Designing a deprivation payment for general practitioners: the UPA(8) wonderland.

OBJECTIVE--To analyse critically the deprived area payment introduced in the new general practitioner contract. The payment formula is based on the Jarman underprivileged area index (UPA(8)) and aims at compensating general practitioners for increases in workload. DESIGN--Evaluation of the deprived area payment against the stated policy objective with a set of criteria for developing resource allocation formulas. MAIN OUTCOME MEASURES--The degree to which the components of the Jarman index predict the workload of general practitioners; whether construction of the index is sensible and comprehensible; and how the formula incorporates the index and is likely to work in practice. RESULTS--The fact that the index relies on census data and the way the weighting was derived means that the formula will not accurately reflect the workload. The use of statistical transformations obscures the original policy intent. There has been no validation to support the application of the index as part of a national policy. The payments are not linked to the quality of service provided and may have the perverse effect of increasing list size. CONCLUSION--The formula used as the basis of the deprived area payments is poorly suited to the policy objective of compensating general practitioners for increases in workload. More research is urgently needed to enable the effect of the payment to be monitored and a more empirically sound set of incentives to be developed.     

Correlates of HIV Acquisition in a Cohort of Black Men Who Have Sex with Men in the United States: HIV Prevention Trials Network (HPTN) 061

Background

Black men who have sex with men (MSM) in the United States (US) are affected by HIV at disproportionate rates compared to MSM of other race/ethnicities. Current HIV incidence estimates in this group are needed to appropriately target prevention efforts.

Methods

From July 2009 to October 2010, Black MSM reporting unprotected anal intercourse with a man in the past six months were enrolled and followed for one year in six US cities for a feasibility study of a multi-component intervention to reduce HIV infection. HIV incidence based on HIV seroconversion was calculated as number of events/100 person-years. Multivariate proportional hazards modeling with time-dependent covariates was used to identify correlates of HIV acquisition.

Results

Of 1,553 Black MSM enrolled, 1,164 were HIV-uninfected at baseline and included in follow-up. Overall annual HIV incidence was 3.0% (95% confidence interval (CI): 2.0, 4.4%) and 5.9% among men ≤30 years old (95% CI: 3.6, 9.1%). Men ≤30 years old reported significantly higher levels of sexual risk and were more likely to have a sexually transmitted infection diagnosed during follow-up. Younger men also were more likely to not have a usual place for health care, not have visited a health care provider recently, and to have unmet health care needs. In multivariate analysis, age ≤30 years (hazard ratio (HR): 3.4; 95% CI: 1.4, 8.3) and unprotected receptive anal intercourse with HIV-positive or unknown status partners (HR: 4.1; 95% CI: 1.9, 9.1) were significantly associated with HIV acquisition.

Conclusion

In the largest cohort of prospectively-followed Black MSM in the US, HIV incidence was high, particularly among young men. Targeted, tailored and culturally appropriate HIV prevention strategies incorporating behavioral, social and biomedical based interventions are urgently needed to lower these rates.     

Pulmonary Abnormalities in Animal Models Due to Niemann-Pick Type C1 (NPC1) or C2 (NPC2) Disease

Niemann-Pick C (NPC) disease is due to loss of NPC1 or NPC2 protein function that is required for unesterified cholesterol transport from the endosomal/lysosomal compartment. Though lung involvement is a recognized characteristic of Niemann-Pick type C disease, the pathological features are not well understood. We investigated components of the surfactant system in both NPC1 mutant mice and felines and in NPC2 mutant mice near the end of their expected life span. Histological analysis of the NPC mutant mice demonstrated thickened septae and foamy macrophages/leukocytes. At the level of electron microscopy, NPC1-mutant type II cells had uncharacteristically larger lamellar bodies (LB, mean area 2-fold larger), while NPC2-mutant cells had predominantly smaller lamellar bodies (mean area 50% of normal) than wild type. Bronchoalveolar lavage from NPC1 and NPC2 mutant mice had an approx. 4-fold and 2.5-fold enrichment in phospholipid, respectively, and an approx. 9-fold and 35-fold enrichment in cholesterol, consistent with alveolar lipidosis. Phospholipid and cholesterol also were elevated in type II cell LBs and lung tissue while phospholipid degradation was reduced. Enrichment of surfactant protein-A in the lung and surfactant of the mutant mice was found. Immunocytochemical results showed that cholesterol accumulated in the LBs of the type II cells isolated from the affected mice. Alveolar macrophages from the NPC1 and NPC2 mutant mice were enlarged compared to those from wild type mice and were enriched in phospholipid and cholesterol. Pulmonary features of NPC1 mutant felines reflected the disease described in NPC1 mutant mice. Thus, with the exception of lamellar body size, the lung phenotype seen in the NPC1 and NPC2 mutant mice were similar. The lack of NPC1 and NPC2 proteins resulted in a disruption of the type II cell surfactant system contributing to pulmonary abnormalities.     

Diagnosing and Mapping Pulmonary Emphysema on X-Ray Projection Images: Incremental Value of Grating-Based X-Ray Dark-Field Imaging

Purpose

To assess whether grating-based X-ray dark-field imaging can increase the sensitivity of X-ray projection images in the diagnosis of pulmonary emphysema and allow for a more accurate assessment of emphysema distribution.

Materials and Methods

Lungs from three mice with pulmonary emphysema and three healthy mice were imaged ex vivo using a laser-driven compact synchrotron X-ray source. Median signal intensities of transmission (T), dark-field (V) and a combined parameter (normalized scatter) were compared between emphysema and control group. To determine the diagnostic value of each parameter in differentiating between healthy and emphysematous lung tissue, a receiver-operating-characteristic (ROC) curve analysis was performed both on a per-pixel and a per-individual basis. Parametric maps of emphysema distribution were generated using transmission, dark-field and normalized scatter signal and correlated with histopathology.

Results

Transmission values relative to water were higher for emphysematous lungs than for control lungs (1.11 vs. 1.06, p<0.001). There was no difference in median dark-field signal intensities between both groups (0.66 vs. 0.66). Median normalized scatter was significantly lower in the emphysematous lungs compared to controls (4.9 vs. 10.8, p<0.001), and was the best parameter for differentiation of healthy vs. emphysematous lung tissue. In a per-pixel analysis, the area under the ROC curve (AUC) for the normalized scatter value was significantly higher than for transmission (0.86 vs. 0.78, p<0.001) and dark-field value (0.86 vs. 0.52, p<0.001) alone. Normalized scatter showed very high sensitivity for a wide range of specificity values (94% sensitivity at 75% specificity). Using the normalized scatter signal to display the regional distribution of emphysema provides color-coded parametric maps, which show the best correlation with histopathology.

Conclusion

In a murine model, the complementary information provided by X-ray transmission and dark-field images adds incremental diagnostic value in detecting pulmonary emphysema and visualizing its regional distribution as compared to conventional X-ray projections.     

Cellular Effects of Everolimus and Sirolimus on Podocytes

Everolimus (EVL) and Sirolimus (SRL) are potent immunosuppressant agents belonging to the group of mammalian target of rapamycin (mTOR) inhibitors used to prevent transplant rejection. However, some patients develop proteinuria following a switch from a calcineurin inhibitor regimen to mTOR inhibitors. Whether different mTOR inhibitors show similar effects on podocytes is still unknown. To analyze this, human podocytes were incubated with different doses of EVL and SRL. After incubation with EVL or SRL, podocytes revealed a reduced expression of total mTOR. Phosphorylation of p70S6K and Akt was diminished, whereas pAkt expression was more reduced in the SRL group. In both groups actin cytoskeletal reorganization was increased. Synaptopodin and podocin expression was reduced as well as nephrin protein, particularly in the SRL group. NFκB activation and IL-6 levels were lower in EVL and SRL, and even lower in SRL. Apoptosis was more increased in SRL than in the EVL group. Our data suggests that mTOR inhibitors affect podocyte integrity with respect to podocyte proteins, cytoskeleton, inflammation, and apoptosis. Our study is the first to analyze both mTOR inhibitors, EVL and SRL, in parallel in podocytes. Partially, the impact of EVL and SRL on podocytes differs. Nevertheless, it still remains unclear whether these differences are of relevance regarding to proteinuria in transplant patients.     

Stabilities and rates in the laccase/TEMPO-catalyzed oxidation of alcohols

The influence of alcohol, 4-acetylamino,2,2,6,6′-tetramethylpiperidinyloxy (4-acetylamino-TEMPO) and laccase (from Trametes versicolor, TvL) concentration in the aerobic oxidation of furfuryl alcohol was investigated. Studies show that the K_m for 4-acetylamino-TEMPO is around 6.3 mM (V_max=0.18 mM min^?1) using 6.6 U mL^?1 of laccase and a furfuryl alcohol concentration of 140 mM. Under these optimized conditions, the reaction rate is still dependent on the concentration of enzyme in solution. Laccase can be reused, with a residual activity of around 25%. An important conclusion is that laccase is not stable in the presence of oxoammonium salts, presumably due to degradation via oxidation of essential amino acid residues or the glycosyl moieties on the periphery of the enzyme.