Development and validation of outcome prediction models for aneurysmal subarachnoid haemorrhage: the SAHIT multinational cohort study BMJ (IF 20.7) Pub Date : 2018-01-18 Blessing N R Jaja, Gustavo Saposnik, Hester F Lingsma, Erin Macdonald, Kevin E Thorpe, Muhammed Mamdani, Ewout W Steyerberg, Andrew Molyneux, Airton Leonardo de Oliveira Manoel, Bawarjan Schatlo, Daniel Hanggi, David Hasan, George K C Wong, Nima Etminan, Hitoshi Fukuda, James Torner, Karl L Schaller, Jose I Suarez, Martin N Stienen, Mervyn D I Vergouwen, Gabriel J E Rinkel, Julian Spears, Michael D Cusimano, Michael Todd, Peter Le Roux, Peter Kirkpatrick, John Pickard, Walter M van den Bergh, Gordon Murray, S Claiborne Johnston, Sen Yamagata, Stephan Mayer, Tom A Schweizer, R Loch Macdonald
Objective To develop and validate a set of practical prediction tools that reliably estimate the outcome of subarachnoid haemorrhage from ruptured intracranial aneurysms (SAH).Design Cohort study with logistic regression analysis to combine predictors and treatment modality.Setting Subarachnoid Haemorrhage International Trialists’ (SAHIT) data repository, including randomised clinical trials, prospective observational studies, and hospital registries.Participants Researchers collaborated to pool datasets of prospective observational studies, hospital registries, and randomised clinical trials of SAH from multiple geographical regions to develop and validate clinical prediction models.Main outcome measure Predicted risk of mortality or functional outcome at three months according to score on the Glasgow outcome scale.Results Clinical prediction models were developed with individual patient data from 10 936 patients and validated with data from 3355 patients after development of the model. In the validation cohort, a core model including patient age, premorbid hypertension, and neurological grade on admission to predict risk of functional outcome had good discrimination, with an area under the receiver operator characteristics curve (AUC) of 0.80 (95% confidence interval 0.78 to 0.82). When the core model was extended to a “neuroimaging model,” with inclusion of clot volume, aneurysm size, and location, the AUC improved to 0.81 (0.79 to 0.84). A full model that extended the neuroimaging model by including treatment modality had AUC of 0.81 (0.79 to 0.83). Discrimination was lower for a similar set of models to predict risk of mortality (AUC for full model 0.76, 0.69 to 0.82). All models showed satisfactory calibration in the validation cohort.Conclusion The prediction models reliably estimate the outcome of patients who were managed in various settings for ruptured intracranial aneurysms that caused subarachnoid haemorrhage. The predictor items are readily derived at hospital admission. The web based SAHIT prognostic calculator (http://sahitscore.com) and the related app could be adjunctive tools to support management of patients.
Concerns about composite reference standards in diagnostic research BMJ (IF 20.7) Pub Date : 2018-01-18 Nandini Dendukuri, Ian Schiller, Joris de Groot, Michael Libman, Karel Moons, Johannes Reitsma, Maarten van Smeden
Composite reference standards are used to evaluate the accuracy of a new test in the absence of a perfect reference test. A composite reference standard defines a fixed, transparent rule to classify subjects into disease positive and disease negative groups based on existing imperfect tests. The accuracy of the composite reference standard itself has received limited attention. We show that increasing the number of tests used to define a composite reference standard can worsen its accuracy, leading to underestimation or overestimation of the new test’s accuracy. Further, estimates based on composite reference standards vary with disease prevalence, indicating that they may not be comparable across studies. These problems can be attributed to the fact that composite reference standards make a simplistic classification and then ignore the uncertainty in this classification. Latent class models that adjust for the accuracy of the different imperfect tests and the dependence between them should be pursued to make better use of dataComposite reference standards define a fixed, transparent rule to classify subjects into disease positive and disease negative groups based on existing imperfect testsThey are widely regarded as appropriate for determining sensitivity and specificity of a new test in the absence of a perfect reference testThough a composite reference standard is attractive for its simple and transparent construction, it can result in biased estimates as it makes suboptimal use of dataBias due to a composite reference standard can worsen as more information is gathered and the new test’s accuracy can be overestimated if the errors made by the composite reference standard and the new test are correlatedComposite reference standards cannot aid standardisation across settings when disease prevalence variesAppropriately constructed latent class models should be used to make complete use of the information gathered from multiple imperfect testsFor many diseases, a perfect diagnostic test may not exist or cannot be applied owing to costs or ethical concerns. Researchers evaluating a new test for the disease have no perfect reference against which to compare it. For example, GeneXpert (Xpert) is a nucleic acid amplification test for paediatric pulmonary tuberculosis (TB). Culture is an inadequate reference standard owing to its poor sensitivity,1 so the accuracy of Xpert is often evaluated by comparing it to a composite reference standard based on multiple imperfect tests.23Table 1 shows a composite reference standard defined using data gathered in a South African cohort study of symptomatic children.6 It classifies a child who is positive on culture, smear microscopy, chest radiography, or the tuberculin skin test as having TB. The apparent advantage of this composite reference standard is that it would identify more TB cases than culture alone. Studies using a standard such as this typically treat it as an error-free reference test to estimate the new test’s sensitivity (proportion of all patients with the disease that are correctly detected by the new test) and specificity (proportion of all patients without the disease who are correctly detected by the new test).37 Ensuring the new test is not used to define the composite reference standard is thought to protect against overestimating the new test’s accuracy.8A composite reference standard for childhood TB compared with the results of a latent class analysis in a cohort of 749 childrenComposite reference standards are used for diverse conditions including Chlamydia trachomatis infection, apathy, and prostate cancer (see web table 1). Some are required by regulatory authorities for approval of new tests.9 Despite their widespread use, the number of tests necessary to define an adequate standard is unknown. Composite reference standards based on two or three tests are most common,710 but some are based on upwards of eight or nine tests (web table 1).211Consequences of both the composite reference standard and the new test making the same errors are also not well understood. We discuss previously ignored concerns related to composite reference standards using numerical examples and data from a study of childhood TB and draw attention to better methods. We focus on composite reference standards based on the OR rule, which classifies patients with at least one positive test as disease positive and those with all negative tests as disease negative.3 Other possible composite rules include the AND rule, which classifies a patient as disease positive only if all tests are positive, or K positive rules, which classify a patient as disease positive only if at least K tests are positive.12In these examples, the sensitivities of the component tests used to define the composite reference standard are moderate to high and their specificities are near perfect. An OR rule composite reference standard is, therefore, anticipated to have higher sensitivity than a single imperfect reference test.We generated data for a sample of 1000 people assuming the composite reference standard was made up of component tests with sensitivity of 70% and specificities of 98-100% (detailed explanation in the web appendix). Disease prevalence was assumed to be 10%—that is, 100 patients were disease positive and 900 were disease negative. The new test under evaluation was set to have a sensitivity of 90% and a specificity of 98%.Depending on their accuracy, adding more component tests to the composite reference standard might cause more misclassification rather than less. We start with the ideal situation where each component test has perfect specificity of 100% and where the different component tests are conditionally independent (meaning that they are not prone to making the same false positive or false negative errors). Table 2 lists the frequency of results on the component tests and the composite reference standards based on them. As we move from a single reference test to a composite reference standard based on two or three component tests, the number of patients correctly classified as having the disease increases from 70 (34+15+15+6) to 91 (34+15+15+6+15+6) to 97 (34+15+15+6+15+6+6). The gain at the second step is less than at the first. After about five component tests (data not shown), additional tests increase costs but don’t result in any gain, as all 1000 patients are correctly identified.Expected frequency of results on individual tests and OR rule based composite reference standards in 1000 subjects*Table 2 shows how misclassification changes when the specificity of the component tests decreases to 98%. The classification of disease positive patients remains the same, but the number of misclassified disease negative patients increases from 17 to 51 as we move from a single reference test to a composite reference standard with three component tests. For this example, the composite reference standard with three component tests resulted in more misclassified patients overall (three false positives and 51 false negatives) than the single reference test (30 false positives and 17 false negatives). The overall number of misclassified patients will continue to rise as more component tests are added to the composite reference standard.12Using the data in table 2 we can show that when all component tests have perfect specificity and are conditionally independent, the sensitivity of the new test is estimated accurately at its value of 90% irrespective of the number of tests in the composite reference standard (fig 1a). The estimate of the specificity of the new test steadily improves with every added test until it reaches the true value (fig 1b).Change in estimates of sensitivity and specificity of the new test with increasing number of component tests in the composite reference standard.When the specificity of the component tests falls to 98%, the specificity estimates of the new test are almost identical to those obtained previously, but the sensitivity of the new test is now underestimated (fig 1). When the composite reference standard was composed of three tests, for example, the estimated sensitivity was 59%, much lower than the true value of 90%. This underestimation worsens with every test added to the composite reference standard.So far, we have assumed that all tests—component tests in the composite reference standard and the new test—are conditionally independent. In practice, however, errors made by multiple tests might be correlated.13 In studies evaluating new tests for Chlamydia trachomatis, for example, the component tests and the new test are typically nucleic acid amplification tests, which risk making the same false positive error of detecting a non-viable organism.14 In these situations, the composite reference standard can overestimate the accuracy of the new test because it does not adjust for the presence of conditional dependence—that is, the errors of the new test remain undetected.To study the effects of conditional dependence, we generated data from a setting where both tests are likely to make the same false positive errors even though their specificity remains high at 98% (see web table 2 for details).6 As in our previous example, the sensitivity of the new test is underestimated, and this worsens with each component test added to the composite reference standard (fig 1). The specificity of the new test is underestimated when compared to a single imperfect test but becomes overestimated as component tests are added to the composite reference standard (fig 1). As the number of component tests increases, the estimated specificity of the new test converges to a value higher than the true value.12 In our example, the new test’s specificity will converge at 99.94%, compared with its true specificity of 98%. This may not seem like a large magnitude of bias but could lead to an important underestimate of the number of false positives the new test will produce in a low prevalence population.When a new test is compared to the same composite reference standard in two different studies, the reported value of the new test’s accuracy will depend on the disease prevalence in each study. Using a standardised composite reference standard therefore does not ensure comparability across studies. We considered a composite reference standard based on three conditionally independent component tests, each with sensitivity 70% and specificity 98%. Disease prevalence ranged from low (5%) to high (30%), as might be expected across geographic regions or healthcare settings. The new test’s sensitivity was assumed to be 90% and its specificity 98%, as before. We found the estimated sensitivity of the new test ranged from 43% when the prevalence was 5% to 79% when the prevalence is 30% (web figure 1). Estimated specificity did not vary greatly with prevalence for the settings we used.The drawbacks of the composite reference standard can be overcome using a statistical modelling approach called latent class analysis.3 Instead of classifying subjects into fixed disease categories, latent class analysis estimates the probability that each patient has the disease using all observed tests, including the test under evaluation (web figure 2). It adjusts for the sensitivity and specificity of each test as well as the possibility of conditional dependence between them. Simply put, latent class analysis considers how certain we are about classifying patients into diseased or non-diseased groups rather than making a black and white decision. Column 8 of table 1 shows the estimated risk of TB for each observed combination of tests based on a recent latent class analysis for the childhood TB data.6Notably, the estimated risk of TB from this latent class analysis follows the gradation proposed by an expert group’s clinical case definition (column 9 of table 1),4 which classifies subjects into confirmed TB, probable TB, possible TB, and unlikely TB groups, using the same four tests as the composite reference standard. Our data show that composite reference standard would classify confirmed, probable and possible TB cases all as having TB, resulting in an estimated prevalence of 94%. Using culture as a reference would only consider the confirmed TB cases, resulting in an underestimate of the prevalence (16.4%). Latent class analysis estimates a 100% risk of TB for most cases of confirmed TB, though the risk is lower for unusual patterns. The risk of TB among the probable and possible TB cases ranges from 9% to 52% among patients with a negative Xpert test but increases when Xpert is positive. The resulting prevalence estimate based on latent class analysis is 26.7%. Because the latent class analysis adjusts for conditional dependence between culture and Xpert, it also provides a more realistic estimate of Xpert sensitivity (49.4%) than would be obtained with culture (74.4%) or the composite reference standard (22.5%) (see web material for how the latent class analysis estimates were calculated).The advantages of latent class analysis are accompanied by the challenges of using a more sophisticated analytical technique. Construction of these models requires interdisciplinary expertise of both methodologists and clinicians6 to determine the particular tests, covariates, conditional dependence structure, and previous knowledge to be considered. Validation of these models against a perfect reference may not always be possible. Sometimes competing models cannot be distinguished using standard statistical methods.15 This is not a drawback of latent class analysis, but a reflection of the uncertainty in our knowledge due to the lack of a perfect reference test. Comparison with external information, such as the experts’ clinical case definition, can aid in assessing whether the model provides sensible results. This step is important because, as with all statistical models, incorrect model specification can lead to biased results.16Composite reference standards are considered valid for estimating diagnostic accuracy when no perfect reference standard exists.37 But we have shown that the OR rule based composite reference standard leads to biased estimates of the accuracy of a new test unless stringent conditions hold. The additional information gathered from each component test results in worsening bias. Our previous work has shown these observations also apply to composite reference standards based on the AND rule and or the K positive rule.12Composite reference standards may be considered clinically meaningful17 as they resemble clinical decision rules, which classify patients into mutually exclusive categories to support decision making—for example, rules identifying whether a subject is a candidate for TB treatment. Such decision rules are not necessary in research settings as no black or white decision needs to be made. Clinical decision rules might indicate the best possible management strategy, but are recognised by clinicians as imperfect.16 Yet similar rules are used to define composite reference standards for a diagnostic accuracy studies with no such recognition.In the absence of a perfect reference test, a new test could be evaluated in terms of outcomes such as diagnostic yield or effect on patient management instead of accuracy.18 Latent class analysis would also be relevant in such analyses to estimate percentage of overdiagnosis or overtreatment,619 eventually supporting the development of optimal clinical decision rules.As our ability to measure results on multiple tests/biomarkers increases, development of appropriate latent class models should be pursued in the absence of a perfect reference test to make optimal use of the data gathered.More detail on the problems with composite reference standards https://www.ncbi.nlm.nih.gov/pubmed/26555849A review paper on use of latent class models for diagnostic research https://www.ncbi.nlm.nih.gov/pubmed/24272278Applications of latent class models with free accompanying software https://www.ncbi.nlm.nih.gov/pubmed/27737841, https://www.ncbi.nlm.nih.gov/pubmed/7840100Guidelines for reporting latent class models https://www.equator-network.org/reporting-guidelines/stard-blcm/Contributors and sources: The authors include biostatisticians, epidemiologists, and clinicians with expertise in diagnostic research and a particular interest in methods for evaluating diagnostic accuracy in the absence of a perfect reference test. All authors participated in planning and writing the paper. IS generated the numerical examples. ND is the guarantor.Funding: This work was supported by funding from the Canadian Institutes of Health Research (Grant number 89857).Competing interests: All authors have completed the ICMJE uniform disclosure form at http://www.icmje.org/coi_disclosure.pdf and declare support from the Canadian Institutes of Health Research for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years, no other relationships or activities that could appear to have influenced the submitted work.
Retreat From Human Rights and Adverse Consequences for Health JAMA (IF 44.405) Pub Date : 2018-01-18 Diederik Lohman
The international environment for human rights has rapidly deteriorated in recent years. Populist leaders have come to power in an increasing number of countries, often on political platforms that are explicitly hostile to human rights. These leaders tend to portray respect for human rights as an inconvenient obstacle to their agendas rather than as an essential limit on their power. Meanwhile, many governments that have traditionally been proponents of human rights, although often with records that do not entirely reflect human rights, have encountered internal challenges from authoritarian populists or far-right political parties that have turned their focus inward and weakened their willingness to stand up for human rights internationally.
China’s ban on imported plastic waste could be a game changer Nature (IF 40.137) Pub Date : Tony R. Walker
China’s ban on imported plastic waste could be a game changer China’s ban on imported plastic waste could be a game changer, Published online: 18 January 2018; doi:10.1038/d41586-018-00933-6 China’s ban on imported plastic waste could be a game changer
China declared world's largest producer of scientific articles Nature (IF 40.137) Pub Date : Jeff Tollefson
China declared world's largest producer of scientific articles China declared world's largest producer of scientific articles, Published online: 18 January 2018; doi:10.1038/d41586-018-00927-4 Report shows increasing international competition, but suggests that United States remains a scientific powerhouse.
What a US government shutdown would mean for science Nature (IF 40.137) Pub Date : Lauren Morello
What a US government shutdown would mean for science What a US government shutdown would mean for science, Published online: 18 January 2018; doi:10.1038/d41586-018-00928-3 The National Institutes of Health would stop processing grants, but astronauts in space would keep working.
Centimetre-scale electron diffusion in photoactive organic heterostructures Nature (IF 40.137) Pub Date : 2018-01-18 Quinn Burlingame, Caleb Coburn, Xiaozhou Che, Anurag Panda, Yue Qu, Stephen R. Forrest
The unique properties of organic semiconductors, such as flexibility and lightness, are increasingly important for information displays, lighting and energy generation. But organics suffer from both static and dynamic disorder, and this can lead to variable-range carrier hopping1,2, which results in notoriously poor electrical properties, with low electron and hole mobilities and correspondingly short charge-diffusion lengths of less than a micrometre3,4. Here we demonstrate a photoactive (light-responsive) organic heterostructure comprising a thin fullerene channel sandwiched between an electron-blocking layer and a blended donor:C70 fullerene heterojunction that generates charges by dissociating excitons. Centimetre-scale diffusion of electrons is observed in the fullerene channel, and this can be fitted with a simple electron diffusion model. Our experiments enable the direct measurement of charge diffusivity in organic semiconductors, which is as high as 0.83 ± 0.07 square centimetres per second in a C60 channel at room temperature. The high diffusivity of the fullerene combined with the extraordinarily long charge-recombination time yields diffusion lengths of more than 3.5 centimetres, orders of magnitude larger than expected for an organic system.
Tackling hearing loss to improve the care of older adults BMJ (IF 20.7) Pub Date : 2018-01-18 Jan Blustein, Barbara E Weinstein, Joshua Chodosh
Many older adults have difficulty understanding speech in acute healthcare settings owing to hearing loss, but the effect on patient care is often overlooked, argue Jan Blustein and colleagues Many healthcare settings are difficult listening situations, with beeping alarms, competing conversations, and poor sound insulation Communication is key for healthcare quality and safety, so people with hearing loss are at risk of receiving poor care Clinicians should be aware that older patients might have trouble understanding speech and should use established strategies to improve communication Hospitals might be able to provide hearing assistive devices and could routinely screen older patients for hearing loss The World Health Organization estimates that disabling hearing loss affects nearly a third (32.8%) of people aged 65 years and over around the world.1 The prevalence of hearing loss is growing; it is now the fourth leading cause of years lived with disability globally.2 But the implications tend to be overlooked. Clinical care is often delivered in settings where people with hearing loss struggle to understand speech. Communication is key for healthcare quality and safety, so people with hearing loss are at risk of receiving poor care. Simple steps can improve communication in clinical encounters. Changes in practice environments, processes, and policies could substantially improve the quality of medical care. But first, we need greater awareness. Typically hearing loss isn’t a problem of hearing sounds, but rather of understanding speech. People with mild to moderate presbycusis (age related hearing loss) can often detect sound well and have good speech understanding in ideal circumstances; for example, in rooms with little competing ambient noise, in conversation with one speaker who is facing them. Understanding can decrease when the setting is less than ideal—when the speaker turns away, when there are multiple simultaneous speakers, or when ambient sound …
Health and social care, together at last? BMJ (IF 20.7) Pub Date : 2018-01-18 Fiona Godlee
How much of the rising pressure on the NHS could be relieved by proper funding and organisation of public health and social care? We are far from achieving either: cuts to public health are making people ill; failures of social care are keeping people in hospital when they could be at home. Pressure on the NHS is nothing new. “Disseminating hyporesourcitis” was The BMJ’s diagnosis back in the Thatcher 1980s (www.bmj.com/content/bmj/292/6529/1212.full.pdf). But the looming crisis is now big enough to be seen if not from space then at least from the United States (https://www.nytimes.com/2018/01/16/opinion/nhs-britain-crisis.html). On BMJ Opinion (blogs.bmj.com/bmj) this week the independently minded politician Sarah Wollaston calls for a whole system approach, encompassing public health and social care. These systems cannot be considered in isolation, she says. So what difference can we expect now that health and social care are both the responsibility of a newly dubbed secretary of state for health and social care (doi:10.1136/bmj.k208)? Not much, says David Oliver (doi:10.1136/bmj.k136). For one thing, the group advising Jeremy Hunt on social care includes people long associated with the current muddle. “The problems facing the social care system are just the kind of thorny issue we elect governments to solve,” he says. But he’s not holding his breath. Jon Glasby is similarly cautious (doi:10.1136/bmj.k201). Hunt’s new title feels like progress, he says. But our health and social care services are fundamentally different and not designed for integration: one is national, universal, and largely free at the point of delivery; the other is local, targeted, and means tested. A single department changes nothing, Glasby says. Wollaston now wants to see all options for funding and integration clearly set out for the public to consider. These should include ways of achieving intergenerational fairness, she says, perhaps through a hypothecated tax borne by wealthier over 40s. Hypothecation is gaining popularity. It was, however, roundly dismissed by John Appleby (doi:10.1136/bmj.j471). Also dismissed, by Nigel Crisp, was the idea of a royal commission (doi:10.1136/bmj.j1621). But while Brexit continues to steal the political oxygen (doi:10.1136/bmj.k189), it’s hard to see what else will lift this precious public service out of the mire of short term party politics and give it the long term visionary thinking it urgently needs. Follow Fiona Godlee on Twitter @fgodlee
Hyperpigmentation in the skin folds BMJ (IF 20.7) Pub Date : 2018-01-18 Xiao Ke Liu, Jun Li
A 62 year old man presented with a one year history of asymptomatic hyperpigmentation of the flexural and intertriginous areas, especially in the groin (fig 1). He had thickened skin on his palms, feet, and neck, had lost 15 kg in three years, and had experienced nail dystrophy (melanonychia and onychoatrophy) for two years. He had recently received a diagnosis of unexplained hypothyroidism and hypogonadism. What is the most likely diagnosis? Hyperpigmented, velvety skin lesions in the groin Acanthosis …
GMC erasure case: how we learn from human error BMJ (IF 20.7) Pub Date : 2018-01-18 Jonathan Cusack
The BMJ refers to Hadiza Bawa-Garba as a senior trainee1: this is incorrect. She had completed her fifth year of specialty training (ST5) and was on her first shifts back from maternity leave. Even the best doctors are human …
Letter to the GMC chair regarding Hadiza Bawa-Garba BMJ (IF 20.7) Pub Date : 2018-01-18 Nick Ross
The following is a letter to the chair of the General Medical Council. Dear Professor Stephenson, I write to you about what seems to be a serious misjudgment by the GMC regarding Hadiza Bawa-Garba.1 To set the context for my concerns, I am, among other things, a non-executive director of a major acute hospital trust, president of the charity Healthwatch, which promotes evidence based medicine, and the longest serving member of the Royal College of Physicians’ committee on ethics in medicine. On all three criteria—management, evidence, and ethics—I fear the GMC has misjudged this case. As a journalist and broadcaster I suspect that one of the factors might have been pressure from the media, and I remind you that newspaper reporters are out to make a story, not nuanced judgments, and their printed …
GMC erasure case: we must improve systems to mitigate inevitable mistakes BMJ (IF 20.7) Pub Date : 2018-01-18 Phil Whitaker
David Sellu, the London surgeon whose conviction for gross negligence manslaughter was eventually quashed by the Court of Appeal, should serve as a cautionary tale for those at the General Medical Council who seem determined to pursue trainee paediatrician …
Practising larvae removal . . . and other stories BMJ (IF 20.7) Pub Date : 2018-01-18 British Medical Journal Publishing Group
The way to treat cutaneous myiasis—parasitic infection of skin by the larvae of certain species of fly—is first to occlude the punctum and then, as the larvae move towards the skin surface in search of oxygen, remove them surgically. This is a straightforward procedure for experienced operators, but beginners might feel squeamish and need practice. The Journal of the Royal Army Medical Corps explains how to create a realistic training model using a pig’s trotter from a butcher and maggots from a fishing tackle shop (J Royal Army Med Corps doi:10.1136/jramc-2016-000737). What’s the difference between an interrupted time series and a before-after study? Or between a …
Seven days in medicine: 10-16 January 2018 BMJ (IF 20.7) Pub Date : 2018-01-18 British Medical Journal Publishing Group
NHS Improvement, which supports trusts and independent providers of NHS services, said that it had deployed staff to the six biggest hospital sites affected by the collapse of the Carillion construction company, which declared insolvency on 15 January. Overall, the NHS was a “relatively small” customer of Carillion, said NHS Improvement, as 13 trusts use Carillion through a private finance initiative (PFI) provider for building maintenance, catering, cleaning, or facilities management. Three trusts also contract Carillion directly for some services, as do several smaller primary and community care properties. Two trusts also have sites under construction. The Care Quality Commission suspended inspections of all general practices and urgent services such as NHS 111 or GP out-of-hours that have a “good” or “outstanding” rating for the rest of January, to help services manage intense pressures this winter. But re-inspections of services rated as “requires improvement” or “inadequate” will continue as scheduled, as will inspections to follow up specific concerns. The BMA welcomed the move and urged NHS England to consider suspending other bureaucratic tasks that divert GPs and other professionals from delivering frontline care. (Full story doi:10.1136/bmj.k137) Poor access to general practice services is not associated with more emergency department visits, showed an analysis of linked primary and secondary care records of 819 590 patients registered with GPs in east London, which found that patients more frequently using emergency departments also saw GPs more often. “This analysis provides strong evidence …
Management of incidental adrenal tumours BMJ (IF 20.7) Pub Date : 2018-01-18 Fahmy W F Hanna, Basil G Issa, Julius Sim, Brian Keevil, Anthony A Fryer
An adrenal incidentaloma is an adrenal lesion found incidentally in asymptomatic patients undergoing imaging scans not performed for suspected adrenal disease. Adrenal incidentalomas are becoming more common due to increased scanning, as well as an older population Most incidentalomas are benign and non-functioning (~85%) and require only minimal evaluation (but are frequently over investigated). The remaining 15% (functioning and/or malignant lesions) are at risk of under investigation, delay, or even being missed Patients with adrenal incidentalomas can experience anxiety once an adrenal incidentaloma is detected and while awaiting investigations or appointments References were selected from Medline search, focusing on published guidelines. Sub-references were selected to ensure full coverage of the areas identified within the initial search. An incidental adrenal tumour, described in this article as an “adrenal incidentaloma,” is an adrenal mass discovered during imaging that was not performed for suspected adrenal disease. These are being detected more frequently in an ageing population1 through the increased use of computed tomography (eg, computed tomography urogram, or colonoscopy) and magnetic resonance imaging (MRI) scans with enhanced resolution.2 This article highlights the management of adrenal incidentalomas, collating recommendations from international guidelines, and is aimed at non-specialists. Adrenal incidentalomas are defined as adrenal masses incidentally discovered during imaging that was not performed for suspected adrenal disease. Hence, an adrenal lesion discovered while investigating raised catecholamines would not be classified as an adrenal incidentaloma. Most definitions have restricted the diagnosis to lesions ≥10 mm34 unless there are clinical stigmas of adrenal hormone over-production identified after the detection of the lesion that warrant further investigation. In view of variation in diagnostic criteria, referral patterns, and surgical rates, it is challenging to precisely classify the underlying adrenal incidentaloma pathology from published literature.2Figure 1 provides a simplified description of the adrenal gland …
Ageing-related receptors resolved Nature (IF 40.137) Pub Date : Makoto Kuro-o
Ageing-related receptors resolved Ageing-related receptors resolved, Published online: 17 January 2018; doi:10.1038/d41586-017-09032-4 Ageing is a regulated process in which hormones have pivotal roles. Crystal structures of two hormone co-receptors should be informative for drug discovery focused on age-related disorders.
Molecular mechanism of promoter opening by RNA polymerase III Nature (IF 40.137) Pub Date : 2018-01-17 Matthias K. Vorländer, Heena Khatter, Rene Wetzel, Wim J. H. Hagen, Christoph W. Müller
RNA polymerase III (Pol III) and transcription factor IIIB (TFIIIB) assemble together on different promoter types to initiate the transcription of small, structured RNAs. Here we present structures of Pol III preinitiation complexes, comprising the 17-subunit Pol III and the heterotrimeric transcription factor TFIIIB, bound to a natural promoter in different functional states. Electron cryo-microscopy reconstructions, varying from 3.7 Å to 5.5 Å resolution, include two early intermediates in which the DNA duplex is closed, an open DNA complex, and an initially transcribing complex with RNA in the active site. Our structures reveal an extremely tight, multivalent interaction between TFIIIB and promoter DNA, and explain how TFIIIB recruits Pol III. Together, TFIIIB and Pol III subunit C37 activate the intrinsic transcription factor-like activity of the Pol III-specific heterotrimer to initiate the melting of double-stranded DNA, in a mechanism similar to that of the Pol II system.
Chromosomal instability drives metastasis through a cytosolic DNA response Nature (IF 40.137) Pub Date : 2018-01-17 Samuel F. Bakhoum, Bryan Ngo, Ashley M. Laughney, Julie-Ann Cavallo, Charles J. Murphy, Peter Ly, Pragya Shah, Roshan K. Sriram, Thomas B. K. Watkins, Neil K. Taunk, Mercedes Duran, Chantal Pauli, Christine Shaw, Kalyani Chadalavada, Vinagolu K. Rajasekhar, Giulio Genovese, Subramanian Venkatesan, Nicolai J. Birkbak, Nicholas McGranahan, Mark Lundquist, Quincey LaPlant, John H. Healey, Olivier Elemento, Christine H. Chung, Nancy Y. Lee, Marcin Imielenski, Gouri Nanjangud, Dana Pe’er, Don W. Cleveland, Simon N. Powell, Jan Lammerding, Charles Swanton, Lewis C. Cantley
Chromosomal instability is a hallmark of cancer that results from ongoing errors in chromosome segregation during mitosis. Although chromosomal instability is a major driver of tumour evolution, its role in metastasis has not been established. Here we show that chromosomal instability promotes metastasis by sustaining a tumour cell-autonomous response to cytosolic DNA. Errors in chromosome segregation create a preponderance of micronuclei whose rupture spills genomic DNA into the cytosol. This leads to the activation of the cGAS–STING (cyclic GMP-AMP synthase–stimulator of interferon genes) cytosolic DNA-sensing pathway and downstream noncanonical NF-κB signalling. Genetic suppression of chromosomal instability markedly delays metastasis even in highly aneuploid tumour models, whereas continuous chromosome segregation errors promote cellular invasion and metastasis in a STING-dependent manner. By subverting lethal epithelial responses to cytosolic DNA, chromosomally unstable tumour cells co-opt chronic activation of innate immune pathways to spread to distant organs.
Erratum: Moving beyond microbiome-wide associations to causal microbe identification Nature (IF 40.137) Pub Date : 2018-01-17 Neeraj K. Surana, Dennis L. Kasper
Erratum: Moving beyond microbiome-wide associations to causal microbe identification Erratum: Moving beyond microbiome-wide associations to causal microbe identification, Published online: 17 January 2018; doi:10.1038/nature25471 Erratum: Moving beyond microbiome-wide associations to causal microbe identification
Clonal evolution mechanisms in NT5C2 mutant-relapsed acute lymphoblastic leukaemia Nature (IF 40.137) Pub Date : 2018-01-17 Gannie Tzoneva, Chelsea L. Dieck, Koichi Oshima, Alberto Ambesi-Impiombato, Marta Sánchez-Martín, Chioma J. Madubata, Hossein Khiabanian, Jiangyan Yu, Esme Waanders, Ilaria Iacobucci, Maria Luisa Sulis, Motohiro Kato, Katsuyoshi Koh, Maddalena Paganin, Giuseppe Basso, Julie M. Gastier-Foster, Mignon L. Loh, Renate Kirschner-Schwabe, Charles G. Mullighan, Raul Rabadan, Adolfo A. Ferrando
Relapsed acute lymphoblastic leukaemia (ALL) is associated with resistance to chemotherapy and poor prognosis1. Gain-of-function mutations in the 5′-nucleotidase, cytosolic II (NT5C2) gene induce resistance to 6-mercaptopurine and are selectively present in relapsed ALL2,3. Yet, the mechanisms involved in NT5C2 mutation-driven clonal evolution during the initiation of leukaemia, disease progression and relapse remain unknown. Here we use a conditional-and-inducible leukaemia model to demonstrate that expression of NT5C2(R367Q), a highly prevalent relapsed-ALL NT5C2 mutation, induces resistance to chemotherapy with 6-mercaptopurine at the cost of impaired leukaemia cell growth and leukaemia-initiating cell activity. The loss-of-fitness phenotype of NT5C2+/R367Q mutant cells is associated with excess export of purines to the extracellular space and depletion of the intracellular purine-nucleotide pool. Consequently, blocking guanosine synthesis by inhibition of inosine-5′-monophosphate dehydrogenase (IMPDH) induced increased cytotoxicity against NT5C2-mutant leukaemia lymphoblasts. These results identify the fitness cost of NT5C2 mutation and resistance to chemotherapy as key evolutionary drivers that shape clonal evolution in relapsed ALL and support a role for IMPDH inhibition in the treatment of ALL.
Sexual Harassment in Medicine — #MeToo N. Engl. J. Med. (IF 72.406) Pub Date : 2017-12-13 Reshma Jagsi
The problem of sexual harassment seems as severe in medicine as elsewhere, and standing up to harassers is hard for victims and institutions alike. As we work to become more proactive, it’s valuable to participate in the now open conversation about workplace harassment.
Hepatitis A Outbreak in California — Addressing the Root Cause N. Engl. J. Med. (IF 72.406) Pub Date : 2017-12-06 Margot Kushel
Most people affected by California’s hepatitis A outbreak are homeless, and infectious diseases are one of many health threats they face. To address the root cause of their health problems, we will need sustained efforts to fix the housing-affordability crisis.
Nudge Units to Improve the Delivery of Health Care N. Engl. J. Med. (IF 72.406) Pub Date : 2018-01-17 Mitesh S. Patel, Kevin G. Volpp, David A. Asch
Household-Contact Investigation for Detection of Tuberculosis in Vietnam N. Engl. J. Med. (IF 72.406) Pub Date : 2018-01-17 Greg J. Fox, Nguyen V. Nhung, Dinh N. Sy, Nghiem L.P. Hoa, Le T.N. Anh, Nguyen T. Anh, Nguyen B. Hoa, Nguyen H. Dung, Tran N. Buu, Nguyen T. Loi, Le T. Nhung, Nguyen V. Hung, Phan T. Lieu, Nguyen K. Cuong, Pham D. Cuong, Jessica Bestrashniy, Warwick J. Britton, Guy B. Marks
Hyperthermic Intraperitoneal Chemotherapy in Ovarian Cancer N. Engl. J. Med. (IF 72.406) Pub Date : 2018-01-17 Willemien J. van Driel, Simone N. Koole, Karolina Sikorska, Jules H. Schagen van Leeuwen, Henk W.R. Schreuder, Ralph H.M. Hermans, Ignace H.J.T. de Hingh, Jacobus van der Velden, Henriëtte J. Arts, Leon F.A.G. Massuger, Arend G.J. Aalbers, Victor J. Verwaal, Jacobien M. Kieffer, Koen K. Van de Vijver, Harm van Tinteren, Neil K. Aaronson, Gabe S. Sonke
Long-Term Follow-up of Monoclonal Gammopathy of Undetermined Significance N. Engl. J. Med. (IF 72.406) Pub Date : 2018-01-17 Robert A. Kyle, Dirk R. Larson, Terry M. Therneau, Angela Dispenzieri, Shaji Kumar, James R. Cerhan, S. Vincent Rajkumar
Background Monoclonal gammopathy of undetermined significance (MGUS) occurs in approximately 3% of persons 50 years of age or older. Methods We studied 1384 patients who were residing in southeastern Minnesota and in whom MGUS was diagnosed at the Mayo Clinic in the period from 1960 through 1994; the median follow-up was 34.1 years (range, 0.0 to 43.6). The primary end point was progression to multiple myeloma or another plasma-cell or lymphoid disorder. Results During 14,130 person-years of follow-up, MGUS progressed in 147 patients (11%), a rate that was 6.5 times (95% confidence interval [CI], 5.5 to 7.7) as high as the rate in the control population. The risk of progression without accounting for death due to competing causes was 10% at 10 years, 18% at 20 years, 28% at 30 years, 36% at 35 years, and 36% at 40 years. Among patients with IgM MGUS, the presence of two adverse risk factors — namely, an abnormal serum free light-chain ratio (ratio of kappa to lambda free light chains) and a high serum monoclonal protein (M protein) level (≥1.5 g per deciliter) — was associated with a risk of progression at 20 years of 55%, as compared with 41% among patients who had one adverse risk factor and 19% among patients who had neither risk factor. Among patients with non-IgM MGUS, the risk of progression at 20 years was 30% among those who had the two risk factors, 20% among those who had one risk factor, and 7% among those who had neither risk factor. Patients with MGUS had shorter survival than was expected in the control population of Minnesota residents of matched age and sex (median, 8.1 vs. 12.4 years; P<0.001). Conclusions Significant differences were noted in the risk of progression between patients with IgM MGUS and those with non-IgM MGUS. Overall survival was shorter among patients with MGUS than was expected in a matched control population. (Funded by the National Cancer Institute.) Supported in part by research grants (CA107476, CA168762, and CA186781) from the National Cancer Institute. Disclosure forms provided by the authors are available with the full text of this article at NEJM.org. Source Information From the Divisions of Hematology (R.A.K., A.D., S.K., S.V.R.), Biostatistics (D.R.L., T.M.T.), and Epidemiology (J.R.C.), Mayo Clinic, Rochester, MN. Address reprint requests to Dr. Kyle at the Division of Hematology, Mayo Clinic, 200 First St. SW, Rochester, MN 55905, or at firstname.lastname@example.org.
Somatic Activating KRAS Mutations in Arteriovenous Malformations of the Brain N. Engl. J. Med. (IF 72.406) Pub Date : 2018-01-03 Sergey I. Nikolaev, Sandra Vetiska, Ximena Bonilla, Emilie Boudreau, Suvi Jauhiainen, Behnam Rezai Jahromi, Nadiya Khyzha, Peter V. DiStefano, Santeri Suutarinen, Tim-Rasmus Kiehl, Vitor Mendes Pereira, Alexander M. Herman, Timo Krings, Hugo Andrade-Barazarte, Takyee Tung, Taufik Valiante, Gelareh Zadeh, Mike Tymianski, Tuomas Rauramaa, Seppo Ylä-Herttuala, Joshua D. Wythe, Stylianos E. Antonarakis, Juhana Frösen, Jason E. Fish, Ivan Radovanovic
Background Sporadic arteriovenous malformations of the brain, which are morphologically abnormal connections between arteries and veins in the brain vasculature, are a leading cause of hemorrhagic stroke in young adults and children. The genetic cause of this rare focal disorder is unknown. Methods We analyzed tissue and blood samples from patients with arteriovenous malformations of the brain to detect somatic mutations. We performed exome DNA sequencing of tissue samples of arteriovenous malformations of the brain from 26 patients in the main study group and of paired blood samples from 17 of those patients. To confirm our findings, we performed droplet digital polymerase-chain-reaction (PCR) analysis of tissue samples from 39 patients in the main study group (21 with matching blood samples) and from 33 patients in an independent validation group. We interrogated the downstream signaling pathways, changes in gene expression, and cellular phenotype that were induced by activating KRAS mutations, which we had discovered in tissue samples. Results We detected somatic activating KRAS mutations in tissue samples from 45 of the 72 patients and in none of the 21 paired blood samples. In endothelial cell–enriched cultures derived from arteriovenous malformations of the brain, we detected KRAS mutations and observed that expression of mutant KRAS (KRASG12V) in endothelial cells in vitro induced increased ERK (extracellular signal-regulated kinase) activity, increased expression of genes related to angiogenesis and Notch signaling, and enhanced migratory behavior. These processes were reversed by inhibition of MAPK (mitogen-activated protein kinase)–ERK signaling. Conclusions We identified activating KRAS mutations in the majority of tissue samples of arteriovenous malformations of the brain that we analyzed. We propose that these malformations develop as a result of KRAS-induced activation of the MAPK–ERK signaling pathway in brain endothelial cells. (Funded by the Swiss Cancer League and others.) Supported by research grants to Dr. Nikolaev from the Swiss Cancer League (LSCC 2939-02-2012 and KSF-3985-08-2016), Dinu Lipatti (2014), and Novartis (14B065). Ms. Khyzha was supported by a Canada Graduate Scholarship from the Natural Sciences and Research Council of Canada. Dr. DiStefano was supported by a Postdoctoral Fellowship from the Toronto General Hospital Research Institute. Dr. Suutarinen was supported by a research grant from the Petri Honkanen Foundation. Dr. Herman was supported by a grant from the National Institutes of Health (2T32HL007676). Dr. Wythe was supported by an American Heart Association Grant-in-Aid (16GRNT31330023). Dr. Antonarakis was supported by a grant from the European Research Council. Dr. Frösen was supported by research grants from the Finnish Medical Foundation and Kuopio University Hospital. Dr. Fish was supported by an operating grant from the Canadian Institutes of Health Research (CIHR) (MOP-119506) and a Team Project Award from the University of Toronto Medicine by Design initiative, which receives funding from the Canada First Research Excellence Fund and a Canada Foundation for Innovation equipment grant; he also received an Early Researcher Award from the Ontario Ministry of Research and Innovation and funding from the Canada Research Chair Program from the CIHR. Dr. Radovanovic was supported by the Timothy P. Susco Chair of Research Award from the Brain Aneurysm Foundation, the Toronto General and Western Hospital Foundation, and received seed support from the Department of Surgery and Division of Neurosurgery at the University Health Network. Disclosure forms provided by the authors are available with the full text of this article at NEJM.org. Drs. Nikolaev, Vetiska, Frösen, Fish, and Radovanovic contributed equally to this article. This article was published on January 3, 2018, at NEJM.org. We thank the staff of the Princess Margaret Genomics Centre and Bioinformatics Services (C. Virtanen and Z. Lu) for generating the RNA and DNA sequencing data used in this study; the staff of the Centre for Applied Genomics at the Toronto Hospital for Sick Children (T. Paton) for performing droplet digital polymerase-chain-reaction analyses; Zhiqi Chen from University Health Network for help with cell biology assays; and Melanie Peralta from the Pathology Research Program, University Health Network, Toronto, for technical help with immunohistochemical analyses. Source Information From the Department of Genetic Medicine and Development, University of Geneva Medical School (S.I.N., X.B., S.E.A.), Service of Genetic Medicine, University Hospitals of Geneva (S.I.N., S.E.A.), and iGE3, Institute of Genetics and Genomics of Geneva (S.E.A.) — all in Geneva; the Department of Fundamental Neurobiology, Krembil Research Institute (S.V., M.T., I.R.), Toronto General Hospital Research Institute (E.B., N.K., P.V.D., J.E.F.), the Department of Pathology (T.-R.K.), the Division of Neurosurgery, Department of Surgery (V.M.P., T.K., H.A.-B., T.T., T.V., G.Z., M.T., I.R.), and the Joint Division of Medical Imaging, Department of Medical Imaging (V.M.P., T.K.), Toronto Western Hospital, University Health Network, the Department of Laboratory Medicine and Pathobiology, University of Toronto (E.B., N.K., P.V.D., T.-R.K., J.E.F.), and the Heart and Stroke Richard Lewar Centre of Excellence in Cardiovascular Research (E.B., N.K., P.V.D., J.E.F.) — all in Toronto; the Department of Molecular Medicine, AIV Institute, University of Eastern Finland (S.J., B.R.J., S.S., S.Y.-H., J.F.), and the Hemorrhagic Brain Pathology Research Group, Department of Neurosurgery and NeuroCenter (S.J., B.R.J., S.S., T.R., J.F.), and the Department of Pathology (T.R.), Kuopio University Hospital — all in Kuopio, Finland; and the Cardiovascular Research Institute and the Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston (A.M.H., J.D.W.). Address reprint requests to Dr. Nikolaev at email@example.com, to Dr. Frösen at firstname.lastname@example.org, to Dr. Fish at email@example.com, or to Dr. Radovanovic at firstname.lastname@example.org.
Elimination of Cost Sharing for Screening Mammography in Medicare Advantage Plans N. Engl. J. Med. (IF 72.406) Pub Date : 2018-01-17 Amal N. Trivedi, Bryan Leyva, Yoojin Lee, Orestis A. Panagiotou, Issa J. Dahabreh
Rib Fracture Associated with Bordetella pertussis Infection N. Engl. J. Med. (IF 72.406) Pub Date : 2018-01-17 John A. Zambrano, Talia N. Herman
Case 2-2018 — A 41-Year-Old Woman with Vision Disturbances and Headache N. Engl. J. Med. (IF 72.406) Pub Date : 2018-01-17 Richard C. Cabot, Eric S. Rosenberg, Virginia M. Pierce, David M. Dudzinski, Meridale V. Baggett, Dennis C. Sgroi, Jo-Anne O. Shepard, Allison R. Bond, Emily K. McDonald, Sally H. Ebeling
Ovarian Cancer Treatment — Are We Getting Warmer? N. Engl. J. Med. (IF 72.406) Pub Date : 2018-01-17 David R. Spriggs, Oliver Zivanovic
Disclosure forms provided by the authors are available with the full text of this editorial at NEJM.org. Source Information From Memorial Sloan Kettering Cancer Center, New York.
Bivalirudin versus Heparin Monotherapy in Myocardial Infarction N. Engl. J. Med. (IF 72.406) Pub Date : 2018-01-17
To the Editor: In the VALIDATE-SWEDEHEART trial, Erlinge et al. (Sept. 21 issue)1 compared bivalirudin with heparin monotherapy in patients with acute myocardial infarction who were undergoing percutaneous coronary intervention (PCI). Treatment included the use of one of the new P2Y12 inhibitors (ticagrelor, cangrelor, or prasugrel), which was given at least 60 minutes before PCI. Patients who received or were planned to receive glycoprotein IIb/IIIa inhibitors were excluded from enrollment, and the low rates of ischemic events and stent thrombosis are probably attributable to the early administration of the new P2Y12 inhibitors. In the current era, in which immediate reperfusion . . .
Evaluation and Management of Lower-Extremity Ulcers N. Engl. J. Med. (IF 72.406) Pub Date : 2018-01-17
To the Editor: In their review article, Singer et al. (Oct. 19 issue)1 mention the use of linezolid alone for the coverage of gram-positive and gram-negative and anaerobe bacteria in patients with diabetes who have lower-extremity infected ulcers. Linezolid is a synthetic oxazolidinone that inhibits the formation of the initiation complex for protein synthesis.2 It has excellent skin and soft-tissue penetration,3 and in vitro studies suggest that linezolid may inhibit the bacterial toxin synthesis and modulate the host immune response.4 However, its antibacterial spectrum is mostly restricted . . .
Noninferiority Trials N. Engl. J. Med. (IF 72.406) Pub Date : 2018-01-17
To the Editor: Mauri and D’Agostino (Oct. 5 issue)1 address the challenges in noninferiority trials. Yet an ethical issue was not discussed — how to convince candidate participants2 that it is worth giving up part of the benefit provided by the current standard of care in exchange for advantages (e.g., convenience or fewer side effects) that are often of different clinical value than enhanced efficacy and are in any case not known at the outset of the trial.3 The authors illustrate their discussion using the case of noninferiority trials of new oral anticoagulants for the prevention of stroke and thromboembolism . . .
Crisis in the Sustainability of the U.S. Blood System N. Engl. J. Med. (IF 72.406) Pub Date : 2018-01-17
To the Editor: Unbundling blood products from diagnosis-related group–based comprehensive reimbursement for medical procedures, along with establishing Medicare reimbursement schedules for blood products on the basis of current costs rather than historical charges, would provide some relief from the financial crisis in the blood industry that Klein et al. (Oct. 12 issue)1 describe. However, inefficiencies of the blood market that the authors also describe would remain. These include the monopsonistic structure of the market, which limits blood suppliers’ pricing power and, consequently, their reserve capacity to respond to future biologic threats to products that are inherently vulnerable to them. The . . .
Enhanced preclinical antitumor activity of M7824, a bifunctional fusion protein simultaneously targeting PD-L1 and TGF-β Sci. Transl. Med. (IF 16.796) Pub Date : 2018-01-17 Yan Lan, Dong Zhang, Chunxiao Xu, Kenneth W. Hance, Bo Marelli, Jin Qi, Huakui Yu, Guozhong Qin, Aroop Sircar, Vivian M. Hernández, Molly H. Jenkins, Rachel E. Fontana, Amit Deshpande, George Locke, Helen Sabzevari, Laszlo Radvanyi, Kin-Ming Lo
Antibodies targeting immune checkpoints are emerging as potent and viable cancer therapies, but not all patients respond to these as single agents. Concurrently targeting additional immunosuppressive pathways is a promising approach to enhance immune checkpoint blockade, and bifunctional molecules designed to target two pathways simultaneously may provide a strategic advantage over the combination of two single agents. M7824 (MSB0011359C) is a bifunctional fusion protein composed of a monoclonal antibody against programmed death ligand 1 (PD-L1) fused to the extracellular domain of human transforming growth factor–β (TGF-β) receptor II, which functions as a “trap” for all three TGF-β isoforms. We demonstrate that M7824 efficiently, specifically, and simultaneously binds PD-L1 and TGF-β. In syngeneic mouse models, M7824 suppressed tumor growth and metastasis more effectively than treatment with either an anti–PD-L1 antibody or TGF-β trap alone; furthermore, M7824 extended survival and conferred long-term protective antitumor immunity. Mechanistically, the dual anti-immunosuppressive function of M7824 resulted in activation of both the innate and adaptive immune systems, which contributed to M7824’s antitumor activity. Finally, M7824 was an effective combination partner for radiotherapy or chemotherapy in mouse models. Collectively, our preclinical data demonstrate that simultaneous blockade of the PD-L1 and TGF-β pathways by M7824 elicits potent and superior antitumor activity relative to monotherapies.
Identifying DNA methylation biomarkers for non-endoscopic detection of Barrett’s esophagus Sci. Transl. Med. (IF 16.796) Pub Date : 2018-01-17 Helen R. Moinova, Thomas LaFramboise, James D. Lutterbaugh, Apoorva Krishna Chandar, John Dumot, Ashley Faulx, Wendy Brock, Omar De la Cruz Cabrera, Kishore Guda, Jill S. Barnholtz-Sloan, Prasad G. Iyer, Marcia I. Canto, Jean S. Wang, Nicholas J. Shaheen, Prashanti N. Thota, Joseph E. Willis, Amitabh Chak, Sanford D. Markowitz
We report a biomarker-based non-endoscopic method for detecting Barrett’s esophagus (BE) based on detecting methylated DNAs retrieved via a swallowable balloon-based esophageal sampling device. BE is the precursor of, and a major recognized risk factor for, developing esophageal adenocarcinoma. Endoscopy, the current standard for BE detection, is not cost-effective for population screening. We performed genome-wide screening to ascertain regions targeted for recurrent aberrant cytosine methylation in BE, identifying high-frequency methylation within the CCNA1 locus. We tested CCNA1 DNA methylation as a BE biomarker in cytology brushings of the distal esophagus from 173 individuals with or without BE. CCNA1 DNA methylation demonstrated an area under the curve of 0.95 for discriminating BE-related metaplasia and neoplasia cases versus normal individuals, performing identically to methylation of VIM DNA, an established BE biomarker. When combined, the resulting two biomarker panel was 95% sensitive and 91% specific. These results were replicated in an independent validation cohort of 149 individuals who were assayed using the same cutoff values for test positivity established in the training population. To progress toward non-endoscopic esophageal screening, we engineered a well-tolerated, swallowable, encapsulated balloon device able to selectively sample the distal esophagus within 5 min. In balloon samples from 86 individuals, tests of CCNA1 plus VIM DNA methylation detected BE metaplasia with 90.3% sensitivity and 91.7% specificity. Combining the balloon sampling device with molecular assays of CCNA1 plus VIM DNA methylation enables an efficient, well-tolerated, sensitive, and specific method of screening at-risk populations for BE.
Inhalation of peptide-loaded nanoparticles improves heart failure Sci. Transl. Med. (IF 16.796) Pub Date : 2018-01-17 Michele Miragoli, Paola Ceriotti, Michele Iafisco, Marco Vacchiano, Nicolò Salvarani, Alessio Alogna, Pierluigi Carullo, Gloria Belén Ramirez-Rodríguez, Tatiana Patrício, Lorenzo Degli Esposti, Francesca Rossi, Francesca Ravanetti, Silvana Pinelli, Rossella Alinovi, Marco Erreni, Stefano Rossi, Gianluigi Condorelli, Heiner Post, Anna Tampieri, Daniele Catalucci
Peptides are highly selective and efficacious for the treatment of cardiovascular and other diseases. However, it is currently not possible to administer peptides for cardiac-targeting therapy via a noninvasive procedure, thus representing scientific and technological challenges. We demonstrate that inhalation of small (<50 nm in diameter) biocompatible and biodegradable calcium phosphate nanoparticles (CaPs) allows for rapid translocation of CaPs from the pulmonary tree to the bloodstream and to the myocardium, where their cargo is quickly released. Treatment of a rodent model of diabetic cardiomyopathy by inhalation of CaPs loaded with a therapeutic mimetic peptide that we previously demonstrated to improve myocardial contraction resulted in restoration of cardiac function. Translation to a porcine large animal model provides evidence that inhalation of a peptide-loaded CaP formulation is an effective method of targeted administration to the heart. Together, these results demonstrate that inhalation of biocompatible tailored peptide nanocarriers represents a pioneering approach for the pharmacological treatment of heart failure.
Personalized printing for stroke prevention, hand in glove Sci. Transl. Med. (IF 16.796) Pub Date : 2018-01-17 Kevin R. King
3D-printed patient-specific left atrial appendage occluders overcome anatomic variability to personalize stroke prevention.
Methicillin-resistant Staphylococcus aureus causes sustained collecting lymphatic vessel dysfunction Sci. Transl. Med. (IF 16.796) Pub Date : 2018-01-17 Dennis Jones, Eelco F. J. Meijer, Cedric Blatter, Shan Liao, Ethel R. Pereira, Echoe M. Bouta, Keehoon Jung, Shan Min Chin, Peigen Huang, Lance L. Munn, Benjamin J. Vakoc, Michael Otto, Timothy P. Padera
Methicillin-resistant Staphylococcus aureus (MRSA) is a major cause of morbidity and mortality worldwide and is a frequent cause of skin and soft tissue infections (SSTIs). Lymphedema—fluid accumulation in tissue caused by impaired lymphatic vessel function—is a strong risk factor for SSTIs. SSTIs also frequently recur in patients and sometimes lead to acquired lymphedema. However, the mechanism of how SSTIs can be both the consequence and the cause of lymphatic vessel dysfunction is not known. Intravital imaging in mice revealed an acute reduction in both lymphatic vessel contractility and lymph flow after localized MRSA infection. Moreover, chronic lymphatic impairment is observed long after MRSA is cleared and inflammation is resolved. Associated with decreased collecting lymphatic vessel function was the loss and disorganization of lymphatic muscle cells (LMCs), which are critical for lymphatic contraction. In vitro, incubation with MRSA-conditioned supernatant led to LMC death. Proteomic analysis identified several accessory gene regulator (agr)–controlled MRSA exotoxins that contribute to LMC death. Infection with agr mutant MRSA resulted in sustained lymphatic function compared to animals infected with wild-type MRSA. Our findings suggest that agr is a promising target to preserve lymphatic vessel function and promote immunity during SSTIs.
Engineering precision biomaterials for personalized medicine Sci. Transl. Med. (IF 16.796) Pub Date : 2018-01-17 Brian A. Aguado, Joseph C. Grim, Adrianne M. Rosales, Jana J. Watson-Capps, Kristi S. Anseth
As the demand for precision medicine continues to rise, the “one-size-fits-all” approach to designing medical devices and therapies is becoming increasingly outdated. Biomaterials have considerable potential for transforming precision medicine, but individual patient complexity often necessitates integrating multiple functions into a single device to successfully tailor personalized therapies. Here, we introduce an engineering strategy based on unit operations to provide a unified vocabulary and contextual framework to aid the design of biomaterial-based devices and accelerate their translation.
Commentary: Let’s talk about sex BMJ (IF 20.7) Pub Date : 2018-01-17 Tamás Bereczky
Because HIV is often transmitted sexually, it is normal for healthcare workers to ask patients with HIV/AIDS about their sexual orientation and behaviour. Unfortunately, for many years healthcare professionals sought to notify and test previous and current sexual partners to try to understand the epidemiology. When compulsory, such “partner mapping” denies patients’ right to privacy, and in most parts of Europe it is now up to patients whether they inform their sexual partners about any infection discovered. Surprisingly, much of the discourse in the UK about doctors discussing patients’ sexual orientation is about the embarrassment felt—by doctors and patients alike—when talking about sexuality. But healthcare professionals need to be able to talk about all sorts of sensitive things, such as pee, poo, and phlegm. It should come as no surprise, even to more conservative doctors, that people have sex—and in all sorts of ways. The discussion shows that morality, as well as health arguments, continues to hold sway in this area. But sexual health is an integral part of general health. Non-heterosexual people are disproportionately affected by specific health problems, and admitting this is the start of constructive consultation about the reasons and solutions. Visibility and honesty can also eventually reduce stigma. HIV/AIDS activists have fought long and hard for evidence based sex education in schools. Belonging to a sexual minority can be risky—being gay is associated with a higher risk of mental health problems, drug and alcohol misuse, and discrimination—even in societies that do not criminalise homosexuality. Asking about sexual orientation could and should introduce a longer conversation about sexual health. Patients and patients’ organisations should fight to ensure that sexual health related data are kept safe, because all societies discriminate against people on the grounds of their sexuality. Provenance and peer review: Commissioned; not externally peer reviewed. Competing interests: I have read and understood the BMJ policy on declaration of interests and have no relevant interests to declare.
Should all patients be asked about their sexual orientation? BMJ (IF 20.7) Pub Date : 2018-01-17 Richard Ma, Michael Dixon
NHS England’s recent recommendation that professionals ask patients their sexual orientation at every opportunity is essential to improve services for non-heterosexual patients, says Richard Ma. But Michael Dixon thinks this erosion of medical autonomy is political correctness gone mad After decades of campaigning by lesbian, gay, bisexual, and trans (LGBT) charities such as Stonewall and the LGBT Foundation, sexual orientation became one of the nine protected characteristics written into the Equality Act 2010.1 It would seem a logical and welcome step for NHS England to include sexual orientation monitoring (SOM) in health and social care systems.2 In practice all professionals would ask patients how they define their sexuality during every encounter. Patients can, of course, refuse to answer. However, some doctors and patients have expressed concerns about this policy, citing reasons such as intrusion or invasion of privacy, fear of causing offence, doubts about relevance, data security, and that it is a tokenistic gesture that will not make a difference. While I understand these concerns, they result in inertia; and failure to act undermines hard fought rights of LGBT patients to better healthcare. We already fail the LGBT community by not recognising, or by making incorrect assumptions about, their needs. A Stonewall commissioned survey of nearly 7000 gay and bisexual men found that smoking, alcohol, and drug use were more prevalent in this group compared with men in general.3 More specific health needs include mental health: 6% of gay and bisexual men aged 16 to 24 have attempted to take their own life in the past year compared with less than 1% of men of the same age in general; 15% have reported self harm compared with 7% of other men. Some people think SOM is relevant in sexual health related consultations only. This is a narrow view. Ethnicity is more than colour of your skin. Gender is more than your chromosomes. Similarly, SOM isn’t just about sex. History, culture, lifestyles, as well as struggles against discrimination, are some commonalities that unite non-heterosexual identities. Even if SOM were just about sex, we are not even getting that right. Despite men who have sex with men being at higher risk, only a quarter and a third have been tested for sexually transmitted infections and HIV, respectively.3 A Stonewall commissioned survey of over 6000 lesbian and bisexual women reported that 15% of eligible women have not had a cervical smear compared with 7% of other women.4 Some think that treating everyone equally should be good enough. But equal treatment is not fair treatment. You would not offer vulnerable patients equal access to care like other patients—you make a special effort because of the special need. Neither can you say that you offer equitable care to LGBT patients without knowing who they are—unless you count them. We must reflect on why we think asking about sexual orientation is “intrusive” and “insensitive”; and why some patients refuse to disclose such information. This is surprising given that a large probability sample survey of over 15 000 adults in Britain (the third National Sexual Attitudes and Lifestyles Survey) reports that 11% of women and 8% of men have had same sex sexual experience; and we have more liberal attitudes to same sex relationships than 20 years ago.5 We must create an environment where people can disclose information on their sexual orientation safely. According to a survey of more than 3000 health and social care staff, only 9% received training on needs of LGBT people; but half said that their training covered only sexual health; 16% admitted they would feel uncomfortable asking patients about their sexuality and, in contrast, they felt more comfortable asking about other protected characteristics, such as disability.6 Perhaps the health service has outdated sexual attitudes and we need to catch up. I agree that we must make the public feel confident in how their data are used. We need to make our data secure and show that we are using them intelligently—from contextualising a person’s care and management, to service improvements. Sexual orientation monitoring is necessary to make the health service for LGBT patients fairer. If we don’t count our LGBT patients, they don’t count. Making doctors ask all their patients about their sexual orientation is political correctness gone mad. No one doubts that there can be great health benefits from knowing a patient’s sexuality, when offered voluntarily. There are also many occasions when, and patients for whom, it is quite appropriate for a doctor to ask. It is the “all patients” bit that is wrong. If I start asking my 17 or 70 year olds about their sexuality, the former will think that I am weird and the latter that I have gone bonkers after being their GP for 35 years. If I then apologise and say that I am only asking because of the Equality Act and because the Care Quality Commission will be checking on me, then they might rightly wonder whether I have their best interests in mind. Sexuality, for many people, is a private thing and not an appropriate descriptor of who they are. A patient asked about their sexual orientation has three options. To tell the truth, which is easy for many and especially, I expect, for those who support this idea. Alternatively, a patient may feel that he or she has to lie, which is bad for them, for the doctor-patient relationship, and for later consultations, when the question might be more appropriately asked and more truthfully answered. The third and quite understandable option is that the patient tells the doctor to take a running jump, in which case we are to record, in Kafkaesque terms, “The patient declined to answer.” This implies that he or she has either got something to hide or is a difficult patient. Apparently, this is all to stop discrimination under the Equality Act, but surely the best way to avoid discrimination is by not knowing people’s sexuality in the first place. Is there good evidence that people with different sexualities are treated differently, and, much more to the point, is there any good evidence that asking them will improve things? The powers that be, NHS England, say that it won’t affect patient treatment—prompting the question of why bother? This stupid idea symbolises the continuing erosion of medical autonomy beckoning an age when GPs become politically correct robots practising medicine by numbers. It is yet another example of overmanagement in general practice and will see yet another flood of clinicians escaping to the Antipodes or out of medicine altogether in order to elude Big Brother’s silly rules. The secretary of state for health recently warned that we are on the verge of losing the family doctor.7 Surely someone should be doing something about that rather than filling our time with more useless tasks? In good medical practice, the patient’s own needs, wishes, choices, beliefs, culture, and perspective should come first—not the rules or diktats of any higher body. Ultimately it should be up to the judgment of each GP as to when it is appropriate or useful to ask such questions. The NHS needs to assert itself as a kind, compassionate, and intelligent service rather than a nosey parker grinding us all into cynical submission. What about the patient? I asked my 97 year old mother what she would think if her GP asked her about her sexual orientation. “He wouldn’t,” she said confidently. “Yes, but suppose you were registering with a new doctor, and he or she asked about your sexuality?” “Well dear, I would find another doctor.” Competing interests: We have read and understood the BMJ policy on declaration of interests and have no relevant interests to declare. Provenance and peer review: Commissioned; not externally peer reviewed.
GMC should deal forcefully with repeatedly dishonest doctors BMJ (IF 20.7) Pub Date : 2018-01-17 Peter T Wilmshurst
I am very sorry that Jack Adcock died and for the distress that his death caused his family.1 I have read that Hadiza Bawa-Garba is a conscientious doctor who made mistakes in the care of Jack Adcock. Had she not made those mistakes he might have survived. There were also system problems …
Doctors do not feel protected when things go wrong BMJ (IF 20.7) Pub Date : 2018-01-17 Ellen S Wright
The appeal being brought by the General Medical Council to erase Hadiza Bawa-Garba from the register is inhumane, disproportionate, and will not protect the public against further incidents.1 It is more likely to discourage doctors, especially trainees, from disclosing and learning from errors. Trainers are already advising their trainees to record only the …
CCG criticises NHS England after being ordered to cut GP funding BMJ (IF 20.7) Pub Date : 2018-01-17 Gareth Iacobucci
The head of a financially stricken clinical commissioning group (CCG) has launched an outspoken attack on NHS England after the group was ordered to cut GP funding to balance its books. In a starkly written letter to local GPs sent on 12 January that was leaked to The BMJ, Paul Williams, chair of West Norfolk CCG, said that the group faced a “dire” financial situation, warning of “very unpleasant consequences” from decisions it was being forced to take. Williams said that the CCG had been ordered by NHS England to cut local enhanced services payments to general practices, which fund work outside the core GP contract such as minor injury consultations, wound care, and phlebotomy. He wrote that “it …
Boris Johnson is criticised for repeating claims that NHS will benefit from Brexit BMJ (IF 20.7) Pub Date : 2018-01-17 Gareth Iacobucci
Michael Marmot, a leading public health expert, has censured the UK foreign secretary and Brexit campaigner Boris Johnson for repeating a claim that the NHS would benefit from at least £350m (€395m; $483m) extra income a week once it leaves the European Union. Marmot said that the figure, which was infamously emblazoned on the Vote Leave campaign’s “battle bus” before the referendum, had twice been discredited by the UK Statistics Authority, and he accused Johnson of misleading the British people. The rebuke came after Johnson told …
Sixty seconds on . . . the Lansley diaries BMJ (IF 20.7) Pub Date : 2018-01-17 Anne Gulland
Andrew Lansley—the former health secretary who, in opposition, promised no more top-down reorganisations of the NHS but did just that in office with the introduction of the Health and Social Care Act in 2012. Unfortunately, they’re not those kinds of diaries—no Adrian Mole-style revelations of secret crushes or details of his calorie intake (vv good) in …
Some contents have been Reproduced by permission of The Royal Society of Chemistry.
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