RESUMO
Consideration of the properties of the sources of selection potentially helps biologists account for variation in selection. Here we explore how the variability of natural selection is affected by organisms that regulate the experienced environment through their activities (whether by constructing components of their local environments, such as nests, burrows, or pupal cases, or by choosing suitable resources). Specifically, we test the predictions that organism-constructed sources of selection that buffer environmental variation will result in (i) reduced variation in selection gradients, including reduced variation between (a) years (temporal variation) and (b) locations (spatial variation), and (ii) weaker directional selection relative to nonconstructed sources. Using compiled data sets of 1,045 temporally replicated selection gradients, 257 spatially replicated selection gradients, and a pooled data set of 1,230 selection gradients, we find compelling evidence for reduced temporal variation and weaker selection in response to constructed compared to nonconstructed sources of selection and some evidence for reduced spatial variation in selection. These findings, which remained robust to alternative data sets, taxa, analytical methods, definitions of constructed/nonconstructed, and other tests of reliability, suggest that organism-manufactured or chosen components of environments may have qualitatively different properties from other environmental features.
Assuntos
Ecossistema , Seleção Genética , Animais , Modelos Biológicos , PlantasRESUMO
Over 20,000 rabies deaths occur annually in India, representing one-third of global human rabies. The Indian state of Tamil Nadu has pioneered a "One Health" committee to address the challenge of rabies in dogs and humans. Currently, rabies control in Tamil Nadu involves postexposure vaccination of humans after dog bites, whereas potential supplemental approaches include canine vaccination and sterilization. We developed a data-driven rabies transmission model fit to human rabies autopsy data and human rabies surveillance data from Tamil Nadu. Integrating local estimates for canine demography and costs, we predicted the impact of canine vaccination and sterilization on human health outcomes and evaluated cost-effectiveness according to the WHO criteria for India, which correspond to thresholds of $1,582 and $4,746 per disability-adjusted life-years (DALYs) for very cost-effective and cost-effective strategies, respectively. We found that highly feasible strategies focused on stray dogs, vaccinating as few as 7% of dogs annually, could very cost-effectively reduce human rabies deaths by 70% within 5 y, and a modest expansion to vaccinating 13% of stray dogs could cost-effectively reduce human rabies by almost 90%. Through integration over parameter uncertainty, we find that, for a cost-effectiveness threshold above $1,400 per DALY, canine interventions are at least 95% likely to be optimal. If owners are willing to bring dogs to central point campaigns at double the rate that campaign teams can capture strays, expanded annual targets become cost-effective. This case study of cost-effective canine interventions in Tamil Nadu may have applicability to other settings in India and beyond.
Assuntos
Controle de Doenças Transmissíveis/economia , Raiva/economia , Raiva/prevenção & controle , Animais , Mordeduras e Picadas/economia , Análise Custo-Benefício , Demografia , Doenças do Cão/economia , Doenças do Cão/prevenção & controle , Cães , Feminino , Custos de Cuidados de Saúde , Humanos , Índia/epidemiologia , Masculino , Saúde Única , Sensibilidade e Especificidade , Vacinação/economiaRESUMO
BACKGROUND: In January 2018, Afghanistan introduced the monovalent oral rotavirus vaccine (Rotarix) nationwide, administered as a 2-dose series at six and ten weeks of age. We describe characteristics of intussusception cases and assess potential intussusception risk associated with Rotarix vaccination in Afghan infants. METHODS: Multi-center prospective active hospital-based surveillance for intussusception was conducted from May 2018 to March 2022 in four sentinel sites in Afghanistan. We applied the Brighton Level 1 criteria for intussusception and verified vaccination status by reviewing vaccine cards. We used the self-controlled case series (SCCS) methodology to compare intussusception incidence in the 1 to 21 days after each dose of Rotarix vaccination against non-risk periods. RESULTS: A total of 468 intussusception cases were identified in infants under 12 months, with 264 cases aged between 28 and 245 days having confirmed vaccination status contributing to the SCCS analysis. Most case-patients (98 %) required surgery for treatment, and over half (59 %) of those who underwent surgery required intestinal resection. Nineteen (7 %) case-patients died. Eighty-six percent of case-patients received the first dose of Rotarix, and 69 % received the second dose before intussusception symptom onset. There was no increased risk of intussusception in the 1-7 days (relative incidence: 0.9, 95 % CI: 0.1, 7.5), 8-21 days (1.3, 95 % CI: 0.4, 4.2), or 1-21 days (1.1, 95 % CI: 0.4, 3.4) following receipt of the first dose or in the 1-7 days (0.2, 95 % CI: 0.3, 1.8), 8-21 days (0.7, 95 % CI: 0.3, 1.5), or 1-21 days (0.6, 95 % CI: 0.3, 1.2) following the second dose. CONCLUSION: Rotarix vaccination was not associated with an increased intussusception risk, supporting its continued use in Afghanistan's immunization program. However, there was a high level of death and resection due to intussusception among Afghan infants.
Assuntos
Intussuscepção , Infecções por Rotavirus , Vacinas contra Rotavirus , Lactente , Humanos , Vacinas contra Rotavirus/efeitos adversos , Intussuscepção/induzido quimicamente , Intussuscepção/epidemiologia , Afeganistão/epidemiologia , Estudos Prospectivos , Vacinas Atenuadas/efeitos adversos , Vacinação/efeitos adversos , Vigilância de Produtos Comercializados , Infecções por Rotavirus/epidemiologia , Infecções por Rotavirus/prevenção & controle , Infecções por Rotavirus/complicaçõesRESUMO
BACKGROUND: Afghanistan introduced monovalent rotavirus vaccine (Rotarix) into its national immunisation schedule in January, 2018. While post-licensure studies have shown substantial declines in rotavirus gastroenteritis cases and deaths globally, there is little evidence of rotavirus vaccine effectiveness and impact from low-income countries in Asia. We aimed to evaluate the effectiveness of the Rotarix vaccine and the impact of Rotarix vaccine on rotavirus gastroenteritis hospitalisations (ie, hospital admissions) among children younger than 5 years in Afghanistan. METHODS: We used a test-negative case-control design embedded in an active sentinel surveillance platform to evaluate vaccine effectiveness. Children born on or after Jan 1, 2018, who had documentation of their rotavirus vaccination status and who were admitted for acute gastroenteritis at one of four sentinel hospitals from May, 2018 to December, 2021 were eligible to be included. We used an unconditional logistic regression model to estimate vaccine effectiveness and 95% CIs for a complete series of doses compared with no rotavirus vaccine doses among patients admitted with acute gastroenteritis. Vaccine effectiveness against hospitalisation was calculated as (1â-â[odds of being vaccinated in cases]â/â[odds of being vaccinated in controls])â×â100%. We compared pre-vaccine (2013-15) and post-vaccine (2019-21) surveillance data from two sites to calculate vaccine impact. FINDINGS: The vaccine effectiveness analysis included 1172 cases and 2173 controls. Approximately 2108 (63·0%) of 3345 cases and controls were male, 1237 (37·0%) were female, and 2171 (65·0%) were aged 6-11 months. Two doses of Rotarix were 45% (95% CI 22-62) effective against rotavirus hospitalisation in children aged 6-59 months, adjusting for age, severity, admission year, and rotavirus season. Rotavirus positivity decreased from 51% pre-vaccine to 39% post-vaccine, resulting in a 39% adjusted reduction in rotavirus positivity among children younger than 5 years admitted with acute gastroenteritis. INTERPRETATION: Rotarix showed moderate effectiveness in preventing rotavirus gastroenteritis hospitalisations, consistent with findings in other low-income countries. These findings support the continued administration of the rotavirus vaccine in Afghanistan. FUNDING: Gavi, the Vaccine Alliance. TRANSLATION: For the Dari translation of the abstract see Supplementary Materials section.
Assuntos
Gastroenterite , Infecções por Rotavirus , Vacinas contra Rotavirus , Eficácia de Vacinas , Humanos , Vacinas contra Rotavirus/administração & dosagem , Infecções por Rotavirus/prevenção & controle , Infecções por Rotavirus/epidemiologia , Afeganistão/epidemiologia , Estudos de Casos e Controles , Lactente , Masculino , Feminino , Pré-Escolar , Gastroenterite/prevenção & controle , Gastroenterite/virologia , Gastroenterite/epidemiologia , Eficácia de Vacinas/estatística & dados numéricos , Vacinas Atenuadas/administração & dosagem , Hospitalização/estatística & dados numéricos , Vigilância de Evento Sentinela , Vacinação/estatística & dados numéricosRESUMO
OBJECTIVE: To estimate the potential health impact and cost-effectiveness of nationwide Haemophilus influenzae type b (Hib) vaccination in India. STUDY DESIGN: A decision support model was used, bringing together estimates of demography, epidemiology, Hib vaccine effectiveness, Hib vaccine costs, and health care costs. Scenarios favorable and unfavorable to the vaccine were evaluated. State-level analyses indicate where the vaccine might have the greatest impact and value. RESULTS: Between 2012 and 2031, Hib conjugate vaccination is estimated to prevent over 200â000 child deaths (â¼1% of deaths in children <5 years of age) in India at an incremental cost of US$127 million per year. From a government perspective, state-level cost-effectiveness ranged from US$192 to US$1033 per discounted disability adjusted life years averted. With the inclusion of household health care costs, cost-effectiveness ranged from US$155-US$939 per discounted disability adjusted life year averted. These values are below the World Health Organization thresholds for cost effectiveness of public health interventions. CONCLUSIONS: Hib conjugate vaccination is a cost-effective intervention in all States of India. This conclusion does not alter with plausible changes in key parameters. Although investment in Hib conjugate vaccination would significantly increase the cost of the Universal Immunization Program, about 15% of the incremental cost would be offset by health care cost savings. Efforts should be made to expedite the nationwide introduction of Hib conjugate vaccination in India.
Assuntos
Infecções por Haemophilus/economia , Vacinas Anti-Haemophilus/economia , Haemophilus influenzae tipo b/imunologia , Programas de Imunização/economia , Meningite por Haemophilus/economia , Vacinas Conjugadas/economia , Cápsulas Bacterianas , Criança , Efeitos Psicossociais da Doença , Análise Custo-Benefício , Técnicas de Apoio para a Decisão , Infecções por Haemophilus/imunologia , Infecções por Haemophilus/prevenção & controle , Custos de Cuidados de Saúde , Humanos , Índia , Meningite por Haemophilus/epidemiologia , Meningite por Haemophilus/imunologia , Vacinas Conjugadas/imunologiaRESUMO
BACKGROUND: With the recent postlicensure identification of an increased risk of intussusception with rotavirus vaccine, the 14 Latin American countries currently using rotavirus vaccine must now weigh the health benefits versus risks to assess whether to continue vaccination. To inform policy considerations, we estimated excess intussusception cases and mortality potentially caused by rotavirus vaccine for each of the 14 countries and compared these estimates to hospitalizations and deaths expected to be averted through vaccination. METHODS: We used regional rotavirus disease burden and rotavirus vaccine efficacy data, global natural intussusception and regional rotavirus vaccine-related risk estimates, and country-specific diphtheria, tetanus, and pertussus vaccination coverage rates to estimate rotavirus vaccine coverage rates. We performed a probabilistic sensitivity analysis to account for uncertainty in these parameters. RESULTS: For an aggregate hypothetical birth cohort of 9.5 million infants in these 14 countries, rotavirus vaccine would annually prevent 144 746 (90% confidence interval [CI], 128 821-156 707) hospitalizations and 4124 deaths (90% CI, 3740-4239) due to rotavirus in their first 5 years of life but could cause an additional 172 hospitalizations (90% CI, 126-293) and 10 deaths (90% CI, 6-17) due to intussusception, yielding benefit-risk ratios for hospitalization and death of 841:1 (90% CI, 479:1 to 1142:1) and 395:1 (90% CI, 207:1 to 526:1), respectively. In an uncertainty analysis using 10 000 simulations of our probabilistic parameters, in comparing rotavirus disease averted to intussusception events caused, the hospitalization ratio was never below 100:1, and our death ratio fell below 100:1 only once. CONCLUSIONS: The health benefits of vaccination far outweigh the short-term risks and support continued rotavirus vaccination in Latin America.
Assuntos
Intussuscepção/induzido quimicamente , Intussuscepção/epidemiologia , Infecções por Rotavirus/epidemiologia , Infecções por Rotavirus/prevenção & controle , Vacinas contra Rotavirus/efeitos adversos , Vacinas contra Rotavirus/imunologia , Vacinação/efeitos adversos , Pré-Escolar , Feminino , Hospitalização/estatística & dados numéricos , Humanos , Lactente , Recém-Nascido , Benefícios do Seguro/estatística & dados numéricos , Intussuscepção/mortalidade , América Latina/epidemiologia , Masculino , Medição de Risco , Infecções por Rotavirus/mortalidade , Infecções por Rotavirus/patologia , Vacinas contra Rotavirus/administração & dosagem , Análise de SobrevidaRESUMO
BACKGROUND: To minimize potential risk of intussusception, the World Health Organization (WHO) recommended in 2009 that rotavirus immunization should be initiated by age 15 weeks and completed before 32 weeks. These restrictions could adversely impact vaccination coverage and thereby its health impact, particularly in developing countries where delays in vaccination often occur. METHODS AND FINDINGS: We conducted a modeling study to estimate the number of rotavirus deaths prevented and the number of intussusception deaths caused by vaccination when administered on the restricted schedule versus an unrestricted schedule whereby rotavirus vaccine would be administered with DTP vaccine up to age 3 years. Countries were grouped on the basis of child mortality rates, using WHO data. Inputs were estimates of WHO rotavirus mortality by week of age from a recent study, intussusception mortality based on a literature review, predicted vaccination rates by week of age from USAID Demographic and Health Surveys, the United Nations Children's Fund (UNICEF) Multiple Indicator Cluster Surveys (MICS), and WHO-UNICEF 2010 country-specific coverage estimates, and published estimates of vaccine efficacy and vaccine-associated intussusception risk. On the basis of the error estimates and distributions for model inputs, we conducted 2,000 simulations to obtain median estimates of deaths averted and caused as well as the uncertainty ranges, defined as the 5th-95th percentile, to provide an indication of the uncertainty in the estimates. We estimated that in low and low-middle income countries a restricted schedule would prevent 155,800 rotavirus deaths (5th-95th centiles, 83,300-217,700) while causing potentially 253 intussusception deaths (76-689). In contrast, vaccination without age restrictions would prevent 203,000 rotavirus deaths (102,000-281,500) while potentially causing 547 intussusception deaths (237-1,160). Thus, removing the age restrictions would avert an additional 47,200 rotavirus deaths (18,700-63,700) and cause an additional 294 (161-471) intussusception deaths, for an incremental benefit-risk ratio of 154 deaths averted for every death caused by vaccine. These extra deaths prevented under an unrestricted schedule reflect vaccination of an additional 21%-25% children, beyond the 63%-73% of the children who would be vaccinated under the restricted schedule. Importantly, these estimates err on the side of safety in that they assume high vaccine-associated risk of intussusception and do not account for potential herd immunity or non-fatal outcomes. CONCLUSIONS: Our analysis suggests that in low- and middle-income countries the additional lives saved by removing age restrictions for rotavirus vaccination would far outnumber the potential excess vaccine-associated intussusception deaths. Please see later in the article for the Editors' Summary.
Assuntos
Infecções por Rotavirus/prevenção & controle , Vacinas contra Rotavirus/uso terapêutico , Fatores Etários , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Medição de Risco , Infecções por Rotavirus/epidemiologia , Infecções por Rotavirus/mortalidadeRESUMO
OBJECTIVE: The purpose of this study was to estimate the total annual societal cost of uterine fibroid tumors in the United States, based on direct and indirect costs that include associated obstetric complications. STUDY DESIGN: A systematic review of the literature was conducted to estimate the number of women who seek treatment for symptomatic fibroid tumors annually, the costs of medical and surgical treatment, the amount of work time lost, and obstetric complications that are attributable to fibroid tumors. Total annual costs were converted to 2010 US dollars. A sensitivity analysis was performed. RESULTS: The estimated annual direct costs (surgery, hospital admissions, outpatient visits, and medications) were $4.1-9.4 billion. Estimated lost work-hour costs ranged from $1.55-17.2 billion annually. Obstetric outcomes that were attributed to fibroid tumors resulted in a cost of $238 million to $7.76 billion annually. Uterine fibroid tumors were estimated to cost the United States $5.9-34.4 billion annually. CONCLUSION: Obstetric complications that are associated with fibroid tumors contributed significantly to their economic burden. Lost work-hour costs may account for the largest proportion of societal costs because of fibroid tumors.
Assuntos
Leiomiomatose/economia , Neoplasias Uterinas/economia , Absenteísmo , Adulto , Efeitos Psicossociais da Doença , Feminino , Custos de Cuidados de Saúde , Humanos , Pessoa de Meia-Idade , Estados Unidos/epidemiologiaRESUMO
BACKGROUND: Gabapentin has been shown to reduce opioid use in head and neck cancer patients. Here, we examine the efficacy of prophylactic gabapentin at reducing opioid use in these patients at our institution. METHODS: A retrospective study of patients receiving radiation was performed, using patients from our previous study as controls. Risk factors for opioid use at 3 and 6 months were determined using univariate and multivariate analyses. RESULTS: In total, 53/185 patients were treated with gabapentin, 39.6% of which took opioids at 3 months vs. 58.3% in the non-gabapentin cohort (p = 0.021). Gabapentin was independently associated with less opioid use on multivariate analysis at 3 months (OR 0.47, 95% CI 0.24-0.9). Gastrostomy tube dependence and pretreatment opioid use were associated with chronic opioid use despite gabapentin. CONCLUSIONS: Gabapentin is effective at expediting opioid tapering in head and neck cancer patients who are not gastrostomy tube dependent or taking opioids pretreatment.
Assuntos
Neoplasias de Cabeça e Pescoço , Transtornos Relacionados ao Uso de Opioides , Analgésicos Opioides/uso terapêutico , Gabapentina/uso terapêutico , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/radioterapia , Humanos , Estudos RetrospectivosRESUMO
To characterize the transport of respiratory pathogens during commercial air travel, Computational Fluid Dynamics simulations were performed to track particles expelled by coughing by a passenger assigned to different seats on a Boeing 737 aircraft. Simulation data were post-processed to calculate the amounts of particles inhaled by nearby passengers. Different airflow rates were used, as well as different initial conditions to account for random fluctuations of the flow field. Overall, 80% of the particles were removed from the cabin in 1.3-2.6 min, depending on conditions, and 95% of the particles were removed in 2.4-4.6 min. Reducing airflow increased particle dispersion throughout the cabin but did not increase the highest exposure of nearby passengers. The highest exposure was 0.3% of the nonvolatile mass expelled by the cough, and the median exposure for seats within 3 feet of the cough discharge was 0.1%, which was in line with recent experimental testing.
Assuntos
Movimentos do Ar , Poluição do Ar em Ambientes Fechados/análise , Aeronaves/instrumentação , Simulação por Computador , Tosse/patologia , Hidrodinâmica , Pulmão/fisiopatologia , HumanosRESUMO
OBJECTIVE: To investigate the relationship between treatment modality and chronic opioid use in a large cohort of patients with head and neck cancer. STUDY DESIGN: Retrospective cohort study. SETTING: Single academic center. METHODS: There were 388 patients with head and neck cancer treated between January 2011 and December 2017 who met inclusion criteria. Clinical risk factors for opioid use at 3 and 6 months were determined with univariate and multivariate analyses. RESULTS: The prevalence of opioid use was 43.0% at 3 months and 33.2% at 6 months. On multivariate analysis, primary chemoradiation (odds ratio [OR], 4.04; 95% CI, 1.91-8.55) and surgery with adjuvant chemoradiation (OR, 2.39; 95% CI, 1.09-5.26) were associated with opioid use at 3 months. Additional risk factors at that time point included pretreatment opioid use (OR, 7.63; 95% CI, 4.09-14.21) and decreasing age (OR, 1.03; 95% CI, 1.01-1.06). At 6 months, primary chemoradiation (OR, 2.40; 95% CI, 1.34-4.28), pretreatment opioid use (OR, 5.86; 95% CI, 3.30-10.38), current tobacco use (OR, 2.00; 95% CI, 1.18-3.40), and psychiatric disorder (OR, 1.79; 95% CI, 1.02-3.14) were associated with opioid use. CONCLUSION: Of the patients who receive different treatment modalities, those receiving primary chemoradiation are independently at highest risk for chronic opioid use. Other risk factors include pretreatment opioid use, tobacco use, and a psychiatric disorder. In an effort to reduce their risk of chronic opioid use, preventative strategies should be especially directed to these patients.
Assuntos
Analgésicos Opioides/uso terapêutico , Neoplasias de Cabeça e Pescoço/terapia , Transtornos Relacionados ao Uso de Opioides/epidemiologia , Idoso , Doença Crônica , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Fatores de TempoRESUMO
BACKGROUND: There are plans to introduce the oral rotavirus vaccine Rotarix (GlaxoSmithKline), 1 of 2 recently developed vaccines against rotavirus, in Peru. METHODS: We modeled the cost-effectiveness of adding a rotavirus vaccine to the Peruvian immunization program under 3 scenarios for the timing of vaccination: (1) strictly according to schedule, at 2 and 4 months of age (on time); (2) distributed around the target ages in the same way as the actual timings in the program (flexible); and (3) flexible but assuming vaccination is not initiated for infants >12 weeks of age (restricted). We assumed an introductory price of US $7.50 per dose, and varied the annual rate of price decrease in sensitivity analyses. RESULTS: The discounted cost per disability-adjusted life-year averted for restricted, flexible, and on-time schedules was $621, $615, and $581, respectively. For each of the 3 scenarios, the percentage reduction in deaths due to rotavirus infection was 53%, 66%, and 69%, respectively. The cost per disability-adjusted life-year averted for alternative "what-if" scenarios ranged from $229 (assuming a 1-dose schedule, administered on time) to $1491 (assuming a 2-dose schedule, with half the baseline vaccine efficacy rates and a restricted timing policy). CONCLUSIONS: On the basis of current World Health Organization guidelines, rotavirus vaccination represents a highly cost-effective intervention in Peru. Withholding the vaccine from children who present for their first dose after 12 weeks of age would reduce the number of deaths averted by approximately 20%. A single dose may be more cost-effective than 2 doses, but more evidence on the protection conferred by a single dose is required.
Assuntos
Vacinas contra Rotavirus/economia , Vacinação/economia , Pré-Escolar , Análise Custo-Benefício , Humanos , Lactente , Peru , Infecções por Rotavirus/mortalidadeRESUMO
The duration of the developmental period represents a fundamental axis of life-history variation, yet broad insights regarding the drivers of this diversity are currently lacking. Here, we test mechanistic and ecological explanations for the evolution of developmental duration using embryological data and information on incubation and fledging for 3096 avian species. Developmental phases associated primarily with growth are the longest and most variable, consistent with a role for allometric constraint in determining the duration of development. In addition, developmental durations retain a strong imprint of deep evolutionary history and body size differences among species explain less variation than previously thought. Finally, we reveal ecological correlates of developmental durations, including variables associated with the relative safety of the developmental environment and pressures of breeding phenology. Overall, our results provide broad-scale insight into the relative importance of mechanistic, ecological and evolutionary constraints in shaping the diversification of this key life-history trait.
Assuntos
Aves/fisiologia , Desenvolvimento Embrionário/fisiologia , Características de História de Vida , Modelos Biológicos , Animais , Tamanho Corporal/fisiologia , Conjuntos de Dados como Assunto , Ecologia/métodos , Embrião não Mamífero , Feminino , Masculino , Comportamento de Nidação/fisiologia , Fatores de TempoRESUMO
BACKGROUND: In some countries that have introduced oral rotavirus vaccines, a small but elevated risk of intussusception-a rare bowel disorder-has been reported. Updated estimates on the global epidemiology of intussusception are needed to help predict the potential number of intussusception cases that could be caused by the vaccine in different settings. METHODS: We estimated incidence rates, age distributions and case-fatality ratios (CFRs) for intussusception hospital admissions among children aged <5 years, before the introduction of rotavirus vaccines. We included all articles identified in a systematic review between January 2002 and January 2018, and contacted authors for more granular unpublished data on age distributions. RESULTS: We identified 128 articles containing 227 country datasets (61 age distributions, 71 incidence rates and 95 CFRs). The median age of intussusception ranged from 29 weeks in Africa (83% of cases in the first year of life) to 70 weeks in the Western Pacific region (35% of cases in the first year of life). The median (range) annual incidence of intussusception hospital admissions per 100 000 aged <1 year ranged from 34 (13-56) in Africa to 90 (9-380) in the Western Pacific region. We found extreme differences between the CFRs in Africa (1 death in every 10 hospital admissions) and the rest of the world (fewer than 1 death in every 100-2000 hospital admissions). CONCLUSION: Intussusception epidemiology varies by country and region. Understanding and recognizing these differences will be important when assessing the potential number of intussusception cases associated with rotavirus vaccines.
Assuntos
Intussuscepção/epidemiologia , Intussuscepção/etiologia , Vacinas contra Rotavirus/efeitos adversos , Distribuição por Idade , Pré-Escolar , Hospitalização , Humanos , Incidência , Lactente , Intussuscepção/mortalidade , Infecções por Rotavirus/prevenção & controle , Vacinação/métodosRESUMO
We evaluated the role of allogeneic hematopoietic stem cell transplantation (allo-HSCT) in transplant-naïve patients with relapsed/refractory Hodgkin lymphoma (HL) who failed to attain metabolic complete response (mCR) to 1 to 2 lines of salvage chemotherapyThose with residual but nonprogressive disease assessed by positron emission tomography/computed tomography scanning were eligible. An additional 1 to 2 cycles of salvage therapy were permissible in those with progressive disease or when required to bridge to allo-HSCT, with additional imaging at baseline before transplantation. Conditioning consisted of carmustine, etoposide, cytarabine, melphalan, and alemtuzumab. Donor lymphocyte infusions (DLI) were administered for mixed chimerism or residual or relapsed disease. Eleven patients had sibling donors, 13 had HLA-matched unrelated donors, and 7 had HLA-mismatched unrelated donors. There were no graft failures, and no episodes of grade 4 acute graft-versus-host disease (GVHD); only 19.4% of patients had grade 2 to 3 GVHD, and 22.2% had extensive chronic GVHD. The non-relapse mortality rate was 16.1% (95% confidence interval [CI], 7.1%-34.5%). Relapse incidence was 18.7% (95% CI, 8.2%-39.2%). The study met its primary objective, with a 3-year progression-free survival of 67.7% (95% CI, 48.4%-81.2%). Survival outcomes were equivalent in those with residual metabolically active disease immediately before transplantation (n = 24 [70.8%; 95% CI, 17.2%-83.7%]). Two of the 5 patients who relapsed received DLI and remained in mCR at latest follow-up, with a 3-year overall survival of 80.7% (95% CI, 61.9%-90.8%). We demonstrate encouraging results that establish a potential role for allo-HSCT in selected high-risk patients with HL. This trial was registered at www.clinicaltrials.gov as #NCT00908180.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Doença de Hodgkin/terapia , Adolescente , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Feminino , Doença Enxerto-Hospedeiro/diagnóstico , Doença Enxerto-Hospedeiro/etiologia , Transplante de Células-Tronco Hematopoéticas/métodos , Doença de Hodgkin/diagnóstico , Doença de Hodgkin/mortalidade , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Tomografia por Emissão de Pósitrons , Prognóstico , Recidiva , Indução de Remissão , Análise de Sobrevida , Condicionamento Pré-Transplante/métodos , Transplante Homólogo , Resultado do Tratamento , Adulto JovemRESUMO
OBJECTIVE: Tumor necrosis factor-alpha (TNF-alpha) has been linked to obesity-related insulin resistance and impaired endothelium-dependent vasodilatation, but the mechanisms have not been elucidated. To investigate whether TNF-alpha directly impairs insulin-mediated vasoreactivity in skeletal muscle resistance arteries and the role of c-Jun N-terminal kinase (JNK) in this interference. METHODS AND RESULTS: Insulin-mediated vasoreactivity of isolated resistance arteries of the rat cremaster muscle to insulin (4 to 3400 microU/mL) was studied in the absence and presence of TNF-alpha (10 ng/mL). Although insulin or TNF-alpha alone did not affect arterial diameter, insulin induced dose-dependent vasoconstriction of cremaster resistance arteries in the presence of TNF-alpha, (-12+/-1% at 272 microU/mL). Blocking endothelin receptors in the absence of TNF-alpha uncovered insulin-mediated vasodilatation (18+/-6% at 272 microU/mL) but not in the presence of TNF-alpha (2+/-2% at 272 microU/mL), showing that TNF-alpha inhibits vasodilator effects of insulin. Using digital imaging microscopy, we discovered that TNF-alpha activates JNK in arterial endothelium, visible as an increase in phosphorylated JNK. Moreover, inhibition of JNK with the cell-permeable peptide inhibitor L-JNKI abolished insulin-mediated vasoconstriction in the presence of TNF-alpha, showing that JNK is required for interaction between TNF-alpha and insulin. CONCLUSIONS: TNF-alpha inhibits vasodilator but not vasoconstrictor effects of insulin in skeletal muscle resistance arteries, resulting in insulin-mediated vasoconstriction in the presence of TNF-alpha. This effect of TNF-alpha is critically dependent on TNF-alpha-mediated activation of JNK.
Assuntos
Hipoglicemiantes/farmacologia , Insulina/farmacologia , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Vasoconstrição/efeitos dos fármacos , Acetilcolina/farmacologia , Animais , Artérias/efeitos dos fármacos , Artérias/fisiologia , Endotelina-1/antagonistas & inibidores , Endotelina-1/metabolismo , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/fisiologia , Músculo Esquelético/irrigação sanguínea , Oligopeptídeos/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Ratos Wistar , Resistência Vascular , Vasoconstrição/fisiologia , Vasodilatação/efeitos dos fármacos , Vasodilatação/fisiologia , Vasodilatadores/farmacologiaRESUMO
Insulin-mediated hemodynamic effects in muscle were assessed in relation to insulin resistance in obese and lean Zucker rats. Whole-body glucose infusion rate (GIR), femoral blood flow (FBF), hindleg glucose extraction (HGE), hindleg glucose uptake (HGU), 2-deoxyglucose (DG) uptake into muscles of the lower leg (R(g)), and metabolism of infused 1-methylxanthine (1-MX) to measure capillary recruitment were determined for isogylcemic (4.8 +/- 0.2 mmol/l, lean; 11.7 +/- 0.6 mmol/l, obese) insulin-clamped (20 mU. min(-1). kg(-1) x 2 h) and saline-infused control anesthetized age-matched (20 weeks) lean and obese animals. Obese rats (445 +/- 5 g) were less responsive to insulin than lean animals (322 +/- 4 g) for GIR (7.7 +/- 1.4 vs. 22.2 +/- 1.1 mg. min(-1). kg(-1), respectively), and when compared with saline-infused controls there was no increase due to insulin by obese rats in FBF, HGE, HGU, and R(g) of soleus, plantaris, red gastrocnemius, white gastrocnemius, extensor digitorum longus (EDL), or tibialis muscles. In contrast, lean animals showed marked increases due to insulin in FBF (5.3-fold), HGE (5-fold), HGU (8-fold), and R(g) ( approximately 5.6-fold). Basal (saline) hindleg 1-MX metabolism was 1.5-fold higher in lean than in obese Zucker rats, and insulin increased in only that of the lean. Hindleg 1-MX metabolism in the obese decreased slightly in response to insulin, thus postinsulin lean was 2.6-fold that of the postinsulin obese. We conclude that muscle insulin resistance of obese Zucker rats is accompanied by impaired hemodynamic responses to insulin, including capillary recruitment and FBF.
Assuntos
Insulina/metabolismo , Músculo Esquelético/irrigação sanguínea , Obesidade/fisiopatologia , Animais , Glicemia/metabolismo , Hemodinâmica/fisiologia , Ratos , Ratos Zucker , Xantinas/sangueRESUMO
INTRODUCTION: Rotavirus is the leading cause of acute severe diarrhea among children under 5 globally and one of the leading causes of death attributable to diarrhea. Among African children hospitalized with diarrhea, 38% of the cases are due to rotavirus. In Senegal, rotavirus deaths are estimated to represent 5.4% of all deaths among children under 5. Along with the substantial disease burden, there is a growing awareness of the economic burden created by diarrheal disease. This analysis aims to provide policymakers with more consistent and reliable economic evidence to support the decision-making process about the introduction and maintenance of a rotavirus vaccine program. METHODS: The study was conducted using the processes and tools first established by the Pan American Health Organization's ProVac Initiative in the Latin American region. TRIVAC version 2.0, an Excel-based model, was used to perform the analysis. The costs and health outcomes were calculated for 20 successive birth cohorts (2014-2033). Model inputs were gathered from local, national, and international sources with the guidance of a Senegalese group of experts including local pediatricians, personnel from the Ministry of Health and the World Health Organization, as well as disease-surveillance and laboratory specialists. RESULTS: The cost per disability-adjusted life-year (DALY) averted, discounted at 3%, is US$ 92 from the health care provider perspective and US$ 73 from the societal perspective. For the 20 cohorts, the vaccine is projected to prevent more than 2 million cases of rotavirus and to avert more than 8500 deaths. The proportion of rotavirus deaths averted is estimated to be 42%. For 20 cohorts, the discounted net costs of the program were estimated to be US$ 17.6 million from the healthcare provider perspective and US$ 13.8 million from the societal perspective. CONCLUSION: From both perspectives, introducing the rotavirus vaccine is highly cost-effective compared to no vaccination. The results are consistent with those found in many African countries. The ProVac process and tools contributed to a collaborative, country-led process in Senegal that provides a platform for gathering and reporting evidence for vaccine decision-making.
Assuntos
Infecções por Rotavirus/economia , Infecções por Rotavirus/prevenção & controle , Vacinas contra Rotavirus/economia , Vacinas contra Rotavirus/imunologia , Vacinação/economia , Pré-Escolar , Análise Custo-Benefício , Diarreia/economia , Diarreia/epidemiologia , Diarreia/prevenção & controle , Política de Saúde , Humanos , Programas de Imunização , Lactente , Recém-Nascido , Modelos Estatísticos , Infecções por Rotavirus/epidemiologia , Vacinas contra Rotavirus/administração & dosagem , Senegal/epidemiologia , Vacinação/métodosRESUMO
INTRODUCTION: The Pan American Health Organization (PAHO) created the ProVac Initiative in 2004 with the goal of strengthening national technical capacity to make evidence-based decisions on new vaccine introduction, focusing on economic evaluations. In view of the 10th anniversary of the ProVac Initiative, this article describes its progress and reflects on lessons learned to guide the next phase. METHODS: We quantified the output of the Initiative's capacity-building efforts and critically assess its progress toward achieving the milestones originally proposed in 2004. Additionally, we reviewed how country studies supported by ProVac have directly informed and strengthened the deliberations around new vaccine introduction. RESULTS: Since 2004, ProVac has conducted four regional workshops and supported 24 health economic analyses in 15 Latin American and Caribbean countries. Five Regional Centers of Excellence were funded, resulting in six operational research projects and nine publications. Twenty four decisions on new vaccine introductions were supported with ProVac studies. Enduring products include the TRIVAC and CERVIVAC cost-effectiveness models, the COSTVAC program costing model, methodological guides, workshop training materials and the OLIVES on-line data repository. Ten NITAGs were strengthened through ProVac activities. DISCUSSION: The evidence accumulated suggests that initiatives with emphasis on sustainable training and direct support for countries to generate evidence themselves, can help accelerate the introduction of the most valuable new vaccines. International and Regional Networks of Collaborators are necessary to provide technical support and tools to national teams conducting analyses. Timeliness, integration, quality and country ownership of the process are four necessary guiding principles for national economic evaluations to have an impact on policymaking. It would be an asset to have a model that offers different levels of complexity to choose from depending on the vaccine being evaluated, the availability of data, and the time frame of the decision. CONCLUSION: Decision support for new vaccine introduction in low- and middle-income countries is critical to maximizing the efficiency and impact of vaccination programs. Global technical cooperation will be required. In the future, PAHO and WHO have an opportunity to expand the reach of the ProVac philosophy, models, and methods to additional regions and countries requiring real-time support. The ProVac Global Initiative is proposed as an effective mechanism to do so.
Assuntos
Doenças Transmissíveis/economia , Técnicas de Apoio para a Decisão , Custos de Cuidados de Saúde , Programas de Imunização/economia , Vacinação/economia , Vacinas/economia , Vacinas/imunologia , Financiamento de Capital , Região do Caribe , Doenças Transmissíveis/epidemiologia , Política de Saúde , Humanos , Programas de Imunização/organização & administração , América Latina , Vacinação/métodos , Vacinas/administração & dosagemRESUMO
OBJECTIVES: To evaluate the impact and cost-effectiveness of introducing universal human papillomavirus (HPV) vaccination into the National Immunization Program (NIP) in Brazil. METHODS: The Excel-based CERVIVAC decision support model was used to compare two strategies: (1) status quo (with current screening program) and (2) vaccination of a cohort of 11-year-old girls. National parameters for the epidemiology and costs of cervical cancer were estimated in depth. The estimates were based on data from the health information systems of the public health system, the PNAD 2008 national household survey, and relevant scientific literature on Brazil. Costs are expressed in 2008 United States dollars (US$), and a 5% discount rate is applied to both future costs and future health benefits. RESULTS: Introducing the HPV vaccine would reduce the burden of disease. The model estimated there would be 229 deaths avoided and 6677 disability-adjusted life years (DALYs) averted in the vaccinated cohort. The incremental cost-effectiveness ratios (ICERs) per DALY averted from the perspectives of the government (US$ 7663), health system (US$ 7412), and society (US$ 7298) would be considered cost-effective, according to the parameters adopted by the World Health Organization. In the sensitivity analysis, the ICERs were most sensitive to variations in discount rate, disease burden, vaccine efficacy, and proportion of cervical cancer caused by types 16 and 18. However, universal HPV vaccination remained a cost-effective strategy in most variations of the key estimates. CONCLUSIONS: Vaccine introduction could contribute additional benefits in controlling cervical cancer, but it requires large investments by the NIP. Among the essential conditions for attaining the expected favorable results are immunization program sustainability, equity in a population perspective, improvement of the screening program, and development of a surveillance system.