Summary Background In 2004, a randomised phase III trial by the European Organisation for Research and Treatment of Cancer (EORTC) and National Cancer Institute of Canada Clinical Trials Group (NCIC) ...reported improved median and 2-year survival for patients with glioblastoma treated with concomitant and adjuvant temozolomide and radiotherapy. We report the final results with a median follow-up of more than 5 years. Methods Adult patients with newly diagnosed glioblastoma were randomly assigned to receive either standard radiotherapy or identical radiotherapy with concomitant temozolomide followed by up to six cycles of adjuvant temozolomide. The methylation status of the methyl-guanine methyl transferase gene, MGMT , was determined retrospectively from the tumour tissue of 206 patients. The primary endpoint was overall survival. Analyses were by intention to treat. This trial is registered with Clinicaltrials.gov , number NCT00006353. Findings Between Aug 17, 2000, and March 22, 2002, 573 patients were assigned to treatment. 278 (97%) of 286 patients in the radiotherapy alone group and 254 (89%) of 287 in the combined-treatment group died during 5 years of follow-up. Overall survival was 27·2% (95% CI 22·2–32·5) at 2 years, 16·0% (12·0–20·6) at 3 years, 12·1% (8·5–16·4) at 4 years, and 9·8% (6·4–14·0) at 5 years with temozolomide, versus 10·9% (7·6–14·8), 4·4% (2·4–7·2), 3·0% (1·4–5·7), and 1·9% (0·6–4·4) with radiotherapy alone (hazard ratio 0·6, 95% CI 0·5–0·7; p<0·0001). A benefit of combined therapy was recorded in all clinical prognostic subgroups, including patients aged 60–70 years. Methylation of the MGMT promoter was the strongest predictor for outcome and benefit from temozolomide chemotherapy. Interpretation Benefits of adjuvant temozolomide with radiotherapy lasted throughout 5 years of follow-up. A few patients in favourable prognostic categories survive longer than 5 years. MGMT methylation status identifies patients most likely to benefit from the addition of temozolomide. Funding EORTC, NCIC, Nélia and Amadeo Barletta Foundation, Schering-Plough.
Summary Background Every year, 1·1 million babies die from prematurity, and many survivors are disabled. Worldwide, 15 million babies are born preterm (<37 weeks' gestation), with two decades of ...increasing rates in almost all countries with reliable data. The understanding of drivers and potential benefit of preventive interventions for preterm births is poor. We examined trends and estimate the potential reduction in preterm births for countries with very high human development index (VHHDI) if present evidence-based interventions were widely implemented. This analysis is to inform a rate reduction target for Born Too Soon. Methods Countries were assessed for inclusion based on availability and quality of preterm prevalence data (2000–10), and trend analyses with projections undertaken. We analysed drivers of rate increases in the USA, 1989–2004. For 39 countries with VHHDI with more than 10 000 births, we did country-by-country analyses based on target population, incremental coverage increase, and intervention efficacy. We estimated cost savings on the basis of reported costs for preterm care in the USA adjusted using World Bank purchasing power parity. Findings From 2010, even if all countries with VHHDI achieved annual preterm birth rate reductions of the best performers for 1990–2010 (Estonia and Croatia), 2000–10 (Sweden and Netherlands), or 2005–10 (Lithuania, Estonia), rates would experience a relative reduction of less than 5% by 2015 on average across the 39 countries. Our analysis of preterm birth rise 1989–2004 in USA suggests half the change is unexplained, but important drivers include non-medically indicated labour induction and caesarean delivery and assisted reproductive technologies. For all 39 countries with VHHDI, five interventions modelling at high coverage predicted a 5% relative reduction of preterm birth rate from 9·59% to 9·07% of livebirths: smoking cessation (0·01 rate reduction), decreasing multiple embryo transfers during assisted reproductive technologies (0·06), cervical cerclage (0·15), progesterone supplementation (0·01), and reduction of non-medically indicated labour induction or caesarean delivery (0·29). These findings translate to roughly 58 000 preterm births averted and total annual economic cost savings of about US$3 billion. Interpretation We recommend a conservative target of a relative reduction in preterm birth rates of 5% by 2015. Our findings highlight the urgent need for research into underlying mechanisms of preterm births, and development of innovative interventions. Furthermore, the highest preterm birth rates occur in low-income settings where the causes of prematurity might differ and have simpler solutions such as birth spacing and treatment of infections in pregnancy than in high-income countries. Urgent focus on these settings is also crucial to reduce preterm births worldwide. Funding March of Dimes, USA, Eunice Kennedy Shriver National Institute of Child Health and Human Development, and National Institutes of Health, USA.
Summary The end of 2015 will signal the end of the Millennium Development Goal era, when the world can take stock of what has been achieved. The Countdown to 2015 for Maternal, Newborn, and Child ...Survival (Countdown) has focused its 2014 report on how much has been achieved in intervention coverage in these groups, and on how best to sustain, focus, and intensify efforts to progress for this and future generations. Our 2014 results show unfinished business in achievement of high, sustained, and equitable coverage of essential interventions. Progress has accelerated in the past decade in most Countdown countries, suggesting that further gains are possible with intensified actions. Some of the greatest coverage gaps are in family planning, interventions addressing newborn mortality, and case management of childhood diseases. Although inequities are pervasive, country successes in reaching of the poorest populations provide lessons for other countries to follow. As we transition to the next set of global goals, we must remember the centrality of data to accountability, and the importance of support of country capacity to collect and use high-quality data on intervention coverage and inequities for decision making. To fulfill the health agenda for women and children both now and beyond 2015 requires continued monitoring of country and global progress; Countdown is committed to playing its part in this effort.
Both pulsatile-flow and continuous-flow left ventricular assist devices (LVADs) successfully provide patients a bridge to transplantation. Some data suggest that continuous-flow pumps increase the ...risk of allograft rejection, contributing to posttransplantation morbidity and mortality. We sought to analyze the relationship between LVAD flow characteristics and subsequent allograft rejection in bridge to transplant (BTT) patients.
Patients with LVADs from the UTAH Transplant Affiliated Hospitals were retrospectively analyzed. Rejection was determined pathologically according to the International Society for Heart and Lung Transplantation revised cardiac allograft rejection scale. Multimodal statistical analyses were applied.
Of 1,076 patients who underwent transplantation over a 26-year period, 151 had LVADs. Of these, 111 (77 pulsatile flow, 34 continuous flow) patients had pathologic data available. There was no difference in overall rejection (grades 1R to 3R) between the pulsatile-flow LVAD and continuous-flow LVAD groups (2.00 ± 1.43 versus 1.50 ± 1.16 episodes/year; p = 0.076.) Patients with pulsatile-flow LVADs had more clinically relevant (grades 2R to 3R) rejection than did patients with continuous-flow LVADs (0.49 ± 0.72 versus 0.12 ± 0.33 episodes/year; p < 0.001). There was no survival difference at 1 year (p = 0.920) or 4 years (p = 0.721) after transplantation.
Patients with continuous-flow LVADs have similar overall rejection rates and a reduced rate of clinically relevant rejection compared with patients with pulsatile-flow LVADs during the first year after transplantation. Although there is theoretical concern that nonphysiologic, nonpulsatile flow could alter the neurohormonal profile of patients in heart failure, we are encouraged that the type of LVAD circulation does not influence posttransplantation allograft survival.
Obesity is a disease state with polygenic inheritance, the phenotypic penetrance of which has been greatly expanded by the attributes of modern civilization. More than two-thirds of obese persons ...have comorbidities, many of which are characteristic of cardiometabolic risk syndrome (CMRS) in addition to other life-quality-reducing complaints. The CMRS is associated with increased cardiovascular events and mortality. Individuals with a body mass index greater than 35 infrequently achieve or maintain weight loss adequate to resolve these metabolic and anatomic issues by lifestyle or pharmacologic strategies. Data suggest that some of these patients may be better served by bariatric surgery.
Summary The Countdown to 2015 for Maternal, Newborn, and Child Survival monitors coverage of priority interventions to achieve the Millennium Development Goals (MDGs) for child mortality and maternal ...health. We reviewed progress between 1990 and 2010 in coverage of 26 key interventions in 68 Countdown priority countries accounting for more than 90% of maternal and child deaths worldwide. 19 countries studied were on track to meet MDG 4, in 47 we noted acceleration in the yearly rate of reduction in mortality of children younger than 5 years, and in 12 countries progress had decelerated since 2000. Progress towards reduction of neonatal deaths has been slow, and maternal mortality remains high in most Countdown countries, with little evidence of progress. Wide and persistent disparities exist in the coverage of interventions between and within countries, but some regions have successfully reduced longstanding inequities. Coverage of interventions delivered directly in the community on scheduled occasions was higher than for interventions relying on functional health systems. Although overseas development assistance for maternal, newborn, and child health has increased, funding for this sector accounted for only 31% of all development assistance for health in 2007. We provide evidence from several countries showing that rapid progress is possible and that focused and targeted interventions can reduce inequities related to socioeconomic status and sex. However, much more can and should be done to address maternal and newborn health and improve coverage of interventions related to family planning, care around childbirth, and case management of childhood illnesses.
Summary A new Global Investment Framework for Women's and Children's Health demonstrates how investment in women's and children's health will secure high health, social, and economic returns. We ...costed health systems strengthening and six investment packages for: maternal and newborn health, child health, immunisation, family planning, HIV/AIDS, and malaria. Nutrition is a cross-cutting theme. We then used simulation modelling to estimate the health and socioeconomic returns of these investments. Increasing health expenditure by just $5 per person per year up to 2035 in 74 high-burden countries could yield up to nine times that value in economic and social benefits. These returns include greater gross domestic product (GDP) growth through improved productivity, and prevention of the needless deaths of 147 million children, 32 million stillbirths, and 5 million women by 2035. These gains could be achieved by an additional investment of $30 billion per year, equivalent to a 2% increase above current spending.
Summary Remarkable progress has been made towards halving of maternal deaths and deaths of children aged 1–59 months, although the task is incomplete. Newborn deaths and stillbirths were largely ...invisible in the Millennium Development Goals, and have continued to fall between maternal and child health efforts, with much slower reduction. This Series and the Every Newborn Action Plan outline mortality goals for newborn babies (ten or fewer per 1000 livebirths) and stillbirths (ten or fewer per 1000 total births) by 2035, aligning with A Promise Renewed target for children and the vision of Every Woman Every Child. To focus political attention and improve performance, goals for newborn babies and stillbirths must be recognised in the post-2015 framework, with corresponding accountability mechanisms. The four previous papers in this Every Newborn Series show the potential for a triple return on investment around the time of birth: averting maternal and newborn deaths and preventing stillbirths. Beyond survival, being counted and optimum nutrition and development is a human right for all children, including those with disabilities. Improved human capital brings economic productivity. Efforts to reach every woman and every newborn baby, close gaps in coverage, and improve equity and quality for antenatal, intrapartum, and postnatal care, especially in the poorest countries and for underserved populations, need urgent attention. We have prioritised what needs to be done differently on the basis of learning from the past decade about what has worked, and what has not. Needed now are four most important shifts: (1) intensification of political attention and leadership; (2) promotion of parent voice, supporting women, families, and communities to speak up for their newborn babies and to challenge social norms that accept these deaths as inevitable; (3) investment for effect on mortality outcome as well as harmonisation of funding; (4) implementation at scale, with particular attention to increasing of health worker numbers and skills with attention to high-quality childbirth care for newborn babies as well as mothers and children; and (5) evaluation, tracking coverage of priority interventions and packages of care with clear accountability to accelerate progress and reach the poorest groups. The Every Newborn Action Plan provides an evidence-based roadmap towards care for every woman, and a healthy start for every newborn baby, with a right to be counted, survive, and thrive wherever they are born.
Summary Background Back pain remains a challenge for primary care internationally. One model that has not been tested is stratification of the management according to the patient's prognosis (low, ...medium, or high risk). We compared the clinical effectiveness and cost-effectiveness of stratified primary care (intervention) with non-stratified current best practice (control). Methods 1573 adults (aged ≥18 years) with back pain (with or without radiculopathy) consultations at ten general practices in England responded to invitations to attend an assessment clinic. Eligible participants were randomly assigned by use of computer-generated stratified blocks with a 2:1 ratio to intervention or control group. Primary outcome was the effect of treatment on the Roland Morris Disability Questionnaire (RMDQ) score at 12 months. In the economic evaluation, we focused on estimating incremental quality-adjusted life years (QALYs) and health-care costs related to back pain. Analysis was by intention to treat. This study is registered, number ISRCTN37113406. Findings 851 patients were assigned to the intervention (n=568) and control groups (n=283). Overall, adjusted mean changes in RMDQ scores were significantly higher in the intervention group than in the control group at 4 months (4·7 SD 5·9 vs 3·0 5·9, between-group difference 1·81 95% CI 1·06–2·57) and at 12 months (4·3 6·4 vs 3·3 6·2, 1·06 0·25–1·86), equating to effect sizes of 0·32 (0·19–0·45) and 0·19 (0·04–0·33), respectively. At 12 months, stratified care was associated with a mean increase in generic health benefit (0·039 additional QALYs) and cost savings (£240·01 vs £274·40) compared with the control group. Interpretation The results show that a stratified approach, by use of prognostic screening with matched pathways, will have important implications for the future management of back pain in primary care. Funding Arthritis Research UK.
Objective To describe common associated symptoms within the 10 days before diagnosis in subjects enrolled in the Pediatric Heart Network's trial of steroid therapy in Kawasaki disease (KD). Study ...design Patients with acute KD were enrolled between days 4 and 10 of illness at 8 centers between 2002 and 2004. We defined common associated symptoms as those occurring in ≥10% of patients. Principal clinical criteria for KD were not included in this analysis. Results Among 198 patients, irritability was reported in 98 (50%), vomiting in 88 (44%), decreased food/fluid intake in 73 (37%), cough in 55 (28%), diarrhea in 52 (26%), rhinorrhea in 37 (19%), weakness in 37 (19%), abdominal pain in 35 (18%), and joint pain (arthralgia or arthritis) in 29 (15%). One or more gastrointestinal symptom (vomiting, diarrhea, or abdominal pain) was present in 120 patients (61%) and 69 patients (35%) had ≥ 1 respiratory symptom (rhinorrhea or cough). Conclusions Nonspecific symptoms occur commonly in children with KD. To reduce delays in diagnosis, clinicians should be educated that such symptoms may comprise a significant component in the chief complaint.
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