Scientific dissent and public policy

The temptation to silence dissenters whose non-mainstream views negatively affect public policies is powerful. However, silencing dissent, no matter how scientifically unsound it might be, can cause the public to mistrust science in general.Dissent is crucial for the advancement of science. Disagreement is at the heart of peer review and is important for uncovering unjustified assumptions, flawed methodologies and problematic reasoning. Enabling and encouraging dissent also helps to generate alternative hypotheses, models and explanations. Yet, despite the importance of dissent in science, there is growing concern that dissenting voices have a negative effect on the public perception of science, on policy-making and public health. In some cases, dissenting views are deliberately used to derail certain policies. For example, dissenting positions on climate change, environmental toxins or the hazards of tobacco smoke [1,2] seem to laypeople as equally valid conflicting opinions and thereby create or increase uncertainty. Critics often use legitimate scientific disagreements about narrow claims to reinforce the impression of uncertainty about general and widely accepted truths; for instance, that a given substance is harmful [3,4]. This impression of uncertainty about the evidence is then used to question particular policies [1,2,5,6].The negative effects of dissent on establishing public polices are present in cases in which the disagreements are scientifically well-grounded, but the significance of the dissent is misunderstood or blown out of proportion. A study showing that many factors affect the size of reef islands, to the effect that they will not necessarily be reduced in size as sea levels rise [7], was simplistically interpreted by the media as evidence that climate change will not have a negative impact on reef islands [8].In other instances, dissenting voices affect the public perception of and motivation to follow public-health policies or recommendations. For example, the publication of a now debunked link between the measles, mumps and rubella vaccine and autism [9], as well as the claim that the mercury preservative thimerosal, which was used in childhood vaccines, was a possible risk factor for autism [10,11], created public doubts about the safety of vaccinating children. Although later studies showed no evidence for these claims, doubts led many parents to reject vaccinations for their children, risking the herd immunity for diseases that had been largely eradicated from the industrialized world [12,13,14,15]. Many scientists have therefore come to regard dissent as problematic if it has the potential to affect public behaviour and policy-making. However, we argue that such concerns about dissent as an obstacle to public policy are both dangerous and misguided.Whether dissent is based on genuine scientific evidence or is unfounded, interested parties can use it to sow doubt, thwart public policies, promote problematic alternatives and lead the public to ignore sound advice. In response, scientists have adopted several strategies to limit these negative effects of dissent—masking dissent, silencing dissent and discrediting dissenters. The first strategy aims to present a united front to the public. Scientists mask existing disagreements among themselves by presenting only those claims or pieces of evidence about which they agree [16]. Although there is nearly universal agreement among scientists that average global temperatures are increasing, there are also legitimate disagreements about how much warming will occur, how quickly it will occur and the impact it might have [7,17,18,19]. As presenting these disagreements to the public probably creates more doubt and uncertainty than is warranted, scientists react by presenting only general claims [20].A second strategy is to silence dissenting views that might have negative consequences. This can take the form of self-censorship when scientists are reluctant to publish or publicly discuss research that might—incorrectly—be used to question existing scientific knowledge. For example, there are genuine disagreements about how best to model cloud formation, water vapour feedback and aerosols in general circulation paradigms, all of which have significant effects on the magnitude of global climate change predictions [17,19]. Yet, some scientists are hesitant to make these disagreements public, for fear that they will be accused of being denialists, faulted for confusing the public and policy-makers, censured for abating climate-change deniers, or criticized for undermining public policy [21,22,23,24].…there is growing concern that dissenting voices can have a negative effect on the public perception of science, on policy-making and public healthAnother strategy is to discredit dissenters, especially in cases in which the dissent seems to be ideologically motivated. This could involve publicizing the financial or political ties of the dissenters [2,6,25], which would call attention to their probable bias. In other cases, scientists might discredit the expertise of the dissenter. One such example concerns a 2007 study published in the Proceedings of the National Academy of Sciences USA, which claimed that cadis fly larvae consuming Bt maize pollen die at twice the rate of flies feeding on non-Bt maize pollen [26]. Immediately after publication, both the authors and the study itself became the target of relentless and sometimes scathing attacks from a group of scientists who were concerned that anti-GMO (genetically modified organism) interest groups would seize on the study to advance their agenda [27]. The article was criticized for its methodology and its conclusions, the Proceedings of the National Academy of Sciences USA was criticized for publishing the article and the US National Science Foundation was criticized for funding the study in the first place.Public policies, health advice and regulatory decisions should be based on the best available evidence and knowledge. As the public often lack the expertise to assess the quality of dissenting views, disagreements have the potential to cast doubt over the reliability of scientific knowledge and lead the public to question relevant policies. Strategies to block dissent therefore seem reasonable as a means to protect much needed or effective health policies, advice and regulations. However, even if the public were unable to evaluate the science appropriately, targeting dissent is not the most appropriate strategy to prevent negative side effects for several reasons. Chiefly, it contributes to the problems that the critics of dissent seek to address, namely increasing the cacophony of dissenting voices that only aim to create doubt. Focusing on dissent as a problematic activity sends the message to policy-makers and the public that any dissent undermines scientific knowledge. Reinforcing this false assumption further incentivizes those who seek merely to create doubt to thwart particular policies. Not surprisingly, think-tanks, industry and other organizations are willing to manufacture dissent simply to derail policies that they find economically or ideologically undesirable.Another danger of targeting dissent is that it probably stifles legitimate crucial voices that are needed for both advancing science and informing sound policy decisions. Attacking dissent makes scientists reluctant to voice genuine doubts, especially if they believe that doing so might harm their reputations, damage their careers and undermine prevailing theories or policies needed. For instance, a panel of scientists for the US National Academy of Sciences, when presenting a risk assessment of radiation in 1956, omitted wildly different predictions about the potential genetic harm of radiation [16]. They did not include this wide range of predictions in their final report precisely because they thought the differences would undermine confidence in their recommendations. Yet, this information could have been relevant to policy-makers. As such, targeting dissent as an obstacle to public policy might simply reinforce self-censorship and stifle legitimate and scientifically informed debate. If this happens, scientific progress is hindered.Second, even if the public has mistaken beliefs about science or the state of the knowledge of the science in question, focusing on dissent is not an effective way to protect public policy from false claims. It fails to address the presumed cause of the problem—the apparent lack of understanding of the science by the public. A better alternative would be to promote the public''s scientific literacy. If the public were educated to better assess the quality of the dissent and thus disregard instances of ideological, unsupported or unsound dissent, dissenting voices would not have such a negative effect. Of course, one might argue that educating the public would be costly and difficult, and that therefore, the public should simply listen to scientists about which dissent to ignore and which to consider. This is, however, a paternalistic attitude that requires the public to remain ignorant ‘for their own good''; a position that seems unjustified on many levels as there are better alternatives for addressing the problem.Moreover, silencing dissent, rather than promoting scientific literacy, risks undermining public trust in science even if the dissent is invalid. This was exemplified by the 2009 case of hacked e-mails from a computer server at the University of East Anglia''s Climate Research Unit (CRU). After the selective leaking of the e-mails, climate scientists at the CRU came under fire because some of the quotes, which were taken out of context, seemed to suggest that they were fudging data or suppressing dissenting views [28,29,30,31]. The stolen e-mails gave further ammunition to those opposing policies to reduce greenhouse emissions as they could use accusations of data ‘cover up'' as proof that climate scientists were not being honest with the public [29,30,31]. It also allowed critics to present climate scientists as conspirators who were trying to push a political agenda [32]. As a result, although there was nothing scientifically inappropriate revealed in the ‘climategate'' e-mails, it had the consequence of undermining the public''s trust in climate science [33,34,35,36].A significant amount of evidence shows that the ‘deficit model'' of public understanding of science, as described above, is too simplistic to account correctly for the public''s reluctance to accept particular policy decisions [37,38,39,40]. It ignores other important factors such as people''s attitudes towards science and technology, their social, political and ethical values, their past experiences and the public''s trust in governmental institutions [41,42,43,44]. The development of sound public policy depends not only on good science, but also on value judgements. One can agree with the scientific evidence for the safety of GMOs, for instance, but still disagree with the widespread use of GMOs because of social justice concerns about the developing world''s dependence on the interests of the global market. Similarly, one need not reject the scientific evidence about the harmful health effects of sugar to reject regulations on sugary drinks. One could rationally challenge such regulations on the grounds that informed citizens ought to be able to make free decisions about what they consume. Whether or not these value judgements are justified is an open question, but the focus on dissent hinders our ability to have that debate.Focusing on dissent as a problematic activity sends the message to policy-makers and the public that any dissent undermines scientific knowledgeAs such, targeting dissent completely fails to address the real issues. The focus on dissent, and the threat that it seems to pose to public policy, misdiagnoses the problem as one of the public misunderstanding science, its quality and its authority. It assumes that scientific or technological knowledge is the only relevant factor in the development of policy and it ignores the role of other factors, such as value judgements about social benefits and harms, and institutional trust and reliability [45,46]. The emphasis on dissent, and thus on scientific knowledge, as the only or main factor in public policy decisions does not give due attention to these legitimate considerations.Furthermore, by misdiagnosing the problem, targeting dissent also impedes more effective solutions and prevents an informed debate about the values that should guide public policy. By framing policy debates solely as debates over scientific facts, the normative aspects of public policy are hidden and neglected. Relevant ethical, social and political values fail to be publicly acknowledged and openly discussed.Controversies over GMOs and climate policies have called attention to the negative effects of dissent in the scientific community. Based on the assumption that the public''s reluctance to support particular policies is the result of their inability to properly understand scientific evidence, scientists have tried to limit dissenting views that create doubt. However, as outlined above, targeting dissent as an obstacle to public policy probably does more harm than good. It fails to focus on the real problem at stake—that science is not the only relevant factor in sound policy-making. Of course, we do not deny that scientific evidence is important to the develop.ment of public policy and behavioural decisions. Rather, our claim is that this role is misunderstood and often oversimplified in ways that actually contribute to problems in developing sound science-based policies.? Open in a separate windowInmaculada de Melo-MartínOpen in a separate windowKristen Intemann     

Protection by natural IgG: a sweet partnership with soluble lectins does the trick!

EMBO J 32: 2905–2919 10.1038/emboj.2013.199; published online September032013Some B cells of the adaptive immune system secrete polyreactive immunoglobulin G (IgG) in the absence of immunization or infection. Owing to its limited affinity and specificity, this natural IgG is thought to play a modest protective role. In this issue, a report reveals that natural IgG binds to microbes following their opsonization by ficolin and mannan-binding lectin (MBL), two carbohydrate receptors of the innate immune system. The interaction of natural IgG with ficolins and MBL protects against pathogenic bacteria via a complement-independent mechanism that involves IgG receptor FcγRI expressing macrophages. Thus, natural IgG enhances immunity by adopting a defensive strategy that crossovers the conventional boundaries between innate and adaptive microbial recognition systems.The adaptive immune system generates protective somatically recombined antibodies through a T cell-dependent (TD) pathway that involves follicular B cells. After recognizing antigen through the B-cell receptor (BCR), follicular B cells establish a cognate interaction with CD4⁺ T follicular helper (T_FH) cells and thereafter either rapidly differentiate into short-lived IgM-secreting plasmablasts or enter the germinal centre (GC) of lymphoid follicles to complete class switch recombination (CSR) and somatic hypermutation (SHM) (Victora and Nussenzweig, 2012). CSR from IgM to IgG, IgA and IgE generates antibodies with novel effector functions, whereas SHM provides the structural correlate for the induction of affinity maturation (Victora and Nussenzweig, 2012). Eventually, this canonical TD pathway generates long-lived bone marrow plasma cells and circulating memory B cells that produce protective class-switched antibodies capable to recognize specific antigens with high affinity (Victora and Nussenzweig, 2012).In addition to post-immune monoreactive antibodies, B cells produce pre-immune polyreactive antibodies in the absence of conventional antigenic stimulation (Ehrenstein and Notley, 2010). These natural antibodies form a vast and stable repertoire that recognizes both non-protein and protein antigens with low affinity (Ehrenstein and Notley, 2010). Natural antibodies usually emerge from a T cell-independent (TI) pathway that involves innate-like B-1 and marginal zone (MZ) B cells. These are extrafollicular B-cell subsets that rapidly differentiate into short-lived antibody-secreting plasmablasts after detecting highly conserved microbial and autologus antigens through polyreactive BCRs and nonspecific germline-encoded pattern recognition receptors (Pone et al, 2012; Cerutti et al, 2013).The most studied natural antibody is IgM, a pentameric complement-activating molecule with high avidity but low affinity for antigen (Ehrenstein and Notley, 2010). In addition to promoting the initial clearance of intruding microbes, natural IgM regulates tissue homeostasis, immunological tolerance and tumour surveillance (Ochsenbein et al, 1999; Zhou et al, 2007; Ehrenstein and Notley, 2010). Besides secreting IgM, B-1 and MZ B cells produce IgG and IgA after receiving CSR-inducing signals from dendritic cells (DCs), macrophages and neutrophils of the innate immune system (Cohen and Norins, 1966; Cerutti et al, 2013). In humans, certain natural IgG and IgA are moderately mutated and show some specificity, which may reflect the ability of human MZ B cells to undergo SHM (Cerutti et al, 2013). Yet, natural IgG and IgA are generally perceived as functionally quiescent.In this issue, Panda et al show that natural IgG bound to a broad spectrum of bacteria with high affinity by cooperating with ficolin and MBL (Panda et al, 2013), two ancestral soluble lectins of the innate immune system (Holmskov et al, 2003). This binding involved some degree of specificity, because it required the presence of ficolin or MBL on the microbial surface as well as lower pH and decreased calcium concentration in the extracellular environment as a result of infection or inflammation (see Figure 1).Open in a separate windowFigure 1Ficolins and MBL are produced by hepatocytes and various cells of the innate immune system and opsonize bacteria after recognizing conserved carbohydrates. Low pH and calcium concentrations present under infection-inflammation conditions promote the interaction of ficolin or MBL with natural IgG on the surface of bacteria. The resulting immunocomplex is efficiently phagocytosed by macrophages through FcγR1 independently of the complement protein C3, leading to the clearance of bacteria.Ficolins and MBL are soluble pattern recognition receptors that opsonize microbes after binding to glycoconjugates through distinct carbohydrate recognition domain (CRD) structures (Holmskov et al, 2003). While ficolins use a fibrinogen domain, MBL and other members of the collectin family use a C-type lectin domain attached to a collagen-like region (Holmskov et al, 2003). Similar to pentraxins, ficolins and MBL are released by innate effector cells and hepatocytes, and thus may have served as ancestral antibody-like molecules prior to the inception of the adaptive immune system (Holmskov et al, 2003; Bottazzi et al, 2010). Of note, MBL and the MBL-like complement protein C1q are recruited by natural IgM to mediate complement-dependent clearance of autologous apoptotic cells and microbes (Holmskov et al, 2003; Ehrenstein and Notley, 2010). Panda et al found that a similar lectin-dependent co-optation strategy enhances the protective properties of natural IgG (Panda et al, 2013).By using bacteria and the bacterial glycan N-acetylglicosamine, Panda et al show that natural IgG isolated from human serum or T cell-deficient mice interacted with the fibrinogen domain of microbe-associated ficolins (Panda et al, 2013). The resulting immunocomplex was phagocytosed by macrophages via the IgG receptor FcγRI in a complement-independent manner (Panda et al, 2013). The additional involvement of MBL was demonstrated by experiments showing that natural IgG retained some bacteria-binding activity in the absence of ficolins (Panda et al, 2013).Surface plasmon resonance provided some clues regarding the molecular requirements of the ficolin–IgG interaction (Panda et al, 2013), but the conformational changes required by ficolin to interact with natural IgG remain to be addressed. In particular, it is unclear what segment of the effector Fc domain of natural IgG binds to ficolins and whether Fc-associated glycans are involved in this binding. Specific glycans have been recently shown to mitigate the inflammatory properties of IgG emerging from TI responses (Hess et al, 2013) and this process could implicate ficolins and MBL. Moreover, it would be important to elucidate whether and how the antigen-binding Fab portion of natural IgG regulates its interaction with ficolins and MBL.The in vivo protective role of natural IgG was elegantly demonstrated by showing that reconstitution of IgG-deficient mice lacking the CSR-enzyme activation-induced cytidine deaminase with natural IgG from T cell-insufficient animals enhanced resistance to pathogenic Pseudomonas aeruginosa (Panda et al, 2013). This protective effect was associated with reduced production of proinflammatory cytokines, occurred independently of the complement protein C3 and was impaired by peptides capable to inhibit the binding of natural IgG to ficolin (Panda et al, 2013). Additional in vivo studies will be needed to determine whether natural IgG exerts protective activity in mice lacking ficolin, MBL or FcγRI, and to ascertain whether these molecules also enhance the protective properties of canonical or natural IgG and IgA released by bone marrow plasma cells and mucosal plasma cells, respectively.In conclusion, the findings by Panda et al show that natural IgG adopts ‘crossover'' defensive strategies that blur the conventional boundaries between the innate and adaptive immune systems. The sophisticated integration of somatically recombined and germline-encoded antigen recognition systems described in this new study shall stimulate immunologists to further explore the often underestimated protective virtues of our vast natural antibody repertoire. This effort may lead to the development of novel therapies against infections.     

A qualitative investigation of smoke-free policies on hospital property

Background:

Many hospitals have adopted smoke-free policies on their property. We examined the consequences of such polices at two Canadian tertiary acute-care hospitals.

Methods:

We conducted a qualitative study using ethnographic techniques over a six-month period. Participants (n = 186) shared their perspectives on and experiences with tobacco dependence and managing the use of tobacco, as well as their impressions of the smoke-free policy. We interviewed inpatients individually from eight wards (n = 82), key policy-makers (n = 9) and support staff (n = 14) and held 16 focus groups with health care providers and ward staff (n = 81). We also reviewed ward documents relating to tobacco dependence and looked at smoking-related activities on hospital property.

Results:

Noncompliance with the policy and exposure to secondhand smoke were ongoing concerns. Peoples’ impressions of the use of tobacco varied, including divergent opinions as to whether such use was a bad habit or an addiction. Treatment for tobacco dependence and the management of symptoms of withdrawal were offered inconsistently. Participants voiced concerns over patient safety and leaving the ward to smoke.

Interpretation:

Policies mandating smoke-free hospital property have important consequences beyond noncompliance, including concerns over patient safety and disruptions to care. Without adequately available and accessible support for withdrawal from tobacco, patients will continue to face personal risk when they leave hospital property to smoke.Canadian cities and provinces have passed smoking bans with the goal of reducing people’s exposure to secondhand smoke in workplaces, public spaces and on the property adjacent to public buildings.^1,2 In response, Canadian health authorities and hospitals began implementing policies mandating smoke-free hospital property, with the goals of reducing the exposure of workers, patients and visitors to tobacco smoke while delivering a public health message about the dangers of smoking.^2–5 An additional anticipated outcome was the reduced use of tobacco among patients and staff. The impetuses for adopting smoke-free policies include public support for such legislation and the potential for litigation for exposure to second-hand smoke.^2,4Tobacco use is a modifiable risk factor associated with a variety of cancers, cardiovascular diseases and respiratory conditions.^6–11 Patients in hospital who use tobacco tend to have more surgical complications and exacerbations of acute and chronic health conditions than patients who do not use tobacco.^6–11 Any policy aimed at reducing exposure to tobacco in hospitals is well supported by evidence, as is the integration of interventions targetting tobacco dependence.¹² Unfortunately, most of the nearly five million Canadians who smoke will receive suboptimal treatment,¹³ as the routine provision of interventions for tobacco dependence in hospital settings is not a practice norm.^14–16 In smoke-free hospitals, two studies suggest minimal support is offered for withdrawal, ^17,18 and one reports an increased use of nicotine-replacement therapy after the implementation of the smoke-free policy.¹⁹Assessments of the effectiveness of smoke-free policies for hospital property tend to focus on noncompliance and related issues of enforcement.^17,20,21 Although evidence of noncompliance and litter on hospital property^2,17,20 implies ongoing exposure to tobacco smoke, half of the participating hospital sites in one study reported less exposure to tobacco smoke within hospital buildings and on the property.¹⁸ In addition, there is evidence to suggest some decline in smoking among staff.^18,19,21,22We sought to determine the consequences of policies mandating smoke-free hospital property in two Canadian acute-care hospitals by eliciting lived experiences of the people faced with enacting the policies: patients and health care providers. In addition, we elicited stories from hospital support staff and administrators regarding the policies.     

Gut microbiota of healthy Canadian infants: profiles by mode of delivery and infant diet at 4 months

Background:

The gut microbiota is essential to human health throughout life, yet the acquisition and development of this microbial community during infancy remains poorly understood. Meanwhile, there is increasing concern over rising rates of cesarean delivery and insufficient exclusive breastfeeding of infants in developed countries. In this article, we characterize the gut microbiota of healthy Canadian infants and describe the influence of cesarean delivery and formula feeding.

Methods:

We included a subset of 24 term infants from the Canadian Healthy Infant Longitudinal Development (CHILD) birth cohort. Mode of delivery was obtained from medical records, and mothers were asked to report on infant diet and medication use. Fecal samples were collected at 4 months of age, and we characterized the microbiota composition using high-throughput DNA sequencing.

Results:

We observed high variability in the profiles of fecal microbiota among the infants. The profiles were generally dominated by Actinobacteria (mainly the genus Bifidobacterium) and Firmicutes (with diverse representation from numerous genera). Compared with breastfed infants, formula-fed infants had increased richness of species, with overrepresentation of Clostridium difficile. Escherichia–Shigella and Bacteroides species were underrepresented in infants born by cesarean delivery. Infants born by elective cesarean delivery had particularly low bacterial richness and diversity.

Interpretation:

These findings advance our understanding of the gut microbiota in healthy infants. They also provide new evidence for the effects of delivery mode and infant diet as determinants of this essential microbial community in early life.The human body harbours trillions of microbes, known collectively as the “human microbiome.” By far the highest density of commensal bacteria is found in the digestive tract, where resident microbes outnumber host cells by at least 10 to 1. Gut bacteria play a fundamental role in human health by promoting intestinal homeostasis, stimulating development of the immune system, providing protection against pathogens, and contributing to the processing of nutrients and harvesting of energy.^1,2 The disruption of the gut microbiota has been linked to an increasing number of diseases, including inflammatory bowel disease, necrotizing enterocolitis, diabetes, obesity, cancer, allergies and asthma.¹ Despite this evidence and a growing appreciation for the integral role of the gut microbiota in lifelong health, relatively little is known about the acquisition and development of this complex microbial community during infancy.³Two of the best-studied determinants of the gut microbiota during infancy are mode of delivery and exposure to breast milk.^4,5 Cesarean delivery perturbs normal colonization of the infant gut by preventing exposure to maternal microbes, whereas breastfeeding promotes a “healthy” gut microbiota by providing selective metabolic substrates for beneficial bacteria.^3,5 Despite recommendations from the World Health Organization,⁶ the rate of cesarean delivery has continued to rise in developed countries and rates of breastfeeding decrease substantially within the first few months of life.^7,8 In Canada, more than 1 in 4 newborns are born by cesarean delivery, and less than 15% of infants are exclusively breastfed for the recommended duration of 6 months.^9,10 In some parts of the world, elective cesarean deliveries are performed by maternal request, often because of apprehension about pain during childbirth, and sometimes for patient–physician convenience.¹¹The potential long-term consequences of decisions regarding mode of delivery and infant diet are not to be underestimated. Infants born by cesarean delivery are at increased risk of asthma, obesity and type 1 diabetes,¹² whereas breastfeeding is variably protective against these and other disorders.¹³ These long-term health consequences may be partially attributable to disruption of the gut microbiota.^12,14Historically, the gut microbiota has been studied with the use of culture-based methodologies to examine individual organisms. However, up to 80% of intestinal microbes cannot be grown in culture.^3,15 New technology using culture-independent DNA sequencing enables comprehensive detection of intestinal microbes and permits simultaneous characterization of entire microbial communities. Multinational consortia have been established to characterize the “normal” adult microbiome using these exciting new methods;¹⁶ however, these methods have been underused in infant studies. Because early colonization may have long-lasting effects on health, infant studies are vital.^3,4 Among the few studies of infant gut microbiota using DNA sequencing, most were conducted in restricted populations, such as infants delivered vaginally,¹⁷ infants born by cesarean delivery who were formula-fed¹⁸ or preterm infants with necrotizing enterocolitis.¹⁹Thus, the gut microbiota is essential to human health, yet the acquisition and development of this microbial community during infancy remains poorly understood.³ In the current study, we address this gap in knowledge using new sequencing technology and detailed exposure assessments²⁰ of healthy Canadian infants selected from a national birth cohort to provide representative, comprehensive profiles of gut microbiota according to mode of delivery and infant diet.     

Effect of nasal balloon autoinflation in children with otitis media with effusion in primary care: an open randomized controlled trial

Background:Otitis media with effusion is a common problem that lacks an evidence-based nonsurgical treatment option. We assessed the clinical effectiveness of treatment with a nasal balloon device in a primary care setting.Methods:We conducted an open, pragmatic randomized controlled trial set in 43 family practices in the United Kingdom. Children aged 4–11 years with a recent history of ear symptoms and otitis media with effusion in 1 or both ears, confirmed by tympanometry, were allocated to receive either autoinflation 3 times daily for 1–3 months plus usual care or usual care alone. Clearance of middle-ear fluid at 1 and 3 months was assessed by experts masked to allocation.Results:Of 320 children enrolled, those receiving autoinflation were more likely than controls to have normal tympanograms at 1 month (47.3% [62/131] v. 35.6% [47/132]; adjusted relative risk [RR] 1.36, 95% confidence interval [CI] 0.99 to 1.88) and at 3 months (49.6% [62/125] v. 38.3% [46/120]; adjusted RR 1.37, 95% CI 1.03 to 1.83; number needed to treat = 9). Autoinflation produced greater improvements in ear-related quality of life (adjusted between-group difference in change from baseline in OMQ-14 [an ear-related measure of quality of life] score −0.42, 95% CI −0.63 to −0.22). Compliance was 89% at 1 month and 80% at 3 months. Adverse events were mild, infrequent and comparable between groups.Interpretation:Autoinflation in children aged 4–11 years with otitis media with effusion is feasible in primary care and effective both in clearing effusions and improving symptoms and ear-related child and parent quality of life. Trial registration: ISRCTN, No. 55208702.Otitis media with effusion, also known as glue ear, is an accumulation of fluid in the middle ear, without symptoms or signs of an acute ear infection. It is often associated with viral infection.^1–3 The prevalence rises to 46% in children aged 4–5 years,⁴ when hearing difficulty, other ear-related symptoms and broader developmental concerns often bring the condition to medical attention.^3,5,6 Middle-ear fluid is associated with conductive hearing losses of about 15–45 dB HL.⁷ Resolution is clinically unpredictable,^8–10 with about a third of cases showing recurrence.¹¹ In the United Kingdom, about 200 000 children with the condition are seen annually in primary care.^12,13 Research suggests some children seen in primary care are as badly affected as those seen in hospital.^7,9,14,15 In the United States, there were 2.2 million diagnosed episodes in 2004, costing an estimated $4.0 billion.¹⁶ Rates of ventilation tube surgery show variability between countries,^17–19 with a declining trend in the UK.²⁰Initial clinical management consists of reasonable temporizing or delay before considering surgery.¹³ Unfortunately, all available medical treatments for otitis media with effusion such as antibiotics, antihistamines, decongestants and intranasal steroids are ineffective and have unwanted effects, and therefore cannot be recommended.^21–23 Not only are antibiotics ineffective, but resistance to them poses a major threat to public health.^24,25 Although surgery is effective for a carefully selected minority,^13,26,27 a simple low-cost, nonsurgical treatment option could benefit a much larger group of symptomatic children, with the purpose of addressing legitimate clinical concerns without incurring excessive delays.Autoinflation using a nasal balloon device is a low-cost intervention with the potential to be used more widely in primary care, but current evidence of its effectiveness is limited to several small hospital-based trials²⁸ that found a higher rate of tympanometric resolution of ear fluid at 1 month.^29–31 Evidence of feasibility and effectiveness of autoinflation to inform wider clinical use is lacking.^13,28 Thus we report here the findings of a large pragmatic trial of the clinical effectiveness of nasal balloon autoinflation in a spectrum of children with clinically confirmed otitis media with effusion identified from primary care.     

Suicidality among sexual minority and transgender adolescents: a nationally representative population-based study of youth in Canada

Background:Very little research has described risk of suicidal ideation and suicide attempt among transgender youth using high-quality, nationally representative data. We aimed to assess risk of suicidality among transgender and sexual minority adolescents in Canada.Methods:We analyzed a subsample of adolescents aged 15–17 years from the 2019 Canadian Health Survey on Children and Youth, a nationally representative, cross-sectional survey. We defined participants’ transgender identity (self-reported gender different from sex assigned at birth) and sexual minority status (self-reported attraction to people of the same gender) as exposures, and their self-reported previous-year suicidal ideation and lifetime suicide attempt as outcomes.Results:We included 6800 adolescents aged 15–17 years, including 1130 (16.5%) who indicated some degree of same-gender attraction, 265 (4.3%) who were unsure of their attraction and 50 (0.6%) who reported a transgender identity. Compared with cisgender, heterosexual adolescents, transgender adolescents showed 5 times the risk of suicidal ideation (95% confidence interval [CI] 3.63 to 6.75; 58% v. 10%) and 7.6 times the risk of suicide attempt (95% CI 4.76 to 12.10; 40% v. 5%). Among cisgender adolescents, girls attracted to girls had 3.6 times the risk of previous-year suicidal ideation (95% CI 2.59 to 5.08) and 3.3 times the risk of having ever attempted suicide (95% CI 1.81 to 6.06), compared with their heterosexual peers. Adolescents attracted to multiple genders had 2.5 times the risk of suicidal ideation (95% CI 2.12 to 2.98) and 2.8 times the risk of suicide attempt (95% CI 2.18 to 3.68). Youth questioning their sexual orientation had twice the risk of having attempted suicide in their lifetime (95% CI 1.23 to 3.36).Interpretation:We observed that transgender and sexual minority adolescents were at increased risk of suicidal ideation and attempt compared with their cisgender and heterosexual peers. These findings highlight the need for inclusive prevention approaches to address suicidality among Canada’s diverse youth population.

Suicide is the second leading cause of death among adolescents and young adults aged 15–24 years in Canada.^1,2 Suicidal ideation and suicide attempt are common among adolescents³ and are risk factors for death by suicide.⁴ Sexual minority youth (i.e., youth who are attracted to the same gender or multiple genders, or who identify as lesbian, gay, bisexual or queer)⁵ are known to be at increased risk of poor mental health,^6–8 including suicidal ideation and attempt.^5–10 Over the previous 2 decades, stigma around identifying as a sexual minority has reduced;⁷ however, the risk of poor mental health and of suicidality remains high among sexual minority youth.^7,11 This population is still more likely to experience bullying and peer victimization,^9,12,13 which is associated with suicidality among sexual minority adolescents.⁵Transgender youth are those whose gender identity does not match their sex assigned at birth.¹⁴ Among other terms, gender-nonconforming, nonbinary, genderqueer and genderfluid are used to describe the gender identity of a subset of young people who identify outside the gender binary (i.e., as neither male nor female) or who experience fluidity between genders.⁹ Suicidality among transgender and gender-nonconforming adolescents is not as well studied. In a Canadian survey of transgender and gender-nonconforming youth aged 14–25 years, 64% of participants reported that they had seriously considered suicide in the previous 12 months.¹⁵ Transgender and gender-nonconforming youth seem to have a higher probability of many risk factors for suicidality, including peer victimization,^8,16 family dysfunction^7,17 and barriers to accessing mental health care.¹⁸ However, the epidemiology of suicidality among transgender and gender-nonconforming youth remains understudied in population-based samples; most research on the mental health of transgender youth comes from small community samples of help-seeking youth or targeted surveys of transgender adolescents.^5,19,20 Two population-based studies from California²¹ and New Zealand²² suggested that transgender youth are at increased risk of suicidal ideation and suicide attempt. However, only the New Zealand study²² used the gold-standard measure of gender identity, contrasting adolescents’ sex assigned at birth with their self-identified gender.²³Further epidemiological research employing large, representative samples and adequate measures of gender identity is needed to understand the burden of suicidality among lesbian, gay, bisexual, transgender and queer youth. We sought to build on existing evidence to assess risk of suicidal ideation and attempt among transgender and sexual minority adolescents in Canada, as compared with their cisgender and heterosexual peers, as well as to explore the relation between suicidality and experience of bullying.     

Erythropoietin Receptor (EpoR) Agonism Is Used to Treat a Wide Range of Disease

The erythropoietin receptor (EpoR) was discovered and described in red blood cells (RBCs), stimulating its proliferation and survival. The target in humans for EpoR agonists drugs appears clear—to treat anemia. However, there is evidence of the pleitropic actions of erythropoietin (Epo). For that reason, rhEpo therapy was suggested as a reliable approach for treating a broad range of pathologies, including heart and cardiovascular diseases, neurodegenerative disorders (Parkinson’s and Alzheimer’s disease), spinal cord injury, stroke, diabetic retinopathy and rare diseases (Friedreich ataxia). Unfortunately, the side effects of rhEpo are also evident. A new generation of nonhematopoietic EpoR agonists drugs (asialoEpo, Cepo and ARA 290) have been investigated and further developed. These EpoR agonists, without the erythropoietic activity of Epo, while preserving its tissue-protective properties, will provide better outcomes in ongoing clinical trials. Nonhematopoietic EpoR agonists represent safer and more effective surrogates for the treatment of several diseases such as brain and peripheral nerve injury, diabetic complications, renal ischemia, rare diseases, myocardial infarction, chronic heart disease and others.In principle, the erythropoietin receptor (EpoR) was discovered and described in red blood cell (RBC) progenitors, stimulating its proliferation and survival. Erythropoietin (Epo) is mainly synthesized in fetal liver and adult kidneys (1–3). Therefore, it was hypothesized that Epo act exclusively on erythroid progenitor cells. Accordingly, the target in humans for EpoR agonists drugs (such as recombinant erythropoietin [rhEpo], in general, called erythropoiesis-simulating agents) appears clear (that is, to treat anemia). However, evidence of a kaleidoscope of pleitropic actions of Epo has been provided (4,5). The Epo/EpoR axis research involved an initial journey from laboratory basic research to clinical therapeutics. However, as a consequence of clinical observations, basic research on Epo/EpoR comes back to expand its clinical therapeutic applicability.Although kidney and liver have long been considered the major sources of synthesis, Epo mRNA expression has also been detected in the brain (neurons and glial cells), lung, heart, bone marrow, spleen, hair follicles, reproductive tract and osteoblasts (6–17). Accordingly, EpoR was detected in other cells, such as neurons, astrocytes, microglia, immune cells, cancer cell lines, endothelial cells, bone marrow stromal cells and cells of heart, reproductive system, gastrointestinal tract, kidney, pancreas and skeletal muscle (18–27). Conversely, Sinclair et al.(28) reported data questioning the presence or function of EpoR on nonhematopoietic cells (endothelial, neuronal and cardiac cells), suggesting that further studies are needed to confirm the diversity of EpoR. Elliott et al.(29) also showed that EpoR is virtually undetectable in human renal cells and other tissues with no detectable EpoR on cell surfaces. These results have raised doubts about the preclinical basis for studies exploring pleiotropic actions of rhEpo (30).For the above-mentioned data, a return to basic research studies has become necessary, and many studies in animal models have been initiated or have already been performed. The effect of rhEpo administration on angiogenesis, myogenesis, shift in muscle fiber types and oxidative enzyme activities in skeletal muscle (4,31), cardiac muscle mitochondrial biogenesis (32), cognitive effects (31), antiapoptotic and antiinflammatory actions (33–37) and plasma glucose concentrations (38) has been extensively studied. Neuro- and cardioprotection properties have been mainly described. Accordingly, rhEpo therapy was suggested as a reliable approach for treating a broad range of pathologies, including heart and cardiovascular diseases, neurodegenerative disorders (Parkinson’s and Alzheimer’s disease), spinal cord injury, stroke, diabetic retinopathy and rare diseases (Friedreich ataxia).Unfortunately, the side effects of rhEpo are also evident. Epo is involved in regulating tumor angiogenesis (39) and probably in the survival and growth of tumor cells (25,40,41). rhEpo administration also induces serious side effects such as hypertension, polycythemia, myocardial infarction, stroke and seizures, platelet activation and increased thromboembolic risk, and immunogenicity (42–46), with the most common being hypertension (47,48). A new generation of nonhematopoietic EpoR agonists drugs have hence been investigated and further developed in animals models. These compounds, namely asialoerythropoietin (asialoEpo) and carbamylated Epo (Cepo), were developed for preserving tissue-protective properties but reducing the erythropoietic activity of native Epo (49,50). These drugs will provide better outcome in ongoing clinical trials. The advantage of using nonhematopoietic Epo analogs is to avoid the stimulation of hematopoiesis and thereby the prevention of an increased hematocrit with a subsequent procoagulant status or increased blood pressure. In this regard, a new study by van Rijt et al. has shed new light on this topic (51). A new nonhematopoietic EpoR agonist analog named ARA 290 has been developed, promising cytoprotective capacities to prevent renal ischemia/reperfusion injury (51). ARA 290 is a short peptide that has shown no safety concerns in preclinical and human studies. In addition, ARA 290 has proven efficacious in cardiac disorders (52,53), neuropathic pain (54) and sarcoidosis-induced chronic neuropathic pain (55). Thus, ARA 290 is a novel nonhematopoietic EpoR agonist with promising therapeutic options in treating a wide range of pathologies and without increased risks of cardiovascular events.Overall, this new generation of EpoR agonists without the erythropoietic activity of Epo while preserving tissue-protective properties of Epo will provide better outcomes in ongoing clinical trials (49,50). Nonhematopoietic EpoR agonists represent safer and more effective surrogates for the treatment of several diseases, such as brain and peripheral nerve injury, diabetic complications, renal ischemia, rare diseases, myocardial infarction, chronic heart disease and others.     

Direct Mg2+ Binding Activates Adenylate Kinase from Escherichia coli

We report evidence that adenylate kinase (AK) from Escherichia coli can be activated by the direct binding of a magnesium ion to the enzyme, in addition to ATP-complexed Mg²⁺. By systematically varying the concentrations of AMP, ATP, and magnesium in kinetic experiments, we found that the apparent substrate inhibition of AK, formerly attributed to AMP, was suppressed at low magnesium concentrations and enhanced at high magnesium concentrations. This previously unreported magnesium dependence can be accounted for by a modified random bi-bi model in which Mg²⁺ can bind to AK directly prior to AMP binding. A new kinetic model is proposed to replace the conventional random bi-bi mechanism with substrate inhibition and is able to describe the kinetic data over a physiologically relevant range of magnesium concentrations. According to this model, the magnesium-activated AK exhibits a 23- ± 3-fold increase in its forward reaction rate compared with the unactivated form. The findings imply that Mg²⁺ could be an important affecter in the energy signaling network in cells.Adenylate kinase (AK)² is a ∼24-kDa enzyme involved in cellular metabolism that catalyzes the reversible phosphoryl transfer reaction (1) as in Reaction 1. Mg2+⋅ATP+AMP⇌reverseforwardMg2+⋅ADP+ADPREACTION 1It is recognized to play an important role in cellular energetic signaling networks (2, 3). A deficiency in human AK function may lead to such illness as hemolytic anemia (4–8) and coronary artery disease (9); the latter is thought to be caused by a disruption of the AMP signaling network of AK (10). The ubiquity of AK makes it an ideal candidate for investigating evolutionary divergence and natural adaptation at a molecular level (11, 12). Indeed, extensive structure-function studies have been carried out for AK (reviewed in Ref. 13). Both structural and biophysical studies have suggested that large-amplitude conformational changes in AK are important for catalysis (14–19). More recently, the functional roles of conformational dynamics have been investigated using NMR (20–22), computer simulations (23–27), and single-molecule spectroscopy (28). Given the critical role of AK in regulating cellular energy networks and its use as a model system for understanding the functional roles of conformational changes in enzymes, it is imperative that the enzymatic mechanism of AK be thoroughly characterized and understood.The enzymatic reaction of adenylate kinase has been shown to follow a random bi-bi mechanism using isotope exchange experiments (29). Isoforms of adenylate kinases characterized from a wide range of species have a high degree of sequence, structure, and functional conservation. Although all AKs appear to follow the same random bi-bi mechanistic framework (15, 29–33), a detailed kinetic analysis reveals interesting variations among different isoforms. For example, one of the most puzzling discrepancies is the change in turnover rates with increasing AMP concentration between rabbit muscle AK and Escherichia coli AK. Although the reactivity of rabbit muscle AK is slightly inhibited at higher AMP concentrations (29, 32), E. coli AK exhibits its maximum turnover rate around 0.2 mm AMP followed by a steep drop, which plateaus at still higher AMP concentrations (33–35). This observation has been traditionally attributed to greater substrate inhibition by AMP in E. coli AK compared with the rabbit isoform; yet, the issue of whether the reaction involves competitive or non-competitive inhibition by AMP at the ATP binding site remains unresolved (15, 33, 35–37).Here, we report a comprehensive kinetic study of the forward reaction of AK, exploring concentrations of nucleotides and Mg²⁺ that are comparable to those inside E. coli cells, [Mg²⁺] ∼ 1–2 mm (38) and [ATP] up to 3 mm (39). We discovered a previously unreported phenomenon: an increase in the forward reaction rate of AK with increasing Mg²⁺ concentrations, where the stoichiometry of Mg²⁺ to the enzyme is greater than one. The new observation leads us to propose an Mg²⁺-activation mechanism augmenting the commonly accepted random bi-bi model for E. coli AK. Our model can fully explain AK’s observed kinetic behavior involving AMP, ATP, and Mg²⁺ as substrates, out-performing the previous model requiring AMP inhibition. The new Mg²⁺-activation model also explains the discrepancies in AMP inhibition behavior and currently available E. coli AK kinetic data. Given the central role of AK in energy regulation and our new experimental evidence, it is possible that Mg²⁺ and its regulation may participate in respiratory network through AK (40–42), an exciting future research direction.     

Stimulating cROSstalk between commensal bacteria and intestinal stem cells

EMBO J (2013) 32 23, 3017–3028 10.1038/emboj.2013.224; published online October182013Commensal gut bacteria benefit their host in many ways, for instance by aiding digestion and producing vitamins. In a new study in The EMBO Journal, Jones et al (2013) report that commensal bacteria can also promote intestinal epithelial renewal in both flies and mice. Interestingly, among commensals this effect is most specific to Lactobacilli, the friendly bacteria we use to produce cheese and yogurt. Lactobacilli stimulate NADPH oxidase (dNox/Nox1)-dependent ROS production by intestinal enterocytes and thereby activate intestinal stem cells.The human gut contains huge numbers of bacteria (∼10¹⁴/person) that play beneficial roles for our health, including digestion, building our immune system and competing with harmful microbes (Sommer and Backhed, 2013). Both commensal and pathogenic bacteria can elicit antimicrobial responses in the intestinal epithelium and also stimulate epithelial turnover (Buchon et al, 2013; Sommer and Backhed, 2013). In contrast to gut pathogens, relatively little is known about how commensal bacteria influence intestinal turnover. In a simple yet elegant study reported recently in The EMBO Journal, Jones et al (2013) show that among several different commensal bacteria tested, only Lactobacilli promoted much intestinal stem cell (ISC) proliferation, and it did so by stimulating reactive oxygen species (ROS) production. Interestingly, the specific effect of Lactobacilli was similar in both Drosophila and mice. In addition to distinguishing functional differences between species of commensals, this work suggests how the ingestion of Lactobacillus-containing probiotic supplements or food (e.g., yogurt) might support epithelial turnover and health.In both mammals and insects, ISCs give rise to intestinal enterocytes, which not only absorb nutrients from the diet but must also interact with the gut microbiota (Jiang and Edgar, 2012). The metazoan intestinal epithelium has developed conserved responses to enteric bacteria, for instance the expression of antimicrobial peptides (AMPs; Gallo and Hooper, 2012; Buchon et al, 2013), presumably to kill harmful bacteria while allowing symbiotic commensals to flourish. In addition to AMPs, intestinal epithelial cells use NADPH family oxidases to generate ROS that are used as microbicides (Lambeth and Neish, 2013). High ROS levels during enteric infections likely act non-discriminately against both commensals and pathogens, but controlled, low-level ROS can act as signalling molecules that regulate various cellular processes including proliferation (Lambeth and Neish, 2013). In flies, exposure to pathogenic Gram-negative bacteria has been reported to result in ROS (H₂O₂) production by an enzyme called dual oxidase (Duox; Ha et al, 2005). Duox activity in the fly intestine (and likely also the mammalian one) has recently been discovered to be stimulated by uracil secretion by pathogenic bacteria (Lee et al, 2013). In the mammalian intestine another enzyme, NADPH oxidase (Nox), has also been shown to produce ROS in the form of superoxide (O₂⁻), in this case in response to formylated bacterial peptides (Lambeth and Neish, 2013). A conserved role for Nox in the Drosophila intestinal epithelium had not until now been explored.Jones et al (2013) checked seven different commensal bacterial to see which would stimulate ROS production by the fly''s intestinal epithelium, and found that only one species, a Gram-positive Lactobacillus, could stimulate significant production of ROS in intestinal enterocytes. Five bacterial species were checked in mice or cultured intestinal cells, and again it was a Lactobacillus that generated the strongest ROS response. Although not all of the most prevalent enteric bacteria were assayed, those others that were—such as E. coli—induced only mild, barely detectable levels of ROS in enterocytes. Surprisingly, although bacteria pathogenic to Drosophila, like Erwinia caratovora, were expected to stimulate ROS production via Duox, Jones et al (2013) did not observe this using the ROS detecting dye hydrocyanine-Cy3, or a ROS-sensitive transgene reporter, Glutatione S-transferase-GFP, in flies. Further, Jones et al (2013) found that genetically suppressing Nox in either Drosophila or mice decreased ROS production after Lactobacillus ingestion. Consistent with the important role of Nox, Duox appeared not to be required for ROS production after Lactobacillus ingestion. In addition, Jones et al (2013) found that Lactobacilli also promoted DNA replication—a metric of cell proliferation and epithelial renewal—in the fly''s intestine, and that this was also ROS- and Nox-dependent. Again, the same relationship was found in the mouse small intestine. Together, these results suggest a conserved mechanism by which Lactobacilli can stimulate Nox-dependent ROS production in intestinal enterocytes and thereby promote ISC proliferation and enhance gut epithelial renewal.In the fly midgut, uracil produced by pathogenic bacteria can stimulate Duox-dependent ROS production, which is thought to act as a microbicide (Lee et al, 2013), and can also promote ISC proliferation (Buchon et al, 2009). However, Duox-produced ROS may also damage the intestinal epithelium itself and thereby promote epithelial regeneration indirectly through stress responses. In this disease scenario, ROS appears to be sensed by the stress-activated Jun N-terminal Kinase (JNK; Figure 1A), which can induce pro-proliferative cytokines of the Leptin/IL-6 family (Unpaireds, Upd1–3) (Buchon et al, 2009; Jiang et al, 2009). These cytokines activate JAK/STAT signalling in the ISCs, promoting their growth and proliferation, and accelerating regenerative repair of the gut epithelium (Buchon et al, 2009; Jiang et al, 2009). It is also possible, however, that low-level ROS, or specific types of ROS (e.g., H₂O₂) might induce ISC proliferation directly by acting as a signal between enterocytes and ISCs. Since commensal Lactobacillus stimulates ROS production via Nox rather than Duox, this might be a case in which a non-damaging ROS signal promotes intestinal epithelial renewal without stress signalling or a microbicidal effect (Figure 1B). However, Jones et al (2013) stopped short of ruling out a role for oxidative damage, cell death or stress signalling in the intestinal epithelium following colonization by Lactobacilli, and so these parameters must be checked in future studies. Perhaps even the friendliest symbiotes cause a bit of ‘healthy'' damage to the gut lining, stimulating it to refresh and renew. Whether damage-dependent or not, the stimulation of Drosophila ISC proliferation by commensals and pathogens alike appears to involve the same cytokine (Upd3; Buchon et al, 2009), and so some of the differences between truly pathogenic and ‘friendly'' gut microbes might be ascribed more to matters of degree than qualitative distinctions. Future studies exploring exactly how different types of ROS signals stimulate JNK activity, gut cytokine expression and epithelial renewal should be able to sort this out, and perhaps help us learn how to better manage the ecosystems in our own bellies. From the lovely examples reported by Jones et al (2013), an experimental back-and-forth between the Drosophila and mouse intestine seems an informative way to go.Open in a separate windowFigure 1Metazoan intestinal epithelial responses to commensal and pathogenic bacteria. (A) High reactive oxygen species (ROS) levels generated by dual oxidase (Duox) in response to uracil secretion by pathogenic bacteria. (B) Low ROS levels generated by NADPH oxidase (Nox) in response to commensal bacteria. In addition to acting as a microbiocide, ROS in flies may stimulate JNK signaling and cytokine (Upd 1–3) expression in enterocytes, thereby stimulating ISC proliferation and epithelial turnover or regeneration. Whether this stimulation required damage to or loss of enterocytes has yet to be explored.     

Oral administration of morphine versus ibuprofen to manage postfracture pain in children: a randomized trial

Background:

Recent warnings from Health Canada regarding codeine for children have led to increased use of nonsteroidal anti-inflammatory drugs and morphine for common injuries such as fractures. Our objective was to determine whether morphine administered orally has superior efficacy to ibuprofen in fracture-related pain.

Methods:

We used a parallel group, randomized, blinded superiority design. Children who presented to the emergency department with an uncomplicated extremity fracture were randomly assigned to receive either morphine (0.5 mg/kg orally) or ibuprofen (10 mg/kg) for 24 hours after discharge. Our primary outcome was the change in pain score using the Faces Pain Scale — Revised (FPS-R). Participants were asked to record pain scores immediately before and 30 minutes after receiving each dose.

Results:

We analyzed data from 66 participants in the morphine group and 68 participants in the ibuprofen group. For both morphine and ibuprofen, we found a reduction in pain scores (mean pre–post difference ± standard deviation for dose 1: morphine 1.5 ± 1.2, ibuprofen 1.3 ± 1.0, between-group difference [δ] 0.2 [95% confidence interval (CI) −0.2 to 0.6]; dose 2: morphine 1.3 ± 1.3, ibuprofen 1.3 ± 0.9, δ 0 [95% CI −0.4 to 0.4]; dose 3: morphine 1.3 ± 1.4, ibuprofen 1.4 ± 1.1, δ −0.1 [95% CI −0.7 to 0.4]; and dose 4: morphine 1.5 ± 1.4, ibuprofen 1.1 ± 1.2, δ 0.4 [95% CI −0.2 to 1.1]). We found no significant differences in the change in pain scores between morphine and ibuprofen between groups at any of the 4 time points (p = 0.6). Participants in the morphine group had significantly more adverse effects than those in the ibuprofen group (56.1% v. 30.9%, p < 0.01).

Interpretation:

We found no significant difference in analgesic efficacy between orally administered morphine and ibuprofen. However, morphine was associated with a significantly greater number of adverse effects. Our results suggest that ibuprofen remains safe and effective for outpatient pain management in children with uncomplicated fractures. Trial registration: ClinicalTrials.gov, no. {"type":"clinical-trial","attrs":{"text":"NCT01690780","term_id":"NCT01690780"}}NCT01690780.There is ample evidence that analgesia is underused,¹ underprescribed,² delayed in its administration² and suboptimally dosed ³ in clinical settings. Children are particularly susceptible to suboptimal pain management⁴ and are less likely to receive opioid analgesia.⁵ Untreated pain in childhood has been reported to lead to short-term problems such as slower healing⁶ and to long-term issues such as anxiety, needle phobia,⁷ hyperesthesia⁸ and fear of medical care.⁹ The American Academy of Pediatrics has reaffirmed its advocacy for the appropriate use of analgesia for children with acute pain.¹⁰Fractures constitute between 10% and 25% of all injuries.¹¹ The most severe pain after an injury occurs within the first 48 hours, with more than 80% of children showing compromise in at least 1 functional area.¹² Low rates of analgesia have been reported after discharge from hospital.¹³ A recently improved understanding of the pharmacogenomics of codeine has raised significant concerns about its safety,^14,15 and has led to a Food and Drug Administration boxed warning¹⁶ and a Health Canada advisory¹⁷ against its use. Although ibuprofen has been cited as the most common agent used by caregivers to treat musculoskeletal pain,^12,13 there are concerns that its use as monotherapy may lead to inadequate pain management.^6,18 Evidence suggests that orally administered morphine¹³ and other opioids are increasingly being prescribed.¹⁹ However, evidence for the oral administration of morphine in acute pain management is limited.^20,21 Thus, additional studies are needed to address this gap in knowledge and provide a scientific basis for outpatient analgesic choices in children. Our objective was to assess if orally administered morphine is superior to ibuprofen in relieving pain in children with nonoperative fractures.     

Mediterranean diets and metabolic syndrome status in the PREDIMED randomized trial

Background:

Little evidence exists on the effect of an energy-unrestricted healthy diet on metabolic syndrome. We evaluated the long-term effect of Mediterranean diets ad libitum on the incidence or reversion of metabolic syndrome.

Methods:

We performed a secondary analysis of the PREDIMED trial — a multicentre, randomized trial done between October 2003 and December 2010 that involved men and women (age 55–80 yr) at high risk for cardiovascular disease. Participants were randomly assigned to 1 of 3 dietary interventions: a Mediterranean diet supplemented with extra-virgin olive oil, a Mediterranean diet supplemented with nuts or advice on following a low-fat diet (the control group). The interventions did not include increased physical activity or weight loss as a goal. We analyzed available data from 5801 participants. We determined the effect of diet on incidence and reversion of metabolic syndrome using Cox regression analysis to calculate hazard ratios (HRs) and 95% confidence intervals (CIs).

Results:

Over 4.8 years of follow-up, metabolic syndrome developed in 960 (50.0%) of the 1919 participants who did not have the condition at baseline. The risk of developing metabolic syndrome did not differ between participants assigned to the control diet and those assigned to either of the Mediterranean diets (control v. olive oil HR 1.10, 95% CI 0.94–1.30, p = 0.231; control v. nuts HR 1.08, 95% CI 0.92–1.27, p = 0.3). Reversion occurred in 958 (28.2%) of the 3392 participants who had metabolic syndrome at baseline. Compared with the control group, participants on either Mediterranean diet were more likely to undergo reversion (control v. olive oil HR 1.35, 95% CI 1.15–1.58, p < 0.001; control v. nuts HR 1.28, 95% CI 1.08–1.51, p < 0.001). Participants in the group receiving olive oil supplementation showed significant decreases in both central obesity and high fasting glucose (p = 0.02); participants in the group supplemented with nuts showed a significant decrease in central obesity.

Interpretation:

A Mediterranean diet supplemented with either extra virgin olive oil or nuts is not associated with the onset of metabolic syndrome, but such diets are more likely to cause reversion of the condition. An energy-unrestricted Mediterranean diet may be useful in reducing the risks of central obesity and hyperglycemia in people at high risk of cardiovascular disease. Trial registration: ClinicalTrials.gov, no. ISRCTN35739639.Metabolic syndrome is a cluster of 3 or more related cardiometabolic risk factors: central obesity (determined by waist circumference), hypertension, hypertriglyceridemia, low plasma high-density lipoprotein (HDL) cholesterol levels and hyperglycemia. Having the syndrome increases a person’s risk for type 2 diabetes and cardiovascular disease.^1,2 In addition, the condition is associated with increased morbidity and all-cause mortality.^1,3–5 The worldwide prevalence of metabolic syndrome in adults approaches 25%^6–8 and increases with age,⁷ especially among women,^8,9 making it an important public health issue.Several studies have shown that lifestyle modifications,¹⁰ such as increased physical activity,¹¹ adherence to a healthy diet^12,13 or weight loss,^14–16 are associated with reversion of the metabolic syndrome and its components. However, little information exists as to whether changes in the overall dietary pattern without weight loss might also be effective in preventing and managing the condition.The Mediterranean diet is recognized as one of the healthiest dietary patterns. It has shown benefits in patients with cardiovascular disease^17,18 and in the prevention and treatment of related conditions, such as diabetes,^19–21 hypertension^22,23 and metabolic syndrome.²⁴Several cross-sectional^25–29 and prospective^30–32 epidemiologic studies have suggested an inverse association between adherence to the Mediterranean diet and the prevalence or incidence of metabolic syndrome. Evidence from clinical trials has shown that an energy-restricted Mediterranean diet³³ or adopting a Mediterranean diet after weight loss³⁴ has a beneficial effect on metabolic syndrome. However, these studies did not determine whether the effect could be attributed to the weight loss or to the diets themselves.Seminal data from the PREDIMED (PREvención con DIeta MEDiterránea) study suggested that adherence to a Mediterranean diet supplemented with nuts reversed metabolic syndrome more so than advice to follow a low-fat diet.³⁵ However, the report was based on data from only 1224 participants followed for 1 year. We have analyzed the data from the final PREDIMED cohort after a median follow-up of 4.8 years to determine the long-term effects of a Mediterranean diet on metabolic syndrome.     

Comparison of black–white disparities in preterm birth between Canada and the United States

Background:

A higher risk of preterm birth among black women than among white women is well established in the United States. We compared differences in preterm birth between non-Hispanic black and white women in Canada and the US, hypothesizing that disparities would be less extreme in Canada given the different historical experiences of black populations and Canada’s universal health care system.

Methods:

Using data on singleton live births in Canada and the US for 2004–2006, we estimated crude and adjusted risk ratios and risk differences in preterm birth (< 37 wk) and very preterm birth (< 32 wk) among non-Hispanic black versus non-Hispanic white women in each country. Adjusted models for the US were standardized to the covariate distribution of the Canadian cohort.

Results:

In Canada, 8.9% and 5.9% of infants born to black and white mothers, respectively, were preterm; the corresponding figures in the US were 12.7% and 8.0%. Crude risk ratios for preterm birth among black women relative to white women were 1.49 (95% confidence interval [CI] 1.32 to 1.66) in Canada and 1.57 (95% CI 1.56 to 1.58) in the US (p value for heterogeneity [p_H] = 0.3). The crude risk differences for preterm birth were 2.94 (95% CI 1.91 to 3.96) in Canada and 4.63 (95% CI 4.56 to 4.70) in the US (p_H = 0.003). Adjusted risk ratios for preterm birth (p_H = 0.1) were slightly higher in Canada than in the US, whereas adjusted risk differences were similar in both countries. Similar patterns were observed for racial disparities in very preterm birth.

Interpretation:

Relative disparities in preterm birth and very preterm birth between non-Hispanic black and white women were similar in magnitude in Canada and the US. Absolute disparities were smaller in Canada, which reflects a lower overall risk of preterm birth in Canada than in the US in both black and white populations.In the United States, a higher risk of preterm birth among black women than among white women is well established.^1–3 This racial disparity is of great concern because preterm birth is a leading cause of perinatal mortality and is predictive of developmental problems and adverse health outcomes later in life.⁴ The underlying causes of the racial disparity in preterm birth in the US are not well understood, although research has suggested contributing roles for a wide range of factors, including socioeconomic disadvantage,⁵ poor neighbourhood conditions (e.g., poverty, crime),^5,6 lack of access to health care,⁷ psychosocial stress,⁸ racial discrimination⁹ and adverse health behaviours.¹⁰Rates of preterm birth have consistently been lower in Canada than in the US.^11,12 However, in contrast to the US, little is known about differences in rates by race or ethnicity in Canada. There is evidence that African-born and Caribbean-born women in the provinces of Quebec and Ontario have higher rates of preterm birth than Canadian-born women.^13–15 Although the magnitude of these differences is smaller than the disparity in preterm births between black and white women in the US,¹⁶ foreign-born black women in the US have been found to be at lower risk of preterm birth than US-born black women.^17,18In both Canada and the US, socioeconomic conditions at both individual and neighbourhood levels are important predictors of preterm birth.^19–21 Although the income gap between black and white people is markedly smaller in Canada than in the US,²² black populations in both countries have lower education levels, higher unemployment rates and a greater likelihood of living in low-quality neighbourhoods compared with white populations.²³ Canada and the US share similar social and economic influences, yet the historical experiences of black populations and the social welfare systems (e.g., universal health care) are quite different in the 2 countries. Black people constitute about 13% of the total US population, but only about 3% of the Canadian population.^24,25 The overwhelming majority of Canada’s black population are immigrants who entered the country after 1960 and their descendants, whereas more than 85% of black Americans can trace their ancestry 3 or more generations in the US, with most being descendants of slaves.²²The objectives of our study are twofold. First, using data from a new cohort linking birth registrations with information from the 2006 Canadian long-form census, we present Canada-wide estimates of differences in preterm birth rates between black and white populations. Second, we use comparable methodology to compare racial differences in preterm birth rates between Canada and the US. Given different historical experiences of black populations in the 2 countries, as well as Canada’s commitment to universal health care and its general perception as a more egalitarian society than the US,²² we hypothesized that we would observe smaller racial disparities in the rates in Canada than in the US.     

Use of acid-suppressive drugs and risk of pneumonia: a systematic review and meta-analysis

Background

Observational studies and randomized controlled trials have yielded inconsistent findings about the association between the use of acid-suppressive drugs and the risk of pneumonia. We performed a systematic review and meta-analysis to summarize this association.

Methods

We searched three electronic databases (MEDLINE [PubMed], Embase and the Cochrane Library) from inception to Aug. 28, 2009. Two evaluators independently extracted data. Because of heterogeneity, we used random-effects meta-analysis to obtain pooled estimates of effect.

Results

We identified 31 studies: five case–control studies, three cohort studies and 23 randomized controlled trials. A meta-analysis of the eight observational studies showed that the overall risk of pneumonia was higher among people using proton pump inhibitors (adjusted odds ratio [OR] 1.27, 95% confidence interval [CI] 1.11–1.46, I² 90.5%) and histamine₂ receptor antagonists (adjusted OR 1.22, 95% CI 1.09–1.36, I² 0.0%). In the randomized controlled trials, use of histamine₂ receptor antagonists was associated with an elevated risk of hospital-acquired pneumonia (relative risk 1.22, 95% CI 1.01–1.48, I² 30.6%).

Interpretation

Use of a proton pump inhibitor or histamine₂ receptor antagonist may be associated with an increased risk of both community- and hospital-acquired pneumonia. Given these potential adverse effects, clinicians should use caution in prescribing acid-suppressive drugs for patients at risk.Recently, the medical literature has paid considerable attention to unrecognized adverse effects of commonly used medications and their potential public health impact.¹ One group of medications in widespread use is acid-suppressive drugs, which represent the second leading category of medication worldwide, with sales totalling US$26.9 billion in 2005.²Over the past 40 years, the development of potent acid-suppressive drugs, including proton pump inhibitors, has led to considerable improvements in the treatment of acid-related disorders of the upper gastrointestinal tract.³ Experts have generally viewed proton pump inhibitors as safe.⁴ However, potential complications such as gastrointestinal neoplasia, malabsorption of nutrients and increased susceptibility to infection have caused concern.⁵Of special interest is the possibility that acid-suppressive drugs could increase susceptibility to respiratory infections because these drugs increase gastric pH, thus allowing bacterial colonization.^6,7 Several previous studies have shown that treatment with acid-suppressive drugs might be associated with an increased risk of respiratory tract infections⁸ and community-acquired pneumonia in adults^6,7 and children.⁹ However, the association between use of acid-suppressive drugs and risk of pneumonia has been inconsistent.^10–13Given the widespread use of proton pump inhibitors and histamine₂ receptor antagonists, clarifying the potential impact of acid-suppressive therapy on the risk of pneumonia is of great importance to public health.¹⁴ Previous meta-analyses have focused on the role of acid-suppressive drugs in preventing stress ulcer,^11,13,15 but none have examined pneumonia as the primary outcome.The aim of this study was to summarize the association between the use of acid-suppressive drugs and the risk of pneumonia in observational studies and randomized controlled trials.