National Health and Medical Research Council

Systematic reviews should build on a protocol that describes the rationale, hypothesis, and planned methods of the review; few reviews report whether a protocol exists. Detailed, well-described protocols can facilitate the understanding and appraisal of the review methods, as well as the detection of modifications to methods and selective reporting in completed reviews. We describe the development of a reporting guideline, the Preferred Reporting Items for Systematic reviews and Meta-Analyses for Protocols 2015 (PRISMA-P 2015). PRISMA-P consists of a 17-item checklist intended to facilitate the preparation and reporting of a robust protocol for the systematic review. Funders and those commissioning reviews might consider mandating the use of the checklist to facilitate the submission of relevant protocol information in funding applications. Similarly, peer reviewers and editors can use the guidance to gauge the completeness and transparency of a systematic review protocol submitted for publication in a journal or other medium.

Protocols of systematic reviews and meta-analyses allow for planning and documentation of review methods, act as a guard against arbitrary decision making during review conduct, enable readers to assess for the presence of selective reporting against completed reviews, and, when made publicly available, reduce duplication of efforts and potentially prompt collaboration. Evidence documenting the existence of selective reporting and excessive duplication of reviews on the same or similar topics is accumulating and many calls have been made in support of the documentation and public availability of review protocols. Several efforts have emerged in recent years to rectify these problems, including development of an international register for prospective reviews (PROSPERO) and launch of the first open access journal dedicated to the exclusive publication of systematic review products, including protocols (BioMed Central's Systematic Reviews). Furthering these efforts and building on the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses) guidelines, an international group of experts has created a guideline to improve the transparency, accuracy, completeness, and frequency of documented systematic review and meta-analysis protocols--PRISMA-P (for protocols) 2015. The PRISMA-P checklist contains 17 items considered to be essential and minimum components of a systematic review or meta-analysis protocol.This PRISMA-P 2015 Explanation and Elaboration paper provides readers with a full understanding of and evidence about the necessity of each item as well as a model example from an existing published protocol. This paper should be read together with the PRISMA-P 2015 statement. Systematic review authors and assessors are strongly encouraged to make use of PRISMA-P when drafting and appraising review protocols.

BACKGROUND: In systematic reviews and meta-analyses, time-to-event outcomes are most appropriately analysed using hazard ratios (HRs). In the absence of individual patient data (IPD), methods are available to obtain HRs and/or associated statistics by carefully manipulating published or other summary data. Awareness and adoption of these methods is somewhat limited, perhaps because they are published in the statistical literature using statistical notation. METHODS: This paper aims to 'translate' the methods for estimating a HR and associated statistics from published time-to-event-analyses into less statistical and more practical guidance and provide a corresponding, easy-to-use calculations spreadsheet, to facilitate the computational aspects. RESULTS: A wider audience should be able to understand published time-to-event data in individual trial reports and use it more appropriately in meta-analysis. When faced with particular circumstances, readers can refer to the relevant sections of the paper. The spreadsheet can be used to assist them in carrying out the calculations. CONCLUSION: The methods cannot circumvent the potential biases associated with relying on published data for systematic reviews and meta-analysis. However, this practical guide should improve the quality of the analysis and subsequent interpretation of systematic reviews and meta-analyses that include time-to-event outcomes.

BACKGROUND: Evolocumab is a monoclonal antibody that inhibits proprotein convertase subtilisin-kexin type 9 (PCSK9) and lowers low-density lipoprotein (LDL) cholesterol levels by approximately 60%. Whether it prevents cardiovascular events is uncertain. METHODS: We conducted a randomized, double-blind, placebo-controlled trial involving 27,564 patients with atherosclerotic cardiovascular disease and LDL cholesterol levels of 70 mg per deciliter (1.8 mmol per liter) or higher who were receiving statin therapy. Patients were randomly assigned to receive evolocumab (either 140 mg every 2 weeks or 420 mg monthly) or matching placebo as subcutaneous injections. The primary efficacy end point was the composite of cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization. The key secondary efficacy end point was the composite of cardiovascular death, myocardial infarction, or stroke. The median duration of follow-up was 2.2 years. RESULTS: At 48 weeks, the least-squares mean percentage reduction in LDL cholesterol levels with evolocumab, as compared with placebo, was 59%, from a median baseline value of 92 mg per deciliter (2.4 mmol per liter) to 30 mg per deciliter (0.78 mmol per liter) (P<0.001). Relative to placebo, evolocumab treatment significantly reduced the risk of the primary end point (1344 patients [9.8%] vs. 1563 patients [11.3%]; hazard ratio, 0.85; 95% confidence interval [CI], 0.79 to 0.92; P<0.001) and the key secondary end point (816 [5.9%] vs. 1013 [7.4%]; hazard ratio, 0.80; 95% CI, 0.73 to 0.88; P<0.001). The results were consistent across key subgroups, including the subgroup of patients in the lowest quartile for baseline LDL cholesterol levels (median, 74 mg per deciliter [1.9 mmol per liter]). There was no significant difference between the study groups with regard to adverse events (including new-onset diabetes and neurocognitive events), with the exception of injection-site reactions, which were more common with evolocumab (2.1% vs. 1.6%). CONCLUSIONS: In our trial, inhibition of PCSK9 with evolocumab on a background of statin therapy lowered LDL cholesterol levels to a median of 30 mg per deciliter (0.78 mmol per liter) and reduced the risk of cardiovascular events. These findings show that patients with atherosclerotic cardiovascular disease benefit from lowering of LDL cholesterol levels below current targets. (Funded by Amgen; FOURIER ClinicalTrials.gov number, NCT01764633 .).

BACKGROUND: In patients with coronary heart disease and a broad range of cholesterol levels, cholesterol-lowering therapy reduces the risk of coronary events, but the effects on mortality from coronary heart disease and overall mortality have remained uncertain. METHODS: In a double-blind, randomized trial, we compared the effects of pravastatin (40 mg daily) with those of a placebo over a mean follow-up period of 6.1 years in 9014 patients who were 31 to 75 years of age. The patients had a history of myocardial infarction or hospitalization for unstable angina and initial plasma total cholesterol levels of 155 to 271 mg per deciliter. Both groups received advice on following a cholesterol-lowering diet. The primary study outcome was mortality from coronary heart disease. RESULTS: Death from coronary heart disease occurred in 8.3 percent of the patients in the placebo group and 6.4 percent of those in the pravastatin group, a relative reduction in risk of 24 percent (95 percent confidence interval, 12 to 35 percent; P<0.001). Overall mortality was 14.1 percent in the placebo group and 11.0 percent in the pravastatin group (relative reduction in risk, 22 percent; 95 percent confidence interval, 13 to 31 percent; P<0.001). The incidence of all cardiovascular outcomes was consistently lower among patients assigned to receive pravastatin; these outcomes included myocardial infarction (reduction in risk, 29 percent; P<0.001), death from coronary heart disease or nonfatal myocardial infarction (a 24 percent reduction in risk, P<0.001), stroke (a 19 percent reduction in risk, P=0.048), and coronary revascularization (a 20 percent reduction in risk, P<0.001). The effects of treatment were similar for all predefined subgroups. There were no clinically significant adverse effects of treatment with pravastatin. CONCLUSIONS: Pravastatin therapy reduced mortality from coronary heart disease and overall mortality, as compared with the rates in the placebo group, as well as the incidence of all prespecified cardiovascular events in patients with a history of myocardial infarction or unstable angina who had a broad range of initial cholesterol levels.

BACKGROUND: Treatment with cetuximab, a monoclonal antibody directed against the epidermal growth factor receptor, improves overall and progression-free survival and preserves the quality of life in patients with colorectal cancer that has not responded to chemotherapy. The mutation status of the K-ras gene in the tumor may affect the response to cetuximab and have treatment-independent prognostic value. METHODS: We analyzed tumor samples, obtained from 394 of 572 patients (68.9%) with colorectal cancer who were randomly assigned to receive cetuximab plus best supportive care or best supportive care alone, to look for activating mutations in exon 2 of the K-ras gene. We assessed whether the mutation status of the K-ras gene was associated with survival in the cetuximab and supportive-care groups. RESULTS: Of the tumors evaluated for K-ras mutations, 42.3% had at least one mutation in exon 2 of the gene. The effectiveness of cetuximab was significantly associated with K-ras mutation status (P=0.01 and P<0.001 for the interaction of K-ras mutation status with overall survival and progression-free survival, respectively). In patients with wild-type K-ras tumors, treatment with cetuximab as compared with supportive care alone significantly improved overall survival (median, 9.5 vs. 4.8 months; hazard ratio for death, 0.55; 95% confidence interval [CI], 0.41 to 0.74; P<0.001) and progression-free survival (median, 3.7 months vs. 1.9 months; hazard ratio for progression or death, 0.40; 95% CI, 0.30 to 0.54; P<0.001). Among patients with mutated K-ras tumors, there was no significant difference between those who were treated with cetuximab and those who received supportive care alone with respect to overall survival (hazard ratio, 0.98; P=0.89) or progression-free survival (hazard ratio, 0.99; P=0.96). In the group of patients receiving best supportive care alone, the mutation status of the K-ras gene was not significantly associated with overall survival (hazard ratio for death, 1.01; P=0.97). CONCLUSIONS: Patients with a colorectal tumor bearing mutated K-ras did not benefit from cetuximab, whereas patients with a tumor bearing wild-type K-ras did benefit from cetuximab. The mutation status of the K-ras gene had no influence on survival among patients treated with best supportive care alone. (ClinicalTrials.gov number, NCT00079066.)

BACKGROUND: Contemporary data for causes of vision impairment and blindness form an important basis of recommendations in public health policies. Refreshment of the Global Vision Database with recently published data sources permitted modelling of cause of vision loss data from 1990 to 2015, further disaggregation by cause, and forecasts to 2020. METHODS: In this systematic review and meta-analysis, we analysed published and unpublished population-based data for the causes of vision impairment and blindness from 1980 to 2014. We identified population-based studies published before July 8, 2014, by searching online databases with no language restrictions (MEDLINE from Jan 1, 1946, and Embase from Jan 1, 1974, and the WHO Library Database). We fitted a series of regression models to estimate the proportion of moderate or severe vision impairment (defined as presenting visual acuity of <6/18 but ≥3/60 in the better eye) and blindness (presenting visual acuity of <3/60 in the better eye) by cause, age, region, and year. FINDINGS: We identified 288 studies of 3 983 541 participants contributing data from 98 countries. Among the global population with moderate or severe vision impairment in 2015 (216·6 million [80% uncertainty interval 98·5 million to 359·1 million]), the leading causes were uncorrected refractive error (116·3 million [49·4 million to 202·1 million]), cataract (52·6 million [18·2 million to 109·6 million]), age-related macular degeneration (8·4 million [0·9 million to 29·5 million]), glaucoma (4·0 million [0·6 million to 13·3 million]), and diabetic retinopathy (2·6 million [0·2 million to 9·9 million]). Among the global population who were blind in 2015 (36·0 million [12·9 million to 65·4 million]), the leading causes were cataract (12·6 million [3·4 million to 28·7 million]), uncorrected refractive error (7·4 million [2·4 million to 14·8 million]), and glaucoma (2·9 million [0·4 million to 9·9 million]). By 2020, among the global population with moderate or severe vision impairment (237·1 million [101·5 million to 399·0 million]), the number of people affected by uncorrected refractive error is anticipated to rise to 127·7 million (51·0 million to 225·3 million), by cataract to 57·1 million (17·9 million to 124·1 million), by age-related macular degeneration to 8·8 million (0·8 million to 32·1 million), by glaucoma to 4·5 million (0·5 million to 15·4 million), and by diabetic retinopathy to 3·2 million (0·2 million to 12·9 million). By 2020, among the global population who are blind (38·5 million [13·2 million to 70·9 million]), the number of patients blind because of cataract is anticipated to rise to 13·4 million (3·3 million to 31·6 million), because of uncorrected refractive error to 8·0 million (2·5 million to 16·3 million), and because of glaucoma to 3·2 million (0·4 million to 11·0 million). Cataract and uncorrected refractive error combined contributed to 55% of blindness and 77% of vision impairment in adults aged 50 years and older in 2015. World regions varied markedly in the causes of blindness and vision impairment in this age group, with a low prevalence of cataract (<22% for blindness and 14·1-15·9% for vision impairment) and a high prevalence of age-related macular degeneration (>14% of blindness) as causes in the high-income subregions. Blindness and vision impairment at all ages in 2015 due to diabetic retinopathy (odds ratio 2·52 [1·48-3·73]) and cataract (1·21 [1·17-1·25]) were more common among women than among men, whereas blindness and vision impairment due to glaucoma (0·71 [0·57-0·86]) and corneal opacity (0·54 [0·43-0·66]) were more common among men than among women, with no sex difference related to age-related macular degeneration (0·91 [0·70-1·14]). INTERPRETATION: The number of people affected by the common causes of vision loss has increased substantially as the population increases and ages. Preventable vision loss due to cataract (reversible with surgery) and refractive error (reversible with spectacle correction) continue to cause most cases of blindness and moderate or severe vision impairment in adults aged 50 years and older. A large scale-up of eye care provision to cope with the increasing numbers is needed to address avoidable vision loss. FUNDING: Brien Holden Vision Institute.

Over the last few years there has been increasing interest in conceptualizing disease aetiology within a life course framework.1,2 This approach is not new to Public Health or unique to epidemiology (see below). However, its current resonance and interest within epidemiology reflects the challenging theoretical framework this approach provides. This issue of the International Journal of Epidemiology has several papers with a ‘life course theme’. This accompanying editorial is intended to highlight what we believe are the key conceptual issues around life course epidemiology. We have chosen to use examples from chronic disease epidemiology, but this approach is also applicable within the context of infectious diseases3 and wider notions of health and wellbeing.4 We have defined a life course approach to chronic disease epidemiology1 as the study of long-term effects on chronic disease risk of physical and social exposures during gestation, childhood, adolescence, young adulthood and later adult life. It includes studies of the biological, behavioural and psychosocial pathways that operate across an individual's life course, as well as across generations, to influence the development of chronic diseases. Conventionally, chronic disease cohort studies recruit subjects in mid-life and follow them up for future disease end-points. The risk of developing disease is then related to baseline exposures or changes in exposure measures ascertained at further follow-ups. Even when baseline measures include early life exposures, such as birthweight and childhood socioeconomic position, these would usually be entered into a multivariable model without much attention to the temporal relationship between variables. Merely the collection of exposure data across the life course is not synonymous with a life course model of disease causation. Surprisingly few epidemiological publications explicitly state the temporal ordering of exposure variables and their inter-relationships, both directly or through intermediary variables, with the outcome measure. One example, where this approach was explicitly undertaken was a study testing the influence of early and later life factors on carotid intima thickness.5 This diagramatically ordered classes of variables across the life course. Such an approach is commonplace in structural equation modelling, path analysis and graphical models where prior conceptual representations, before statistical modelling, are standard practice.6,7 Figure 1 illustrates such a conceptualization with respect to adult respiratory disease and/or impaired respiratory function. This figure illustrates many potential pathways between intrauterine growth and adult disease. Such a life course model enables the researcher to explicitly test not only early life course exposures with later disease, but possible pathways with potential intermediaries or confounding factors. Path (a) would represent a predominantly biological pathway whereby impaired fetal development of the lung architecture is associated with future respiratory insults from infectious agents and greater susceptibility to impaired lung function in adulthood and/or chronic obstructive airways disease. Path (b) would be a predominantly social pathway whereby adverse childhood socioeconomic position influences adverse childhood exposures as well as adult socioeconomic position and smoking behaviour. Path (c) reflects a socio-biological pathway whereby adverse childhood socioeconomic position is associated with post-natal lung function and subsequently with poor adult lung function through its effects on immune function and the likelihood of exposure to infectious agents. Path (d) is a bio-social pathway so that repeated childhood infections results in adverse educational attainment and lower adult socioeconomic position. Even such a crude model highlights the complex inter-relationships and rather arbitrary differentiation between biological and social mechanisms. As Krieger8 asserts a ‘simplistic division of the social and biological will not suffice’. Even such a simplified model (see Strachan9 for detailed discussion) is daunting but importantly challenges both clinical epidemiologists and social scientists to operationalize exposures and conceptualize their inter-relationships across the life course. As well as integrating biological and psychosocial pathways, a life course approach essentially requires some understanding of the natural history and physiological trajectory of normal biological systems (Figure 2). As can be seen for lung function, (but it applies to many other continuous physiological measures e.g. muscle strength, cognitive function), different periods across the life course influence phases of biological development, stability or decline. This alternative diagrammatic representation of disease aetiology is important for understanding how exposures may differentially act in critical and/or sensitive periods (see below). For example, an exposure acting in early life may adversely affect lung function during the development period (line B) resulting in a diminished physiological reserve without having any appreciable effect on the rate of decline (line C) Given the wide range of potential exposures and the importance of the timing of an exposure, it is unsurprising that exposures may affect disease risk in more than one way. We have previously proposed a simple classification (Table 1) of potential life course models of health.10 Some have misinterpreted a life course approach as precluding a critical period model and only encompassing accumulation of risk.11 The ‘critical period model’ is when an exposure acting during a specific period has lasting or lifelong effects on the structure or function of organs, tissues and body systems which are not modified in any dramatic way by later experience. This is also known as ‘biological programming’ or it is sometimes referred to as a ‘latency model’12 and is the basis of the ‘fetal origins of adult disease’ hypothesis.13 For example, evidence suggests that poor growth in utero leads to a variety of chronic disorders such as cardiovascular disease, non-insulin dependent diabetes, and hypertension. Exposures acting in later life may still influence disease risk in a simple additive way but it is argued that fetal exposures permanently alter anatomical structures and a variety of metabolic systems.14 In its purest form, this model advocates that an exposure in a critical period results in permanent and irreversible damage or disease. A stark example of such an exposure would be maternal exposure to thalidomide in pregnancy and limb development. However, within the context of chronic disease, it is important to distinguish the effects of exposure on structure from those on function. Poor intrauterine development may have an adverse effect on the number of muscle cells that develop in the fetus so that at birth a small growth retarded fetus may have a permanent reduction in the number of muscle cells (structure). Such a child, however, may still compensate by muscle hypertrophy so that in functional terms there may be no evident difference. Such an adaptive facility would make evolutionary sense and may only be unmasked at older ages when the underlying structural deficits may become more important as adaptive processes begin to fail.14 The same is likely to apply to metabolic and hormonal systems, which may be up or down regulated during fetal life but are still capable of modification by many adult exposures. The second model extends the ‘critical period’ concept as it recognizes the importance of later life effect modifiers. For example, studies have shown that the relationships of coronary heart disease, high blood pressure and insulin resistance with low birthweight are particularly strong or sometimes only observed for subjects who become obese in childhood, adulthood or both.11,15–17 Such subtle differentiation is important as the critical period may again only be critical for those individuals who experience some other exposure. Whilst statistical interaction is not the same as biological interaction, it is plausible to envisage that a biologically compromised system may only result in pathology with the subsequent addition of other physiological or metabolic stressors. In contrast, factors that raise disease risk or promote good health may accumulate gradually over the life course, although there may be developmental periods when their effects have greater impact on later health than factors operating at other times (see below). This idea is complementary to the notion of allostatic load18 so that as the number and/or duration of exposures increase, there is increasing cumulative damage to biological systems. Environmental or behavioural insults may cause long-term, gradual damage to health in separate and independent ways, or they may cluster together in socially patterned ways. For example, a subject may experience a variety of independent exposures (such as a road traffic accident, subsequent unemployment and finally the death of a spouse), where each event was unrelated to the proceeding one. However, it is far more common for adverse exposures to be clustered. For example, children living in adverse social circumstances are more likely to be of low birthweight, be exposed to poor diets, experience passive smoke exposure, and have worse educational opportunities. In this case, understanding the effects of childhood social class by identifying specific aspects of the early physical or psychosocial environment (such exposure to air pollution or family conflict) or possible mechanisms (such as nutrition, infection or stress) that are associated with adult disease will provide further aetiological insights. Risk factors at different life stages may also accumulate over time because of ‘chains of risk’ where one adverse (beneficial) exposure or experience tends to lead to another, and so on. For example, unemployment will lead to financial insecurity, which in turn will increase the likelihood of marital conflict and possibly physical abuse leading to marital separation and divorce. These links are probabilistic rather than deterministic but are likely to be sequential. In this scenario it is possible to conceive that each exposure increases the risk of separation in a simply cumulative fashion (‘additive effect‘). Alternatively, it may be only the final link in the chain, physical abuse, which results in separation (‘trigger effect‘). From a preventive point of view, these chains of events help to identify points of intervention where chains of risk may be broken and a new life course trajectory established. Stopping the additive effect will have health benefits but residual damage will remain. Preventing a trigger effect will more dramatically abolish any adverse risk associated with exposures experienced earlier in the chain. The terms critical and sensitive periods are often used loosely in epidemiology without much distinction. In the natural sciences a critical period of development refers to a time window when change in the organization of living systems or subsystems towards increasing complexity, greater adaptivity and more efficient functioning is occurring rapidly and may be most easily modifiable by a variety of factors in a favourable or unfavourable direction.19 The intrinsic changes that occur in critical developmental periods are wholly or partially irreversible; sensitive developmental periods are also times of rapid change but there is more scope to modify or even reverse those changes outside the time window. We suggest the following distinctions for the use of these terms in life course chronic disease epidemiology. In this context, the relevance of changes during a critical period is in respect of their long-term effects on intermediate markers of disease risk or manifestation of disease, usually many years after the critical period. A critical period is defined as a limited time window in which an exposure can have adverse or protective effects on development and subsequent disease outcome. Outside this window, this developmental mechanism for mediating exposure and disease risk is no longer available. A sensitive period is a time period when an exposure has a stronger effect on development and hence disease risk than it would at other times; in other words the same exposure outside this time period may still be associated with increased risk but this association is weaker than during the sensitive period. In epidemiological terms both critical and sensitive periods may be understood as qualitatively different exposure-time interactions. For critical periods, there is no excess disease risk associated with exposure outside this time window, whilst for sensitive periods it is merely weaker. Whilst critical period exposures appear obvious if they act during fetal development, they are not limited in this way. For example, the elevated risk of multiple sclerosis amongst European migrants to South Africa is only observed if migration occurred after the age of 15 years.20 Sensitive period effects for chronic diseases are far harder to demonstrate empirically. Hall et al. discuss how clinical disease severity seen with infectious agents varies with age at exposure.3 Critical periods may be more evident for chronic disease risk associated with developmental mechanisms in biological subsystems whereas sensitive periods are likely to be more common in behavioural development. Most of us are familiar with the ease by which children learn a second language and the difficulties encountered in adulthood. Most existing life course studies have limited their scope in examining exposures within a single cohort. Whilst studies in the past have examined disease and/or risk factor concordance rates or correlations across generations, it is only more recently that investigators have started to test inter-generational exposure disease associations. Several studies have now shown that both maternal and paternal cardiovascular mortality are associated with offspring birthweight.21–23 Such associations are complex and may reflect long-term adverse socioeconomic circumstances, maternal health, determined by mother's own birthweight and childhood growth, lifestyle factors such as smoking, and genomic or epigenetic processes.22 Recently the potential for a life course approach to aid understanding of variations in the health and disease of populations over time, across countries and between social groups has been given more attention.24–27 Davey Smith and his colleagues25 suggest that explanations for social inequalities in cause-specific adult mortality lie in socially patterned exposures at different stages of the life course. A life course perspective is being increasingly used in developing the ‘social inequalities in health’ debate.28–31 More broadly, Keating and Hertzman26 argue that the fundamental processes such as neural sculpting that affect brain and behavioural development interact with the growing chaos in the lives of children and adolescents with long-term effects on human capital and hence the wealth of nations. Leon24 suggests that a life course perspective may help understand the underlying geographical patterns of mortality, particularly East-West differences. He states ‘the assumption that inequalities in health today, whether between or within countries are caused by contemporaneous differences in circumstances of life is not sustainable for a range of important diseases that appear to be driven instead by poor socioeconomic circumstances in early life and childhood’.24 The end of the 20th century has seen much debate around the need for epidemiological theory, particularly in relation to health inequalities.32,33 Alongside the development of life course epidemiology with its focus on time, has been a growing interest in eco-social or models that risk factors operating at a variety of from the to the life course they the need to have an approach between biological and social the of social into the they also the temporal relationship between exposures. The between life course and eco-social has been by in a life course approach the of psychosocial Whilst a life course approach psychosocial it is far than and to life course with and measures of into a We have previously that a life course approach to eco-social influences on In this respect we that both models may be increasingly used We not believe that life course a conceptual approach but rather that both temporal and are complementary and We would also argue that a life course approach is not limited to individuals within a single but biological and social of risk across It any exposure both within a structure as well as in relation to geographical and which may be unique to that cohort of We have the by and to these points (Figure and children are across both by common and/or social The potential of and influences are acting across time and across For example, adverse affect a and exposures time may be specific to a single cohort or period effects may be experienced by individuals The idea that childhood is important for adult health is not new in epidemiology or health but was the model of health in the of the 20th The idea that of risk to adult health in early life was given during the years following the The childhood origins of adult chronic and data from the origins of adult was a natural of epidemiology where cohort and long-term effects of early or exposures in adult and birth been to childhood The of the effects of the during the of on subsequent human development, particularly a life course and the for life course epidemiology when they that ‘the of each cohort at from the of at the time, and with the of and experience. The adult the of these favourable and unfavourable during has and mortality has their in a way specific to each in his of Epidemiology also the importance of inter-generational and childhood of adult disease (see by Davey In cardiovascular epidemiology, the adult lifestyle model the some but interest in early life factors was from the with natural history studies of adult risk factors (such as smoking, and in of This was then by that poor childhood living (see accompanying by and accompanying in this and impaired early to adult cardiovascular disease. The most model of human development has been the idea that ‘the few years of life have effects later development and adult The of development at the of the 20th century development as an of developmental where change was cumulative and usually The of the environment was to provide the and for growth and to Environmental insults or of during critical periods at the or during during childhood more have long-term effects on physical or development. was systems to be From the this early life was increasingly It was that of the rather than early evidence of long-term effects on adult of a critical period in behavioural development social or language was by a of some behavioural from the effects of critical period exposure or for irreversible biological changes during critical periods of growth was as a to this a life perspective in developmental in the where development was seen as a lifelong The of early developmental be again and again by later and the course of development into In the argued that ‘simplistic of effects need to be and by more notions of the over time but between early and adult psychosocial we have ‘chains of provide an for these whereby one leads to another, a good experience it more likely that one will be and have how the individual's life course is by and and social and changes in processes (such as the increase in life the cohort effects occur because of different ages and those who different are differentially exposed to and by social and such as the of the The life course perspective in has life to how the life course is in the and individuals be in a The life course perspective in human development to has on the in which early factors can have influences on human and function across the life This approach has been by biological and epidemiologists with their focus on its and functional or disease and by those for lifelong of and in the of may promote and but at the of later disease. there is a different in developmental with the has been a from and of developmental processes to and context specific development. The is for the range of and its changes and This the of epidemiological to underlying mechanisms. a life course approach challenges for both the and analysis of epidemiological are to have to a birth cohort study with measures of both psychosocial and biological Such studies can common disease or continuous measures of function, but may be with common diseases. such studies will have no for biological or data in of one of the most to test life course In from the same but different time periods can directly and can provide into whether associations across and provide an efficient to test early life exposures. However, they are limited to usually one or exposures acting in a specific time window and have limited or no data on other periods of the life course. This that possible periods of aetiological importance may be but between early and later life exposures or accumulation models be studies are also and can use measures for early life exposures or exposures. to be to the of early life exposures in natural such as can be used to test exposure acting during specific time usually for different to test specific mechanisms or pathways both for biological exposures or social Whilst exposure measures across the life course may be so is the analysis of such and complex We that as interest in life course will to help us test some of the theoretical models proposed in but in epidemiological for example structural equation modelling, path and modelling, will become more course epidemiology has the of the adult lifestyle model of chronic disease It has particularly as a for new in the of social inequalities in health and has biological, and social models of disease causation. A life course approach is as on the one it is obvious we need to demonstrate risk and on the other is complex we have much evidence in of these It to be seen whether as we can with this The future of a life course approach will for its on new mechanisms and disease pathways as well as its to geographical and temporal patterns of disease life course models life course models representation of biological and psychosocial exposures acting across the life course that may influence lung function and/or respiratory disease importance of exposures acting across different life course time in terms of the natural history of lung function the possible influences of and life course exposures on disease risk across related individuals The would to the of the in where some of these and for at the course

OBJECTIVES: To assess the public's recognition of mental disorders and their beliefs about the effectiveness of various treatments ("mental health literacy"). DESIGN: A cross-sectional survey, in 1995, with structured interviews using vignettes of a person with either depression or schizophrenia. PARTICIPANTS: A representative national sample of 2031 individuals aged 18-74 years; 1010 participants were questioned about the depression vignette and 1021 about the schizophrenia vignette. RESULTS: Most of the participants recognised the presence of some sort of mental disorder: 72% for the depression vignette (correctly labelled as depression by 39%) and 84% for the schizophrenia vignette (correctly labelled by 27%). When various people were rated as likely to be helpful or harmful for the person described in the vignette for depression, general practitioners (83%) and counsellors (74%) were most often rated as helpful, with psychiatrists (51%) and psychologists (49%) less so. Corresponding data for the schizophrenia vignette were: counsellors (81%), GPs (74%), psychiatrists (71%) and psychologists (62%). Many standard psychiatric treatments (antidepressants, antipsychotics, electroconvulsive therapy, admission to a psychiatric ward) were more often rated as harmful than helpful, and some nonstandard treatments were rated highly (increased physical or social activity, relaxation and stress management, reading about people with similar problems). Vitamins and special diets were more often rated as helpful than were antidepressants and antipsychotics. CONCLUSION: If mental disorders are to be recognised early in the community and appropriate intervention sought, the level of mental health literacy needs to be raised. Further, public understanding of psychiatric treatments can be considerably improved.

Hundreds of individual human cancer genome sequences are expected to be published in 2010, and thousands per year after that. The International Cancer Genome Consortium (ICGC) was launched with the aim of keeping track of the data relating to large-scale cancer genome studies of all major cancers in adults and children — a total of 50 different cancer types and/or subtypes. In this issue the ICGC team ( http://www.icgc.org ) spells out the policies and planning for the project. The International Cancer Genome Consortium (ICGC) was launched to coordinate large-scale cancer genome studies in tumours from 50 different cancer types and/or subtypes that are of clinical and societal importance across the globe. Systematic studies of more than 25,000 cancer genomes at the genomic, epigenomic and transcriptomic levels will reveal the repertoire of oncogenic mutations, uncover traces of the mutagenic influences, define clinically relevant subtypes for prognosis and therapeutic management, and enable the development of new cancer therapies.

Advances in communication technologies offer new opportunities for the conduct of qualitative research. Among these, Zoom—an innovative videoconferencing platform—has a number of unique features that enhance its potential appeal to qualitative and mixed-methods researchers. Although studies have explored the use of information and communication technologies for conducting research, few have explored both researcher and participant perspectives on the use of web and videoconferencing platforms. Further, data are lacking on the benefits and challenges of using Zoom as a data collection method. In this study, we explore the feasibility and acceptability of using Zoom to collect qualitative interview data within a health research context in order to better understand its suitability for qualitative and mixed-methods researchers. We asked 16 practice nurses who participated in online qualitative interviews about their experiences of using Zoom and concurrently recorded researcher observations. Although several participants experienced technical difficulties, most described their interview experience as highly satisfactory and generally rated Zoom above alternative interviewing mediums such as face-to-face, telephone, and other videoconferencing services, platforms, and products. Findings suggest the viability of Zoom as a tool for collection of qualitative data because of its relative ease of use, cost-effectiveness, data management features, and security options. Further research exploring the utility of Zoom is recommended in order to critically assess and advance innovations in online methods.

BACKGROUND: Due to the high prevalence of overweight and obesity there is a need to identify cost-effective approaches for weight loss in primary care and community settings. OBJECTIVE: We evaluated the cost effectiveness of two weight loss programmes of 1-year duration, either standard care (SC) as defined by national guidelines, or a commercial provider (Weight Watchers) (CP). DESIGN: This analysis was based on a randomised controlled trial of 772 adults (87% female; age 47.4±12.9 years; body mass index 31.4±2.6 kg m(-2)) recruited by health professionals in primary care in Australia, United Kingdom and Germany. Both a health sector and societal perspective were adopted to calculate the cost per kilogram of weight loss and the ICER, expressed as the cost per quality adjusted life year (QALY). RESULTS: The cost per kilogram of weight loss was USD122, 90 and 180 for the CP in Australia, the United Kingdom and Germany, respectively. For SC the cost was USD138, 151 and 133, respectively. From a health-sector perspective, the ICER for the CP relative to SC was USD18 266, 12 100 and 40 933 for Australia, the United Kingdom and Germany, respectively. Corresponding societal ICER figures were USD31,663, 24,996 and 51,571. CONCLUSION: The CP was a cost-effective approach from a health funder and societal perspective. Despite participants in the CP group attending two to three times more meetings than the SC group, the CP was still cost effective even including these added patient travel costs. This study indicates that it is cost effective for general practitioners (GPs) to refer overweight and obese patients to a CP, which may be better value than expending public funds on GP visits to manage this problem.

BACKGROUND: There are limited data from retrospective studies regarding whether survival outcomes after laparoscopic or robot-assisted radical hysterectomy (minimally invasive surgery) are equivalent to those after open abdominal radical hysterectomy (open surgery) among women with early-stage cervical cancer. METHODS: In this trial involving patients with stage IA1 (lymphovascular invasion), IA2, or IB1 cervical cancer and a histologic subtype of squamous-cell carcinoma, adenocarcinoma, or adenosquamous carcinoma, we randomly assigned patients to undergo minimally invasive surgery or open surgery. The primary outcome was the rate of disease-free survival at 4.5 years, with noninferiority claimed if the lower boundary of the two-sided 95% confidence interval of the between-group difference (minimally invasive surgery minus open surgery) was greater than -7.2 percentage points (i.e., closer to zero). RESULTS: A total of 319 patients were assigned to minimally invasive surgery and 312 to open surgery. Of the patients who were assigned to and underwent minimally invasive surgery, 84.4% underwent laparoscopy and 15.6% robot-assisted surgery. Overall, the mean age of the patients was 46.0 years. Most patients (91.9%) had stage IB1 disease. The two groups were similar with respect to histologic subtypes, the rate of lymphovascular invasion, rates of parametrial and lymph-node involvement, tumor size, tumor grade, and the rate of use of adjuvant therapy. The rate of disease-free survival at 4.5 years was 86.0% with minimally invasive surgery and 96.5% with open surgery, a difference of -10.6 percentage points (95% confidence interval [CI], -16.4 to -4.7). Minimally invasive surgery was associated with a lower rate of disease-free survival than open surgery (3-year rate, 91.2% vs. 97.1%; hazard ratio for disease recurrence or death from cervical cancer, 3.74; 95% CI, 1.63 to 8.58), a difference that remained after adjustment for age, body-mass index, stage of disease, lymphovascular invasion, and lymph-node involvement; minimally invasive surgery was also associated with a lower rate of overall survival (3-year rate, 93.8% vs. 99.0%; hazard ratio for death from any cause, 6.00; 95% CI, 1.77 to 20.30). CONCLUSIONS: In this trial, minimally invasive radical hysterectomy was associated with lower rates of disease-free survival and overall survival than open abdominal radical hysterectomy among women with early-stage cervical cancer. (Funded by the University of Texas M.D. Anderson Cancer Center and Medtronic; LACC ClinicalTrials.gov number, NCT00614211 .).

STUDY QUESTION: What is the recommended assessment and management of women with polycystic ovary syndrome (PCOS), based on the best available evidence, clinical expertise, and consumer preference? SUMMARY ANSWER: International evidence-based guidelines including 166 recommendations and practice points, addressed prioritized questions to promote consistent, evidence-based care and improve the experience and health outcomes of women with PCOS. WHAT IS KNOWN ALREADY: Previous guidelines either lacked rigorous evidence-based processes, did not engage consumer and international multidisciplinary perspectives, or were outdated. Diagnosis of PCOS remains controversial and assessment and management are inconsistent. The needs of women with PCOS are not being adequately met and evidence practice gaps persist. STUDY DESIGN, SIZE, DURATION: International evidence-based guideline development engaged professional societies and consumer organizations with multidisciplinary experts and women with PCOS directly involved at all stages. Appraisal of Guidelines for Research and Evaluation (AGREE) II-compliant processes were followed, with extensive evidence synthesis. The Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) framework was applied across evidence quality, feasibility, acceptability, cost, implementation and ultimately recommendation strength. PARTICIPANTS/MATERIALS, SETTING, METHODS: Governance included a six continent international advisory and a project board, five guideline development groups (GDGs), and consumer and translation committees. Extensive health professional and consumer engagement informed guideline scope and priorities. Engaged international society-nominated panels included pediatrics, endocrinology, gynecology, primary care, reproductive endocrinology, obstetrics, psychiatry, psychology, dietetics, exercise physiology, public health and other experts, alongside consumers, project management, evidence synthesis, and translation experts. Thirty-seven societies and organizations covering 71 countries engaged in the process. Twenty face-to-face meetings over 15 months addressed 60 prioritized clinical questions involving 40 systematic and 20 narrative reviews. Evidence-based recommendations were developed and approved via consensus voting within the five guideline panels, modified based on international feedback and peer review, with final recommendations approved across all panels. MAIN RESULTS AND THE ROLE OF CHANCE: The evidence in the assessment and management of PCOS is generally of low to moderate quality. The guideline provides 31 evidence based recommendations, 59 clinical consensus recommendations and 76 clinical practice points all related to assessment and management of PCOS. Key changes in this guideline include: (a) considerable refinement of individual diagnostic criteria with a focus on improving accuracy of diagnosis; (b) reducing unnecessary testing; (c) increasing focus on education, lifestyle modification, emotional wellbeing and quality of life; and (d) emphasizing evidence based medical therapy and cheaper and safer fertility management. LIMITATIONS, REASONS FOR CAUTION: Overall evidence is generally low to moderate quality, requiring significantly greater research in this neglected, yet common condition, especially around refining specific diagnostic features in PCOS. Regional health system variation is acknowledged and a process for guideline and translation resource adaptation is provided. WIDER IMPLICATIONS OF THE FINDINGS: The international guideline for the assessment and management of PCOS provides clinicians with clear advice on best practice based on the best available evidence, expert multidisciplinary input and consumer preferences. Research recommendations have been generated and a comprehensive multifaceted dissemination and translation program supports the guideline with an integrated evaluation program.

BACKGROUND: Cetuximab, an IgG1 chimeric monoclonal antibody against epidermal growth factor receptor (EGFR), has activity against colorectal cancers that express EGFR. METHODS: From December 2003 to August 2005, 572 patients who had colorectal cancer expressing immunohistochemically detectable EGFR and who had been previously treated with a fluoropyrimidine, irinotecan, and oxaliplatin or had contraindications to treatment with these drugs underwent randomization to an initial dose of 400 mg of cetuximab per square meter of body-surface area followed by a weekly infusion of 250 mg per square meter plus best supportive care (287 patients) or best supportive care alone (285 patients). The primary end point was overall survival. RESULTS: In comparison with best supportive care alone, cetuximab treatment was associated with a significant improvement in overall survival (hazard ratio for death, 0.77; 95% confidence interval [CI], 0.64 to 0.92; P=0.005) and in progression-free survival (hazard ratio for disease progression or death, 0.68; 95% CI, 0.57 to 0.80; P<0.001). These benefits were robust after adjustment in a multivariable Cox proportional-hazards model. The median overall survival was 6.1 months in the cetuximab group and 4.6 months in the group assigned to supportive care alone. Partial responses occurred in 23 patients (8.0%) in the cetuximab group but in none in the group assigned to supportive care alone (P<0.001); the disease was stable in an additional 31.4% of patients assigned to cetuximab and in 10.9% of patients assigned to supportive care alone (P<0.001). Quality of life was better preserved in the cetuximab group, with less deterioration in physical function and global health status scores (both P<0.05). Cetuximab treatment was associated with a characteristic rash; a rash of grade 2 or higher was strongly associated with improved survival (hazard ratio for death, 0.33; 95% CI, 0.22 to 0.50; P<0.001). The incidence of any adverse event of grade 3 or higher was 78.5% in the cetuximab group and 59.1% in the group assigned to supportive care alone (P<0.001). CONCLUSIONS: Cetuximab improves overall survival and progression-free survival and preserves quality-of-life measures in patients with colorectal cancer in whom other treatments have failed. (ClinicalTrials.gov number, NCT00079066 [ClinicalTrials.gov].).

Despite the high efficacy of continuous positive airway pressure (CPAP) to reverse upper airway obstruction in sleep apnea, treatment effectiveness is limited by variable adherence to prescribed therapy. When adherence is defined as greater than 4 hours of nightly use, 46 to 83% of patients with obstructive sleep apnea have been reported to be nonadherent to treatment. Evidence suggests that use of CPAP for longer than 6 hours decreases sleepiness, improves daily functioning, and restores memory to normal levels. The decision to embrace CPAP occurs during the first few days of treatment. Although many strategies in patient interface with CPAP or machine modality are marketed to improve CPAP usage, there are few data to support this. No single factor has been consistently identified as predictive of adherence. Patient perception of symptoms and improvement in sleepiness and daily functioning may be more important in determining patterns of use than physiologic aspects of disease severity. Emerging data suggest that various behavioral interventions may be effective in improving CPAP adherence.

BACKGROUND: Enzalutamide, an androgen-receptor inhibitor, has been associated with improved overall survival in men with castration-resistant prostate cancer. It is not known whether adding enzalutamide to testosterone suppression, with or without early docetaxel, will improve survival in men with metastatic, hormone-sensitive prostate cancer. METHODS: In this open-label, randomized, phase 3 trial, we assigned patients to receive testosterone suppression plus either open-label enzalutamide or a standard nonsteroidal antiandrogen therapy (standard-care group). The primary end point was overall survival. Secondary end points included progression-free survival as determined by the prostate-specific antigen (PSA) level, clinical progression-free survival, and adverse events. RESULTS: A total of 1125 men underwent randomization; the median follow-up was 34 months. There were 102 deaths in the enzalutamide group and 143 deaths in the standard-care group (hazard ratio, 0.67; 95% confidence interval [CI], 0.52 to 0.86; P = 0.002). Kaplan-Meier estimates of overall survival at 3 years were 80% (based on 94 events) in the enzalutamide group and 72% (based on 130 events) in the standard-care group. Better results with enzalutamide were also seen in PSA progression-free survival (174 and 333 events, respectively; hazard ratio, 0.39; P<0.001) and in clinical progression-free survival (167 and 320 events, respectively; hazard ratio, 0.40; P<0.001). Treatment discontinuation due to adverse events was more frequent in the enzalutamide group than in the standard-care group (33 events and 14 events, respectively). Fatigue was more common in the enzalutamide group; seizures occurred in 7 patients in the enzalutamide group (1%) and in no patients in the standard-care group. CONCLUSIONS: Enzalutamide was associated with significantly longer progression-free and overall survival than standard care in men with metastatic, hormone-sensitive prostate cancer receiving testosterone suppression. The enzalutamide group had a higher incidence of seizures and other toxic effects, especially among those treated with early docetaxel. (Funded by Astellas Scientific and Medical Affairs and others; ENZAMET (ANZUP 1304) ANZCTR number, ACTRN12614000110684; ClinicalTrials.gov number, NCT02446405; and EU Clinical Trials Register number, 2014-003190-42.).

BACKGROUND: Whether rapid lowering of elevated blood pressure would improve the outcome in patients with intracerebral hemorrhage is not known. METHODS: We randomly assigned 2839 patients who had had a spontaneous intracerebral hemorrhage within the previous 6 hours and who had elevated systolic blood pressure to receive intensive treatment to lower their blood pressure (with a target systolic level of <140 mm Hg within 1 hour) or guideline-recommended treatment (with a target systolic level of <180 mm Hg) with the use of agents of the physician's choosing. The primary outcome was death or major disability, which was defined as a score of 3 to 6 on the modified Rankin scale (in which a score of 0 indicates no symptoms, a score of 5 indicates severe disability, and a score of 6 indicates death) at 90 days. A prespecified ordinal analysis of the modified Rankin score was also performed. The rate of serious adverse events was compared between the two groups. RESULTS: Among the 2794 participants for whom the primary outcome could be determined, 719 of 1382 participants (52.0%) receiving intensive treatment, as compared with 785 of 1412 (55.6%) receiving guideline-recommended treatment, had a primary outcome event (odds ratio with intensive treatment, 0.87; 95% confidence interval [CI], 0.75 to 1.01; P=0.06). The ordinal analysis showed significantly lower modified Rankin scores with intensive treatment (odds ratio for greater disability, 0.87; 95% CI, 0.77 to 1.00; P=0.04). Mortality was 11.9% in the group receiving intensive treatment and 12.0% in the group receiving guideline-recommended treatment. Nonfatal serious adverse events occurred in 23.3% and 23.6% of the patients in the two groups, respectively. CONCLUSIONS: In patients with intracerebral hemorrhage, intensive lowering of blood pressure did not result in a significant reduction in the rate of the primary outcome of death or severe disability. An ordinal analysis of modified Rankin scores indicated improved functional outcomes with intensive lowering of blood pressure. (Funded by the National Health and Medical Research Council of Australia; INTERACT2 ClinicalTrials.gov number, NCT00716079.).

STUDY QUESTION: What is the recommended assessment and management of women with polycystic ovary syndrome (PCOS), based on the best available evidence, clinical expertise and consumer preference? SUMMARY ANSWER: International evidence-based guidelines, including 166 recommendations and practice points, addressed prioritized questions to promote consistent, evidence-based care and improve the experience and health outcomes of women with PCOS. WHAT IS KNOWN ALREADY: Previous guidelines either lacked rigorous evidence-based processes, did not engage consumer and international multidisciplinary perspectives, or were outdated. Diagnosis of PCOS remains controversial, and assessment and management are inconsistent. The needs of women with PCOS are not being adequately met and evidence practice gaps persist. STUDY DESIGN, SIZE, DURATION: International evidence-based guideline development engaged professional societies and consumer organizations with multidisciplinary experts and women with PCOS directly involved at all stages. Appraisal of Guidelines for Research and Evaluation (AGREE) II-compliant processes were followed, with extensive evidence synthesis. The Grading of Recommendations, Assessment, Development and Evaluation (GRADE) framework was applied across evidence quality, feasibility, acceptability, cost, implementation and ultimately recommendation strength. PARTICIPANTS/MATERIALS, SETTING, METHODS: Governance included a six continent international advisory and a project board, five guideline development groups, and consumer and translation committees. Extensive health professional and consumer engagement informed guideline scope and priorities. Engaged international society-nominated panels included pediatrics, endocrinology, gynecology, primary care, reproductive endocrinology, obstetrics, psychiatry, psychology, dietetics, exercise physiology, public health and other experts, alongside consumers, project management, evidence synthesis and translation experts. In total, 37 societies and organizations covering 71 countries engaged in the process. Twenty face-to-face meetings over 15 months addressed 60 prioritized clinical questions involving 40 systematic and 20 narrative reviews. Evidence-based recommendations were developed and approved via consensus voting within the five guideline panels, modified based on international feedback and peer review, with final recommendations approved across all panels. MAIN RESULTS AND THE ROLE OF CHANCE: The evidence in the assessment and management of PCOS is generally of low to moderate quality. The guideline provides 31 evidence based recommendations, 59 clinical consensus recommendations and 76 clinical practice points all related to assessment and management of PCOS. Key changes in this guideline include: (i) considerable refinement of individual diagnostic criteria with a focus on improving accuracy of diagnosis; (ii) reducing unnecessary testing; (iii) increasing focus on education, lifestyle modification, emotional wellbeing and quality of life; and (iv) emphasizing evidence based medical therapy and cheaper and safer fertility management. LIMITATIONS, REASONS FOR CAUTION: Overall evidence is generally low to moderate quality, requiring significantly greater research in this neglected, yet common condition, especially around refining specific diagnostic features in PCOS. Regional health system variation is acknowledged and a process for guideline and translation resource adaptation is provided. WIDER IMPLICATIONS OF THE FINDINGS: The international guideline for the assessment and management of PCOS provides clinicians with clear advice on best practice based on the best available evidence, expert multidisciplinary input and consumer preferences. Research recommendations have been generated and a comprehensive multifaceted dissemination and translation program supports the guideline with an integrated evaluation program. STUDY FUNDING/COMPETING INTEREST(S): The guideline was primarily funded by the Australian National Health and Medical Research Council of Australia (NHMRC) supported by a partnership with ESHRE and the American Society for Reproductive Medicine. Guideline development group members did not receive payment. Travel expenses were covered by the sponsoring organizations. Disclosures of conflicts of interest were declared at the outset and updated throughout the guideline process, aligned with NHMRC guideline processes. Full details of conflicts declared across the guideline development groups are available at https://www.monash.edu/medicine/sphpm/mchri/pcos/guideline in the Register of disclosures of interest. Of named authors, Dr Costello has declared shares in Virtus Health and past sponsorship from Merck Serono for conference presentations. Prof. Laven declared grants from Ferring, Euroscreen and personal fees from Ferring, Euroscreen, Danone and Titus Healthcare. Prof. Norman has declared a minor shareholder interest in an IVF unit. The remaining authors have no conflicts of interest to declare. The guideline was peer reviewed by special interest groups across our partner and collaborating societies and consumer organizations, was independently assessed against AGREE-II criteria, and underwent methodological review. This guideline was approved by all members of the guideline development groups and was submitted for final approval by the NHMRC.

OBJECTIVE: Early operative debridement is a major determinant of outcome in necrotizing fasciitis. However, early recognition is difficult clinically. We aimed to develop a novel diagnostic scoring system for distinguishing necrotizing fasciitis from other soft tissue infections based on laboratory tests routinely performed for the evaluation of severe soft tissue infections: the Laboratory Risk Indicator for Necrotizing Fasciitis (LRINEC) score. DESIGN: Retrospective observational study of patients divided into a developmental cohort (n = 314) and validation cohort (n = 140) SETTING: Two teaching tertiary care hospitals. PATIENTS: One hundred forty-five patients with necrotizing fasciitis and 309 patients with severe cellulitis or abscesses admitted to the participating hospitals. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The developmental cohort consisted of 89 consecutive patients admitted for necrotizing fasciitis. Control patients (n = 225) were randomly selected from patients admitted with severe cellulitis or abscesses during the same period. Hematologic and biochemical results done on admission were converted into categorical variables for analysis. Univariate and multivariate logistic regression was used to select significant predictors. Total white cell count, hemoglobin, sodium, glucose, serum creatinine, and C-reactive protein were selected. The LRINEC score was constructed by converting into integer the regression coefficients of independently predictive factors in the multiple logistic regression model for diagnosing necrotizing fasciitis. The cutoff value for the LRINEC score was 6 points with a positive predictive value of 92.0% and negative predictive value of 96.0%. Model performance was very good (Hosmer-Lemeshow statistic, p =.910); area under the receiver operating characteristic curve was 0.980 and 0.976 in the developmental and validation cohorts, respectively. CONCLUSIONS: The LRINEC score is a robust score capable of detecting even clinically early cases of necrotizing fasciitis. The variables used are routinely measured to assess severe soft tissue infections. Patients with a LRINEC score of > or = 6 should be carefully evaluated for the presence of necrotizing fasciitis.