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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.

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.

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. 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. 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. 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. EORTC, NCIC, Nélia and Amadeo Barletta Foundation, Schering-Plough.

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.

The CATNON trial investigated the addition of concurrent, adjuvant, and both current and adjuvant temozolomide to radiotherapy in adults with newly diagnosed 1p/19q non-co-deleted anaplastic gliomas. The benefit of concurrent temozolomide chemotherapy and relevance of mutations in the IDH1 and IDH2 genes remain unclear. This randomised, open-label, phase 3 study done in 137 institutions across Australia, Europe, and North America included patients aged 18 years or older with newly diagnosed 1p/19q non-co-deleted anaplastic gliomas and a WHO performance status of 0–2. Patients were randomly assigned (1:1:1:1) centrally using a minimisation technique to radiotherapy alone (59·4 Gy in 33 fractions; three-dimensional conformal radiotherapy or intensity-modulated radiotherapy), radiotherapy with concurrent oral temozolomide (75 mg/m2 per day), radiotherapy with adjuvant oral temozolomide (12 4-week cycles of 150–200 mg/m2 temozolomide given on days 1–5), or radiotherapy with both concurrent and adjuvant temozolomide. Patients were stratified by institution, WHO performance status score, age, 1p loss of heterozygosity, the presence of oligodendroglial elements on microscopy, and MGMT promoter methylation status. The primary endpoint was overall survival adjusted by stratification factors at randomisation in the intention-to-treat population. A second interim analysis requested by the independent data monitoring committee was planned when two-thirds of total required events were observed to test superiority or futility of concurrent temozolomide. This study is registered with ClinicalTrials.gov, NCT00626990. Between Dec 4, 2007, and Sept 11, 2015, 751 patients were randomly assigned (189 to radiotherapy alone, 188 to radiotherapy with concurrent temozolomide, 186 to radiotherapy and adjuvant temozolomide, and 188 to radiotherapy with concurrent and adjuvant temozolomide). Median follow-up was 55·7 months (IQR 41·0–77·3). The second interim analysis declared futility of concurrent temozolomide (median overall survival was 66·9 months [95% CI 45·7–82·3] with concurrent temozolomide vs 60·4 months [45·7–71·5] without concurrent temozolomide; hazard ratio [HR] 0·97 [99·1% CI 0·73–1·28], p=0·76). By contrast, adjuvant temozolomide improved overall survival compared with no adjuvant temozolomide (median overall survival 82·3 months [95% CI 67·2–116·6] vs 46·9 months [37·9–56·9]; HR 0·64 [95% CI 0·52–0·79], p<0·0001). The most frequent grade 3 and 4 toxicities were haematological, occurring in no patients in the radiotherapy only group, 16 (9%) of 185 patients in the concurrent temozolomide group, and 55 (15%) of 368 patients in both groups with adjuvant temozolomide. No treatment-related deaths were reported. Adjuvant temozolomide chemotherapy, but not concurrent temozolomide chemotherapy, was associated with a survival benefit in patients with 1p/19q non-co-deleted anaplastic glioma. Clinical benefit was dependent on IDH1 and IDH2 mutational status. Merck Sharpe & Dohme.

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.

Cefiderocol is a novel siderophore cephalosporin with potent activity against gram-negative bacteria, including multidrug-resistant strains. This Phase I study was conducted to assess the tolerability of single-ascending doses of cefiderocol (part 1) and the effect of cefiderocol on cardiac repolarization, assessed using the electrocardiographic corrected QT interval (QTcF) and other ECG parameters (part 2), in healthy adult subjects. Part 1 was a randomized, double-blind, placebo-controlled, single-ascending dose study in healthy adult male and female subjects. Part 2 was a 4-period crossover study in which subjects received a single 2-g dose of cefiderocol (therapeutic dose), a single 4-g dose of cefiderocol (supratherapeutic dose), or saline (placebo), each infused over 3 hours, and a single oral 400-mg dose of moxifloxacin. In each treatment period, continuous cardiac monitoring was used to assess the effects of cefiderocol on ECG parameters. The QT interval corrected using the Fridericia formula (QTcF) was the primary ECG parameter; the time-matched placebo- and baseline-adjusted (dd)-QTcF interval was the primary end point. The plasma pharmacokinetic properties of cefiderocol were calculated on the basis of concentration–time profiles in all evaluable subjects. All point estimates for the ddQTcF interval were <5 ms and the upper bound of the 90% CIs were <10 ms at each timepoint after the initiation of the cefiderocol 3-hour infusion. Concentration-effect modeling showed a slightly negative slope and predicted modestly negative values of the ddQTcF interval at the Cmax of cefiderocol. Both doses of cefiderocol were well tolerated. All adverse events were mild in severity, with no deaths or serious adverse events reported. Overall, therapeutic and supratherapeutic doses of cefiderocol had no apparent clinically significant effect on the QTcF.

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). 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. 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. 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. Arthritis Research UK.

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.

The CATNON trial investigated the benefit of the addition of concurrent or adjuvant temozolomide to radiotherapy in individuals with anaplastic astrocytoma. We report the long-term follow-up of the study focusing on the individuals with isocitrate dehydrogenase (IDH) mutated (IDHmt) tumours. This randomised, open-label, phase 3 study in 137 institutions across Australia, Europe, and North America included participants aged 18 years or older with newly diagnosed 1p/19q non-co-deleted anaplastic gliomas and a WHO performance status of 0–2. Participants were randomly assigned (1:1:1:1) centrally using a minimisation technique to radiotherapy alone (59·4 Gy in 33 fractions), radiotherapy with concurrent oral temozolomide (75 mg/m2 per day), radiotherapy with adjuvant oral temozolomide (12 4-week cycles of 150–200 mg/m2 temozolomide given on days 1–5), or radiotherapy with both concurrent and adjuvant temozolomide. Participants were stratified by institution, WHO performance status score, age, 1p loss of heterozygosity, the presence of oligodendroglial elements on microscopy, and MGMT promoter methylation status. The primary endpoint was overall survival adjusted by stratification factors at randomisation in the intention-to-treat population. The eighth amendment of the study protocol (June 27, 2011) incorporated analysis of IDH mutational status into the study. We report the intention-to-treat analysis and the exploratory analysis within the population of participants with astrocytoma with an IDH mutation. As the safety data have been published previously, no safety data are reported. This trial is registered with ClinicalTrials.gov, NCT00626990, and is completed. Between Dec 4, 2007, and Sept 11, 2015, 1407 participants were registered and 751 participants were randomly allocated, 444 of whom were diagnosed with an IDHmt tumour. After a median follow-up for overall survival of 10·9 years (IQR 9·5–12·7), in the intention-to-treat population, adjuvant temozolomide improved overall survival compared with no adjuvant temozolomide (hazard ratio [HR] 0·65 [95% CI 0·54–0·77]), but concurrent did not compared with no concurrent temozolomide (HR 0·91 [0·76–1·08]). In univariable analysis of the participants with an IDHmt tumour, concurrent temozolomide had no statistically significant effect on overall survival (median 9·7 years [8·2–12·5] vs 7·2 years [6·2–9·4]; HR 0·81 [0·63–1·04]), but median overall survival was 12·5 years (95% CI 9·4–15·0) with adjuvant temozolomide compared with 6·0 years (5·1–7·2) with no adjuvant temozolomide (HR 0·54 [0·42–0·69]). No benefit of temozolomide, neither concurrent nor adjuvant, was observed in participants with IDH wild-type tumours. Methylation-based subtyping and several DNA alterations (eg, amplification of PDGFRA and CDK4, homozygous deletion of CDKN2A, and total copy number variation) were associated with worse outcome, none of which was predictive for benefit to temozolomide. Long-term follow-up confirms that radiotherapy followed by 12 cycles of adjuvant temozolomide without concurrent temozolomide during radiotherapy improves survival for individuals with aggressive IDHmt astrocytoma. MSD.