Costs analysis of a population level rabies control programme in Tamil Nadu, India

The study aimed to determine costs to the state government of implementing different interventions for controlling rabies among the entire human and animal populations of Tamil Nadu. This built upon an earlier assessment of Tamil Nadu’s efforts to control rabies. Anti-rabies vaccines were made available at all health facilities. Costs were estimated for five different combinations of animal and human interventions using an activity-based costing approach from the provider perspective. Disease and population data were sourced from the state surveillance data, human census and livestock census. Program costs were extrapolated from official documents. All capital costs were depreciated to estimate annualized costs. All costs were inflated to 2012 Rupees. Sensitivity analysis was conducted across all major cost centres to assess their relative impact on program costs. It was found that the annual costs of providing Anti-rabies vaccine alone and in combination with Immunoglobulins was \$0.7 million (Rs 36 million) and \$2.2 million (Rs 119 million), respectively. For animal sector interventions, the annualised costs of rolling out surgical sterilisation-immunization, injectable immunization and oral immunizations were estimated to be \$ 44 million (Rs 2,350 million), \$23 million (Rs 1,230 million) and \$ 11 million (Rs 590 million), respectively. Dog bite incidence, health systems coverage and cost of rabies biologicals were found to be important drivers of costs for human interventions. For the animal sector interventions, the size of dog catching team, dog population and vaccine costs were found to be driving the costs. Rabies control in Tamil Nadu seems a costly proposition the way it is currently structured. Policy makers in Tamil Nadu and other similar settings should consider the long-term financial sustainability before embarking upon a state or nation-wide rabies control programme

Roles of tetrahydrobiopterin in promoting tumor angiogenesis.

Nitric oxide (NO), which is derived from endothelial NO synthase (eNOS), provides crucial signals for angiogenesis in the tumor microenvironment. Tetrahydrobiopterin (BH4) is an absolute requirement for eNOS activity. In this study, we investigated whether this activation is both maintained by a wild-type Ras/phosphatidylinositol 3-kinase (PI3K)/Akt-positive feedback loop in endothelial cells and affects tumor angiogenesis. We found that supplementation of BH4 (via the pterin salvage pathway with Sep) increased Akt/eNOS phosphorylation in both human eNOS-transfected COS-7 cells and endothelial cells concomitant with increases in NO production, cell proliferation, migration, and tube formation. This augmentation was abrogated by a PI3K inhibitor. Sepiapterin (Sep) also increased GTP-bound wild-type Ras and PI3K/Akt/eNOS activation, which was prevented by the eNOS inhibitor, Nω-Nitro-L-arginine methyl ester (L-NAME). Furthermore, expression of GTP cyclohydrolase I (the rate-limiting enzyme in de novo BH4 synthesis) under doxycycline control potentiated in vivo tumorigenesis, tumor cell proliferation, as well as angiogenesis. Conversely, both switching off GTP cyclohydrolase I expression as well as inhibiting its enzymatic activity significantly decreased eNOS expression and tumor vascularization. This study demonstrates an important role for BH4 synthesis in angiogenesis by the activation of eNOS for NO production, which is maintained by a PI3K/Akt-positive feedback loop through effects on wild-type Ras in endothelial cells. Our findings suggest that BH4 synthesis may be a rational target for antiangiogenesis therapy for tumors

Preliminary Evidence for the Cross-Cultural Utility of the Type D Personality Construct in the Ukraine

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Extreme genetic fragility of the HIV-1 capsid

Genetic robustness, or fragility, is defined as the ability, or lack thereof, of a biological entity to maintain function in the face of mutations. Viruses that replicate via RNA intermediates exhibit high mutation rates, and robustness should be particularly advantageous to them. The capsid (CA) domain of the HIV-1 Gag protein is under strong pressure to conserve functional roles in viral assembly, maturation, uncoating, and nuclear import. However, CA is also under strong immunological pressure to diversify. Therefore, it would be particularly advantageous for CA to evolve genetic robustness. To measure the genetic robustness of HIV-1 CA, we generated a library of single amino acid substitution mutants, encompassing almost half the residues in CA. Strikingly, we found HIV-1 CA to be the most genetically fragile protein that has been analyzed using such an approach, with 70% of mutations yielding replication-defective viruses. Although CA participates in several steps in HIV-1 replication, analysis of conditionally (temperature sensitive) and constitutively non-viable mutants revealed that the biological basis for its genetic fragility was primarily the need to coordinate the accurate and efficient assembly of mature virions. All mutations that exist in naturally occurring HIV-1 subtype B populations at a frequency >3%, and were also present in the mutant library, had fitness levels that were >40% of WT. However, a substantial fraction of mutations with high fitness did not occur in natural populations, suggesting another form of selection pressure limiting variation in vivo. Additionally, known protective CTL epitopes occurred preferentially in domains of the HIV-1 CA that were even more genetically fragile than HIV-1 CA as a whole. The extreme genetic fragility of HIV-1 CA may be one reason why cell-mediated immune responses to Gag correlate with better prognosis in HIV-1 infection, and suggests that CA is a good target for therapy and vaccination strategies

Cost-Effectiveness of a Chemoprophylactic Intervention with Single Dose Rifampicin in Contacts of New Leprosy Patients

In 2008, 249,007 new leprosy patients were detected in the world. It therefore remains necessary to develop new and effective interventions to interrupt the transmission of M. leprae. We assessed the economic benefits of single dose rifampicin (SDR) for contacts as chemoprophylactic intervention in the control of leprosy. The study is based on a large trial including 21,711 contacts of 1,037 patients with newly diagnosed leprosy. We gave a single dose of rifampicin or placebo to contacts and followed them up for four years. The main outcome measure was the development of clinical leprosy. The cost effectiveness was expressed in US dollars per prevented leprosy case. Chemoprophylaxis with SDR for preventing leprosy among contacts of leprosy patients is cost-effective at all contact levels and thereby a cost-effective prevention strategy. In total $6,009 was invested and 38 leprosy cases were prevented after 2 years, costing$158 per prevented leprosy case. Implementation studies are necessary to establish whether this intervention is acceptable and feasible in other leprosy endemic areas of the world

MRI follow-up of conservatively treated meniscal knee lesions in general practice

Objective: To evaluate meniscal status change on follow-up MRI after 1 year, prognostic factors and association with clinical outcome in patients with conservatively treated knee injury. Methods: We analysed 403 meniscal horns in 101 conservatively treated patients (59 male; mean age 40 years) in general practice who underwent initial knee MRI within 5 weeks of trauma. We performed ordinal logistic regression analysis to analyse prognostic factors for meniscal change on follow-up MRI after 1 year, and we assessed the association with clinical outcome. Results: On follow-up MRI 49 meniscal horns had deteriorated and 18 had improved. Age (odds ratio [OR] 1.3/decade), body weight (OR 1.2/10 kg), total anterior cruciate ligament (ACL) rupture on initial MRI (OR 2.4), location in the posterior horn of the medial meniscus (OR 3.0) and an initial meniscal lesion (OR 0.3) were statistically significant predictors of meniscal MRI appearance change after 1 year, which was not associated with clinical outcome. Conclusion: In conservatively treated patients, meniscal deterioration on follow-up MRI 1 year after trauma is predicted by higher age and body weight, initial total ACL rupture, and location in the medial posterior horn. Change in MRI appearance is not associated with clinical outcome

Decisions at the end of life: have we come of age?

Decision making is a complex process and it is particularly challenging to make decisions with, or for, patients who are near the end of their life. Some of those challenges will not be resolved - due to our human inability to foresee the future precisely and the human proclivity to change stated preferences when faced with reality. Other challenges of the decision-making process are manageable. This commentary offers a set of approaches which may lead to progress in this field

Cost-effectiveness of febrile neutropenia prevention with primary versus secondary G-CSF prophylaxis for adjuvant chemotherapy in breast cancer: a systematic review

The adoption of primary (PP) versus secondary prophylaxis (SP) of febrile neutropenia (FN), with granulocyte colony-stimulating factors (G-CSF), for adjuvant chemotherapy (AC) regimens in breast cancer (BC) could be affected by its “value for money”. This systematic review examined (i) cost-effectiveness of PP versus SP, (ii) FN threshold at which PP is cost-effective including the guidelines 20 % threshold and (iii) potential impact of G-CSF efficacy assumptions on outcomes. The systematic review identified all cost-effectiveness/cost-utility analyses (CEA/CUA) involving PP versus SP G-CSF for AC in BC that met predefined inclusion/exclusion criteria. Five relevant CEA/CUA were identified. These CEA/CUA examined different AC regimens (TAC = 2; FEC-D = 1; TC = 2) and G-CSF formulations (filgrastim “F” = 4; pegfilgrastim “P” = 4) with varying baseline FN—risk (range 22–32 %), mortality (range 1.4–6.0 %) and utility (range 0.33–0.47). The potential G-CSF benefit, including FN risk reduction with P versus F, varied among models. Overall, relative to SP, PP was not associated with good value for money, as per commonly utilized CE thresholds, at the baseline FN rates examined, including the consensus 20 % FN threshold, in most of these studies. The value for money associated with PP versus SP was primarily dependent on G-CSF benefit assumptions including reduced FN mortality and improved BC survival. PP G-CSF for FN prevention in BC patients undergoing AC may not be a cost-effective strategy at the guidelines 20 % FN threshold