Bacterial resistance to antibiotic treatment is a huge concern: introduction of any new antibiotic is shortly followed by the emergence of resistant bacterial isolates in the clinic. This issue is compounded by a severe lack of new antibiotics reaching the market. The significant rise in clinical resistance to antibiotics is especially problematic in nosocomial infections, where already vulnerable patients may fail to respond to treatment, causing even greater health concern. A recent focus has been on the development of anti-virulence drugs as a second line of defence in the treatment of antibiotic-resistant infections. This treatment, which weakens bacteria by reducing their virulence rather than killing them, should allow infections to be cleared through the body׳s natural defence mechanisms. In this way there should be little to no selective pressure exerted on the organism and, as such, a predominantly resistant population should be less likely to emerge. However, before the likelihood of resistance to these novel drugs emerging can be predicted, we must first establish whether such drugs can actually be effective. Many believe that anti-virulence drugs would not be powerful enough to clear existing infections, restricting their potential application to prophylaxis. We have developed a mathematical model that provides a theoretical framework to reveal the circumstances under which anti-virulence drugs may or may not be successful. We demonstrate that by harnessing and combining the advantages of antibiotics with those provided by anti-virulence drugs, given infection-specific parameters, it is possible to identify treatment strategies that would efficiently clear bacterial infections, while preventing the emergence of antibiotic-resistant subpopulations. Our findings strongly support the continuation of research into anti-virulence drugs and demonstrate that their applicability may reach beyond infection prevention. •Combined antibiotic & anti-virulence drugs can clear antibiotic-resistant infections.•Delay between delivery of drug types can render the treatment successful.•Fitness cost associated with antibiotic-resistance shapes the optimal treatment. Given that every patient, infection and strain of bacteria are different, it is impossible to obtain a conclusive set of parameters which will suit all situations. We therefore exploit parameter surveys to ascertain under what conditions certain behaviour will occur.We adopt a modelling approach to investigate the viability of anti-virulence drugs This work lays the foundations for more detailed models incorporating mechanisms of specific types of anti-virulence drugs. This will facilitate testing of the likelihood that microbial resistance to these novel drugs could emerge. We address this briefly in 22.1There are two main approaches usually taken when modelling the emergence of antibiotic-resistant bacteria: within-host models, or within-hospital compartmental models. Models of hospital resistance usually follow a similar form to the classic “Susceptible–Infectious–Resistant” (SIR) models of epidemiology, looking specifically at how nosocomial infections will spread throughout the hospital, for example Existing mathematical models that focus on the within-host emergence of antibiotic-resistance examine how treatment strategies can both cause and be adapted to prevent the emergence of antibiotic resistance, for example S), antibiotic-resistant bacteria (R) and immune cells e.g. phagocytes (P), and concentrations of antibiotic (A) and anti-virulence drug (A⁎). These interact as demonstrated in The system consists of five interacting components: populations of antibiotic-susceptible bacteria .The growth of bacteria within a host is likely to saturate over time as a result of space and nutrient limitations. We therefore use a logistic growth term with baseline growth rate c, lowering their growth rate  and natural clearance (at rate We assume that bacteria are consumed by phagocytes (immune cells) at rate  in Pmax . Phagocyrate δP) .A50i, for Antibiotic is either administered in one dose or assumed to be present at constant level (e.g. intravenous delivery) and rapidly absorbed to the site of infection . Eliminaor i=S,R . Note thxR<EmaxS .γ50, the anti-virulence drug concentration for half maximum effect. We assume that the anti-virulence drug has the same effect on both the antibiotic-resistant and susceptible bacteria.We assume that the anti-virulence drug increases the effectiveness of the host׳s immune response by weakening the bacteria׳s ability to counteract the host׳s immune mechanisms. The vast majority of bacterial virulence mechanisms interfere with the host immune response so this approach allows us to capture the action of a generic anti-virulence drug without needing to model specific mechanisms. Some anti-virulence compounds may directly inhibit the action of bacteria on immune cells . InterfePseudomonas aeruginosa infections, see Combining the above, we obtain the following model of bacterial population dynamics during antibiotic treatment:ode15s for time-dependent solutions and multi-parameter steady-state analyses. The software XPPAUT is employed for single parameter steady-state surveys  .Firstly we establish that our parameter set represents an infection where an initially small subpopulation of antibiotic-resistant bacteria emerges to become dominant when the infection is treated with antibiotics. In Antibiotics can either be administered in doses . The limits Partial resistance is governed by the two parameters Though the results so far are in no way surprising, they illustrate the power of adopting a modelling approach to predict the outcome of a particular infection: if the infecting strain can be isolated and the relevant parameters can be determined, it is possible to predict the number of bacteria remaining at an infection site and therefore identify an optimal treatment strategy.c increases, we see the bacteria unable to compete against this antibiotic pressure and once We recall that a fitness cost can be incurred as a consequence of the bacteria bearing the plasmid that confers antibiotic resistance. It has been shown that, depending on the plasmid in question, the fitness cost incurred can vary from 0.09 to 0.25  as a proρ, the rate at which a plasmid-bearing bacteria loses its plasmid and reverts to being antibiotic-susceptible , delayed combination therapy again works, this time with delays of 0.03 days if the anti-virulence drug is administered first and 0.5 days if vice versa , again underlining the need to fully understand the infection-type to design the treatment strategy correctly.So far, all our simulations have focused on an infection where the antibiotic-resistant population are initially in the minority. In 4in silico.Bacterial resistance to antibiotics is an increasing problem in today׳s society, more specifically in hospital settings where already vulnerable patients are exposed to strains of bacteria upon which conventional antibiotics have no effect. It has been widely suggested that in order to combat this emergence of resistance, research focus needs to shift from developing new antibiotics to novel treatment strategies that target bacterial virulence: an anti-virulence drug that promotes natural clearance through a weakening of their ability to counteract the immune response. This has given rise to much discussion of the potential success of such an approach with experimental investigations revealing, in general, attenuation but not clearance of infections. Would these drugs be better suited to infection prevention or can they be enhanced to treat existing infections? Since these drugs are still in the very early stages of development, we have developed a mathematical model to test their potential efficacy and treatment strategies Our model suggests that, if used in isolation, an anti-virulence drug may not be capable of clearing an infection as it relies too heavily on the host immune system which was not strong enough to clear the infection itself in the first place (hence the need for treatment). The immune-related parameters are highly host-specific, though, and if taken to be representative of a healthy individual then the anti-virulence drug could well deal with an infection, suggesting that the drug could be useful for prophylaxis. However, since antibiotic resistance is mainly a problem in hospital settings, where patients are more vulnerable and are likely to have a weaker immune response, this dependence on the immune system is likely to be a limitation of the proposed treatment. Nevertheless, regardless of not being able to completely clear the bacterial infection in such immunocompromised patients, we do find some promising results. The persisting bacterial load is not only at a much lower level than the model predicted after antibiotic treatment (remembering that the simulated infection consists of a mixed population of antibiotic-susceptible and -resistant bacteria), but importantly the antibiotic-resistant bacteria were eliminated (due to the fitness cost associated with resistance) leaving only antibiotic-susceptible bacteria at the infection site. These results led us to investigate the potential of combination therapy. Treatment by both anti-virulence drugs and antibiotics could fully clear an infection if the fitness cost associated with antibiotic-resistance was sufficiently high. If this cost was lower, combination therapy could still be successful through the imposition of a time delay between treatment types, but the success of this approach was sensitive to the choice of delay between the drug types. This ‘delay’ result is not intuitive and highlights the benefits of adopting a modelling approach.While underpinning the potential of anti-virulence drugs in a theoretical framework, this study also highlights the benefits of better understanding patient- and site-specific parameters pertinent to an infection in order to use a mathematical model to predict required treatment strategies. Though some  of the parameter surveys presented in this study are fairly intuitive, they illustrate the usefulness of mathematical models in this context. Treatment strategies are likely to be dependent on specific parameters within an infection, for example the level of resistance the infecting strain displays to a particular antibiotic, the likely bacterial load at an infection site or the time taken for treatment to reach the infection site. Thus, mathematical modelling will prove an extremely useful tool to provide tailored treatments that will optimise our use of drugs (unlike what has been seen with the over- and often mis-use of antibiotics).The model can be extended to represent a specific anti-virulence drug. For example, anti-adhesive drugs that prevent bacteria binding to host cells should increase the natural clearance rate and this can be accounted for in extensions to the model. Such efforts will greatly enhance the predictive powers of this type of model and contribute to the future design of effective treatment regimen for bacterial infections. Crucially, these extensions to the model will also facilitate predictions on the likelihood that bacteria develop resistance to anti-virulence drugs in general and on whether the specific target of the drug will impact upon this, as argued in 5Antibiotic resistance in bacteria has long been recognised as a problem for effective treatment of infections, yet it is only more recently that the urgent need for antibiotic alternatives has become widely accepted. We have presented here a model of a generalised treatment strategy for changing the target of the drug to promote natural clearance. Our results support the continuation of research into anti-virulence drugs both in the context of treating infections and in aiding with the elimination of the spread of antibiotic-resistant bacteria from an infection and through hospital settings.Throughout our analysis of these models we have highlighted some important issues that need to be considered when designing treatment strategies such as the importance of tailoring treatment to specific conditions of the host and how the success of combination therapy (use of more than one drug type) depends critically on the dosing schedule. Most importantly, however, we have shown conditions under which treatment strategies will be successful (some of which are non-intuitive) and hence provided a proof of concept for the potential such treatments should have to help eliminate the problem of antibiotic resistance.


To analyze if the distribution of specialized care services for HIV/AIDS is associated with AIDS rates. Ecological study, for which the distribution of 10 specialized care services in the Ceara state, Northeastern Brazil, was obtained, and the mean rates of the disease were estimated per mesoregion. We evaluated 7,896 individuals who had been diagnosed with AIDS, were aged 13 years or older, lived in Ceara, and had been informed of their condition between 2001 and 2011. Maps were constructed to verify the relationship between the distribution of AIDS cases and institutionalized support networks in the 2001-2006 and 2007-2011 periods. BoxMap and LisaMap were used for data analysis. The Voronoi diagram was applied for the distribution of the studied services.Noroeste Cearense and west of the Sertoes Cearenses had high AIDS rates, but a low number of specialized care services over time. Two of these services were implemented where clusters of the disease exist in the second period. The application of the Voronoi diagram showed that the specialized care services located outside the metropolitan area covered a large territory. We identified one polygon that had no services. Specialized care services concentrated in AIDS clusters in the metropolitan area. The Noroeste Cearense and north of Jaguaribe. The scenario of AIDS cases spread away from major urban areas demands the creation of social support services in areas other than the capital and the metropolitan area of the state; this can reduce access barriers to these institutions. It is necessary to create specialized care services for HIV/AIDS in the  Social support requirements involve, in addition to that given by family and friends, social relationships at institutionalized facilities. Social support networks can provide direct and indirect services, which are part of or complementary to the health service. These services can improve quality of life and disease management and help the adoption of new lifestyles – actions that may culminate in autonomy for the individual and his/her consequent empowerment.,,The specialized care services (SCS) for people living with HIV/AIDS seek to promote material and emotional support, as well as provide care to the patient and their families, which can take the form of clarifying rights, prevention policies, and health promotion.Health promotion policies involve intersectoral actions that are always directed towards improving the living conditions for the individual and the population. In the midst of the AIDS epidemic and using the SUS principles and guidelines as a basis, activities that focus on the population’s quality of life have emerged. Public policies geared towards these individuals were encouraged, ensuring the free distribution of antiretroviral therapy and looking to expand the SCS.In Brazil, the HIV/AIDS epidemic is characterized by the geographical diffusion of the disease towards small cities,Despite it not being an isolated factor, access to health services has been considered an important, impacting factor on the use of health-related services. Thus, the location of health facilities is a critical variable for providing quality health care. Identifying deficiencies in care coverage and disadvantaged groups is essential for managing health resources.Despite the advances in AIDS research, there are holes regarding the study of distributing specialized care services, which limits a true picture of these patients access to such institutions. The existence of accessible institutions that can meet the requirements that result from AIDS, along with the current dynamics of the disease, is a necessary challenge for modern society. The aim of this study was to analyze whether the distribution of the Specialized Care Services in HIV/AIDS is associated with AIDS rates.This ecological study used a geographical information system (GIS) as a tool. These types of systems make it possible to build a set of data and arrange them to process spatially referenced information using computational techniques, which enables the conditions of vulnerable populations to be evaluated in relation to one variable.Cadastro Nacional de Estabelecimentos de Saúde ,The address and first year of operation of 10 SCS specialized in AIDS and included in the institutional support network for the disease in Ceara, Northeastern Brazil, were taken from the Each city was an analysis unit. The variables studied were the mean AIDS rates by municipality and the geographic location of the SCS. We used the geographical coordinates of addresses of institutions, and the code from the Brazilian Institute of Geography and Statistics (IBGE) referring to the city of residence of people who reported having the disease within the studied period.2. In 2012, its population was estimated at approximately 8.6 million inhabitants, with a population density of 57.8 inhab./km2 .The evaluation included 7,896 individuals diagnosed with AIDS, aged 13 years or older, who lived in Ceara, and had been informed of their condition between 2001 and 2011, based on records from the The mean rate of AIDS per city was calculated for the 2001-2006 and 2007-2011 periods. In the first period, the mean number of cases and the mean population were respectively obtained through the total number of cases between 2001 and 2006 and through the total added population in those six years, and both totals were then divided by six. In the second period (a five-year period), the mean number of cases and the mean population were obtained by dividing the totals by five. The AIDS rate in each period represents the mean number of cases divided by the mean population, multiplied by 100,000 inhabitants.The global Moran’s index was also used, regarding the mean rate, to test for the existence of spatial autocorrelation. This index, whose calculation tests whether surrounding areas differ from what would be expected in a pattern of complete spatial randomness, gives values ranging from -1 to +1. Spatial aggregation is expressed for positive values, while inverse autocorrelation expresses negative values; spatial autocorrelation is absent when its value tends to zero.The presence of spatial aggregates was evaluated by the local Moran’s index  and can be seen on the LisaMap. This index makes it possible to identify spatial dependence and quantify the degree of spatial association at each location of the sample set. The values of significance are divided into four groups: non-significant, with a 95.0% significance, with a 99.0% significance, and with a 99.9% significance.The BoxMap was used to graphically visualize a Moran scatter plot, which divides the area into quadrants with specific characteristics. The areas located in quadrants Q1 (High-High) and Q2 (Low-Low) have positive spatial autocorrelation, meaning that these are cities with AIDS rates similar to their neighbors, characterizing spatial aggregates. Quadrants Q3 (High-Low) and Q4 (Low-High) have negative spatial autocorrelation, which represents cities that have disparate disease rates compared with nearby cities.To describe the areas under the influence of the SCS, a Voronoi diagram was built based on the points formed by the geographical coordinates of each institution’s address, distributed over the two study periods. This diagram makes it possible to define regions associated with each individual point on a map, rather than segmenting a geographical area into legally defined boundaries, whose polygons are divided in the space according to points, events, or both.® v.2.4.0 software was used.Maps were constructed for both periods, 2001 to 2006 and 2007 to 2011, along with the AIDS rates and the spatial distribution of the SCS. The state’s available health facilities were analyzed to find whether they were distributed near areas with high concentrations of AIDS cases. QuantumGisThis study is part of expanded research on the spatial distribution and social determinants of health in AIDS sufferers in the Brazilian state of Ceara, approved by the The Ethics Committee of the State Department of Health in Ceara .Noroeste Cearense, next to the border with the state of Piaui; and north of the Jaguaribe city  and in Sul Cearense. After the Lisa method was applied, significant growth was observed in cases of AIDS in the southwestern cities of the Sertões Cearenses (mesoregion in Ceara), which had previously not been affected by the disease. Between 2007 and 2011, there was a significant distribution of AIDS in as many cities as in the previous period, and still in the same regions .Almost the entire Ceara coastline showed high rates of AIDS  às pessoas vivendo com HIV/aids busca promover ações de apoio material e emocional, além de assistência à clientela e aos seus familiares, esclarecendo direitos, políticas de prevenção e promoção da saúde.A política de promoção da saúde envolve ações intersetoriais sempre direcionadas para melhoria das condições de vida do indivíduo e da população. Em meio à epidemia da aids e tendo como base os princípios e diretrizes do SUS, emergem ações que visam à qualidade de vida dessa população. Houve incentivo às políticas públicas voltadas para essa clientela, garantindo a distribuição gratuita da terapia antirretroviral e a expansão dos SAE.No País, a epidemia de HIV/aids vem caracterizando-se pela interiorização dos casos, ou seja, difusão geográfica da doença e em direção a municípios de pequeno porte,Apesar de não ser fator isolado, o acesso aos serviços de saúde tem sido considerado fator importante, gerando impacto no uso dos serviços de saúde relacionados. Assim, a localização das instalações de saúde é fundamental para prestação de assistência de qualidade. Identificar deficiências na cobertura e populações desfavorecidas é essencial para a gestão dos recursos de saúde.Apesar dos avanços nas pesquisas sobre aids, existem lacunas no estudo da distribuição dos serviços de assistência especializada, limitando uma visão real sobre a acessibilidade dessa clientela às instituições. A existência de instituições acessíveis que atendam às necessidades consequentes da aids de acordo com a dinâmica atual da doença é um desafio necessário para a sociedade moderna. Este estudo objetivou analisar se a distribuição dos serviços de assistência especializada em HIV/aids está associada às taxas de aids.Neste estudo ecológico, empregou-se como ferramenta um Sistema de Informação Geográfica (SIG). Essa classe de sistemas permite constituir um conjunto de dados e organizá-los no tratamento de informações, espacialmente referenciadas, por meio de técnicas computacionais, possibilitando a avaliação das condições de populações vulneráveis em relação a uma variável.Os endereços e os anos de início de atendimento de 10 SAE vinculados à aids e que fazem parte da rede de apoio institucional da doença, no estado, foram extraídos do Cadastro Nacional de Estabelecimentos de Saúde (CNES),A unidade de análise foi o município. As variáveis estudadas foram as taxas médias de aids por município e a localização geográfica dos SAE. Utilizaram-se as coordenadas geográficas dos endereços das instituições e o código do Instituto Brasileiro de Geografia e Estatística (IBGE) referente ao município de residência das pessoas notificadas com a doença no período estudado.2. Sua população é estimada em aproximadamente 8,6 milhões de habitantes, em 2012, com densidade populacional de 57,8 hab./km2 .A taxa média da aids por município foi calculada para os períodos de 2001 a 2006 e de 2007 a 2011. No primeiro período, o número médio de casos e a população média foram obtidos pela soma do número de casos ocorridos entre 2001 e 2006 e pela soma da população estimada de cada ano, ambos divididos por seis. No segundo período, a média dos casos e a média da população foram divididas por cinco. A taxa em cada período representa o número de casos médios dividido pela população média, multiplicado por 100.000 habitantes.Realizou-se também a medida do índice de Moran global sobre a taxa média para testar a existência de autocorrelação espacial. Esse índice, cujo cálculo permite testar se áreas vizinhas diferem do que seria esperado em um padrão de completa aleatoriedade espacial, assume valores que variam de -1 a +1. A agregação espacial é expressa por valores positivos, enquanto os negativos expressam autocorrelação inversa, verificando-se ausência de autocorrelação espacial quando seu valor tende a zero.Local Indicators of Spatial Association – LISA) e apresentados no LisaMap. Esse índice possibilita identificar a dependência espacial e quantificar o grau de associação espacial em cada localidade do conjunto amostral. Os valores de significância são divididos em quatro grupos: não significantes, com significância de 95,0%, com significância de 99,0% e com significância de 99,9%.A presença de agregados espaciais foi avaliada pelo índice I de Moran local  e Q2 (Baixo-Baixo) possuem autocorrelação espacial positiva, significando cidades com valores das taxas de aids semelhantes às suas vizinhas, caracterizando agregados espaciais. Os quadrantes Q3 (Alto-Baixo) e Q4 (Baixo-Alto) constituem autocorrelação espacial negativa, com cidades apresentando taxas da doença discrepantes entre as localidades próximas.Para descrever as áreas de influência dos SAE, construiu-se o Diagrama de Voronoi a partir dos pontos formados pelas coordenadas geográficas do endereço de cada instituição distribuídos nos dois períodos do estudo. Este diagrama permite definir regiões associadas a cada ponto individual em um mapa, em vez de segmentar uma área geográfica em limites legalmente definidos, cujos polígonos são divididos no espaço de acordo com pontos, eventos, ou ambos.® v.2.4.0.Foram construídos mapas para os períodos de 2001 a 2006 e 2007 a 2011 com as taxas de aids e a distribuição espacial dos SAE. Foi identificado se as ações de saúde disponíveis no estado se distribuem próximas de áreas com altas densidades de casos de aids. Utilizou-se o programa QuantumGisEste estudo é parte da investigação ampliada sobre a distribuição espacial e determinantes sociais de saúde na população com aids no Ceará, aprovada pelo Comitê de Ética da Secretaria de Saúde do Estado do Ceará (Protocolo 203.911).A distribuição da aids nos dois períodos estudados apresentou aglomerações dos casos nas seguintes regiões: capital cearense e no seu entorno; Noroeste Cearense, próximo à região fronteira com Piauí; e norte do Jaguaribe (Quase todo o litoral do estado apresentou altas taxas de aids (cluster de aids estatisticamente significante. Entretanto, aglomerados da doença em outras localidades, como o oeste dos Sertões Cearenses e o sul do Jaguaribe, não possuíam SAE próximos. No segundo período, observou-se acréscimo de dois SAE: um deles instalado em Fortaleza e outro no norte do Jaguaribe, localidade com elevadas taxas da doença. Entretanto, existia apenas um SAE em região com significativa aglomeração de casos no Noroeste Cearense e não foi instalado outro serviço.Confrontando a distribuição dos SAE com a distribuição da aids no estado , observaAplicando o diagrama de Voronoi na distribuição dos SAE , observoApesar da concentração da aids na Região Metropolitana, o estado do Ceará apresenta aglomerações da doença em outras regiões, como o norte do Jaguaribe, Noroeste Cearense e oeste dos Sertões Cearenses, presentes ao longo dos dois períodos do estudo. No contexto da interiorização da epidemia, o acesso aos serviços de saúde tem implicância sobre a qualidade de vida das pessoas vivendo com HIV/aids.clusters de aids na Região Metropolitana, o que pode influenciar na acessibilidade dos pacientes a esses serviços. Existe o consenso de que a concentração de atendimento em unidades de referência pode dificultar a acessibilidade geográfica do paciente, pois há mais dispêndio com transporte, licença no trabalho, entre outros fatores. Entretanto, pessoas que apresentam doenças estigmatizantes, como no caso do HIV/aids, preferem que seus domicílios não sejam tão próximos às unidades de assistência, na perspectiva da manutenção do anonimato e do não reconhecimento por outros indivíduos que frequentam o serviço.Verificou-se também a predominância dos SAE e dos A pesquisa indica desproporção da quantidade de SAE no noroeste e no oeste dos Sertões Cearenses em relação às taxas de aids, os quais possuem elevados valores. Entretanto, um SAE foi criado no Jaguaribe no segundo período, acompanhando a demanda da localidade em relação à assistência às pessoas vivendo com HIV/aids.A distribuição espacial da localização de unidades de saúde interfere diretamente na acessibilidade geográfica que, no caso de grandes distâncias aliada a tempo de marcha e ausência de transporte, compromete o tratamento de pessoas que necessitam de assistência especializada.Ainda, a decisão, pelos gestores, de implantar um serviço de saúde deve surgir a partir das demandas. Essas podem ser monitoradas por diversos sistemas de informação em saúde e junto a pesquisadores, instituições acadêmicas e usuários do Sistema Único de Saúde,A região centro-sul cearense não apresentou nenhum SAE. A distância dos municípios menores para os grandes centros urbanos, que concentram os SAE, dificultam o acesso aos recursos disponibilizados por esses serviços. Isso torna as pessoas mais vulneráveis às consequências da doença, o que constitui um desafio para os avanços contra essa epidemia.O estudo limita-se pela ausência de pesquisas semelhantes, dificultando o confrontamento dos dados obtidos com a situação em outras localidades. Não foram possíveis informações sobre o número mínimo de SAE preconizados por população ou pessoas vivendo com HIV/aids, dificultando análise de maior amplitude sobre a disponibilidade do serviço no estado.Sugere-se a necessidade de estudos com abordagem qualitativa na compreensão da dinâmica social e comportamental da relação indivíduo/SAE, o que poderia ampliar o entendimento dessas distâncias ou proximidades com os serviços de apoio.A informação sobre a epidemia da aids ainda necessita de avanços para viabilizar o geoprocessamento e a análise espacial. Além disso, é necessário que haja retorno das informações geradas por meio das pesquisas às instituições de saúde e políticas para a mudança da realidade apreendida pelos estudos.O estudo mostrou que o interior do estado possui tanto localizações com altas taxas de aids e baixa quantidade de SAE, quanto o inverso, apontando regiões que podem ser favorecidas com a implantação de novos serviços, como algumas localidades que foram beneficiadas no segundo período do estudo. A atenção básica pode contribuir na assistência a essa clientela, visto que possibilita maior acessibilidade, reservando as instituições secundárias e terciárias para situações mais complexas.O recurso metodológico pode ser ampliado, na perspectiva de que os SAE interferem no processo saúde-doença de pessoas vivendo com HIV/aids, pois auxiliam nas atividades de assistência, prevenção e tratamento desses pacientes.


This is the first case report of focal seizure as a manifestation of Immunoglobulin G4 (IgG4)-related hypophysitis. IgG4-related hypophysitis is a novel category of hypophysitis. The clinical presentations, imaging studies and initial pathology studies can mimic lymphocytic hypophysitis. Here we report additional clinical clues in differentiating these two conditions.A 43-year-old Thai male presented with focal seizure, headache, and anterior pituitary hypofunction. His MRI study showed typical hypophysitis lesion with abnormal cerebral parenchymal signal intensity at right frontal lobe. The pituitary biopsied was obtained and the patient was initially diagnosed with lymphocytic hypophysitis. Following initial low-dose steroid therapy, his seizure and headache resolved but his anterior pituitary hormones remained deficient. However, during steroid tapering, he developed new onset acute visual loss. Upon rigorous pathologic review, his diagnosis of IgG4-related hypophysitis with suspected CNS involvement was established. He was subsequently treated with high-dose steroid and rapidly regained his sight.This case report highlights the important distinguishing features of IgG4-related hypophysitis from lymphocytic hypophysitis. These include the relapsing clinical course of hypophysitis after steroid decrement and concomitant pachymeningitis particularly in middle-aged to elderly Asian male who presented with hypophysitis. With appropriate dosage of steroids, medical treatment is usually sufficient to control the disease and surgical interventions are usually not required. Immunoglobulin G4 (IgG4)-related disease is a fibroinflammatory disease characterized by fibrous tissue and lymphoplasmocytic infiltration . IgG4-reIn September 2013, a 43-year-old Thai man was admitted to the hospital with three consecutive episodes of rhythmic jerky movement of left face and arm, as well as speech arrest. These symptoms spontaneously resolved prior to hospital arrival. He also had a two-year history of malaise, loss of appetite, cold intolerance, 10-kg weight loss, headache, and loss of libido. Upon initial physical examination, there was no residual neurological deficit. His visual acuity and visual fields were normal in both eyes. A brain MRI revealed T1W hypointense and T2W hyperintense lesion at right frontal lobe with gyral enhancement Fig. , b. TherSince the diagnosis was subacute cerebral infarction, the pituitary biopsy was postponed until six weeks follow-up. We sent separated pituitary tissue for pathologic examination, one for a local pathologist and other to an external pathology laboratory. The tissue that was sent to the local pathologist revealed segments of pituitary tissue, partly infiltrated by lymphocytes plasma cells and fibrous Fig. , b. No oThree months later, he developed new onset frontal headache and acute visual loss. Ocular examination demonstrated bitemporal hemianopsia. Pituitary MRI revealed slightly decrease in size and less bulbous appearance of the sellar-suprasellar mass but the lesion still abutted to the optic chiasm with mild compression and mild upward displacement of the optic chiasm. The study also showed more hyperintense T2W change and mild heterogeneous enhancement at the optic chiasm, suggesting an increase in swelling of the optic chiasm Fig. , d. His We report a case of biopsy-proven IgG4-related hypophysitis which clinically mimicked a recurrent lymphocytic hypophysitis. Our patient presented with focal seizure and multiple anterior pituitary hormone deficiency. He had typical imaging changes for hypophysitis with vividly enhanced sellar-suprasellar mass and stalk enlargement. The pituitary histopathology showed infiltration of lymphocytes, plasma cells and fibrosis, reflecting chronic inflammatory lesions. From the combination of clinical manifestation, imaging, and initial histopathology; the first impression was lymphocytic hypophysitis. The diagnosis of IgG-4 related hypophysitis was obtained one year later after pathological review.IgG4-related hypophysitis is a new entity of primary hypophysitis. Like other organ involvements in IgG4-related disease, histopathology is the cornerstone for diagnosis. It is characterized by the infiltration of IgG4-containing plasma cells, lymphocytes, and storiform fibrosis. In 2011, Leporati et al. proposed three criteria for diagnosis of IgG4-related hypophysitis [To diagnose IgG4-related hypophysitis without evidence of other organ involvement is challenging. Routine H&E staining in histopathology is not sufficient to differentiate IgG4-related hypophysitis from other causes of chronic hypophysitis. The immunohistochemistry stain for IgG4 in the pituitary tissue biopsy is a useful tool to help establish a diagnosis. However, certain limitations exist in this technique. Firstly sampling error from inadequate specimens can result in a negative report. Secondly, clusters of IgG4-positive cells can also be found in other causes of hypophysitis . Lastly,Patient backgrounds and clinical courses can serve as useful tools in differentiating isolated-IgG4 related hypophysitis from Lymphocytic hypophysitis. Lymphocytic hypophysitis is typically found in female whereas IgG4-related hypophysitis is more common in elderly male with Asian ethnicity . The recThis patient presented with frontal lobe seizure semiology that did not recur after steroid initiation. Frontal lobe lesion in MRI also completely regressed after low dose steroid administration. This clinical picture is unusual for cerebral infarctions, therefore statin and aspirin are futile for secondary prevention of stroke. Although, no parenchymal tissue was obtained, IgG4-related disease involvement was highly suspected. Biopsy-proven central nervous system involvement in IgG4-related disease was also reported , 36. UnlDespite an absence of posterior bright spot in MRI, the patient had no sign and symptom of diabetes insipidus. The absence of posterior bright spot in MRI was reported in about 0 to 25 % of normal subjects , 38. HowThis is the first case report in patient with IgG4-related hypophysitis who initially presented with focal seizures and relapsing lymphocytic hypophysitis. Due to its rarity and the overlapping clinical picture, it is often difficult to differentiate IgG4-related hypophysitis from lymphocytic hypophysitis with initial clinical manifestations, imaging studies, and routine histopathology. This case report highlights the distinctive clinical course between the two diseases. A close clinical follow-up is, therefore, essential in patients with lymphocytic hypophysitis. A diagnosis of IgG4-related hypophysitis should be considered in patients with worsening clinical course during the steroids decrement or patients with concomitant pachymeningitis. These patients should undergo further evaluation including clinical assessment for other organ involvement, measuring serum IgG4 level and additional tissue immunostaining. Timely treatment with high dose steroid is advised to prevent permanent disability and unnecessary invasive surgical interventions.Written informed consent was obtained from the patient for publication of this Case report and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.


Idiopathic pulmonary fibrosis (IPF) is a chronic disease with a poor prognosis and is characterized by the accumulation of fibrotic tissue in lungs resulting from a dysfunction in the healing process. In humans, the pathological process is patchy and temporally heterogeneous and the exact mechanisms remain poorly understood. Different animal models were thus developed. Among these, intratracheal administration of bleomycin (BML) is one of the most frequently used methods to induce lung fibrosis in rodents. In the present study, we first characterized histologically the time-course of lung alteration in rats submitted to BLM instillation. Heterogeneous damages were observed among lungs, consisting in an inflammatory phase at early time-points. It was followed by a transition to a fibrotic state characterized by an increased myofibroblast number and collagen accumulation. We then compared instillation and aerosolization routes of BLM administration. The fibrotic process was studied in each pulmonary lobe using a modified Ashcroft scale. The two quantification methods were confronted and the interobserver variability evaluated. Both methods induced fibrosis development as demonstrated by a similar progression of the highest modified Ashcroft score. However, we highlighted that aerosolization allows a more homogeneous distribution of lesions among lungs, with a persistence of higher grade damages upon time. Idiopathic pulmonary fibrosis (IPF) is a severe form of fibrosing interstitial lung disease with unknown etiology and characterized by a progressive loss of lung function associated with dyspnea and cough. This heterogeneous pathology carries an invariable poor prognosis , with a  In vitro [ in vivo [IPF pathogenesis remains poorly understood but increased evidence suggests the involvement of complex interactions between genetic predisposition, epigenetics, environment, and comorbidities . HistoloIn vitro  and in v in vivo , 9 studi in vivo  but the  in vivo .β activation [Different animal models have been developed to study the mechanisms involved in lung fibrogenesis and to evaluate potential therapies . Among these, bleomycin (BLM) administration is a widely used model and the best characterized in a variety of animals and through different routes of delivery . BLM indtivation –15. Couptivation . Contrartivation , reportetivation . Repetittivation . Howevertivation . In additivation .IT instillation, which is the most commonly used route for BLM administration in rodent, has the advantage of its low cost and its ability to deliver a well-defined dose to the lungs. Aerosol inhalation, in contrast, could result in a deposition in the upper respiratory tract. But, the most consistent disparity between these two methods relates to the BLM intrapulmonary distribution. While aerosol inhalation allows a relatively homogeneous distribution of particles throughout the lungs, IT instillation can result in focally high doses of material or, at opposite, to nontreated lung area , 21. Impn = 22; BLM diluted in 200 μL saline buffer) or by aerosolization . Sham (n = 17) received the vehicle only  and controls (n = 3) had no intervention. Instillation was realized by transtracheal injection using a 30 G needle at a flow of 40 μL/second. Concerning intratracheal aerosolization, the oropharynx was first anesthetized using a local administration of lidocaine. A microsprayer  connected to a High Pressure Syringue  was then inserted transorally into the tracheal lumen. The BLM solution was then aerosolized according manufacturer's instructions, at a rate of about 15 μL/second . This procedure was realized under fiberoptic laryngoscope to visualize epiglottis and ensure a good positioning of the microsprayer. Immediately after surgery, to minimize the risk of infection, rats received an intramuscular injection of antibiotic . At the end of the procedure, BLM and sham animals were sacrificed by exsanguination after Sodium Pentobarbital anesthesia  at days 3, 7, 14, 21, or 56 after BLM/saline administration.All procedures met the standards of the national Belgian requirements regarding animal care and were carried out in accordance with the Animal Ethics and Welfare Committee of the University of Mons. All experiments were performed on 8-week-old male Wistar rats (about 250 g body weight) bred in our animal facility (accreditation number LA1500022). Rats were housed in cages at a room temperature (RT) of 22°C, with an ad libitum access to water and food. All efforts were made to minimize stress and animals were sedated before surgical procedure with an intraperitoneal injection of ketamine  and xylazine . For the present study, 47 Wistar rats received 2 IU/kg b.w. of BLM (Sanofi Aventia) intratracheally either by instillation  using a light microscope.Immediately after exsanguination, a bronchoalveolar lavage  was performed for further biochemical investigations. Lungs were then fixed by a transtracheal injection of a solution of Duboscq-Brasil fixator (10 mL). After ligature of the trachea and the opening of the ribcage, lungs were removed, incubated 48 hours in the Duboscq-Brasil fixator, and dehydrated. Lobes were then identified and embedded separately in paraffin. Sequential 5-α-SMA  (2) incubation with a biotinylated goat anti-rabbit IgG antibody  for 30 min, and (3) incubation with ABC complexes  for 30 minutes. Washing steps were performed in PBS. Bound peroxidase activity was visualized by incubation with DAB  0.05% in PBS-0.02% H2O2. The sections were counterstained with Hemalun and Luxol fast blue and were finally mounted in a permanent medium. Controls for the specificity of immunolabeling included the omission of the primary antibody. Stained cells were numbered on ten fields of 0.0625 mm2 (excluding bronchovascular axis), by random sampling and using a single blind method.Myofibroblast staining was performed on deparaffinized and rehydrated lung sections by immunohistochemistry. Sections were immunostained using the streptavidin-biotin immunoperoxidase method (ABC method) as described in . BrieflyDetermination of Collagen Surface. The sections were observed on a Leitz Orthoplan microscope (10x magnification) equipped with a Ploem system for epi-illumination. Pictures were obtained by a PC-driven digital camera . For each of the lung regions, 3 fields of 0.3816 mm2 were visualized. The computer software  allowed the morphometric analysis of images. Percentage of surface occupied by collagen was determined by calculating the ratio between blue and nonblue pixels after exclusion of alveolar airspace.Modified Ashcroft Scale. Fibrosis was quantified using a modified Ashcroft scale (grade 0 to 8) designed for a standardized fibrosis evaluation in small animals [ animals . Stages P < 0.05. Interobserver agreement was evaluated with the kappa index.Results are presented as mean ± SEM. Data concerning change in body weight, total cells, collagen surface, and myofibroblasts in the BLM instillation model were submitted to an analysis of variance (ANOVA) and a post hoc Duncan's test . Fibrosis evolution over time (modified Ashcroft score) in both BLM models was compared using an ANOVA on ranks followed by a Kruskal Wallis test. The level of fibrotic damages after BLM instillation and aerosolization in late time-points was compared by the same method. Distribution in both lungs was compared by computing absolute differences between left and right scores. Levels of significance were taken as http://dx.doi.org/10.1155/2015/198418 . Despite a slight decrease of body weight after BLM administration, no statistical difference between sham and BLM animals can be reported concerning those parameters. Macroscopic observation of lungs from BLM rats revealed the presence of atelectatic violaceous bands and white area of various sizes which alternated with apparently healthy lung tissue. Microscopic visualization confirmed the heterogeneity of histological lesions. Some lobes were totally devoid of damages and others exhibited inflammatory infiltrates centered on bronchovascular axes at day 3 and day 7. Inflammation decreased at day 14 giving rise to fibrotic lesions . Because these cells appeared to exhibit different morphological characteristics upon time, the presence of myofibroblasts was assessed by α-SMA immunostaining . Microphotographs of the most representative pulmonary lesions at each time-point are illustrated in To improve distribution of fibrotic damages in the BLM model, we compare IT instillation to IT aerosolization of this drug. As a preliminary test, macroscopic analysis after Lissamine Green IT aerosolization has shown a homogeneous distribution of the dye among lungs. Histological alterations were then assessed after 3, 7, 14, 21, and 56 days after either BLM IT instillation or aerosolization. Data about animal body weight, water consumption, and urine volume in aerosolized animals are presented in Supplementary Material . As presented in When randomly chosen fields were considered , whereas the kappa index disclosed only to a slight agreement for the instillation group whatever the field selection. The difference of fibrotic-lesion distribution between lungs (absolute difference between modified Ashcroft score in left and right lungs) is represented at The increased loss of body weight induced by the aerosol method  suggestsBoth intratracheal instillation and aerosolization of BLM induce the development of fibrosis following an initial inflammatory phase. However, the fibrotic process is more localized after BLM instillation and is restricted to overwhelmed area, which is a major drawback for the tissue sampling. In the present study, we demonstrate that the IT aerosolization route allows a more homogeneous distribution of fibrosis and is associated with more severe lesions upon time. As compared to intranasal delivery, the IT spraying allows the delivery of a precise dose, avoiding drug loss in upper respiratory tracts.Finally, it is necessary to consider whether BLM rodent models could be directly applicable to human IPF. In terms of histological alterations, both conditions result in the development of fibroblastic foci. In IPF, their location is heterogeneous and mostly basal and subpleural. In contrast, lesions are initially bronchocentric in several BLM IT models, although our conditions led to more peripheral damages. Moreover, BLM rodent models and IPF do not share a similar pattern of development and progression, and functional assessment has to be further realized to better understand similarities and differences between the two pathological states (reviewed in ).In conclusion, despite the fact that BLM delivery in rodent does not perfectly reproduce IPF, it still constitutes a well-characterized model of pulmonary fibrosis which is still widely used today. IT aerosolization is a good alternative to the instillation method, allowing a homogeneous fibrosis thus limiting sample-dependent variability for subsequent biochemical analysis or testing of new therapeutic options.Supporting Material represents time course of body weight, daily consumption of water and urinary volumes, measured using metabolic cages for sham and BLM animals. Figure S1 is related to the BLM instillation group and figure S2 concerns the BLM aerosolization group.


Background: We conducted a case study of the Zimbabwe National AIDS Trust Fund (‘AIDS Levy’) as an approach to domestic government financing of the response to HIV and AIDS.Methods: Data came from three sources: a literature review, including a search for grey literature, review of government documents from the Zimbabwe National AIDS Council (NAC), and key informant interviews with representatives of the Zimbabwean government, civil society and international organizations.Findings: The literature search yielded 139 sources, and 20 key informants were interviewed. Established by legislation in 1999, the AIDS Levy entails a 3% income tax for individuals and 3% tax on profits of employers and trusts (which excluded the mining industry until 2015). It is managed by the parastatal NAC through a decentralized structure of AIDS Action Committees. Revenues increased from inception to 2006 through 2008, a period of economic instability and hyperinflation. Following dollarization in 2009, annual revenues continued to increase, reaching US$38.6 million in 2014. By policy, at least 50% of funds are used for purchase of antiretroviral medications. Other spending includes administration and capital costs, HIV prevention, and monitoring and evaluation. Several financial controls and auditing systems are in place. Key informants perceived the AIDS Levy as a ‘homegrown’ solution that provided country ownership and reduced dependence on donor funding, but called for further increased transparency, accountability, and reduced administrative costs, as well as recommended changes to increase revenue.Conclusions: The Zimbabwe AIDS Levy has generated substantial resources, recently over US$35 million per year, and signals an important commitment by Zimbabweans, which may have helped attract other donor resources. Many key informants considered the Zimbabwe AIDS Levy to be a best practice for other countries to follow. Financing the response to HIV infection and AIDS is particularly challenging in resource-poor countries that have a high burden of disease  the legislative history, (2) the roles of government agencies and external partners, (3) historical budget figures, (4) how and what the AIDS Levy finances, (5) financial controls, and (6) perceived strengths, weaknesses and potential areas for improvement. Findings are intended to strengthen the Zimbabwe AIDS Levy and also have wider application outside of Zimbabwe where other countries can consider adopting similar polices to finance their response to HIV and AIDS.et al. The paper is a qualitative case study of a public policy and health financing mechanism  and universities. Second, a review was conducted of government documents provided by NAC collaborators. The types of documents reviewed included national policies and guidelines, financial documents, budgets, audit reports, monitoring and evaluation documents, and documents on programmatic planning.Lastly, key informant interviews were conducted with three groups of stakeholders: representatives of Zimbabwean government, representatives of Zimbabwean civil society and representatives of international organizations. Key informants were selected purposively for their specialized knowledge or perspective on the AIDS Levy and represented a spectrum of viewpoints. Subsequent key informants were interviewed based on recommendations of initial key informants during their interviews. Key informant interviews took place from November 2012 to January 2013 in Zimbabwe.Each interview participant was asked the same set of open-ended questions. Interviews were conducted in-person or by telephone, when an in-person interview was not feasible. The interviews were documented by note taking. Each interview broadly covered the following topics: the respondent's professional background and how it relates to the AIDS Levy; their knowledge of the AIDS Levy; their opinion on the strengths and weaknesses of the AIDS Levy; their recommendations to improve the AIDS Levy and whether they believed the AIDS Levy could serve as a model for other countries to adopt. Responses to the interviews were summarized with the participant responses to each question, anecdotes and interviewer's impressions, organized by question. Descriptive coding was the primary method of analysis of the key informant interviews. After four interviews, initial descriptive codes were developed on key themes, concepts, questions, and ideas. These were refined based on results of subsequent interviews and responses were synthesized to describe the role of different agencies in the AIDS Levy and perceived strengths and weaknesses of the AIDS Levy.The study protocol was approved by the Office of Associate Director for Science of CDC Center for Global Health. Key informants provided verbal informed consent and were assured that neither their decision to participate or not, nor their responses would affect their employment status. Key informant responses are presented anonymously. Respondents did not receive any compensation for their participation.The literature search yielded 139 articles, chapters and reports that mentioned the Zimbabwe AIDS Levy and 39 that mentioned the Zimbabwe NAC. Gray literature included reports on the AIDS Levy done by organizations including NAC, SADC and universities. Relevant and informative publications and reports were used for this case study report Baird . InterviThe idea of the AIDS Levy was developed in the early 1990s, but did not become law until 1999. A convergence of several political factors allowed for the successful enactment of the AIDS Levy. The enactment of the AIDS Levy reflected political will, engagement of stakeholders and collaboration between the Office of the President, Parliament, the Ministry of Finance, the Ministry of Health and Child Welfare , and labor groups. Much of the political will and support for the AIDS Levy was garnered as it was viewed as a homegrown solution that could attract additional donor support. The AIDS Levy was modeled after a similar tax called the Drought Levy which had been enacted to support food imports during the 1992 drought, which allowed the public to already have familiarity with the mechanisms of such a levy.Two key pieces of legislation established the policy framework of the AIDS Levy. In 1999, Parliament enacted Section 14, Subsection 14 and 15 of the Finance Act, Chapter 23:04, which established the National AIDS Trust Fund as a 3% income tax for individuals and 3% tax on profits of employers and trusts. The mining industry, though not its employees, was initially exempted from contributing to the AIDS Levy. Second, Parliament enacted the NAC of Zimbabwe Act in 2000, which established the responsibilities of the NAC, including the administration of the AIDS Levy. By law, NAC was established as a non-profit, parastatal organization. The NAC Act established the NAC Board, a multi-sectoral Board, appointed by the President that develops the annual strategic plan for NAC. The AIDS Levy and NAC legislation along with the National HIV and AIDS Policy and National HIV and AIDS Strategic Framework in 1999 were the key foundations for AIDS policy in Zimbabwe. The 2015 National Budget calls for extension of the AIDS Levy to the mining industry  and laboratory equipment.A unique aspect of the AIDS Levy is that many of the activities supported are conducted through a decentralized structure of AIDS action committees that administer some AIDS Levy funds. Committees exist at provincial and district levels. In 2015, each of the 10 provinces is receiving US$500,000 to support implementation of HIV prevention interventions by the districts. Ward focal persons collect data and coordinate activities at the community level.The Zimbabwe Revenue Authority (ZIMRA) collects and transfers the AIDS Levy directly to the National AIDS Trust Fund on a monthly basis. Unlike other taxes that are managed by the Ministry of Finance, the AIDS Levy funds are directly transferred to the National AIDS Trust Fund to be used only for the purpose of the HIV and AIDS response. The MOHCC is involved in several aspects of the AIDS Levy; it approves its annual work plan and budget for the AIDS Levy, implements programs funded by the AIDS Levy, and participates in monitoring and evaluation activities under NAC coordination. The Ministry of Public Service, Labor and Social Welfare implemented one of the programs supported by the AIDS Levy, Basic Education Assistance Module that provided support to orphans and vulnerable children.The revenues and success of the AIDS Levy has depended on the strength of the economy. The AIDS Levy grew steadily from its inception in 2000 until 2006 through 2008, when Zimbabwe was faced with significant economic instability and hyperinflation. During the period of economic instability the AIDS Levy continued, though its purchasing power was limited and due to extreme hyperinflation, and was ultimately rendered essentially valueless. In February 2009, the Zimbabwean government abandoned the Zimbabwean dollar and switched to the US dollar. As the economy stabilized, the AIDS Levy began to grow and collected US$38.6 million in 2014. The annual AIDS Levy collection amounts are listed in Strategic activities in the following categories receive funding from the AIDS Levy based on the allocations shown in Since 2005, the majority of the AIDS Levy has been directed toward the procurement and distribution of ARV. By policy, at least 50% of the AIDS Levy is allocated toward the purchase of ARV, with NAC is responsible for their procurement through guidance from the MOHCC on the ARV needs for the upcoming year, NAC follows the Zimbabwe's procurement laws under the State Procurement Act to purchase the appropriate drug supply. NAC follows a formal tender process for larger procurements  and competitive bidding with minimum of three bidders for procurements that are less than US$300,000. An adjudication process with the MOHCC, the Medicine Control Authority of Zimbabwe, and the National Pharmaceutical Company is conducted to award the procurement. The purchased drugs are then managed and distributed by the National Pharmaceutical Company together with donor-procured ARV.Under the prevention programs, the AIDS Levy supports condom promotion, prevention of mother-to-child transmission of HIV, safe blood, youth and workplace programs, and more recently initiated support for voluntary medical male circumcision programs.The other strategic areas that the AIDS Levy supports are programs to support creating an enabling environment, which involves support for advocacy for people living with HIV and AIDS and programs that support gender mainstreaming, orphans and vulnerable children, and the meaningful involvement of people living with HIV and AIDS. The AIDS Levy has directly supported advocacy groups including Zimbabwe National Network of People living with HIV and Southern Africa HIV and AIDS Information Dissemination Service.The AIDS Levy supports monitoring and evaluation projects conducted by NAC in collaboration with the MOHCC, including the production of annual and quarterly monitoring and evaluation reports. Finally, the AIDS Levy supports administration of NAC, including capital costs, management and salaries.There are several financial controls in place to ensure the effectiveness of the AIDS Levy. ZIMRA and NAC validate that the amount collected by ZIMRA is the amount that NAC can account for in the National AIDS Trust Fund. Several audits of NAC's financial statements are conducted, including annual audits conducted by Zimbabwe's Office of the Comptroller and Auditor General and internal audits by NAC-employed auditors for all provinces and districts every two years. Furthermore, NAC provides quarterly financial reports to the MOHCC, the Ministry of Finance, and Parliament. The NAC Board Finance Committee reviews financial information quarterly. In addition, an audited annual report is publicly distributed and posted on the NAC website. External auditors such as the Local Fund Agent of the Global Fund have reviewed audits and financial reports as part of their capacity assessments.In 2012, there was a series of protests and communications from Zimbabwean AIDS activists calling for increased accountability and transparency in the administration of AIDS Levy funds. In response, NAC re-published the most recent audited financial statements in the popular press. NAC representatives also held stakeholders meetings which included representatives of AIDS service organizations and of groups of people living with HIV to determine program gaps. One result of those meetings was the initiation of community monitoring quarterly assessments of antiretroviral treatment clinics. Another outcome was a series of quarterly meetings with news editors.From the key informant interviews, several themes were identified on perceived strengths of the AIDS Levy. One theme was the tangible benefits of the use of the funds, specifically that the majority of the funds were being used to purchase ARV. Secondly, the nature of the AIDS Levy as a ‘homegrown' solution which provided country ownership and reduced dependence on donor funding was seen as an important strength. Related to this, key informants reported that the creation of NAC and the AIDS Levy contributed substantially to the coordination of the national response by creating coordination structures at subnational levels that are responsible for planning, data collection, and reporting. Lastly, the basis of the AIDS Levy as an entity created by laws and not simply by administrative policy was also seen as a strength.Several themes were also identified from the key informant interviews regarding weaknesses of the AIDS Levy. The need for more transparency and accountability was a common concern, despite the regular reporting described above. One respondent said, ‘We know 50 percent of the money goes for ARVs, but we don't know what the other 50 percent goes towards.' Related to this, there was a perception that the administrative costs were too high and objections to provisions of the NAC Act, which, like other parastatal organizations in Zimbabwe, catered for benefits for employees such as loans for houses. Other reported weaknesses related to the tax burden of the AIDS Levy on working Zimbabweans and that the informal sector was not contributing. Lastly, there were related concerns about the availability of resources. Since the revenue of the AIDS Levy depended on the vibrancy of the economy, the resources to date have been insufficient. In the words of one respondent, ‘There is always not enough money. Not enough cake. There is constant competition for resources.'The themes of the recommendations from key informants related closely to the perceived weaknesses. Key informants suggested that communication from NAC be improved to further promote accountability and transparency. A specific recommendation was to make available the quarterly reports that are submitted in Parliament. A second general recommendation was to reduce the administration and overhead costs funded through the AIDS Levy and increase the proportion of the funds dedicated to procurement of commodities and program implementation. The last thematic area of recommendations related to increasing the revenue for the AIDS Levy. Specific recommendations included increasing revenue from informal sector through a value added tax, from employers from which tax was only levied on profits, and from the mining sector (which was exempted as the time of the interviews).Finally, key informants were asked if they thought the Zimbabwe AIDS Levy should be identified as a best practice which could be recommended for replication in other countries. Many responded positively; comments included: ‘In principle, it is a best practice.' ‘Yes, it removes a culture of dependency.' ‘It should be a model that should be replicated and studied so it can be enhanced.' One respondent endorsed specific features of the Zimbabwe AIDS Levy: ‘Countries should be encouraged to have a health fund. The fund should be administered by an independent board. They should have the courage to administer and audit.' Other key informants had a qualified response, for example: ‘It depends on the country. It could be taken out of the budget for health if the country has a well-managed budget.' ‘It depends on the economy of the country.'This case study documents the establishment of the Zimbabwe AIDS Levy through legislation in 1999 and key elements of its subsequent implementation. Through a 3% tax on formal sector income and business profits (which excluded the mining sector until 2015), the AIDS Levy has raised well over US$100 million for the national response to HIV and AIDS, including US$38.6 million in 2014 alone. Multiple Zimbabwean government agencies are engaged in the administration of the AIDS Levy, led by the NAC. While half of the funds are used for procurement of ARV, other activities including prevention and monitoring and evaluation are implemented through a decentralized structure down to the village level. While key informants had suggestions to strengthen the AIDS Levy including increasing transparency and accountability and reducing administrative costs, the AIDS Levy was generally endorsed as a potential best practice for other countries to consider emulating.et al. How did the existence of the AIDS Levy impact the overall response to HIV and AIDS in Zimbabwe? While other low- and middle-income countries have committed increasing resources to the HIV and AIDS response, the Zimbabwe AIDS Levy is notable for having been established in the late 1990s, relatively early in comparison to the responses and funding from other low-income countries (Ávila There are several methodological limitations of this case study. The first limitation is the lack of generalizability typically found in case study research. Secondly, much of the data collection and analysis were limited to the government documents made available. Some information may not be documented. Third, some key informants may have been biased or felt restricted in their responses due to perceived potential repercussions, which may have affected the study results. Finally, while a robust methodology was followed, the authors recognize that, due to the nature of qualitative research, alternative interpretations of the evidence are possible.The Zimbabwe AIDS Levy has been successful in raising substantial resources to address the epidemic of HIV and AIDS in Zimbabwe, recently over US$30 million per year. It is a visible indicator of a long-term commitment on the part of the government and citizens of Zimbabwe, and may have had a role in attracting other donor resources. Success factors have included the solid legal basis for the Levy, the engagement of multiple agencies as stakeholders, the decentralized implementation of some of the activities, and the financial controls over the use of the funds. Key informants recommended further increasing transparency, accountability and efficiency in the use of funds, and taking steps to increase the resources available. Many consider the Zimbabwe AIDS Levy to be a best practice which other countries may want to emulate.


As 2015 draws to a close so too do the many celebrations of the 150th anniversary of Mendel's presentation of his work entitled “Experiments in Plant Hybridization” to the Natural History Society of Brno. MGGM marked the beginning of the year with an invited commentary by Drs. John Opitz and Diana Bianchi reflecting on Mendel and his accomplishments (Opitz and Bianchi MGGM editor, Dr. Max Muenke, hosted two parties to mark the occasion. The first was held in Maryland and featured several types of pea soup. A presentation on Mendel's life and work was presented by one of the Clinical Genetics residents, Dr. Mauricio De Castro. Dr. De Castro's Invited Commentary, which includes information on Mendel's scientific work outside of genetics, will be published in the January 2016 issue of MGGM. Max Muenke also hosted a party in Freiberg, Germany where the guest of honor was Mendel's great‐great‐grandnephew, Father Clemens Richter. This issue of the journal contains an Invited Commentary by Father Clemens reflecting on the life of his famous uncle. The 2015 American Society of Human Genetics annual meeting, held in Baltimore MD in October, had an exhibit dedicated to the 150th anniversary. The exhibit from the Mendel Museum of Mararyk University, Brno featured informative, hands‐on exhibits. Figure MGGM, we are happy to help acknowledge Mendel's legacy and contributions to science.As 2015 draws to a close so too do the many celebrations of the 150th anniversary of Mendel's presentation of his work entitled “Experiments in Plant Hybridization” to the Natural History Society of Brno. His handwritten manuscript is shown in Figure


Immunoglobulin G4 (IgG4)-associated disease is a recently recognized disease entity that is characterized by elevated serum IgG4 concentrations, abundant IgG4 lymphoplasmacytic infiltration, and dramatic steroid responses. IgG4-associated cholangitis is one manifestation of IgG4-associated disease. However, it is clinically challenging to make a preoperative differentiation between this rare disease and cholangiocarcinoma, especially for those with serum concentrations of IgG4 in the normal range. This article reports on a 57-year-old man with jaundice and upper abdominal discomfort. Imaging examination showed biliary stricture that closely resembled cholangiocarcinoma, and the patient’s serum IgG4 concentration was normal. The patient underwent a laparoscopic choledochectomy with Roux-en-Y hepaticojejunostomy using an intracorporeal hand-sewn technique. He recovered quickly without any complications. We also present our experience in laparoscopic intracorporeal hand-sewn hepaticojejunostomy. IgG4-associated systemic disease (ISD) is a systemic disorder involving multiple organs associated with increased IgG4 serum levels or IgG4 positive plasma cell infiltrates. IgG4-associated cholangitis (IAC) is one manifestation of ISD. However, the clinical, biochemical, and imaging features of IAC mimic cholangiocarcinoma, making preoperative accurate diagnosis difficult ; therefoSince the development of minimally invasive surgical approaches , laparosA 57-year-old man was admitted to our department; he had jaundice and had been experiencing upper abdominal discomfort for the previous month. Laboratory data were as follows: alkaline phosphatase, 303 U/l; alanine aminotransferase, 266 IU/l; aspartate aminotransferase, 70 IU/l; γ-glutamyltransferase, 555 U/l; total bilirubin, 126 μmol/dl; direct bilirubin, 102.0 μmol/l. The patient’s serum levels of carcinoembryonic antigen and α-fetoprotein were within normal limits; however, serum carbohydrate antigen 19-9 concentration was 306 IU/ml. Other test results, including IgG4 serum levels, were all within normal ranges.Enhanced abdominal computed tomography revealed a mass involving the common hepatic duct Figure A. MagnetThe patients’ position and the placement of trocars were similar to our previous studies  Figure . The hepThe incision was sutured, and the pneumoperitoneum was reestablished. After exploring the upper jejunum about 25 cm distally from the ligament of Treitz, an incision was made in the mesentery of this loop, and a transection of the jejunum was performed with an endoscopic linear stapler Figure A. The leThe operative time was 210 min and blood loss was 60 ml. The intraoperative frozen pathological diagnosis was probably IAC, rather than cholangiocarcinoma, and the margins were negative. The gross finding was a 20 × 15 mm mass located in the middle part of the common bile duct, in communication with a dilated proximal bile duct  and apparently elevated levels of CA19-9, the images showing segmental biliary stricture and no other organ involvement were assumed to indicate ISD; it is extremely difficult to distinguish IAC from cholangiocarcinoma preoperatively. Although endoscopic retrograde cholangiopancreatography is the most commonly performed procedure for cholangiocarcinoma and can provide a tissue diagnosis through brush cytology of the bile duct, the sensitivity of biliary brush cytology to diagnose cholangiocarcinoma may be as low as 30% . AlthougThe laparoscopic technique is indispensable in biliary surgery. Compared with traditional open surgery, most studies have reported that laparoscopic techniques can achieve better cosmesis, shorter hospital stay, and faster postoperative recovery –24. By cOur case suggests that totally laparoscopic Roux-en-Y hepaticojejunostomy using an intracorporeal hand-sewn technique is a feasible procedure. Adequate preoperative evaluation, appropriate intraoperative hand-sewn techniques, and highly skilled laparoscopic techniques are the key factors of success in laparoscopic hepaticojejunostomy.Written informed consent was obtained from the patient for the publication of this case report and any accompanying images.