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Introduction With limited funds available, meeting global health targets requires countries to both mobilize and prioritize their health spending. Within this context, countries have recognized the importance of allocating funds for HIV as efficiently as possible to maximize impact. Over the past six years, the governments of 23 countries in Africa, Asia, Eastern Europe and Latin America have used the Optima HIV tool to estimate the optimal allocation of HIV resources. Methods Each study commenced with a request by the national government for technical assistance in conducting an HIV allocative efficiency study using Optima HIV. Each study team validated the required data, calibrated the Optima HIV epidemic model to produce HIV epidemic projections, agreed on cost functions for interventions, and used the model to calculate the optimal allocation of available funds to best address national strategic plan targets. From a review and analysis of these 23 country studies, we extract common themes around the optimal allocation of HIV funding in different epidemiological contexts. Results and discussion The optimal distribution of HIV resources depends on the amount of funding available and the characteristics of each country's epidemic, response and targets. Universally, the modelling results indicated that scaling up treatment coverage is an efficient use of resources. There is scope for efficiency gains by targeting the HIV response towards the populations and geographical regions where HIV incidence is highest. Across a range of countries, the model results indicate that a more efficient allocation of HIV resources could reduce cumulative new HIV infections by an average of 18% over the years to 2020 and 25% over the years to 2030, along with an approximately 25% reduction in deaths for both timelines. However, in most countries this would still not be sufficient to meet the targets of the national strategic plan, with modelling results indicating that budget increases of up to 185% would be required. Conclusions Greater epidemiological impact would be possible through better targeting of existing resources, but additional resources would still be required to meet targets. Allocative efficiency models have proven valuable in improving the HIV planning and budgeting process.

With limited funds available, meeting global health targets requires countries to both mobilize and prioritize their health spending. Within this context, countries have recognized the importance of allocating funds for HIV as efficiently as possible to maximize impact. Over the past six years, the governments of 23 countries in Africa, Asia, Eastern Europe and Latin America have used the Optima HIV tool to estimate the optimal allocation of HIV resources. Each study commenced with a request by the national government for technical assistance in conducting an HIV allocative efficiency study using Optima HIV. Each study team validated the required data, calibrated the Optima HIV epidemic model to produce HIV epidemic projections, agreed on cost functions for interventions, and used the model to calculate the optimal allocation of available funds to best address national strategic plan targets. From a review and analysis of these 23 country studies, we extract common themes around the optimal allocation of HIV funding in different epidemiological contexts. The optimal distribution of HIV resources depends on the amount of funding available and the characteristics of each country's epidemic, response and targets. Universally, the modelling results indicated that scaling up treatment coverage is an efficient use of resources. There is scope for efficiency gains by targeting the HIV response towards the populations and geographical regions where HIV incidence is highest. Across a range of countries, the model results indicate that a more efficient allocation of HIV resources could reduce cumulative new HIV infections by an average of 18% over the years to 2020 and 25% over the years to 2030, along with an approximately 25% reduction in deaths for both timelines. However, in most countries this would still not be sufficient to meet the targets of the national strategic plan, with modelling results indicating that budget increases of up to 185% would be required. Greater epidemiological impact would be possible through better targeting of existing resources, but additional resources would still be required to meet targets. Allocative efficiency models have proven valuable in improving the HIV planning and budgeting process.

There is considerable debate on the health impacts of soil-transmitted helminth infections. We assessed effects of deworming on physical fitness and strength of children in an area in Yunnan, People's Republic of China, where soil-transmitted helminthiasis is highly endemic. The double-blind, randomized, placebo-controlled trial was conducted between October 2011 and May 2012. Children, aged 9-12 years, were treated with either triple-dose albendazole or placebo, and monitored for 6 months post-treatment. The Kato-Katz and Baermann techniques were used for the diagnosis of soil-transmitted helminth infections. Physical fitness was assessed with a 20-m shuttle run test, where the maximum aerobic capacity within 1 min of exhaustive exercise (VO2 max estimate) and the number of 20-m laps completed were recorded. Physical strength was determined with grip strength and standing broad jump tests. Body height and weight, the sum of skinfolds, and hemoglobin levels were recorded as secondary outcomes. Children receiving triple-dose albendazole scored slightly higher in the primary and secondary outcomes than placebo recipients, but the difference lacked statistical significance. Trichuris trichiura-infected children had 1.6 ml kg(-1) min(-1) (P = 0.02) less increase in their VO2 max estimate and completed 4.6 (P = 0.04) fewer 20-m laps than at baseline compared to non-infected peers. Similar trends were detected in the VO2 max estimate and grip strength of children infected with hookworm and Ascaris lumbricoides, respectively. In addition, the increase in the VO2 max estimate from baseline was consistently higher in children with low-intensity T. trichiura and hookworm infections than in their peers with high-intensity infections of all soil-transmitted helminths (range: 1.9-2.1 ml kg(-1) min(-1); all P<0.05). We found no strong evidence for significant improvements in physical fitness and anthropometric indicators due to deworming over a 6-month follow-up period. However, the negative effect of T. trichiura infections on physical fitness warrants further investigation.

To report technical details and 15-month outcomes of a patient with node-positive external auditory canal (EAC) squamous cell carcinoma (SCC) treated with definitive intracavitary high-dose-rate (HDR) brachytherapy to primary tumor, and external beam radiotherapy (EBRT) to draining lymphatics. A 21-year-old male was diagnosed with SCC of the right EAC. The patient underwent definitive HDR intracavitary brachytherapy, 340 cGy/fraction for 14 twice-daily fractions, followed by EBRT using intensity-modulated radiation therapy (IMRT) to cover the grossly enlarged pre-auricular node, ipsilateral intra-parotid, and cervical lymph node levels II and III. The approved brachytherapy plan had an average high-risk clinical tumor volume (CTV-HR) D of 341 cGy with a total dose of 47.7 Gy (BED, 80.3 Gy, EQD , 66.6 Gy). For the approved IMRT plan, the prescription to the involved right pre-auricular node was 66 Gy in 33 fractions, and more than 95% of the target received at least 62.7 Gy. High-risk nodal regions were simultaneously prescribed: 59.4 Gy in 1.8 Gy fractions, and more than 95% received at least 56.4 Gy. Organs at risk (OARs) were kept below their dose constraints.The patient tolerated both the procedures with no grade ≥ 2 treatment-related adverse events. Grade 1 dermatitis in the right pre-auricular and cervical areas during the course of EBRT was experienced. Fifteen months post-RT, the patient has no evidence of disease, and was noted to have EAC stenosis, which translated to moderate conductive hearing loss of the right ear. Thyroid function was normal at 15 months after EBRT. This case report illustrates that the delivered definitive radiotherapy is technically feasible, effective, and well-tolerated in patients with SCC of EAC.

Many real world problems have requirements and constraints which conflict with each other. One approach for dealing with such over-constrained problems is with constraint hierarchies. In the constraint hierarchy framework, constraints are classified into ranks, and appropriate solutions are selected using a comparator which takes into account the constraints and their ranks. In this paper, we present a local search solution to solving hierarchical constraint problems over finite domains (HCPs). This is an extension of local search for over-constrained integer programs WSAT(OIP) to constraint hierarchies and general finite domain constraints.The motivation for this work arose from solving large airport gate allocation problems. We show how gate allocation problems can be formulated as HCPs using typical gate allocation constraints. Using the gate allocation benchmarks, we investigate how constraint heirarchy selection strategies and the problem formulation using two models: a 0–1 linear constraint hierarchy model and a nonlinear finite domain constraint hierarchy model.

Defective apoptosis mediated by BAK or BAX underlies various human pathologies including autoimmune and degenerative conditions. The mitochondrial channel protein VDAC2 interacts with BAK and BAX through a common interface to either inhibit BAK or to facilitate BAX apoptotic activity. Using a newly developed small molecule (WEHI-3773) that inhibits the interaction between VDAC2 and BAK or BAX, we reveal contrasting effects on BAX and BAK apoptotic activity. WEHI-3773 inhibits apoptosis mediated by BAX by blocking VDAC2-mediated BAX recruitment to mitochondria. Conversely, WEHI-3773 primes BAK for apoptosis by impairing its inhibitory sequestration by VDAC2 on the mitochondrial membrane. In cells expressing both BAX and BAK, repressing their association with VDAC2 promotes apoptosis, because once BAK is activated, it further activates BAX through a feed-forward mechanism. In some leukemias, mutation or loss of BAX is a key driver of resistance to the BH3-mimetic anti-cancer drug venetoclax. Strikingly, promoting BAK-mediated killing by small molecule dissociation of the VDAC2 interaction can overcome this resistance in different leukemia models. These data reveal a hitherto unappreciated level of coordination of BAX and BAK apoptotic activity through their interaction with VDAC2 that may be targeted therapeutically.