Nanofarmacologia na leishmaniose visceral empregando uma mistura de lipossomas convencionais e peguilados com antimoniato de meglumina e vacinas.

Programa de P?s-Gradua??o em Ci?ncias Farmac?uticas. CIPHARMA, Escola de Farm?cia, Universidade Federal de Ouro Preto.Os antimoniais pentavalentes s?o f?rmacos de 1? escolha no tratamento das leishmanioses no Brasil. Em virtude dos v?rios efeitos colaterais do tratamento, a associa??o do f?rmaco em lipossomas poderia aumentar a ades?o e a efic?cia terap?utica. Sendo assim, o objetivo deste estudo foi avaliar diferentes protocolos de tratamento aplicados ? leishmaniose visceral (LV) experimental empregando uma mistura de lipossomas convencionais e peguilados com antimoniato de meglumina e a sua associa??o com as vacinas LBSap e LBMPL. Para avalia??o da quimioterapia com as formula??es lipossomais, foram utilizados camundongos BALB/c (n=12/grupo), divididos nos seguintes grupos experimentais: (i) infectados e tratados apenas com solu??o salina (PBS); (ii) infectados e tratados com a mistura de lipossomas convencionais e peguilados vazios (Lip V); (iii) infectados e tratados com antimoniato de meglumina na forma livre - 20 mg/kg (AM) e (iv) infectados e tratados com a mistura de lipossomas convencionais e peguilados contendo antimoniato de meglumina - 20 mg/kg (AML). Ap?s o tratamento os animais foram submetidos ? infec??o experimental com 1x107 promastigotas de L. infantum, em fase estacion?ria de crescimento, por via endovenosa. Os camundongos receberam uma dose ?nica do tratamento no 14o dia p?s-infec??o (d.p.i) e a eutan?sia foi realizada no 28o d.p.i. A formula??o lipossomal consistiu na mistura de lipossomas convencionais - DSPC, CHO e DCP e lipossomas peguilados - DSPC, CHO, DCP e 2000-DSPE-PEG. As caracteriza??es f?sico-qu?micas das formula??es lipossomais demonstraram uma taxa de encapsula??o do f?rmaco de 20,5% e 30,6% para as formula??es lipossomais convencionais e peguiladas, respectivamente. A mistura das formula??es lipossomais convencionais e peguiladas apresentaram um di?metro m?dio de 229 nm e uma libera??o est?vel do f?rmaco em 24 horas. Para avalia??o da resposta compartimentalizada em rela??o ao tratamento com lipossomas, foi avaliada de forma quantitativa a presen?a de c?lulas inflamat?rias no f?gado. Foi observada uma diminui??o significativa do processo inflamat?rio nos grupos tratados com antimoniais (AM e AML) e aus?ncia de granulomas hep?ticos nos animais do grupo AML. A estimula??o in vitro de esplen?citos com ant?geno sol?vel de L. infantum (ASLi) revelou um aumento significativo de linf?citos T CD8+ produtores de IFN-? e uma redu??o nos linf?citos T CD4+ e T CD8+ produtores de IL-10 apenas no grupo AML. Al?m disso, os animais do grupo AML apresentaram um aumento na raz?o IFN-?/IL-10 para os linf?citos T CD4+ e T CD8+ espec?ficos. Quando avaliada a efic?cia do tratamento, foi observada uma positividade na detec??o de DNA do parasito no ba?o de 41,7%, 50,0%, 25,0% e 0,0% para os grupos PBS, Lip V, AM e AML, respectivamente. J? no compartimento hep?tico, a positividade foi de 83,3%, 100,0%, 83,3% e 41,4% para os grupos PBS, Lip V, AM e AML respectivamente, demonstrando assim, a efic?cia obtida com a formula??o lipossomal peguilada do antimoniato. Uma alternativa para melhorar a efic?cia da terap?utica convencional ? o uso da imunoterapia atuando no reestabelecimento do sistema imune, sendo esta utilizada isoladamente ou em associa??o com a quimioterapia (imunoquimioterapia). Dessa forma, n?s avaliamos em um protocolo de imunoquimioterapia (lipossomas + vacinas), a capacidade de indu??o de mem?ria imunol?gica nos animais infectados. Foram utilizados camundongos BALB/c (n=12/grupo), divididos nos seguintes grupos experimentais: (i) infectados e tratados com ant?geno de L. braziliensis (LB); (ii) infectados e tratados com a vacina LBMPL (LBMPL); (iii) infectados e tratados com a vacina LBSap (LBSap); (iv) infectados e tratados com a associa??o da vacina LBMPL e a mistura de lipossomas convencionais e peguilados contendo antimoniato de meglumina (LBMPL+AML); e (v) infectados e tratados com a associa??o da vacina LBSap e a mistura de lipossomas convencionais e peguilados contendo antimoniato de meglumina (LBSap+AML). A infec??o foi realizada com 1x107 promastigotas de L. infantum, em fase estacion?ria de crescimento, por via endovenosa. O esquema terap?utico utilizando vacinoterapia foi realizado com tr?s doses vacinais no 28?, 35? e 42? d.p.i e a formula??o lipossomal foi administrada em dose ?nica no 35? d.p.i. No 49o d.p.i foi realizada a eutan?sia dos animais para an?lise dos fen?tipos de mem?ria central (CD62Lhi CD44hi CD27hi CD197hi) e efetora (CD62Llow CD44hi) em esplen?citos estimulados com ASLi. Foi demonstrado que a associa??o imunoquimioter?pica da vacina LBMPL+AML induziu um maior percentual de c?lulas de mem?ria central em linf?citos T CD4+ e T CD8+. J? a associa??o da vacina LBSap+AML induziu uma resposta imunol?gica de mem?ria efetora na subpopula??o de linf?citos T CD4+. Dessa forma, o conjunto de resultados obtidos neste trabalho permite concluir que o emprego da quimioterapia com a nanoformula??o composta por uma mistura de lipossomas convencionais e peguilados contendo antimonial ? promissora no tratamento da LV. Este protocolo quimioter?pico foi capaz de diminuir o processo inflamat?rio, impedir o comprometimento da arquitetura hep?tica e induzir a polariza??o de uma resposta imune do tipo 1 (Th1), associada a redu??o da carga parasit?ria em ?rg?os-alvo (ba?o e f?gado). Al?m disso, a avalia??o imunol?gica da imunoquimioterapia pela associa??o da formula??o lipossomal com a vacinoterapia, demonstrou resultados relevantes por induzir a estimula??o de c?lulas de mem?ria central (LBMPL+AML) e efetora (LBSap+AML). Portanto, as formula??es lipossomais compostas pela mistura de lipossomas convencionais e peguilados contendo antimoniato de meglumina s?o excelentes alternativas para o tratamento da LV, tanto isoladamente quanto em combina??o com a vacinoterapia.Pentavalent antimonials are drugs of first choice in the treatment of leishmaniasis in Brazil. Due to various side effects of standard treatment, the liposome drug combination could increase the acceptance and therapeutic efficacy. The objective of this study was to evaluate different treatment protocols applied to experimental visceral leishmaniasis (VL) using a mixture of conventional and pegylated liposomes with meglumine antimoniate and its association with LBSap and LBMPL vaccines. For the evaluation of chemotherapy with the liposomal formulations, BALB/c mice were used (n =12/group), divided into the following experimental groups: (i) infected and treated with saline solution (PBS); (ii) infected and treated with the mixture of conventional and pegylated liposomes (Lip V); (iii) infected and treated with meglumine antimoniate in free form - 20 mg/kg (AM) and (iv) infected and treated with the mixture of conventional and pegylated liposomes containing meglumine antimoniate; 20 mg/kg (AML). After treatment the animals were submitted to experimental infection with 1x107 promastigotes of L. infantum, in stationary phase of growth, by intravenous route. Mice received a single dose of treatment on the 14th day post infection (d.p.i) and euthanasia was performed on the 28th d.p.i. The liposomal formulation consisted of mixing conventional liposomes - DSPC, CHO and DCP and pegylated liposomes - DSPC, CHO, DCP and 2000-DSPE-PEG. The physico-chemical characterization of the liposomal formulations demonstrated a 20.5% and 30.6% drug encapsulation rate for conventional and pegylated liposomal formulations, respectively. The mixture of the conventional and pegylated liposomal formulations had a mean diameter of 229 nm and a stable release of the drug in 24 hours. The presence of inflammatory cells in the liver was quantitatively evaluated to assess the compartmentalized response to liposome treatment. A significant decrease in the inflammatory process was observed in the groups treated with antimonials (AM and AML) and absence of hepatic granulomas in the animals of the group AML. In vitro stimulation of splenocytes with soluble L. infantum antigen (ASLi) revealed a significant increase in IFN-?-producing CD8+ T lymphocytes and a reduction in IL-10 producing CD4+ and CD8+ T lymphocytes only in the AML group. In addition, animals in the AML group showed an increase in the IFN-?/IL-10 ratio for specific CD4+ and CD8+ T lymphocytes. Regarding the efficacy of the treatment, the spleen DNA detection showed a positivity 41.7%, 50.0%, 25.0% and 0.0% for the PBS, Lip V, AM and AML groups, respectively. In the hepatic compartment, the positivity was 83.3%, 100.0%, 83.3% and 41.4% for the PBS, Lip V, AM and AML groups respectively, thus it demonstrated an efficacy obtained with the formulation liposomal antimoniate. An alternative to improve the efficacy of conventional therapy is the use of immunotherapy by acting on the reestablishment of the immune system, which is used alone or in combination with chemotherapy (immunochemotherapy). Thus, we evaluated in an immunochemotherapy protocol (liposomes + vaccines) the ability to induce immune memory in infected animals. In this protocol, BALB/c mice (n =12/group) were used, divided into: (i) infected and treated with L. braziliensis antigen (LB); (ii) infected and treated with the LBMPL vaccine (LBMPL); (iii) infected and treated with the LBSap vaccine (LBSap); (iv) infected and treated with combination of the LBMPL vaccine and the mixture of conventional and pegylated liposomes containing meglumine antimoniate (LBMPL+AML); and (v) infected and treated with the association of the LBSap vaccine and the mixture of conventional and pegylated liposomes containing meglumine antimoniate (LBSap+AML). The infection was performed with 1x107 promastigotes of L. infantum, in stationary phase of growth, by intravenous route. The therapeutic regimen using vaccinotherapy was performed with three vaccine doses at 28th, 35th and 42th d.p.i and the liposomal formulation was administered as a single dose at 35th d.p.i. At the 49th day, the animals were euthanized to analyze the central (CD62Lhi CD44hi CD27hi197hi) and effector (CD62Llow CD44hi) memory phenotypes in ASLi-stimulated splenocytes. The immunochemotherapy association of the LBMPL+AML vaccine induced a higher percentage of central memory cells in CD4+ and CD8+ T lymphocytes. The association of the LBSap+AML vaccine induced an effector memory phenotypein the subpopulation of CD4+ T lymphocytes. Thus, the set of results obtained in this work allows to conclude that the use of chemotherapy with the nanoformulation composed by a mixture of conventional and pegylated liposomes containing antimonial is promising in the treatment of VL. This chemotherapeutic protocol was able to reduce the inflammatory process, prevent hepatic architecture impairment and induce the polarization of a type 1 (Th1) immune response, associated with reduction of parasite load on target organs (spleen and liver). In addition, the immunological evaluation of immunochemotherapy by the association of the liposomal formulation with the vaccinotherapy, showed relevant results by inducing stimulation of central (LBMPL+AML) and effector (LBSap+AML) memory cells. Therefore, liposomal formulations composed of the mixture of conventional and pegylated liposomes containing meglumine antimoniate are excellent alternatives for the treatment of VL, either alone or in combination with the vaccinotherapy

HPV-positive women living in isolated areas in Amazonas, Brazil: Clinical–epidemiological profile and cytological findings

Abstract Background: Cervical cancer (CC) is associated with persistent high-risk human papillomavirus (HPV) infection and it causes about 265,000 deaths per year worldwide, thus becoming an important public health problem. Objective: This study aimed to describe the epidemiological profile, clinical history, and cytological findings of 55 women infected with HPV living in remote areas in Amazonas, Brazil. Method: The samples were obtained by self-collection using the Rovers® Evalyn® Brush for HPV detection through PCR. The cytological examination was performed by liquid-based cytology. Results: The mean age of participants was 35 years (SD=14). Most of the women presented low or no schooling (52.7%), lived in stable relationship with a partner (74.5%), and had three to five children (32.7%). Inconsistent use of condoms by most of the participants (“never” — 34.5% and “sometimes” — 41.8%) was observed. Cytopathological examinations showed that 14 (25.4%) women had cytological alterations: 7 atypical squamous cells of undetermined significance (50.0%), 5 low-grade squamous intraepithelial lesions (35.7%), and 2 high-grade squamous intraepithelial lesions (14.3%). Conclusion: As cervical lesions have been caused by persistent HPV infection over the years, CC Prevention Programs use effective strategies to follow up on HPV-positive women living in remote areas

Synthetic peptides elicit strong cellular immunity in Visceral Leishmaniasis natural reservoir and contribute to long-lasting polyfunctional T-cells in BALB/c mice.

Reverse vaccinology or immunoinformatics is a computational methodology which integrates data from in silico epitope prediction, associated to other important information as, for example, the predicted subcellular location of the proteins used in the design of the context of vaccine development. This approach has the potential to search for new targets for vaccine development in the predicted proteome of pathogenic organisms. To date, there is no effective vaccine employed in vaccination campaigns against visceral leishmaniasis (VL). For the first time, herein, an in silico, in vitro, and in vivo peptide screening was performed, and immunogenic peptides were selected to constitute VL peptide-based vaccines. Firstly, the screening of in silico potential peptides using dogs naturally infected by L. infantum was conducted and the peptides with the best performance were selected. The mentioned peptides were used to compose Cockt-1 (cocktail 1) and Cockt-2 (cocktail 2) in combination with saponin as the adjuvant. Therefore, tests for immunogenicity, polyfunctional T-cells, and the ability to induce central and effector memory in T-lymphocytes capacity in reducing the parasite load on the spleen for Cockt-1 and Cockt-2 were performed. Among the vaccines under study, Cockt-1 showed the best results, eliciting CD4+ and CD8+ polyfunctional T-cells, with a reduction in spleen parasitism that correlates to the generation of T CD4+ central memory and T CD8+ effector memory cells. In this way, our findings corroborate the use of immunoinformatics as a tool for the development of future vaccines against VL

A vaccine therapy for canine visceral leishmaniasis promoted significant improvement of clinical and immune status with reduction in parasite burden.

Herein, we evaluated the treatment strategy employing a therapeutic heterologous vaccine composed of antigens of Leishmania braziliensis associated with MPL adjuvant (LBMPL vaccine) for visceral leishmaniasis (VL) in symptomatic dogs naturally infected by Leishmania infantum. Sixteen dogs received immunotherapy with MPL adjuvant (n = 6) or with a vaccine composed of antigens of L. braziliensis associated with MPL (LBMPL vaccine therapy, n = 10). Dogs were submitted to an immunotherapeutic scheme consisting of 3 series composed of 10 subcutaneous doses with 10-day interval between each series. The animals were evaluated before (T0) and 90 days after treatment (T90) for their biochemical/hematological, immunological, clinical, and parasitological variables. Our major results showed that the vaccine therapy with LBMPL was able to restore and normalize main biochemical (urea, AST, ALP, and bilirubin) and hematological (erythrocytes, hemoglobin, hematocrit, and platelets) parameters. In addition, in an ex vivo analysis using flow cytometry, dogs treated with LBMPL vaccine showed increased CD3+ T lymphocytes and their subpopulations (TCD4+ and TCD8+), reduction of CD21+ B lymphocytes, increased NK cells (CD5?CD16+) and CD14+ monocytes. Under in vitro conditions, the animals developed a strong antigen- specific lymphoproliferation mainly by TCD4+ and TCD8+ cells; increasing in both TCD4+IFN-?+ and TCD8+IFN-?+ as well as reduction of TCD4+IL-4+ and TCD8+IL-4+ lymphocytes with an increased production of TNF-? and reduced levels of IL-10. Concerning the clinical signs of canine visceral leishmaniasis, the animals showed an important reduction in the number and intensity of the disease signs; increase body weight as well as reduction of splenomegaly. In addition, the LBMPL immunotherapy also promoted a reduction in parasite burden assessed by real-time PCR. In the bone marrow, we observed seven times less parasites in LBMPL animals compared with MPL group. The skin tissue showed a reduction in parasite burden in LBMPL dogs 127.5 times higher than MPL. As expected, with skin parasite reduction promoted by immunotherapy, we observed a blocking transmission to sand flies in LBMPL dogs with only three positive dogs after xenodiagnosis. The results obtained in this study highlighted the strong potential for the use of this heterologous vaccine therapy as an important strategy for VL treatment

A vaccine therapy for canine visceral leishmaniasis promoted significant improvement of clinical and immune status with reduction in parasite burden.

Herein, we evaluated the treatment strategy employing a therapeutic heterologous vaccine composed of antigens of Leishmania braziliensis associated with MPL adjuvant (LBMPL vaccine) for visceral leishmaniasis (VL) in symptomatic dogs naturally infected by Leishmania infantum. Sixteen dogs received immunotherapy with MPL adjuvant (n = 6) or with a vaccine composed of antigens of L. braziliensis associated with MPL (LBMPL vaccine therapy, n = 10). Dogs were submitted to an immunotherapeutic scheme consisting of 3 series composed of 10 subcutaneous doses with 10-day interval between each series. The animals were evaluated before (T0) and 90 days after treatment (T90) for their biochemical/hematological, immunological, clinical, and parasitological variables. Our major results showed that the vaccine therapy with LBMPL was able to restore and normalize main biochemical (urea, AST, ALP, and bilirubin) and hematological (erythrocytes, hemoglobin, hematocrit, and platelets) parameters. In addition, in an ex vivo analysis using flow cytometry, dogs treated with LBMPL vaccine showed increased CD3+ T lymphocytes and their subpopulations (TCD4+ and TCD8+), reduction of CD21+ B lymphocytes, increased NK cells (CD5?CD16+) and CD14+ monocytes. Under in vitro conditions, the animals developed a strong antigen- specific lymphoproliferation mainly by TCD4+ and TCD8+ cells; increasing in both TCD4+IFN-?+ and TCD8+IFN-?+ as well as reduction of TCD4+IL-4+ and TCD8+IL-4+ lymphocytes with an increased production of TNF-? and reduced levels of IL-10. Concerning the clinical signs of canine visceral leishmaniasis, the animals showed an important reduction in the number and intensity of the disease signs; increase body weight as well as reduction of splenomegaly. In addition, the LBMPL immunotherapy also promoted a reduction in parasite burden assessed by real-time PCR. In the bone marrow, we observed seven times less parasites in LBMPL animals compared with MPL group. The skin tissue showed a reduction in parasite burden in LBMPL dogs 127.5 times higher than MPL. As expected, with skin parasite reduction promoted by immunotherapy, we observed a blocking transmission to sand flies in LBMPL dogs with only three positive dogs after xenodiagnosis. The results obtained in this study highlighted the strong potential for the use of this heterologous vaccine therapy as an important strategy for VL treatment

Prevalence and Factors Associated with Leishmania infantum Infection of Dogs from an Urban Area of Brazil as Identified by Molecular Methods

Visceral leishmaniasis (VL) is a disease caused by the parasite Leishmania infantum, and dogs are the most important domestic reservoirs of the agent. During recent decades, VL has expanded to large Brazilian urban centers. In the present work, we have demonstrated by using molecular techniques that the rate of canine infection as detected by serology has been considerably underestimated. Two groups of seronegative dogs (infected and non-infected according to molecular methods) were further evaluated from data obtained through interviews with owners of the animals. The factors associated with Leishmania infection in dogs were a family income of less than two minimum salaries, the knowledge of the owner regarding the vector, the dog spending most of its time in the backyard and the dog never having had a previous serological examination. Awareness regarding the factors associated with canine infection will improve health services and the understanding of the disease's expansion in urban areas

Alcohol use and burden for 195 countries and territories, 1990-2016 : a systematic analysis for the Global Burden of Disease Study 2016

Background Alcohol use is a leading risk factor for death and disability, but its overall association with health remains complex given the possible protective effects of moderate alcohol consumption on some conditions. With our comprehensive approach to health accounting within the Global Burden of Diseases, Injuries, and Risk Factors Study 2016, we generated improved estimates of alcohol use and alcohol-attributable deaths and disability-adjusted life-years (DALYs) for 195 locations from 1990 to 2016, for both sexes and for 5-year age groups between the ages of 15 years and 95 years and older. Methods Using 694 data sources of individual and population-level alcohol consumption, along with 592 prospective and retrospective studies on the risk of alcohol use, we produced estimates of the prevalence of current drinking, abstention, the distribution of alcohol consumption among current drinkers in standard drinks daily (defined as 10 g of pure ethyl alcohol), and alcohol-attributable deaths and DALYs. We made several methodological improvements compared with previous estimates: first, we adjusted alcohol sales estimates to take into account tourist and unrecorded consumption; second, we did a new meta-analysis of relative risks for 23 health outcomes associated with alcohol use; and third, we developed a new method to quantify the level of alcohol consumption that minimises the overall risk to individual health. Findings Globally, alcohol use was the seventh leading risk factor for both deaths and DALYs in 2016, accounting for 2.2% (95% uncertainty interval [UI] 1.5-3.0) of age-standardised female deaths and 6.8% (5.8-8.0) of age-standardised male deaths. Among the population aged 15-49 years, alcohol use was the leading risk factor globally in 2016, with 3.8% (95% UI 3.2-4-3) of female deaths and 12.2% (10.8-13-6) of male deaths attributable to alcohol use. For the population aged 15-49 years, female attributable DALYs were 2.3% (95% UI 2.0-2.6) and male attributable DALYs were 8.9% (7.8-9.9). The three leading causes of attributable deaths in this age group were tuberculosis (1.4% [95% UI 1. 0-1. 7] of total deaths), road injuries (1.2% [0.7-1.9]), and self-harm (1.1% [0.6-1.5]). For populations aged 50 years and older, cancers accounted for a large proportion of total alcohol-attributable deaths in 2016, constituting 27.1% (95% UI 21.2-33.3) of total alcohol-attributable female deaths and 18.9% (15.3-22.6) of male deaths. The level of alcohol consumption that minimised harm across health outcomes was zero (95% UI 0.0-0.8) standard drinks per week. Interpretation Alcohol use is a leading risk factor for global disease burden and causes substantial health loss. We found that the risk of all-cause mortality, and of cancers specifically, rises with increasing levels of consumption, and the level of consumption that minimises health loss is zero. These results suggest that alcohol control policies might need to be revised worldwide, refocusing on efforts to lower overall population-level consumption.Peer reviewe

Measuring performance on the Healthcare Access and Quality Index for 195 countries and territories and selected subnational locations: A systematic analysis from the Global Burden of Disease Study 2016

Background: A key component of achieving universal health coverage is ensuring that all populations have access to quality health care. Examining where gains have occurred or progress has faltered across and within countries is crucial to guiding decisions and strategies for future improvement. We used the Global Burden of Diseases, Injuries, and Risk Factors Study 2016 (GBD 2016) to assess personal health-care access and quality with the Healthcare Access and Quality (HAQ) Index for 195 countries and territories, as well as subnational locations in seven countries, from 1990 to 2016. Methods Drawing from established methods and updated estimates from GBD 2016, we used 32 causes from which death should not occur in the presence of effective care to approximate personal health-care access and quality by location and over time. To better isolate potential effects of personal health-care access and quality from underlying risk factor patterns, we risk-standardised cause-specific deaths due to non-cancers by location-year, replacing the local joint exposure of environmental and behavioural risks with the global level of exposure. Supported by the expansion of cancer registry data in GBD 2016, we used mortality-to-incidence ratios for cancers instead of risk-standardised death rates to provide a stronger signal of the effects of personal health care and access on cancer survival. We transformed each cause to a scale of 0-100, with 0 as the first percentile (worst) observed between 1990 and 2016, and 100 as the 99th percentile (best); we set these thresholds at the country level, and then applied them to subnational locations. We applied a principal components analysis to construct the HAQ Index using all scaled cause values, providing an overall score of 0-100 of personal health-care access and quality by location over time. We then compared HAQ Index levels and trends by quintiles on the Socio-demographic Index (SDI), a summary measure of overall development. As derived from the broader GBD study and other data sources, we examined relationships between national HAQ Index scores and potential correlates of performance, such as total health spending per capita. Findings In 2016, HAQ Index performance spanned from a high of 97\ub71 (95% UI 95\ub78-98\ub71) in Iceland, followed by 96\ub76 (94\ub79-97\ub79) in Norway and 96\ub71 (94\ub75-97\ub73) in the Netherlands, to values as low as 18\ub76 (13\ub71-24\ub74) in the Central African Republic, 19\ub70 (14\ub73-23\ub77) in Somalia, and 23\ub74 (20\ub72-26\ub78) in Guinea-Bissau. The pace of progress achieved between 1990 and 2016 varied, with markedly faster improvements occurring between 2000 and 2016 for many countries in sub-Saharan Africa and southeast Asia, whereas several countries in Latin America and elsewhere saw progress stagnate after experiencing considerable advances in the HAQ Index between 1990 and 2000. Striking subnational disparities emerged in personal health-care access and quality, with China and India having particularly large gaps between locations with the highest and lowest scores in 2016. In China, performance ranged from 91\ub75 (89\ub71-93\ub76) in Beijing to 48\ub70 (43\ub74-53\ub72) in Tibet (a 43\ub75-point difference), while India saw a 30\ub78-point disparity, from 64\ub78 (59\ub76-68\ub78) in Goa to 34\ub70 (30\ub73-38\ub71) in Assam. Japan recorded the smallest range in subnational HAQ performance in 2016 (a 4\ub78-point difference), whereas differences between subnational locations with the highest and lowest HAQ Index values were more than two times as high for the USA and three times as high for England. State-level gaps in the HAQ Index in Mexico somewhat narrowed from 1990 to 2016 (from a 20\ub79-point to 17\ub70-point difference), whereas in Brazil, disparities slightly increased across states during this time (a 17\ub72-point to 20\ub74-point difference). Performance on the HAQ Index showed strong linkages to overall development, with high and high-middle SDI countries generally having higher scores and faster gains for non-communicable diseases. Nonetheless, countries across the development spectrum saw substantial gains in some key health service areas from 2000 to 2016, most notably vaccine-preventable diseases. Overall, national performance on the HAQ Index was positively associated with higher levels of total health spending per capita, as well as health systems inputs, but these relationships were quite heterogeneous, particularly among low-to-middle SDI countries. Interpretation GBD 2016 provides a more detailed understanding of past success and current challenges in improving personal health-care access and quality worldwide. Despite substantial gains since 2000, many low-SDI and middle- SDI countries face considerable challenges unless heightened policy action and investments focus on advancing access to and quality of health care across key health services, especially non-communicable diseases. Stagnating or minimal improvements experienced by several low-middle to high-middle SDI countries could reflect the complexities of re-orienting both primary and secondary health-care services beyond the more limited foci of the Millennium Development Goals. Alongside initiatives to strengthen public health programmes, the pursuit of universal health coverage hinges upon improving both access and quality worldwide, and thus requires adopting a more comprehensive view-and subsequent provision-of quality health care for all populations

Measuring performance on the Healthcare Access and Quality Index for 195 countries and territories and selected subnational locations: A systematic analysis from the Global Burden of Disease Study 2016

Copyright © 2018 The Author(s). Published by Elsevier Ltd. Background A key component of achieving universal health coverage is ensuring that all populations have access to quality health care. Examining where gains have occurred or progress has faltered across and within countries is crucial to guiding decisions and strategies for future improvement. We used the Global Burden of Diseases, Injuries, and Risk Factors Study 2016 (GBD 2016) to assess personal health-care access and quality with the Healthcare Access and Quality (HAQ) Index for 195 countries and territories, as well as subnational locations in seven countries, from 1990 to 2016. Methods Drawing from established methods and updated estimates from GBD 2016, we used 32 causes from which death should not occur in the presence of effective care to approximate personal health-care access and quality by location and over time. To better isolate potential effects of personal health-care access and quality from underlying risk factor patterns, we risk-standardised cause-specific deaths due to non-cancers by location-year, replacing the local joint exposure of environmental and behavioural risks with the global level of exposure. Supported by the expansion of cancer registry data in GBD 2016, we used mortality-to-incidence ratios for cancers instead of risk-standardised death rates to provide a stronger signal of the effects of personal health care and access on cancer survival. We transformed each cause to a scale of 0-100, with 0 as the first percentile (worst) observed between 1990 and 2016, and 100 as the 99th percentile (best); we set these thresholds at the country level, and then applied them to subnational locations. We applied a principal components analysis to construct the HAQ Index using all scaled cause values, providing an overall score of 0-100 of personal health-care access and quality by location over time. We then compared HAQ Index levels and trends by quintiles on the Socio-demographic Index (SDI), a summary measure of overall development. As derived from the broader GBD study and other data sources, we examined relationships between national HAQ Index scores and potential correlates of performance, such as total health spending per capita. Findings In 2016, HAQ Index performance spanned from a high of 97·1 (95% UI 95·8-98·1) in Iceland, followed by 96·6 (94·9-97·9) in Norway and 96·1 (94·5-97·3) in the Netherlands, to values as low as 18·6 (13·1-24·4) in the Central African Republic, 19·0 (14·3-23·7) in Somalia, and 23·4 (20·2-26·8) in Guinea-Bissau. The pace of progress achieved between 1990 and 2016 varied, with markedly faster improvements occurring between 2000 and 2016 for many countries in sub-Saharan Africa and southeast Asia, whereas several countries in Latin America and elsewhere saw progress stagnate after experiencing considerable advances in the HAQ Index between 1990 and 2000. Striking subnational disparities emerged in personal health-care access and quality, with China and India having particularly large gaps between locations with the highest and lowest scores in 2016. In China, performance ranged from 91·5 (89·1-93·6) in Beijing to 48·0 (43·4-53·2) in Tibet (a 43·5-point difference), while India saw a 30·8-point disparity, from 64·8 (59·6-68·8) in Goa to 34·0 (30·3-38·1) in Assam. Japan recorded the smallest range in subnational HAQ performance in 2016 (a 4·8-point difference), whereas differences between subnational locations with the highest and lowest HAQ Index values were more than two times as high for the USA and three times as high for England. State-level gaps in the HAQ Index in Mexico somewhat narrowed from 1990 to 2016 (from a 20·9-point to 17·0-point difference), whereas in Brazil, disparities slightly increased across states during this time (a 17·2-point to 20·4-point difference). Performance on the HAQ Index showed strong linkages to overall development, with high and high-middle SDI countries generally having higher scores and faster gains for non-communicable diseases. Nonetheless, countries across the development spectrum saw substantial gains in some key health service areas from 2000 to 2016, most notably vaccine-preventable diseases. Overall, national performance on the HAQ Index was positively associated with higher levels of total health spending per capita, as well as health systems inputs, but these relationships were quite heterogeneous, particularly among low-to-middle SDI countries. Interpretation GBD 2016 provides a more detailed understanding of past success and current challenges in improving personal health-care access and quality worldwide. Despite substantial gains since 2000, many low-SDI and middle- SDI countries face considerable challenges unless heightened policy action and investments focus on advancing access to and quality of health care across key health services, especially non-communicable diseases. Stagnating or minimal improvements experienced by several low-middle to high-middle SDI countries could reflect the complexities of re-orienting both primary and secondary health-care services beyond the more limited foci of the Millennium Development Goals. Alongside initiatives to strengthen public health programmes, the pursuit of universal health coverage hinges upon improving both access and quality worldwide, and thus requires adopting a more comprehensive view - and subsequent provision - of quality health care for all populations