terça-feira, 31 de julho de 2012

Essas medalhas são para comemorar


Brasileiros ganham ouro em olimpíada de matemática



COLABORAÇÃO PARA A FOLHA


Em ritmo de Olimpíada, os brasileiros Renan Henrique Finder, Matheus Secco, Hugo Fonseca Araújo e Davi Lopes Alves de Medeiros conquistaram medalha de ouro. Mas, ao contrário do esporte, a Competição Internacional de Matemática para Estudantes Universitários não é realizada em Londres, mas em Blagoevgrad, na Bulgária.

A competição que reúne 318 estudantes de vários países começou no dia 26 e será encerrada amanhã (1°).
O Brasil também ganhou duas medalhas de prata e nove de bronze. A delegação brasileira, selecionada por meio da Olimpíada Brasileira de Matemática, contou com 23 participantes de dez universidades. Os vencedores do ouro são da Universidade Federal do Ceará.
Eles foram liderados pelos professores Samuel Barbosa Feitosa, de Salvador (BA), e Fábio Dias Moreira, do Rio de Janeiro (RJ).

COMPETIÇÃO
Os estudantes têm cinco horas para responder cada uma das provas aplicadas em dois dias consecutivos. Os testes envolvem os campos da álgebra, análise real e complexa e combinatória. As questões devem ser respondidas em inglês.
Segundo o Instituto Nacional de Matemática Pura e Aplicada, o Brasil já conquistou 99 medalhas desde 2003, quando entrou na competição mundial.
No total, o país tem uma medalha de ouro especial, 16 ouros, 31 de prata e 51 de bronze.

domingo, 29 de julho de 2012

Tuberculose em crianças - The New england J Med


Review Article
Current Concepts

Tuberculosis in Children

Carlos M. Perez-Velez, M.D., and Ben J. Marais, M.D., Ph.D.
N Engl J Med 2012; 367:348-361July 26, 2012

Widespread implementation of the strategy of directly observed treatment short course (DOTS) during the 1990s resulted in improved global control of tuberculosis.1 However, its effectiveness has been limited in areas where poverty and infection with the human immunodeficiency virus (HIV) or drug-resistant tuberculosis are prevalent, and the emphasis on a positive sputum smear as the diagnostic criterion actually excludes most children from care.2 Tuberculosis remains a major but often unrecognized cause of disease and death among children in areas where the disease is endemic3; service delivery in such areas is hampered by the absence of pragmatic strategies to guide diagnosis and management. This article provides a brief overview of basic principles, current controversies, and recent advances related to the care of children with tuberculosis, with an emphasis on intrathoracic disease.

Disease Burden and Recent Epidemiologic Shifts

Poor ascertainment and reporting of cases of tuberculosis prevent accurate estimation of the global burden of disease from tuberculosis in children.4 Among the 4,452,860 new cases reported in 2010 by the 22 countries with the highest burden of disease from tuberculosis, only 157,135, or 3.5% (range, 0.1 to 15.0), were in children. Best estimates suggest that children (defined as persons younger than 15 years of age) account for approximately 11% of the burden of disease from tuberculosis,5 suggesting that just over 332,000 cases of tuberculosis in children went undiagnosed or unreported in these countries. Although overdiagnosis does occur, underdiagnosis is the rule in most areas where there is a high burden of disease and children with tuberculosis can access services only through referral hospitals. The problem of underdiagnosis in children is illustrated by the low pediatric caseload reported in four countries with a high disease burden, where rates exceeding 10% of all reported cases would be expected: Russia, 0.8%; India, 1.1%; Nigeria, 1.4%; and Brazil, 3.5%.1 In areas such as North America and Western Europe, where there is minimal internal transmission and routine provision of postexposure prophylaxis, a smaller proportion of children is affected, and most cases of childhood tuberculosis occur in immigrant populations.6,7
Coinfection with HIV has had a major epidemiologic effect, especially in sub-Saharan Africa. Apart from leading to an increase in the absolute number of patients with tuberculosis, it has induced a pronounced shift in the age and sex of patients toward young women of childbearing age.8 The effect of this demographic shift can be seen in the high rates of exposure to tuberculosis among infants born to mothers infected with HIV9 and in the high rates of tuberculosis among infants infected with HIV.10 Early initiation of antiretroviral therapy is the single most important intervention for reducing overall mortality and the risk of tuberculosis among HIV-infected infants,11 with isoniazid preventive therapy providing additional benefit.12
The emergence of drug-resistant tuberculosis poses a major threat to global tuberculosis control.13 The initial complacency in addressing the problem was influenced by studies indicating that the acquisition of isoniazid resistance reduced the pathogenicity of the strain.14 However, the development of multidrug-resistant tuberculosis (characterized by resistance to isoniazid and rifampin) in children exposed to persons with infectious drug-resistant tuberculosis,15 as well as its clonal spread in New York City16 and the Russian prison system,17 has provided clinical evidence of the transmissibility of multidrug-resistant strains. Additional proof was provided by an explosive outbreak of extensively drug-resistant tuberculosis (multidrug-resistant bacteria with additional resistance to a fluoroquinolone and a second-line injectable agent) among patients with HIV infection in South Africa.18 Although the incidence of drug-resistant tuberculosis among children is unknown, pediatric cases provide a valuable epidemiologic perspective, since they reflect ongoing transmission within communities. In places where the rates of drug-resistant tuberculosis in children have been monitored, the rates among children were similar to those among adults from the same community.15 The World Health Organization (WHO) estimated that in 2008, 3.6% of incident tuberculosis cases globally were of the multidrug-resistant or extensively drug-resistant type, which suggests that there was a similar burden of this type of disease among children.13

Natural History of Disease

An understanding of the natural history of tuberculosis is required to appreciate both the variations in susceptibility to disease and the diverse spectrum of clinical manifestations observed in children. Meticulous descriptions of tuberculosis in the literature published before the introduction of chemotherapy provide valuable insight into the sequence of events that follows primary infection with Mycobacterium tuberculosis (Table 1Table 1Clinical Syndromes Associated with Tuberculosis in Children. and Figure 1Figure 1Clinical Syndromes of Intrathoracic Tuberculosis in Children.).19,20 An important observation documented in these earlier studies was the presence of transient hilar adenopathy, and even excretion of M. tuberculosis, in children who had never had progression to disease.21 This finding poses a major problem in case definition for studies, such as vaccine efficacy trials, that use active case-finding strategies in populations of asymptomatic children who have been exposed to persons with infectious disease.22 The recent formulation of an international consensus on reference standards and uniform research methodology should facilitate progress.23-25
The sequence of events that follows reinfection (which is common in areas where tuberculosis is endemic) remains poorly defined. In cases of recurrent tuberculosis, strain typing makes it possible to differentiate relapse from reinfection but cannot be used to quantify the risk of reinfection. Composite data analysis suggests that there is a 79% reduction in the risk of disease progression among previously infected immunocompetent adults as compared with previously uninfected adults after documented exposure26; however, the epidemic contribution made by reinfection depends on the frequency of its occurrence in a particular environment.
It is important to differentiate infection from disease, since infection is a common event and the approaches to managing the two conditions are very different. Disease progression is usually indicated by persistent, nonremitting symptoms, although the rate of progression is variable.21 In the vast majority of cases (>90%), disease occurs within 1 year after the primary infection, with the youngest children at greatest risk for progression. The risk profile is bimodal, with adolescents being at increased risk.21 Exploring the mechanisms underlying the increased risk and the sudden switch in phenotype toward adult-type cavitary disease that occurs with the onset of puberty should provide new insights into the immunopathogenesis of tuberculosis.27

Approaches to Diagnosis

Children are usually evaluated for tuberculosis after presenting with symptoms or signs suggestive of disease (passive case finding) or as a result of contact investigation or routine immigration screening (active case finding). The clinical presentation of children whose infection is detected through active case finding differs from that of children whose infection is detected through passive case finding, with the former group often having infection but not disease or having disease in a very early phase. Among children in whom M. tuberculosis infection is detected, young children and those with recent exposure are at increased risk for progression to disease. Knowledge of the child's status regarding the likelihood of exposure changes the pretest probability of disease and the positive predictive value of subsequent investigations.

Clinical Evaluation

Taking a careful patient history is essential for exploring the nature of the exposure and accurately characterizing the symptoms.28 The diversity of the clinical presentation and the nonspecific nature of most symptoms complicate diagnosis. Constitutional symptoms often include failure to thrive (deviation from the expected growth-curve trajectory) and reduced playfulness; low-grade or intermittent fever is seen less frequently.28 With airway involvement, the usual presenting symptom is a persistent, nonremitting cough or wheeze that is unresponsive to the treatment for likely alternative causes. Clinical signs are often subtle, and no diagnostic scoring system has been adequately validated29; the sensitivity and specificity of the clinical diagnostic approaches for tuberculosis are particularly poor in children with HIV infection.30

Imaging Studies

In clinical practice, chest radiography is one of the most useful diagnostic studies. Both frontal and lateral views should be obtained, since a lateral view assists in the assessment of the mediastinal and hilar areas. The radiographic findings vary, but pronounced hilar adenopathy, with or without airway compression, is highly suggestive of tuberculosis. The International Union against Tuberculosis and Lung Disease compiled an atlas of illustrative cases.31 Unfortunately, the technical quality of the radiographs obtained in areas where tuberculosis is endemic is often poor or radiographic facilities are not available.
Ultrasonography is useful in confirming the presence of pericardial or pleural effusions and abdominal lymphadenopathy. High-resolution computed tomography (CT) offers excellent anatomical visualization,32 but because of the high cost of CT and the high level of radiation to which the patient is exposed, as compared with other forms of imaging, it should be reserved for complicated cases. Both CT and magnetic resonance imaging (MRI) are particularly helpful in visualizing the intracranial effects of disease, although MRI is more sensitive to the detection of brain-stem lesions and early perfusion defects in patients with tuberculous meningitis, and it also allows superior evaluation of the spine and soft tissues.33

Laboratory Studies


Table 2Table 2Diagnostic Studies for Tuberculosis in Children. provides an overview of the laboratory examinations used in the diagnosis of tuberculosis. (See the Supplementary Appendix, available with the full text of this article at NEJM.org, for a list of references that includes recent comprehensive studies that focus on children.) Microscopical examination of sputum smears is the cornerstone of diagnosis in most countries, but its usefulness is limited in young children with paucibacillary disease who are unable to expectorate. Both the tuberculin skin test and the interferon-γ release assay fail to differentiate M. tuberculosis infection from active disease. The WHO recommends that the assay not be used in place of the tuberculin skin test,34 although the two tests may be complementary, improving the sensitivity or specificity of the assessment in specific clinical circumstances.35
Collecting specimens of spontaneously produced sputum in young children is problematic; gastric aspiration and sputum induction (with or without laryngopharyngeal suction) are feasible alternative methods of collection.36 The “string test” (which involves the use of an esophagogastroduodenal nylon yarn that can absorb swallowed sputum) works well in adults with HIV infection who have little sputum,37 and preliminary test results in children seem promising.38 Fine-needle aspiration biopsy is very useful in children with a peripheral lymph-node mass.39 Although the Xpert-MTB/RIF assay (Cepheid) is less sensitive than liquid cultures for the detection of M. tuberculosis in both children and adults, it provides results quickly, is highly specific, and detects resistance to rifampin. When two sputum samples are used, the assay detects three times as many cases as when microscopy is used40 but only about 70% of the cases when liquid culture is used.41,42 Currently, access to the Xpert-MTB/RIF assay is limited, but the efforts of the Global Laboratory Initiative, a working group of the Stop TB Partnership, should increase its availability.
Each of the diagnostic approaches described has limitations. However, when a combination of clinical, radiologic, laboratory, and histopathologic findings are consistent with a diagnosis of tuberculosis and there is epidemiologic evidence of exposure to tuberculosis or immunologic evidence of M. tuberculosis infection, an accurate diagnosis is possible in most cases.42

Principles of Disease Management

Although every effort should be made to attain bacteriologic confirmation of disease, confirmation rates remain low, and treatment initiation should not be delayed in immunologically vulnerable children. Unfortunately, some tuberculosis-control programs will not initiate treatment without bacteriologic confirmation, citing the risk of adverse events from treatment and concerns about amplifying drug resistance. However, adverse events are rare in young children who are treated with first-line tuberculosis drugs, and they are at low risk for acquiring or transmitting drug-resistant tuberculosis. Despite differences between adult and pediatric tuberculosis (see Table S1 in the Supplementary Appendix), the principles of disease management are similar. The purpose of tuberculosis treatment is to cure the individual patient, whereas the intent of public health efforts is to terminate transmission and prevent the emergence of drug resistance. Rapidly metabolizing bacilli are quickly killed by bactericidal agents with high activity, thereby terminating transmission, ameliorating symptoms, and decreasing the risk of drug resistance (by reducing the population from which drug-resistant mutants emerge). The use of drugs with sterilizing activity is required to eradicate persistent subpopulations of intermittently metabolizing bacilli, thereby preventing relapse and effecting a long-term cure. Pragmatic disease classification should guide case management (Figure 2Figure 2Algorithm for the Diagnosis and Classification of Tuberculosis in Children.).
The most important variables to consider in disease management are bacillary load and anatomical location. Drug resistance should be considered in children from areas with a high prevalence of drug-resistant tuberculosis and in those who have had documented contact with a person with drug-resistant disease, with someone who died during treatment for tuberculosis or who is not adhering to therapy, or with someone who is undergoing retreatment for tuberculosis. Young children with uncomplicated disease who are from areas with a low prevalence of isoniazid resistance can be treated with three drugs (isoniazid, rifampin, and pyrazinamide) during the 2-month intensive phase of treatment, followed by isoniazid and rifampin only during the 4-month continuation phase.43 However, children who have extensive or cavitary lung disease (either of which suggests a high bacillary load) or who are from areas with a high prevalence of isoniazid resistance should receive a fourth drug (ethambutol, which is safe in children of all ages) during the 2-month intensive phase of treatment.43 Table S2 in the Supplementary Appendix summarizes the mechanism of action, main adverse effects, and recommended pediatric dosages of drugs prescribed for the first-line treatment of tuberculosis.
In the absence of drug resistance, the most frequent cause of a poor response to treatment is nonadherence to the regimen. Although empirical evidence of the value of DOT is limited, as a method of medication administration, it is preferable to unsupervised administration and to administration by a parent.44 In most instances, a recurrence of tuberculosis more than 12 months after treatment represents reinfection. Standard first-line treatment is appropriate in the absence of exposure to a person who is believed to have drug-resistant tuberculosis. Use of an escalated retreatment regimen that includes streptomycin is discouraged.43 When there is a poor clinical response in a patient with a history of adherence to treatment, a reevaluation of the diagnosis should be conducted, including consideration of the immune reconstitution inflammatory syndrome (IRIS) and drug resistance. Principles for the management of drug-resistant tuberculosis in children have been summarized elsewhere,45 and excellent outcomes have been reported.46
Immune recovery after the initiation of antiretroviral treatment for HIV-coinfected individuals or nutritional rehabilitation may unmask subclinical disease or induce paradoxical deterioration, despite adequate treatment for tuberculosis. A finding of IRIS does not indicate treatment failure, and treatment should not be interrupted; patients with severe IRIS may require a course of glucocorticoids. Despite the risk of IRIS, data on adults indicate that antiretroviral therapy is most effective when initiated within 8 weeks after the start of tuberculosis treatment, or for patients with severely compromised immune systems, within 2 to 4 weeks after the start of treatment.47 The only exception would be patients with central nervous system tuberculosis, in whom IRIS can have devastating consequences.48 With HIV-associated tuberculosis, treatment should be given daily, and a prolonged course may be required, depending on the degree to which the patient's immune system has been compromised and the extent of disease.49,50

Prevention and Control

Transmission of tuberculosis within health care facilities is a particular concern in settings where immunologically vulnerable children may be exposed. In hospitals and clinics, careful consideration should be given to areas where patients are treated and to air-exchange patterns. It is also important to recognize that symptomatic parents or caregivers may pose transmission risks.51 Vaccination with bacille Calmette–Guérin (BCG) reduces the risk of disseminated (miliary) disease and tuberculosis meningitis in young children but offers no consistent protection against adult-type tuberculosis.52 No benefit of BCG vaccination has been established in HIV-infected children, and it is contraindicated in such children because of the risk of disseminated BCG disease.53 The development of a safe and effective vaccine remains a top priority among global health researchers.
With good adherence, a 6-month course of isoniazid preventive therapy provides excellent protection against tuberculosis disease.54 Despite universal recommendations regarding the provision of preventive therapy and strong evidence of the greatly increased risk of tuberculosis and the increased mortality among children in close contact with persons who have tuberculosis,55 the implementation of preventive strategies remains poor. Pragmatic solutions are required to close the pronounced gap between policy and practice.56 Parents are often reluctant to provide preventive treatment for an otherwise well child, and the long duration of preventive therapy is a source of further discouragement. One study showed that a 3-month course of preventive therapy with isoniazid and rifampin was similar in efficacy to a 9-month course of isoniazid alone.57 A regimen of 12 doses of weekly rifapentine and isoniazid has been shown to be efficacious in adults,58 but this regimen is not yet recommended for children younger than 12 years of age because specific data on safety and efficacy in this age group are required. The efficacy of abbreviated regimens has not been well studied in children with HIV infection. A disadvantage of the regimens that include rifampin or rifapentine is the interactivity of these drugs with the protease inhibitors included in the antiretroviral therapy provided for infection with HIV49,50; rifabutin is less reactive, but its use in preventive therapy regimens has not been evaluated.
Although the value of postexposure prophylaxis is universally acknowledged, the value of preexposure prophylaxis remains in question. Successive randomized, controlled trials of preexposure prophylaxis in children with HIV infection have had contradictory findings. The first of these trials, involving children with minimal access to antiretroviral therapy, was discontinued because of increased mortality in the placebo group.59 The reduction in mortality among those receiving isoniazid preventive therapy was confined to the first 2 to 3 months of treatment, raising the possibility that subclinical tuberculosis was present at trial entry. The second trial enrolled young infants (3 to 4 months of age) who had been exposed to HIV but had no known exposure to tuberculosis.60 The infants were randomly assigned to receive open-label isoniazid or placebo; those who were infected with HIV also received early antiretroviral therapy. All infants were closely monitored for subsequent exposure to tuberculosis. The investigators found no significant difference in the incidence of tuberculosis or mortality between the treatment and placebo groups, suggesting that preexposure prophylaxis against tuberculosis has little value if HIV-infected infants are enrolled in management programs early, with meticulous monitoring for tuberculosis exposure and provision of postexposure prophylaxis. However, the value of preexposure prophylaxis in areas where monitoring for tuberculosis exposure is likely to be poor remains unresolved.49,54
With the use of isoniazid preventive therapy after the completion of tuberculosis treatment in HIV-infected adults, it has been estimated that 83 recurrences can be prevented for every 1000 cases treated.12 The WHO recommends isoniazid preventive therapy for 6 to 36 months after the completion of tuberculosis treatment in all patients with HIV infection, including children who live in areas with a high prevalence of tuberculosis. However, the added value of preventive therapy as compared with ongoing screening for tuberculosis exposure and meticulous postexposure prophylaxis has not been evaluated.
It is possible to drastically reduce the morbidity and mortality associated with pediatric tuberculosis if case detection is improved and preventive therapy and curative treatment are made more accessible globally. Many challenges and research priorities remain (Table S3 in the Supplementary Appendix), but while we await the development of new vaccines, better diagnostics, and shorter treatment regimens, much can be achieved with pragmatic approaches and sensible application of existing tools.
Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.
No potential conflict of interest relevant to this article was reported.
We thank Mario Perez, M.D., for his valuable assistance with an earlier version of Figure 1.

Source Information

From Grupo Tuberculosis Valle-Colorado and Clínica León XIII, IPS Universidad de Antioquia, Medellín, Colombia (C.M.P.-V.); and the Sydney Emerging Infections and Biosecurity Institute and Children's Hospital at Westmead, University of Sydney, Sydney (B.J.M.).
Address reprint requests to Dr. Marais at the Clinical School, Children's Hospital at Westmead, Locked Bag 4001, Westmead, Sydney, NSW 2145, Australia, or at .

O mensalão comentado no The economics

Justice delayed

The politicians accused of involvement in a vast vote-buying scheme, along with their associates, will face trial at last


A SLEAZY reputation has historically been little impediment to a long career in Brazilian politics. Fernando Collor, a former president impeached in 1992 and found guilty of corruption while in office, is back in the Senate. Paulo Maluf, who has been charged in the United States with theft related to a kickback scheme during his terms as governor and mayor of São Paulo, is now a congressman. Congressional permission is required for ministers and legislators to be investigated for crimes committed in office, and only the Supreme Court can try them. That lets politicians get away with murder—sometimes literally. Arnon de Mello, a senator (and Mr Collor’s father) shot and killed another politician in the Senate in 1963, but was never tried.
Against this backdrop, the trial, due to start on August 2nd, of 38 people accused of involvement in Brazil’s biggest corruption scandal of recent years is a rarity. The central accusation in the “mensalão” (big monthly stipend) case is that, after coming to power in 2003, the Workers’ Party (PT) diverted money from the advertising budgets and pension schemes of state-controlled firms to pay off legislators from allied parties, in return for their support. The allegations first surfaced in 2005, and the Supreme Court took on the case in 2007. Only now are the judges ready to try it.
The defendants face a range of charges including corruption, conspiracy, embezzlement, money-laundering and misusing public funds. Some admit they helped finance political parties off the books, which is illegal but common in Brazil. Others deny any role in the illicit payments.
Simply hearing the charges, evidence and statements will take months. The proceedings may be strung out further: some defendants’ lawyers will probably argue that trying their clients at the Supreme Court denies their constitutional right to appeal against any guilty verdict. (Only a few defendants held high office, but the Supreme Court will try them all together, since the charges are interconnected.)
Such legal manoeuvring could push many of the crimes past Brazil’s criminal-friendly statute of limitations. The few defendants still active within the PT may also want to delay the verdict until after municipal elections later this year, lest any convictions hurt the party in tight races.
The political fallout from the mensalão trial will probably be modest. The scandal shredded the PT’s claim to represent a new, cleaner politics, and Brazilians tell pollsters they disapprove of corruption. However, says Alberto Almeida of Instituto Análise, a political consultancy, they also assume that most politicians are dirty, and hence ignore even blatant graft when they vote. Luiz Inácio Lula da Silva, the president when the payments occurred, was re-elected one year after the news broke. He was popular for improving the lives of the poor, not for crusading against corruption, and neither his friends nor his foes are likely to change their views based on the mensalão verdicts.
Lula’s chosen successor, Dilma Rousseff, is even less likely to suffer political harm. None of the defendants in the case is close to her. And by sacking a string of ministers accused of corruption early in her term, she largely shielded herself from the threat of taint by association.
Instead, the main effect of the trial will be to chip away at Brazil’s culture of impunity for the powerful. Politicians regularly use their immunity to block inquiries involving their allies. Other wrongdoers remain free while their wily lawyers mount appeal after appeal. Antônio Pimenta Neves, a journalist convicted in 2006 of killing his ex-girlfriend in 2000, appealed all the way to the Supreme Court and was jailed only last year.
Abolishing such tactics demands ambitious reforms, which are unlikely in the near future. Without them, efforts to clean up government must work within the existing legal framework. That the mensalão affair has even come to trial is progress: jail for corrupt politicians may still be unlikely, but it is no longer unthinkable.
Meanwhile, greater transparency about public spending is making theft from the treasury harder. Strong regulatory bodies can close down government projects if they suspect budgets have been padded (though such safeguards can be bypassed in supposedly urgent situations, such as building stadiums for the 2014 World Cup). A new freedom-of-information law should make it harder for politicians to stuff the public payroll with cronies. “The good news”, says João Castro Neves of the Eurasia Group, a consultancy, “is that to be corrupt in Brazil you need to be more creative now than ten or 15 years ago.”

sábado, 21 de julho de 2012

A falta de exercicios físicos entre os paises do Mundo

Veja como que no Brasil 40-50% da população não prática exercicios. 

One potato, two potato, three potato

An effort to count the world’s sloths

A PAPER in the Lancet, shamelessly timed to coincide with the Olympic games, compares countries’ rates of physical activity. The study it describes, led by Pedro Hallal of the Federal University of Pelotas, in Brazil, is the most complete portrait yet of the world’s busy bees and couch potatoes. It suggests that nearly a third of adults, 31%, are not getting enough exercise.
That rates of exercise have declined is hardly a new discovery. Since the beginning of the industrial revolution, technology and economic growth have conspired to create a world in which the flexing of muscles is more and more an option rather than a necessity. But only recently have enough good data been collected from enough places to carry out the sort of analysis Dr Hallal and his colleagues have engaged in.
In all, they were able to pool data from 122 countries, covering 89% of the world’s population. They considered sufficient physical activity to be 30 minutes of moderate exercise five days a week, 20 minutes of vigorous exercise three days a week, or some combination of the two.
There are common themes in different places. Unsurprisingly, people in rich countries are less active than those in poor ones, and old people are less active than young ones. Less obviously, women tend to exercise less than men—34% are inactive, compared with 28% of men. But there are exceptions. The women of Croatia, Finland, Iraq and Luxembourg, for example, move more than their male countrymen.
Malta wins the race for most slothful country, with 72% of adults getting too little exercise. Swaziland and Saudi Arabia slouch in close behind, with 69%. In Bangladesh, by contrast, just 5% of adults fail to exercise enough. Surprisingly, America does not live up to its sluggish reputation. Six Americans in ten are sufficiently active by Dr Hallal’s definition, compared with fewer than four in ten Britons.
In an accompanying analysis of people’s habits, Dr Hallal found equally wide differences. In South-East Asia fewer than a quarter sit for at least four hours each day; in Europe 64% do. And even neighbours may differ. Only 2% of Swiss walk to work, whereas 23% of Germans do so.
These high rates of inactivity are worrying. Paradoxically, human beings seem to have evolved to benefit from exercise while eschewing it whenever they can. In a state of nature it would be impossible to live a life that did not provide enough of it to be beneficial, while over-exercising would use up scarce calories to little advantage. But that no longer pertains. According to another paper in the Lancet, insufficient activity these days has nearly the same effect on life expectancy as smoking

Tradução

Um trabalho publicado no Lancet,  programado para coincidir com os Jogos Olímpicos, compara taxas de países de atividade física. O estudo descreve, liderada por Pedro Hallal da Universidade Federal de Pelotas, no Brasil, é o retrato mais completo ainda de abelhas ocupadas do mundo e batatas de sofá. Sugere-se que quase um terço dos adultos, 31%, não estão recebendo bastante exercício.

Que taxas de exercício tem diminuído é quase uma nova descoberta. Desde o início da revolução industrial, a tecnologia e o crescimento económico conspiraram para criar um mundo em que a flexão dos músculos é mais uma opção, em vez de uma necessidade. Mas só recentemente bastante bons dados foram coletados a partir de locais suficientes para o tipo de análise Dr Hallal e seus colegas se envolveram em.

Ao todo, puderam para dados do pool de 122 países, abrangendo 89% da população mundial. Considera-se atividade física suficiente para ser 30 minutos de exercício moderado, cinco dias por semana, 20 minutos de exercício vigoroso três dias por semana, ou alguma combinação dos dois.

Existem temas comuns em lugares diferentes. Sem surpresa, as pessoas nos países ricos são menos ativas do que os pobres, e as pessoas idosas são menos ativas do que os jovens. Menos obviamente, as mulheres tendem a exercer menos que os homens — 34% são inativos, em comparação com 28% dos homens. Mas há exceções. As mulheres da Croácia, Finlândia, Iraque e Luxemburgo, por exemplo, mover mais do que seus compatriotas masculinos.

Malta ganha a corrida para o país mais preguiçoso, com 72% dos adultos, recebendo muito pouco exercício. Suazilândia e Arábia Saudita desleixo no logo atrás, com 69%. Em Bangladesh, por outro lado, apenas 5% dos adultos não exercício suficiente. Surpreendentemente, América não faz jus à sua reputação de lenta. Os seis americanos dez são suficientemente ativos por definição do Dr Hallal, comparada com menos de quatro em cada dez britânicos.

Em uma análise de acompanhamento de hábitos, Dr Hallal encontrados igualmente grandes diferenças. No sudeste da Ásia, menos de um quarto sentar-se, pelo menos, quatro horas por dia; em fazer de 64% de Europa. E até mesmo vizinhos podem ser diferentes. Apenas 2% dos suíços de pé para trabalhar, Considerando que 23% dos alemães fazê-lo.
Essas altas taxas de inatividade são preocupantes. Paradoxalmente, os seres humanos parecem ter evoluído para se beneficiar de exercício enquanto abstendo-se de sempre que podem. Em um estado de natureza é impossível viver uma vida que não forneceu suficiente para ser benéfico, enquanto o excesso de exercício usaria escassas calorias para pouca vantagem. Mas que já não pertence. Noutro artigo no Lancet, falta de actividade nos dias de hoje tem quase o mesmo efeito sobre a expectativa de vida como fumar.


quinta-feira, 12 de julho de 2012

O discurso é bonito, mas a preatica!!!

Nesse discurso no link abaixo Dilma prega os valores dos professores, mas qual a razão do Ministerio da Educação ou Planejamento não abrirem negaociação com os professores universitarios em greve

domingo, 8 de julho de 2012

Vergonha do salário de funcionários públicos que nem pagam impostos, diz o The Economist - Com tradução

Public-sector pay in Brazil

Shaming the unshameable

How the bureaucrats rob the taxpayers


WHEN his time as São Paulo’s mayor finishes at the end of the year, jokes Gilberto Kassab, he will look for work in the garages of the city’s municipal assembly. This month the city’s legislature published, for the first time, the salaries of some of its 2,000 employees. Half the 700 people named, paulistanos were surprised to learn, take home more each month than the assembly’s chairman, who earns 7,223 reais ($3,508) after tax.
As well as parking attendants, the fat cats included press officers and a nurse in charge of a drop-in clinic for municipal workers who earns 18,300 reais a month after tax, 12 times the average private-sector wage. Their pay cheques were boosted by annual increments, long-service bonuses and the practice, standard in Brazil’s public sector, of claiming a large pension in your early 50s and staying on the job.
Publication of the data angered public-sector unions, which claimed it put their members at risk of theft or kidnap. Taxpayers doubtless feel that the robbery has been inflicted on them. But São Paulo is one of the better-governed bits of Brazil, and even more shocking revelations are in store. The president, Dilma Rousseff, is using a freedom-of-information law passed last month, originally aimed at uncovering atrocities under Brazil’s military dictatorship, to expose the fat salaries of politicians and bureaucrats.
Rather than leaving activists to piece together many separate requests for information, Ms Rousseff has promised that the federal government will put all its employees’ names and salaries online from the end of June. The supreme court and Congress have agreed to follow suit. Local governments and other bits of the judiciary will then find it hard to hold out.
The constitution stipulates that no public employee can earn more than a supreme-court judge, whose salary is currently 26,700 reais a month. But according to Congresso em Foco, a watchdog and magazine, a third of ministers and nearly 4,000 other federal employees breach the pay ceiling. For example, José Sarney, an undistinguished but influential former president, earns 62,000 reais a month between his pay as a senator and two pensions from past stints as governor and a judge in his home state of Maranhão. None of the agencies that pay him is willing to stop unilaterally.
Munificent allowances are another wheeze to rob the taxpayer. Most Brazilians earn 13 monthly salaries annually, but congressmen get 15, the extra two being a “clothing allowance”. The payroll is further stretched by political appointees: each senator can appoint 50 and each congressman 25. All told, the Congress spends 6 billion reais a year on staff.
Many federal civil servants are doubtless paid along the same generous lines as those who work for São Paulo’s legislative assembly. Some long-serving lift attendants in the Congress in Brasília are said to earn 17,000 reais a month.
By law, public-sector workers cannot be fired or have their pay cut. But publication of pay details will give the government ammunition during pay negotiations, says Raul Velloso, a public-finance specialist. Salaries are one of the few bits of government spending where the public has a good notion of what constitutes value for money, he thinks. “People will be able to tell that the services they are receiving could be much cheaper.”

TRADUCÃO

Setor público pagar no Brasil envergonhando o unshameable como os burocratas roubam os contribuintes de 16 de junho de 2012 | SÃO PAULO | a partir da edição impressa quando seu tempo como prefeito de São Paulo termina no final do ano, piadas, Gilberto Kassab, ele vai procurar trabalho nas garagens da Assembleia municipal da cidade. Publicou este mês o legislador da cidade, pela primeira vez, os salários de alguns dos seus 2.000 funcionários. Metade das 700 pessoas nomeado, paulistanos se surpreenderam ao aprender, levar para casa mais cada mês do que o Presidente da Assembléia, que ganha ($3.508) de 7.223 reais após impostos.

Bem como flanelinhas, os assessores de imprensa de gatos gordos incluídos e uma enfermeira responsável por uma clínica de drop-in para trabalhadores municipais que ganha r $ 18.300, um mês depois de impostos, 12 vezes o salário médio do setor privado. Seus cheques de pagamento foram impulsionados por incrementos anuais, bônus de longos anos de serviço e a prática, o padrão no setor de público do Brasil, de requerer uma pensão grande em seu 50s adiantado e permanecer no local de trabalho.
Nesta seção o Hugo da última hurrah pouca dor para Peña» envergonhando o unshameable o olho da tempestade autodeterminação na correção Atlântico Sul: os tópicos relacionados de reimpressões de dólar azuis política brasileira política política política latino americana política mundial publicação dos dados irritou uniões de setor público, que alegaram que ele colocar seus membros em risco de roubo ou seqüestro. Os contribuintes, sem dúvida, sinto que o roubo tenha sido infligido sobre eles. Mas São Paulo é um dos bits geridos do Brasil, e ainda mais chocantes revelações estão na loja. O Presidente, Dilma Rousseff, é usando uma lei de liberdade de informação aprovada no mês passado, originalmente destinada a revelar atrocidades sob a ditadura militar do Brasil, para expor os gorduras salários dos políticos e burocratas.

Ao invés de deixar ativistas para reunir muitas solicitações separadas para obter informações, Ms Dilma Rousseff prometeu que o governo federal vai colocar nomes e salários on-line de todos os seus colaboradores a partir do final de junho. O Supremo Tribunal Federal e o Congresso decidiram seguir o exemplo. Os governos locais e outros pedaços do judiciário então achará difícil de aguentar.

A Constituição estipula que nenhum funcionário público pode ganhar mais do que um juiz do Supremo Tribunal, cujo salário está atualmente 26.700 reais por mês. Mas, de acordo com o Congresso em Foco, um cão de guarda e a revista, um terço dos Ministros e quase 4.000 funcionários federais violem o teto de remuneração. Por exemplo, José Sarney, um medíocre, mas influente ex-Presidente, ganha 62.000 reais ao mês entre a sua remuneração como senador e duas pensões de passagens anteriores como governador e um juiz em seu estado de origem do Maranhão. Nenhuma das agências que lhe pagam está disposta a parar de forma unilateral.

Munificent subsídios são outro Chiado para roubar o contribuinte. A maioria dos brasileiros ganha 13 salários por ano, mas congressistas obter 15, os dois extras, sendo um "subsídio de vestuário". A folha de pagamento é mais esticada por nomeados políticos: cada senador pode nomear 50 e cada congressista 25. Tudo dito, o Congresso gasta r $ 6 bilhões por ano em pessoal.

Muitos funcionários públicos federais, sem dúvida, são pagas no mesmo sentido generoso como aqueles que trabalham para a Assembléia Legislativa de São Paulo. Alguns atendentes do longo-serving lift no Congresso em Brasília são disse a ganhar 17.000 reais por mês.

Por lei, os trabalhadores do setor público não podem ser demitidos ou ter seu salário cortado. Mas a publicação de informações de pagamento dará a munição do governo durante as negociações de salário, diz Raul Velloso, especialista em finanças públicas. Os salários são um dos poucos bits de gastos do governo onde o público tem uma boa noção do que constitui o valor para o dinheiro, ele pensa. "As pessoas será capazes de dizer que os serviços estão recebendo poderiam ser muito mais baratos."

video explicando os experimentos para revelar a particula de Higgs

Tratamento para leucemia- Vislumbres do futuro - NY Times Science

In Treatment for Leukemia, Glimpses of the Future

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http://nyti.ms/N7h4vI

ST. LOUIS — Genetics researchers at Washington University, one of the world’s leading centers for work on the human genome, were devastated. Dr. Lukas Wartman, a young, talented and beloved colleague, had the very cancer he had devoted his career to studying. He was deteriorating fast. No known treatment could save him. And no one, to their knowledge, had ever investigated the complete genetic makeup of a cancer like his.
Multimedia
Dilip Vishwanat for The New York Times
Dr. Lukas Wartman, a leukemia patient in remission, being examined by his doctor, John DiPersio, in January in St. Louis.

So one day last July, Dr. Timothy Ley, associate director of the university’s genome institute, summoned his team. Why not throw everything we have at seeing if we can find a rogue gene spurring Dr. Wartman’s cancer, adult acute lymphoblastic leukemia, he asked? “It’s now or never,” he recalled telling them. “We will only get one shot.”
Dr. Ley’s team tried a type of analysis that they had never done before. They fully sequenced the genes of both his cancer cells and healthy cells for comparison, and at the same time analyzed his RNA, a close chemical cousin to DNA, for clues to what his genes were doing.
The researchers on the project put other work aside for weeks, running one of the university’s 26 sequencing machines and supercomputer around the clock. And they found a culprit — a normal gene that was in overdrive, churning out huge amounts of a protein that appeared to be spurring the cancer’s growth.
Even better, there was a promising new drug that might shut down the malfunctioning gene — a drug that had been tested and approved only for advanced kidney cancer. Dr. Wartman became the first person ever to take it for leukemia.
And now, against all odds, his cancer is in remission and has been since last fall.
While no one can say that Dr. Wartman is cured, after facing certain death last fall, he is alive and doing well. Dr. Wartman is a pioneer in a new approach to stopping cancer. What is important, medical researchers say, is the genes that drive a cancer, not the tissue or organ — liver or brain, bone marrow, blood or colon — where the cancer originates.
One woman’s breast cancer may have different genetic drivers from another woman’s and, in fact, may have more in common with prostate cancer in a man or another patient’s lung cancer.
Under this new approach, researchers expect that treatment will be tailored to an individual tumor’s mutations, with drugs, eventually, that hit several key aberrant genes at once. The cocktails of medicines would be analogous to H.I.V. treatment, which uses several different drugs at once to strike the virus in a number of critical areas.
Researchers differ about how soon the method, known as whole genome sequencing, will be generally available and paid for by insurance — estimates range from a few years to a decade or so. But they believe that it has enormous promise, though it has not yet cured anyone.
With a steep drop in the costs of sequencing and an explosion of research on genes, medical experts expect that genetic analyses of cancers will become routine. Just as pathologists do blood cultures to decide which antibiotics will stop a patient’s bacterial infection, so will genome sequencing determine which drugs might stop a cancer.
“Until you know what is driving a patient’s cancer, you really don’t have any chance of getting it right,” Dr. Ley said. “For the past 40 years, we have been sending generals into battle without a map of the battlefield. What we are doing now is building the map.”
Large drug companies and small biotechs are jumping in, starting to test drugs that attack a gene rather than a tumor type.
Leading cancer researchers are starting companies to find genes that might be causing an individual’s cancer to grow, to analyze genetic data and to find and test new drugs directed against these genetic targets. Leading venture capital firms are involved.
For now, whole genome sequencing is in its infancy and dauntingly complex. The gene sequences are only the start — they come in billions of small pieces, like a huge jigsaw puzzle. The arduous job is to figure out which mutations are important, a task that requires skill, experience and instincts.
So far, most who have chosen this path are wealthy and well connected. When Steve Jobs had exhausted other options to combat pancreatic cancer, he consulted doctors who coordinated his genetic sequencing and analysis. It cost him $100,000, according to his biographer. The writer Christopher Hitchens went to the head of the National Institutes of Health, Dr. Francis Collins, who advised him on where to get a genetic analysis of his esophageal cancer.
Harvard Medical School expects eventually to offer whole genome sequencing to help cancer patients identify treatments, said Heidi L. Rehm, who heads the molecular medicine laboratory at Harvard’s Partners Healthcare Center for Personalized Genetic Medicine. But later this year, Partners will take a more modest step, offering whole genome sequencing to patients with a suspected hereditary disorder in hopes of identifying mutations that might be causing the disease.
Whole genome sequencing of the type that Dr. Wartman had, Dr. Rehm added, “is a whole other level of complexity.”
Dr. Wartman was included by his colleagues in a research study, and his genetic analysis was paid for by the university and research grants. Such opportunities are not available to most patients, but Dr. Ley noted that the group had done such an analysis for another patient the year before and that no patients were being neglected because of the urgent work to figure out Dr. Wartman’s cancer.
“The precedent for moving quickly on a sample to make a key decision was already established,” Dr. Ley said.
COMENTÁRIOS

Mr. Blandings New York NYT pegar bandeira bom velho Pfizer. Afinal, o que mais você espera da empresa que tem sido sido atingido com o maior crime na história dos EUA para a comercialização fraudulenta de drogas (no valor de r $1,30 bilhões em 2009), para não mencionar mais tarde multas por suborno. Fabricante de medicamentos éticos na verdade...

    8 De julho de 2012, às 09:01
    bruce quinn, los angeles, é interessante que essa história envolva o rótulo de uso de uma droga Pfizer aparece na mesma semana que os EUA multado Glaxo Smith Kline (GSK) US $3 bilhões para promover o uso da etiqueta de um medicamento. Tudo o que fez de Pfizer para promover, fornecer, suporte, este uso de Sutent tem ser feito extraordinariamente cautelosamente, cuidadosamente, lentamente ou - mais simples, não em todos - a fim de evitar acusações de promoção de rótulo e ministério público.

    8 De julho de 2012, às 09:00
    JD Norwalk, CT NYT Pick "E encontraram um culpado — um gene normal que foi em overdrive, produzindo grandes quantidades de uma proteína que pareciam estar estimulando o crescimento do câncer.
 
 TRADUÇÃO
St. LOUIS — Pesquisadores de genética na Universidade de Washington, um do mundo levando a centros de trabalho sobre o genoma humano, foram devastados. Dr. Lukas Wartman, um jovem, talentoso e querido colega, tinha o câncer muito ele dedicou sua carreira para estudar. Ele foi se deteriorando rapidamente. Não há tratamento conhecido poderia salvá-lo. E ninguém, para seu conhecimento, nunca tinha investigado a composição genética completa de um cancro como a dele.
Gráfico multimídia que procura vulnerável alvo ampliar esta imagem Dilip Vishwanat um câncer para The New York Times Dr. Lukas Wartman, um paciente de leucemia em remissão, sendo examinado pelo seu médico, John DiPersio, em Janeiro, em St. Louis.
Comentários dos leitores compartilham seus pensamentos.

    Postar um comentário» Leia todos os comentários (145)» então um dia em julho passado, Dr. Timothy Ley, diretor adjunto do Instituto de genoma da Universidade, convocou sua equipe. Por que não jogar tudo o que temos a ver que se podemos encontrar um gene de desonestos, estimulando o câncer do Dr. Wartman, adulta leucemia linfoblástica aguda, ele perguntou? "É agora ou nunca", lembrou-me dizer-lhes. "Só teremos um tiro".

Equipe do Dr. Ley tentou um tipo de análise que nunca tinham feito antes. Eles totalmente seqüenciados os genes de suas células cancerosas e células saudáveis para comparação e ao mesmo tempo analisaram seu RNA, um primo químico próximo ao DNA, em busca de pistas para que seus genes estavam fazendo.

Os pesquisadores do projeto colocar outros trabalhos de lado por semanas, executando um dos 26 máquinas de seqüenciamento e supercomputador da Universidade em torno do relógio. E eles encontraram um culpado — um gene normal que foi em overdrive, produzindo grandes quantidades de uma proteína que pareciam estar estimulando o crescimento do câncer.

Melhor ainda, houve uma nova droga promissora que pode desligar o gene com defeito — uma droga que tinha sido testada e aprovada apenas para avançado câncer de rim. Dr. Wartman tornou-se a primeira pessoa a levá-lo para a leucemia.

E agora, contra todas as probabilidades, o câncer está em remissão e tem sido desde o outono passado.

Embora ninguém possa dizer que o Dr. Wartman é curada, depois de enfrentar a morte certa no outono passado, ele está vivo e bem. Dr. Wartman é pioneira em uma nova abordagem para parar o câncer. O importante, dizem pesquisadores médicos, é os genes que levam a um câncer, e não o tecido ou órgão —, fígado ou cérebro, medula óssea, sangue ou cólon — onde o câncer se origina.

Câncer de mama de uma mulher pode ter diferentes drivers de genéticas de outra mulher e, na verdade, pode ter mais em comum com câncer de próstata no homem ou câncer de pulmão de outro paciente.

Sob esta nova abordagem, os pesquisadores esperam que o tratamento vai ser adaptado para mutações de um individuais do tumor, com drogas, eventualmente, que bateu vários genes aberrantes chaves ao mesmo tempo. Os coquetéis de medicamentos seria análogos ao tratamento do HIV, que usa vários medicamentos diferentes ao mesmo tempo para atacar o vírus em um número de áreas críticas.

Pesquisadores divergem sobre quanto tempo o método, conhecido como seqüenciamento de genoma completo, estarão disponíveis e pago pelo seguro — as estimativas variam de alguns anos para uma década ou mais. Mas eles acreditam que ele tem enorme promessa, apesar de que ainda não tenha curado alguém.

Com uma queda acentuada nos custos de seqüenciamento e uma explosão de pesquisa sobre os genes, médicos especialistas esperam que análises genéticas do câncer vão se tornar rotina. Assim como patologistas sangue culturas para decidir quais antibióticos vão parar a infecção bacteriana de um paciente, então o sequenciamento do genoma determinará que as drogas podem parar um câncer.

"Até que você saiba o que está impulsionando o câncer de um paciente, você realmente não tem qualquer chance de acertar," disse Dr. Ley. "Nos últimos 40 anos, podemos ter enviando generais para a batalha sem um mapa do campo de batalha. O que estamos fazendo agora é a construção do mapa."

As empresas farmacêuticas de grandes e pequenas empresas de biotecnologia estão pulando, começando a testar drogas que atacam um gene, ao invés de um tipo de tumor.

Principais pesquisadores de câncer estão começando a empresas para encontrar genes que podem estar causando câncer de um indivíduo para crescer, para analisar dados genéticos e encontrar e testar novas drogas contra esses alvos genéticos. Principais empresas de capital de risco estão envolvidas.

Agora, o sequenciamento do genoma inteiro é em sua infância e desanimada complexo. As sequências de genes são só o começo — vêm em bilhões de pedaços pequenos, como um enorme quebra-cabeça. O trabalho árduo é descobrir quais as mutações são importantes, uma tarefa que requer habilidade, experiência e instintos.

Até agora, mais que escolheu esse caminho são ricos e bem ligado. Quando Steve Jobs tinha esgotado outras opções para combater o câncer de pâncreas, ele consultou médicos que coordenou o seu seqüenciamento genético e análise. Custou-lhe US $100.000, segundo seu biógrafo. O escritor Christopher Hitchens foi o chefe dos institutos nacionais de saúde, Dr. Francis Collins, que o aconselhou sobre onde obter uma análise genética de seu câncer de esôfago.

Harvard Medical School espera eventualmente oferecer o sequenciamento de genoma inteiro para ajudar pacientes com câncer a identificar tratamentos, disse Heidi L. Rehm, que dirige o laboratório de medicina molecular no centro de saúde de parceiros de Harvard para medicina genética personalizada. Mas ainda este ano, parceiros terá um passo mais modesto, oferecendo o seqüenciamento do genoma inteiro para pacientes com um distúrbio hereditário suspeito na esperança de identificar mutações que podem estar causando a doença.

O sequenciamento de genoma inteiro do tipo que tinha Dr. Wartman, Dr. Rehm acrescentou, "é um outro nível de complexidade".

Dr. Wartman foi incluído por seus colegas em um estudo de pesquisa e, em seguida, sua análise genética foi pago por bolsas de pesquisa e Universidade. Tais oportunidades não estão disponíveis para a maioria dos pacientes, mas o Dr. Ley observou que o grupo tinha feito uma análise por outro paciente no ano anterior e que nenhum paciente eram negligenciada por causa do trabalho urgente para descobrir o câncer do Dr. Wartman.

"O precedente para mover-se rapidamente em uma amostra fazer uma decisão-chave já foi estabelecido", disse Dr. Ley.

sábado, 7 de julho de 2012

Uma nova droga para Tb resistente


ORIGINAL ARTICLE

Delamanid for Multidrug-Resistant Pulmonary Tuberculosis

Maria Tarcela Gler, M.D., Vija Skripconoka, M.D., Epifanio Sanchez-Garavito, M.D., Heping Xiao, M.D., Jose L. Cabrera-Rivero, M.D., Dante E. Vargas-Vasquez, M.D., Mengqiu Gao, M.D., Ph.D., Mohamed Awad, M.B., B.Ch., M.D., Seung-Kyu Park, M.D., Ph.D., Tae Sun Shim, M.D., Ph.D., Gee Young Suh, M.D., Manfred Danilovits, M.D., Hideo Ogata, M.D., Anu Kurve, M.D., Joon Chang, M.D., Ph.D., Katsuhiro Suzuki, M.D., Thelma Tupasi, M.D., Won-Jung Koh, M.D., Barbara Seaworth, M.D., Lawrence J. Geiter, Ph.D., and Charles D. Wells, M.D.
N Engl J Med 2012; 366:2151-2160June 7, 2012
 Comments open through June 13, 2012
Abstract
Article
References
Citing Articles (1)
Comments (1)
The emergence over the past two decades of multidrug-resistant tuberculosis, or tuberculosis caused by strains of Mycobacterium tuberculosis that are resistant to isoniazid and rifampin, with or without resistance to other agents, has greatly complicated efforts to control the global tuberculosis epidemic. Approximately 440,000 cases of multidrug-resistant tuberculosis occur worldwide annually, accounting for nearly 5% of the global burden of tuberculosis.1 Multidrug-resistant tuberculosis requires treatment with combination therapy consisting of four to six medications, including the more toxic and less potent second-line drugs, administered for up to 2 years. Cure rates are lower and mortality is higher with multidrug-resistant tuberculosis than with drug-susceptible tuberculosis, even with the most effective treatments.2-6 As a result, the Global Plan to Stop TB, 2011 through 2015, calls for urgent development of new drugs involving new mechanisms to treat tuberculosis, including multidrug-resistant tuberculosis, as a key component of the response to the epidemic.7
Delamanid (OPC-67683), a new agent derived from the nitro-dihydro-imidazooxazole class of compounds that inhibits mycolic acid synthesis, has shown potent in vitro and in vivo activity against both drug-susceptible and drug-resistant strains of M. tuberculosis in preclinical development.8,9 In a subsequent assessment of the 14-day early bactericidal activity of the compound against M. tuberculosis in patients in South Africa, delamanid administered at doses of 200 and 300 mg daily resulted in a decrease in the sputum M. tuberculosis burden that was similar to that of the potent antituberculosis drug rifampin in previous studies of early bactericidal activity.10,11
On the basis of results from five decades of controlled trials showing the predictive value of status with respect to sputum-culture conversion at 2 months for disease relapse among patients with tuberculosis, as well as cohort studies showing its predictive value for treatment outcomes in multidrug-resistant tuberculosis, we conducted a multinational, randomized, double-blind, placebo-controlled trial to assess the safety, pharmacokinetic profile, and efficacy of delamanid in patients with multidrug-resistant tuberculosis.12-14 We present the results for patients with sputum culture–positive multidrug-resistant pulmonary tuberculosis who received 2 months of treatment with delamanid, at a higher or lower dose, or placebo in combination with a background drug regimen developed according to World Health Organization (WHO) guidelines.2

METHODS

Patients

This study included patients 18 to 64 years of age who had sputum culture–positive multidrug-resistant tuberculosis and chest radiographic findings consistent with tuberculosis. Patients with sputum smears that were positive for acid-fast bacilli and positive rapid tests for rifampin resistance were also enrolled, but they were excluded from the efficacy analysis if baseline cultures (i.e., results from cultures at day −1 and day 1) proved to be negative for multidrug-resistant tuberculosis. Patients were excluded from the trial if they had Karnofsky scores of less than 50%; those with human immunodeficiency virus (HIV) infection were excluded if they had a CD4 cell count of less than 350 per cubic millimeter or were receiving antiretroviral treatment. Patients who were receiving antiarrhythmic agents or who had clinically relevant cardiovascular disease or electrocardiographic (ECG) findings of conduction abnormalities or QT-interval prolongation (>450 msec in men or >470 msec in women) were also excluded, and the use of moxifloxacin was prohibited. Additional standard exclusion criteria were substance abuse, concomitant illness, drug hypersensitivity, abnormal renal and hepatic laboratory results, pregnancy, and breast-feeding. Women with childbearing potential were required to use birth control.

Trial Design

This multicenter, double-blind, stratified, randomized, placebo-controlled trial was conducted in 17 centers in nine countries: the Philippines, Peru, Latvia, Estonia, China, Japan, Korea, Egypt, and the United States. During the 8-week treatment period, all patients were hospitalized for intensive safety monitoring and weekly sputum-culture status assessments. The design included an additional 4-week period of patient monitoring to confirm the sputum-culture status while patients continued to receive the background drug regimen. The objective of the trial was to evaluate the safety, efficacy, and pharmacokinetics of two doses of delamanid (100 mg twice daily or 200 mg twice daily) plus the background drug regimen for 2 months, as compared with placebo plus the standard drug regimen for 2 months.
Randomization was centralized, with patients stratified into two groups according to the extent of pulmonary tuberculosis (presence or absence of lung cavities) on baseline chest radiography as assessed by local radiologists. Patients were randomly assigned in a 1:1:1 ratio to receive the background drug regimen plus delamanid at a dose of 100 mg or 200 mg or placebo twice daily for 8 weeks.
The study drug, provided as delamanid in 50-mg tablets (Otsuka Pharmaceutical Development and Commercialization) or matching placebo, was administered with morning and evening meals 10 hours apart, since systemic exposure increases when delamanid is taken with food; ingestion of all doses was observed. For 12 weeks, all patients received the background drug regimen developed according to WHO guidelines for treating multidrug-resistant tuberculosis; this regimen generally consisted of four or five antituberculosis medications, including any first-line medications to which a patient's disease remained susceptible, an injectable antituberculosis medication (an aminoglycoside or capreomycin), a fluoroquinolone, and other medications.2 The background drug regimen could be adjusted by the site investigators as needed. After 8 weeks of blinded treatment, patients could continue the background drug regimen as outpatients and were assessed weekly for 4 additional weeks for sputum-culture status and safety findings.
The trial protocol, available with the full text of this article at NEJM.org, was approved by independent ethics committees and institutional review boards for all sites. All patients provided written informed consent in their native language before enrollment occurred. The trial was performed in accordance with the Good Clinical Practice guidelines of the International Conference on Harmonization, adhered to the ethical principles of the Declaration of Helsinki, and was monitored by an independent data and safety monitoring committee. Otsuka sponsored the study, which was designed by employees of the sponsor with input from an academic author. Employees of the sponsor wrote the manuscript. All authors participated in the collection and analysis of the data and made the decision to submit the manuscript for publication. All authors vouch for the completeness and accuracy of the data presented and the fidelity of the study to the protocol.

Study Procedures

Microbiologic Assessments

Morning sputum specimens were obtained during the 8-week treatment period and during the 4-week post-treatment period on days −1, 1, 8, 15, 22, 29, 36, 43 50, 57, 63, 70, 77, and 84. If patients were unable to expectorate sputum, attempts were made to induce sputum expectoration with the use of aerosol inhalation. Sputum samples were deemed unobtainable if no sputum could be obtained after induction. Samples were cultured in liquid broth medium (in an automated mycobacterial growth indicator tube [MGIT] system) (Becton Dickinson) and in solid mycobacteriologic culture medium (with the use of egg-based Löwenstein–Jensen medium for ≥90% of the patients). Mycobacterial cultures were identified according to the growth and morphologic characteristics of the colony and with the use of commercial identification methods, including DNA hybridization systems (e.g., Accuprobe), DNA amplification methods (e.g., INNO-LiPA Rif.TB [Innogenetics] and GenoType MTBDRplus [Hain Lifescience]), or other standardized methods. Microbiologic tests were performed in local laboratories in accordance with guidelines from the Clinical and Laboratory Standards Institute for sputum processing, smear microscopy, culture techniques, drug-susceptibility testing, and identification of mycobacteria.15-17
On the basis of previous studies showing that in 18% of patients with multidrug-resistant tuberculosis who received the background drug regimen, the initial monthly cultures reverted from being negative to positive for M. tuberculosis, 14 sputum-culture conversion was defined as five or more consecutive weekly cultures that were negative for growth of M. tuberculosis (without subsequent positive cultures). The time of sputum-culture conversion was defined as the day of sputum collection for the first of five cultures that were negative for M. tuberculosis. Meeting this criterion required patients to have a negative culture by the end of the treatment period with the investigational medication (day 57) and at all subsequent weekly assessments during the treatment period during which they received the background drug regimen alone (days 57, 63, 70, 77, and 84). In addition, since MGIT is automated, allowing for standardization of processes across laboratories, and studies have shown that it is more sensitive than solid-culture media for detecting viable M. tuberculosis organisms,18 assessment of sputum-culture conversion with the use of MGIT served as the primary efficacy analysis.

Pharmacokinetic Assessments

Serial blood samples were obtained over a 24-hour period on days 1, 14, 28, and 56. Plasma concentrations of delamanid were determined with the use of a validated liquid chromatography–mass spectrometry method at Tandem Labs, Salt Lake City. Summary tables were generated according to study-drug group for plasma concentrations per time point and for pharmacokinetic measures obtained with the use of WinNonlin software (Pharsight).

Safety Assessments

Safety tests included the following: monthly physical examinations, weekly assessment of vital signs, standard 12-lead ECG, clinical laboratory tests (including a hematologic profile, coagulation measurements, a urinalysis, and measurements of hepatic aminotransferase and thyroid and adrenal hormone levels), and baseline audiometry. The QT-interval duration for each ECG was corrected with the use of Fridericia's formula19: corrected QT interval=QT×(1000÷RR interval in milliseconds)0.33. Use of concomitant medications was recorded daily, and adverse events were documented; immediately reportable events and clinically significant abnormal laboratory results were evaluated as appropriate.

Statistical Analysis

Safety evaluations were performed in all patients who underwent randomization and who received at least one dose of study medication (the intention-to-treat population). Efficacy evaluations were performed in all patients who had positive multidrug-resistant tuberculosis cultures at baseline and who met no exclusion criteria (the modified intention-to-treat population). The primary efficacy end point was the proportion of patients in the modified intention-to-treat population who had sputum-culture conversion with the use of MGIT by 2 months (day 57) of treatment. Each of the delamanid groups was compared with the placebo group with the use of the Cochran–Mantel–Haenszel test, stratified according to randomization factor. The overall nominal significance level for testing the two pairwise comparisons was maintained at 0.05 (two-sided) with the use of the Hochberg multiple-testing procedure. Multiple secondary efficacy end points were also assessed, including sputum-culture conversion at 2 months, with the use of solid medium and time to sputum-culture conversion with the use of both medium types in a proportional-hazards model. We analyzed the results of the sensitivity data sets of both the MGIT and solid-medium cultures with the use of the last-observation-carried-forward, observed-cases, and per-protocol methods; the analysis was not controlled for site. A single-imputation method was used for any missing culture data. All end points were prespecified in a formal statistical analysis plan that was developed, finalized, and filed with regulatory authorities before database locking and unblinding. The Supplementary Appendix, including further details regarding study conduct and analyses, is available at NEJM.org.

RESULTS

Study Population

Recruitment began in May 2008, and the last patient visit was in June 2010. A total of 611 patients with suspected multidrug-resistant tuberculosis were assessed for eligibility; 481 met eligibility requirements and were stratified into two groups according to the presence or absence of cavities observed in lung fields on chest radiography. Among the 481 patients in the intention-to-treat population, 402 (83.6%) met the criteria for the modified intention-to-treat population (positive sputum culture for multidrug-resistant tuberculosis at baseline) and were assessed for efficacy (141 patients who received delamanid at a dose of 100 mg twice daily, 136 who received delamanid at a dose of 200 mg twice daily, and 125 who received placebo) (Figure 1
FIGURE 1Enrollment, Study-Drug Assignments, Follow-up, and Assessment of Patients.). Of 402 patients who were assessed for efficacy, 217 were from Asia (54.0%), and 275 were men (68.4%); the median age was 35 years (range, 18 to 63) (Table 1TABLE 1Demographic and Baseline Clinical Characteristics of the Modified Intention-to-Treat Population for the Primary Efficacy Analysis.
). No significant differences in demographic or baseline clinical characteristics between the intention-to-treat and modified intention-to-treat populations or among the three study-drug groups were identified. Although lung cavities were identified on chest radiography at baseline in equal proportions of patients across the groups, slightly fewer patients in the placebo group than in the two delamanid groups had bilateral cavities. More than 90% of patients had received treatment for tuberculosis before randomization; of these patients, more than 50% had received first-line antituberculosis drugs alone and nearly 40% had received a second-line or third-line antituberculosis drug. Details on the use of antituberculosis medication during the trial are included in the Supplementary Appendix. Four patients with HIV coinfection were enrolled, with at least one patient randomly assigned to each group. Approximately 85% of patients were fully adherent to the study-drug regimen; only 1% of patients had adherence of 80% or less, and the proportion did not differ among the groups.

Safety

The safety analysis included the 481 patients in the intention-to-treat population (Figure 1). Similar proportions of patients in the three study-drug groups completed the 8-week drug regimen (≥89%); a total of 14 patients (2.9%), evenly distributed across the groups, discontinued the study drug because of adverse events (see the Supplementary Appendix for details).
Table 2TABLE 2Incidence of Adverse Events (Occurring in ≥10% of Patients in Either Delamanid Group and with Greater Frequency Than in the Placebo Group). lists the adverse events that occurred in 10% or more of the patients in either or both of the delamanid groups and at a higher frequency than that in the placebo group. There were fewer adverse events in the group of patients who received delamanid at a dose of 100 mg twice daily than in the group that received delamanid at a dose of 200 mg twice daily; many of these events were of similar frequency to those in the placebo group. No episodes of a prolonged QT interval as measured on ECG were associated with clinical manifestations such as syncope or arrhythmias. However, the frequency of a prolonged QT interval was higher in the group that received 200 mg of delamanid twice daily (13.1%) than in the group that received 100 mg twice daily (9.9%), and both rates were higher than that in the placebo group (3.8%). Concomitant conditions that exacerbate QT-interval prolongation, particularly hypokalemia, which often result from the use of injectable antituberculosis medications, were noted.20 The percentage of patients with hepatotoxicity was not higher in the delamanid groups than in the placebo group. One patient died from tuberculosis during the trial. The Supplementary Appendix provides a summary of adverse events, including serious adverse events, discontinuation of the study drug due to adverse events, frequency of severe adverse events that developed during treatment, adverse events potentially related to the study drug, and details of all adverse events (>400) that occurred in one or more patients.

Pharmacokinetics

Delamanid steady-state exposure increased less than proportionally with the dose. An increase in the dose of delamanid from 100 mg twice daily to 200 mg twice daily yielded a 50% increase in exposure. Plasma concentrations of delamanid decreased rapidly (half-life, 38 hours) after drug discontinuation. Pharmacokinetic measures (maximum concentration after morning and evening doses, minimum concentration, and area under the plasma concentration–time curve from 0 to 24 hours) for delamanid on day 56 are shown in the Supplementary Appendix.

Sputum-Culture Conversion

Of 481 patients who underwent randomization, 402 (83.6%) had cultures that were positive for multidrug-resistant tuberculosis with the use of MGIT at baseline (the modified intention-to-treat population) and were included in the primary efficacy analysis. Of these 402 patients, the proportion who had sputum-culture conversion with MGIT by 2 months in the group of patients who received delamanid at a dose of 100 mg twice daily was 45.4%, as compared with 29.6% in the placebo group (Figure 2A
FIGURE 2Proportion of Patients with Sputum-Culture Conversion by Day 57.); this was a significant increase (53%; 95% CI, 11 to 112; P=0.008). The proportion who had sputum-culture conversion in the 200-mg group was similar (41.9%) and was significantly higher than that in the placebo group (P=0.04). Results from the secondary analysis of sputum-culture conversion, assessed with the use of solid medium (Figure 2B), as well as sensitivity analyses of the primary analysis, were consistent with the results of the primary analysis. These analyses included examination of data sets of sputum-culture conversion with the use of last-observation-carried-forward, observed-cases, and per-protocol methods for both MGIT and solid medium, as well as evaluation of the data with the use of various less stringent definitions of sputum-culture conversion, including one routinely used in clinical practice (two consecutive negative cultures obtained 1 month apart) and a single negative culture at 2 months. In addition, a multiple-imputation strategy for dealing with missing sputum-culture results was used. In all cases, the proportion of patients with sputum-culture conversion was higher in the groups receiving delamanid plus the background drug regimen, and in nearly all analyses, the difference was significant.
An additional key secondary analysis assessed differences among the groups with respect to time to sputum-culture conversion. For this analysis, Kaplan–Meier curves representing the time to conversion according to culture medium type (Figure 3FIGURE 3Survival Analysis of Days to Sputum-Culture Conversion, According to Culture Medium Type.) showed 10% separation between the delamanid groups and the placebo group by day 36 with MGIT. By the end of the 2-month treatment period, the difference in sputum-culture conversion between the delamanid groups and the placebo group was significant (P=0.001 for the comparisons of the 100-mg and 200-mg doses of delamanid with placebo); the same trend was observed with the use of solid medium (P=0.0004 and P<0.0001, respectively, by the log-rank test). In a Cox regression analysis of sputum-culture conversion, including study-drug assignment and the presence or absence of cavitation on chest radiography (a stratification variable), the hazard ratio for increased time to conversion to a negative sputum culture as assessed with the use of MGIT was 0.58 (95% confidence interval [CI], 0.39 to 0.89) in the 100-mg group and 0.63 (95% CI, 0.42 to 0.96) in the 200-mg group. The hazard ratio for increased time to conversion to a negative sputum culture as assessed with the use of solid medium was 0.54 (95% CI, 0.36 to 0.81) in the 100-mg group and 0.44 (95% CI, 0.29 to 0.64) in the 200-mg group.

DISCUSSION

In this study, which used a stringent definition of sputum-culture conversion (five successive weekly cultures that were negative for M. tuberculosis) and a more sensitive culture system (MGIT) than solid medium for detecting viable M. tuberculosis, 18 45.4% of patients who received delamanid at a dose of 100 mg twice daily plus the background drug regimen had sputum-culture conversion after 2 months, as compared with 29.6% of those who received placebo plus the background drug regimen; this was a significant increase (53%; 95% CI, 11 to 112). This benefit, which was observed with both doses, was also observed with the use of solid-culture medium and was supported by sensitivity analyses and imputation strategies for missing sputum-culture results. Likewise, among patients who had sputum-culture conversion, those who received either delamanid dose plus the background drug regimen had sputum-culture conversion significantly earlier than those who received placebo plus a background drug regimen.
The safety analyses showed that delamanid at either dose did not have dose-limiting toxicity; however, patients who received delamanid plus the background drug regimen had more episodes of QT-interval prolongation on scheduled ECG, as compared with those who received placebo plus the background drug regimen. None of these episodes were associated with clinical manifestations such as syncope or arrhythmias.
An analysis by Wallis and colleagues of multiple controlled clinical trials of tuberculosis treatment involving 30 pairs of regimens and more than 5500 patients showed a strong association between increases in sputum-culture conversion at 2 months and lower tuberculosis relapse rates with the use of stepwise adjustments to treatment (e.g., adding a strong bactericidal agent to an existing regimen).12 Similarly, cohort studies have shown more favorable long-term treatment outcomes among patients with multidrug-resistant tuberculosis who had sputum-culture conversion by 2 months as compared with those who did not.13,14 This trial shows that delamanid administered with the background drug regimen for multidrug-resistant tuberculosis enhanced and accelerated sputum-culture conversion. Long-term, open-label surveillance of patients with multidrug-resistant tuberculosis treated with delamanid and the background drug regimen is under way to extend efficacy and safety observations from this trial and to further document the durability of response. Further analyses addressing pharmacology, long-term follow-up, and microbiologic data are also under way. A second large, randomized, controlled trial (ClinicalTrials.gov number, NCT01424670) of 6 months of treatment with delamanid as part of a full background drug regimen and including patients who have coinfection with HIV and multidrug-resistant tuberculosis and who are receiving antiretroviral drugs has been initiated and is designed to provide data on 30 months of follow-up of patients. It is important to learn more about the use of delamanid in combination with other new and existing antimycobacterial agents to develop better regimens for multidrug-resistant tuberculosis.
Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.
We thank the members of the data and safety monitoring committee — Drs. Charles Daley, Thomas Fleming, Martin Keane, and Tom Shinnick — for their close monitoring of patient safety and their expert guidance during the conduct of this trial.

SOURCE INFORMATION

From the Makati Medical Center, Manila (M.T.G.), and the Tropical Disease Foundation, Makati City (M.T.G., T.T.) — both in the Philippines; the State Agency of Tuberculosis and Lung Diseases, Riga, Latvia (V.S.); Hospital Nacional Sergio E. Bernales (E.S.-G.), Unidad de Investigacion, Hospital Nacional Daniel A. Carrión (J.L.C.-R.), and Hospital Nacional Hipólito Unanue (D.E.V.-V.) — all in Lima, Peru; Shanghai Pulmonary Hospital, Shanghai (H.X.), and Beijing Chest Hospital, Beijing (M.G.) — both in China; Sadr Abassia Hospital, Cairo (M.A.); National Masan Hospital, Masan (S.-K.P.), Asan Medical Center, Seoul (T.S.S.), Samsung Medical Center, Seoul (G.Y.S., W.-J.K.), and Yonsei University Medical Center, Severance Hospital, Seoul (J.C.) — all in South Korea; Tartu University Lung Hospital, Tartu (M.D.), and North Estonian Medical Center Foundation, Center of Pulmonology, Tallinn (A.K.) — both in Estonia; Fukujuji Hospital, Tokyo (H.O.), and National Hospital Organization Kinki-Chuo Chest Medical Center, Osaka (K.S.) — both in Japan; the University of Texas Health Center at Tyler, Tyler (B.S.); and Otsuka Pharmaceutical Development and Commercialization, Rockville, MD (L.J.G., C.D.W.).
Address reprint requests to Dr. Geiter at Otsuka Novel Products/OPDC, 2440 Research Blvd., Rockville, MD 20850, or at .