Summary Background Platinum-based chemotherapy doublets are a standard of care for women with ovarian cancer recurring 6 months after completion of initial therapy. In this study, we aimed to explore ...the roles of secondary surgical cytoreduction and bevacizumab in this population, and report the results of the bevacizumab component here. Methods The multicentre, open-label, randomised phase 3 GOG-0213 trial was done in 67 predominantly academic centres in the USA (65 centres), Japan (one centre), and South Korea (one centre). Eligible patients were adult women (aged ≥18 years) with recurrent measurable or evaluable epithelial ovarian, primary peritoneal, or fallopian tube cancer, and a clinical complete response to primary platinum-based chemotherapy, who had been disease-free for at least 6 months following last infused cycle of platinum. Patients were randomly assigned (1:1) to standard chemotherapy (six 3-weekly cycles of paclitaxel 175 mg/m2 of body surface area and carboplatin area under the curve 5) or the same chemotherapy regimen plus bevacizumab (15 mg/kg of bodyweight) every 3 weeks and continued as maintenance every 3 weeks until disease progression or unacceptable toxicity. Individuals who participated in both the bevacizumab objective and surgical objective (which is ongoing) were randomly assigned (1:1:1:1) to receive either of these two chemotherapy regimens with or without prior secondary cytoreductive surgery. Randomisation for the bevacizumab objective was stratified by treatment-free interval and participation in the surgical objective. The primary endpoint was overall survival, analysed by intention to treat. This study is registered with ClinicalTrials.gov , number NCT00565851. Findings Between Dec 10, 2007, and Aug 26, 2011, 674 women were enrolled and randomly assigned to standard chemotherapy (n=337) or chemotherapy plus bevacizumab (n=377). Median follow-up at the end of the trial on Nov 5, 2014, was 49·6 months in each treatment group (IQR 41·5–62·2 for chemotherapy plus bevacizumab; IQR 40·8–59·3 for chemotherapy), at which point 415 patients had died (214 in the chemotherapy group and 201 in the chemotherapy plus bevacizumab group). Based on pretreatment stratification data, median overall survival in the chemotherapy plus bevacizumab group was 42·2 months (95% CI 37·7–46·2) versus 37·3 months (32·6–39·7) in the chemotherapy group (hazard ratio HR 0·829; 95% CI 0·683–1·005; p=0·056). We identified incorrect treatment-free interval stratification data for 45 (7%) patients (equally balanced between treatment groups); a sensitivity analysis of overall survival based on the audited treatment-free interval stratification data gave an adjusted HR of 0·823 (95% CI 0·680–0·996; p=0·0447). In the safety population (all patients who initiated treatment), 317 (96%) of 325 patients in the chemotherapy plus bevacizumab group had at least one grade 3 or worse adverse event compared with 282 (86%) of 332 in the chemotherapy group; the most frequently reported of these in the chemotherapy plus bevacizumab group compared with the chemotherapy group were hypertension (39 12% vs two 1%), fatigue (27 8% vs eight 2%), and proteinuria (27 8% vs none). Two (1%) treatment-related deaths occurred in the chemotherapy group (infection n=1 and myelodysplastic syndrome n=1) compared with nine (3%) in the chemotherapy plus bevacizumab group (infection n=1, febrile neutropenia n=1, myelodysplastic syndrome n=1, secondary malignancy n=1; deaths not classified with CTCAE terms: disease progression n=3, sudden death n=1, and not specified n=1). Interpretation The addition of bevacizumab to standard chemotherapy, followed by maintenance therapy until progression, improved the median overall survival in patients with platinum-sensitive recurrent ovarian cancer. Although the intention-to-treat analysis for overall survival was not significant, our sensitivity analysis based on corrected treatment-free interval stratification indicates that this strategy might be an important addition to the therapeutic armamentarium in these patients. Funding National Cancer Institute and Genentech.
Maternal and child malnutrition in low-income and middle-income countries encompasses both undernutrition and a growing problem with overweight and obesity. Low body-mass index, indicative of ...maternal undernutrition, has declined somewhat in the past two decades but continues to be prevalent in Asia and Africa. Prevalence of maternal overweight has had a steady increase since 1980 and exceeds that of underweight in all regions. Prevalence of stunting of linear growth of children younger than 5 years has decreased during the past two decades, but is higher in south Asia and sub-Saharan Africa than elsewhere and globally affected at least 165 million children in 2011; wasting affected at least 52 million children. Deficiencies of vitamin A and zinc result in deaths; deficiencies of iodine and iron, together with stunting, can contribute to children not reaching their developmental potential. Maternal undernutrition contributes to fetal growth restriction, which increases the risk of neonatal deaths and, for survivors, of stunting by 2 years of age. Suboptimum breastfeeding results in an increased risk for mortality in the first 2 years of life. We estimate that undernutrition in the aggregate—including fetal growth restriction, stunting, wasting, and deficiencies of vitamin A and zinc along with suboptimum breastfeeding—is a cause of 3·1 million child deaths annually or 45% of all child deaths in 2011. Maternal overweight and obesity result in increased maternal morbidity and infant mortality. Childhood overweight is becoming an increasingly important contributor to adult obesity, diabetes, and non-communicable diseases. The high present and future disease burden caused by malnutrition in women of reproductive age, pregnancy, and children in the first 2 years of life should lead to interventions focused on these groups.
Summary Background Resistance from antagonistic muscle groups might be a crucial factor reducing function in chronic hemiparesis. The resistance due to spastic co-contraction might be reduced by ...botulinum toxin injections. We assessed the effects of abobotulinumtoxinA injection in the upper limb muscles on muscle tone, spasticity, active movement, and function. Methods In this randomised, placebo-controlled, double-blind study, we enrolled adults (aged 18–80 years) at least 6 months after stroke or brain trauma from 34 neurology or rehabilitation clinics in Europe and the USA. Eligible participants were randomly allocated in a 1:1:1 ratio with a computer-generated list to receive a single injection session of abobotulinumtoxinA 500 U or 1000 U or placebo into the most hypertonic muscle group among the elbow, wrist, or finger flexors (primary target muscle group PTMG), and into at least two additional muscle groups from the elbow, wrist, or finger flexors or shoulder extensors. Patients and investigators were masked to treatment allocation. The primary endpoint was the change in muscle tone (Modified Ashworth Scale MAS) in the PTMG from baseline to 4 weeks. Secondary endpoints were Physician Global Assessment (PGA) at week 4 and change from baseline to 4 weeks in the perceived function (Disability Assessment Scale DAS) in the principal target of treatment, selected by the patient together with physician from four functional domains (dressing, hygiene, limb position, and pain). Analysis was by intention to treat. This study is registered with ClinicalTrials.gov , number NCT01313299. Findings 243 patients were randomly allocated to placebo (n=81), abobotulinumtoxinA 500 U (n=81), or abobotulinumtoxinA 1000 U (n=81). Mean change in MAS score from baseline at week 4 in the PTMG was −0·3 (SD 0·6) in the placebo group (n=79), −1·2 (1·0) in the abobotulinumtoxinA 500 U group (n=80; difference −0·9, 95% CI −1·2 to −0·6; p<0·0001 vs placebo), and −1·4 (1·1) in the abobotulinumtoxinA 1000 U group (n=79; −1·1, −1·4 to −0·8; p<0·0001 vs placebo). Mean PGA score at week 4 was 0·6 (SD 1·0) in the placebo group (n=78), 1·4 (1·1) in the abobotulinumtoxinA 500 U group (n=80; p=0·0003 vs placebo), and 1·8 (1·1) in the abobotulinumtoxinA 1000 U group (n=78; p<0·0001 vs placebo). Mean change from baseline at week 4 in DAS score for the principal target of treatment was −0·5 (0·7) in the placebo group (n=79), −0·7 (0·8) in the abobotulinumtoxinA 500 U group (n=80; p=0·2560 vs placebo), and −0·7 (0·7) in the abobotulinumtoxinA 1000 U group (n=78; p=0·0772 vs placebo). Three serious adverse events occurred in each group and none were treatment related; two resulted in death (from pulmonary oedema in the placebo group and a pre-existing unspecified cardiovascular disorder in the abobotulinumtoxinA 500 U group). Adverse events that were thought to be treatment related occurred in two (2%), six (7%), and seven (9%) patients in the placebo, abobotulinumtoxinA 500 U, and abobotulinumtoxinA 1000 U groups, respectively. The most common treatment-related adverse event was mild muscle weakness. All adverse events were mild or moderate. Interpretation AbobotulinumtoxinA at doses of 500 U or 1000 U injected into upper limb muscles provided tone reduction and clinical benefit in hemiparesis. Future research into the treatment of spastic paresis with botulinum toxin should use active movement and function as primary outcome measures. Funding Ipsen.
Summary Maternal undernutrition contributes to 800 000 neonatal deaths annually through small for gestational age births; stunting, wasting, and micronutrient deficiencies are estimated to underlie ...nearly 3·1 million child deaths annually. Progress has been made with many interventions implemented at scale and the evidence for effectiveness of nutrition interventions and delivery strategies has grown since The Lancet Series on Maternal and Child Undernutrition in 2008. We did a comprehensive update of interventions to address undernutrition and micronutrient deficiencies in women and children and used standard methods to assess emerging new evidence for delivery platforms. We modelled the effect on lives saved and cost of these interventions in the 34 countries that have 90% of the world's children with stunted growth. We also examined the effect of various delivery platforms and delivery options using community health workers to engage poor populations and promote behaviour change, access and uptake of interventions. Our analysis suggests the current total of deaths in children younger than 5 years can be reduced by 15% if populations can access ten evidence-based nutrition interventions at 90% coverage. Additionally, access to and uptake of iodised salt can alleviate iodine deficiency and improve health outcomes. Accelerated gains are possible and about a fifth of the existing burden of stunting can be averted using these approaches, if access is improved in this way. The estimated total additional annual cost involved for scaling up access to these ten direct nutrition interventions in the 34 focus countries is Int$9·6 billion per year. Continued investments in nutrition-specific interventions to avert maternal and child undernutrition and micronutrient deficiencies through community engagement and delivery strategies that can reach poor segments of the population at greatest risk can make a great difference. If this improved access is linked to nutrition-sensitive approaches—ie, women's empowerment, agriculture, food systems, education, employment, social protection, and safety nets—they can greatly accelerate progress in countries with the highest burden of maternal and child undernutrition and mortality.
Diarrhoea and pneumonia are the leading infectious causes of childhood morbidity and mortality. We comprehensively reviewed the epidemiology of childhood diarrhoea and pneumonia in 2010–11 to inform ...the planning of integrated control programmes for both illnesses. We estimated that, in 2010, there were 1·731 billion episodes of diarrhoea (36 million of which progressed to severe episodes) and 120 million episodes of pneumonia (14 million of which progressed to severe episodes) in children younger than 5 years. We estimated that, in 2011, 700 000 episodes of diarrhoea and 1·3 million of pneumonia led to death. A high proportion of deaths occurs in the first 2 years of life in both diseases—72% for diarrhoea and 81% for pneumonia. The epidemiology of childhood diarrhoea and that of pneumonia overlap, which might be partly because of shared risk factors, such as undernutrition, suboptimum breastfeeding, and zinc deficiency. Rotavirus is the most common cause of vaccine-preventable severe diarrhoea (associated with 28% of cases), and Streptococcus pneumoniae (18·3%) of vaccine-preventable severe pneumonia. Morbidity and mortality from childhood pneumonia and diarrhoea are falling, but action is needed globally and at country level to accelerate the reduction.
Summary Discovery of intestinal sodium-glucose transport was the basis for development of oral rehydration solution, and was hailed as potentially the most important medical advance of the 20th ...century. Before widespread use of oral rehydration solution, treatment for diarrhoea was restricted to intravenous fluid replacement, for which patients had to go to a health-care facility to access appropriate equipment. These facilities were usually neither available nor reasonable to use in the resource-poor settings most affected by diarrhoea. Use of oral rehydration solution has stagnated, despite being effective, inexpensive, and widely available. Thus, diarrhoea continues to be a leading cause of child death with consistent mortality rates during the past 5 years. New methods for prevention, management, and treatment of diarrhoea—including an improved oral rehydration formulation, zinc supplementation, and rotavirus vaccines—make now the time to revitalise efforts to reduce diarrhoea mortality worldwide.
Summary Background Up-to-date information on the causes of child deaths is crucial to guide global efforts to improve child survival. We report new estimates for 2008 of the major causes of death in ...children younger than 5 years. Methods We used multicause proportionate mortality models to estimate deaths in neonates aged 0–27 days and children aged 1–59 months, and selected single-cause disease models and analysis of vital registration data when available to estimate causes of child deaths. New data from China and India permitted national data to be used for these countries instead of predictions based on global statistical models, as was done previously. We estimated proportional causes of death for 193 countries, and by application of these proportions to the country-specific mortality rates in children younger than 5 years and birth rates, the numbers of deaths by cause were calculated for countries, regions, and the world. Findings Of the estimated 8·795 million deaths in children younger than 5 years worldwide in 2008, infectious diseases caused 68% (5·970 million), with the largest percentages due to pneumonia (18%, 1·575 million, uncertainty range UR 1·046 million–1·874 million), diarrhoea (15%, 1·336 million, 0·822 million–2·004 million), and malaria (8%, 0·732 million, 0·601 million–0·851 million). 41% (3·575 million) of deaths occurred in neonates, and the most important single causes were preterm birth complications (12%, 1·033 million, UR 0·717 million–1·216 million), birth asphyxia (9%, 0·814 million, 0·563 million–0·997 million), sepsis (6%, 0·521 million, 0·356 million–0·735 million), and pneumonia (4%, 0·386 million, 0·264 million–0·545 million). 49% (4·294 million) of child deaths occurred in five countries: India, Nigeria, Democratic Republic of the Congo, Pakistan, and China. Interpretation These country-specific estimates of the major causes of child deaths should help to focus national programmes and donor assistance. Achievement of Millennium Development Goal 4, to reduce child mortality by two-thirds, is only possible if the high numbers of deaths are addressed by maternal, newborn, and child health interventions. Funding WHO, UNICEF, and Bill & Melinda Gates Foundation.
Summary Background Thrombophilias are common disorders that increase the risk of pregnancy-associated venous thromboembolism and pregnancy loss and can also increase the risk of placenta-mediated ...pregnancy complications (severe pre-eclampsia, small-for-gestational-age infants, and placental abruption). We postulated that antepartum dalteparin would reduce these complications in pregnant women with thrombophilia. Methods In this open-label randomised trial undertaken in 36 tertiary care centres in five countries, we enrolled consenting pregnant women with thrombophilia at increased risk of venous thromboembolism or with previous placenta-mediated pregnancy complications. Eligible participants were randomly allocated in a 1:1 ratio to either antepartum prophylactic dose dalteparin (5000 international units once daily up to 20 weeks' gestation, and twice daily thereafter until at least 37 weeks' gestation) or to no antepartum dalteparin (control group). Randomisation was done by a web-based randomisation system, and was stratified by country and gestational age at randomisation day with a permuted block design (block sizes 4 and 8). At randomisation, site pharmacists (or delegates) received a randomisation number and treatment allocation (by fax and/or e-mail) from the central web randomisation system and then dispensed study drug to the local coordinator. Patients and study personnel were not masked to treatment assignment, but the outcome adjudicators were masked. The primary composite outcome was independently adjudicated severe or early-onset pre-eclampsia, small-for-gestational-age infant (birthweight <10th percentile), pregnancy loss, or venous thromboembolism. We did intention-to-treat and on-treatment analyses. This trial is registered with ClinicalTrials.gov , number NCT00967382 , and with Current Controlled Trials, number ISRCTN87441504. Findings Between Feb 28, 2000, and Sept 14, 2012, 292 women consented to participate and were randomly assigned to the two groups. Three women were excluded after randomisation because of ineligibility (two in the antepartum dalteparin group and one in the control group), leaving 146 women assigned to antepartum dalteparin and 143 assigned to no antepartum dalteparin. Some patients crossed over to the other group during treatment, and therefore for on-treatment and safety analysis there were 143 patients in the dalteparin group and 141 in the no dalteparin group. Dalteparin did not reduce the incidence of the primary composite outcome in both intention-to-treat analysis (dalteparin 25/146 17·1%; 95% CI 11·4–24·2% vs no dalteparin 27/143 18·9%; 95% CI 12·8–26·3%; risk difference −1·8% 95% CI −10·6% to 7·1%)) and on-treatment analysis (dalteparin 28/143 19·6% vs no dalteparin 24/141 17·0%; risk difference +2·6% 95% CI −6·4 to 11·6%). In safety analysis, the occurrence of major bleeding did not differ between the two groups. However, minor bleeding was more common in the dalteparin group (28/143 19·6%) than in the no dalteparin group (13/141 9·2%; risk difference 10·4%, 95% CI 2·3–18·4; p=0·01). Interpretation Antepartum prophylactic dalteparin does not reduce the occurrence of venous thromboembolism, pregnancy loss, or placenta-mediated pregnancy complications in pregnant women with thrombophilia at high risk of these complications and is associated with an increased risk of minor bleeding. Funding Canadian Institutes of Health Research, Heart and Stroke Foundation of Canada, and Pharmacia and UpJohn.
Global mortality in children younger than 5 years has fallen substantially in the past two decades from more than 12 million in 1990, to 6·9 million in 2011, but progress is inconsistent between ...countries. Pneumonia and diarrhoea are the two leading causes of death in this age group and have overlapping risk factors. Several interventions can effectively address these problems, but are not available to those in need. We systematically reviewed evidence showing the effectiveness of various potential preventive and therapeutic interventions against childhood diarrhoea and pneumonia, and relevant delivery strategies. We used the Lives Saved Tool model to assess the effect on mortality when these interventions are applied. We estimate that if implemented at present annual rates of increase in each of the 75 Countdown countries, these interventions and packages of care could save 54% of diarrhoea and 51% of pneumonia deaths by 2025 at a cost of US$3·8 billion. However, if coverage of these key evidence-based interventions were scaled up to at least 80%, and that for immunisations to at least 90%, 95% of diarrhoea and 67% of pneumonia deaths in children younger than 5 years could be eliminated by 2025 at a cost of $6·715 billion. New delivery platforms could promote equitable access and community platforms are important catalysts in this respect. Furthermore, several of these interventions could reduce morbidity and overall burden of disease, with possible benefits for developmental outcomes.
Summary As part of Disease Control Priorities 3rd Edition , the World Bank will publish a volume on Reproductive, Maternal, Newborn, and Child Health that identifies essential cost-effective health ...interventions that can be scaled up to reduce maternal, newborn, and child deaths, and stillbirths. This Review summarises the volume's key findings and estimates the effect and cost of expanded implementation of these interventions. Recognising that a continuum of care from the adolescent girl, woman, or mother to child is needed, the volume includes details of preventive and therapeutic health interventions in integrated packages: Maternal and Newborn Health and Child Health (along with folic acid supplementation, a key reproductive health intervention). Scaling up all interventions in these packages from coverage in 2015 to hypothetically immediately achieve 90% coverage would avert 149 000 maternal deaths, 849 000 stillbirths, 1 498 000 neonatal deaths, and 1 515 000 additional child deaths. In alternative calculations that consider only the effects of reducing the number of pregnancies by provision of contraceptive services as part of a Reproductive Health package, meeting 90% of the unmet need for contraception would reduce global births by almost 28 million and consequently avert deaths that could have occurred at 2015 rates of fertility and mortality. Thus, 67 000 maternal deaths, 440 000 neonatal deaths, 473 000 child deaths, and 564 000 stillbirths could be averted from avoided pregnancies. Particularly effective interventions in the Maternal and Newborn Health and Child Health packages would be management of labour and delivery, care of preterm births, and treatment of serious infectious diseases and acute malnutrition. Nearly all of these essential interventions can be delivered by health workers in the community or in primary health centres, which can increase population access to needed services. The annual incremental cost of immediately scaling up these essential interventions would be US$6·2 billion in low-income countries, $12·4 billion in lower-middle-income countries, and $8·0 billion in upper-middle-income countries. With the additional funding, greater focus on high-effect integrated interventions and innovations in service delivery, such as task shifting to other groups of health workers and supply and demand incentives, can help rectify major gaps in accessibility and quality of care. In recent decades, reduction of avoidable maternal and child deaths has been a global priority. With continued priority and expansion of essential reproductive, maternal, newborn, and child health interventions to high coverage, equity, and quality, as well as interventions to address underlying problems such as women's low status in society and violence against women, these deaths and substantial morbidity can be largely eliminated in another generation.
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