Recently, someone posed a question that made me think hard about the immediate relevance of our research to those affected by autism. I had been explaining Autism Speaks’ new focus on developing medicines that, one day, will target autism’s core symptoms in ways that reduce disabilities and improve learning abilities. Someone commented that this would likely take years to accomplish. I had to agree. His follow-up question: So, how does research help families today?
For the answer, I found myself thinking about how the Cystic Fibrosis Foundation faced this same question decades ago. Like Autism Speaks, the Cystic Fibrosis Foundation was grappling with a disorder in its medical infancy. Cystic fibrosis was defined as a medical condition in 1938. The Foundation followed in 1955. At that time, the median age of survival for those affected by the disorder was just ten years.
The leadership of the Cystic Fibrosis Foundation knew they were grappling with a complex disorder that would take years to fully understand. So they developed parallel research efforts. One focused on the immediate development of improved diagnosis and treatments that could ease symptoms. The other focused on basic science with the goal of ultimately revolutionizing treatment with therapies that target the disorder’s root causes.
Their short-term efforts included support for a network of clinical care and research centers, a patient registry and studies that focused on improving treatment of chronic symptoms and associated medical conditions. Within a relatively short time, diagnostic methods improved and physicians began adopting new gold-standard practices, including new methods for fighting lung infections and improving lung function – all made possible through research that the Cystic Fibrosis Foundation helped support. The median age of survival jumped from 10 years to 37 years!
Meanwhile, long-term research efforts focused on understanding the causes and biology of cystic fibrosis. In 1989, scientists made major breakthroughs in genetic understanding. This, in turn, led to tremendous insights into the disorder’s underlying biology. Then, just last week, the FDA approved the first drug to treat the underlying cause of cystic fibrosis, rather than its symptoms. One doctor described how his patient was able to “shovel snow for the first time.” Not coincidentally, the Cystic Fibrosis Foundation had contributed millions of dollars to the development of this drug (Kalydeco). Its early funding had been essential to convince drug companies to make the larger financial investment needed to bring any successful drug to market. In the process, the foundation negotiated a deal to earn drug royalties, which will now be reinvested in further research advancements. Just as exciting, other “disease-modifying” cystic fibrosis drugs are moving through the research pipeline.
This is the same strategy that Autism Speaks is taking with investments in both research that improves quality of life in the short term and longer-term research that promises to transform how autism is treated.
Here are just a few examples of funded research projects with the potential to improve quality of life in the near future:
- Identification of preventable environmental risk factors for autism spectrum disorder (ASD)
- Validation of questionnaires that pediatricians can use to screen babies for ASD and, so, offer earlier intervention that will improve outcomes
- Biomarkers (e.g. immune alterations) that could identify infants at risk for ASD
- Development of effective early interventions for babies before the full syndrome develops
- Support of technological inventions to enhance communication in nonverbal persons
- Development of physician guidelines for assessment and treatment of medical conditions associated with ASD
- Development of more effective treatments for associated conditions, including sleep disturbances, GI disorders, seizures and anxiety
- Development of interventions to improve employment success and relationship skills in adults
- Development of cognitive rehabilitation interventions for adults
Even as we support the development of these improved services, we are also investing in research that can identify the most effective ways to broadly implement new gold-standard practices to produce positive changes in community healthcare, education and support services for all persons who struggle with autism. This type of “dissemination research” also tells us how to best target limited resources.
Meanwhile, our long-term investments are advancing the understanding of autism’s underlying biology and the genetic and environmental factors that contribute to its development. These investments are exploring the role of the immune system, brain signaling pathways and the GI system, among other topics. Over the last five years, tremendous progress in these areas has advanced research to the point where we are now collaborating with industry to develop novel drugs with the potential to ease severe and disabling core symptoms – in adults as well as children. Fortunately, the tools we have available today will make drug discovery and development much faster than before.
Connecting the dots
At Autism Speaks, the research we fund interconnects with all parts of our mission, including awareness, advocacy and family services. Our awareness campaign, for example, is shaped by research that has revealed great disparities in access to services by communities such as ethnic-minority and low-income families.
Our advocacy of insurance reform, in turn, critically depends on research that demonstrates how early intervention improves outcomes. Research also plays a critical role in bolstering our advocacy for adolescents and adults. For example, a recent study demonstrated that adults with ASD face greater challenges in employment and social participation than do adults with other common disabilities. More importantly, this same study suggests that providing transition services immediately after high school is the most cost effective way to improve outcomes. We can use this information to advocate for improved services during the transition from high school to adulthood. Other currently funded studies promise to help us advance insurance reform to assure coverage of other interventions with proven benefits for school-age children and adults.
Similarly, Autism Speaks is funding research aimed at determining the real-world effects of proposed changes in the diagnostic criteria for autism. Will these new criteria exclude people previously diagnosed with ASD? Will they affect access to vital services? These answers will be crucial to our ability to advocate for any necessary changes in the proposed criteria.
While we see our research improving lives now, we remain committed to our long-term goals of revolutionizing treatment of ASD. I know in my heart that someday we will be making the kind of breathtaking announcement that we heard from the Cystic Fibrosis Foundation last week. The day is coming. In the meantime, we will ensure that our scientific mission remains relevant to our families today.
Chief Science Officer, Autism Speaks
Today’s guest blog post is from Gottfried Schlaug, MD, PhD, director of the Music and Neuroimaging Laboratory and associate professor of neurology at Beth Israel Deaconess Medical Center and Harvard Medical School, in Boston. He is a recent recipient of an Autism Speaks Treatment Research Grant.
As many as three in ten children with autism are nonverbal. Yet many children with autism have superior auditory skills and a particular attraction to music. Based on these observations, I and my colleagues have been using forms of music-making that encourage vocalization as a pathway to developing language.
We call our therapy Auditory-Motor Mapping Training (AMMT), and our approach is built on two findings.
First research has shown that music-making creates clear changes in the human brain. In particular we know that it engages and strengthens connections between the auditory and motor regions and improves mapping of sounds to actions. Second, here at our Music and Neuroimaging Lab, we have successfully used a form of singing (i.e., Melodic Intonation Therapy) to help stroke patients regain speech lost after a stroke (aphasia). In essence, our therapies involve having the patient sing words and phrases while using a coordinated movement of the hand not affected by the stroke. This helps their brains map sounds to actions.
In recent years, we’ve adapted our music-motor therapy for stroke victims in ways that allow us to use it with children who have autism and little or no speech. In simplified terms: Our team members sing words and phrases with social connotations (for example, “more please,” “mommy,” “all done”) to the children and with the children, while showing them pictures of the action, person or object. At the same time, we guide each child’s hand to play two drum pads tuned to different pitches.
We believe that intensive, repetitive training—pairing sound with actions–can engage and strengthen the brain pathways needed to speak. In our recently published “proof of concept” study, each participant received 40 treatment sessions, conducted 5 days per week over an 8 week period, with each session lasting 45 minutes. Further analysis revealed that the therapy’s benefits probably occur in the first 25 sessions.
We have seen very encouraging results in our pilot and proof-of-concept studies and are now excited to expand our research and therapy program with a 2011 treatment grant from Autism Speaks. In other words, this funding and this study are being made possible by you—Autism Speaks’ community of supporters. Thank you. We look forward to reporting back our results! Meanwhile, please visit our lab’s website: http://www.musicianbrain.com.
As researchers and parents, we’ve long known that autism often travels with attention deficit and hyperactivity disorder (ADHD). What we haven’t known before is why that is. Also, few studies have examined how ADHD affects the quality of life of those with autism.
In the past month, two studies have come together to help connect our understanding of autism with behavioral issues such as hyperactivity and attention deficit. The first study looked at gene changes in ADHD and autism. The second looked at how frequently parents see the symptoms of ADHD in their children and how seriously these symptoms affect their children’s daily functioning and quality of life.
The upshot of the first study is that the genetic changes seen in children with ADHD often involve the same genes that are associated with autism. This finding helps explain why children with autism often have ADHD symptoms. In other words, if these disorders share a genetic risk factor, it’s logical that they often occur in the same individuals. Genetic insights, in turn, can help scientists understand underlying causes and, so, may improve how we diagnose and treat these issues.
The second study, described in our science news section, helps clarify both how commonly children on the autism spectrum are affected by ADHD symptoms and documents how this affects their daily function and quality of life. Perhaps the most notable observation was that, even though over half of the children in the study had ADHD symptoms that worsened both daily function and quality of life, only about 1 in 10 was receiving medication to relieve such symptoms.
Clearly, we need more research on whether standard ADHD medications benefit children struggling with both autism and hyperactivity and attention deficits. However, studies have long shown that these medications improve the quality of life of many children with ADHD alone. Autism specialists such as Dan Coury, M.D., medical director of Autism Speaks Autism Treatment Network (ATN), recommend that parents discuss with their child’s physician whether a trial of such medications could be of benefit. (Dr. Coury co-authored the second study.)
On a deeper level, this research raises a question: Why is it, given the same genetic changes, some children develop autism alone, some develop autism and ADHD symptoms, and some develop neither—or something completely different?
I and other geneticists have seen how a given genetic change can alter normal development in various ways—if it does so at all. We have good evidence, for example, that outside influences affect how and whether autism develops in those who are genetically predisposed to it. These influences include a variety of stresses and exposures during critical periods of brain development—particularly in the womb and around the time of birth.
Still, by better understanding how altered genes produce symptoms—be they hyperactivity or social difficulties—we gain important insights into how to develop treatments that can improve the daily function and quality of life of those affected.
Ultimately there’s no substitute for working with your child’s physician and behavioral specialist to address your child’s behavioral challenges and needs within the context of your goals and values. To this end, the specialists at Autism Speaks Autism Treatment Network have developed a medication decision aid—“Should My Child Take Medicine for Challenging Behavior?”—available for free download on our website. Please let us know what you think.
Nancy Jones, Ph.D., Director of the Autism Treatment Network and Clinical Trials Network
In one of the final sessions at IMFAR, several presentations provided updates in three important areas of intervention and treatment research.
Using technology to make interventions more accessible
Laurie Vismara, Ph.D. from UC Davis, MIND Institute reported on a new approach to make training for families on the Early Start Denver Model (ESDM) more accessible. Typically, families and clinicians attend training and coaching sessions in person at the clinic. Using web and DVD technology, Dr. Vismara and her colleagues have developed a program where families use web-based video conferencing for training sessions with a therapist. Families also had access to an interactive DVD including modules covered in training sessions that provide summaries of the key sessions, video examples, supportive videos, and feedback exercises. The study examined how this new web-based approach compared to in-person sessions. In a small pilot group of ten families, the researchers found that parents’ ability to implement the activities from the intervention was comparable to that found in families trained in-person. Improvement in the children’s word production and imitation skills were also comparable to children whose families had in-person ESDM sessions. A manual of this web-based approach is currently being developed. This approach holds promise to make interventions accessible to more families and to ensure children get timely intervention of the appropriate intensity.
Effectiveness of melatonin for sleep disorders in ASD
Many families and individuals with ASD report sleep problems. To alleviate these sleep problems, some individuals use melatonin, a hormone that is readily available and sold over-the-counter as a supplement. But despite melatonin’s easy accessibility and wide-spread use, there are not a large number of systematic studies of its use for sleep disorders in ASD.
Beth Malow, M.D., a neurologist and sleep specialist, and her team at Vanderbilt University Medical Center (VUCM), reported results from a pilot open-label study of melatonin for improving sleep onset. Many children suffer from sleep onset insomnia, which is a delay in their ability to fall asleep. The study examined the effectiveness of using melatonin to help children (ages 3-10) who have difficulty falling asleep (more than 30 minutes delay on more than three days a week). In addition to the melatonin, all families also were provided with sleep education on how to improve sleep. Twenty-four of the twenty-five children in the study showed an improvement at moderate doses that were well tolerated, decreasing the time it took them to fall asleep on more than three days a week. This study was an open label study, which means that families were aware of the treatment they were receiving. This study provides initial evidence for the potential effectiveness and safety of the treatment and also preliminary information to guide development of a planned multi-site, randomized controlled trial of melatonin.
Arbaclofen shows potential to treat social and communication problems in ASD children with high irritability
In a previous clinical trial on individuals with Fragile X, arbaclofen was found to lessen children’s tendency to withdraw socially and improved social behavior. The study reported at IMFAR examined the effectiveness of arbaclofen in improving social and communication skills in children with ASD. The children were 6-17 years of age, had a diagnosis of autism or PDD-NOS and also had high levels of irritability. The study was an 8-week, open-label study. Craig Erikson, M.D., of Indiana University School of Medicine reported the findings of the multi-site trial. Key improvements were noted for irritability, social withdrawal and communication. A double-blind, placebo-controlled trial is planned to begin early in 2011.
In honor of Autism Awareness month, the National Institutes of Health in conjunction with the Department of Health and Human Services held an hour-long lecture and live videocast with two seasoned autism researchers. The talk series was titled “Advances in Treatment Research” and addressed the current state of treatment research in autism including promising new areas and the barriers to getting to effective treatments faster.
Susan Swedo, M.D., a board-certified pediatrician and the Chief of the Pediatrics & Developmental Neuropsychiatry Branch at the National Institute of Mental Health (NIMH), spoke about empirically-supported treatment options in autism, including behavioral and medical treatments. She noted that methods of behavioral intervention have been the most studied. A recent review published in Pediatrics highlighted the positive effects demonstrated in randomized controlled trials of early intervention, including the UCLA Lovass model and the Early Start Denver model of early intervention.
For medical interventions aimed at addressing core symptoms of ASD, such as social and communication impairments, the challenge of evaluating treatments has been greater. Objectively measuring improvements in social and communication is challenging because these impairments differ widely across individuals with ASD. For example, for some the difficulty may be establishing eye contact whereas for others it might be learning how to carry on a conversation. Thus, defining what makes a treatment successful has been surprisingly elusive. For medical conditions where someone became acutely ill, a return to that individual’s former health status would be considered a success. However, autism spectrum disorders are developmental in nature, and difficulties in meeting milestones and acquiring new information about the world tend to compound. For these reasons, it is not clear what the “baseline” is or could be for each individual and that makes the definition of success less clear-cut. This is an even greater concern when considering the costs of treatment, including monetary and potential side effects. For an intervention with a high probability of unpleasant side effects, the likelihood of substantial gain in function must be greater than for an intervention with little risk of negative effects.
Secondly, there appears to be a surprisingly strong placebo effect in autism studies. For some individuals, the psychological effect of receiving “treatment”—even if it is not an active substance– is beneficial in some way. For this reason, small and uncontrolled trials of interventions can be misleading. Large, randomized, controlled trials are considered to be the gold standard method for evaluating effective treatments. Another challenge is that, given that ASD is not one condition but a group of different conditions, what will work for one person may not work for another. When individuals are studied in groups, such as in clinical trials, it might obscure the positive effects of a treatment for a small subgroup of people with ASD.
Dr. Swedo offered the historical example of secretin as a case-in-point. Secretin is a hormone that was claimed to be a successful treatment for autism in many “open label” (ie. uncontrolled) trials. The hormone was both very expensive and difficult to administer. When placebo-controlled trials were completed, it was clear that there weren’t beneficial effect of the drug, but valuable treatment time and dollars were spent on something ineffective in the interim.
Dr. Swedo collaborates with Autism Speaks’ Autism Treatment Network, a group of 17 hospitals offering a comprehensive model of medical care for children on the spectrum. The well-organized network of sites offers an excellent platform for studies of medical effectiveness where the children’s medical needs are well-attended and followed over time.
Dr. Swedo’s talk ended by discussing some new data from her research group at NIMH showing that the sleep EEG patterns of children with autism are different in a surprising way. Young children with autism in her study spend much less time in rapid eye movement (REM) sleep and much greater time in slow wave sleep instead. This is an interesting finding because REM sleep has been hypothesized as important for consolidating memories made during waking hours. Dr. Swedo’s group is currently engaged in the beginning phases of a study using a low dose of Aricept, a drug indicated for dementia associated with Alzheimer’s disease that has the side effect of increasing REM sleep. Autism Speaks is currently funding a study that is examining the relationship between REM sleep and other aspects of sleep and memory in children with ASD. We look forward to hearing the results as they emerge.
Rebecca Landa, Ph.D., CCC-SLP, is an Associate Professor of Psychiatry and Johns Hopkins School of Medicine and Director of the Center for Autism and Related Disorders and of the REACH research program at the Kennedy Krieger Institute. Dr. Landa explores the early signs and interventions for autism during the infant-toddler period.
Dr. Landa views early intervention as “an investment of a lifetime”, because it is during this early time that children set expectations and learn what they are capable of, and the dynamic of the parent-child relationship is established. Her objective in all interventions is to “thwart the spiraling effects” of developmental disorders by improving functioning as quickly as possible.
“I like to think of intervention experience as nourishment for the brain”, says Dr. Landa. New experiences help young children learn how to functionally interact with the world. As young children, the sensory and motor abilities are primary and help set up more complex cognitive and social skills. A good example is in the ‘sticky mittens’ Dr. Amy Needham uses to help young infants learn to grasp. With the special mittens, the young infants had success at a motor skill that they could not previously perform, and this provided a scaffold for building other behaviors. Dr. Landa’s interventions are influenced by the perspective that the mind develops in a manner compelled by the physical abilities and actions of the body.
Dr. Landa also described a randomized controlled behavioral intervention for 16 month old children who have autism or were at high risk for developing autism. Some of the children were randomized into an intensive parent education class to help the parents have more effective interactions with their infants. Other children were enrolled in a full experimental treatment group, involving a classroom-based gathering of one year olds and their parents twice a week. In the experimental group parents learn to observe and implement strategies for engaging their children socially, with toys, and in adaptive routines that help parents generalize to the home through weekly home visits. The children in the experimental group made substantial improvements in their gaze behavior, spending more time engaged in the sort of joint attention interactions that precede more complex social interactions. Meeting these early milestones offer the scaffold for the development of later and more complex social and communicative behaviors.
In addition to their prepared talks, both investigators answered questions from the live audience. The videocast will be archived and available for viewing in the next few days.
The Science Webinar and Podcast Series is a new service from Autism Speaks to help keep our community informed about the latest in autism research. Each month we will feature a leading expert to share with us the exciting progress being made and what it means for individuals and families affected by autism. Our goal is to help our community better understand all the new and exciting science being supported by Autism Speaks and other funders. We plan to be comprehensive in our coverage, including everything from genetics and environmental sciences to medical care and clinical trials. Occasionally, we will also feature special topics, like awareness and family support, that while not part of the Autism Speaks science program, are informed by our research and development efforts.
We are very pleased that our inaugural episode of the Autism Speaks Science Webinar and Podcast Series features Autism Speaks’ Chief Science Officer, Dr. Geri Dawson. Dr. Dawson will share with us two new exciting science initiatives at Autism Speaks aimed to deliver better medical care and develop novel treatments for our community.
Please find the webinar video below this post, or you may access the audio-only podcast here:
Simple conversation often provides our organization with valuable insight into the lives of our families, their triumphs, struggles, issues impacting their lives and helps us understand how to better serve the autism community’s needs. That’s why we took the conversation one step forward and conducted Autism Speaks’ very first online “Community Survey.” Designed as a “conversation starter,” the survey explored why their community is, or is not, a good place to live if you have autism. We asked if they were happy with the availability of services in their community, and specifically explored access to medical and clinical care including diagnosis, therapeutic services, educational services in public and private schools, inclusive or adaptive recreation and respite for families and caregivers.
We wanted to hear from all corners of the country, from people with autism, their parents, siblings, clinicians, therapists and anyone else with perspective on this issue — and the response could not have been better. Almost 1500 people engaged in the survey which was open for a three week period and more than 800 members of the autism community in the 48 contiguous states and the District of Columbia completed the survey. Thanks to everyone’s input, we came away with a wealth of opinions, personal experiences and information that has allowed us to identify the best communities to live in if you have autism. More importantly we heard what characteristics are valued by our families that make a community livable. We encourage everyone take a look at the rankings, which were just announced today, and see if your community made the list. We also want to know your thoughts on the issues presented in the survey to keep this vital conversation moving forward and in the public spotlight. To view the results of the Autism Speaks Community Survey, please click here.
Autism is a complex disorder. Answers will be found by taking multi-disciplinary approaches. A broad vision of autism spectrum disorder (ASD) considers how the brain develops and affects cognition, what treatments work for core symptoms, and how ASD changes over the lifespan. However, opportunities for scientists to appreciate the broad vision and diversity of approaches are unfortunately few.
This year a special 2-day conference on autism was held prior to the annual Society for Neuroscience meeting in San Diego, giving scientists an opportunity to focus on ASD and share ideas. The conference, called The Emerging Neuroscience of Autism Spectrum Disorders: Etiologic Insights; Treatment Opportunities, offered an overview of current autism research from many of the world’s leading autism researchers.
There were two strong themes in the meeting. The first was that autism research has historically studied different groups of children at specific time points. This kind of study is known as cross-sectional research. There has been comparatively little research on how children change over time, known as longitudinal research. Given that ASD is a developmental disorder which changes over the lifespan, more longitudinal research is needed. The second theme highlighted what we can learn from the incredible diversity of symptom and subtypes of ASD. Future ASD research demands a greater focus on individual differences instead of the common comparisons between averages derived from groups of individuals with ASD and typically-developed individuals.
The first session of the meeting included a review of what is known about autism risk genes. Steve Scherer, M.D. (University of Toronto) described how small variations in the number of copies of a piece of genetic code (copy number variations, CNVs) can be risk factors for ASD. These CNVs may be inherited or occur for the first time in the individual with ASD (de novo). Similar CNVs have also been identified in ADHD, schizophrenia and bipolar disorder, suggesting that there may be some common pathways underlying related developmental and psychiatric disorders. The incredible advances in genetic research, in no small part from Dr. Scherer and the Autism Genome Project, enable scientists to explore how these genetic variations affect brain development in animal models and provide clues into the underlying biology of ASD.
Declan Murphy, M.D. (Institute of Psychiatry, UK) impressed the audience with his proposal that brain imaging could be used to assist future clinicians in the diagnosis of ASD. The high costs of diagnosing individuals with ASD in Dr. Murphy’s South London community clinic motivated him to explore new methods. He used statistical methods combined with functional brain imaging to identify brain networks that may be different in adults with ASD. The use of brain scans may one day make the diagnosing ASD cheaper, quicker and potentially more accurate.
Cognition and new treatments
Day 2 of the meeting shifted focus away from biology to cognitive development and the evaluation of behavioral interventions. Tony Charman, Ph.D., (Institute of Education, London) described his study of cognitive strengths and weaknesses in a large sample of children with ASD. He argued for the importance of understanding the unique pattern of cognitive skills found in ASD to guide neuroimaging research and developing assessments of skills for early intervention programs. Dr. Charman also identified challenges in this area of research, noting that the field must address issues, such as small sample sizes and reliance on group comparisons if we are to progress.
Cathy Lord, Ph.D., (University of Michigan) showed longitudinal data collected using the Autism Diagnostic Observation Schedule (ADOS)—a tool to identify and quantify features of ASD. Her data revealed individual differences in the development of particular skills, such as eye contact, and joint attention skills, even though overall ADOS scores remain mostly constant. Language IQ remains an important predictor of children’s expected progress. Perhaps in the future, the ADOS diagnostic tool can also be used to monitor the long-term benefits of interventions.
The final two sessions focused on interventions. Fred Frankel, Ph.D. (UCLA) presented data from new interventions in friendship training. Judith Reaven, Ph.D., (University of Colorado School of Medicine) showed her data on cognitive behavioral therapy for anxiety in ASD. Aubyn Stahmer, Ph.D., (Rady Children’s Hospital, San Diego) evaluated the use of an integrated intervention model in community settings. Sally Rogers, Ph.D. (MIND Institute) concluded this session with a summary of the challenges in developing good outcome measures for intervention studies.
The last session summarized the evidence behind pharmacological treatments for ASD. One of the real challenges for behavioral pharmacologists is how to identify drug treatments for core social and communication skills. Currently only two drugs are approved for treating irritability in ASD. Several other drug treatments have been tested in clinical trials with minimal or no evidence for their effectiveness. Individual differences and variation in symptoms over time make finding treatments for the core symptoms of ASD like trying to hit a moving target.
Putting it all together
David Amaral, Ph.D. of the MIND Institute and current president of the International Society for Autism Research, summarized the meeting by focusing on autism research ‘Promises and Pitfalls’. On the positive side, he noted a dramatic rise in research, supported by increases in public and private funding, such as the major contribution by Autism Speaks. As for pitfalls, Dr. Amaral underscored the significant variability among individuals with autism that must be recognized if research results are to be meaningful. He also encouraged the continuation of brain research across the lifespan acknowledging age-related changes in brain development and behavior over time.
Progress in the field of brain research will require an on-going partnership among people with autism, families and researchers. We are both optimistic about progress and impatient to find answers. We all look forward to IMFAR 2011 in May when autism researchers return to San Diego with a broader perspective and new insights.