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1.  The health of homeless people in high-income countries: descriptive epidemiology, health consequences, and clinical and policy recommendations 
Lancet (London, England)  2014;384(9953):1529-1540.
In the European Union, more than 400 000 individuals are homeless on any one night and more than 600 000 are homeless in the USA. The causes of homelessness are an interaction between individual and structural factors. Individual factors include poverty, family problems, and mental health and substance misuse problems. The availability of low-cost housing is thought to be the most important structural determinant for homelessness. Homeless people have higher rates of premature mortality than the rest of the population, especially from suicide and unintentional injuries, and an increased prevalence of a range of infectious diseases, mental disorders, and substance misuse. High rates of non-communicable diseases have also been described with evidence of accelerated ageing. Although engagement with health services and adherence to treatments is often compromised, homeless people typically attend the emergency department more often than non-homeless people. We discuss several recommendations to improve the surveillance of morbidity and mortality in homeless people. Programmes focused on high-risk groups, such as individuals leaving prisons, psychiatric hospitals, and the child welfare system, and the introduction of national and state-wide plans that target homeless people are likely to improve outcomes.
PMCID: PMC4520328  PMID: 25390578
2.  The future of life expectancy and life expectancy inequalities in England and Wales: Bayesian spatiotemporal forecasting 
Lancet (London, England)  2015;386(9989):163-170.
To plan for pensions and health and social services, future mortality and life expectancy need to be forecast. Consistent forecasts for all subnational units within a country are very rare. Our aim was to forecast mortality and life expectancy for England and Wales' districts.
We developed Bayesian spatiotemporal models for forecasting of age-specific mortality and life expectancy at a local, small-area level. The models included components that accounted for mortality in relation to age, birth cohort, time, and space. We used geocoded mortality and population data between 1981 and 2012 from the Office for National Statistics together with the model with the smallest error to forecast age-specific death rates and life expectancy to 2030 for 375 of England and Wales' 376 districts. We measured model performance by withholding recent data and comparing forecasts with this withheld data.
Life expectancy at birth in England and Wales was 79·5 years (95% credible interval 79·5–79·6) for men and 83·3 years (83·3–83·4) for women in 2012. District life expectancies ranged between 75·2 years (74·9–75·6) and 83·4 years (82·1–84·8) for men and between 80·2 years (79·8–80·5) and 87·3 years (86·0–88·8) for women. Between 1981 and 2012, life expectancy increased by 8·2 years for men and 6·0 years for women, closing the female–male gap from 6·0 to 3·8 years. National life expectancy in 2030 is expected to reach 85·7 (84·2–87·4) years for men and 87·6 (86·7–88·9) years for women, further reducing the female advantage to 1·9 years. Life expectancy will reach or surpass 81·4 years for men and reach or surpass 84·5 years for women in every district by 2030. Longevity inequality across districts, measured as the difference between the 1st and 99th percentiles of district life expectancies, has risen since 1981, and is forecast to rise steadily to 8·3 years (6·8–9·7) for men and 8·3 years (7·1–9·4) for women by 2030.
Present forecasts underestimate the expected rise in life expectancy, especially for men, and hence the need to provide improved health and social services and pensions for elderly people in England and Wales. Health and social policies are needed to curb widening life expectancy inequalities, help deprived districts catch up in longevity gains, and avoid a so-called grand divergence in health and longevity.
UK Medical Research Council and Public Health England.
PMCID: PMC4502253  PMID: 25935825
3.  Liberal versus restrictive blood transfusion strategy: 3-year survival and cause of death results from the FOCUS randomised controlled trial 
Lancet (London, England)  2014;385(9974):1183-1189.
Blood transfusion might affect long-term mortality by changing immune function and thus potentially increasing the risk of subsequent infections and cancer recurrence. Compared with a restrictive transfusion strategy, a more liberal strategy could reduce cardiac complications by lowering myocardial damage, thereby reducing future deaths from cardiovascular disease. We aimed to establish the effect of a liberal transfusion strategy on long-term survival compared with a restrictive transfusion strategy.
In the randomised controlled FOCUS trial, adult patients aged 50 years and older, with a history of or risk factors for cardiovascular disease, and with postoperative haemoglobin concentrations lower than 100 g/L within 3 days of surgery to repair a hip fracture, were eligible for enrolment. Patients were recruited from 47 participating hospitals in the USA and Canada, and eligible participants were randomly allocated in a 1:1 ratio by a central telephone system to either liberal transfusion in which they received blood transfusion to maintain haemoglobin level at 100 g/L or higher, or restrictive transfusion in which they received blood transfusion when haemoglobin level was lower than 80 g/L or if they had symptoms of anaemia. In this study, we analysed the long-term mortality of patients assigned to the two transfusion strategies, which was a secondary outcome of the FOCUS trial. Long-term mortality was established by linking the study participants to national death registries in the USA and Canada. Treatment assignment was not masked, but investigators who ascertained mortality and cause of death were masked to group assignment. Analyses were by intention to treat. The FOCUS trial is registered with, number NCT00071032.
Between July 19, 2004, and Feb 28, 2009, 2016 patients were enrolled and randomly assigned to the two treatment groups: 1007 to the liberal transfusion strategy and 1009 to the restrictive transfusion strategy. The median duration of follow-up was 3·1 years (IQR 2·4–4·1 years), during which 841 (42%) patients died. Long-term mortality did not differ significantly between the liberal transfusion strategy (432 deaths) and the restrictive transfusion strategy (409 deaths) (hazard ratio 1·09 [95% CI 0·95–1·25]; p=0·21).
Liberal blood transfusion did not affect mortality compared with a restrictive transfusion strategy in a high-risk group of elderly patients with underlying cardiovascular disease or risk factors. The underlying causes of death did not differ between the trial groups. These findings do not support hypotheses that blood transfusion leads to long-term immunosuppression that is severe enough to affect long-term mortality rate by more than 20–25% or cause of death.
National Heart, Lung, and Blood Institute.
PMCID: PMC4498804  PMID: 25499165
4.  Age-dependent effects of RPE65 gene therapy for Leber’s congenital amaurosis: a phase 1 dose-escalation trial 
Lancet (London, England)  2009;374(9701):1597-1605.
Gene therapy has the potential to reverse disease or prevent further deterioration of vision in patients with incurable inherited retinal degeneration. We therefore did a phase 1 trial to assess the effect of gene therapy on retinal and visual function in children and adults with Leber’s congenital amaurosis.
We assessed the retinal and visual function in 12 patients (aged 8–44 years) with RPE65-associated Leber’s congenital amaurosis given one subretinal injection of adeno-associated virus (AAV) containing a gene encoding a protein needed for the isomerohydrolase activity of the retinal pigment epithelium (AAV2-hRPE65v2) in the worst eye at low (1·5×1010 vector genomes), medium (4·8×1010 vector genomes), or high dose (1·5×1011 vector genomes) for up to 2 years.
AAV2-hRPE65v2 was well tolerated and all patients showed sustained improvement in subjective and objective measurements of vision (ie, dark adaptometry, pupillometry, electroretinography, nystagmus, and ambulatory behaviour). Patients had at least a 2 log unit increase in pupillary light responses, and an 8-year-old child had nearly the same level of light sensitivity as that in age-matched normal-sighted individuals. The greatest improvement was noted in children, all of whom gained ambulatory vision. The study is registered with, number NCT00516477.
The safety, extent, and stability of improvement in vision in all patients support the use of AAV-mediated gene therapy for treatment of inherited retinal diseases, with early intervention resulting in the best potential gain.
Center for Cellular and Molecular Therapeutics at the Children’s Hospital of Philadelphia, Foundation Fighting Blindness, Telethon, Research to Prevent Blindness, F M Kirby Foundation, Mackall Foundation Trust, Regione Campania Convenzione, European Union, Associazione Italiana Amaurosi Congenita di Leber, Fund for Scientific Research, Fund for Research in Ophthalmology, and National Center for Research Resources.
PMCID: PMC4492302  PMID: 19854499
5.  Preconception Low Dose Aspirin and Pregnancy Outcomes: Findings from the EAGeR (Effects of Aspirin in Gestation and Reproduction) Randomized Trial 
Lancet  2014;384(9937):29-36.
Our objective was to determine whether preconception-initiated low dose aspirin (LDA) improved live birth rates in women with one to two prior pregnancy losses.
This multi-center, block-randomized, double-blind, placebo-controlled trial recruited from four medical centers in the US (2006–2012). Women aged 18–40 years attempting pregnancy were stratified by eligibility criteria: “original”: women with one loss <20 weeks’ gestation during the past year; or “expanded”: women with one to two prior losses regardless of gestational length or time of loss. Women were block-randomized (615 LDA, 613 placebo) by center and eligibility stratum. Preconception-initiated daily LDA (81 mg/day) was compared with placebo for up to six menstrual cycles; for those who conceived, study treatment continued until 36 weeks’ gestation. The primary outcome was live birth rate. The trial was registered on (#NCT00467363).
Overall, 1078 women completed the trial (LDA 535, placebo 543). Live birth rates were 58% (309/535) in women assigned LDA vs. 53% placebo (286/543; risk difference [RD] 5%; 95% confidence interval [CI] −0·8, 11). Pregnancy loss rates were similar between groups (13% [68/535] LDA, 12% [65/543] placebo; p=0·7812). In the original stratum, live birth rates were 62% (151/242) LDA vs. 53% (133/250) placebo (RD 9%; 95% CI 0·5, 18), and in the expanded, 54% (158/293) LDA vs. 52% (153/293) placebo (RD 2%; 95% CI −6, 10). Major adverse events were similar between treatment arms. LDA was associated with increased bleeding per vaginam, but this was not associated with losses.
Preconception-initiated LDA was not significantly associated with live birth or pregnancy loss among women with one to two prior losses. However, higher live birth rates were observed among women with a single documented loss at <20 weeks’ gestation during the previous year. LDA is not recommended for the prevention of pregnancy loss.
PMCID: PMC4181666  PMID: 24702835
low dose aspirin; conception; pregnancy loss; fertility; live birth
6.  Phase 1 Trial of Subcutaneous rAvPAL-PEG in Subjects with Phenylketonuria 
Lancet  2014;384(9937):37-44.
Phenylketonuria is an inherited disease caused by impaired activity of phenylalanine hydroxylase, the enzyme that converts phenylalanine to tyrosine, leading to accumulation of phenylalanine and subsequent neurocognitive dysfunction. A phenylalanine-restricted diet initiated early in life can ameliorate the toxic effects of phenylalanine. However, the diet is onerous and compliance is extremely difficult. Phenylalanine ammonia lyase (PAL) is a prokaryotic enzyme that converts phenylalanine to ammonia and trans-cinnamic acid. This Phase 1, multicenter clinical trial evaluated the safety, tolerability, pharmacokinetics and efficacy of rAvPAL-PEG (recombinant Anabaena variabilis PAL produced in E. coli conjugated with polyethylene glycol [PEG] to reduce immunogenicity) in reducing phenylalanine levels in subjects with phenylketonuria.
Single subcutaneous injections of rAvPAL-PEG in escalating doses (0·001, 0·003, 0·01, 0·03, and 0·1 mg/kg) were administered to 25 adults with phenylketonuria recruited from those attending metabolic clinics in North America whose blood phenylalanine concentrations were ≥600 μmol/L.
The most frequently reported adverse events were injection-site reactions and dizziness. Reactions were self-limited without sequelae. During the trial, two subjects had adverse reactions to intramuscular (IM) medroxyprogesterone acetate, a drug containing polyethylene glycol as an excipient. Three subjects developed a generalized skin rash at the highest rAvPAL-PEG dose (0·1 mg/kg). Drug levels peaked ∼5 days after the injection. Treatment was effective in reducing blood phenylalanine in all five subjects receiving the highest dose (0·1 mg/kg, mean percent change of -58 from baseline), with a nadir ∼6 days after injection and inverse correlation between drug and phenylalanine concentrations in plasma. Phenylalanine concentrations returned to near-baseline levels ∼20 days after the single injection.
Subcutaneous administration of rAvPAL-PEG in a single dose of up to 0·1 mg/kg is safe and well tolerated in subjects with phenylketonuria. At the highest dose tested, rAvPAL-PEG reduced blood phenylalanine concentrations. (NCT00925054 in
PMCID: PMC4447208  PMID: 24743000
7.  Stem-cell-based, tissue engineered tracheal replacement in a child: a 2-year follow-up study 
Lancet (London, England)  2012;380(9846):994-1000.
Stem-cell-based, tissue engineered transplants might offer new therapeutic options for patients, including children, with failing organs. The reported replacement of an adult airway using stem cells on a biological scaffold with good results at 6 months supports this view. We describe the case of a child who received a stem-cell-based tracheal replacement and report findings after 2 years of follow-up.
A 12-year-old boy was born with long-segment congenital tracheal stenosis and pulmonary sling. His airway had been maintained by metal stents, but, after failure, a cadaveric donor tracheal scaffold was decellularised. After a short course of granulocyte colony stimulating factor, bone marrow mesenchymal stem cells were retrieved preoperatively and seeded onto the scaffold, with patches of autologous epithelium. Topical human recombinant erythropoietin was applied to encourage angiogenesis, and transforming growth factor β to support chondrogenesis. Intravenous human recombinant erythropoietin was continued postoperatively. Outcomes were survival, morbidity, endoscopic appearance, cytology and proteomics of brushings, and peripheral blood counts.
The graft revascularised within 1 week after surgery. A strong neutrophil response was noted locally for the first 8 weeks after surgery, which generated luminal DNA neutrophil extracellular traps. Cytological evidence of restoration of the epithelium was not evident until 1 year. The graft did not have biomechanical strength focally until 18 months, but the patient has not needed any medical intervention since then. 18 months after surgery, he had a normal chest CT scan and ventilation-perfusion scan and had grown 11 cm in height since the operation. At 2 years follow-up, he had a functional airway and had returned to school.
Follow-up of the first paediatric, stem-cell-based, tissue-engineered transplant shows potential for this technology but also highlights the need for further research.
Great Ormond Street Hospital NHS Trust, The Royal Free Hampstead NHS Trust, University College Hospital NHS Foundation Trust, and Region of Tuscany.
PMCID: PMC4487824  PMID: 22841419
8.  Meeting Demand for Family Planning within a Generation: the Post-2015 Agenda 
Lancet (London, England)  2014;385(9981):1928-1931.
PMCID: PMC4393371  PMID: 24993915
9.  National, regional, and global trends in body mass index since 1980: Systematic analysis of health examination surveys and epidemiological studies with 960 country-years and 9.1 million participants 
Lancet (London, England)  2011;377(9765):557-567.
Rising body weight is a major public health concern. However there have been few worldwide comparative analyses of long-term trends of body mass index (BMI), and none that have used recent national health examination surveys.
We estimated trends in mean in BMI and their uncertainties for adults 20 years of age and older in 199 countries and territories. Data were from published and unpublished health examination surveys and epidemiologic studies. For each sex, we used a Bayesian hierarchical model to estimate BMI by age, country, and year, accounting for whether a given study was nationally representative.
Between 1980 and 2008, global mean BMI increased at an annualized rate of 0.4 (95% uncertainty interval 0.2, 0.6, posterior probability (PP) of being a true increase > 0.999) kg/m2/decade for men and 0.5 (0.3–0.7, PP > 0.999) for women. National BMI change for women ranged from non-significant declines in 19 countries to rising over 2.5 (PP > 0.999) kg/m2/decade in Tonga and Cook Islands. There was an increase in male BMI in all but a few countries, reaching over 2 kg/m2/decade in Nauru and Cook Islands, PP > 0.999. Male and female BMIs in 2008 were highest in some Oceania countries, reaching 33.9 (32.8, 35.0) kg/m2 (men) and 35.0 (33.6, 36.3) (women) in Nauru. Female BMI was lowest in Bangladesh (20.5; 19.8, 21.3) kg/m2 and male BMI in Democratic Republic of the Congo 19.9 (18.2, 21.5), with BMI also below 21.5 kg/m2 for both sexes in a few countries in sub-Saharan Africa, and East, South, and Southeast Asia. USA had the highest BMI among high-income countries, followed by New Zealand. In 2008, an estimated 1.47 billion adults worldwide had BMI ≥ 25 kg/m2; of these 205 (193, 217) million men and 297 (280, 315) million women were obese.
Globally, mean BMI increased since 1980. The trends since 1980, and mean population BMI in 2008, varied substantially across nations. Interventions and policies that can curb or reverse the increase, and mitigate the health effects of high BMI by targeting its metabolic mediators, are needed in most countries.
PMCID: PMC4472365  PMID: 21295846
10.  Hypercaloric enteral nutrition in Amyotrophic Lateral Sclerosis: a randomized double-blind placebo-controlled trial 
Lancet  2014;383(9934):2065-2072.
Amyotrophic Lateral Sclerosis (ALS) is a rapidly fatal neurodegenerative disease with few therapeutic options. Mild obesity is associated with greater survival in ALS patients and calorie-dense diets increase survival in an ALS mouse model. We therefore hypothesized that hypercaloric diets might lead to weight gain and slow ALS disease progression.
In this double-blind, placebo-controlled, multi-center clinical trial, we enrolled adults with ALS without a history of diabetes, significant liver or cardiovascular disease, who were already receiving percutaneous enteral nutrition. We randomly assigned participants to one of three dietary interventions: replacement calories using an isocaloric diet (controls) vs. a high-carbohydrate hypercaloric diet (HC/HC), vs. a high-fat hypercaloric diet (HF/HC). Participants received the intervention diets for four months and were followed for five months. The primary outcomes were safety and tolerability. Secondary outcomes included measures of disease progression, survival, and metabolism. This trial is registered with, number NCT00983983.
A total of 24 participants were enrolled of whom 20 initiated study diet (six control, eight HC/HC, six HF/HC). Baseline demographics were similar among the three study arms. The HC/HC diet was better tolerated with fewer serious adverse events than the control diet (zero vs. nine, p<0·001) and fewer dose discontinuations due to adverse events (0% vs. 50%). There were no deaths in the HC/HC arm vs. three deaths (43%) in the control arm (logrank p = 0·03). The HF/HC arm was not statistically different from the controls in adverse events, tolerability, deaths or disease progression.
Our results suggest that hypercaloric enteral nutrition is safe and tolerable in ALS and support the study of nutritional interventions at earlier stages of the disease.
The Muscular Dystrophy Association with additional support from the National Center for Research Resources, the National Institutes of Health, and the Harvard NeuroDiscovery Center.
PMCID: PMC4176708  PMID: 24582471
11.  Outdoor air pollution and asthma 
Lancet  2014;383(9928):1581-1592.
Traffic and power generation are the main sources of urban air pollution. The idea that outdoor air pollution can cause exacerbations of pre-existing asthma is supported by an evidence base that has been accumulating for several decades, with several studies suggesting a contribution to new-onset asthma as well. In this Series paper, we discuss the effects of particulate matter (PM), gaseous pollutants (ozone, nitrogen dioxide, and sulphur dioxide), and mixed traffic-related air pollution. We focus on clinical studies, both epidemiological and experimental, published in the previous 5 years. From a mechanistic perspective, air pollutants probably cause oxidative injury to the airways, leading to inflammation, remodelling, and increased risk of sensitisation. Although several pollutants have been linked to new-onset asthma, the strength of the evidence is variable. We also discuss clinical implications, policy issues, and research gaps relevant to air pollution and asthma.
PMCID: PMC4465283  PMID: 24792855
12.  Childhood Cancer, Endocrine Disorders, and Cohort Studies 
Lancet  2014;383(9933):1950-1952.
PMCID: PMC4094362  PMID: 24556021
13.  Imaging insights into basal ganglia function, Parkinson’s disease, and dystonia 
Lancet  2014;384(9942):532-544.
Recent advances in structural and functional imaging have greatly improved our ability to assess normal functions of the basal ganglia, diagnose parkinsonian syndromes, understand the pathophysiology of parkinsonism and other movement disorders, and detect and monitor disease progression. Radionuclide imaging is the best way to detect and monitor dopamine deficiency, and will probably continue to be the best biomarker for assessment of the effects of disease-modifying therapies. However, advances in magnetic resonance enable the separation of patients with Parkinson’s disease from healthy controls, and show great promise for differentiation between Parkinson’s disease and other akinetic-rigid syndromes. Radionuclide imaging is useful to show the dopaminergic basis for both motor and behavioural complications of Parkinson’s disease and its treatment, and alterations in non-dopaminergic systems. Both PET and MRI can be used to study patterns of functional connectivity in the brain, which is disrupted in Parkinson’s disease and in association with its complications, and in other basal-ganglia disorders such as dystonia, in which an anatomical substrate is not otherwise apparent. Functional imaging is increasingly used to assess underlying pathological processes such as neuroinflammation and abnormal protein deposition. This imaging is another promising approach to assess the effects of treatments designed to slow disease progression.
PMCID: PMC4454525  PMID: 24954673 CAMSID: cams4603
14.  Lancet Seminar: Cardiovascular Remodelling in Coronary Artery Disease and Heart Failure+ 
Lancet  2014;383(9932):1933-1943.
PMCID: PMC4330973  PMID: 24831770
15.  Nurse staffing and education and hospital mortality in nine European countries: a retrospective observational study 
Lancet  2014;383(9931):1824-1830.
Austerity measures and health-system redesign to minimise hospital expenditures risk adversely affecting patient outcomes. The RN4CAST study was designed to inform decision making about nursing, one of the largest components of hospital operating expenses. We aimed to assess whether differences in patient to nurse ratios and nurses’ educational qualifications in nine of the 12 RN4CAST countries with similar patient discharge data were associated with variation in hospital mortality after common surgical procedures.
For this observational study, we obtained discharge data for 422 730 patients aged 50 years or older who underwent common surgeries in 300 hospitals in nine European countries. Administrative data were coded with a standard protocol (variants of the ninth or tenth versions of the International Classification of Diseases) to estimate 30 day in-hospital mortality by use of risk adjustment measures including age, sex, admission type, 43 dummy variables suggesting surgery type, and 17 dummy variables suggesting comorbidities present at admission. Surveys of 26 516 nurses practising in study hospitals were used to measure nurse staffing and nurse education. We used generalised estimating equations to assess the effects of nursing factors on the likelihood of surgical patients dying within 30 days of admission, before and after adjusting for other hospital and patient characteristics.
An increase in a nurses’ workload by one patient increased the likelihood of an inpatient dying within 30 days of admission by 7% (odds ratio 1·068, 95% CI 1·031–1·106), and every 10% increase in bachelor’s degree nurses was associated with a decrease in this likelihood by 7% (0·929, 0·886–0·973). These associations imply that patients in hospitals in which 60% of nurses had bachelor’s degrees and nurses cared for an average of six patients would have almost 30% lower mortality than patients in hospitals in which only 30% of nurses had bachelor’s degrees and nurses cared for an average of eight patients.
Nurse staffing cuts to save money might adversely affect patient outcomes. An increased emphasis on bachelor’s education for nurses could reduce preventable hospital deaths.
European Union’s Seventh Framework Programme, National Institute of Nursing Research, National Institutes of Health, the Norwegian Nurses Organisation and the Norwegian Knowledge Centre for the Health Services, Swedish Association of Health Professionals, the regional agreement on medical training and clinical research between Stockholm County Council and Karolinska Institutet, Committee for Health and Caring Sciences and Strategic Research Program in Care Sciences at Karolinska Institutet, Spanish Ministry of Science and Innovation.
PMCID: PMC4035380  PMID: 24581683
16.  Effect of treatment delay, age, and stroke severity on the effects of intravenous thrombolysis with alteplase for acute ischaemic stroke: a meta-analysis of individual patient data from randomised trials 
Lancet  2014;384(9958):1929-1935.
Alteplase is effective for treatment of acute ischaemic stroke but debate continues about its use after longer times since stroke onset, in older patients, and among patients who have had the least or most severe strokes. We assessed the role of these factors in affecting good stroke outcome in patients given alteplase.
We did a pre-specified meta-analysis of individual patient data from 6756 patients in nine randomised trials comparing alteplase with placebo or open control. We included all completed randomised phase 3 trials of intravenous alteplase for treatment of acute ischaemic stroke for which data were available. Retrospective checks confirmed that no eligible trials had been omitted. We defined a good stroke outcome as no significant disability at 3–6 months, defined by a modified Rankin Score of 0 or 1. Additional outcomes included symptomatic intracranial haemorrhage (defined by type 2 parenchymal haemorrhage within 7 days and, separately, by the SITS-MOST definition of parenchymal type 2 haemorrhage within 36 h), fatal intracranial haemorrhage within 7 days, and 90-day mortality.
Alteplase increased the odds of a good stroke outcome, with earlier treatment associated with bigger proportional benefit. Treatment within 3.0 h resulted in a good outcome for 259 (32.9%) of 787 patients who received alteplase versus 176 (23.1%) of 762 who received control (OR 1.75, 95% CI 1.35–2.27); delay of greater than 3.0 h, up to 4.5 h, resulted in good outcome for 485 (35.3%) of 1375 versus 432 (30.1%) of 1437 (OR 1.26, 95% CI 1.05–1.51); and delay of more than 4.5 h resulted in good outcome for 401 (32.6%) of 1229 versus 357 (30.6%) of 1166 (OR 1.15, 95% CI 0.95–1.40). Proportional treatment benefits were similar irrespective of age or stroke severity. Alteplase significantly increased the odds of symptomatic intracranial haemorrhage (type 2 parenchymal haemorrhage definition 231 [6.8%] of 3391 vs 44 [1.3%] of 3365, OR 5.55, 95% CI 4.01–7.70, p<0.0001; SITS-MOST definition 124 [3.7%] vs 19 [0.6%], OR 6.67, 95% CI 4.11–10.84, p<0.0001) and of fatal intracranial haemorrhage within 7 days (91 [2.7%] vs 13 [0.4%]; OR 7.14, 95% CI 3.98–12.79, p<0.0001). The relative increase in fatal intracranial haemorrhage from alteplase was similar irrespective of treatment delay, age, or stroke severity, but the absolute excess risk attributable to alteplase was bigger among patients who had more severe strokes. There was no excess in other early causes of death and no significant effect on later causes of death. Consequently, mortality at 90 days was 608 (17.9%) in the alteplase group versus 556 (16.5%) in the control group (hazard ratio 1.11, 95% CI 0.99–1.25, p=0.07). Taken together, therefore, despite an average absolute increased risk of early death from intracranial haemorrhage of about 2%, by 3–6 months this risk was offset by an average absolute increase in disability-free survival of about 10% for patients treated within 3.0 h and about 5% for patients treated after 3.0 h, up to 4.5 h.
Irrespective of age or stroke severity, and despite an increased risk of fatal intracranial haemorrhage during the first few days after treatment, alteplase significantly improves the overall odds of a good stroke outcome when delivered within 4.5 h of stroke onset, with earlier treatment associated with bigger proportional benefits.
UK Medical Research Council, British Heart Foundation, University of Glasgow, University of Edinburgh.
PMCID: PMC4441266  PMID: 25106063
17.  Early identification of children likely to develop persistent asthma: atopy is an integral component of the high risk phenotype 
Lancet  2008;372(9643):1100-1106.
There is a growing consensus that the long term solution to the asthma epidemic lies in prevention and not in treatment of established disease. Atopic asthma arises from gene x environment interactions which most commonly occur during a relatively narrow window period in pre- and postnatal development. These interactions are incompletely understood, and hence the holy grail of primary prevention remains an elusive goal. We contend that a lack of understanding of the role of atopy in early life in the development of persistent asthma in children exists amongst primary care physicians, paediatricians and specialists. In this review we argue that early identification of high risk children is feasible based on currently available technology, and worthwhile in relation to potential benefits to the children so identified. Knowledge of an asthmatic child's atopic status in early life has practical clinical and prognostic implications, as well as forming the basis for future preventative strategies.
PMCID: PMC4440493  PMID: 18805338
18.  14TL3893 Hypertension in populations of different ethnic origins 
Lancet  2014;384(9939):234.
PMCID: PMC4438759  PMID: 25042233
19.  The Art of Medicine 
Lancet  2010;376(9744):866-867.
PMCID: PMC4430080  PMID: 20842769
20.  Menopausal hormone use and ovarian cancer risk: individual participant meta-analysis of 52 epidemiological studies 
Lancet  2015;385(9980):1835-1842.
Half the epidemiological studies with information about menopausal hormone therapy and ovarian cancer risk remain unpublished, and some retrospective studies could have been biased by selective participation or recall. We aimed to assess with minimal bias the effects of hormone therapy on ovarian cancer risk.
Individual participant datasets from 52 epidemiological studies were analysed centrally. The principal analyses involved the prospective studies (with last hormone therapy use extrapolated forwards for up to 4 years). Sensitivity analyses included the retrospective studies. Adjusted Poisson regressions yielded relative risks (RRs) versus never-use.
During prospective follow-up, 12 110 postmenopausal women, 55% (6601) of whom had used hormone therapy, developed ovarian cancer. Among women last recorded as current users, risk was increased even with <5 years of use (RR 1·43, 95% CI 1·31–1·56; p<0·0001). Combining current-or-recent use (any duration, but stopped <5 years before diagnosis) resulted in an RR of 1·37 (95% CI 1·29–1·46; p<0·0001); this risk was similar in European and American prospective studies and for oestrogen-only and oestrogen-progestagen preparations, but differed across the four main tumour types (heterogeneity p<0·0001), being definitely increased only for the two most common types, serous (RR 1·53, 95% CI 1·40–1·66; p<0·0001) and endometrioid (1·42, 1·20–1·67; p<0·0001). Risk declined the longer ago use had ceased, although about 10 years after stopping long-duration hormone therapy use there was still an excess of serous or endometrioid tumours (RR 1·25, 95% CI 1·07–1·46, p=0·005).
The increased risk may well be largely or wholly causal; if it is, women who use hormone therapy for 5 years from around age 50 years have about one extra ovarian cancer per 1000 users and, if its prognosis is typical, about one extra ovarian cancer death per 1700 users.
Medical Research Council, Cancer Research UK.
PMCID: PMC4427760  PMID: 25684585
21.  Radiotherapy plus Chemotherapy with or without Surgical Resection for Stage III Non-Small Cell Lung Cancer 
Lancet  2009;374(9687):379-386.
Concurrent chemotherapy plus radiation therapy (chemoRT) is the standard treatment for stage IIIA(N2) non-small cell lung cancer (NSCLC), a common disease entity. Phase II studies demonstrated feasibility of resection after chemoRT with encouraging survival rates. This phase III trial compared both approaches.
Patients with stage T1-3pN2M0 NSCLC were randomized before induction chemoRT (2 cycles of cisplatin and etoposide [PE] concurrent with 45 Gy RT). If no progression, arm 1 underwent resection, and arm 2 continued RT uninterrupted to 61 Gy. Two additional cycles of PE were given. The primary endpoint was overall survival (OS).
Progression-free survival for 396 eligible patients was superior in arm 1: median 12.8 versus 10.5 months, p=0.017, hazard ratio (HR) 0.77 (0.62,0.96); 5-yr 22.4% versus 11.1%. Median OS was 23.6 versus 22.2 months, p=0.24, HR 0.87 (0.70,1.10). Five-year survivals were arm 1, 27.2% and arm 2, 20.3%; odds ratio 0.63 (0.36,1.10, p=0.10). N0 status at thoracotomy predicted median OS of 33.5 months (5-year, 41.8%). Major chemoRT toxicities were neutropenia and esophagitis. Treatment-related death occurred in 16 (7.9%) patients on arm 1, of which 14 were post-pneumonectomy; and in 4 (2.1%) on arm 2. An exploratory analysis showed improved OS for patients who underwent lobectomy versus a matched cohort on chemoRT alone, but not for those undergoing pneumonectomy (matched similarly).
There was no significant survival advantage to surgery after chemoRT, despite improved PFS. Both chemoRT with definitive RT and chemoRT followed by resection (preferably lobectomy) are options for patients with stage IIIA(N2) NSCLC.
PMCID: PMC4407808  PMID: 19632716
22.  Worldwide application of prevention science in adolescent health 
Lancet  2012;379(9826):1653-1664.
The burden of morbidity and mortality from non-communicable disease has risen worldwide and is accelerating in low-income and middle-income countries, whereas the burden from infectious diseases has declined. Since this transition, the prevention of non-communicable disease as well as communicable disease causes of adolescent mortality has risen in importance. Problem behaviours that increase the short-term or long-term likelihood of morbidity and mortality, including alcohol, tobacco, and other drug misuse, mental health problems, unsafe sex, risky and unsafe driving, and violence are largely preventable. In the past 30 years new discoveries have led to prevention science being established as a discipline designed to mitigate these problem behaviours. Longitudinal studies have provided an understanding of risk and protective factors across the life course for many of these problem behaviours. Risks cluster across development to produce early accumulation of risk in childhood and more pervasive risk in adolescence. This understanding has led to the construction of developmentally appropriate prevention policies and programmes that have shown short-term and long-term reductions in these adolescent problem behaviours. We describe the principles of prevention science, provide examples of efficacious preventive interventions, describe challenges and potential solutions to take efficacious prevention policies and programmes to scale, and conclude with recommendations to reduce the burden of adolescent mortality and morbidity worldwide through preventive intervention.
PMCID: PMC4398056  PMID: 22538180
23.  Africans in south China face social and health barriers 
Lancet  2014;383(9925):1291-1292.
PMCID: PMC4214379  PMID: 24725568
25.  Retinopathy of prematurity 
Lancet  2013;382(9902):1445-1457.
The immature retinas of preterm neonates are susceptible to insults that disrupt neurovascular growth, leading to retinopathy of prematurity. Suppression of growth factors due to hyperoxia and loss of the maternal–fetal interaction result in an arrest of retinal vascularisation (phase 1). Subsequently, the increasingly metabolically active, yet poorly vascularised, retina becomes hypoxic, stimulating growth factor-induced vasoproliferation (phase 2), which can cause retinal detachment. In very premature infants, controlled oxygen administration reduces but does not eliminate retinopathy of prematurity. Identification and control of factors that contribute to development of retinopathy of prematurity is essential to prevent progression to severe sight-threatening disease and to limit comorbidities with which the disease shares modifiable risk factors. Strategies to prevent retinopathy of prematurity will depend on optimisation of oxygen saturation, nutrition, and normalisation of concentrations of essential factors such as insulin-like growth factor 1 and ω-3 polyunsaturated fatty acids, as well as curbing of the effects of infection and inflammation to promote normal growth and limit suppression of neurovascular development.
PMCID: PMC4389630  PMID: 23782686

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