, analysed by multilevel logistic regression. Data were extracted from 793 practices (83% of Scottish general practices) serving 4.4 million patients across Scotland from 2010/2011 to 2012/2013, for 29 CDM indicators covering 11 incentivised diseases. This provided 68,991 observations, representing a total of 15 million opportunities for exception reporting. Results: Across all observations, the median overall exception reporting rate was 7.0% (7.04% in 2010–2011; 7.02% in 2011–2012 and 6.92% in 2012–2013). The median non-attendance rate due to ID was 0.9% (0.76% in 2010–2011; 0.88% in 2011–2012 and 0.96% in 2012–2013). Median population achievement was 83.5% (83.51% in 2010–2011; 83.41% in 2011–2012 and 83.63% in 2012–2013). The odds of ID reporting in 2012/2013 were 16.0% greater than in 2010/2011 (p < 0.001). Practices in Scotland’s most deprived communities were twice as likely to report non-attendance due to ID (odds ratio 2.10, 95% confidence interval 1.83–2.40, p < 0.001) compared with those in the least deprived; rural practices reported lower levels of non-attendance due to ID. These predictors were also independently associated with overall exceptions. Rates of population achievement did not change over time, with higher levels (higher remuneration) associated with increased rates of overall and ID exception and more affluent practices. Conclusions: Non-attendance for CDM due to ID has risen over time, and higher rates are seen in patients from practices located in disadvantaged areas. This suggests that CDM incentivisation does not conform to the inverse equity hypothesis, because inequalities are widening over time with lower uptake of anticipatory care health checks and CDM reviews noted among those most in need. Incentivised CDM needs to include incentives for engaging with the ‘hard to reach’ if inequalities in healthcare delivery are to be tackled

Paradoxical signaling pathways in developing thymocytes

Thymocytes are subjected to processes of selection during their life in the thymus; negative selection for autoreactive thymocytes and positive selection for self-MHC restricted self-tolerant cells. Interestingly, signals for positive or negative selection originate from the same receptor. More importantly, evidence showed that both death and survival signals are mediated by the MAPK pathway. The degree and order of ERK activation, but not other MAPK proteins, has been found to be different in either cases of cell fate. Therefore, it is suspected that the kinetics of ERK after activation may dictate cell death or survival. There are two important GEF proteins that are involved in Ras/ERK activation, RasGRP and SOS. It is thought that the level, order and kinetics of ERK are influenced upstream by the type of GEF. This review discusses the role of both GEF proteins in positive and negative selection and how this reflects on ERK activation.Peer reviewed: YesNRC publication: Ye

Induction of tolerogenic dendritic cells by IL-6-secreting CT26 colon carcinoma

One scenario by which tumors escape immune recognition is the constitutive activation of signal transducer and activator of transcription 3 (STAT3). This transcription factor mediates the production of tumor-derived factors that negatively influence target immune cells, such as dendritic cells, and polarize them toward immune-tolerance also through the induction of STAT3 activation. In the current study, the effect of p-STAT3-positive murine colon carcinoma cell line (CT26) on bone marrow-derived DCs was examined. The results showed a remarkable increase in p-STAT3 in dendritic cells (DCs) only after CT26-CM incubation. The induction of p-STAT3 in CT26-CM exposed DCs was attributed at least in part to the high levels of interleukin-6 secreted by CT26 in culture. This was also accompanied by a significant reduction in the response to the immunostimulatory adjuvant lipopolysaccharide by lowering the expression of co-stimulatory molecules CD86 and CD40. Taken together, the results suggest an inhibitory effect of CT26 colon carcinoma on DC maturation through induction of STAT3 phosphorylation. Therefore, tumor-induced p-STAT3 in DCs can be seen as a promising target for colon cancer immunotherapy. \ua9 2012 Informa Healthcare USA, Inc.Peer reviewed: YesNRC publication: Ye

Exclusion of patients from quality measurement of diabetes care in the UK pay-for-performance programme.

BACKGROUND: We examined associations between patient and practice characteristics and exclusions from quality indicators for diabetes during the first 3 years of the Quality and Outcomes Framework, a major pay-for-performance scheme in the UK. METHODS: Three cross-sectional analyses, conducted using data from the electronic medical records of all patients with diabetes registered in 23 general practices in Brent, North West London between 2004/2005 and 2006/2007. Patterns of exclusions were examined for three intermediate outcome indicators. RESULTS: Excluded patients were less likely to achieve treatment targets for HbA(1c) (2004/2005, 2006/2007), blood pressure (2005/2006, 2006/2007) and cholesterol (2005/2006). Black and South Asian patients were more likely to be excluded from the HbA(1c) indicator than White patients [adjusted odds ratio = 1.64 (1.17-2.29) in 2005/2006]. Patients diagnosed with diabetes duration of > 10 years [adjusted odds ratio = 2.01 (1.65-2.45) for HbA(1c) in 2006-2007] and those with co-morbidities (adjusted odds ratio, ≥ 3 co-morbidities compared with no co-morbidity for HbA(1c) adjusted odds ratio = 1.90 (1.24-2.90) in 2004/2005] were more likely to be excluded. Larger practices excluded more patients from the HbA(1c) indicator [adjusted odds ratio, practice ≥ 7000 compared with < 3000, 3.52 (2.35-5.27) in 2005-2006]. More deprived practices consistently excluded more patients from all indicators, whilst in 2007 older patients were excluded to a larger degree [adjusted odds ratio = 2.52 (1.21-5.28) ≥ 75 compared with 18-44 for blood pressure control]. CONCLUSIONS: Patients excluded from pay-for-performance programmes may be less likely to achieve treatment goals and disproportionately come from disadvantaged groups. Permitting physicians to exclude patients from pay-for-performance programmes may worsen health disparities