David Michael Gallagher, MD

• Associate Professor of Medicine

https://medicine.duke.edu/faculty/david-michael-gallagher-md

Stem Cells Stem cell technology has greatly advanced our understanding of typical and atypical neurobiological processes symptoms zoloft overdose tolterodine 4mg otc, thereby offering new opportunities for treating neurodevelopmental disorders including autism medicine stone music festival generic tolterodine 2 mg without a prescription. Increasing evidence suggests that the pathophysiology of autism may involve neuroinflammation symptoms diagnosis generic tolterodine 4 mg mastercard, at least in a subgroup of cases symptoms of pregnancy cheap tolterodine 1 mg online. Thanks to basic science discoveries describing the molecular pathogenesis of these disorders medications jaundice 4mg tolterodine amex, researchers have begun efforts to evaluate treatments targeting specific proteins in the implicated biological pathways treatment 7th feb cardiff 4mg tolterodine fast delivery. These strategies are designed to address either the underlying gene defect or downstream pathways implicated in the disorder. Read-through strategies as well as gene transfer approaches using adeno-associated viral vectors are being actively pursued. This trial will examine outcome measures, including language, for all participants with a parent-implemented language intervention provided to all participants and psychopharmacologic intervention provided only to some. Intellectual disability commonly affecting individuals with these neurogenetic disorders is an additional obstacle in study design in this field. Next steps will need to include biomarkers to help detect objective improvements in response to treatment and to identify optimal developmental periods to apply the treatment trials. Yet a number of challenges and gaps have been highlighted, which are also shared by speech-generating devices, virtual reality, video games and computer-assisted instruction, mobile applications, and telemedicine. Technology-based interventions have tremendous potential to benefit individuals on the autism spectrum in many ways, including by helping them improve social and communication skills and gain greater independence, all of which can improve the overall quality of life. A major challenge in determining whether new treatment approaches are efficacious has been the measurement of treatment response. Moreover, many existing assessment measures were developed for screening and diagnosis and are not sensitive to assessing change in symptoms over time. Considerable effort has been directed toward evaluating which existing measures are suitable for clinical trials and for developing quantitative, objective, and sensitive measures of treatment response. Increasingly, the input of key stakeholders, including caregivers and persons on the autism spectrum, is solicited to ensure that outcome measures reflect the priorities and needs of persons for which the treatments are being developed. Several reviews and consensus statements have been published that have evaluated the appropriateness of existing parent report and observational measures for clinical trials, including measures of social communication, anxiety, and repetitive behaviors. These measures include eye tracking, electrophysiological responses, and magnetic resonance imaging, among others. Early efficacy markers can be used to identify which individuals are most likely to benefit from a given treatment and/or in adaptive study designs to indicate early in the trial whether modifications in the treatment. In future work, prior to these measures being useful as potential biomarkers, it will be important to demonstrate their ability to reliably predict a signature of dysfunction at the individual subject level, as opposed to group averaged data. However, this appears to be rapidly changing, with several recent studies expanding on earlier work. The ability of technology-based systems, such as mobile applications, wearables, and internet resources, to automatically record and generate data will increasingly provide richer, denser, and more meaningful information to researchers. Novel analytic methods, such as machine learning and computer vision analysis, can provide new insights into patterns of behavior. Thus, studies that explore their utility as a method of treatment monitoring should be pursued. As the understanding of these data streams matures, new methods and systems will need to be created to harness the power of this data and to manage the massive flows of information reaching data consumers. Furthermore, regular communication, data sharing agreements, and shared measures across the existing consortia will increase the scientific utility of these investments. In sum, multiple laboratories are conducting studies to develop better ways of measuring treatment response. Continued investment in such studies will ensure that, as new behavioral and medical treatments are developed, we will have the capability of testing their efficacy. Such investments will also be essential for developing improved methods for identifying subgroups that are responsive to specific treatments and identifying neural mechanisms underlying treatment response. One example would be the combination of psychopharmacology and behavioral treatments. But, the possibility of combining drugs with behavioral interventions still holds promise for improvement in these core areas. A few of these studies are in progress, but none have been reported during this review period. This is an area of great need and can especially help address co-occurring conditions, such as anxiety, aggression, and depression. Similarly, adaptive interventions, which incorporate more flexible study designs, can make more efficient use of existing clinical, research, and participant resources, providing more information to researchers and potentially greater benefit to participants. To encourage adoption, investment in study design methodology research (including dissemination of methods and development of trial design resources) will be of significant value. First, high-quality intervention studies are expensive to conduct and require substantial specialized expertise to oversee. Additional investment in human and research infrastructure is likely to yield compounding gains in autism intervention research progress. These networks can be leveraged to promote testing of novel interventions, exploration of unique scientific perspectives, and commitment to a culture of non-exclusive innovation transcending traditional boundaries. Additional investment should focus on bridging gaps between scientific evidence and clinical and/or community applications of interventions. Additional opportunities may emerge from standardization of reporting and protocols so as to facilitate aggregation or comparison of clinical trial data at meta-analytic levels. Examination of evidence at a higher analytical level may Further resources should be directed towards promoting the development of applied scientific tools, including more robust statistical methods, data mining techniques, basic science methods, laboratory techniques, and optimized pipelines for discovery. Additional resources could also be spent at the tail end of intervention science, on the wider dissemination of implementable discoveries. Incorporation of business and operations perspectives into autism research infrastructure development may help to optimize intervention deployment efficiency, enabling more studies to be conducted in a sustainable fashion. By focusing on practical barriers to ultimate treatment 57 provide more comprehensive information about treatment effectiveness when clinical uncertainty is matched with appropriate variation along key implementation parameters. Similarly, sharing data at finer level of detail may additionally facilitate data mining investigations that may help to identify more streamlined assessment or nuanced precursors and predictors of treatment response. Development of tools to help stakeholders manage and maintain research, educational, behavioral, and clinical records could help them better advocate for participation in studies most relevant to their needs or most aligned with their personal goals. With a focus on usability and controlled data sharing, such tools could become interfaces by which information could be bi-directionally shared with researchers and relevant providers, reducing redundancy in information requests, streamlining study deployments, and reducing participant burden. Currently, several incarnations of such systems have been developed, including Microsoft HealthVault and Apple HealthKit. However, efforts towards tailoring interfaces, cross-platform interoperability, and common standards must be pursued so as to best meet the specific needs of the autism community, to prevent data from becoming unnecessarily locked to proprietary platforms or formats, and to better enable data exchange. Creation of user-friendly research registries that promote awareness of relevant ongoing intervention studies or technologies, that can be personalized by user preferences (including constraints on geography, participation characteristics, and study facets), that are updated regularly and managed in a sustainable fashion, and that facilitate connections between legitimate researchers and qualified research participants (with appropriate governance of privacy and participant 58 rights) would further enable stakeholders to direct their research agenda. Adaptation of stakeholder-held records, including genomic information, for the purposes of creating an interface that would facilitate recruitment of participants with extremely specific characteristics. Measuring such outcomes can occur both in the short- and long-term and can be developed based on the needs of the individual in terms of their level of skills, functioning, and ability. When such indicators are maximized, the individual will be able to fully live a life maximizing long-term success. Researchers must continue to develop new treatments as well as adapt existing treatments for diverse settings and populations, including males and females, individuals with co-occurring conditions and varying levels of ability across multiple domains, individuals across the lifespan, and those in settings or communities that are under-resourced or underserved. First, it will be important to leverage advances in our understanding of the neuroscience and neurobiological mechanisms underlying all therapeutic approaches. Second, researchers need to consider designs and recruitment strategies that allow for testing ways to maximize effectiveness and precise matching of treatment plans to individual needs and neurobehavioral profiles by combining therapeutic approaches. More robust, standardized outcome measures should be developed, including adaptive measures, predictive measures, biologically based metrics, measures that address heterogeneity, and measures of practical outcomes and quality of life that will help better target therapies to individual needs and goals. It will also be important to study combination therapies that mimic how therapies may be delivered in real-world settings, and that offer the opportunity to provide greater benefits than any individual therapy alone. Finally, it will be essential to provide more tools to practitioners through translation of research to community-based practice and to deploy effective, novel dissemination strategies. A lack of sufficient funding raises considerable barriers for researchers to develop, test, and implement service system delivery models that increase the supply of care and address the gaps between research and practice. Adequate, cost-effective services are still lacking, as are strategies to decrease financial stress for families. In this chapter, we describe gains and opportunities in specific service-related areas. A growing body of research suggests a nationwide problem of ineffective educational programming and the need for stronger educational workforce development, support, training, and supervision. With relatively little research on developing specific guidance for addressing challenges within the education system, it is necessary for educators working with students on the autism spectrum to address the complex and growing set of challenges. While Federal and state legislation has placed a greater focus on accountability and performance standards, there is little agreement or standardization of how performance should be measured. Unfortunately, implementation of evidence-based practices remains the exception rather than the rule; implementation of innovative interventions is challenging due to limited fit with classroom needs and lack of professional support. New research in implementation science highlights the need for a systems approach that includes involving leadership in and across schools to develop a strong culture and climate for quality implementation. Our definition of autism and our understanding of how autism co-occurs with other mental health challenges has expanded. Recent research has focused attention on co-occurring anxiety9,10,11 and depression,12,13 as well as suicide risk. Many schools have not fulfilled the promise of educating children with autism in the least restrictive and most integrated environment suited to their needs. Currently, the public education system is not adequately preparing all children with autism for adulthood. During the transition to adulthood it is important to teach youth with autism the social and vocational skills necessary to have successful outcomes after leaving the education system. Outside of Medicaid, there are large disparities in insurance coverage and reimbursement rates based on differences in state health coverage mandates. The healthcare system needs to emphasize increasing access in underserved populations and increasing cultural competency among service providers. Disparities in access and utilization may be due to the lack of cultural competency of providers, perceived low quality of care, or the lack of family-centered care, among other factors. We need to better understand what portfolio of services will result in the best outcomes for diverse populations. Overall, it is important to continue to support research to test quality services and supports as well as evidence-based interventions that can eventually be implemented in a community setting and be accessible through medical coverage. A systematic, evidence-based, collaborative approach can facilitate the scaling up of evidence-based practices in community settings. Factors identified to aid in scaling up evidence-based interventions in community settings are organizational support and readiness, program and implementer characteristics, and sustainability planning. Also, fewer adults with autism were legally independent adults without guardianship (37%) than were adults without autism (53%). In recent years, there have been greater efforts to advocate for use of person-centered planning models, particularly in Federal service systems. More research is needed regarding the effectiveness of these services for different parent populations and across different types of parent educators. Further, studies are needed to examine the transition of care from parents to other family members, once parents are no longer able to provide care. Specific needs included career counseling/job skills training and life skills training. Barriers included cost, geographic access to services, and lack of providers who accepted their insurance. Results from the Pennsylvania Autism Needs Assessment survey, which represented people with autism ages 2-59 years indicated that, compared to other age groups, adults received fewer services for their specific unmet needs in social skills training (43%), speech-language therapy (22%), individual supports (21%), and occupational therapy (21%). For example, organizations trying to implement evidence-based practices might not be able to maintain the cost to fund these services and supports long-term. Current and future research initiatives need to consider improving the service infrastructure. Specifically, they report needing more information about services and more in-home services, while higher-income parents report needing higher-quality services. However, these strategies do not address more fundamental issues related to attracting highly qualified individuals to relevant professions, creating pre-service training programs that prepare individuals to deliver evidence-based care, and keeping individuals in the field once they complete their education and/or training. There are other systematic barriers for families such as differences in the type and amount of services supported by insurance plans and the inequities and disparities in type and amount of services available among geographic location. Individuals with autism often require services provided through different agencies and paid for through different systems. Care delivered across these systems often is inefficiently and ineffectively coordinated. Some of the challenges are endemic to systems that are providing care concurrently. The same report found that adult service systems did not routinely provide a coordinated plan of services or objectives for youth making transition to adulthood. While there is a lack of research in this area, families face multifaceted challenges to access services that often delay the receipt of early intervention services for a child. Also, families must deal with different sources of funding for services, frequently with different rules for who, what, and how many services can be provided, with no clear sources of information about what these sources are and how they interact. The different service sectors are not coordinated and often do not communicate with each other, particularly across health and social service agencies. The Committee continues to highlight the need for researchers to focus on developing practical, affordable, and culturally competent services and support approaches that can be used in a variety of settings, and for these approaches to be able to be adapted to the required scale to meet community needs. There also needs to be an understanding of what portfolio of services will result in the best outcomes for diverse populations.

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If a tumor assessment was done on multiple days medicine x ed generic tolterodine 2mg on line, use the earliest date for that visit medicine 1975 lyrics buy tolterodine 4 mg fast delivery. Progressed 6 7 Death without documented progression Documented progression or death after missing 2 consecutive post-baseline tumor assessments New anticancer treatment started and no tumor progression or death within 14 days Date of death Date of last adequate tumor assessment before missed assessments or date of randomization symptoms bipolar purchase tolterodine 1 mg online, whichever is later Date of adequate tumor assessment prior to start of new anticancer treatment +14 days or date of randomization, whichever is later Progressed Censored 8 Censored Note: Progression-free survival and associated outcome is determined by the earliest of the dates above, if more than 1 situation applies. A spending function in rho family with parameter 16 was used to derive the efficacy bound to maintain the cumulative one sided type I error 0. All the testing boundaries will be adjusted based on actual number of events at each analysis, according to the alpha spending functions. Sensitivity Analysies Page 152 Sensitivity analyses will be undertaken for calculation of the primary endpoint in order to evaluate the robustness of the analysis. Discordance statistics, such as those defined by the Pharmaceutical Research and Manufacturers of America methodology (Amit et al. These analyses will be conducted on a randomly selected subset of patients to evaluate the presence of investigator bias with the intention of evaluating the reliability of the treatment effect based on investigator assessment. The interim efficacy analysis will be conducted to provide early efficacy information and could potentially result in early communication with regulatory agencies. May 2020 We are pleased to introduce the second annual report of the Sabin-Aspen Vaccine Science & Policy Group: Meeting the Challenge of Vaccination Hesitancy. The package of "big ideas" presented here, and the rigorous evidence and consensus-driven insights on which they rest, reassure us that smart strategies are available not only to maintain, restore, and strengthen confidence in the value of vaccines, but also to underscore the broad societal obligation to promote their use. Implementing those strategies requires concerted commitment, and we are deeply grateful to the members of the Vaccine Science & Policy Group, who have helped us identify pathways to progress. Tilghman, president emerita and professor of molecular biology and public affairs at Princeton University. They are joined by 22 remarkable individuals drawn from the ranks of government, industry, and advocacy-both within the U. Both organizations have a long track record of engaging in non-partisan, cross-disciplinary dialogue that helps to meet the greatest challenges facing society. We are proud of the synergy we have built together and thankful for the opportunity all of us have had to learn from one another. The strength and credibility of our collaboration has already been reflected in the positive response to our inaugural report, Accelerating the Development of a Universal Influenza Vaccine, issued in July 2019. We are confident that this current report will also generate welcome attention from policymakers, immunization leaders, researchers, and journalists-and contribute to lifesaving advances in the use of vaccines. While development of an effective vaccine to control the resulting pandemic is likely at least a year away, the danger of infectious diseases has been made shockingly real across the globe, and the gift of effective immunization has once again become apparent. Although vaccination remains a well-accepted social norm worldwide, a combination of factors-including misinformation spread on social media; decreased trust in institutions including government, science, and industry; and weaknesses within health systems-has emerged to diminish confidence among some populations. As co-chairs of the Sabin-Aspen Vaccine Science & Policy Group (the Group), we recognize a profound responsibility to bring forward an innovative plan to strengthen vaccine acceptance and tame the risk of hesitancy. We are truly grateful to 9 Foreword this able team of leaders, who represent both domestic and global perspectives and bring professional experience across a wide range of disciplines to our convening. Their vigorous discussions, informed by background research papers and expert presentations, generated three "big ideas" for addressing vaccine hesitancy and promoting the critical importance of timely immunization. Together, these ideas address the primary barriers to vaccine acceptance and provide a framework for progress. We are committed to sharing these big ideas through the rich networks of the Group, the Sabin Vaccine Institute, the Aspen Institute, and our many partners, and advocating for strategies that will turn them into action. Along with our dedicated members, we are especially grateful to our funder, the Bill & Melinda Gates Foundation, which understood the urgency of combatting vaccine hesitancy and gave us the support so essential to doing so. The teams at Sabin and at the Health, Medicine, and Society Program are deeply committed to this initiative, and offer leadership, insight, and attention to detail. Together, we can overcome the risks posed by vaccine hesitancy and ensure continued and widening support for one of the most powerful tools ever developed to protect public health. Lower-than-optimal vaccination rates arise from a variety of problems, including vaccine shortages, restrictions in the convenience and affordability of vaccines, diminished confidence in government authority structures, and ironically, the very success of vaccines in making vaccinepreventable illnesses less common and feared. Because the dimensions of hesitancy are complex and not fully understood, the medical and public health communities and their allies must rapidly expand their understanding of the problem and the actions needed to address it. A global resurgence of measles since 2018 has underscored the pressing need to bolster vaccine acceptance ("Vaccine hesitancy: A generation at risk," 2019). Vaccines are a remarkably safe and effective method of preventing deadly and disabling infectious diseases. But millions of children-especially but not exclusively those living in areas of conflict and poverty-still miss out on lifesaving vaccines because of a lack of access. Despite the ample base of reassuring evidence behind it, vaccination requires an ongoing, high degree of social confidence and trust in the system that delivers it-including discovery and development; Because the dimensions of hesitancy are complex and not fully understood, the medical and public health communities and their allies must rapidly expand their understanding of the problem and the actions needed to address it. The Sabin-Aspen Vaccine Science & Policy Group (the Group) met at the Aspen Institute in Colorado in September 2019 to examine the trends and drivers of vaccination acceptance and devise approaches to counter the growing trend of hesitancy. These discussions led to a clear recognition of three points: (1) vaccination levels, after reaching record heights, have plateaued or even declined slightly in many countries (Paules, Marston, & Fauci, 2019); (2) various factors have undermined confidence in or contributed to complacency about vaccination (Wellcome Global Monitor, 2019); and (3) the vaccination enterprise needs new knowledge and tools to overcome challenges to vaccine acceptance. Globally, vaccination is a success and has been established as a norm throughout the world. Another indicator is measles-a highly contagious infection that can be effectively prevented with two doses of a vaccine that has a long track record of safety and effectiveness-which declined 80% worldwide from 2000 to 2018, saving some 23 million lives. The circulation of false information about vaccines, when combined with faltering trust in the institutions that deliver them, undercuts confidence in vaccination. In places where vaccination, and medicine in general, have lowered the deadliest risks of vaccine-preventable infectious disease, vaccination can come to seem less pressing. The value of vaccination speaks for itself to those who understand the historical decline of the targeted diseases, but vaccines and vaccination have long attracted skepticism and generated conspiracy theories (Colgrove, 2006). Unlike climate change and evolutionary theory-other areas where noisy polemics have engendered challenges to scientific fact-vaccination is a tangible and personal issue for every family. As with any complex subject, many people continue to rely on surrogate authority figures to inform their decisions. But in the information age, the internet and social media have brought crushing waves of vaccine misinformation to new parents, raising doubts among enormous groups of people who previously might have been unaware of any "controversy" over this eminently sensible activity. Yet the extent to which misinformation contributes to declines in vaccination is not always clear, in part because comprehensive data describing which communities are under-vaccinated, and why, is lacking. A polarized, politicized, post-fact environment has an undeniable impact both on trust and 17 In the information age, the internet and social media have brought crushing waves of vaccine misinformation to new parents. But demand problems may also reflect poor experiences in the clinics of a failing public health system or real or perceived failures in immunization safety. Access, rather than demand problems-ranging from wars and refugee movements to limited clinic hours for two-job parents-can be a further cause of vaccination gaps that officials misattribute to parental hesitation. The Group examined findings on why people accept or delay vaccines, or reject them altogether, and explored ways to shape education, communication, and methods of behavioral change to maintain vaccination as a social norm. It also discussed strategies to counter misinformation as it arises in different contexts. Trust: Community Immunity Versus Herd Mentality Trust in vaccination depends not only on the nurse, doctor, or mobile team that administers the vaccine, but also on the authorities who enable and drive vaccination. Thus, vaccine uptake may be threatened in any country, region, or community where there is waning confidence in the government, doctors, or public health officials who recommend, oversee, and mandate vaccination, as Muhammad Ali Pate of the World Bank told the Group. In countries such as Nigeria, Sudan, Afghanistan, and Congo, conflicts and gravely polarized societies have led entire groups to identify vaccinators and their mission with their foes, and therefore to consider them untrustworthy (Hussain, Boyle, Patel, & Sullivan, 2016). Scores of vaccinators have lost their lives while on the job in these countries (Smith, 2014)-including 95 in Pakistan alone since 2012 (Janjua, 2019). In countries where corruption and violence have created fear, mistrust, or open opposition to government-endorsed vaccination programs, the problem of trust may extend beyond the scope of vaccination policy. That said, public health authorities have managed to convince warring parties in countries such as El Salvador and Colombia in the 1980s, and more recently in Yemen, to give safe passage to vaccination teams (Ferguson, 2019). In some tribal regions in India, for example, a history of neglect has lowered confidence in governmentrun vaccination programs unless they employ local healers (Priya, Pathak, & Giri, 2020). Anti-vaccine groups can make inroads through such leaders; by the same token, leaders who are immune to such propaganda can reassure followers and tamp down the influence of falsehoods. Decades of assiduous vaccination campaigns have created herd immunity-where the percentage of a population immune to a disease is high enough to prevent its spread-in most U. Smaller pockets of non-vaccinating families were often sheltered within larger, more fully vaccinated populations that kept out disease. However, because of its extreme contagiousness, immunization rates against measles must remain above 95% to provide this community-level protection, which is at risk in many U. In countries such as France and the United Kingdom-as well as Ukraine and Pakistan-the lack of herd immunity has enabled measles outbreaks in broad swaths of the population. Social Networks and Social Norms Developing strategies to counter vaccine hesitancy will require the public health community to engage with new disciplines, especially from the social and behavioral sciences, and to improve its communication strategies, building on a base of expanded research into the nature and volume of the hesitancy problem. Work in areas such as behavioral economics and cognitive psychology indicates that people frequently base difficult decisions less on rational processes than values and heuristics-that is, on cognitive shortcuts. The current peril in which vaccination programs find themselves results from the interaction of these basic human foibles with false and misleading information carried on massive social media platforms (DiResta & Wardle, this volume). People frequently base difficult decisions less on rational processes than values and heuristics-that is, on cognitive shortcuts. Sociologist Damon Centola (2019) describes anti-vaccine sentiment as a "complex contagion" that requires reinforcement by multiple social peers to reinforce its legitimacy. People in general feel a greater moral responsibility for any harm that comes about through something they have done than for a task they have neglected, and the hypothesized harm from vaccination may appear more immediate than the danger of the pathogens against which vaccines protect. Beyond that fundamental decision, external factors that impinge on behavior, such as convenience, incentives, costs, and mandates, also affect vaccination decision-making. It has been sharing best practices, including gathering data on vaccine demand and hesitancy in low- and middle-income countries in 20 FraminG the challenGe order to use this knowledge to nudge and support national programs (VaccinesToday, 2019). The Demand Hub also has begun to engage with social media companies to examine the vaccine-related content of searches and conversations. The group hopes to anticipate problems with vaccine confidence, such as the collapse in measles vaccination in the Philippines after a dengue virus vaccination campaign was suspended. The suspension occurred after children vaccinated during the campaign died, some of them possibly as a result of complex immune responses to the vaccine and subsequent dengue infection (Wilder-Smith, Flasche, & Smith, 2019). While the latter has successfully eradicated wild Type 2 and Type 3 polio strains, its endgame increasingly involves battling outbreaks linked to mutant viruses from the live attenuated polio vaccine and the communication challenges that surround this phenomenon. The Mechanization of Doubt Changes in how people gather and digest science and health information have fed vaccination hesitancy. While newspapers once presented a relatively unitary-and therefore unifying-version of basic political and health facts, the internet fragments information. Search engines and social media companies target readers based on their previous selections under the assumption that they will click on information that interests them already, or perhaps, that confirms their biases (Del Vicario, Scala, Caldarelli, Stanley, & Quattrociocchi, 2017; DiResta, 2018). While news coverage has always trended toward topics that stimulate fear, doubt, outrage, and polarizing attitudes, journalistic principles of fairness and accuracy, if unevenly achieved, have had a salutary impact on the presentation of health news. A recent survey found that those who rely on social media for news are far more likely than traditional media consumers to be misinformed about the safety of vaccines (Stecula, Kuru, & Jamieson, 2020). This is part of a larger problem of bias confirmation among consumers of social media (Self, 2016). For decades, public health essentially ignored the anti-vaccine movement and its theories, concentrating on presenting facts and fact-based information in response to any unsubstantiated theories of harm. But while the core of the movement remains small, the internet and social media allow its ideas to circulate much more broadly than in the past. Some even claim that vaccines have been intentionally laced with ingredients that cause cancer or infertility. Anti-vaccine communications inevitably include testimony from people whose children have diseases or conditions allegedly brought on by vaccination. Thus, the emotional battlefield is asymmetric-on the one hand, naive parents see serious infirmities that loud voices attribute to vaccines, while on the other, they hear gentle admonitions to continue a procedure whose benefits may be nearly invisible. Public health scientists have demonstrated little expertise in creating stories that generate emotion and engage popular attention, and vaccine foes have manipulated internet search engines to steer people toward false information-in the United States and Europe, as well as in Pakistan, the Philippines, Brazil, Egypt, India, and Nigeria (DiResta & Wardle, this volume). In the past, social media and search engines generally ranked sites by popularity rather than any evaluation of their worth, meaning parents seeking information about vaccines for the first time were likely to encounter distorted information about their safety before arriving at reliable sources (Centola, 2019). In addition, anti-vaccine activists on social media have found ways to 22 Anti-vaccine activists on social media have found ways to expand their constituency by reaching out to groups with other unconventional, paranoid, or conspiratorial beliefs. FraminG the challenGe expand their constituency by reaching out to groups with other unconventional, paranoid, or conspiratorial beliefs. As the California legislature moved to tighten restrictions on vaccine exemptions in 2015, for example, anti-vaccine activists repeatedly changed their messaging to attract people interested in tangential controversies and theories, as internet researcher Renee DiResta has reported (DiResta & Lotan, 2015). However, revelations about the clandestine use of social media to sway audiences, including the massive Russian campaign against the 2016 U. Companies such as Facebook, Twitter, YouTube, and Google have recently devoted more resources to nudge viewers toward science-based health information. They have changed the way they present information on vaccination to highlight more legitimate sources, but do not ban or earmark verifiably false information (DiResta & Wardle, this volume; Schiff, 2019).

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Grade of Recommendation: A Ghahreman et al1 reported results from a prospective randomized controlled trial assessing the efficacy of transforaminal injection of steroid and local anesthetic conventional medicine buy tolterodine 1 mg cheap, local anesthetic alone treatment quadriceps tendonitis discount 4 mg tolterodine overnight delivery, normal saline alone medicine vs nursing discount tolterodine 4mg line, intramuscular injection of steroid or normal saline on radicular pain secondary to lumbar disc herniation medicine x ed buy 2 mg tolterodine mastercard. Patients who did not obtain relief from the first transforaminal epidural steroid injection were offered a second "rescue" transforaminal epidural steroid injection symptoms 9dp5dt cheap tolterodine 4 mg otc. The authors concluded that transforaminal epidural steroid injection is a viable alternative to surgery for lumbar radicular pain due to disc herniation medicine hat horse purchase tolterodine 1mg online. For long-term efficacy, proof beyond a reasonable doubt would require prohibitively large studies. Karppinen et al (May 2001)2 and (December 2001)3 performed a randomized controlled trial to test the efficacy of periradicular corticosteroid injection for sciatica. The study published in December 2001 provided subgroup analyses by type of herniation. For extrusions, there was significant improvement with transforaminal normal saline at six months. For contained disc herniations, leg pain at four weeks and Nottingham Health Profile emotional scores at three months were significantly better for the transforaminal epidural steroid injections compared to transforaminal normal saline. The authors concluded that transforaminal epidural steroid injection is superior to transforaminal normal saline injection for treatment of leg pain due to most contained disc herniations. These two studies provide Level I therapeutic evidence that transforaminal epidural steroid injection is an effective treatment for a proportion of patients with symptomatic lumbar disc herniations, as compared with saline injection, for short-term (four weeks) pain relief. Interlaminar epidural steroid injections may be considered in the treatment of patients with lumbar disc herniation with radiculopathy. Grade of Recommendation: C Manchikanti et al4 described a prospective randomized controlled trial to compare interlaminar epidural corticosteroid injection to interlaminar epidural local anesthetic injection. Of the 120 patients included in the study, 60 received interlaminar epidural corticosteroid injection and 60 received interlaminar epidural local anesthetic injection. At three months and 12 months, this clinical guideline should not be construed as including all proper methods of care or excluding or other acceptable methods of care reasonably directed to obtaining the same results. This paper included many patients with chronic and bilateral pain, and the work group questioned the underlying diagnosis. Ackerman et al5 conducted a prospective randomized controlled trial to test the null hypothesis that these three methods of lumbar epidural steroid injections (caudal, interlaminar, transforaminal) are equally effective for the management of radicular pain associated with lumbar disc herniation at L5-S1. Of the 90 consecutively assigned patients included in the study, 30 were treated with each of the following: caudal epidural steroid injection, interlaminar epidural steroid injection and transforaminal epidural steroid injection. All groups showed significant improvement in functional and depression outcome measures two weeks following their last treatment. At 24 weeks, the transforaminal epidural steroid group had significantly more patients reporting complete (30%) or partial relief (53%). At 24 weeks, complete or partial pain relief in the transforaminal, interlaminar, and caudal groups was reported in 25, 18, and 17 patients respectively. All groups showed significant improvement in functional and depression outcome measures two weeks after their last injection. The authors concluded that the transforaminal approach offers the benefit of increased analgesic efficacy compared to the caudal and interlaminar approaches. This study provides Level I therapeutic evidence that transforaminal injections are more effective than caudal or interlaminar injections in the treatment of patients with lumbar disc herniation with radiculopathy. There is insufficient evidence to make a recommendation for or against the 12 month efficacy of transforaminal epidural steroid injection in the treatment of patients with lumbar disc herniations with radiculopathy. Grade of Recommendation: I (Insufficient Evidence) Ghahreman et al1 reported results from a prospective randomized controlled trial assessing the efficacy of transforaminal injection of steroid and local anesthetic, local anesthetic alone, normal saline alone, intramuscular injection of steroid or normal saline on radicular pain secondary to lumbar disc herniation. Of the 150 consecutively assigned patients, 28 received transforaminal steroid and local anesthetic, 27 had transforaminal local anesthetic, 27 received transforaminal normal saline, 30 had intramuscular steroid and 28 received intramuscular normal saline. This outcome was statistically significant compared to the transforaminal normal saline, transforaminal local anesthetic, intramuscular normal saline and intramuscular steroid groups. The transforaminal steroid group had concomitant improvements in function and disability. Among the patients who accepted a rescue transforaminal epidural steroid injection, 50% obtained relief. Transforaminal steroid injection was found to be more effective than intramuscular steroid injection for the treatment of lumbar radiculopathy secondary to lumbar disc herniation. This study provides Level I therapeutic evidence that transforaminal epidural steroid injection is an effective treatment for a proportion of patients with symptomatic lumbar disc herniations and is superior to intramuscular saline, intramuscular steroids, transforaminal saline, and transforaminal local anesthetics for short-term (30 days) pain relief and functional improvement. Vad et al6 described a prospective randomized controlled trial comparing transforaminal epidural steroid injection with saline trigger point injection used in the treatment of lumbosacral radiculopathy secondary to herniated nucleus pulposus. Of the 50 consecutive patients included in the study, 25 were treated with transforaminal epidural steroid injection and 25 received saline trigger point injection. The success rate was significantly better in the transforaminal epidural steroid group OutcOme nterventiOnal treatment medical/i measures fOr treatment this clinical guideline should not be construed as including all proper methods of care or excluding or other acceptable methods of care reasonably directed to obtaining the same results. Is there an optimal frequency or quantity of injections for the treatment of lumbar disc herniations with radiculopathy Does the approach (interlaminar, transforaminal, caudal) influence the risks or effectiveness of epidural steroid injections in the treatment of lumbar disc herniations with radiculopathy There is insufficient evidence to make a recommendation for or against the effectiveness of one injection approach over another in the delivery of epidural steroids for patients with lumbar disc herniation with radiculopathy. Grade of Recommendation: I (Insufficient Evidence) Ackerman et al5 conducted a prospective randomized controlled trial to test the null hypothesis that these three methods of lumbar epidural steroid injections (caudal, interlaminar, transforaminal) are equally effective for the management of radicular pain associated with lumbar disc herniation at L5-S1. Pain scores improved in all groups, but were significantly lower in the transforaminal group. At 24 weeks, complete or partial pain relief in the transforaminal, interlaminar, and caudal groups was reported in 25, 18 and 17 patients, respectively. However, no differences were noted between groups in depression and functional outcomes. Kolsi et al7 described a prospective randomized controlled trial comparing the short-term efficacy on pain and functional impairment of nerve root sheath and interspinous glucocorticoid injection. Of the 30 patients included in the study, 17 were treated with nerve root sheath and 13 received interspinous glucocorticosteroid injection. Both treatment groups had improvement in their pain and disability with no significant difference between treatment groups. At the eightmonth follow-up, three patients in each group had surgery, and the remaining patients were pain free. The authors concluded that it remains to be proven whether nerve root sheath is superior to interspinous glucocorticosteroid injection. Because of the small sample size and improper method of randomization, this this clinical guideline should not be construed as including all proper methods of care or excluding or other acceptable methods of care reasonably directed to obtaining the same results. Schaufele et al8 reported results of a retrospective case-control study to assess whether there is a difference in short-term pain improvement and long-term surgical rates between interlaminar and transforaminal epidural steroid injection techniques. Of the 40 consecutive patients included in the study, 20 received interlaminar and 20 received transforaminal epidural steroid injections. Outcomes were assessed using the Numeric Rating Scale at 18 days, and at one year patients were contacted to determine whether they had proceeded to surgery. There was a statistically significant improvement in the Numeric Rating Scale scores at follow-up for the transforaminal group. The average Numeric Rating Scale improvement was 46% in the transforaminal group and 19% in the interlaminar group. Surgery was performed in 25% of the interlaminar group and 10% of the transforaminal group. The authors concluded that transforaminal epidural steroid injections for treatment of radicular pain due to lumbar disc herniation resulted in better short-term pain improvement and fewer long-term surgeries compared with interlaminar epidural steroid injections. Future Directions for Research the work group identified the following potential studies that would generate meaningful evidence to assist in further defining the role of epidural steroid injection in the treatment of lumbar disc herniation with radiculopathy. Recommendation #1: A large double-blinded, randomized controlled clinical trial with at least one-year follow-up in patients with lumbar disc herniation with radiculopathy treated by fluoroscopically-guided interlaminar or caudal epidural steroid injections in which the control group receives saline placebo injections. Recommendation #2: A large double-blinded, randomized controlled clinical trial with at least one-year follow-up comparing patients with lumbar disc herniation with radiculopathy treated by fluoroscopicallyguided transforaminal, interlaminar and caudal epidural steroid injections. Cost effectiveness of periradicular infiltration for sciatica: subgroup analysis 4. The Efficacy of Transforaminal Injection of Steroids for the Treatment of Lumbar Radicular Pain. Cost effectiveness of periradicular infiltration for sciatica: subgroup analysis of a randomized controlled trial. Efficacy of nerve root versus interspinous injections of glucocorticoids in the treatment of disk-related sciatica. Transforaminal epidural steroid OutcOme nterventiOnal treatment medical/i measures fOr treatment this clinical guideline should not be construed as including all proper methods of care or excluding or other acceptable methods of care reasonably directed to obtaining the same results. Evaluation of the effectiveness of lumbar interlaminar epidural injections in managing chronic pain of lumbar disc herniation or radiculitis: a randomized, double-blind, controlled trial. Efficacy of Steroid and Nonsteroid Caudal Epidural Injections for Low Back Pain and Sciatica A Prospective, Randomized, Double-Blind Clinical Trial. Interlaminar versus transforaminal epidural injections for the treatment of symptomatic 39 13. Corticosteroids in periradicular infiltration for radicular pain: a randomised double blind controlled trial. Efficacy of transforaminal versus interspinous corticosteroid injectionin discal radiculalgia - a prospective, randomised, double-blind study. Epidural corticosteroid injections for sciatica: a randomised, double blind, controlled clinical trial. This is an indirect visualization technique using the endoscope and fluoroscopic guidance. There is insufficient evidence to make a recommendation for or against the use of intradiscal ozone in the treatment of patients with lumbar disc herniation with radiculopathy. Grade of Recommendation: I (Insufficient Evidence) Gallucci et al1 conducted a prospective randomized controlled trial to prospectively compare the clinical effectiveness of intraforaminal and intradiscal injections of a mixture of a steroid, a local anaesthetic and oxygen-ozone (O2-O3) to intraforaminal and intradiscal injections of a steroid and an anesthetic in the management of radicular pain related to acute lumbar disc herniation. Group A, the control group, underwent intraforaminal and intradiscal injections of 2 mL of triamcinolone acetonide (40 mg/mL Kenacort; Bristol-Myers Squibb, Sermoneta, Italy), this clinical guideline should not be construed as including all proper methods of care or excluding or other acceptable methods of care reasonably directed to obtaining the same results. Group B, the treatment group, received the same treatment with the addition of an O2O3 mixture, with an ozone concentration of 28 mcg/mL. Of the 158 consecutively assigned patients, 77 were included in Group A (control) and 82 were assigned to Group B to receive the O2-O3 mixture. The authors concluded that O2-O3 chemodiscolysis should be regarded as a useful treatment for the management of lumbar disc herniation. This study provides Level I therapeutic evidence that intraforaminal and intradiscal local anesthetic, steroid and O2-O3 injections are superior to intraforaminal and intradiscal local anesthetic and steroid injections alone at six months in the treatment of radicular pain caused by lumbar disc herniation. Endoscopic percutaneous discectomy may be considered for the treatment of lumbar disc herniation with radiculopathy. Grade of Recommendation: C Ahn et al2 described a retrospective case series of 45 patients assessing the clinical outcome, prognostic factors and the technical pitfalls of percutaneous endoscopic lumbar discectomy for upper lumbar disc herniation. The authors concluded that patient selection and an anatomically modified surgical technique promote a more successful outcome after percutaneous endoscopic discectomy for upper lumbar disc herniation. Ahn et al3 reported a retrospective case series of 43 patients evaluating the efficacy of endoscopic discectomy for recurrent disc herniations and to determine the prognostic factors affecting surgical outcome. Based on the MacNab criteria, the surgical outcomes were rated as follows: excellent in 12 patients (27. The authors concluded that percutaneous endoscopic lumbar discectomy is effective for recurrent disc herniation in selected cases. Patients younger than 40 years, with shorter symptom duration (less than three months) and without concurrent lateral recess stenosis tended to have better outcomes. Several members opposed its inclusion because the paper evaluated the treatment of recurrent herniations. Furthermore, the question serving as the basis for the literature review and guideline formulation did not specifically exclude recurrent herniation (although all committee members inferred that the guideline development was intended to address virgin disc herniations). Cervellini et al4 described a retrospective case series describing experiences in the treatment of 17 patients with extraforaminal disc herniation via the microendoscopic far lateral approach. The authors concluded that the minimally invasive surgical treatment via the microendoscopic far lateral approach has a high rate of success. Hermantin et al5 performed a prospective comparative study to evaluate the results of endoscopic percutaneous lumbar discectomy compared with open discectomy in patients with lumbar disc herniation and radiculopathy. Of the sixty patients included in the study, 30 were treated with endoscopic discectomy and 30 with open discectomy. There was no difference in satisfactory outcomes between the groups: 93% satisfactory outcome in open discectomy, 97% in endoscopic. Narcotic use was longer (25 days versus seven days) in patients treated with open discectomy. Average post- OutcOme nterventiOnal treatment medical/i measures fOr treatment this clinical guideline should not be construed as including all proper methods of care or excluding or other acceptable methods of care reasonably directed to obtaining the same results. The ultimate judgment regarding any specific procedure or treatment is to be made by the physician and patient in light of all circumstances presented by the patient and the needs and resources particular to the locality or institution OutcOme nterventiOnal treatment medical/i measures fOr treatment operative disability was 49 and 27 days in the open discectomy and endoscopic discectomy groups, respectively. Although described by the authors as a randomized controlled trial, randomization was limited to patients not sent for one procedure or another and only performed in select patients who agreed to randomization, who met inclusion criteria for endoscopic percutaneous lumbar discectomy. Jang et al6 reported a retrospective case series documenting the outcome for 35 consecutive patients with intraforaminal and extraforaminal herniated discs who were surgically treated with transforaminal percutaneous endoscopic lumbar discectomies. In the immediate postoperative period, six patients (17%) developed burning dysesthesia in the sensory distribution of the operated nerve root. The authors concluded that the posterolateral endoscopic approach to foraminal and extraforaminal lumbar disc herniations for the decompression of the exiting root contributes a minimally invasive procedure that seems to be safe and effective.

These reviews provide comprehensive medications medicare covers generic 4mg tolterodine fast delivery, science-based information on common symptoms pancreatitis discount 4mg tolterodine free shipping, costly medical conditions medicine zoloft discount 4mg tolterodine with mastercard, and new health care technologies and strategies medications you cant crush tolterodine 1 mg generic. Systematic reviews are the building blocks underlying evidence-based practice; they focus attention on the strength and limits of evidence from research studies about the effectiveness and safety of a clinical intervention medications 377 best tolterodine 2mg. In the context of developing recommendations for practice 5ht3 medications discount tolterodine 1 mg on-line, systematic reviews can help clarify whether assertions about the value of the intervention are based on strong evidence from clinical studies. Transparency and stakeholder input are essential to the Effective Health Care Program. Director Center for Evidence and Practice Improvement Agency for Healthcare Research and Quality Suchitra Iyer, Ph. Task Order Officer Center for Evidence and Practice Improvement Agency for Healthcare Research and Quality Stephanie Chang, M. Director Evidence-based Practice Center Program Center for Evidence and Practice Improvement Agency for Healthcare Research and Quality iv Acknowledgments the authors thank Naomi Davis, Ph. Key Informants are not involved in the analysis of the evidence or the writing of the report. Therefore, in the end, study questions, design, methodological approaches, and/or conclusions do not necessarily represent the views of individual Key Informants. Key Informants must disclose any financial conflicts of interest greater than $10,000 and any other relevant business or professional conflicts of interest. Because of their role as end-users, individuals with potential conflicts may be retained. The list of Key Informants who provided input to this report follows: Barry Anton, Ph. Divergent and conflicting opinions are common and perceived as healthy scientific discourse that results in a thoughtful, relevant systematic review. Therefore, in the end, study questions, design, methodologic approaches, and/or conclusions do not necessarily represent the views of individual technical and content experts. Technical Experts must disclose any financial conflicts of interest greater than $10,000 and any other relevant business or professional conflicts of interest. Because of their unique clinical or content expertise, individuals with potential conflicts may be retained. The list of Technical Experts who provided input to this report follows: Coleen Boyle, Ph. However, the conclusions and synthesis of the scientific literature presented in this report do not necessarily represent the views of individual reviewers. Peer Reviewers must disclose any financial conflicts of interest greater than $10,000 and any other relevant business or professional conflicts of interest. Because of their unique clinical or content expertise, individuals with potential nonfinancial conflicts may be retained. Two investigators screened each abstract and full-text article for inclusion, abstracted the data, and performed quality ratings and evidence grading. Random-effects models were used to compute summary estimates of effects when sufficient data were available for meta-analysis. Twenty-one studies related to diagnosis, 69 studies related to treatment, and no studies were identified on monitoring. For atomoxetine and methylphenidate, the most commonly reported adverse events were somnolence and mild gastrointestinal problems. Across all treatments, little evidence was reported on the risk of serious adverse events, including cardiovascular risk. This targeted update found insufficient evidence regarding new approaches to the viii diagnosis. No information was identified regarding the optimal strategy for monitoring after diagnosis. Strength of evidence for major outcomes-comparisons between pharmacologic and placebo/usual care treatments. Strength of evidence for major outcomes-comparisons between pharmacologic and nonpharmacologic treatments. Strength of evidence for major outcomes-child or parent training or behavioral interventions. Strength of evidence for major outcomes-herbal interventions or dietary approaches. Meta-analysis for effects of omega-3/6 supplementation compared with placebo- parent ratings. Meta-analysis for effects of omega-3/6 supplementation compared with placebo- teacher ratings. Also, symptoms need to be present for at least 6 months, occur in at least two different settings, be present before 12 years of age, and not be better explained by another disorder. For older adolescents and adults, the number of required symptoms per category is reduced to five out of nine. Psychostimulants can be effective in reducing distractibility, improving sustained attention, reducing impulsive behaviors, and improving activity level. Understanding the role of nonpharmacologic therapies can be challenging because they encompass a broad range of approaches to care, ranging from highly structured behavioral interventions to complementary medicines. Ensuring appropriate diagnosis and avoidance of misdiagnosis is a key concern for clinical practice. For treatment, Key Questions include how to best tailor therapy to individuals based on their characteristics. Population this systematic review focuses on children through 17 years of age, categorized to reflect broad developmental stages (less than 4 years, 4 through 6 years, 7 through 12 years, and 13 through 17 years). These include sex because the clinical presentation can vary as can the response to therapy. We evaluated these subpopulations by stratifying outcomes based on common these risk factors when available. Rating scales, which can be completed by parents, teachers, and/or patients, are used to evaluate the presence of each of the 18 symptoms as well as the degree of impairment that results from symptoms. Rating scale data are integrated with a clinical interview to determine the onset, course, duration, and impairment associated with symptoms. In addition, screening and clinical evaluation of potential comorbid psychiatric conditions is a key part of the diagnostic process. Important questions remain about the accuracy of this approach in primary care settings. The main categories of pharmacologic therapies include stimulants, selective norepinephrine reuptake inhibitors, alpha-2 agonists, and antidepressants. Nonpharmacologic therapies include psychosocial interventions, behavioral interventions, school interventions, cognitive training therapies, learning training, biofeedback or neurofeedback, parent behavior training. Treatment can also lead to personality changes or loss of spontaneity as perceived by the treated individual, family members, or other close acquaintances. Individuals who are initially misdiagnosed may be overtreated, and those who have inadequate monitoring may be overtreated or undertreated. Because many of the pharmacologic treatments are controlled substances, overtreatment could also lead to abuse of a drug to which the treated individual might not otherwise have access. Stimulant prescription refills are often required monthly, which can also support the need for frequent re-evaluations. There are variations in the frequency of monitoring, often based on the age of the child, the specific treatment, duration of treatment, previous symptoms and comorbid conditions, and family and health care provider preferences. Rating scale results are intermediate monitoring outcomes associated with the outcomes described below. In adulthood, outcomes may include limited workforce participation and/or difficulty maintaining a steady job. Although different in scope, the current report primarily builds on the foundation of the 2011 report. However, most of the previous studies were developed before the release of these criteria, which were released in 2013. Patient Preferences There are differences in patient and family preferences related to both pharmacologic and nonpharmacologic treatment18 and potential outcomes. These treatment preferences have been shown to be associated with treatment initiation and choice. Findings from this systematic review are intended to help inform patient and family decisions based on the benefits and harms of specific treatments. A separate report on disruptive behavior disorder is nearly complete and was therefore not targeted in this systematic review. How do these outcomes vary by presentation (inattentive, hyperactive/impulsive, and combined) or other comorbid conditions The analytic framework presented in Figure 1 illustrates the population, interventions, outcomes, and adverse effects that guided the literature search and synthesis. However, for children 7 through 17 years, we focused on novel approaches only because other reports have assessed the standard screening instruments used for older children. Although the studies were not restricted to primary care settings, the methods have to be ones available directly or easily upon referral to primary care clinicians based on feedback from the Technical Expert Panel and internal clinical experts. Each results section also describes "Findings in Relation to What Is Known" to provide appropriate context for the reader. The discussion section offers our conclusions, summarizes our findings, and provides other information relevant to interpreting this work for clinical practice and future research. Appendix H presents detailed data tables for the different outcomes and comparisons of interest. Topic Refinement and Review Protocol During topic refinement, we engaged in a public process to develop a draft and final protocol for the review. We then drafted a protocol for the systematic review and recruited a panel of technical experts to provide clinical content and methodological expertise throughout the development of the review. This panel included medical professional and Federal agency representation similar to that of the key informant group. These databases were selected based on internal expert opinion that they would identify most of the relevant literature on this topic and following prior related systematic reviews. We believe that the evidence published from 2009 forward both represents the current standard of care for the population of interest in this review and allows this report to build on the previous systematic review published in 2011 (which included literature through May 31, 2010). We supplemented the electronic searches with a manual search of citations from a set of key primary and review articles. Note that studies with individuals greater than 18 years of age are included as long as findings are reported separately for individuals 18 years and under, or if the mean patient age plus the standard deviation is not greater than 21 years of age. Also note that for long-term studies, the age of the individuals may be greater than 18, but these studies are only considered for inclusion if the age at enrollment in the study was 18 years or younger. These sample size limits were seen as representing population study sizes that would be needed to substantially impact the assessment of the existing evidence base. At the full-text screening stage, two independent reviewers were required to agree on a final inclusion/exclusion decision. At random intervals during screening, quality checks by senior team members were made to ensure that screening and abstraction were consistent with inclusion/exclusion criteria and abstraction guidelines.